US20040213848A1 - Modified release dosage forms - Google Patents

Modified release dosage forms Download PDF

Info

Publication number
US20040213848A1
US20040213848A1 US10/476,504 US47650404A US2004213848A1 US 20040213848 A1 US20040213848 A1 US 20040213848A1 US 47650404 A US47650404 A US 47650404A US 2004213848 A1 US2004213848 A1 US 2004213848A1
Authority
US
United States
Prior art keywords
dosage form
active ingredient
release
shell
core
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/476,504
Inventor
Shun-Por Li
David Wynn
Narendra Parikh
Dan McTeigue
Harry Sowden
Martin Thomas
Der-Yang Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Johnson and Johnson Consumer Inc
Original Assignee
McNeil PPC Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/966,939 external-priority patent/US6837696B2/en
Priority claimed from US09/966,509 external-priority patent/US6767200B2/en
Priority claimed from US09/967,414 external-priority patent/US6742646B2/en
Priority claimed from US09/966,450 external-priority patent/US6982094B2/en
Priority claimed from US09/966,497 external-priority patent/US7122143B2/en
Application filed by McNeil PPC Inc filed Critical McNeil PPC Inc
Priority to US10/476,504 priority Critical patent/US20040213848A1/en
Assigned to MCNEIL-PPC, INC. reassignment MCNEIL-PPC, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MCTEIGUE, DAN, SOWDEN, HARRY S., THOMAS, MARTIN, WYNN, DAVID, PARIKH, NARENDRA, LE, SHUN-POR, LEE, DER-YANG
Publication of US20040213848A1 publication Critical patent/US20040213848A1/en
Priority to US12/360,579 priority patent/US20090186082A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23GCOCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G3/00Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/02Apparatus specially adapted for manufacture or treatment of sweetmeats or confectionery; Accessories therefor
    • A23G3/04Sugar-cookers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23GCOCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G1/00Cocoa; Cocoa products, e.g. chocolate; Substitutes therefor
    • A23G1/30Cocoa products, e.g. chocolate; Substitutes therefor
    • A23G1/50Cocoa products, e.g. chocolate; Substitutes therefor characterised by shape, structure or physical form, e.g. products with an inedible support
    • A23G1/54Composite products, e.g. layered laminated, coated, filled
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23GCOCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G3/00Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/0002Processes of manufacture not relating to composition and compounding ingredients
    • A23G3/0004Processes specially adapted for manufacture or treatment of sweetmeats or confectionery
    • A23G3/0019Shaping of liquid, paste, powder; Manufacture of moulded articles, e.g. modelling, moulding, calendering
    • A23G3/0025Processes in which the material is shaped at least partially in a mould in the hollows of a surface, a drum, an endless band, or by a drop-by-drop casting or dispensing of the material on a surface, e.g. injection moulding, transfer moulding
    • A23G3/0029Moulding processes for hollow products, e.g. opened shell
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23GCOCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G3/00Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/34Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
    • A23G3/36Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds
    • A23G3/364Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins
    • A23G3/368Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins containing vitamins, antibiotics
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23GCOCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G3/00Sweetmeats; Confectionery; Marzipan; Coated or filled products
    • A23G3/34Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
    • A23G3/50Sweetmeats, confectionery or marzipan; Processes for the preparation thereof characterised by shape, structure or physical form, e.g. products with supported structure
    • A23G3/54Composite products, e.g. layered, coated, filled
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/30Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/005Coating of tablets or the like
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/06Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/10Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • A61K9/2018Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2095Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/282Organic compounds, e.g. fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/282Organic compounds, e.g. fats
    • A61K9/2826Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/284Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/2873Proteins, e.g. gelatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893Tablet coating processes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B30PRESSES
    • B30BPRESSES IN GENERAL
    • B30B11/00Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
    • B30B11/02Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space
    • B30B11/08Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space co-operating with moulds carried by a turntable
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B30PRESSES
    • B30BPRESSES IN GENERAL
    • B30B11/00Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
    • B30B11/34Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses for coating articles, e.g. tablets
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B30PRESSES
    • B30BPRESSES IN GENERAL
    • B30B15/00Details of, or accessories for, presses; Auxiliary measures in connection with pressing
    • B30B15/30Feeding material to presses
    • B30B15/302Feeding material in particulate or plastic state to moulding presses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2068Compounds of unknown constitution, e.g. material from plants or animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/13Hollow or container type article [e.g., tube, vase, etc.]
    • Y10T428/1352Polymer or resin containing [i.e., natural or synthetic]

Definitions

  • This invention relates to modified release dosage forms such as modified release pharmaceutical compositions. More particularly, this invention relates to modified release dosage forms comprising a molded core, and a shell residing upon at least a portion of the core.
  • Modified release pharmaceutical dosage forms have long been used to optimize drug delivery and enhance patient compliance, especially by reducing the number of doses of medicine the patient must take in a day.
  • the rate at which an orally delivered pharmaceutical active ingredient reaches its site of action in the body depends on a number of factors, including the rate and extent of drug absorption through the g.i. mucosa.
  • the drug To be absorbed into the circulatory system (blood), the drug must first be dissolved in the g.i. fluids.
  • diffusion across the g.i. membranes is relatively rapid compared to dissolution.
  • the dissolution of the active ingredient is the rate limiting step in drug absorption, and controlling the rate of dissolution allows the formulator to control the rate of drug absorption into the circulatory system of a patient.
  • modified release dosage forms provide a desired blood concentration versus time (pharmacokinetic, or PK) profile for the drug.
  • PK profile for a drug is governed by the rate of absorption of the drug into the blood, and the rate of elimination of the drug from the blood.
  • the type of PK profile desired depends, among other factors, on the particular active ingredient, and physiological condition being treated.
  • One particularly desirable PK profile for a number of drugs and conditions is one in which the level of drug in the blood is maintained essentially constant (i.e. the rate of drug absorption is approximately equal to the rate of drug elimination) over a relatively long period of time.
  • Such systems have the benefit of reducing the frequency of dosing, improving patient compliance, as well as minimizing side effects while maintaining full therapeutic efficacy.
  • a dosage form which provides a “zero-order,” or constant, release rate of the drug is useful for this purpose. Since zero-order release systems are difficult to achieve, systems which approximate a constant release rate, such as for example first-order and square root of time profiles are often used to provide sustained (prolonged, extended, or retarded) release of a drug.
  • Another particularly desirable PK profile is achieved by a dosage form that delivers a delayed release dissolution profile, in which the release of drug from the dosage form is delayed for a pre-determined time after ingestion by the patient.
  • the delay period (“lag time”) can be followed either by prompt release of the active ingredient (“delayed burst”), or by sustained (prolonged, extended, or retarded) release of the active ingredient (“delayed then sustained”).
  • a dosage form or drug delivery system
  • a controlled rate e.g. sustained, prolonged, extended or retarded release
  • diffusion erosion, and osmosis
  • One classic diffusion-controlled release system comprises a “reservoir” containing the active ingredient, surrounded by a “membrane” through which the active ingredient must diffuse in order to be absorbed into the bloodstream of the patient.
  • the rate of drug release, (dM/dt) depends on the area (A) of the membrane, the diffusional pathlength (l), the concentration gradient ( ⁇ C) of the drug across the membrane, the partition coefficient (K) of the drug into the membrane, and the diffusion coefficient (D):
  • diffusion-controlled systems generally deliver a non-constant release rate.
  • rate of drug release from diffusion-controlled release systems typically follows first order kinetics.
  • One disadvantage of membrane-reservoir type systems is their vulnerability to “dose dumping.” The diffusional membrane must remain intact without breach throughout the functional life of the dosage form in order to prevent this occurrence and the possibility of overdose along with the associated toxic side effects.
  • One typical type of diffusional membrane-reservoir systems comprises a compressed tablet core which acts as the reservoir, surrounded by a shell (or coating) which functions as the diffusional membrane.
  • a shell, or coating, which confers modified release properties is typically applied via conventional methods, such as for example, spray-coating in a coating pan. Pan-coating produces a single shell which essentially surrounds the core. Defects that commonly occur during coating, include “picking,” “sticking,” and “twinning,” all of which result in undesired holes in the coating, which lead to dose dumping.
  • the coating compositions that can be applied via spraying are limited by their viscosity. High viscosity solutions are difficult or impractical to pump and deliver through a spray nozzle. Spray coating methods suffer the further limitations of being time-intensive and costly. Several hours of spraying may be required to spray an effective amount of coating to control the release of an active ingredient. Coating times of 8 to 24 hours are not uncommon.
  • Another common type of diffusion-controlled release system comprises active ingredient, distributed throughout an insoluble porous matrix through which the active ingredient must diffuse in order to be absorbed into the bloodstream of the patient.
  • the amount of drug (M) released at a given time at sink conditions i.e. drug concentration at the matrix surface is much greater than drug concentration in the bulk solution, depends on the area (A) of the matrix, the diffusion coefficient (D), the porosity (E) and tortuosity (T) of the matrix, the drug solubility (Cs) in the dissolution medium, time (t) and the drug concentration (Cp) in the dosage form:
  • the amount of drug released is generally proportional to the square root of time. Assuming factors such as matrix porosity and tortuosity are constant within the dosage form, a plot of amount of drug released versus the square root of time should be linear.
  • One typical type of diffusional matrix system may be prepared by compression of the active ingredient along with a mixture of soluble and insoluble materials designed to produce a desired porosity and tortuosity as the soluble materials dissolve in the dissolution medium or gastro-intestinal fluids.
  • a commonly used erosion-controlled release system comprises a “matrix” throughout which the drug is distributed.
  • the matrix typically comprises a material which swells at the surface, and slowly dissolves away layer by layer, liberating drug as it dissolves.
  • the rate of drug release, (dM/dt) depends on the rate of erosion (dx/dt) of the matrix, the concentration profile in the matrix, and the surface area (A) of the system:
  • variation in one or more terms typically leads to a non-constant release rate of drug.
  • rate of drug release from erosion-controlled release systems typically follows first order kinetics.
  • One typical method of preparing such eroding matrix systems is by compression of the active ingredient blended with a mixture of compressible excipients comprising water swellable erodible materials which create a temporary barrier as they swell, and allow small amounts of active ingredient to be released as the continuously receding surface layer slowly dissolves in the dissolution medium or gastro-intestinal fluids.
  • Another type of erosion controlled delivery system employs materials which swell and dissolve slowly by surface erosion to provide a delayed release of pharmaceutical active ingredient. Delayed release is useful, for example in pulsatile or repeat action delivery systems, in which an immediate release dose is delivered, followed by a pre-determined lag time before a subsequent dose is delivered from the system.
  • the lag time (T l ) depends on the thickness (h) of the erodible layer, and the rate of erosion (dx/dt) of the matrix, which in turn depends on the swelling rate and solubility of the matrix components:
  • dM/dt is generally described by either the diffusion-controlled or erosion-controlled equations above, and T l is the lag time.
  • Modified release dosage forms prepared via compression to obtain either diffusional or eroding matrices are exemplified in U.S. Pat. Nos. 5,738,874 and 6,294,200, and WO 99/51209. Compressed dosage forms are limited by the achievable geometry's, as well as the suitable materials for producing them.
  • WO 97/49384 describes a hot-melt extrudable mixture of a therapeutic compound and a high molecular weight poly(ethylene oxide).
  • the formulation further comprises poly(ethylene glycol).
  • the high molecular weight poly(ethylene oxide)s employed have molecular weights ranging from about 1 to about 10 million Daltons.
  • the minimum ratio of high molecular weight poly(ethylene oxide) to active ingredient is 80:20.
  • the dosage forms of this reference are limited in the amount of active ingredient they can deliver.
  • the maximum amount of active ingredient that may be delivered in the composition is not more that 20 weight percent of the composition.
  • Typical hot-melt systems are additionally limited by high processing temperatures, and are therefore not optimal for delivering low melting, or heat labile active ingredients.
  • Typical hot-melt systems are additionally not optimal for delivering coated particles of active ingredients, due to both the high processing temperatures, and the high shear imparted during processing through extruders or spray nozzles.
  • Typical hot-melt systems are additionally not optimal for applying a coating thereon by conventional methods such as spraying, dipping, or compression.
  • modified release matrix systems It would be desirable to have a versatile and cost-effective method for preparing modified release matrix systems, which are not susceptible to dose dumping. It would additionally be desirable to have a method for preparing modified release matrix systems in a variety of shapes, for either functional purposes, e.g. achieving a desired release profile using certain advantageous geometries, or for consumer preference purposes, such as swallowability, dosage form elegance, and product identification and differentiation. It would additionally be desirable to have a controlled release matrix systems capable of delivering a relatively high level of active ingredient in a relatively small dosage form. It would additionally be desirable to have modified release matrix systems for delivering low-melting or heat labile active ingredients. It would additionally be desirable to have modified release matrix systems capable of delivering coated particles of active ingredient. It would additionally be desirable to have a method of applying a shell to a molded core.
  • the dosage form of this invention comprises: (a) at least one active ingredient; (b) a molded core which is solid at room temperature; and (c) a shell which is in contact with at least a portion of the core, wherein the dosage form provides modified release of the active ingredient upon contacting of the dosage form with a liquid medium.
  • the molded core comprises one or more active ingredients dispersed in a molded matrix.
  • the shell is capable of providing modified release of at least one active ingredient upon contacting of the dosage form with a liquid medium.
  • the shell is capable of providing a time delay prior to the release o fat least one active ingredient upon contacting of the dosage form with a liquid medium.
  • the time delay is independent of the pH of the liquid medium.
  • the shell comprises at least about 30 percent by weight of a thermal-reversible carrier.
  • the shell comprises at least one active ingredient.
  • the core comprises a molded matrix.
  • the core comprises at least one active ingredient.
  • the core is capable of providing modified release of at least one active ingredient upon contacting of the dosage form with a liquid medium.
  • the core comprises one or more release-modifying excipients.
  • the release modifying excipient is selected from the group consisting of swellable erodible hydrophilic materials, pH-dependent polymers, insoluble edible materials, and pore-formers, and derivatives, copolymers, and combinations thereof.
  • the core comprises at least 30% of thermal-reversible carrier.
  • the thermal-reversible carrier is selected from the group consisting of polyethylene glycol, thermoplastic polyethylene oxide, shellac, and derivatives, copolymers, and combinations thereof.
  • the thermal-reversible carrier has a melting point of about 20 to about 110° C.
  • the core comprises a plurality of particles which comprise at least one active ingredient.
  • At least a portion of the particles are coated with a coating capable of providing modified release of the active ingredient contained therein upon contacting of the coated particles with a liquid medium.
  • At least a portion of the particles are coated with a coating comprising 10-100 wt. % of a release-modifying polymer selected from the group consisting of pH-dependent polymers, water-soluble polymer, water-insoluble polymers, and copolymers and derivatives and mixtures thereof.
  • a release-modifying polymer selected from the group consisting of pH-dependent polymers, water-soluble polymer, water-insoluble polymers, and copolymers and derivatives and mixtures thereof.
  • a time delay occurs prior to release of at least a portion of the active ingredient.
  • the portion of the active ingredient released after the time delay is released in a sustained manner.
  • the dosage form comprises first and second active ingredients which are the same or different, and upon contacting of the dosage form with a liquid medium, the first active ingredient is released in a sustained manner, and a time delay precedes release of the second active ingredient.
  • the shell comprises a first active ingredient and the core comprises a second active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by a time delay, followed by release of the second active ingredient.
  • the shell comprises a first active ingredient and the core comprises a second active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by sustained release of the second active ingredient.
  • the shell comprises a first active ingredient and the core comprises particles comprising a second active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by sustained release of the second active ingredient.
  • the level of active ingredient is at least about 25 weight percent of the core.
  • the molded matrix comprises a thermal reversible carrier having a melting point from about 20 to about 100° C.
  • the molded matrix comprises a thermal reversible carrier selected from the group consisting of thermoplastic polyalkalene oxides, low melting hydrophobic materials, thermoplastic polymers, the thermoplastic starches, and combinations thereof.
  • the molded matrix comprises a low-melting thermal-reversible carrier selected from the group consisting of polycaprolactones, polyvinyl acetate, polyalkylene glycols, and combinations thereof at a level of about 30 to about 70 weight percent of the matrix.
  • the molded matrix comprises a thermal-reversible carrier selected from the group consisting of polyethylene glycol or polyethylene oxide at a level from about 10 to about 100 weight percent of the matrix.
  • the molded matrix further comprises a thermoplastic polyethylene oxide at a level of about 15 to about 25%.
  • the shell has a thickness from about 300 to about 2000 microns.
  • the shell has a thickness from about 150 to about 400 microns.
  • the weight of the shell is from about 50 to about 400 percent of the weight of the core.
  • the weight of the shell is from about 20 to about 100 percent of the weight of the core.
  • the core is substantially free of pores having a diameter of 0.5 to 5.0 microns.
  • the thermal reversible carrier is polyethylene glycol having a molecular weight from about 100 to about 8000 Daltons.
  • the molded matrix comprises a release-modifying excipient.
  • the release modifying polymer is shellac.
  • the release-modifying excipient is croscarmellose sodium.
  • the dosage form further comprises tributyl citrate as a plasticizer.
  • the shell comprises a film-former selected from the group consisting of cellulose acetate, ammonio methacrylate copolymer type B, shellac, hydroxyporoylmethylcellulose, polyethylene oxide, and combinations thereof.
  • the shell comprises a release-modifying excipient selected from swellable erodible hydrophilic materials.
  • the release-modifying excipient is croscarmellose sodium.
  • the shell comprises triethyl citrate as a plasticizer.
  • FIG. 1A depicts a cross-sectional side view of one embodiment of the dosage form of this invention.
  • FIG. 1B depicts a cross-sectional side view of another embodiment of the dosage from of this invention.
  • FIG. 2 depicts the % release of active ingredient vs. hours measured for the dosage form of Example 1.
  • the term “dosage form” applies to any solid object, semi-solid, or liquid composition designed to contain a specific pre-determined amount (i.e. dose) of a certain ingredient, for example an active ingredient as defined below.
  • Suitable dosage forms may be pharmaceutical drug delivery systems, including those for oral administration, buccal administration, rectal administration, topical or mucosal delivery, or subcutaneous implants, or other implanted drug delivery systems; or compositions for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorants, and the like.
  • the dosage forms of the present invention are considered to be solid, however they may contain liquid or semi-solid components.
  • the dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the gastro-intestinal tract of a human.
  • the dosage forms of the invention exhibit modified release of one or more active ingredients contained therein.
  • One or more active ingredients may be found within the shell, molded matrix, or coated or uncoated particles distributed therethrough.
  • the term “modified release” shall apply to dosage forms, matrices, particles, coatings, portions thereof, or compositions that alter the release of an active ingredient in any manner.
  • the active ingredient or ingredients that are released in a modified manner may be contained within the shell, core, composition, or portion thereof providing the modification.
  • the modified release active ingredient may be contained in a different portion of the dosage form from the shell, core, composition, or portion thereof providing the modification; for example the modified release active ingredient may be contained in the core, and the modification may be provided by an overlaying shell portion.
  • Types of modified release include controlled, prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like. Suitable mechanisms for achieving these types of modified release include diffusion, erosion, surface area control via geometry and/or impermeable barriers, or other mechanisms known in the art. Moreover, the modified release properties of the dosage form may be achieved through design of the core or a portion thereof, or the shell or a portion thereof, or a combination of these parts of the dosage form.
  • FIG. 1A is a cross-sectional side view of a dosage form 202 which comprises a molded core 204 comprising a molded matrix and a shell 203 which is in contact with at least a portion of the core 204 .
  • the core 204 comprises a plurality of uncoated particles 206 although this is not required in this embodiment of the invention.
  • the active ingredient may be contained within the matrix, the uncoated particles (if employed), the shell; or a combination thereof.
  • the dosage form provides modified release of the active ingredient upon contacting of the dosage form with a liquid medium such as water, gastrointestinal fluid and the like. Either the shell or the matrix or a combination thereof may provide modified release of the active ingredient.
  • FIG. 1B is a cross-sectional side view of a dosage form 252 which comprises a molded core 254 comprising a molded matrix and a shell 253 which is in contact with at least a portion of the core 254 .
  • the core 254 comprises a plurality of coated particles 256 .
  • the active ingredient may be contained within the matrix, the coated particles, the shell, or a combination thereof.
  • the dosage form provides modified release of the active ingredient upon contacting of the dosage form with a liquid medium such as water, gastrointestinal fluid and the like. Any of the shell, the coating, the matrix or a combination thereof may provide modified release of the active ingredient
  • the active ingredient employed in the dosage forms of this invention may be found within the core, the particles (whether coated or uncoated), the shell or a combination thereof.
  • Suitable active ingredients for use in this invention include for example pharmaceuticals, minerals, vitamins and other nutraceuticals, oral care agents, flavorants and mixtures thereof.
  • Suitable pharmaceuticals include analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, diuretics, expectorants, gastrointestinal agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tract agents and mixtures thereof.
  • Suitable oral care agents include breath fresheners, tooth whiteners, antimicrobial agents, tooth mineralizers, tooth decay inhibitors, topical anesthetics, mucoprotectants, and the like.
  • Suitable flavorants include menthol, peppermint, mint flavors, fruit flavors, chocolate, vanilla, bubble gum flavors, coffee flavors, liqueur flavors and combinations and the like.
  • Suitable gastrointestinal agents include antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum sodium carbonate; stimulant laxatives, such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists, such as famotadine, ranitidine, cimetadine, nizatidine; proton pump inhibitors such as omeprazole or lansoprazole; gastrointestinal cytoprotectives, such as sucraflate and misoprostol; gastrointestinal prokinetics, such as prucalopride, antibiotics for H.
  • antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum
  • pylori such as clarithromycin, amoxicillin, tetracycline, and metronidazole
  • antidiarrheals such as diphenoxylate and loperamide
  • glycopyrrolate such as glycopyrrolate
  • antiemetics such as ondansetron
  • analgesics such as mesalamine.
  • the active ingredient or agent may be selected from bisacodyl, famotadine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • the active agent is selected from analgesics, anti-inflammatories, and antipyretics, e.g. non-steroidal anti-inflammatory drugs (NSAIDs), including propionic acid derivatives, e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acid derivatives, e.g. indomethacin, diclofenac, sulindac, tolmetin, and the like; fenamic acid derivatives, e.g. mefanamic acid, meclofenamic acid, flufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the active agent is selected from propionic acid derivative NSAID, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof.
  • NSAID e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof.
  • the active ingredient may be selected from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • the active ingredient may be selected from pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, astemizole, norastemizole, terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • Suitable polydimethylsiloxanes which include, but are not limited to dimethicone and simethicone, are those disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each is expressly incorporated herein by reference.
  • simethicone refers to the broader class of polydimethylsiloxanes, including but not limited to simethicone and dimethicone.
  • the active ingredient or ingredients are present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, the particular active ingredient being administered, the bioavailability characteristics of the active ingredient, the dose regime, the age and weight of the patient, and other factors must be considered, as known in the art.
  • the dosage form comprises one or more active ingredient or ingredients at a combined level of more than about 20 weight percent, e.g. at least about 25 weight percent, or at least about 30 weight percent, or at least about 50 weight percent of the dosage form.
  • the active ingredient or ingredients may be present in the dosage form in any form.
  • the active ingredient may be dispersed at the molecular level, e.g. melted or dissolved, within the dosage form, or may be in the form of particles, which in turn may be coated or uncoated.
  • the particles typically have an average particle size of about 1-2000 microns. In one preferred embodiment, such particles are crystals having an average particle size of about 1-300 microns. In another preferred embodiment, the particles are granules or pellets having an average particle size of about 50-2000 microns, preferably about 50-1000 microns, most preferably about 100-800 microns.
  • the molded matrix of the present invention is made by molding, preferably using a solvent-free process.
  • the matrix comprises a flowable material.
  • the flowable material may be any edible material that is flowable at a temperature between about 37° C. and about 250° C., and that is solid, semi-solid, or can form a gel at a temperature between about ⁇ 10° C. and about 80° C.
  • the flowable material comprises 10-100% by weight of a thermal reversible carrier having a melting point of less than about 100° C., preferably from about 20 to about 100° C.; and optionally up to about 30 weight percent of various adjuvants such as for example plasticizers, gelling agents, colorants, stabilizers, preservatives, and the like as known in the art.
  • the matrix may optionally further comprise up to about 55 weight percent of one or more release-modifying excipients as described below.
  • such low melting materials may include, for example thermoplastic polyalkalene oxides, low melting hydrophobic materials, thermoplastic polymers, thermoplastic starches, and the like.
  • Preferred low-melting materials may be selected from thermoplastic polymers, thermoplastic polyalkalene oxides, low melting hydrophobic materials, and combinations thereof.
  • Suitable thermal-reversible carriers for making the molded matrix include are thermoplastic materials typically having a melting point below about 110° C., more preferably between about 20 and about 100° C.
  • suitable thermal-reversible carriers for solvent-free molding include thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, low melting hydrophobic materials, thermoplastic polymers, thermoplastic starches, and the like.
  • Preferred thermal-reversible carriers include polyethylene glycol and polyethylene oxide.
  • Suitable thermoplastic polyalkylene glycols for use as thermal-reversible carriers include polyethylene glycol having molecular weight from about 100 to about 20,000, e.g. from about 100 to about 8,000, say about 1000 to about 8,000 Daltons.
  • Suitable thermoplastic polyalkalene oxides include polyethylene oxide having a molecular weight from about 1,000 to about 900,000 Daltons.
  • Suitable low-melting hydrophobic materials for use as thermal-reversible carriers include fats, fatty acid esters, phospholipids, and waxes which are solid at room temperature, fat-containing mixtures such as chocolate; and the like.
  • suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts.
  • Suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides.
  • suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid.
  • suitable waxes which are solid at room temperature include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax.
  • the matrix comprises a low-melting thermal-reversible carrier selected from polycaprolactones, polyvinyl acetate, polyalkylene glycols and combinations thereof at a level of about 30 to about 70 weight percent, e.g. about 35 to about 50 weight percent of the matrix.
  • the low-melting thermal-reversible polymer has a melting point of less than about 100° C.
  • the matrix further comprises a thermoplastic polyethylene oxide at a level of about 15 to about 25% as a strengthening polymer. Polyethylene oxides having suitable thermoplastic properties for use in the present invention have a molecular weight of about 100,000 to about 900,000.
  • the matrix is substantially free of poly(ethylene oxide), e.g. contains less than 1%, or contains less than 0.1 weight percent of poly(ethylene oxide).
  • the matrix composition may comprise any of the materials set forth above having a melting point of less than 100° C., and the matrix composition may also comprise other materials such as release modifying agents, various adjuvants such as for example plasticizers, gelling agents, colorants, stabilizers, preservatives, and the like as known in the art.
  • Suitable release-modifying moldible excipients for making the molded matrix, or a portion thereof, by molding include but are not limited to swellable erodible hydrophilic materials, pH-dependent polymers, insoluble edible materials, and pore-formers.
  • Suitable swellable erodible hydrophilic materials for use as release-modifying excipients for making the molded matrix, or a portion thereof, by molding include water swellable cellulose derivatives, polyalkalene glycols, thermoplastic polyalkalene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, and swelling cross-linked polymers, and derivatives, copolymers, and combinations thereof.
  • suitable water swellable cellulose derivatives include sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose.
  • suitable polyalkalene glyclols include polyethylene glycol.
  • suitable thermoplastic polyalkalene oxides include poly (ethylene oxide).
  • acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL (high-molceular weight cross-linked acrylic acid homopolymers and copolymers), and the like.
  • suitable hydrocolloids include alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan.
  • Suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof.
  • suitable gelling starches include acid hydrolyzed starches, swelling starches such as sodium starch glycolate, and derivatives thereof.
  • suitable swelling cross-linked polymers include cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylcellose sodium.
  • Suitable pH-dependent polymers for use as release-modifying excipients for making the molded matrix or a portion thereof by molding include enteric cellulose derivatives, for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L, and the like, and derivatives, salts, copolymers, and combinations thereof.
  • Suitable insoluble edible materials for use as release-modifying excipients for making the molded matrix, or a portion thereof, by molding include water-insoluble polymers, and low-melting hydrophobic materials.
  • suitable water-insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof.
  • Suitable low-melting hydrophobic materials include fats, fatty acid esters, phospholipids, and waxes.
  • Suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid.
  • suitable waxes include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like.
  • Suitable pore-formers for use as release-modifying excipients for making the molded matrix or a portion thereof by molding include water-soluble organic and inorganic materials.
  • the pore former is hydroxypropylmethylcellulose.
  • suitable water-soluble organic materials include water soluble polymers including water soluble cellulose derivatives such as hydroxypropylmethylcellulose, and hydroxypropylcellulose; water soluble carbohydrates such as sugars, and starches; water soluble polymers such as polyvinylpyrrolidone and polyethylene glycol, and insoluble swelling polymers such as microcrystalline cellulose.
  • suitable water soluble inorganic materials include salts such as sodium chloride and potassium chloride and the like and/or mixtures thereof.
  • Suitable plasticizers for making the molded matrix, or a portion thereof, by molding include triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyltributyl citrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethyl fumarate, dibutyl succinate, diethylmalonate, dioctylphthalate, dibutylsuccinate, triethylcitrate, tributylcitrate, glyceroltributyrate, propylene glycol, polyethylene glycols, hydrogenated castor oil, fatty acids, substituted triglycerides and glycerides, and the like.
  • the matrix may be in a variety of different shapes.
  • the matrix may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, cylinder, sphere, torus, or the like.
  • the matrix has one or more major faces.
  • matrix surface may have two opposing major faces formed by contact with upper and lower mold surfaces.
  • the core surface may further comprise a “belly-band” located between the two major faces, and formed by contact with the side walls in the mold.
  • the matrix is prepared by thermal cycle molding using the method and apparatus described in copending U.S. patent application Ser. No. 09/966,497, pages 27-51, the disclosure of which is incorporated herein by reference.
  • the matrix is formed by injecting a starting material in flowable form into a heated molding chamber.
  • the starting material preferably comprises an active ingredient and a thermoplastic material at a temperature above the set temperature of the thermoplastic material but below the decomposition temperature of the active ingredient.
  • the starting material is cooled and solidifies in the molding chamber into a shaped form (i.e., having the shape of the mold).
  • the starting material must be in flowable form.
  • it may comprise solid particles suspended in a molten matrix, for example a polymer matrix.
  • the starting material may be completely molten or in the form of a paste.
  • the starting material may comprise an active ingredient dissolved in a molten material.
  • the starting material may be made by dissolving and/or suspending a solid in a solvent, which solvent is then evaporated from the starting material after it has been molded.
  • the particles may comprise active ingredient as described herein, or may be inactive particles included for example to provide a visual distinction to the appearance of the dosage form.
  • the particles may be as described herein, and the particle coating may comprise In particular embodiments of this invention in which coated particles are employed, the particles may be as described herein, and the particle coating may comprise about 10-100 weight percent (based on the weight of the coating) of a film former; optionally up to about 50 weight percent based on the weight of the coating of a pore former; and optionally up to about 30 weight percent of various adjuvants or excipients such as plasticizers etc.
  • suitable film formers may be selected from film forming water insoluble polymers; film forming pH-dependent polymers; and copolymers and combinations thereof.
  • the release-modifying particle coating preferably comprises a pore former.
  • Suitable film forming pH-dependent polymers for use in release-modifying particle coatings include for example enteric cellulose derivatives, such as for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins, such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L; and the like, and derivatives, salts, copolymers, and combinations thereof.
  • enteric cellulose derivatives such as for
  • Suitable pore formers for use in release-modifying particle coatings include water-soluble organic and inorganic materials.
  • the pore former is selected from hydroxypropylcellulose and hydroxypropylmethylcellulose.
  • suitable water-soluble organic materials include water soluble cellulose derivatives such as hydroxypropylmethylcellulose, and hydroxypropylcellulose; water soluble carbohydrates such as sugars, and starches; water soluble polymers such as polyvinylpyrrolidone and polyethylene glycol, and insoluble swelling polymers such as microcrystalline cellulose.
  • suitable water soluble inorganic materials include salts such as sodium chloride and potassium chloride and the like and/or mixtures thereof.
  • the dosage form releases at least first and second active ingredients contained therein in a sustained, extended, prolonged, or retarded manner.
  • the first and second active ingredients have different unmodified release characteristics; however the dosage form advantageously provides different types of modification to the first and second active ingredients, such that the dissolution profiles of the first and second active ingredients from the dosage form are similar.
  • the dosage form advantageously provides different types of modification to the first and second active ingredients, such that the dissolution profiles of the first and second active ingredients from the dosage form are substantially different, e.g. the first and second active ingredients are released from the dosage for at different rates or times upon contacting of the dosage form with a liquid medium.
  • the first and second active ingredient are both released from the dosage form at a substantially constant rate upon contacting of the dosage form with a liquid medium.
  • the dosage form comprises first and second active ingredients which may be the same or different, and upon contacting of the dosage form with a liquid medium, sustained release of the first active ingredient occurs, followed by sustained release of the second active ingredient.
  • the sustained release of first active ingredient is provided by the controlled dissolution of all or a portion of the molded matrix, and the subsequent sustained release of the second active ingredient is provided by one or more coatings on the particles of active ingredient.
  • the molded matrix preferably comprises a release modifying excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, insoluble edible materials, and combinations thereof.
  • the particle coating preferably comprises a release modifying excipient which may be selected from combinations of pore formers and insoluble edible materials; swellable erodible hydrophilic materials; pH-dependent polymers, and combinations thereof.
  • the matrix comprises a first dose of active ingredient and the particles contained therein comprise a second dose of active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first dose of active ingredient occurs, followed by a lag time, which is in turn followed by delayed release of the second dose active ingredient.
  • the matrix preferably comprises materials which exhibit rapid dissolution in gastro-intestinal fluids.
  • the immediate release shell portion or portions may comprise readily soluble materials selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates.
  • suitable non-crystallizable carbohydrates may be selected from polydextrose, starch hydrolysates, and non-crystallizable sugar alcohols, and combinations thereof.
  • the immediate release matrix will preferably liberate the coated particles of delayed release active ingredient by being breached or dissolved within 30 minutes in 900 ml water or 0.1 N HCl, or phosphate buffer solution at 37° C. with stirring by a USP type 2 (Paddle method) at 50 or 100 rpm.
  • the time delay is provided by a coating on the particles containing the second dose of active ingredient.
  • the delayed release particle coating comprises a release-modifying excipient selected from swellable erodible hydrophilic materials, and pH-dependent polymers, and combinations thereof.
  • the matrix comprises a first dose of active ingredient and the particles contained therein comprise a second dose of active ingredient which may be the same or different than the first dose of active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first dose of active ingredient occurs followed by sustained release of the second dose of active ingredient.
  • the matrix preferably comprises materials which exhibit rapid dissolution in gastro-intestinal fluids.
  • the immediate release shell portion or portions may comprise readily soluble materials selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates.
  • the molded matrix of the present invention is made by injecting the flowable material through an orifice into a mold cavity, then solidifying the flowable material, according to the method set forth herein, the disclosure of which is incorporated herein by reference.
  • the orifice has a diameter greater than the diameter of the particles, e.g. from about 1000 to about 4000 microns, say about 2000 to about 3000 microns.
  • the particles are introduced into the mold cavity in the form of a flowable slurry or suspension in the matrix material.
  • the flowable slurry or suspension may be introduced under pressure through the orifice.
  • the mold assembly may be free of a valve at the injection point.
  • the mold assembly may comprise an elastomeric plug type valve which does not crush the particles upon closing.
  • the thickness of the shell portion is critical to the release properties of the dosage form.
  • the dosage forms of the invention can be made with precise control over shell thickness.
  • the shell is made by the thermal cycle or thermal setting injection molding methods and apparatus described herein.
  • the shell typically has a thickness of about 200 to about 4000 microns, e.g. about 300 to about 2000 microns.
  • the flowable starting material may be completely molten or in the form of a paste.
  • the starting material may comprise an active ingredient dissolved in a molten material.
  • the ingredients comprising the starting material are preferably mixed together, and heated to a temperature above the melting temperature of the thermal reversible carrier to produce the flowable starting material.
  • the shell will typically comprise at least about 10 weight percent, e.g. at least about 12 weight percent or at least about 15 weight percent or at least about 20 weight percent or at least about 25 weight percent of a film-former.
  • the solvent-molded shell may optionally further comprise up to about 55 weight percent of a release-modifying excipient.
  • the solvent-molded shell may again also optionally further comprise up to about 30 weight percent total of various plasticizers, adjuvants, and excipients.
  • the shell typically has a thickness of less than about 800 microns, e.g. about 100 to about 600 microns, e.g. about 150 to about 400 microns.
  • the flowable starting material may be made by dissolving and/or suspending a solid in a solvent.
  • the solvent is then evaporated from the starting material after it has been molded.
  • the ingredients comprising the starting material are preferably mixed together, and optionally heated, to disperse the film former and optional other ingredients to produce the flowable starting material.
  • the total weight of the shell portion or portions is preferably about 20 percent to about 400 percent of the weight of the core.
  • the total weight of the shell portion or portions is typically from about 50 percent to about 400 percent, e.g. from about 75 percent to about 400 percent, or about 100 percent to about 200 percent of the weight of the core.
  • the total weight of the shell portion or portions is typically from about 20 percent to about 100 percent of the weight of the core.
  • Suitable thermal-reversible carriers for preparing the shell by solvent-free molding typically have a melting point below about 110° C., e.g. from about 20 to about 100° C.
  • Suitable thermal-reversible carriers for preparing the shell by solvent-free molding may be selected from the thermal-reversible carriers listed herein for preparing the core by solvent-free molding.
  • Particularly preferred thermal-reversible carriers for preparing the shell by solvent-free molding may be selected from polyethylene glycol, thermoplastic polyethylene oxide, shellac, and combinations thereof.
  • Suitable plasticizers for making the shell by solvent-free or solvent-based molding include, but are not limited to polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as castor oil, rape oil, olive oil, and sesame oil; surfactants such as polysorbates, sodium lauryl sulfates, and dioctyl-sodium sulfosuccinates; mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums; triacetin; acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalate; dibutylsuccinate; glyceroltributyrate; hydrogenated castor oil; fatty acids
  • Suitable adjuvants and excipients for making the shell by solvent-free or solvent-based molding include secondary film formers such as for example shellac, secondary gelling agents, such as for example cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate, and the like, as well as preservatives, high intensity sweeteners such as aspartame, acesulfame potassium, sucralose, and saccharin; flavors, antioxidants, surfactants, and coloring agents, many examples of which are known in the art.
  • secondary film formers such as for example shellac
  • secondary gelling agents such as for example cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate, and the like
  • preservatives such as for example cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate, and the like
  • high intensity sweeteners such as aspartame, acesulfame potassium,
  • Suitable film-formers for preparing the shell by solvent-based molding include, but are not limited to, film-forming water soluble polymers, film-forming proteins, film-forming water insoluble polymers, and film-forming pH-dependent polymers.
  • the film-former for making the shell or portion thereof by molding may be selected from cellulose acetate, ammonio methacrylate copolymer type B, shellac, hydroxypropylmethylcellulose, and polyethylene oxide, and combinations thereof.
  • Suitable film-forming water insoluble polymers include for example ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof.
  • Suitable film-forming pH-dependent polymers include enteric cellulose derivatives, such as for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins, such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename, EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename, EUDRAGIT L, and the like, and derivatives, salts, copolymers, and combinations thereof.
  • enteric cellulose derivatives such as for example hydroxypropyl methylcellulose
  • polyvinyl alcohol and polyethylene glycol copolymer are commercially available from BASF Corporation under the tradename KOLLICOAT IR.
  • modified starches include starches that have been modified by crosslinking, chemically modified for improved stability or optimized performance, or physically modified for improved solubility properties or optimized performance.
  • chemically-modified starches are well known in the art and typically include those starches that have been chemically treated to cause replacement of some of its hydroxyl groups with either ester or ether groups.
  • Crosslinking as used herein, may occur in modified starches when two hydroxyl groups on neighboring starch molecules are chemically linked.
  • pre-gelatinized starches or “instantized starches” refers to modified starches that have been pre-wetted, then dried to enhance their cold-water solubility.
  • Another suitable film forming modified starch includes the hydroxypropylated starches, in which some of the hydroxyl groups of the starch have been etherified with hydroxypropyl groups, usually via treatment with propylene oxide.
  • hydroxypropyl starch that possesses film-forming properties is available from Grain Processing Company under the tradename, PURE-COTE B790.
  • Suitable tapioca dextrins for use as film formers include those available from National Starch & Chemical Company under the tradenames CRYSTAL GUM or K-4484, and derivatives thereof such as modified food starch derived from tapioca, which is available from National Starch and Chemical under the tradename PURITY GUM 40, and copolymers and mixtures thereof.
  • the shell is prepared using the molding methods and apparatuses described in copending U.S. patent application Ser. No. 09/966,939, pages 27-51 and 57-63, which is incorporated herein by reference in its entirety.
  • the shell itself may comprise at least one active ingredient.
  • the shell completely surrounds the core.
  • At least one active ingredient contained within the dosage form exhibits a delayed burst release profile.
  • delayed burst release profile it is meant that the release of that particular active ingredient from the dosage form is delayed for a pre-determined time after ingestion by the patient, and the delay period (“lag time”) is followed by prompt (immediate) release of that active ingredient.
  • At least one shell portion of the present invention provides for the delay period and is preferably substantially free of the active ingredient to be released in a delayed burst manner.
  • the delayed burst active ingredient is typically contained within the corresponding underlying core portion.
  • At least one active ingredient contained within the dosage form exhibits a delayed and sustained release profile.
  • delayed then sustained release profile it is meant that the release of that particular active ingredient from the dosage form is delayed for a pre-determined time after ingestion by the patient, and the delay period (“lag time”) is followed by sustained (prolonged, extended, or retarded) release of that active ingredient.
  • At least one shell portion of the present invention provides for the delay period, and is preferably substantially free of the active ingredient to be released in a delayed then sustained manner.
  • the delayed then sustained release active ingredient is preferably contained within the corresponding underlying core portion.
  • the core portion may function for example as an eroding matrix or a diffusional matrix, or an osmotic pump.
  • the core portion preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore-formers.
  • the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated.
  • the core portion functions as an eroding matrix from which dispersed active ingredient is liberated in a sustained, extended, prolonged, or retarded manner
  • the core portion preferably comprises a release-modifying compressible or moldable excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, and combinations thereof.
  • the dosage form comprises first and second active ingredients which may be the same or different, and upon contacting of the dosage form with a liquid medium, delayed release of the first active ingredient occurs followed by sustained release of the second active ingredient.
  • the shell comprises a first active ingredient and the core comprises a second active ingredient (for example, within the matrix or coated or uncoated particles or a combination thereof) which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by delayed release of the second active ingredient.
  • a second active ingredient for example, within the matrix or coated or uncoated particles or a combination thereof
  • the shell comprises a first active ingredient and the core comprises a second active ingredient (for example, within the matrix or coated or uncoated particles or a combination thereof) which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by sustained release of the second active ingredient.
  • a second active ingredient for example, within the matrix or coated or uncoated particles or a combination thereof
  • the core or matrix or shell of the present invention are substantially free of pores having a diameter of 0.5-5.0 microns.
  • substantially free means that the shell portion or portions have a pore volume of less than about 0.02 cc/g, preferably less than about 0.01 cc/g, more preferably less than about 0.005 cc/g in the pore diameter range of 0.5 to 5.0 microns.
  • typical compressed materials have pore volumes of more than about 0.02 cc/g in this diameter range.
  • the core is a molded core and the core or core portions are substantially free of pores having a diameter of 0.5-5.0 microns.
  • the pore volume, pore diameter and density may be determined using a Quantachrome Instruments PoreMaster 60 mercury intrusion porosimeter and associated computer software program known as “Porowin.” The procedure is documented in the Quantachrome Instruments PoreMaster Operation Manual.
  • the PoreMaster determines both pore volume and pore diameter of a solid or powder by forced intrusion of a non-wetting liquid (mercury), which involves evacuation of the sample in a sample cell (penetrometer), filling the cell with mercury to surround the sample with mercury, applying pressure to the sample cell by: (i) compressed air (up to 50 psi maximum); and (ii) a hydraulic (oil) pressure generator (up to 60000 psi maximum).
  • Intruded volume is measured by a change in the capacitance as mercury moves from outside the sample into its pores under applied pressure.
  • the cell (filled with mercury) is then removed and weighed.
  • the cell is then emptied into the mercury reservoir, and two tablets from each sample are placed in the cell and the cell is reassembled.
  • the weight of the cell and sample are then recorded.
  • the cell is then installed in the low-pressure station, the low-pressure option is selected from the menu, and the following parameters are set:
  • Dosage forms according to the invention comprising molded cores with shells thereon were made as follows.
  • the molded cores were made from the following ingredients: Tablet Trade Name Manufacturer Weight % Mg/Tablet Pseudoephedrine BASF 22.0 130 Hydrochloride PharmaChemikalien Crystal GmbH & Co., Ludwigshafen/Rhein. Polyethylene Carbowax ® Union Carbide 45.0 267 Glycol 3350 Corporation, Danbury, CT Shellac Powder Regular bleached Mantrose-Haeuser 7.0 42 shellac Company, Atteboro, MA Croscarmellose Ac-Di-Sol ® FINE MUSCLE 26.0 154 Sodium COORDINATION Corporation, Newark DE
  • a beaker was submersed in a water bath (Ret digi-visc; Antal-Direct, Wayne, Pa.) where the water temperature was set at 70° C.
  • Polyethylene glycol (PEG) 3350 was added to the beaker and was mixed with a spatula until all PEG was melted.
  • Croscarmellose sodium was then added followed by mixing for 2 minutes.
  • Pseudoephedrine hydrochloride crystal was added, followed by mixing for 5 minutes.
  • 570 to 610 mg of the molten mixture was added a round, concave lower punch and die unit (0.4375 inch diameter) which was manually joined with the upper punch to form a molded tablet core.
  • the molded tablet core was ejected from the die.
  • the shells were made of the following ingredients: Shell Trade Name Manufacturer Weight % Mg/Tablet Polyethylene Carbowax ® Union Carbide 45.0 849 Glycol 3350 Corporation, Danbury, CT Polyethylene Oxide Polyox ® Union Carbide 15.0 283 (MW 200,000) WSR N-80 Corporation, Danbury, CT Shellac Powder Regular bleached Mantrose-Haeuser 20.0 377 shellac Company, Atteboro, MA Croscarmellose Ac-Di-Sol ® FMC Corporation, 10.0 188 Sodium Newark, DE Tributyl Citrate Morflex, Inc., 10.0 188 Greensboro, NC
  • a beaker was submersed in a water bath (Ret digi-visc; Antal-Direct, Wayne, Pa.) where the water temperature was set at 70° C.
  • Polyethylene glycol (PEG) 3350 was added to the beaker and was mixed with a spatula until all PEG was melted.
  • Tributyl citrate was added to the molten PEG mixture, followed by mixing for 1 minute.
  • a laboratory scale thermal cycle molding module was used to apply the shell in two portions onto the core.
  • a first mold assembly comprising a cavity was cycled to hot stage at 85° C. for 30 seconds.
  • a first portion of the shell material in flowable form (Example 1B) was added to the cavity.
  • a molded core (Example 1A) was then inserted into the cavity.
  • a blank mold assembly that masked half the core was screwed into the first mold assembly.
  • the joined mold assemblies were cycled to cold stage at 5° C. for 60 seconds to harden the shell on the exposed half of the core.
  • the blank mold assembly was removed and the molded core coated with the first shell portion was ejected form the cavity.
  • a second mold assembly comprising a second cavity was cycled to hot stage at 85° C. for 30 seconds.
  • a second portion of the shell material in flowable form (Example 1B) was added to the cavity.
  • the molded core comprising the first shell portion was inserted into the second mold assembly in such a way that the uncoated half of the core (without the first shell portion) was inserted into the second mold cavity.
  • the first mold assembly which was kept in cold cycle at 5° C., was screwed into the second mold assembly.
  • the second mold assembly was cycled to cold stage at 5° C. for 60 seconds to harden a second shell portion on the core.
  • the first mold assembly was removed and the dosage form, a molded core coated with the first and second shell portions (Example 1C), was ejected from the mold assembly.
  • the weight gain of the dosage form due to the first and second shell portions was recorded.
  • Shell material in flowable form (Example 1B) was added into a flat faced, 0.6875 inch rubber mold and a coated core (Example 1C) was inserted into the mold. Additional shell material was added to fill the mold. The round molded tablet core was removed from the mold after 5 minutes of cooling in the mold. The weight gain of the core due to the shell was recorded.
  • FIG. 2 depicts the % release of active ingredient vs. hours for the dosage form of Example 1 and other dosage forms. More particularly this figure shows the dissolution rate of three different samples of different shell weight gain of the present invention.
  • Curve (a) shows the release rate of pseudoephedrine HCL from the matrix with 314% shell weight gain of this invention.
  • Curve (b) shows the release rate of pseudoephedrine HCL from the matrix with 118% shell weight gain of this invention.
  • Curve (c) shows the release rate of pseudoephedrine HCL from the matrix with 55% shell weight gain of this invention.
  • Dosage forms of the invention are made in a continuous process using an apparatus comprising two thermal cycle molding modules linked in series via a transfer device as described at pages 14-16 of copending U.S. application Ser. No. 09/966,939, the disclosure of which is incorporated herein by reference.
  • the dosage forms comprise a molded core and a shell.
  • the core comprises the ingredients of Example 1A, provided in flowable form as described in Example 1.
  • the shell comprises the ingredients of Example 1B, provided in flowable form as described in Example 1.
  • the thermal cycle molding modules have the general configuration shown in FIG. 3 of copending U.S. application Ser. No. 09/966,497, which depicts a thermal cycle molding module 200 comprising a rotor 202 around which a plurality of mold units 204 are disposed.
  • Each thermal cycle molding module includes its own reservoir 206 (see FIG. 4 of copending U.S. application Ser. No. 09/966,497) for holding the core flowable material, and the shell flowable material, respectively.
  • each thermal cycle molding module is provided with a temperature control system for rapidly heating and cooling the mold units.
  • FIGS. 55 and 56 of copending U.S. application Ser. No. 09/966,497 depict the temperature control system 600 .
  • the cores are made in a first thermal cycle molding module, which is linked via a transfer device to a second thermal cycle molding module.
  • the first thermal cycle molding module has the specific configuration shown in FIG. 26A of copending U.S. application Ser. No. 09/966,497.
  • the first thermal cycle molding module comprises center mold assemblies 212 and upper mold assemblies 214 as shown in FIG. 26C, which mate to form mold cavities having the shape of the cores.
  • Core flowable material which is heated to a flowable state in reservoir 206 , is injected into the resulting mold cavities.
  • the temperature of the core flowable material is then decreased, hardening the core flowable material into cores.
  • the mold assemblies open and eject the cores, which are received by the transfer device.
  • the transfer device has the structure shown as 300 in FIG. 3 and described at pages 51-57 of copending U.S. application Ser. No. 09/966,414, the disclosure of which is incorporated herein by reference. It comprises a plurality of transfer units 304 attached in cantilever fashion to a belt 312 as shown in FIGS. 68 and 69 of copending U.S. application Ser. No. 09/966,414.
  • the transfer device rotates and operates in sync with the thermal cycle molding modules to which it is coupled.
  • Transfer units 304 comprise retainers 330 for holding the cores as they travel around the transfer device.
  • the transfer device transfers the cores to the second thermal cycle molding module, which applies the shell to the cores.
  • the second thermal cycle molding module is of the type shown in FIG. 28A of copending U.S. application Ser. No. 09/966,497.
  • the mold units 204 of the second thermal cycle molding module comprise upper mold assemblies 214 , rotatable center mold assemblies 212 and lower mold assemblies 210 as shown in FIG. 28C. Cores are continuously transferred to the mold assemblies, which then close over the cores.
  • Shell material which is heated to a flowable state in reservoir 206 , is injected into the mold cavities created by the closed mold assemblies. The temperature of the shell material is then decreased, hardening it.
  • the mold assemblies open and eject the coated cores. Coating is performed in two steps, each half of the cores being coated separately as shown in the flow diagram of FIG. 28B of copending U.S. application Ser. No. 09/966,939 via rotation of the center mold assembly.

Abstract

In one embodiment, a dosage form comprises: (a) at least one active ingredient; (b) a molded core which is solid at room temperature; and (c) a shell which is in contact with at least a portion of the core, wherein the dosage form provides modified release of the active ingredient upon contacting of the dosage form with a liquid medium. In another embodiment of this invention, a dosage form comprises: (a) at least one active ingredient; (b) a molded core comprising a plurality of particles; and (c) a shell which is in contact with at least a portion of the core, wherein the dosage form provides modified release of the active ingredient upon contacting of the dosage form with a liquid medium.

Description

    BACKGROUND OF THE INVENTION
  • 1. Field of the Invention [0001]
  • This invention relates to modified release dosage forms such as modified release pharmaceutical compositions. More particularly, this invention relates to modified release dosage forms comprising a molded core, and a shell residing upon at least a portion of the core. [0002]
  • 2. Background Information [0003]
  • Modified release pharmaceutical dosage forms have long been used to optimize drug delivery and enhance patient compliance, especially by reducing the number of doses of medicine the patient must take in a day. For this purpose, it is often desirable to modify the rate of release of a drug (one particularly preferred type of active ingredient) from a dosage form into the gastrointestinal (g.i.) fluids of a patient, especially to slow the release to provide prolonged action of the drug in the body. [0004]
  • The rate at which an orally delivered pharmaceutical active ingredient reaches its site of action in the body depends on a number of factors, including the rate and extent of drug absorption through the g.i. mucosa. To be absorbed into the circulatory system (blood), the drug must first be dissolved in the g.i. fluids. For many drugs, diffusion across the g.i. membranes is relatively rapid compared to dissolution. In these cases, the dissolution of the active ingredient is the rate limiting step in drug absorption, and controlling the rate of dissolution allows the formulator to control the rate of drug absorption into the circulatory system of a patient. [0005]
  • An important objective of modified release dosage forms is to provide a desired blood concentration versus time (pharmacokinetic, or PK) profile for the drug. Fundamentally, the PK profile for a drug is governed by the rate of absorption of the drug into the blood, and the rate of elimination of the drug from the blood. The type of PK profile desired depends, among other factors, on the particular active ingredient, and physiological condition being treated. [0006]
  • One particularly desirable PK profile for a number of drugs and conditions, is one in which the level of drug in the blood is maintained essentially constant (i.e. the rate of drug absorption is approximately equal to the rate of drug elimination) over a relatively long period of time. Such systems have the benefit of reducing the frequency of dosing, improving patient compliance, as well as minimizing side effects while maintaining full therapeutic efficacy. A dosage form which provides a “zero-order,” or constant, release rate of the drug is useful for this purpose. Since zero-order release systems are difficult to achieve, systems which approximate a constant release rate, such as for example first-order and square root of time profiles are often used to provide sustained (prolonged, extended, or retarded) release of a drug. [0007]
  • Another particularly desirable PK profile is achieved by a dosage form that delivers a delayed release dissolution profile, in which the release of drug from the dosage form is delayed for a pre-determined time after ingestion by the patient. The delay period (“lag time”) can be followed either by prompt release of the active ingredient (“delayed burst”), or by sustained (prolonged, extended, or retarded) release of the active ingredient (“delayed then sustained”). [0008]
  • Well known mechanisms by which a dosage form (or drug delivery system) can deliver drug at a controlled rate (e.g. sustained, prolonged, extended or retarded release) include diffusion, erosion, and osmosis. [0009]
  • One classic diffusion-controlled release system comprises a “reservoir” containing the active ingredient, surrounded by a “membrane” through which the active ingredient must diffuse in order to be absorbed into the bloodstream of the patient. The rate of drug release, (dM/dt) depends on the area (A) of the membrane, the diffusional pathlength (l), the concentration gradient (ΔC) of the drug across the membrane, the partition coefficient (K) of the drug into the membrane, and the diffusion coefficient (D): [0010]
  • dM/dt={ADKΔC}/1
  • Since one or more of the above terms, particularly the diffusional pathlength and concentration gradient tend to be non-constant, diffusion-controlled systems generally deliver a non-constant release rate. In general, the rate of drug release from diffusion-controlled release systems typically follows first order kinetics. One disadvantage of membrane-reservoir type systems is their vulnerability to “dose dumping.” The diffusional membrane must remain intact without breach throughout the functional life of the dosage form in order to prevent this occurrence and the possibility of overdose along with the associated toxic side effects. One typical type of diffusional membrane-reservoir systems comprises a compressed tablet core which acts as the reservoir, surrounded by a shell (or coating) which functions as the diffusional membrane. Current core-shell systems are limited by the available methods for manufacturing them, as well as the materials that are suitable for use with the current methods. A shell, or coating, which confers modified release properties is typically applied via conventional methods, such as for example, spray-coating in a coating pan. Pan-coating produces a single shell which essentially surrounds the core. Defects that commonly occur during coating, include “picking,” “sticking,” and “twinning,” all of which result in undesired holes in the coating, which lead to dose dumping. The coating compositions that can be applied via spraying are limited by their viscosity. High viscosity solutions are difficult or impractical to pump and deliver through a spray nozzle. Spray coating methods suffer the further limitations of being time-intensive and costly. Several hours of spraying may be required to spray an effective amount of coating to control the release of an active ingredient. Coating times of 8 to 24 hours are not uncommon. [0011]
  • Another common type of diffusion-controlled release system comprises active ingredient, distributed throughout an insoluble porous matrix through which the active ingredient must diffuse in order to be absorbed into the bloodstream of the patient. The amount of drug (M) released at a given time at sink conditions (i.e. drug concentration at the matrix surface is much greater than drug concentration in the bulk solution), depends on the area (A) of the matrix, the diffusion coefficient (D), the porosity (E) and tortuosity (T) of the matrix, the drug solubility (Cs) in the dissolution medium, time (t) and the drug concentration (Cp) in the dosage form: [0012]
  • M=A(DE/T(2Cp−ECs)(Cs)t)1/2
  • It will be noted in the above relationship that the amount of drug released is generally proportional to the square root of time. Assuming factors such as matrix porosity and tortuosity are constant within the dosage form, a plot of amount of drug released versus the square root of time should be linear. One typical type of diffusional matrix system may be prepared by compression of the active ingredient along with a mixture of soluble and insoluble materials designed to produce a desired porosity and tortuosity as the soluble materials dissolve in the dissolution medium or gastro-intestinal fluids. [0013]
  • A commonly used erosion-controlled release system comprises a “matrix” throughout which the drug is distributed. The matrix typically comprises a material which swells at the surface, and slowly dissolves away layer by layer, liberating drug as it dissolves. The rate of drug release, (dM/dt), in these systems depends on the rate of erosion (dx/dt) of the matrix, the concentration profile in the matrix, and the surface area (A) of the system: [0014]
  • dM/dt=A{dx/dt} {f(C)}
  • Again, variation in one or more terms, such as surface area, typically leads to a non-constant release rate of drug. In general, the rate of drug release from erosion-controlled release systems typically follows first order kinetics. One typical method of preparing such eroding matrix systems is by compression of the active ingredient blended with a mixture of compressible excipients comprising water swellable erodible materials which create a temporary barrier as they swell, and allow small amounts of active ingredient to be released as the continuously receding surface layer slowly dissolves in the dissolution medium or gastro-intestinal fluids. [0015]
  • Another type of erosion controlled delivery system employs materials which swell and dissolve slowly by surface erosion to provide a delayed release of pharmaceutical active ingredient. Delayed release is useful, for example in pulsatile or repeat action delivery systems, in which an immediate release dose is delivered, followed by a pre-determined lag time before a subsequent dose is delivered from the system. In these systems, the lag time (T[0016] l) depends on the thickness (h) of the erodible layer, and the rate of erosion (dx/dt) of the matrix, which in turn depends on the swelling rate and solubility of the matrix components:
  • T l =h(dx/dt)
  • The cumulative amount of drug (M) released from these systems at a given time generally follows the equation: [0017]
  • M=(dM/dt) (t−T l)
  • where dM/dt is generally described by either the diffusion-controlled or erosion-controlled equations above, and T[0018] l is the lag time.
  • Modified release dosage forms prepared via compression to obtain either diffusional or eroding matrices are exemplified in U.S. Pat. Nos. 5,738,874 and 6,294,200, and WO 99/51209. Compressed dosage forms are limited by the achievable geometry's, as well as the suitable materials for producing them. [0019]
  • WO 97/49384 describes a hot-melt extrudable mixture of a therapeutic compound and a high molecular weight poly(ethylene oxide). In some embodiments, the formulation further comprises poly(ethylene glycol). The high molecular weight poly(ethylene oxide)s employed have molecular weights ranging from about 1 to about 10 million Daltons. The minimum ratio of high molecular weight poly(ethylene oxide) to active ingredient is 80:20. The dosage forms of this reference are limited in the amount of active ingredient they can deliver. The maximum amount of active ingredient that may be delivered in the composition is not more that 20 weight percent of the composition. Typical hot-melt systems are additionally limited by high processing temperatures, and are therefore not optimal for delivering low melting, or heat labile active ingredients. Typical hot-melt systems are additionally not optimal for delivering coated particles of active ingredients, due to both the high processing temperatures, and the high shear imparted during processing through extruders or spray nozzles. Typical hot-melt systems are additionally not optimal for applying a coating thereon by conventional methods such as spraying, dipping, or compression. [0020]
  • It would be desirable to have a versatile and cost-effective method for preparing modified release matrix systems, which are not susceptible to dose dumping. It would additionally be desirable to have a method for preparing modified release matrix systems in a variety of shapes, for either functional purposes, e.g. achieving a desired release profile using certain advantageous geometries, or for consumer preference purposes, such as swallowability, dosage form elegance, and product identification and differentiation. It would additionally be desirable to have a controlled release matrix systems capable of delivering a relatively high level of active ingredient in a relatively small dosage form. It would additionally be desirable to have modified release matrix systems for delivering low-melting or heat labile active ingredients. It would additionally be desirable to have modified release matrix systems capable of delivering coated particles of active ingredient. It would additionally be desirable to have a method of applying a shell to a molded core. [0021]
  • It is one object of this invention to provide a dosage form in which at least one active ingredient contained therein exhibits a modified release profile upon contacting of the dosage form with a liquid medium. It is another object of this invention to provide a dosage form in which at least one active ingredient contained therein exhibits a modified release profile upon contacting of the dosage form with a liquid medium. Other objects, features and advantages of the invention will be apparent to those skilled in the art from the detailed description set forth below. [0022]
  • SUMMARY OF THE INVENTION
  • In one embodiment, the dosage form of this invention comprises: (a) at least one active ingredient; (b) a molded core which is solid at room temperature; and (c) a shell which is in contact with at least a portion of the core, wherein the dosage form provides modified release of the active ingredient upon contacting of the dosage form with a liquid medium. [0023]
  • In another embodiment, the molded core comprises one or more active ingredients dispersed in a molded matrix. [0024]
  • In another embodiment, the shell is capable of providing modified release of at least one active ingredient upon contacting of the dosage form with a liquid medium. [0025]
  • In another embodiment, the shell is capable of providing a time delay prior to the release o fat least one active ingredient upon contacting of the dosage form with a liquid medium. [0026]
  • In another embodiment, the time delay is independent of the pH of the liquid medium. [0027]
  • In another embodiment, the shell comprises at least about 30 percent by weight of a thermal-reversible carrier. [0028]
  • In another embodiment, the shell comprises at least one active ingredient. [0029]
  • In another embodiment, the core comprises a molded matrix. [0030]
  • In another embodiment, the core comprises at least one active ingredient. [0031]
  • In another embodiment, the core is capable of providing modified release of at least one active ingredient upon contacting of the dosage form with a liquid medium. [0032]
  • In another embodiment, the core comprises one or more release-modifying excipients. [0033]
  • In another embodiment, the release modifying excipient is selected from the group consisting of swellable erodible hydrophilic materials, pH-dependent polymers, insoluble edible materials, and pore-formers, and derivatives, copolymers, and combinations thereof. [0034]
  • In another embodiment, the core comprises at least 30% of thermal-reversible carrier. [0035]
  • In another embodiment, the thermal-reversible carrier is selected from the group consisting of polyethylene glycol, thermoplastic polyethylene oxide, shellac, and derivatives, copolymers, and combinations thereof. [0036]
  • In another embodiment, the thermal-reversible carrier has a melting point of about 20 to about 110° C. [0037]
  • In another embodiment, the core comprises a plurality of particles which comprise at least one active ingredient. [0038]
  • In another embodiment, at least a portion of the particles are coated with a coating capable of providing modified release of the active ingredient contained therein upon contacting of the coated particles with a liquid medium. [0039]
  • In another embodiment, at least a portion of the particles are coated with a coating comprising 10-100 wt. % of a release-modifying polymer selected from the group consisting of pH-dependent polymers, water-soluble polymer, water-insoluble polymers, and copolymers and derivatives and mixtures thereof. [0040]
  • In another embodiment, upon contacting of the dosage form with a liquid medium, a time delay occurs prior to release of at least a portion of the active ingredient. [0041]
  • In another embodiment, the portion of the active ingredient released after the time delay is released in a sustained manner. [0042]
  • In another embodiment, the dosage form comprises first and second active ingredients which are the same or different, and upon contacting of the dosage form with a liquid medium, the first active ingredient is released in a sustained manner, and a time delay precedes release of the second active ingredient. [0043]
  • In another embodiment, the shell comprises a first active ingredient and the core comprises a second active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by a time delay, followed by release of the second active ingredient. [0044]
  • In another embodiment, the shell comprises a first active ingredient and the core comprises a second active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by sustained release of the second active ingredient. [0045]
  • In another embodiment, the shell comprises a first active ingredient and the core comprises particles comprising a second active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by sustained release of the second active ingredient. [0046]
  • In another embodiment, the level of active ingredient is at least about 25 weight percent of the core. [0047]
  • In another embodiment, the molded matrix comprises a thermal reversible carrier having a melting point from about 20 to about 100° C. [0048]
  • In another embodiment, the molded matrix comprises a thermal reversible carrier selected from the group consisting of thermoplastic polyalkalene oxides, low melting hydrophobic materials, thermoplastic polymers, the thermoplastic starches, and combinations thereof. [0049]
  • In another embodiment, the molded matrix comprises a low-melting thermal-reversible carrier selected from the group consisting of polycaprolactones, polyvinyl acetate, polyalkylene glycols, and combinations thereof at a level of about 30 to about 70 weight percent of the matrix. [0050]
  • In another embodiment, the molded matrix comprises a thermal-reversible carrier selected from the group consisting of polyethylene glycol or polyethylene oxide at a level from about 10 to about 100 weight percent of the matrix. [0051]
  • In another embodiment, the molded matrix further comprises a thermoplastic polyethylene oxide at a level of about 15 to about 25%. [0052]
  • In another embodiment, the shell has a thickness from about 300 to about 2000 microns. [0053]
  • In another embodiment, the shell has a thickness from about 150 to about 400 microns. [0054]
  • In another embodiment, the weight of the shell is from about 50 to about 400 percent of the weight of the core. [0055]
  • In another embodiment, the weight of the shell is from about 20 to about 100 percent of the weight of the core. [0056]
  • In another embodiment, the core is substantially free of pores having a diameter of 0.5 to 5.0 microns. [0057]
  • In another embodiment, the thermal reversible carrier is polyethylene glycol having a molecular weight from about 100 to about 8000 Daltons. [0058]
  • In another embodiment, the molded matrix comprises a release-modifying excipient. [0059]
  • In another embodiment, the release modifying polymer is shellac. [0060]
  • In another embodiment, the release-modifying excipient is croscarmellose sodium. [0061]
  • In another embodiment, the dosage form further comprises tributyl citrate as a plasticizer. [0062]
  • In another embodiment, the shell comprises a film-former selected from the group consisting of cellulose acetate, ammonio methacrylate copolymer type B, shellac, hydroxyporoylmethylcellulose, polyethylene oxide, and combinations thereof. [0063]
  • In another embodiment, the shell comprises a release-modifying excipient selected from swellable erodible hydrophilic materials. [0064]
  • In another embodiment, the release-modifying excipient is croscarmellose sodium. [0065]
  • In another embodiment, the shell comprises triethyl citrate as a plasticizer.[0066]
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1A depicts a cross-sectional side view of one embodiment of the dosage form of this invention. [0067]
  • FIG. 1B depicts a cross-sectional side view of another embodiment of the dosage from of this invention. [0068]
  • FIG. 2 depicts the % release of active ingredient vs. hours measured for the dosage form of Example 1. [0069]
  • DETAILED DESCRIPTION OF THE INVENTION
  • As used herein, the term “dosage form” applies to any solid object, semi-solid, or liquid composition designed to contain a specific pre-determined amount (i.e. dose) of a certain ingredient, for example an active ingredient as defined below. Suitable dosage forms may be pharmaceutical drug delivery systems, including those for oral administration, buccal administration, rectal administration, topical or mucosal delivery, or subcutaneous implants, or other implanted drug delivery systems; or compositions for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorants, and the like. Preferably the dosage forms of the present invention are considered to be solid, however they may contain liquid or semi-solid components. In a particularly preferred embodiment, the dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the gastro-intestinal tract of a human. [0070]
  • The dosage forms of the invention exhibit modified release of one or more active ingredients contained therein. One or more active ingredients may be found within the shell, molded matrix, or coated or uncoated particles distributed therethrough. As used herein, the term “modified release” shall apply to dosage forms, matrices, particles, coatings, portions thereof, or compositions that alter the release of an active ingredient in any manner. The active ingredient or ingredients that are released in a modified manner may be contained within the shell, core, composition, or portion thereof providing the modification. Alternatively the modified release active ingredient may be contained in a different portion of the dosage form from the shell, core, composition, or portion thereof providing the modification; for example the modified release active ingredient may be contained in the core, and the modification may be provided by an overlaying shell portion. Types of modified release include controlled, prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like. Suitable mechanisms for achieving these types of modified release include diffusion, erosion, surface area control via geometry and/or impermeable barriers, or other mechanisms known in the art. Moreover, the modified release properties of the dosage form may be achieved through design of the core or a portion thereof, or the shell or a portion thereof, or a combination of these parts of the dosage form. [0071]
  • A first embodiment of this invention is depicted in FIG. 1A, which is a cross-sectional side view of a [0072] dosage form 202 which comprises a molded core 204 comprising a molded matrix and a shell 203 which is in contact with at least a portion of the core 204. In FIG. 1A the core 204 comprises a plurality of uncoated particles 206 although this is not required in this embodiment of the invention. The active ingredient may be contained within the matrix, the uncoated particles (if employed), the shell; or a combination thereof. The dosage form provides modified release of the active ingredient upon contacting of the dosage form with a liquid medium such as water, gastrointestinal fluid and the like. Either the shell or the matrix or a combination thereof may provide modified release of the active ingredient.
  • Another embodiment of this invention is depicted in FIG. 1B, which is a cross-sectional side view of a [0073] dosage form 252 which comprises a molded core 254 comprising a molded matrix and a shell 253 which is in contact with at least a portion of the core 254. In FIG. 1B the core 254 comprises a plurality of coated particles 256. The active ingredient may be contained within the matrix, the coated particles, the shell, or a combination thereof. The dosage form provides modified release of the active ingredient upon contacting of the dosage form with a liquid medium such as water, gastrointestinal fluid and the like. Any of the shell, the coating, the matrix or a combination thereof may provide modified release of the active ingredient
  • The active ingredient employed in the dosage forms of this invention may be found within the core, the particles (whether coated or uncoated), the shell or a combination thereof. Suitable active ingredients for use in this invention include for example pharmaceuticals, minerals, vitamins and other nutraceuticals, oral care agents, flavorants and mixtures thereof. Suitable pharmaceuticals include analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, diuretics, expectorants, gastrointestinal agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tract agents and mixtures thereof. [0074]
  • Suitable oral care agents include breath fresheners, tooth whiteners, antimicrobial agents, tooth mineralizers, tooth decay inhibitors, topical anesthetics, mucoprotectants, and the like. [0075]
  • Suitable flavorants include menthol, peppermint, mint flavors, fruit flavors, chocolate, vanilla, bubble gum flavors, coffee flavors, liqueur flavors and combinations and the like. [0076]
  • Examples of suitable gastrointestinal agents include antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum sodium carbonate; stimulant laxatives, such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists, such as famotadine, ranitidine, cimetadine, nizatidine; proton pump inhibitors such as omeprazole or lansoprazole; gastrointestinal cytoprotectives, such as sucraflate and misoprostol; gastrointestinal prokinetics, such as prucalopride, antibiotics for [0077] H. pylori, such as clarithromycin, amoxicillin, tetracycline, and metronidazole; antidiarrheals, such as diphenoxylate and loperamide; glycopyrrolate; antiemetics, such as ondansetron, analgesics, such as mesalamine.
  • In one embodiment of the invention, the active ingredient or agent may be selected from bisacodyl, famotadine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. [0078]
  • In another embodiment, the active agent is selected from analgesics, anti-inflammatories, and antipyretics, e.g. non-steroidal anti-inflammatory drugs (NSAIDs), including propionic acid derivatives, e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acid derivatives, e.g. indomethacin, diclofenac, sulindac, tolmetin, and the like; fenamic acid derivatives, e.g. mefanamic acid, meclofenamic acid, flufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g. diflunisal, flufenisal, and the like; and oxicams, e.g. piroxicam, sudoxicam, isoxicam, meloxicam, and the like. In a particularly preferred embodiment, the active agent is selected from propionic acid derivative NSAID, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof. In another embodiment of the invention, the active ingredient may be selected from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. [0079]
  • In another embodiment of the invention, the active ingredient may be selected from pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, astemizole, norastemizole, terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. [0080]
  • Examples of suitable polydimethylsiloxanes, which include, but are not limited to dimethicone and simethicone, are those disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each is expressly incorporated herein by reference. As used herein, the term “simethicone” refers to the broader class of polydimethylsiloxanes, including but not limited to simethicone and dimethicone. [0081]
  • The active ingredient or ingredients are present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, the particular active ingredient being administered, the bioavailability characteristics of the active ingredient, the dose regime, the age and weight of the patient, and other factors must be considered, as known in the art. In a preferred embodiment the dosage form comprises one or more active ingredient or ingredients at a combined level of more than about 20 weight percent, e.g. at least about 25 weight percent, or at least about 30 weight percent, or at least about 50 weight percent of the dosage form. [0082]
  • The active ingredient or ingredients may be present in the dosage form in any form. For example, the active ingredient may be dispersed at the molecular level, e.g. melted or dissolved, within the dosage form, or may be in the form of particles, which in turn may be coated or uncoated. If the active ingredient is in form of particles , the particles (whether coated or uncoated) typically have an average particle size of about 1-2000 microns. In one preferred embodiment, such particles are crystals having an average particle size of about 1-300 microns. In another preferred embodiment, the particles are granules or pellets having an average particle size of about 50-2000 microns, preferably about 50-1000 microns, most preferably about 100-800 microns. [0083]
  • The molded matrix of the present invention is made by molding, preferably using a solvent-free process. In a preferred embodiment, the matrix comprises a flowable material. The flowable material may be any edible material that is flowable at a temperature between about 37° C. and about 250° C., and that is solid, semi-solid, or can form a gel at a temperature between about −10° C. and about 80° C. In a preferred embodiment, the flowable material comprises 10-100% by weight of a thermal reversible carrier having a melting point of less than about 100° C., preferably from about 20 to about 100° C.; and optionally up to about 30 weight percent of various adjuvants such as for example plasticizers, gelling agents, colorants, stabilizers, preservatives, and the like as known in the art. The matrix may optionally further comprise up to about 55 weight percent of one or more release-modifying excipients as described below. [0084]
  • In embodiments of this invention in which the matrix comprises 10-100% by weight of a thermal reversible carrier having a melting point of less than about 100° C., such low melting materials may include, for example thermoplastic polyalkalene oxides, low melting hydrophobic materials, thermoplastic polymers, thermoplastic starches, and the like. Preferred low-melting materials may be selected from thermoplastic polymers, thermoplastic polyalkalene oxides, low melting hydrophobic materials, and combinations thereof. [0085]
  • Suitable thermal-reversible carriers for making the molded matrix include are thermoplastic materials typically having a melting point below about 110° C., more preferably between about 20 and about 100° C. Examples of suitable thermal-reversible carriers for solvent-free molding include thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, low melting hydrophobic materials, thermoplastic polymers, thermoplastic starches, and the like. Preferred thermal-reversible carriers include polyethylene glycol and polyethylene oxide. Suitable thermoplastic polyalkylene glycols for use as thermal-reversible carriers include polyethylene glycol having molecular weight from about 100 to about 20,000, e.g. from about 100 to about 8,000, say about 1000 to about 8,000 Daltons. Suitable thermoplastic polyalkalene oxides include polyethylene oxide having a molecular weight from about 1,000 to about 900,000 Daltons. Suitable low-melting hydrophobic materials for use as thermal-reversible carriers include fats, fatty acid esters, phospholipids, and waxes which are solid at room temperature, fat-containing mixtures such as chocolate; and the like. Examples of suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid. Examples of suitable waxes which are solid at room temperature include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax. [0086]
  • In one preferred embodiment, the matrix comprises a low-melting thermal-reversible carrier selected from polycaprolactones, polyvinyl acetate, polyalkylene glycols and combinations thereof at a level of about 30 to about 70 weight percent, e.g. about 35 to about 50 weight percent of the matrix. The low-melting thermal-reversible polymer has a melting point of less than about 100° C. In one such embodiment, the matrix further comprises a thermoplastic polyethylene oxide at a level of about 15 to about 25% as a strengthening polymer. Polyethylene oxides having suitable thermoplastic properties for use in the present invention have a molecular weight of about 100,000 to about 900,000. In another such embodiment, the matrix is substantially free of poly(ethylene oxide), e.g. contains less than 1%, or contains less than 0.1 weight percent of poly(ethylene oxide). [0087]
  • In other embodiments of this invention in which it is not required that the matrix comprise a material have a melting point of less than 100° C., the matrix composition may comprise any of the materials set forth above having a melting point of less than 100° C., and the matrix composition may also comprise other materials such as release modifying agents, various adjuvants such as for example plasticizers, gelling agents, colorants, stabilizers, preservatives, and the like as known in the art. [0088]
  • Suitable release-modifying moldible excipients for making the molded matrix, or a portion thereof, by molding include but are not limited to swellable erodible hydrophilic materials, pH-dependent polymers, insoluble edible materials, and pore-formers. [0089]
  • Suitable swellable erodible hydrophilic materials for use as release-modifying excipients for making the molded matrix, or a portion thereof, by molding include water swellable cellulose derivatives, polyalkalene glycols, thermoplastic polyalkalene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, and swelling cross-linked polymers, and derivatives, copolymers, and combinations thereof. Examples of suitable water swellable cellulose derivatives include sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples of suitable polyalkalene glyclols include polyethylene glycol. Examples of suitable thermoplastic polyalkalene oxides include poly (ethylene oxide). Examples of suitable acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL (high-molceular weight cross-linked acrylic acid homopolymers and copolymers), and the like. Examples of suitable hydrocolloids include alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan. Examples of suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof. Examples of suitable gelling starches include acid hydrolyzed starches, swelling starches such as sodium starch glycolate, and derivatives thereof. Examples of suitable swelling cross-linked polymers include cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylcellose sodium. [0090]
  • Suitable pH-dependent polymers for use as release-modifying excipients for making the molded matrix or a portion thereof by molding include enteric cellulose derivatives, for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L, and the like, and derivatives, salts, copolymers, and combinations thereof. [0091]
  • Suitable insoluble edible materials for use as release-modifying excipients for making the molded matrix, or a portion thereof, by molding include water-insoluble polymers, and low-melting hydrophobic materials. Examples of suitable water-insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof. Suitable low-melting hydrophobic materials include fats, fatty acid esters, phospholipids, and waxes. Examples of suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid. Examples of suitable waxes include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like. [0092]
  • Suitable pore-formers for use as release-modifying excipients for making the molded matrix or a portion thereof by molding include water-soluble organic and inorganic materials. In one embodiment the pore former is hydroxypropylmethylcellulose. Examples of suitable water-soluble organic materials include water soluble polymers including water soluble cellulose derivatives such as hydroxypropylmethylcellulose, and hydroxypropylcellulose; water soluble carbohydrates such as sugars, and starches; water soluble polymers such as polyvinylpyrrolidone and polyethylene glycol, and insoluble swelling polymers such as microcrystalline cellulose. Examples of suitable water soluble inorganic materials include salts such as sodium chloride and potassium chloride and the like and/or mixtures thereof. [0093]
  • Suitable plasticizers for making the molded matrix, or a portion thereof, by molding, include triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyltributyl citrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethyl fumarate, dibutyl succinate, diethylmalonate, dioctylphthalate, dibutylsuccinate, triethylcitrate, tributylcitrate, glyceroltributyrate, propylene glycol, polyethylene glycols, hydrogenated castor oil, fatty acids, substituted triglycerides and glycerides, and the like. [0094]
  • The matrix may be in a variety of different shapes. For example, the matrix may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, cylinder, sphere, torus, or the like. In certain embodiments, the matrix has one or more major faces. For example in certain embodiments matrix surface may have two opposing major faces formed by contact with upper and lower mold surfaces. In such embodiments the core surface may further comprise a “belly-band” located between the two major faces, and formed by contact with the side walls in the mold. [0095]
  • In one embodiment, the matrix is prepared by thermal setting molding using the method and apparatus described in copending U.S. patent application Ser. No. 09/966,450, pages 57-63, the disclosure of which is incorporated herein by reference. In this embodiment, the matrix is formed by injecting a starting material in flowable form into a molding chamber. The starting material preferably comprises an active ingredient and a thermal setting material at a temperature above the melting point of the thermal setting material but below the decomposition temperature of the active ingredient. The starting material is cooled and solidifies in the molding chamber into a shaped form (i.e., having the shape of the mold). [0096]
  • In another embodiment, the matrix is prepared by thermal cycle molding using the method and apparatus described in copending U.S. patent application Ser. No. 09/966,497, pages 27-51, the disclosure of which is incorporated herein by reference. In this embodiment, the matrix is formed by injecting a starting material in flowable form into a heated molding chamber. The starting material preferably comprises an active ingredient and a thermoplastic material at a temperature above the set temperature of the thermoplastic material but below the decomposition temperature of the active ingredient. The starting material is cooled and solidifies in the molding chamber into a shaped form (i.e., having the shape of the mold). [0097]
  • According to these methods, the starting material must be in flowable form. For example, it may comprise solid particles suspended in a molten matrix, for example a polymer matrix. The starting material may be completely molten or in the form of a paste. The starting material may comprise an active ingredient dissolved in a molten material. Alternatively, the starting material may be made by dissolving and/or suspending a solid in a solvent, which solvent is then evaporated from the starting material after it has been molded. [0098]
  • If particles are contained in the matrix, the particles (whether coated or uncoated) typically have an average particle size of about 1-2000 microns. In one preferred embodiment, the particles are crystals of the active ingredient or ingredients, and the average particle size is about 1-300 microns. In another preferred embodiment, the particles are granules or pellets, and the average particle size is about 50-2000 microns, preferably about 50-1000 microns, most preferably about 100-800 microns. [0099]
  • In particular embodiments of this invention in which uncoated particles are employed, the particles may comprise active ingredient as described herein, or may be inactive particles included for example to provide a visual distinction to the appearance of the dosage form. [0100]
  • In particular embodiments of this invention in which coated particles are employed, the particles may be as described herein, and the particle coating may comprise In particular embodiments of this invention in which coated particles are employed, the particles may be as described herein, and the particle coating may comprise about 10-100 weight percent (based on the weight of the coating) of a film former; optionally up to about 50 weight percent based on the weight of the coating of a pore former; and optionally up to about 30 weight percent of various adjuvants or excipients such as plasticizers etc. The particles may be coated using conventional coating technology which is well known to those skilled in the art including microencapsulation techniques such as coacervation, spray-drying, and fluidized bed coating including tangential spray rotor coating and bottom spray wurster coating. Examples of suitable particle coating methods and materials can be found in U.S. Pat. Nos. 5,286,497; 4,863,742; 4,173,626; 4,980,170; 4,984,240; 5,912,013; 6,270,805; and 6,322,819. Such coated particles may provide controlled release of the active ingredient contained therein in certain embodiments. [0101]
  • Suitable film formers for particle coating include, but are not limited to, film-forming water soluble polymers, film-forming proteins, film-forming water insoluble polymers, and film-forming pH-dependent polymers. In one embodiment, the film-former for particle coating may be selected from cellulose acetate, ammonio methacrylate copolymer type B, shellac, hydroxypropylmethylcellulose, and polyethylene oxide, and combinations thereof. [0102]
  • Suitable film-forming water soluble polymers for particle coating include water soluble vinyl polymers such as polyvinylalcohol; water soluble polycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl starch, carboxymethyl starch, pre-gelatinized starches, and film-forming modified starches; water swellable cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), hydroxyethylmethylcellulose (HEMC), hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose (HEEC), and hydroxyethylhydroxypropylmethyl cellulose (HEMPMC); water soluble copolymers such as methacrylic acid and methacrylate ester copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and polyvinylpyrrolidone copolymers; and derivatives and combinations thereof. [0103]
  • Suitable film-forming proteins may be natural or chemically modified, and include gelatin, whey protein, myofibrillar proteins, coaggulatable proteins such as albumin, casein, caseinates and casein isolates, soy protein and soy protein isolates, zein;; and polymers, derivatives and mixtures thereof. [0104]
  • In embodiments in which the particle coating confers modified release to one or more active ingredients contained in the particle, suitable film formers may be selected from film forming water insoluble polymers; film forming pH-dependent polymers; and copolymers and combinations thereof. In certain such embodiments in which the particle coating functions as a diffusional membrane, the release-modifying particle coating preferably comprises a pore former. [0105]
  • Suitable film forming water insoluble polymers for use in release-modifying particle coatings include for example ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof. [0106]
  • Suitable film forming pH-dependent polymers for use in release-modifying particle coatings include for example enteric cellulose derivatives, such as for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins, such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L; and the like, and derivatives, salts, copolymers, and combinations thereof. [0107]
  • Suitable pore formers for use in release-modifying particle coatings include water-soluble organic and inorganic materials. In one embodiment the pore former is selected from hydroxypropylcellulose and hydroxypropylmethylcellulose. Examples of suitable water-soluble organic materials include water soluble cellulose derivatives such as hydroxypropylmethylcellulose, and hydroxypropylcellulose; water soluble carbohydrates such as sugars, and starches; water soluble polymers such as polyvinylpyrrolidone and polyethylene glycol, and insoluble swelling polymers such as microcrystalline cellulose. Examples of suitable water soluble inorganic materials include salts such as sodium chloride and potassium chloride and the like and/or mixtures thereof. [0108]
  • Examples of suitable adjuvants or excipients for particle coatings include plasticizers, detackifiers, humectants, surfactants, anti-foaming agents, colorants, opacifiers, and the like. Suitable plasticizers for making the core, the shell, or a portion thereof, by molding include, but not be limited to polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as castor oil, rape oil, olive oil, and sesame oil; surfactants such as polysorbates, sodium lauryl sulfates, and dioctyl-sodium sulfosuccinates; mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums; triacetin; acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalate; dibutylsuccinate; glyceroltributyrate; hydrogenated castor oil; fatty acids; substituted triglycerides and glycerides; and the like and/or mixtures thereof. In one embodiment, the plasticizer is triethyl citrate. In certain embodiments, the shell is substantially free of plasticizers, i.e. contains less than about 1%, say less than about 0.01% of plasticizers. [0109]
  • In certain particularly preferred embodiments of this invention, the dosage form releases one or more active ingredients contained therein in a sustained, extended, prolonged, or retarded manner, more preferably at a substantially constant rate upon contacting of the dosage form with a liquid medium. In such embodiments, the molded matrix may function as a diffusional matrix or an eroding matrix. In embodiments in which the molded matrix functions as an eroding matrix from which dispersed active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the molded matrix preferably comprises a release-modifying moldable excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, insoluble edible materials, and combinations thereof. In embodiments in which the molded matrix functions as a diffusional matrix through which active ingredient contained therein is liberated in a sustained, extended, prolonged, or retarded manner, the molded matrix preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore formers. Alternately, in such embodiments in which the matrix is prepared by solvent-free molding, the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated. [0110]
  • In certain other preferred embodiments of this invention, the dosage form releases at least first and second active ingredients contained therein in a sustained, extended, prolonged, or retarded manner. In certain such embodiments, the first and second active ingredients have different unmodified release characteristics; however the dosage form advantageously provides different types of modification to the first and second active ingredients, such that the dissolution profiles of the first and second active ingredients from the dosage form are similar. In certain other such embodiments, the dosage form advantageously provides different types of modification to the first and second active ingredients, such that the dissolution profiles of the first and second active ingredients from the dosage form are substantially different, e.g. the first and second active ingredients are released from the dosage for at different rates or times upon contacting of the dosage form with a liquid medium. In a particularly preferred embodiment, the first and second active ingredient are both released from the dosage form at a substantially constant rate upon contacting of the dosage form with a liquid medium. [0111]
  • In certain other embodiments of this invention, upon contacting of the dosage form with a liquid medium, a time delay occurs prior to release of at least a portion of one or more active ingredients occurs followed by sustained release of the delayed release active ingredient or ingredients. In such embodiments, the time delay is provided by the dissolution of all or a portion of the molded matrix, and the subsequent sustained release is provided by one or more coatings on the particles of active ingredient. In such embodiments, the molded matrix preferably comprises a release modifying excipient selected from pH-dependent polymers. In such embodiments, the particle coating preferably comprises a release modifying excipient which may be selected from combinations of pore formers and insoluble edible materials; swellable erodible hydrophilic materials; pH-dependent polymers; and combinations thereof. [0112]
  • In another particular embodiment of this invention, the dosage form comprises first and second active ingredients which may be the same or different, and upon contacting of the dosage form with a liquid medium, sustained release of the first active ingredient occurs, followed by sustained release of the second active ingredient. In such embodiments, the sustained release of first active ingredient is provided by the controlled dissolution of all or a portion of the molded matrix, and the subsequent sustained release of the second active ingredient is provided by one or more coatings on the particles of active ingredient. In such embodiments, the molded matrix preferably comprises a release modifying excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, insoluble edible materials, and combinations thereof. In such embodiments, the particle coating preferably comprises a release modifying excipient which may be selected from combinations of pore formers and insoluble edible materials; swellable erodible hydrophilic materials; pH-dependent polymers, and combinations thereof. [0113]
  • In another particularly preferred embodiment of this invention, the matrix comprises a first dose of active ingredient and the particles contained therein comprise a second dose of active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first dose of active ingredient occurs, followed by a lag time, which is in turn followed by delayed release of the second dose active ingredient. In such embodiments, the matrix preferably comprises materials which exhibit rapid dissolution in gastro-intestinal fluids. For example the immediate release shell portion or portions may comprise readily soluble materials selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates. In certain such embodiments, suitable water soluble or water swellable thermoplastic film formers may be selected from water swellable cellulose derivatives, thermoplastic starches, polyalkalene glycols, polyalkalene oxides, and amorphous sugar glass, and combinations thereof. In certain other such embodiments, suitable film formers may be selected from film forming water soluble polymers such as for example water soluble vinyl polymers, water soluble polycarbohydrates, water swellable cellulose derivatives, and water soluble copolymers; film-forming proteins, and combinations thereof. In certain other such embodiments, suitable thickeners may be selected from gelling polymers or hydrocolloids; gelling starches, and crystallizable carbohydrates, and combinations thereof. In certain other such embodiments, suitable non-crystallizable carbohydrates may be selected from polydextrose, starch hydrolysates, and non-crystallizable sugar alcohols, and combinations thereof. In such embodiments, the immediate release matrix will preferably liberate the coated particles of delayed release active ingredient by being breached or dissolved within 30 minutes in 900 ml water or 0.1 N HCl, or phosphate buffer solution at 37° C. with stirring by a USP type 2 (Paddle method) at 50 or 100 rpm. In these embodiments, the time delay is provided by a coating on the particles containing the second dose of active ingredient. Preferably the delayed release particle coating comprises a release-modifying excipient selected from swellable erodible hydrophilic materials, and pH-dependent polymers, and combinations thereof. [0114]
  • In another particularly preferred embodiment of this invention, the matrix comprises a first dose of active ingredient and the particles contained therein comprise a second dose of active ingredient which may be the same or different than the first dose of active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first dose of active ingredient occurs followed by sustained release of the second dose of active ingredient. In such embodiments, the matrix preferably comprises materials which exhibit rapid dissolution in gastro-intestinal fluids. For example the immediate release shell portion or portions may comprise readily soluble materials selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates. In certain such embodiments, suitable water soluble or water swellable thermoplastic film formers may be selected from water swellable cellulose derivatives, thermoplastic starches, polyalkalene glycols, polyalkalene oxides, and amorphous sugar glass, and combinations thereof. In certain other such embodiments, suitable film formers may be selected from film forming water soluble polymers such as for example water soluble vinyl polymers, water soluble polycarbohydrates, water swellable cellulose derivatives, and water soluble copolymers; film-forming proteins, and combinations thereof. In certain other such embodiments, suitable thickeners may be selected from gelling polymers or hydrocolloids; gelling starches, and crystallizable carbohydrates. In certain other such embodiments, suitable non-crystallizable carbohydrates may be selected from polydextrose, starch hydrolysates, and non-crystallizable sugar alcohols. In such embodiments, the immediate release matrix will preferably liberate the coated particles of delayed release active ingredient by being breached or dissolved within 30 minutes in 900 ml water or 0.1 N HCl, or phosphate buffer solution at 37° C. with stirring by a USP type 2 (Paddle method) at 50 or 100 rpm. In these embodiments, the sustained release is provided by a coating on the particles containing the second dose of active ingredient. Preferably the sustained release particle coating comprises a release-modifying excipient which may be selected from combinations of pore formers and insoluble edible materials; swellable erodible hydrophilic materials; pH-dependent polymers. [0115]
  • Preferably the molded matrix of the present invention is made by injecting the flowable material through an orifice into a mold cavity, then solidifying the flowable material, according to the method set forth herein, the disclosure of which is incorporated herein by reference. In one such embodiment wherein the dosage form comprises particles, the orifice has a diameter greater than the diameter of the particles, e.g. from about 1000 to about 4000 microns, say about 2000 to about 3000 microns. In certain such embodiments the particles are introduced into the mold cavity in the form of a flowable slurry or suspension in the matrix material. The flowable slurry or suspension may be introduced under pressure through the orifice. In one embodiment, the mold assembly may be free of a valve at the injection point. In another embodiment, the mold assembly may comprise an elastomeric plug type valve which does not crush the particles upon closing. [0116]
  • Advantageously this method provides a versatile and cost-effective process for preparing the modified release molded matrix systems of the present invention. Advantageously, the method of the present invention may be carried out at relatively low processing temperatures, enabling the incorporation of low melting active ingredients, heat labile active ingredients, and coated particles into molded matrix dosage forms. Advantageously the combination of methods and materials of the present invention enable the incorporation of relatively high levels of active ingredient into the molded matrix dosage form, and enable the production of unique elegant dosage forms with transparent, semi-transparent, or translucent matrices. [0117]
  • In certain embodiments of the invention, the shell contains active ingredient which is released essentially immediately upon ingestion of the dosage form. In these embodiments, the shell preferably comprises materials which exhibit rapid dissolution in gastro-intestinal fluids. [0118]
  • In certain other embodiments, the shell functions as a diffusional membrane which contains pores through which fluids can enter the dosage form, and dissolved active ingredient can be released in a sustained, extended, prolonged or retarded manner. In these embodiments, the rate of release of active ingredient from the underlying core will depend upon the total pore area in the shell, the pathlength of the pores, and the solubility and diffusivity of the active ingredient (in addition to its rate of release from the core portion itself). In preferred embodiments in which the shell functions as a diffusional membrane, the release of the active ingredient from the dosage form may be described as controlled, prolonged, sustained or extended. In these embodiments, the contribution to active ingredient dissolution from the shell may follow zero-order, first-order, or square-root of time kinetics. In certain such embodiments, the diffusional membrane shell portion preferably comprises a release-modifying excipient such as a combination of a pore former and an insoluble edible material such as for example a film forming water insoluble polymer. Alternately, in such embodiments in which the shell is prepared by solvent-free molding, the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated. [0119]
  • In certain other embodiments, the shell functions as an eroding matrix from which active ingredient dispersed in the shell is liberated by the dissolution of successive layers of the shell surface. In these embodiments, the rate of active ingredient release will depend on the dissolution rate of the matrix material in the shell. Particularly useful matrix materials for providing surface erosion include those which first absorb liquid, then swell and/or gel prior to dissolving. In certain such embodiments, the eroding matrix shell preferably comprises a swellable erodible hydrophilic material. [0120]
  • In certain other embodiments, the shell functions as a barrier to prevent release therethrough of an active ingredient contained in the underlying core or core portion. In such embodiments, active ingredient is typically released from a portion of the core which is not covered by the barrier shell portion. Such embodiments advantageously allow for control of the surface area for release of the active ingredient. In certain particular embodiments, for example, the surface area for release of active ingredient can be maintained substantially constant over time. In a particularly preferred embodiment, the release of at least one active ingredient follows substantially zero-order kinetics. In certain such embodiments, the barrier shell portion preferably comprises a water insoluble material such as for example a water insoluble polymer. [0121]
  • In certain other embodiments, the shell functions as a delayed release coating to delay release of an active ingredient which is contained in the core or a portion thereof. In these embodiments, the lag-time for onset of active ingredient release may be governed by erosion of the shell or diffusion through the shell, or a combination thereof. In certain such embodiments, the eroding matrix shell preferably comprises a swellable erodible hydrophilic material. [0122]
  • In embodiments in which the shell functions to modify the release of an active ingredient which is contained in the core or the subject shell portion, the thickness of the shell portion is critical to the release properties of the dosage form. Advantageously the dosage forms of the invention can be made with precise control over shell thickness. In a preferred embodiment in which the shell functions to modify the release of an active ingredient which is contained in the core or the shell, the shell is made by the thermal cycle or thermal setting injection molding methods and apparatus described herein. [0123]
  • The shell of the present invention may be prepared by molding, using a solvent-free process, or a solvent-based process, and depending on the method used, typically comprises a variety of excipients which are useful for conferring desired properties to the shell. The shell may optionally further comprise one or more active ingredients. [0124]
  • In embodiments in which the shell is prepared using a solvent-free molding process, the shell will typically comprise at least about 30 percent, e.g. at least about 45 percent by weight of a thermal-reversible carrier. The shell may optionally further comprise up to about 55 weight percent of a release-modifying excipient. The shell may optionally further comprise up to about 30 weight percent total of various plasticizers, adjuvants and excipients. In certain embodiments in which the shell is prepared by solvent-free molding, and functions to delay the release of one or more active ingredients from an underlying core portion, the release modifying excipient is preferably selected from swellable, erodible hydrophilic materials. [0125]
  • In embodiments wherein the shell is prepared by a solvent-free molding process, the shell typically has a thickness of about 200 to about 4000 microns, e.g. about 300 to about 2000 microns. [0126]
  • In embodiments wherein the shell is prepared by a solvent-free molding process, the flowable starting material may be completely molten or in the form of a paste. The starting material may comprise an active ingredient dissolved in a molten material. The ingredients comprising the starting material are preferably mixed together, and heated to a temperature above the melting temperature of the thermal reversible carrier to produce the flowable starting material. [0127]
  • In embodiments in which the shell is prepared using a solvent-based molding process, the shell will typically comprise at least about 10 weight percent, e.g. at least about 12 weight percent or at least about 15 weight percent or at least about 20 weight percent or at least about 25 weight percent of a film-former. Here, the solvent-molded shell may optionally further comprise up to about 55 weight percent of a release-modifying excipient. The solvent-molded shell may again also optionally further comprise up to about 30 weight percent total of various plasticizers, adjuvants, and excipients. In embodiments wherein the shell is prepared by a solvent-based molding process, the shell typically has a thickness of less than about 800 microns, e.g. about 100 to about 600 microns, e.g. about 150 to about 400 microns. [0128]
  • In embodiments wherein the shell is prepared by a solvent-based molding process, the flowable starting material may be made by dissolving and/or suspending a solid in a solvent. The solvent is then evaporated from the starting material after it has been molded. The ingredients comprising the starting material are preferably mixed together, and optionally heated, to disperse the film former and optional other ingredients to produce the flowable starting material. [0129]
  • The total weight of the shell portion or portions is preferably about 20 percent to about 400 percent of the weight of the core. In embodiments wherein the shell portion or portions prepared by a solvent-free molding process, the total weight of the shell portion or portions is typically from about 50 percent to about 400 percent, e.g. from about 75 percent to about 400 percent, or about 100 percent to about 200 percent of the weight of the core. In embodiments wherein the shell portion or portions are prepared by a solvent-based molding process, the total weight of the shell portion or portions is typically from about 20 percent to about 100 percent of the weight of the core. [0130]
  • Suitable thermal-reversible carriers for preparing the shell by solvent-free molding typically have a melting point below about 110° C., e.g. from about 20 to about 100° C. Suitable thermal-reversible carriers for preparing the shell by solvent-free molding may be selected from the thermal-reversible carriers listed herein for preparing the core by solvent-free molding. Particularly preferred thermal-reversible carriers for preparing the shell by solvent-free molding may be selected from polyethylene glycol, thermoplastic polyethylene oxide, shellac, and combinations thereof. [0131]
  • Suitable release modifying agents for making the shell portion by solvent-free or solvent-based molding include but are not limited to swellable erodible hydrophilic materials, film-formers, pH dependent polymers, and pore-formers. [0132]
  • Suitable plasticizers for making the shell by solvent-free or solvent-based molding include, but are not limited to polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as castor oil, rape oil, olive oil, and sesame oil; surfactants such as polysorbates, sodium lauryl sulfates, and dioctyl-sodium sulfosuccinates; mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums; triacetin; acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalate; dibutylsuccinate; glyceroltributyrate; hydrogenated castor oil; fatty acids; substituted triglycerides and glycerides; and the like and/or mixtures thereof. In one embodiment, the plasticizer is triethyl citrate. In certain embodiments, the shell is substantially free of plasticizers, i.e. contains less than about 1%, say less than about 0.01% of plasticizers. [0133]
  • Suitable adjuvants and excipients for making the shell by solvent-free or solvent-based molding include secondary film formers such as for example shellac, secondary gelling agents, such as for example cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone, sodium starch glycolate, and the like, as well as preservatives, high intensity sweeteners such as aspartame, acesulfame potassium, sucralose, and saccharin; flavors, antioxidants, surfactants, and coloring agents, many examples of which are known in the art. [0134]
  • Suitable film-formers for preparing the shell by solvent-based molding include, but are not limited to, film-forming water soluble polymers, film-forming proteins, film-forming water insoluble polymers, and film-forming pH-dependent polymers. In one embodiment, the film-former for making the shell or portion thereof by molding may be selected from cellulose acetate, ammonio methacrylate copolymer type B, shellac, hydroxypropylmethylcellulose, and polyethylene oxide, and combinations thereof. [0135]
  • Suitable film-forming water soluble polymers include water soluble vinyl polymers such as polyvinylalcohol (PVA); water soluble polycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl starch, carboxymethyl starch, pre-gelatinized starches, and film-forming modified starches; water swellable cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), hydroxyethylmethylcellulose (HEMC), hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose (HEEC), and hydroxyethylhydroxypropylmethyl cellulose (HEMPMC); water soluble copolymers such as methacrylic acid and methacrylate ester copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and polyvinylpyrrolidone copolymers; and derivatives and combinations thereof. [0136]
  • Suitable film-forming proteins may be natural or chemically modified, and include gelatin, whey protein, myofibrillar proteins, coaggulatable proteins such as albumin, casein, caseinates and casein isolates, soy protein and soy protein isolates, zein;; and polymers, derivatives and mixtures thereof. [0137]
  • Suitable film-forming water insoluble polymers, include for example ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof. [0138]
  • Suitable film-forming pH-dependent polymers include enteric cellulose derivatives, such as for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins, such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename, EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename, EUDRAGIT L, and the like, and derivatives, salts, copolymers, and combinations thereof. [0139]
  • One suitable hydroxypropylmethylcellulose compound for use as a thermoplastic film-forming water soluble polymer is HPMC 2910, which is a cellulose ether having a degree of substitution of about 1.9 and a hydroxypropyl molar substitution of 0.23, and containing, based upon the total weight of the compound, from about 29% to about 30% methoxyl groups and from about 7% to about 12% hydroxylpropyl groups. HPMC 2910 is commercially available from the Dow Chemical Company under the tradename METHOCEL E. METHOCEL E5, which is one grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 4 to 6 cps (4 to 6 millipascal-seconds) at 20° C. in a 2% aqueous solution as determined by a Ubbelohde viscometer. Similarly, METHOCEL E6, which is another grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 5 to 7 cps (5 to 7 millipascal-seconds) at 20° C. in a 2% aqueous solution as determined by a Ubbelohde viscometer. METHOCEL E15, which is another grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 15000 cps (15 millipascal-seconds) at 20° C. in a 2% aqueous solution as determined by a Ubbelohde viscometer. As used herein, “degree of substitution” shall mean the average number of substituent groups attached to a anhydroglucose ring, and “hydroxypropyl molar substitution” shall mean the number of moles of hydroxypropyl per mole anhydroglucose. [0140]
  • One suitable polyvinyl alcohol and polyethylene glycol copolymer is commercially available from BASF Corporation under the tradename KOLLICOAT IR. [0141]
  • As used herein, “modified starches” include starches that have been modified by crosslinking, chemically modified for improved stability or optimized performance, or physically modified for improved solubility properties or optimized performance. Examples of chemically-modified starches are well known in the art and typically include those starches that have been chemically treated to cause replacement of some of its hydroxyl groups with either ester or ether groups. Crosslinking, as used herein, may occur in modified starches when two hydroxyl groups on neighboring starch molecules are chemically linked. As used herein, “pre-gelatinized starches” or “instantized starches” refers to modified starches that have been pre-wetted, then dried to enhance their cold-water solubility. Suitable modified starches are commercially available from several suppliers such as, for example, A. E. Staley Manufacturing Company, and National Starch & Chemical Company. One suitable film forming modified starch includes the pre-gelatinized waxy maize derivative starches that are commercially available from National Starch & Chemical Company under the tradenames PURITY GUM and FILMSET, and derivatives, copolymers, and mixtures thereof. Such waxy maize starches typically contain, based upon the total weight of the starch, from about 0 percent to about 18 percent of amylose and from about 100% to about 88% of amylopectin. [0142]
  • Another suitable film forming modified starch includes the hydroxypropylated starches, in which some of the hydroxyl groups of the starch have been etherified with hydroxypropyl groups, usually via treatment with propylene oxide. One example of a suitable hydroxypropyl starch that possesses film-forming properties is available from Grain Processing Company under the tradename, PURE-COTE B790. [0143]
  • Suitable tapioca dextrins for use as film formers include those available from National Starch & Chemical Company under the tradenames CRYSTAL GUM or K-4484, and derivatives thereof such as modified food starch derived from tapioca, which is available from National Starch and Chemical under the [0144] tradename PURITY GUM 40, and copolymers and mixtures thereof.
  • In a preferred embodiment, the shell is prepared using the molding methods and apparatuses described in copending U.S. patent application Ser. No. 09/966,939, pages 27-51 and 57-63, which is incorporated herein by reference in its entirety. The shell itself may comprise at least one active ingredient. [0145]
  • In a preferred embodiment of the invention, the shell is applied to the core in the form of a flowable material using the thermal cycle method and apparatus described in copending U.S. patent application Ser. No. 09/966,497, pages 27-51, the disclosure of which is incorporated herein by reference. In this embodiment, the shell is applied using a thermal cycle molding module having the general configuration shown in FIG. 3 therein. The thermal cycle molding module [0146] 200 comprises a rotor 202 around which a plurality of mold units 204 are disposed. The thermal cycle molding module includes a reservoir 206 (see FIG. 4 therein) for holding shell flowable material. In addition, the thermal cycle molding module is provided with a temperature control system for rapidly heating and cooling the mold units. FIGS. 55 and 56 depict the temperature control system 600.
  • The thermal cycle molding module is preferably of the type shown in FIG. 28A of copending U.S. application Ser. No. 09/966,497, comprising a series of [0147] mold units 204. The mold units 204 in turn comprise upper mold assemblies 214, rotatable center mold assemblies 212 and lower mold assemblies 210 as shown in FIG. 28C. Cores are continuously transferred to the mold assemblies, which then close over the cores. The shell flowable material, which is heated to a flowable state in reservoir 206, is injected into the mold cavities created by the closed mold assemblies. The temperature of the shell flowable material is then decreased, hardening it. The mold assemblies open and eject the coated cores. In one particular embodiment, coating is performed in two steps, each half of the cores being coated separately as shown in the flow diagram of FIG. 28B of copending U.S. application Ser. No. 09/966,497 via rotation of the center mold assembly.
  • In a preferred embodiment of the invention, the shell completely surrounds the core. [0148]
  • In one particular embodiment of this invention, at least one active ingredient contained within the dosage form exhibits a delayed burst release profile. By “delayed burst release profile” it is meant that the release of that particular active ingredient from the dosage form is delayed for a pre-determined time after ingestion by the patient, and the delay period (“lag time”) is followed by prompt (immediate) release of that active ingredient. At least one shell portion of the present invention provides for the delay period and is preferably substantially free of the active ingredient to be released in a delayed burst manner. In such embodiments, the delayed burst active ingredient is typically contained within the corresponding underlying core portion. In these embodiments, the core portion may be prepared by compression or molding, and is formulated for immediate release, as is known in the art, so that the core portion is readily soluble upon contact with the dissolution medium. In such embodiments the core portion preferably comprises a disintegrant, and optionally comprises additional excipients such as fillers or thermoplastic materials selected from water-soluble or low-melting materials, and surfactants or wetting agents. In these embodiments, the dissolution of the burst release active ingredient, after the delay period, meets USP specifications for immediate release tablets containing that active ingredient. For example, for acetaminophen tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophen contained in the dosage form is released therefrom within 30 minutes after dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP apparatus [0149] 2 (paddles) at 50 rpm, at least 80% of the ibuprofen contained in the dosage form is released therefrom within 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856 (1999).
  • In another particular embodiment of this invention at least one active ingredient contained within the dosage form exhibits a delayed and sustained release profile. By “delayed then sustained release profile” it is meant that the release of that particular active ingredient from the dosage form is delayed for a pre-determined time after ingestion by the patient, and the delay period (“lag time”) is followed by sustained (prolonged, extended, or retarded) release of that active ingredient. At least one shell portion of the present invention provides for the delay period, and is preferably substantially free of the active ingredient to be released in a delayed then sustained manner. In such embodiments, the delayed then sustained release active ingredient is preferably contained within the corresponding underlying core portion. In such embodiments the core portion may function for example as an eroding matrix or a diffusional matrix, or an osmotic pump. In embodiments in which the core portion functions as a diffusional matrix through which active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core portion preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore-formers. Alternately, in such embodiments in which the core portion is prepared by molding, the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated. In embodiments in which the core portion functions as an eroding matrix from which dispersed active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core portion preferably comprises a release-modifying compressible or moldable excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, and combinations thereof. [0150]
  • In another particularly preferred embodiment of this invention, the dosage form comprises first and second active ingredients which may be the same or different, and upon contacting of the dosage form with a liquid medium, delayed release of the first active ingredient occurs followed by sustained release of the second active ingredient. [0151]
  • In another particularly preferred embodiment of this invention, the shell comprises a first active ingredient and the core comprises a second active ingredient (for example, within the matrix or coated or uncoated particles or a combination thereof) which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by delayed release of the second active ingredient. [0152]
  • In another particularly preferred embodiment of this invention, the shell comprises a first active ingredient and the core comprises a second active ingredient (for example, within the matrix or coated or uncoated particles or a combination thereof) which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by sustained release of the second active ingredient. [0153]
  • In one embodiment of this invention, the core or matrix or shell of the present invention, whether prepared by a solvent-free molding process, or by a solvent-based molding process, are substantially free of pores having a diameter of 0.5-5.0 microns. As used herein, “substantially free” means that the shell portion or portions have a pore volume of less than about 0.02 cc/g, preferably less than about 0.01 cc/g, more preferably less than about 0.005 cc/g in the pore diameter range of 0.5 to 5.0 microns. In contrast, typical compressed materials have pore volumes of more than about 0.02 cc/g in this diameter range. In another embodiment of this invention, the core is a molded core and the core or core portions are substantially free of pores having a diameter of 0.5-5.0 microns. [0154]
  • The pore volume, pore diameter and density may be determined using a [0155] Quantachrome Instruments PoreMaster 60 mercury intrusion porosimeter and associated computer software program known as “Porowin.” The procedure is documented in the Quantachrome Instruments PoreMaster Operation Manual. The PoreMaster determines both pore volume and pore diameter of a solid or powder by forced intrusion of a non-wetting liquid (mercury), which involves evacuation of the sample in a sample cell (penetrometer), filling the cell with mercury to surround the sample with mercury, applying pressure to the sample cell by: (i) compressed air (up to 50 psi maximum); and (ii) a hydraulic (oil) pressure generator (up to 60000 psi maximum). Intruded volume is measured by a change in the capacitance as mercury moves from outside the sample into its pores under applied pressure. The corresponding pore size diameter (d) at which the intrusion takes place is calculated directly from the so-called “Washburn Equation”: d=−(4γ(cos θ))/P where γ is the surface tension of liquid mercury, θ is the contact angle between mercury and the sample surface and P is the applied pressure.
  • Equipment used for pore volume measurements: [0156]
  • 1. [0157] Quantachrome Instruments PoreMaster 60.
  • 2. Analytical Balance capable of weighing to 0.0001 g. [0158]
  • 3. Desiccator. [0159]
  • Reagents used for measurements: [0160]
  • 1. High purity nitrogen. [0161]
  • 2. Triply distilled mercury. [0162]
  • 3. High pressure fluid (Dila AX, available from Shell Chemical Co.). [0163]
  • 4. Liquid nitrogen (for Hg vapor cold trap). [0164]
  • 5. Isopropanol or methanol for cleaning sample cells. [0165]
  • 6. Liquid detergent for cell cleaning. [0166]
  • Procedure: [0167]
  • The samples remain in sealed packages or as received in the dessicator until analysis. The vacuum pump is switched on, the mercury vapor cold trap is filled with liquid nitrogen, the compressed gas supply is regulated at 55 psi., and the instrument is turned on and allowed a warm up time of at least 30 minutes. The empty penetrometer cell is assembled as described in the instrument manual and its weight is recorded. The cell is installed in the low pressure station and “evacuation and fill only” is selected from the analysis menu, and the following settings are employed: [0168]
  • Fine Evacuation time: 1 min. [0169]
  • Fine Evacuation rate: 10 [0170]
  • Coarse Evacuation time: 5 min. [0171]
  • The cell (filled with mercury) is then removed and weighed. The cell is then emptied into the mercury reservoir, and two tablets from each sample are placed in the cell and the cell is reassembled. The weight of the cell and sample are then recorded. The cell is then installed in the low-pressure station, the low-pressure option is selected from the menu, and the following parameters are set: [0172]
  • Mode: Low pressure [0173]
  • Fine evacuation rate: 10 [0174]
  • Fine evacuation until: 200 μ Hg [0175]
  • Coarse evacuation time: 10 min. [0176]
  • Fill pressure: Contact +0.1 [0177]
  • Maximum pressure: 50 [0178]
  • Direction: Intrusion And Extrusion [0179]
  • Repeat: 0 [0180]
  • Mercury contact angle; 140 [0181]
  • Mercury surface tension: 480 [0182]
  • Data acquisition is then begun. The pressure vs. cumulative volume-intruded plot is displayed on the screen. After low-pressure analysis is complete, the cell is removed from the low-pressure station and reweighed. The space above the mercury is filled with hydraulic oil, and the cell is assembled and installed in the high-pressure cavity. The following settings are used: [0183]
  • Mode: Fixed rate [0184]
  • Motor speed: 5 [0185]
  • Start pressure: 20 [0186]
  • End pressure: 60,000 [0187]
  • Direction: Intrusion and extrusion [0188]
  • Repeat: 0 [0189]
  • Oil fill length: 5 [0190]
  • Mercury contact angle: 140 [0191]
  • Mercury surface tension: 480 [0192]
  • Data acquisition is then begun and graphic plot pressure vs. intruded volume is displayed on the screen. After the high pressure run is complete, the low-and high-pressure data files of the same sample are merged. [0193]
  • This invention will be illustrated by the following examples, which are not meant to limit the invention in any way. [0194]
  • EXAMPLE 1
  • Dosage forms according to the invention, comprising molded cores with shells thereon were made as follows. [0195]
  • The molded cores (Example 1A) were made from the following ingredients: [0196]
    Tablet Trade Name Manufacturer Weight % Mg/Tablet
    Pseudoephedrine BASF 22.0 130
    Hydrochloride PharmaChemikalien
    Crystal GmbH & Co.,
    Ludwigshafen/Rhein.
    Polyethylene Carbowax ® Union Carbide 45.0 267
    Glycol 3350 Corporation,
    Danbury, CT
    Shellac Powder Regular bleached Mantrose-Haeuser 7.0 42
    shellac Company, Atteboro,
    MA
    Croscarmellose Ac-Di-Sol ® FINE MUSCLE 26.0 154
    Sodium COORDINATION
    Corporation, Newark
    DE
  • Processing Steps: A beaker was submersed in a water bath (Ret digi-visc; Antal-Direct, Wayne, Pa.) where the water temperature was set at 70° C. Polyethylene glycol (PEG) 3350 was added to the beaker and was mixed with a spatula until all PEG was melted. Shellac powder, screened through a #40 mesh screen, was added to the molten PEG and the combined ingredients were mixed until all powder was dispersed. Croscarmellose sodium was then added followed by mixing for 2 minutes. Pseudoephedrine hydrochloride crystal was added, followed by mixing for 5 minutes. 570 to 610 mg of the molten mixture was added a round, concave lower punch and die unit (0.4375 inch diameter) which was manually joined with the upper punch to form a molded tablet core. The molded tablet core was ejected from the die. [0197]
  • The shells (Example 1B) were made of the following ingredients: [0198]
    Shell Trade Name Manufacturer Weight % Mg/Tablet
    Polyethylene Carbowax ® Union Carbide 45.0 849
    Glycol 3350 Corporation,
    Danbury, CT
    Polyethylene Oxide Polyox ® Union Carbide 15.0 283
    (MW 200,000) WSR N-80 Corporation,
    Danbury, CT
    Shellac Powder Regular bleached Mantrose-Haeuser 20.0 377
    shellac Company, Atteboro,
    MA
    Croscarmellose Ac-Di-Sol ® FMC Corporation, 10.0 188
    Sodium Newark, DE
    Tributyl Citrate Morflex, Inc., 10.0 188
    Greensboro, NC
  • Processing Steps: A beaker was submersed in a water bath (Ret digi-visc; Antal-Direct, Wayne, Pa.) where the water temperature was set at 70° C. Polyethylene glycol (PEG) 3350 was added to the beaker and was mixed with a spatula until all PEG was melted. Shellac powder, screened through a #40 mesh screen, was added to the molten PEG and the ingredients were mixed until all powder was dispersed. Tributyl citrate was added to the molten PEG mixture, followed by mixing for 1 minute. Polyethylene oxide (MW=200,000) was then added, followed by mixing for 10 minutes. Croscarmellose sodium was added, followed by mixing for 2 minutes. [0199]
  • A laboratory scale thermal cycle molding module was used to apply the shell in two portions onto the core. A first mold assembly comprising a cavity was cycled to hot stage at 85° C. for 30 seconds. A first portion of the shell material in flowable form (Example 1B) was added to the cavity. A molded core (Example 1A) was then inserted into the cavity. A blank mold assembly that masked half the core was screwed into the first mold assembly. The joined mold assemblies were cycled to cold stage at 5° C. for 60 seconds to harden the shell on the exposed half of the core. The blank mold assembly was removed and the molded core coated with the first shell portion was ejected form the cavity. [0200]
  • A second mold assembly comprising a second cavity was cycled to hot stage at 85° C. for 30 seconds. A second portion of the shell material in flowable form (Example 1B) was added to the cavity. The molded core comprising the first shell portion was inserted into the second mold assembly in such a way that the uncoated half of the core (without the first shell portion) was inserted into the second mold cavity. The first mold assembly, which was kept in cold cycle at 5° C., was screwed into the second mold assembly. The second mold assembly was cycled to cold stage at 5° C. for 60 seconds to harden a second shell portion on the core. The first mold assembly was removed and the dosage form, a molded core coated with the first and second shell portions (Example 1C), was ejected from the mold assembly. The weight gain of the dosage form due to the first and second shell portions was recorded. [0201]
  • Shell material in flowable form (Example 1B) was added into a flat faced, 0.6875 inch rubber mold and a coated core (Example 1C) was inserted into the mold. Additional shell material was added to fill the mold. The round molded tablet core was removed from the mold after 5 minutes of cooling in the mold. The weight gain of the core due to the shell was recorded. [0202]
  • FIG. 2 depicts the % release of active ingredient vs. hours for the dosage form of Example 1 and other dosage forms. More particularly this figure shows the dissolution rate of three different samples of different shell weight gain of the present invention. Curve (a) shows the release rate of pseudoephedrine HCL from the matrix with 314% shell weight gain of this invention. Curve (b) shows the release rate of pseudoephedrine HCL from the matrix with 118% shell weight gain of this invention. Curve (c) shows the release rate of pseudoephedrine HCL from the matrix with 55% shell weight gain of this invention. All curves were derived using the following dissolution analysis: USP Type II apparatus (paddles, 50 RPM) in 0.1 N HCL and pH 5.6 phosphate buffer at 37° C. Samples were tested at 1, 2, 3, 4, 8, 12, 16, 20, and 24 hours for pseudoephedrine HCl. Dissolution samples were analyzed for pseudoephedrine HCl versus a standard prepared at the theoretical concentration for 100% released of each compound. Samples were analyzed using a HPLC equipped with a Waters® 717 Autoinjector and a Waters® 486 UV detector set at a wavelength of 214 nm. The mobile phase was prepared using 55% acetonitrile and 45% 18 mM Potassium phosphate buffer. The injection volume was 50 μL with a run time of approximately 8 minutes and a pump flow of 2.0 mL/min. The column used was a Zorbax® 300-SCX (4.6mm×25 cm). [0203]
  • EXAMPLE 2
  • Dosage forms of the invention are made in a continuous process using an apparatus comprising two thermal cycle molding modules linked in series via a transfer device as described at pages 14-16 of copending U.S. application Ser. No. 09/966,939, the disclosure of which is incorporated herein by reference. The dosage forms comprise a molded core and a shell. The core comprises the ingredients of Example 1A, provided in flowable form as described in Example 1. The shell comprises the ingredients of Example 1B, provided in flowable form as described in Example 1. [0204]
  • The thermal cycle molding modules have the general configuration shown in FIG. 3 of copending U.S. application Ser. No. 09/966,497, which depicts a thermal cycle molding module [0205] 200 comprising a rotor 202 around which a plurality of mold units 204 are disposed. Each thermal cycle molding module includes its own reservoir 206 (see FIG. 4 of copending U.S. application Ser. No. 09/966,497) for holding the core flowable material, and the shell flowable material, respectively. In addition, each thermal cycle molding module is provided with a temperature control system for rapidly heating and cooling the mold units. FIGS. 55 and 56 of copending U.S. application Ser. No. 09/966,497 depict the temperature control system 600.
  • The cores are made in a first thermal cycle molding module, which is linked via a transfer device to a second thermal cycle molding module. The first thermal cycle molding module has the specific configuration shown in FIG. 26A of copending U.S. application Ser. No. 09/966,497. The first thermal cycle molding module comprises center mold assemblies [0206] 212 and upper mold assemblies 214 as shown in FIG. 26C, which mate to form mold cavities having the shape of the cores. As rotor 202 rotates, the opposing center and upper mold assemblies close. Core flowable material, which is heated to a flowable state in reservoir 206, is injected into the resulting mold cavities. The temperature of the core flowable material is then decreased, hardening the core flowable material into cores. The mold assemblies open and eject the cores, which are received by the transfer device.
  • The transfer device has the structure shown as [0207] 300 in FIG. 3 and described at pages 51-57 of copending U.S. application Ser. No. 09/966,414, the disclosure of which is incorporated herein by reference. It comprises a plurality of transfer units 304 attached in cantilever fashion to a belt 312 as shown in FIGS. 68 and 69 of copending U.S. application Ser. No. 09/966,414. The transfer device rotates and operates in sync with the thermal cycle molding modules to which it is coupled. Transfer units 304 comprise retainers 330 for holding the cores as they travel around the transfer device.
  • The transfer device transfers the cores to the second thermal cycle molding module, which applies the shell to the cores. The second thermal cycle molding module is of the type shown in FIG. 28A of copending U.S. application Ser. No. 09/966,497. The [0208] mold units 204 of the second thermal cycle molding module comprise upper mold assemblies 214, rotatable center mold assemblies 212 and lower mold assemblies 210 as shown in FIG. 28C. Cores are continuously transferred to the mold assemblies, which then close over the cores. Shell material, which is heated to a flowable state in reservoir 206, is injected into the mold cavities created by the closed mold assemblies. The temperature of the shell material is then decreased, hardening it. The mold assemblies open and eject the coated cores. Coating is performed in two steps, each half of the cores being coated separately as shown in the flow diagram of FIG. 28B of copending U.S. application Ser. No. 09/966,939 via rotation of the center mold assembly.
  • Although this invention has been illustrated by reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made which clearly fall within the scope of this invention. [0209]

Claims (50)

1. A dosage form comprising:
(a) at least one active ingredient;
(b) a molded core which is solid at room temperature; and
(c) a shell which is in contact with at least a portion of the molded core,
wherein the dosage form provides modified release of the active ingredient upon contacting of the dosage form with a liquid medium.
2. The dosage form of claim 1, in which the molded core comprises one or more active ingredients dispersed in a molded matrix.
3. The dosage form of claim 1, in which the shell is capable of providing modified release of at least one active ingredient upon contacting of the dosage form with a liquid medium.
4. The dosage form of claim 3, in which the shell is capable of providing a time delay prior to the release of at least one active ingredient upon contacting of the dosage form with a liquid medium.
5. The dosage form of claim 4, in which the time delay is independent of the pH of the liquid medium.
6. The dosage form of claim 1, in which the shell comprises means for providing modified release of at least one active ingredient upon contacting of the dosage form with a liquid medium.
7. The dosage form of claim 3, in which the shell comprises means for releasing at least one active ingredient in a sustained manner upon contacting of the dosage form with a liquid medium.
8. The dosage form of claim 1, wherein the shell comprises at least about 30 percent by weight of a thermal-reversible carrier.
9. The dosage form of claim 1, wherein the shell comprises at least one active ingredient.
10. The dosage form of claim 1, in which the core comprises a molded matrix.
11. The dosage form of claim 1, in which the core comprises at least one active ingredient.
12. The dosage form of claim 11, in which the core is capable of providing modified release of at least one active ingredient upon contacting of the dosage form with a liquid medium.
13. The dosage form of claim 11, in which the core comprises means for providing modified release of at least one active ingredient upon contacting of the dosage form with a liquid medium.
14. The dosage form of claim 11, in which the core comprises one or more release-modifying excipients.
15. The dosage form of claim 14, in which the release modifying excipient is selected from the group consisting of swellable erodible hydrophilic materials, pH-dependent polymers, insoluble edible materials, and pore-formers, and derivatives, copolymers, and combinations thereof.
16. The dosage form of claim 1, in which the core comprises at least 30% of a thermal-reversible carrier.
17. The dosage form of claim 16, in which the thermal-reversible carrier is selected from the group consisting of polyethylene glycol, thermoplastic polyethylene oxide, shellac, and derivatives, copolymers, and combinations thereof.
18. The dosage form of claim 16, in which the thermal-reversible carrier has a melting point of about 20 to about 110° C.
19. The dosage form of claim 1, in which the core comprises a plurality of particles which comprise at least one active ingredient.
20. The dosage form of claim 19, in which at least a portion of the particles are coated with a coating capable of providing modified release of the active ingredient contained therein upon contacting of the coated particles with a liquid medium.
21. The dosage form of claim 19, in which at least a portion of the particles are coated with a coating comprising means for providing modified release of the active ingredient contained therein upon contacting of the dosage form with a liquid medium.
22. The dosage form of claim 19, in which at least a portion of the particles are coated with a coating comprising 10-100wt. % of a release-modifying polymer selected from the group consisting of pH-dependent polymers, water-soluble polymers, water-insoluble polymers, and copolymers and derivatives and mixtures thereof.
23. The dosage form of claim 1, in which upon contacting of the dosage form with a liquid medium, a time delay occurs prior to release of at least a portion the active ingredient.
24. The dosage form of claim 23, in which the portion of the active ingredient released after the time delay is released in a sustained manner.
25. The dosage form of claim 1, in which the dosage form comprises first and second active ingredients which are the same or different, and upon contacting of the dosage form with a liquid medium, the first active ingredient is released in a sustained manner, and a time delay precedes release of the second active ingredient.
26. The dosage form of claim 1, in which the shell comprises a first active ingredient and the core comprises a second active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by a time delay, followed by release of the second active ingredient.
27. The dosage form of claim 1, in which the shell comprises a first active ingredient and the core comprises a second active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by sustained release of the second active ingredient.
28. The dosage form of claim 1, in which the shell comprises a first active ingredient and the core comprises particles comprising a second active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by delayed release of the second active ingredient.
29. The dosage form of claim 1, in which the shell comprises a first active ingredient and the core comprises particles comprising a second active ingredient which may be the same or different than the first active ingredient, and upon contacting of the dosage form with a liquid medium, immediate release of the first active ingredient occurs followed by sustained release of the second active ingredient.
30. The dosage form of claim 2, in which the level of active ingredient is at least about 25 weight percent of the core.
31. The dosage form of claim 2, in which the molded matrix comprises a thermal reversible carrier having a melting point from about 20 to about 100° C.
32. The dosage form of claim 2, in which the molded matrix comprises a thermal reversible carrier selected from the group consisting of thermoplastic polyalkylene oxides, low melting hydrophobic materials, thermoplastic polymers, thermoplastic starches, and combinations thereof.
33. The dosage form of claim 2, in which the molded matrix comprises a low-melting thermal-reversible carrier selected from the group consisting of polycaprolactones, polyvinyl acetate, polyalkylene glycols, and combinations thereof at a level of about 30 to about 70 weight percent of the matrix.
34. The dosage form of claim 2, in which the molded matrix comprises a thermal-reversible carrier selected from the groups consisting of polyethylene glycol or polyethylene oxide at a level from about 10 to about 100 weight percent of the matrix.
35. The dosage form of claim 33, in which the molded matrix further comprises a thermoplastic polyethylene oxide at a level of about 15 to about 25%.
36. The dosage form of claim 1, in which the shell has a thickness from about 300 to about 2000 microns.
37. The dosage form of claim 1, in which the shell has a thickness from about 150 to about 400 microns.
38. The dosage form of claim 1, in which the weight of the shell is from about 50 to about 400 percent of the weight of the core.
39. The dosage form of claim 1, in which the weight of the shell is from about 20 to about 100 percent of the weight of the core.
40. The dosage form of claim 1, in which the core is substantially free of pores having a diameter of 0.5 to 5.0 microns.
41. The dosage form of claim 32, in which the thermal reversible carrier is polyethylene glycol having a molecular weight from about 100 to about 8000 Daltons.
42. The dosage form of claim 2, in which the molded matrix comprises a release-modifying excipient.
43. The dosage form of claim 42, in which the release-modifying polymer is shellac.
44. The dosage form of claim 42, in which the release-modifying excipient is croscarmellose sodium.
45. The dosage form of claim 2, further comprising tributyl citrate as a plasticizer.
46. The dosage form of claim 1, in which the shell comprises a film-former selected from the group consisting of cellulose acetate, ammonia methacrylate copolymer type B, shellac, hydroxypropylmethylcellulose, polyethylene oxide, and combinations thereof.
47. The dosage form of claim 1, in which the shell comprises a release-modifying excipient selected from swellable erodible hydrophilic materials.
48. The dosage form of claim 47, in which the release-modifying excipient is croscarmellose sodium.
49. The dosage form of claim 1, in which the shell comprises triethyl citrate as a plasticizer.
50. The dosage form of claim 33, in which the thermal reversible carrier is polyethylene glycol having a molecular weight from about 100 to about 8000 Daltons.
US10/476,504 2001-09-28 2002-09-28 Modified release dosage forms Abandoned US20040213848A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/476,504 US20040213848A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US12/360,579 US20090186082A1 (en) 2001-09-28 2009-01-27 Method of manufacturing modified release dosage forms

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US09/966,939 US6837696B2 (en) 2001-09-28 2001-09-28 Apparatus for manufacturing dosage forms
US09/966,509 US6767200B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/967,414 US6742646B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,450 US6982094B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,497 US7122143B2 (en) 2001-09-28 2001-09-28 Methods for manufacturing dosage forms
US10/476,504 US20040213848A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
PCT/US2002/031116 WO2003026615A2 (en) 2001-09-28 2002-09-28 Modified release dosage forms

Related Parent Applications (5)

Application Number Title Priority Date Filing Date
US09/966,509 Continuation-In-Part US6767200B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,450 Continuation-In-Part US6982094B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,497 Continuation-In-Part US7122143B2 (en) 2001-09-28 2001-09-28 Methods for manufacturing dosage forms
US09/967,414 Continuation-In-Part US6742646B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,939 Continuation-In-Part US6837696B2 (en) 2001-09-28 2001-09-28 Apparatus for manufacturing dosage forms

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/360,579 Continuation US20090186082A1 (en) 2001-09-28 2009-01-27 Method of manufacturing modified release dosage forms

Publications (1)

Publication Number Publication Date
US20040213848A1 true US20040213848A1 (en) 2004-10-28

Family

ID=27542311

Family Applications (15)

Application Number Title Priority Date Filing Date
US10/476,529 Abandoned US20050019407A1 (en) 2001-09-28 2002-09-28 Composite dosage forms
US10/476,504 Abandoned US20040213848A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10/432,488 Abandoned US20040062804A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10/476,530 Expired - Fee Related US8545887B2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10/484,485 Abandoned US20040241208A1 (en) 2001-09-28 2002-09-28 Fondant-based pharmaceutical composition
US10/476,238 Abandoned US20040241236A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10/476,514 Abandoned US20040170750A1 (en) 2001-09-28 2002-09-28 Edible composition and dosage form comprising an edible shell
US10/477,334 Expired - Fee Related US7968120B2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10/393,610 Abandoned US20030219484A1 (en) 2001-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
US10/393,638 Abandoned US20030232082A1 (en) 2001-09-28 2003-03-21 Modified release dosage forms
US10/393,752 Expired - Fee Related US7635490B2 (en) 2001-09-28 2003-03-21 Modified release dosage form
US10/393,765 Abandoned US20040018327A1 (en) 2001-09-28 2003-03-21 Delayed release dosage forms
US10/393,871 Expired - Fee Related US7416738B2 (en) 2001-09-28 2003-03-21 Modified release dosage form
US12/049,628 Abandoned US20080305150A1 (en) 2001-09-28 2008-03-17 Polymer Composition And Dosage Forms Comprising The Same
US12/391,475 Expired - Fee Related US7972624B2 (en) 2001-09-28 2009-02-24 Method of manufacturing modified release dosage forms

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/476,529 Abandoned US20050019407A1 (en) 2001-09-28 2002-09-28 Composite dosage forms

Family Applications After (13)

Application Number Title Priority Date Filing Date
US10/432,488 Abandoned US20040062804A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10/476,530 Expired - Fee Related US8545887B2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10/484,485 Abandoned US20040241208A1 (en) 2001-09-28 2002-09-28 Fondant-based pharmaceutical composition
US10/476,238 Abandoned US20040241236A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10/476,514 Abandoned US20040170750A1 (en) 2001-09-28 2002-09-28 Edible composition and dosage form comprising an edible shell
US10/477,334 Expired - Fee Related US7968120B2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10/393,610 Abandoned US20030219484A1 (en) 2001-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
US10/393,638 Abandoned US20030232082A1 (en) 2001-09-28 2003-03-21 Modified release dosage forms
US10/393,752 Expired - Fee Related US7635490B2 (en) 2001-09-28 2003-03-21 Modified release dosage form
US10/393,765 Abandoned US20040018327A1 (en) 2001-09-28 2003-03-21 Delayed release dosage forms
US10/393,871 Expired - Fee Related US7416738B2 (en) 2001-09-28 2003-03-21 Modified release dosage form
US12/049,628 Abandoned US20080305150A1 (en) 2001-09-28 2008-03-17 Polymer Composition And Dosage Forms Comprising The Same
US12/391,475 Expired - Fee Related US7972624B2 (en) 2001-09-28 2009-02-24 Method of manufacturing modified release dosage forms

Country Status (20)

Country Link
US (15) US20050019407A1 (en)
EP (12) EP1438028A1 (en)
JP (11) JP2005535558A (en)
KR (11) KR20040045034A (en)
CN (10) CN1592612A (en)
AT (4) ATE476957T1 (en)
AU (1) AU2002330164A1 (en)
BR (11) BR0213593A (en)
CA (12) CA2461870A1 (en)
CO (1) CO5570655A2 (en)
DE (4) DE60223269T2 (en)
ES (3) ES2295427T3 (en)
HK (1) HK1072902A1 (en)
HU (1) HUP0401686A3 (en)
MX (12) MXPA04002891A (en)
NO (4) NO20032363L (en)
NZ (3) NZ532097A (en)
PL (1) PL369134A1 (en)
PT (1) PT1429738E (en)
WO (12) WO2003026626A2 (en)

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009036287A1 (en) * 2007-09-12 2009-03-19 Elan Pharma International Limited Dosing regimen
US20090149479A1 (en) * 1998-11-02 2009-06-11 Elan Pharma International Limited Dosing regimen
US20100189782A1 (en) * 2007-03-02 2010-07-29 Gul Balwani Compositions Comprising Carisoprodol and Methods of Use Thereof
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
US8114383B2 (en) 2003-08-06 2012-02-14 Gruenenthal Gmbh Abuse-proofed dosage form
US8114384B2 (en) 2004-07-01 2012-02-14 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US8192722B2 (en) 2003-08-06 2012-06-05 Grunenthal Gmbh Abuse-proof dosage form
US8383152B2 (en) 2008-01-25 2013-02-26 Gruenenthal Gmbh Pharmaceutical dosage form
US8469036B2 (en) 2003-11-07 2013-06-25 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US8627828B2 (en) 2003-11-07 2014-01-14 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
US8815289B2 (en) 2006-08-25 2014-08-26 Purdue Pharma L.P. Tamper resistant dosage forms
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US9579285B2 (en) 2010-02-03 2017-02-28 Gruenenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form

Families Citing this family (278)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8071128B2 (en) 1996-06-14 2011-12-06 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US6607751B1 (en) * 1997-10-10 2003-08-19 Intellipharamaceutics Corp. Controlled release delivery device for pharmaceutical agents incorporating microbial polysaccharide gum
AU3024399A (en) * 1998-04-03 1999-10-25 Bm Research A/S Controlled release composition
DE10026698A1 (en) 2000-05-30 2001-12-06 Basf Ag Self-emulsifying active ingredient formulation and use of this formulation
US20040234602A1 (en) * 2001-09-21 2004-11-25 Gina Fischer Polymer release system
EP1429744A1 (en) 2001-09-21 2004-06-23 Egalet A/S Morphine polymer release system
EP1438028A1 (en) 2001-09-28 2004-07-21 McNEIL-PPC, INC. Modified release dosage forms
US9358214B2 (en) 2001-10-04 2016-06-07 Adare Pharmaceuticals, Inc. Timed, sustained release systems for propranolol
GB0203296D0 (en) 2002-02-12 2002-03-27 Glaxo Group Ltd Novel composition
US8323692B2 (en) 2002-02-21 2012-12-04 Valeant International Bermuda Controlled release dosage forms
PT1476138E (en) * 2002-02-21 2012-02-14 Valeant Internat Barbados Srl Modified release formulations of at least one form of tramadol
US7169450B2 (en) 2002-05-15 2007-01-30 Mcneil-Ppc, Inc. Enrobed core
US20040161474A1 (en) * 2002-05-24 2004-08-19 Moerck Rudi E. Rare earth metal compounds methods of making, and methods of using the same
US20060083791A1 (en) 2002-05-24 2006-04-20 Moerck Rudi E Rare earth metal compounds methods of making, and methods of using the same
US8637512B2 (en) 2002-07-29 2014-01-28 Glaxo Group Limited Formulations and method of treatment
WO2004052345A1 (en) * 2002-12-11 2004-06-24 Ranbaxy Laboratories Limited Coating composition for taste masking coating and methods for their application and use
GB0229258D0 (en) * 2002-12-16 2003-01-22 Boots Healthcare Int Ltd Medicinal compositions
US8367111B2 (en) 2002-12-31 2013-02-05 Aptalis Pharmatech, Inc. Extended release dosage forms of propranolol hydrochloride
US20050220870A1 (en) * 2003-02-20 2005-10-06 Bonnie Hepburn Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid
US8298581B2 (en) * 2003-03-26 2012-10-30 Egalet A/S Matrix compositions for controlled delivery of drug substances
DE602004031096D1 (en) 2003-03-26 2011-03-03 Egalet As MORPHINE SYSTEM WITH CONTROLLED RELEASE
SI1631251T1 (en) 2003-04-24 2011-10-28 Jagotec Ag Delayed release tablet with defined core geometry
DK1615626T3 (en) * 2003-04-24 2010-02-08 Jagotec Ag Colored core tablet
CN1829499A (en) * 2003-05-29 2006-09-06 格利康科技集团有限责任公司 Method and composition for stable and controlled delivery of (-)-hydroxycitric acid
US8802139B2 (en) 2003-06-26 2014-08-12 Intellipharmaceutics Corp. Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
TW200514579A (en) * 2003-07-24 2005-05-01 Smithkline Beecham Corp Orally dissolving films
AU2004264356B2 (en) 2003-08-12 2011-01-27 Shionogi, Inc. Antibiotic product, use and formulation thereof
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
JP2005075826A (en) * 2003-08-29 2005-03-24 Boehringer Ingelheim Internatl Gmbh Controlled release preparation comprising porous silica support
GB0320854D0 (en) 2003-09-05 2003-10-08 Arrow No 7 Ltd Buccal drug delivery
US7879354B2 (en) * 2004-01-13 2011-02-01 Mcneil-Ppc, Inc. Rapidly disintegrating gelatinous coated tablets
US8067029B2 (en) 2004-01-13 2011-11-29 Mcneil-Ppc, Inc. Rapidly disintegrating gelatinous coated tablets
US20050196446A1 (en) * 2004-03-05 2005-09-08 Huang Hai Y. Polymeric compositions and dosage forms comprising the same
US20050196442A1 (en) * 2004-03-05 2005-09-08 Huang Hai Y. Polymeric compositions and dosage forms comprising the same
US20050196448A1 (en) * 2004-03-05 2005-09-08 Hai Yong Huang Polymeric compositions and dosage forms comprising the same
US20050196447A1 (en) * 2004-03-05 2005-09-08 Huang Hai Y. Polymeric compositions and dosage forms comprising the same
CA2558219C (en) * 2004-03-10 2014-04-08 Taisho Pharmaceutical Co., Ltd. Poorly water-soluble drug-containing solid formulation
US8545881B2 (en) 2004-04-19 2013-10-01 Eurand Pharmaceuticals, Ltd. Orally disintegrating tablets and methods of manufacture
US8383154B2 (en) * 2004-05-11 2013-02-26 Egalet A/S Swellable dosage form comprising gellan gum
US7622137B2 (en) * 2004-05-21 2009-11-24 Accu-Break Technologies, Inc. Dosage forms contained within a capsule or sachet
US8815916B2 (en) 2004-05-25 2014-08-26 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060002986A1 (en) * 2004-06-09 2006-01-05 Smithkline Beecham Corporation Pharmaceutical product
TWI428271B (en) * 2004-06-09 2014-03-01 Smithkline Beecham Corp Apparatus and method for pharmaceutical production
US20050281876A1 (en) * 2004-06-18 2005-12-22 Shun-Por Li Solid dosage form for acid-labile active ingredient
US8394409B2 (en) 2004-07-01 2013-03-12 Intellipharmaceutics Corp. Controlled extended drug release technology
US8609198B2 (en) * 2004-07-21 2013-12-17 Hewlett-Packard Development Company, L.P. Pharmaceutical dose form with a patterned coating and method of making the same
AU2005266882A1 (en) * 2004-07-26 2006-02-02 Teva Pharmaceutical Indudstries, Ltd. Dosage forms with an enterically coated core tablet
US7621734B2 (en) 2004-07-28 2009-11-24 Mars, Incorporated Apparatus and process for preparing confectionery having an inclusion therein using forming rolls and a forming pin
US20060024361A1 (en) * 2004-07-28 2006-02-02 Isa Odidi Disintegrant assisted controlled release technology
US20060024368A1 (en) * 2004-07-30 2006-02-02 Reza Fassihi Compressed composite delivery system for release-rate modulation of bioactives
EP1639899A1 (en) * 2004-08-23 2006-03-29 Friesland Brands B.V. Powdered, cold-water soluble/dispersible, foamable composition
US10624858B2 (en) * 2004-08-23 2020-04-21 Intellipharmaceutics Corp Controlled release composition using transition coating, and method of preparing same
EP1944008A3 (en) * 2004-09-24 2008-07-23 BioProgress Technology Limited Additional improvements in powder compaction and enrobing
CN101065091A (en) * 2004-09-24 2007-10-31 生物进展技术有限公司 Additional improvements in powder compaction and enrobing
AU2005292271A1 (en) * 2004-09-30 2006-04-13 Monosol Rx, Llc Multi-layer films having uniform content
US9884014B2 (en) 2004-10-12 2018-02-06 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
CA2583548A1 (en) * 2004-10-15 2006-04-27 Altairnano, Inc. Phosphate binder with reduced pill burden
ES2409347T3 (en) 2004-10-21 2013-06-26 Aptalis Pharmatech, Inc. Pharmaceutical compositions of masked flavor with gastro-soluble porogenic agents
US20060087051A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20060088586A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20060088593A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20070190133A1 (en) * 2004-10-27 2007-08-16 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US8383159B2 (en) 2004-10-27 2013-02-26 Mcneil-Ppc, Inc. Dosage forms having a microreliefed surface and methods and apparatus for their production
US20070281022A1 (en) * 2004-10-27 2007-12-06 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20060088587A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
GB0423964D0 (en) * 2004-10-28 2004-12-01 Jagotec Ag Dosage form
US20060093560A1 (en) * 2004-10-29 2006-05-04 Jen-Chi Chen Immediate release film coating
AR051654A1 (en) * 2004-11-04 2007-01-31 Astrazeneca Ab NEW FORMULATIONS OF MODIFIED RELEASE PELLETS FOR PROTON PUMP INHIBITORS
AR052225A1 (en) * 2004-11-04 2007-03-07 Astrazeneca Ab FORMULATIONS OF MODIFIED RELEASE TABLETS FOR INHIBITORS OF THE PUMP OF PROTONS
PL1836665T3 (en) 2004-11-19 2013-06-28 Glaxosmithkline Llc Method for customized dispensing of variable dose drug combination products for individualizing of therapies
US7530804B2 (en) * 2004-12-07 2009-05-12 Mcneil-Ppc, Inc. System and process for providing at least one opening in dosage forms
US7404708B2 (en) * 2004-12-07 2008-07-29 Mcneil-Ppc, Inc. System and process for providing at least one opening in dosage forms
US20070129402A1 (en) * 2004-12-27 2007-06-07 Eisai Research Institute Sustained release formulations
MX2007007836A (en) 2004-12-27 2007-08-20 Eisai R&D Man Co Ltd Method for stabilizing anti-dementia drug.
EP1838287B1 (en) * 2005-01-07 2012-05-23 Sandoz Ag Process for preparing granulates comprising amoxicillin
EP1858483A4 (en) * 2005-03-16 2009-07-15 Reddys Lab Ltd Dr Delivery system for multiple drugs
MX2007012220A (en) * 2005-04-06 2007-12-06 Mallinckrodt Inc Matrix-based pulse release pharmaceutical formulation.
AU2006235483B2 (en) * 2005-04-12 2010-11-25 Elan Pharma International Limited Controlled release compositions comprising a cephalosporin for the treatment of a bacterial infection
US8673352B2 (en) 2005-04-15 2014-03-18 Mcneil-Ppc, Inc. Modified release dosage form
US20060233882A1 (en) * 2005-04-15 2006-10-19 Sowden Harry S Osmotic dosage form
US20090023778A1 (en) * 2005-04-28 2009-01-22 Eisai R&D Management Co., Ltd. Composition Containing Anti-Dementia Drug
AU2006239221C1 (en) 2005-04-28 2012-08-16 Otsuka Pharmaceutical Co., Ltd. Pharma-informatics system
US8802183B2 (en) 2005-04-28 2014-08-12 Proteus Digital Health, Inc. Communication system with enhanced partial power source and method of manufacturing same
US9161918B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
DE602006020133D1 (en) * 2005-05-18 2011-03-31 Goemar Lab Sa LAMINARIN-CONTAINING FOODS
JP5161075B2 (en) * 2005-06-03 2013-03-13 エガレット エイ/エス Solid pharmaceutical composition having a first fraction of a dispersion medium and a second fraction of a matrix, wherein the second fraction is first at least partially exposed to gastrointestinal fluid
JP5095615B2 (en) 2005-06-27 2012-12-12 バリアント・インターナショナル・(バルバドス)・ソサイアティーズ・ウィズ・リストリクティッド・ライアビリティ Modified release of bupropion salt
US20070009573A1 (en) * 2005-07-07 2007-01-11 L N K International Method of forming immediate release dosage form
US20070015834A1 (en) * 2005-07-18 2007-01-18 Moshe Flashner-Barak Formulations of fenofibrate containing PEG/Poloxamer
DE102005034043B4 (en) * 2005-07-18 2019-12-12 Südzucker Aktiengesellschaft Mannheim/Ochsenfurt Mixture containing L-carnitine and trehalulose and product containing the mixture
US20080058250A1 (en) * 2005-08-17 2008-03-06 Allison Wren Treatment of chronic renal failure and other conditions in domestic animals: compositions and methods
TWI274889B (en) * 2005-10-06 2007-03-01 Elan Microelectronics Corp Resistive touch screen measurement system
AU2006304889A1 (en) * 2005-10-14 2007-04-26 H. Lundbeck A/S Stable pharmaceutical formulations containing escitalopram and bupropion
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
US8357394B2 (en) 2005-12-08 2013-01-22 Shionogi Inc. Compositions and methods for improved efficacy of penicillin-type antibiotics
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
WO2007086846A1 (en) * 2006-01-24 2007-08-02 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
JP2007224012A (en) * 2006-01-30 2007-09-06 Fujifilm Corp Enzymatically crosslinked protein nanoparticle
US20070184111A1 (en) * 2006-02-03 2007-08-09 Pharmavite Llc Hybrid tablet
US20070190131A1 (en) * 2006-02-10 2007-08-16 Perry Ronald L Press-fit rapid release medicament and method and apparatus of manufacturing
US20070224258A1 (en) * 2006-03-22 2007-09-27 Bunick Frank J Dosage forms having a randomized coating
BRPI0710029A2 (en) * 2006-03-28 2011-08-02 Mcneil Ppc Inc inhomogeneous dosage form coatings
CN104825397A (en) 2006-04-03 2015-08-12 伊萨·奥迪迪 Controlled release delivery device comprising an organosol coat
JP5349290B2 (en) * 2006-04-03 2013-11-20 オディディ,イサ Drug delivery composition, pharmaceutical comprising the same, and method for producing the same
US10960077B2 (en) 2006-05-12 2021-03-30 Intellipharmaceutics Corp. Abuse and alcohol resistant drug composition
WO2007139661A1 (en) * 2006-05-23 2007-12-06 Haley Jeffrey T Xylitol troches and methods of use
US20070293587A1 (en) * 2006-05-23 2007-12-20 Haley Jeffrey T Combating sinus, throat, and blood infections with xylitol delivered in the mouth
US20100239668A1 (en) * 2006-06-19 2010-09-23 Kaplan Allan S Segmented pharmaceutical dosage forms
SG10201503411QA (en) 2006-08-03 2015-06-29 Nitec Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
US8399230B2 (en) * 2006-10-12 2013-03-19 Kemin Industries, Inc. Heat-stable enzyme compositions
EP1916006A1 (en) * 2006-10-19 2008-04-30 Albert Schömig Implant coated with a wax or a resin
BRPI0718171A2 (en) 2006-10-20 2013-11-26 Mcneil Ppc Inc Acetaminophen / IBUPROPHEN COMBINATIONS AND METHOD FOR USE
CA2667207A1 (en) * 2006-10-25 2008-05-02 Mcneil-Ppc, Inc. Ibuprofen composition
WO2008086804A2 (en) * 2007-01-16 2008-07-24 Egalet A/S Use of i) a polyglycol and n) an active drug substance for the preparation of a pharmaceutical composition for i) mitigating the risk of alcohol induced dose dumping and/or ii) reducing the risk of drug abuse
US7767248B2 (en) 2007-02-02 2010-08-03 Overly Iii Harry J Soft chew confectionary with high fiber and sugar content and method for making same
GB0702974D0 (en) * 2007-02-15 2007-03-28 Jagotec Ag Method and apparatus for producing a tablet
JP5224790B2 (en) * 2007-03-02 2013-07-03 株式会社明治 Solid food and method for producing the same
US20080292692A1 (en) * 2007-05-21 2008-11-27 Shira Pilch Impermeable Capsules
US20080300322A1 (en) * 2007-06-01 2008-12-04 Atlantic Pharmaceuticals, Inc. Delivery vehicles containing rosin resins
EP2155167A2 (en) 2007-06-04 2010-02-24 Egalet A/S Controlled release pharmaceutical compositions for prolonged effect
MX2009013494A (en) * 2007-06-11 2010-01-18 Procter & Gamble Benefit agent containing delivery particle.
US20080317678A1 (en) * 2007-06-22 2008-12-25 Szymczak Christopher E Laser Marked Dosage Forms
US20080317677A1 (en) * 2007-06-22 2008-12-25 Szymczak Christopher E Laser Marked Dosage Forms
US20090004248A1 (en) * 2007-06-29 2009-01-01 Frank Bunick Dual portion dosage lozenge form
CA2923102C (en) * 2007-08-13 2019-10-15 Abuse Deterrent Pharmaceutical Llc Abuse resistant drugs, method of use and method of making
US20090060983A1 (en) * 2007-08-30 2009-03-05 Bunick Frank J Method And Composition For Making An Orally Disintegrating Dosage Form
US8741329B2 (en) * 2007-09-21 2014-06-03 Merck Sharp & Dohme B.V. Drug delivery system
FR2921835B1 (en) * 2007-10-05 2012-05-04 Soc Dexploitation De Produits Pour Les Industries Chimiques Seppic COATING COMPOSITION COMPRISING POLYDEXTROSE, PROCESS FOR PREPARING THE SAME, AND USE FOR COATING INFRINGABLE SOLID FORMS
US8789536B2 (en) 2007-10-17 2014-07-29 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US20090105561A1 (en) * 2007-10-17 2009-04-23 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Medical or veterinary digestive tract utilization systems and methods
US8303573B2 (en) 2007-10-17 2012-11-06 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US8707964B2 (en) * 2007-10-31 2014-04-29 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
JP4879351B2 (en) 2007-10-19 2012-02-22 大塚製薬株式会社 Pharmaceutical solid formulation
US8808276B2 (en) * 2007-10-23 2014-08-19 The Invention Science Fund I, Llc Adaptive dispensation in a digestive tract
US8808271B2 (en) * 2007-10-31 2014-08-19 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US8109920B2 (en) * 2007-10-31 2012-02-07 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US20090163894A1 (en) * 2007-10-31 2009-06-25 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Medical or veterinary digestive tract utilization systems and methods
WO2009058798A2 (en) * 2007-10-31 2009-05-07 Mcneil-Ppc, Inc. Orally disintegrated dosage form
US8333754B2 (en) * 2007-10-31 2012-12-18 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US20090137866A1 (en) * 2007-11-28 2009-05-28 Searete Llc, A Limited Liability Corporation Of The State Delaware Medical or veterinary digestive tract utilization systems and methods
EP3090739A1 (en) 2008-01-04 2016-11-09 Schabar Research Associates LLC Compositions composed of naproxen sodium and nizatidine
WO2009154810A2 (en) * 2008-02-25 2009-12-23 Dr. Reddy's Laboratories Ltd. Delivery systems for multiple active agents
CA2720108C (en) 2008-03-11 2016-06-07 Depomed, Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
US8372432B2 (en) 2008-03-11 2013-02-12 Depomed, Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
WO2009137648A1 (en) * 2008-05-09 2009-11-12 Aptapharma, Inc. Multilayer proton pump inhibitor tablets
WO2009140351A2 (en) * 2008-05-14 2009-11-19 Cadbury Adams Usa Llc Confectionery with enzymatically manipulated texture
WO2009146537A1 (en) * 2008-06-02 2009-12-10 Pharmascience Inc. Multilayer control-release drug delivery system
KR200452140Y1 (en) * 2008-06-20 2011-02-08 주식회사 부성시스템 Control device for nonwoven open/closed device of vinyl house
JP5681626B2 (en) * 2008-07-14 2015-03-11 ポリーペイド リミテッドPolypid Ltd. Sustained release drug carrier composition
KR200450450Y1 (en) * 2008-07-16 2010-10-04 이봉석 The case of position limit switch
EP2326316A1 (en) * 2008-08-07 2011-06-01 Avantor Performance Materials, Inc. Sustained release compositions comprising gums and sugar alcohols
US8038424B2 (en) * 2008-09-22 2011-10-18 Xerox Corporation System and method for manufacturing sold ink sticks with an injection molding process
FR2936952A1 (en) * 2008-10-09 2010-04-16 Monique Bellec Product, useful as nutritional supplements, comprises a composition in powder/anhydrous liquid form, having active ingredient and gelling agent e.g. lecithin and alginic acid, where composition is enclosed in edible water-soluble envelope
IT1394597B1 (en) * 2008-11-05 2012-07-05 Politi DRY GRANULATION IN GAS FLOW.
WO2010067478A1 (en) * 2008-12-12 2010-06-17 株式会社ミツヤコーポレーション Food and method for processing the same
AU2010207740B2 (en) * 2009-01-26 2016-06-16 Nitec Pharma Ag Delayed-release glucocorticoid treatment of asthma
NZ594208A (en) * 2009-02-06 2012-10-26 Egalet Ltd Pharmaceutical compositions resistant to abuse
WO2010089132A1 (en) 2009-02-06 2010-08-12 Egalet A/S Immediate release composition resistant to abuse by intake of alcohol
DK2395840T3 (en) * 2009-02-13 2020-06-08 Romark Laboratories Lc Controlled release nitazoxanide pharmaceutical formulations
WO2010129288A2 (en) 2009-04-28 2010-11-11 Proteus Biomedical, Inc. Highly reliable ingestible event markers and methods for using the same
WO2010132205A1 (en) * 2009-05-12 2010-11-18 Bpsi Holdings, Llc. Film coatings containing fine particle size detackifiers and substrates coated therewith
WO2010133961A1 (en) 2009-05-22 2010-11-25 Inventia Healthcare Private Limited Extended release compositions of cyclobenzaprine
WO2010149169A2 (en) 2009-06-24 2010-12-29 Egalet A/S Controlled release formulations
AU2010272167B2 (en) * 2009-07-14 2016-11-17 Polypid Ltd. Sustained-release drug carrier composition
CN102469806A (en) * 2009-07-24 2012-05-23 日本卡夫食品株式会社 Multiple-region candy and manufacturing method therefor
TW201117812A (en) 2009-08-05 2011-06-01 Idenix Pharmaceuticals Inc Macrocyclic serine protease inhibitors
WO2011025673A1 (en) * 2009-08-26 2011-03-03 Aptapharma, Inc. Multilayer minitablets
US20110052685A1 (en) * 2009-08-31 2011-03-03 Depomed, Inc. Gastric retentive pharmaceutical compositions for immediate and extended release of acetaminophen
WO2011028286A1 (en) * 2009-09-01 2011-03-10 Rhodia Operations Polymer compositions
US20110070286A1 (en) * 2009-09-24 2011-03-24 Andreas Hugerth Process for the manufacture of nicotine-comprising chewing gum and nicotine-comprising chewing gum manufactured according to said process
US8313768B2 (en) * 2009-09-24 2012-11-20 Mcneil-Ppc, Inc. Manufacture of tablet having immediate release region and sustained release region
US8343533B2 (en) * 2009-09-24 2013-01-01 Mcneil-Ppc, Inc. Manufacture of lozenge product with radiofrequency
US20110318411A1 (en) 2010-06-24 2011-12-29 Luber Joseph R Multi-layered orally disintegrating tablet and the manufacture thereof
EP2316432A1 (en) * 2009-10-30 2011-05-04 ratiopharm GmbH Compound containing fesoterodine and roughage
WO2011056764A1 (en) 2009-11-05 2011-05-12 Ambit Biosciences Corp. Isotopically enriched or fluorinated imidazo[2,1-b][1,3]benzothiazoles
EP2506836B1 (en) 2009-12-02 2018-02-14 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
UA109424C2 (en) * 2009-12-02 2015-08-25 PHARMACEUTICAL PRODUCT, PHARMACEUTICAL TABLE WITH ELECTRONIC MARKER AND METHOD OF MANUFACTURING PHARMACEUTICAL TABLETS
CA2780347A1 (en) * 2009-12-07 2011-06-16 Mcneil-Ppc, Inc. Partial dip coating of dosage forms for modified release
MY159958A (en) 2009-12-18 2017-02-15 Idenix Pharmaceuticals Inc 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors
US10485770B2 (en) 2009-12-21 2019-11-26 Aptapharma, Inc. Functionally-coated multilayer tablets
CN102892406B (en) 2010-01-19 2015-04-08 波利皮得有限公司 Sustained-release nucleic acid matrix compositions
WO2011094890A1 (en) 2010-02-02 2011-08-11 Argusina Inc. Phenylalanine derivatives and their use as non-peptide glp-1 receptor modulators
US9138309B2 (en) 2010-02-05 2015-09-22 Allergan, Inc. Porous materials, methods of making and uses
US9205577B2 (en) * 2010-02-05 2015-12-08 Allergan, Inc. Porogen compositions, methods of making and uses
GB201003734D0 (en) * 2010-03-05 2010-04-21 Univ Strathclyde Delayed prolonged drug delivery
GB201003731D0 (en) * 2010-03-05 2010-04-21 Univ Strathclyde Immediate/delayed drug delivery
GB201003766D0 (en) 2010-03-05 2010-04-21 Univ Strathclyde Pulsatile drug release
EP2544887A1 (en) * 2010-03-11 2013-01-16 Wockhardt Limited A device for the manufacture of a dosage form with a hole and method of manufacture
WO2011112689A2 (en) 2010-03-11 2011-09-15 Ambit Biosciences Corp. Saltz of an indazolylpyrrolotriazine
US8486013B2 (en) * 2010-03-18 2013-07-16 Biotronik Ag Balloon catheter having coating
US9743688B2 (en) 2010-03-26 2017-08-29 Philip Morris Usa Inc. Emulsion/colloid mediated flavor encapsulation and delivery with tobacco-derived lipids
CA2795746C (en) 2010-04-07 2019-10-01 Timothy Robertson Miniature ingestible device
US11202853B2 (en) * 2010-05-11 2021-12-21 Allergan, Inc. Porogen compositions, methods of making and uses
KR101940207B1 (en) 2010-05-12 2019-01-18 스펙트럼 파마슈티컬즈 인크 Lanthanum carbonate hydroxide, lanthanum oxycarbonate and methods of their manufacture and use
US20110280936A1 (en) * 2010-05-17 2011-11-17 Aptapharma, Inc. Self Breaking Tablets
WO2011161666A2 (en) * 2010-06-21 2011-12-29 White Innovation Ltd. Enclosed liquid capsules
WO2012030885A1 (en) 2010-09-01 2012-03-08 Ambit Biosciences Corporation Hydrobromide salts of a pyrazolylaminoquinazoline
US8703943B2 (en) 2010-09-01 2014-04-22 Ambit Biosciences Corporation Optically active pyrazolylaminoquinazoline, and pharmaceutical compositions and methods of use thereof
EP2642983A4 (en) 2010-11-22 2014-03-12 Proteus Digital Health Inc Ingestible device with pharmaceutical product
AU2011338530B2 (en) 2010-12-06 2017-06-15 Follica, Inc. Methods for treating baldness and promoting hair growth
US10821085B2 (en) * 2010-12-07 2020-11-03 Kimberly-Clark Worldwide, Inc. Wipe coated with a botanical composition having antimicrobial properties
US9233076B2 (en) 2010-12-13 2016-01-12 Purdue Pharma L.P. Controlled release dosage forms
WO2012080050A1 (en) 2010-12-14 2012-06-21 F. Hoffmann-La Roche Ag Solid forms of a phenoxybenzenesulfonyl compound
CN103338753A (en) 2011-01-31 2013-10-02 细胞基因公司 Pharmaceutical compositions of cytidine analogs and methods of use thereof
US9353100B2 (en) 2011-02-10 2016-05-31 Idenix Pharmaceuticals Llc Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections
US20120252721A1 (en) 2011-03-31 2012-10-04 Idenix Pharmaceuticals, Inc. Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor
KR102059698B1 (en) 2011-06-06 2019-12-26 오크 크레스트 인스티튜트 오브 사이언스 Drug delivery device employing wicking release window
USD723766S1 (en) 2011-06-30 2015-03-10 Intercontinental Great Brands Llc Confectionary article
US9756874B2 (en) 2011-07-11 2017-09-12 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
WO2015112603A1 (en) 2014-01-21 2015-07-30 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
US9474303B2 (en) 2011-09-22 2016-10-25 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US9629392B2 (en) 2011-09-22 2017-04-25 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US9084439B2 (en) 2011-09-22 2015-07-21 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US20130078307A1 (en) 2011-09-22 2013-03-28 Niconovum Usa, Inc. Nicotine-containing pharmaceutical composition
CA2851544C (en) 2011-10-14 2016-08-09 Hill's Pet Nutrition, Inc. Process for preparing a pet food composition
KR101384055B1 (en) * 2012-02-02 2014-04-14 한국원자력연구원 Burst type lagged-release controlled composition and preparation method thereof
AU2013205306B2 (en) 2012-03-16 2015-09-17 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US20130261372A1 (en) * 2012-03-30 2013-10-03 Elwha LLC, a limited liability company of the State of Delaware Device, System, and Method for Delivery of Sugar Glass Stabilized Compositions
US9985320B2 (en) * 2012-04-30 2018-05-29 Carnegie Mellon University Water-activated, ingestible battery
US9445971B2 (en) * 2012-05-01 2016-09-20 Johnson & Johnson Consumer Inc. Method of manufacturing solid dosage form
US9511028B2 (en) 2012-05-01 2016-12-06 Johnson & Johnson Consumer Inc. Orally disintegrating tablet
US9233491B2 (en) 2012-05-01 2016-01-12 Johnson & Johnson Consumer Inc. Machine for production of solid dosage forms
WO2013183497A1 (en) * 2012-06-05 2013-12-12 武田薬品工業株式会社 Dry-coated tablet
KR20150059167A (en) 2012-07-06 2015-05-29 에갈렛 리미티드 Abuse deterrent pharmaceutical compositions for controlled release
CN102824640A (en) * 2012-08-06 2012-12-19 济南圣泉唐和唐生物科技有限公司 Capsule shell and preparation method thereof
US20140193543A1 (en) * 2013-01-09 2014-07-10 Alexander Vigneri Decorative hollow chocolate confection with improved writability
JP2016508529A (en) 2013-01-29 2016-03-22 プロテウス デジタル ヘルス, インコーポレイテッド Highly expandable polymer film and composition containing the same
DE102013004263A1 (en) 2013-03-13 2014-09-18 Martin Lipsdorf Fast-dissolving oral dosage form and method of making the same
JP6395800B2 (en) * 2013-03-15 2018-09-26 インキューブ ラブズ, エルエルシー Multi-stage biodegradable drug delivery platform
MX2015013231A (en) 2013-03-15 2016-06-07 Inspirion Delivery Technologies Llc Abuse deterrent compositions and methods of use.
JP5941240B2 (en) 2013-03-15 2016-06-29 プロテウス デジタル ヘルス, インコーポレイテッド Metal detector device, system and method
US9470489B2 (en) * 2013-05-14 2016-10-18 Kerry Thaddeus Bowden Airsoft marking round
US9796576B2 (en) 2013-08-30 2017-10-24 Proteus Digital Health, Inc. Container with electronically controlled interlock
NZ631142A (en) 2013-09-18 2016-03-31 Axikin Pharmaceuticals Inc Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors
US20160229866A1 (en) 2013-09-20 2016-08-11 Idenix Pharmaceuticals Inc. Hepatitis c virus inhibitors
US10084880B2 (en) 2013-11-04 2018-09-25 Proteus Digital Health, Inc. Social media networking based on physiologic information
US10596103B2 (en) 2013-12-11 2020-03-24 Merek Sharp & Dohme B.V. Drug delivery system for delivery of anti-virals
US10413504B2 (en) 2013-12-11 2019-09-17 Merck Sharp & Dohme Corp. Intravaginal ring drug delivery system
WO2015095230A1 (en) * 2013-12-16 2015-06-25 Massachusetts Institute Of Technology Micromolded or 3-d printed pulsatile release vaccine formulations
DK3087980T3 (en) * 2013-12-23 2019-02-18 Xiaoguang Wen DOUBLE LAYER TABLE AND METHOD OF PRODUCING THEREOF
CA2936216C (en) 2014-01-10 2021-10-26 Johnson & Johnson Consumer Inc. Process for making tablet using radiofrequency and lossy coated particles
US9375033B2 (en) 2014-02-14 2016-06-28 R.J. Reynolds Tobacco Company Tobacco-containing gel composition
WO2015134560A1 (en) 2014-03-05 2015-09-11 Idenix Pharmaceuticals, Inc. Solid forms of a flaviviridae virus inhibitor compound and salts thereof
TWI683813B (en) 2014-03-20 2020-02-01 美商卡佩拉醫療公司 Benzimidazole derivatives, and pharmaceutical compositions and methods of use thereof
JP6568926B2 (en) 2014-03-20 2019-08-28 カペラ セラピューティクス,インコーポレーテッド Benzimidazole derivatives as ERBB tyrosine kinase inhibitors for the treatment of cancer
US10729685B2 (en) 2014-09-15 2020-08-04 Ohemo Life Sciences Inc. Orally administrable compositions and methods of deterring abuse by intranasal administration
EA032473B1 (en) 2014-12-23 2019-05-31 Аксикин Фармасьютикалз, Инк. 3,5-diaminopyrazole kinase inhibitors
DE202016008309U1 (en) * 2015-01-22 2017-07-14 Pfeifer & Langen GmbH & Co. KG Cellobiose-containing sugar mass
US10174275B2 (en) * 2015-01-30 2019-01-08 Follmann Gmbh & Co. Kg Thermally opening stable core/shell microcapsules
USD765828S1 (en) 2015-02-19 2016-09-06 Crossford International, Llc Chemical tablet
US9839212B2 (en) 2015-04-16 2017-12-12 Bio-Lab, Inc. Multicomponent and multilayer compacted tablets
US11051543B2 (en) 2015-07-21 2021-07-06 Otsuka Pharmaceutical Co. Ltd. Alginate on adhesive bilayer laminate film
US20190022013A1 (en) 2015-12-19 2019-01-24 First Time Us Generics Llc Soft-chew tablet pharmaceutical formulations
CN108712900A (en) 2015-12-19 2018-10-26 第时间美国泛型药物有限公司 Soft chewable tablet pharmaceutical preparation
JP2017158534A (en) * 2016-03-07 2017-09-14 焼津水産化学工業株式会社 Manufacturing method of chip-like foods and chip-like foods
EP3431079B1 (en) * 2016-03-15 2023-06-07 Astellas Pharma Inc. Tablet
EP3487393A4 (en) 2016-07-22 2020-01-15 Proteus Digital Health, Inc. Electromagnetic sensing and detection of ingestible event markers
EP4091796A1 (en) * 2016-09-09 2022-11-23 Merck Patent GmbH Process for the manufacture of a solid pharmaceutical administration form
MX2019003039A (en) 2016-09-26 2019-07-08 Procter & Gamble Extended relief dosage form.
CN109963499B (en) 2016-10-26 2022-02-25 大冢制药株式会社 Method for manufacturing capsules with ingestible event markers
CN106945323B (en) * 2017-03-14 2018-11-02 常熟市双月机械有限公司 A kind of efficient metal powder hydraulic press
US10493026B2 (en) 2017-03-20 2019-12-03 Johnson & Johnson Consumer Inc. Process for making tablet using radiofrequency and lossy coated particles
CN110382229A (en) * 2017-04-07 2019-10-25 宝洁公司 Water-solubility membrane
DE102017107845A1 (en) 2017-04-11 2018-10-11 Gelita Ag Gelatin product with a core component and process for its preparation
CN110719968A (en) 2017-06-22 2020-01-21 宝洁公司 Film comprising a water-soluble layer and a vapor-deposited inorganic coating
WO2018237212A1 (en) 2017-06-22 2018-12-27 The Procter & Gamble Company Films including a water-soluble layer and a vapor-deposited organic coating
US10537585B2 (en) 2017-12-18 2020-01-21 Dexcel Pharma Technologies Ltd. Compositions comprising dexamethasone
ES2909803T3 (en) * 2018-03-05 2022-05-10 Amneal Complex Products Res Llc Programmable pharmaceutical compositions for the chrono-release of drugs
EP3587467A1 (en) * 2018-06-25 2020-01-01 Rudolf GmbH Functional multi-walled core-shell particle
EP3813540A4 (en) * 2018-06-28 2022-04-06 Mars, Incorporated Improved edible ink formulations including calcium carbonate
KR102151342B1 (en) * 2019-03-18 2020-09-02 박문수 Oral capsule and manufacturing method of the same
CN110006918B (en) * 2019-04-17 2021-04-30 湖北三环锻造有限公司 Penetrant flaw detection agent for penetrant flaw detection process
US10945953B1 (en) * 2019-09-12 2021-03-16 Nulixir Inc. Controlled release core-shell particles and suspensions including the same
IL299845A (en) 2020-07-15 2023-03-01 Schabar Res Associates Llc Unit oral dose compositions composed of ibuprofen and famotidine for the treatment of acute pain and the reduction of the severity and/or risk of heartburn
CA3124579A1 (en) 2020-07-15 2022-01-15 Schabar Research Associates Llc Unit oral dose compositions composed of naproxen sodium and famotidine for the treatment of acute pain and the reduction of the severity of heartburn and/or the risk of heartburn

Citations (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4173626A (en) * 1978-12-11 1979-11-06 Merck & Co., Inc. Sustained release indomethacin
US4286497A (en) * 1979-06-18 1981-09-01 Shamah Alfred A Ratchet-securable toggle retainer
US4523021A (en) * 1981-05-12 1985-06-11 Imperial Chemical Industries Plc 1'-Substituted-spiro[pyrrolidine-3,3'-indoline]-2,2',5-triones
US4572833A (en) * 1982-08-13 1986-02-25 A/S Alfred Benzon Method for preparing a pharmaceutical controlled release composition
US4863742A (en) * 1986-06-20 1989-09-05 Elan Corporation Plc Controlled absorption pharmaceutical composition
US4874614A (en) * 1985-03-25 1989-10-17 Abbott Laboratories Pharmaceutical tableting method
US4906478A (en) * 1988-12-12 1990-03-06 Valentine Enterprises, Inc. Simethicone/calcium silicate composition
US4980170A (en) * 1988-06-30 1990-12-25 Klinge Pharma Gmbh Pharmaceutical formulation as well as a process for its preparation
US4984240A (en) * 1988-12-22 1991-01-08 Codex Corporation Distributed switching architecture for communication module redundancy
US5032406A (en) * 1989-02-21 1991-07-16 Norwich Eaton Pharmaceuticals, Inc. Dual-action tablet
US5100675A (en) * 1989-05-03 1992-03-31 Schering Corporation Sustained release tablet comprising loratadine, ibuprofen and pseudoephedrine
US5158777A (en) * 1990-02-16 1992-10-27 E. R. Squibb & Sons, Inc. Captopril formulation providing increased duration of activity
US5229134A (en) * 1989-12-05 1993-07-20 Laboratories Smith Kline & French Pharmaceutical compositions
US5275822A (en) * 1989-10-19 1994-01-04 Valentine Enterprises, Inc. Defoaming composition
US5397574A (en) * 1993-10-04 1995-03-14 Andrx Pharmaceuticals, Inc. Controlled release potassium dosage form
US5415868A (en) * 1993-06-09 1995-05-16 L. Perrigo Company Caplets with gelatin cover and process for making same
US5558879A (en) * 1995-04-28 1996-09-24 Andrx Pharmaceuticals, Inc. Controlled release formulation for water soluble drugs in which a passageway is formed in situ
US5738874A (en) * 1992-09-24 1998-04-14 Jagotec Ag Pharmaceutical tablet capable of liberating one or more drugs at different release rates
US5807579A (en) * 1995-11-16 1998-09-15 F.H. Faulding & Co. Limited Pseudoephedrine combination pharmaceutical compositions
US5824338A (en) * 1996-08-19 1998-10-20 L. Perrigo Company Caplet and gelatin covering therefor
US5912013A (en) * 1991-07-23 1999-06-15 Shire Laboratories, Inc. Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine
US6103260A (en) * 1997-07-17 2000-08-15 Mcneil-Ppc, Inc. Simethicone/anhydrous calcium phosphate compositions
US6270805B1 (en) * 1998-11-06 2001-08-07 Andrx Pharmaceuticals, Inc. Two pellet controlled release formulation for water soluble drugs which contains an alkaline metal stearate
US6294200B1 (en) * 1996-02-06 2001-09-25 Jagotec Ag Pharmaceutical tablet suitable to deliver the active substance in subsequent and predeterminable times
US6322819B1 (en) * 1998-10-21 2001-11-27 Shire Laboratories, Inc. Oral pulsed dose drug delivery system
US20020028240A1 (en) * 2000-04-17 2002-03-07 Toyohiro Sawada Timed-release compression-coated solid composition for oral administration
US20020102309A1 (en) * 1999-09-14 2002-08-01 Jane C. I. Hirsh Controlled release formulation for administration of an anti-inflammatory naphthalene derivative
US20030068367A1 (en) * 2001-09-28 2003-04-10 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US20030070903A1 (en) * 2001-09-28 2003-04-17 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US20030086973A1 (en) * 2001-09-28 2003-05-08 Sowden Harry S Systems, methods and apparatuses for manufacturing dosage forms
US20030124183A1 (en) * 2001-09-28 2003-07-03 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms

Family Cites Families (408)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US599865A (en) 1898-03-01 Emanuel l
US231024A (en) * 1880-08-10 Machine for lining sheets of straw-board
US231117A (en) * 1880-08-10 Folding boat
US542614A (en) * 1895-07-09 Office
US3371136A (en) * 1968-02-27 United States Borax Chem Detergent tablet forming machine
US582438A (en) * 1897-05-11 John scheidler
US231062A (en) * 1880-08-10 Felt hat
US231129A (en) * 1880-08-10 wiesebrook
US231163A (en) * 1880-08-17 hamlin
US966450A (en) * 1909-06-18 1910-08-09 John W S Jones Couch or bed.
US966509A (en) * 1909-06-25 1910-08-09 Charles A Wulf Flushing-valve.
US967414A (en) * 1910-02-11 1910-08-16 William W Hallam Railway-rail.
US966939A (en) * 1910-05-02 1910-08-09 James V Mitchell Sash-lock.
US996497A (en) * 1911-03-30 1911-06-27 Kokomo Sanitary Mfg Co Tank-cover fastener.
US1036647A (en) 1911-06-19 1912-08-27 St Louis Briquette Machine Company Briquet-machine.
US1437816A (en) 1922-07-26 1922-12-05 Howard S Paine Process for preparing fondant or chocolate soft cream centers
US1505827A (en) * 1923-04-25 1924-08-19 Villasenor Eduardo Tablet-making machine
US1900012A (en) * 1925-09-04 1933-03-07 Western Cartridge Co Process of and apparatus for making wads
US2307371A (en) 1941-08-13 1943-01-05 Ray O Vac Co Molding process
US2415997A (en) * 1946-01-12 1947-02-18 John W Eldred Article handling apparatus
US2823789A (en) * 1952-05-06 1958-02-18 Gilman Engineering & Mfg Corp Parts feeder ribbon
US2996431A (en) 1953-12-16 1961-08-15 Barry Richard Henry Friable tablet and process for manufacturing same
GB759081A (en) 1954-04-15 1956-10-10 John Holroyd And Company Ltd Improvements relating to machines for the production of coated tablets and the like
US2849965A (en) 1954-04-15 1958-09-02 John Holroyd & Company Ltd Machines for use in the production of coated tablets and the like
US2966431A (en) 1956-03-24 1960-12-27 Basf Ag Separation of filter material from carbon black
US2946298A (en) 1957-11-13 1960-07-26 Arthur Colton Company Compression coating tablet press
US2931276A (en) * 1958-02-10 1960-04-05 Jagenberg Werke Ag Methods of and means for producing, processing, and for treating articles
GB866681A (en) 1958-05-22 1961-04-26 May & Baker Ltd N-substituted piperidines
GB888038A (en) * 1959-12-16 1962-01-24 William Warren Triggs C B E Medicinal tablet
GB936386A (en) 1959-01-16 1963-09-11 Wellcome Found Pellets for supplying biologically active substances to ruminants
US2963993A (en) 1959-01-20 1960-12-13 John Holroyd & Company Ltd Machines for making coated tablets by compression
US3096248A (en) 1959-04-06 1963-07-02 Rexall Drug & Chemical Company Method of making an encapsulated tablet
US3029752A (en) * 1959-07-20 1962-04-17 Stokes F J Corp Tablet making machine
GB972128A (en) * 1960-01-21 1964-10-07 Wellcome Found Pellets for supplying biologically active substances to ruminants and the manufacture of such pellets
GB990784A (en) * 1960-05-23 1965-05-05 Dunlop Rubber Co Improvements in or relating to balls
US3173876A (en) * 1960-05-27 1965-03-16 John C Zobrist Cleaning methods and compositions
GB994742A (en) * 1960-09-09 1965-06-10 Wellcome Found Pharmaceutical tablets containing anthelmintics, and the manufacture thereof
US3108046A (en) 1960-11-25 1963-10-22 Smith Kline French Lab Method of preparing high dosage sustained release tablet and product of this method
NL271831A (en) * 1960-11-29
NL272604A (en) * 1960-12-28
US3430535A (en) * 1961-08-25 1969-03-04 Independent Lock Co Key cutter
BE636865A (en) * 1962-08-31
US3185626A (en) * 1963-03-06 1965-05-25 Sterling Drug Inc Tablet coating method
US3279995A (en) 1963-05-31 1966-10-18 Allen F Reid Shaped pellets
US3276586A (en) * 1963-08-30 1966-10-04 Rosaen Filter Co Indicating means for fluid filters
US3300063A (en) * 1965-01-25 1967-01-24 Mayer & Co Inc O Vacuum gripping apparatus
FR1603314A (en) * 1965-02-23 1971-04-05 Pharmaceutical tablets - having a core and a matrix material
US3328840A (en) * 1965-04-23 1967-07-04 Pentronix Inc Powder compacting press
US3279360A (en) 1965-09-13 1966-10-18 Miehle Goss Dexter Inc Machine for printing on cylindrical articles
US3330400A (en) 1966-03-08 1967-07-11 Miehle Goss Dexter Inc Mechanism for transferring cylindrical articles
GB1212535A (en) * 1966-10-12 1970-11-18 Shionogi & Co Method and apparatus for producing molded article
US3458968A (en) 1966-11-16 1969-08-05 Lester Gregory Jr Dispensing and feed mechanism
GB1144915A (en) 1966-11-24 1969-03-12 Armour Pharma Improvements in or relating to pastille formulations
US3546142A (en) * 1967-01-19 1970-12-08 Amicon Corp Polyelectrolyte structures
US3656518A (en) * 1967-03-27 1972-04-18 Perry Ind Inc Method and apparatus for measuring and dispensing predetermined equal amounts of powdered material
US3563170A (en) * 1968-04-16 1971-02-16 Reynolds Metals Co Machine for marking the exterior cylindrical surfaces of cans in a continous nonidexing manner
US3605479A (en) 1968-05-08 1971-09-20 Textron Inc Forming press
US3584114A (en) 1968-05-22 1971-06-08 Hoffmann La Roche Free-flowing powders
NL6808619A (en) * 1968-06-19 1969-12-23
US3541006A (en) * 1968-07-03 1970-11-17 Amicon Corp Ultrafiltration process
FR1581088A (en) 1968-07-17 1969-09-12
US3567043A (en) * 1968-08-05 1971-03-02 Sun Chemical Corp Transfer assembly for use with container printing machines
US3627583A (en) 1969-04-29 1971-12-14 Sucrest Corp Direct compression vehicles
US3604417A (en) * 1970-03-31 1971-09-14 Wayne Henry Linkenheimer Osmotic fluid reservoir for osmotically activated long-term continuous injector device
US3640654A (en) * 1970-06-25 1972-02-08 Wolverine Pentronix Die and punch assembly for compacting powder and method of assembly
US3832252A (en) 1970-09-29 1974-08-27 T Higuchi Method of making a drug-delivery device
CH569482A5 (en) 1970-12-23 1975-11-28 Boehringer Sohn Ingelheim
US3811552A (en) * 1971-01-11 1974-05-21 Lilly Co Eli Capsule inspection apparatus and method
US3760804A (en) 1971-01-13 1973-09-25 Alza Corp Improved osmotic dispenser employing magnesium sulphate and magnesium chloride
US3995631A (en) * 1971-01-13 1976-12-07 Alza Corporation Osmotic dispenser with means for dispensing active agent responsive to osmotic gradient
US3726622A (en) * 1971-08-20 1973-04-10 Wolverine Pentronix Compacting apparatus
DE2157465C3 (en) * 1971-11-19 1975-04-24 Werner & Pfleiderer, 7000 Stuttgart Filling device for a hydraulic block press
GB1371244A (en) * 1971-12-09 1974-10-23 Howorth Air Conditioning Ltd Machines acting on continuously running textile yarns
BE794951A (en) * 1972-02-03 1973-05-29 Parke Davis & Co WATER SOLUBLE PACKAGING
US3851751A (en) 1972-04-26 1974-12-03 Jones & Co Inc R A Method and apparatus for forming, filling and sealing packages
US3975888A (en) 1972-04-26 1976-08-24 R. A. Jones & Company, Inc. Method and apparatus for forming, filling and sealing packages
US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3912441A (en) 1972-12-13 1975-10-14 Yasuo Shimada Compressing roll in rotary power compression molding machine
US3851638A (en) 1973-02-02 1974-12-03 Kam Act Enterprises Inc Force multiplying type archery bow
DE2309202A1 (en) * 1973-02-21 1974-08-29 Schering Ag MEDICINAL FORMS WITH MICRO-ENCAPSULATED MEDICINAL ACTIVE
US3832525A (en) * 1973-03-26 1974-08-27 Raymond Lee Organization Inc Automatic heating device to prevent freezing of water supply lines
US3916899A (en) * 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US3884143A (en) * 1973-09-04 1975-05-20 Hartnett Co R W Conveyor link for tablet printing apparatus
DE2401419A1 (en) 1974-01-12 1975-07-17 Bosch Gmbh Robert VEHICLE WITH A HYDROSTATIC AND MECHANICAL DRIVE
US3891375A (en) 1974-01-21 1975-06-24 Vector Corp Tablet press
GB1497044A (en) * 1974-03-07 1978-01-05 Prodotti Antibiotici Spa Salts of phenyl-alkanoic acids
US3988403A (en) * 1974-07-09 1976-10-26 Union Carbide Corporation Process for producing molded structural foam article having a surface that reproducibly and faithfully replicates the surface of the mold
US4139589A (en) * 1975-02-26 1979-02-13 Monique Beringer Process for the manufacture of a multi-zone tablet and tablet manufactured by this process
US4230693A (en) 1975-04-21 1980-10-28 Armour-Dial, Inc. Antacid tablets and processes for their preparation
FR2312247A1 (en) * 1975-05-30 1976-12-24 Parcor THIENO-PYRIDINE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS
US4097606A (en) 1975-10-08 1978-06-27 Bristol-Myers Company APAP Tablet containing an alkali metal carboxymethylated starch and processes for manufacturing same
US4077407A (en) * 1975-11-24 1978-03-07 Alza Corporation Osmotic devices having composite walls
SE414386B (en) 1976-03-10 1980-07-28 Aco Laekemedel Ab VIEW TO PREPARE AND AT THE SAME PACKAGE PHARMACEUTICAL DOSAGE UNITS
GB1548022A (en) * 1976-10-06 1979-07-04 Wyeth John & Brother Ltd Pharmaceutial dosage forms
US4111202A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system for the controlled and delivery of agent over time
US4218433A (en) * 1977-03-03 1980-08-19 Nippon Kayaku Kabushiki Kaisha Constant-rate eluting tablet and method of producing same
US4139627A (en) * 1977-10-06 1979-02-13 Beecham Inc. Anesthetic lozenges
DE2752971C2 (en) * 1977-11-28 1982-08-19 Lev Nikolaevič Moskva Koškin Injection molding machine for the production of injection molded parts from thermoplastic materials
GB2030042A (en) * 1978-09-21 1980-04-02 Beecham Group Ltd Antacid fondant
DE2849494A1 (en) 1978-11-15 1980-05-29 Voss Gunter M METHOD FOR THE PRODUCTION OF MEDICINAL FORMS
US4198390A (en) * 1979-01-31 1980-04-15 Rider Joseph A Simethicone antacid tablet
US4304232A (en) * 1979-03-14 1981-12-08 Alza Corporation Unit system having multiplicity of means for dispensing useful agent
US4271142A (en) * 1979-06-18 1981-06-02 Life Savers, Inc. Portable liquid antacids
JPS5827162B2 (en) 1979-08-24 1983-06-08 株式会社ヤクルト本社 Constant speed transport mechanism
NL7906689A (en) * 1979-09-06 1981-03-10 Dawsonville Corp Nv TATTOO.
DE2936040C2 (en) * 1979-09-06 1982-05-19 Meggle Milchindustrie Gmbh & Co Kg, 8094 Reitmehring Coating process and means for carrying out the process, consisting essentially of sucrose, at least one other sugar and water
US4271206A (en) 1979-10-26 1981-06-02 General Foods Corporation Gasified candy having a predetermined shape
US4273793A (en) * 1979-10-26 1981-06-16 General Foods Corporation Apparatus and process for the preparation of gasified confectionaries by pressurized injection molding
US4543370A (en) 1979-11-29 1985-09-24 Colorcon, Inc. Dry edible film coating composition, method and coating form
US4318746A (en) * 1980-01-08 1982-03-09 Ipco Corporation Highly stable gel, its use and manufacture
US4473526A (en) 1980-01-23 1984-09-25 Eugen Buhler Method of manufacturing dry-pressed molded articles
US4292017A (en) 1980-07-09 1981-09-29 Doepel Wallace A Apparatus for compressing tablets
US4362757A (en) 1980-10-22 1982-12-07 Amstar Corporation Crystallized, readily water dispersible sugar product containing heat sensitive, acidic or high invert sugar substances
FR2492661A1 (en) * 1980-10-28 1982-04-30 Laruelle Claude NOVEL GALENIC FORM OF ADMINISTRATION OF METOCLOPRAMIDE, ITS PREPARATION METHOD AND MEDICINAL PRODUCT COMPRISING THIS NOVEL FORM
US4683256A (en) * 1980-11-06 1987-07-28 Colorcon, Inc. Dry edible film coating composition, method and coating form
US4327076A (en) * 1980-11-17 1982-04-27 Life Savers, Inc. Compressed chewable antacid tablet and method for forming same
US4327725A (en) * 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US4340054A (en) * 1980-12-29 1982-07-20 Alza Corporation Dispenser for delivering fluids and solids
US5002970A (en) * 1981-07-31 1991-03-26 Eby Iii George A Flavor masked ionizable zinc compositions for oral absorption
US4372942A (en) * 1981-08-13 1983-02-08 Beecham Inc. Candy base and liquid center hard candy made therefrom
DE3144678A1 (en) 1981-11-10 1983-05-19 Eugen Dipl.-Ing. 8871 Burtenbach Bühler METHOD AND DEVICE FOR THE PRODUCTION OF MOLDINGS FROM A GIANT CAPABILITY
JPS58152813A (en) 1982-03-08 1983-09-10 Sumitomo Chem Co Ltd Tablet having clear carved seal and its preparation
US4449983A (en) * 1982-03-22 1984-05-22 Alza Corporation Simultaneous delivery of two drugs from unit delivery device
US4517205A (en) * 1983-01-03 1985-05-14 Nabisco Brands, Inc. Co-deposited two-component hard candy
US4576604A (en) * 1983-03-04 1986-03-18 Alza Corporation Osmotic system with instant drug availability
US4882167A (en) * 1983-05-31 1989-11-21 Jang Choong Gook Dry direct compression compositions for controlled release dosage forms
US4533345A (en) * 1983-06-14 1985-08-06 Fertility & Genetics Associates Uterine catheter
FR2548675B1 (en) * 1983-07-06 1987-01-09 Seppic Sa FILM-FORMING COMPOSITIONS FOR COATING SOLID FORMS OF PHARMACEUTICAL OR FOOD PRODUCTS AND PRODUCTS OBTAINED COATED WITH SUCH COMPOSITIONS
US4749575A (en) 1983-10-03 1988-06-07 Bio-Dar Ltd. Microencapsulated medicament in sweet matrix
AU591171B2 (en) 1983-11-02 1989-11-30 Alza Corporation Dispenser for delivering thermo-responsive composition
US4781714A (en) * 1983-11-02 1988-11-01 Alza Corporation Dispenser for delivering thermo-responsive composition
NL194820C (en) 1983-11-02 2003-04-03 Alza Corp Preparation for the release of a heat-reacting composition.
DE3404108A1 (en) * 1984-02-07 1985-08-14 Kilian & Co GmbH, 5000 Köln TABLET PRESS
US4518335A (en) * 1984-03-14 1985-05-21 Allied Corporation Dilatant mold and dilatant molding apparatus
US4564525A (en) * 1984-03-30 1986-01-14 Mitchell Cheryl R Confection products
JPS60217106A (en) 1984-04-12 1985-10-30 高橋 信之 Inorganic-powder freezing molding method
US4661521A (en) 1984-04-30 1987-04-28 Mallinckrodt, Inc. Direct tableting acetaminophen compositions
US4528335A (en) * 1984-05-18 1985-07-09 Phillips Petroleum Company Polymer blends
US4666212A (en) * 1984-06-15 1987-05-19 Crucible S.A. Metal value recovery
US4610884A (en) 1984-06-29 1986-09-09 The Procter & Gamble Company Confectionery cremes
US4643894A (en) * 1984-07-24 1987-02-17 Colorcon, Inc. Maltodextrin coating
US4828841A (en) * 1984-07-24 1989-05-09 Colorcon, Inc. Maltodextrin coating
US4894234A (en) * 1984-10-05 1990-01-16 Sharma Shri C Novel drug delivery system for antiarrhythmics
JPS61100519A (en) * 1984-10-23 1986-05-19 Shin Etsu Chem Co Ltd Hard capsule for drug
US4684534A (en) * 1985-02-19 1987-08-04 Dynagram Corporation Of America Quick-liquifying, chewable tablet
US4627971A (en) * 1985-04-22 1986-12-09 Alza Corporation Osmotic device with self-sealing passageway
CA1234717A (en) * 1985-06-28 1988-04-05 Leslie F. Knebl Moist chewing gum composition
GB8517073D0 (en) 1985-07-05 1985-08-14 Hepworth Iron Co Ltd Pipe pipe couplings &c
GB8518301D0 (en) * 1985-07-19 1985-08-29 Fujisawa Pharmaceutical Co Hydrodynamically explosive systems
DK8603837A (en) * 1985-08-13 1987-02-14
US4665116A (en) 1985-08-28 1987-05-12 Turtle Wax, Inc. Clear cleaner/polish composition
US4663147A (en) * 1985-09-03 1987-05-05 International Minerals & Chemical Corp. Disc-like sustained release formulation
US5188840A (en) * 1985-09-26 1993-02-23 Chugai Seiyaku Kabushiki Kaisha Slow-release pharmaceutical agent
US4898733A (en) * 1985-11-04 1990-02-06 International Minerals & Chemical Corp. Layered, compression molded device for the sustained release of a beneficial agent
US4853249A (en) 1985-11-15 1989-08-01 Taisho Pharmaceutical Co., Ltd. Method of preparing sustained-release pharmaceutical/preparation
US5229164A (en) * 1985-12-19 1993-07-20 Capsoid Pharma Gmbh Process for producing individually dosed administration forms
DE3601516A1 (en) * 1986-01-20 1987-07-23 Agie Ag Ind Elektronik PHOTOELECTRIC BARRIER
JPS62230600A (en) 1986-03-31 1987-10-09 東洋ゴム工業株式会社 Forklift with expansible fork
DE3610878A1 (en) 1986-04-01 1987-10-08 Boehringer Ingelheim Kg PELLET SHAPES
US4873231A (en) 1986-04-08 1989-10-10 Smith Walton J Decreasing the toxicity of an ibuprofen salt
SE8601624D0 (en) * 1986-04-11 1986-04-11 Haessle Ab NEW PHARMACEUTICAL PREPARATIONS
US4857330A (en) * 1986-04-17 1989-08-15 Alza Corporation Chlorpheniramine therapy
GB2189698A (en) 1986-04-30 1987-11-04 Haessle Ab Coated omeprazole tablets
GB2189699A (en) * 1986-04-30 1987-11-04 Haessle Ab Coated acid-labile medicaments
US4960416A (en) * 1986-04-30 1990-10-02 Alza Corporation Dosage form with improved delivery capability
US5200196A (en) * 1986-05-09 1993-04-06 Alza Corporation Improvement in pulsed drug therapy
US4802924A (en) * 1986-06-19 1989-02-07 Colorcon, Inc. Coatings based on polydextrose for aqueous film coating of pharmaceutical food and confectionary products
US4757090A (en) * 1986-07-14 1988-07-12 Mallinckrodt, Inc. Direct tableting acetaminophen compositions
US4762719A (en) 1986-08-07 1988-08-09 Mark Forester Powder filled cough product
US4816262A (en) * 1986-08-28 1989-03-28 Universite De Montreal Controlled release tablet
DE3629994A1 (en) 1986-09-03 1988-03-17 Weissenbacher Ernst Rainer Pro Device for administration of medicaments in body cavities or on body surfaces
US4803076A (en) * 1986-09-04 1989-02-07 Pfizer Inc. Controlled release device for an active substance
CA1290526C (en) 1986-11-07 1991-10-15 Marianne Wieser Mold and die operation
DE3640574A1 (en) 1986-11-27 1988-06-09 Katjes Fassin Gmbh & Co Kg METHOD FOR PRODUCING AN EDIBLE PRALINE-SHAPED PRODUCT AND DEVICE FOR IMPLEMENTING THE METHOD
US4828845A (en) * 1986-12-16 1989-05-09 Warner-Lambert Company Xylitol coated comestible and method of preparation
IT1201136B (en) 1987-01-13 1989-01-27 Resa Farma TABLET FOR PHARMACEUTICAL USE SUITABLE FOR THE RELEASE OF SUBSTANCES OF ACTIVE SUBSTANCES
US4801461A (en) * 1987-01-28 1989-01-31 Alza Corporation Pseudoephedrine dosage form
US4820524A (en) 1987-02-20 1989-04-11 Mcneilab, Inc. Gelatin coated caplets and process for making same
US5200193A (en) 1987-04-22 1993-04-06 Mcneilab, Inc. Pharmaceutical sustained release matrix and process
US4808413A (en) * 1987-04-28 1989-02-28 E. R. Squibb & Sons, Inc. Pharmaceutical compositions in the form of beadlets and method
US4792448A (en) 1987-06-11 1988-12-20 Pfizer Inc. Generic zero order controlled drug delivery system
US4813818A (en) * 1987-08-25 1989-03-21 Michael Sanzone Apparatus and method for feeding powdered materials
US4978483A (en) 1987-09-28 1990-12-18 Redding Bruce K Apparatus and method for making microcapsules
US4996061A (en) * 1987-10-07 1991-02-26 Merrell Dow Pharmaceuticals Inc. Pharmaceutical composition for piperidinoalkanol-decongestant combination
US4851226A (en) * 1987-11-16 1989-07-25 Mcneil Consumer Products Company Chewable medicament tablet containing means for taste masking
US4894236A (en) * 1988-01-12 1990-01-16 Choong-Gook Jang Direct compression tablet binders for acetaminophen
CA1330886C (en) 1988-01-22 1994-07-26 Bend Research Inc. Osmotic system for delivery of dilute solutions
CH676470A5 (en) * 1988-02-03 1991-01-31 Nestle Sa
US4929446A (en) * 1988-04-19 1990-05-29 American Cyanamid Company Unit dosage form
US5279660A (en) * 1988-05-24 1994-01-18 Berol Nobel Stenungsund Ab Use of viscosity-adjusting agent to counteract viscosity decrease upon temperature increase of a water-based system
US4999226A (en) * 1988-06-01 1991-03-12 Merrell Dow Pharmaceuticals Inc. Pharmaceutical compositions for piperidinoalkanol-ibuprofen combination
GB8820353D0 (en) * 1988-08-26 1988-09-28 Staniforth J N Controlled release tablet
WO1990002546A1 (en) * 1988-09-09 1990-03-22 The Ronald T. Dodge Company Pharmaceuticals microencapsulated by vapor deposited polymers and method
US5194464A (en) * 1988-09-27 1993-03-16 Takeda Chemical Industries, Ltd. Enteric film and preparatoin thereof
JPH0816051B2 (en) 1988-12-07 1996-02-21 エスエス製薬株式会社 Sustained release suppositories
US5610214A (en) * 1988-12-29 1997-03-11 Deknatel Technology Corporation, Inc. Method for increasing the rate of absorption of polycaprolactone
US5030452A (en) * 1989-01-12 1991-07-09 Pfizer Inc. Dispensing devices powered by lyotropic liquid crystals
IL92966A (en) * 1989-01-12 1995-07-31 Pfizer Dispensing devices powered by hydrogel
US5006297A (en) * 1989-02-22 1991-04-09 Acushnet Company Method of molding polyurethane covered golf balls
US4956182A (en) 1989-03-16 1990-09-11 Bristol-Myers Company Direct compression cholestyramine tablet and solvent-free coating therefor
US4931286A (en) * 1989-04-19 1990-06-05 Aqualon Company High gloss cellulose tablet coating
NZ233403A (en) * 1989-04-28 1992-09-25 Mcneil Ppc Inc Simulated capsule-like medicament
US4960169A (en) * 1989-06-20 1990-10-02 Modien Manufacturing Co. Baffle for tubular heat exchanger header
US4992277A (en) * 1989-08-25 1991-02-12 Schering Corporation Immediate release diltiazem formulation
EP0419410A3 (en) 1989-09-19 1991-08-14 Ciba-Geigy Ag Alkanophenones
US5146730A (en) * 1989-09-20 1992-09-15 Banner Gelatin Products Corp. Film-enrobed unitary-core medicament and the like
DK469989D0 (en) * 1989-09-22 1989-09-22 Bukh Meditec PHARMACEUTICAL PREPARATION
US5178878A (en) * 1989-10-02 1993-01-12 Cima Labs, Inc. Effervescent dosage form with microparticles
US5223264A (en) * 1989-10-02 1993-06-29 Cima Labs, Inc. Pediatric effervescent dosage form
JPH03139496A (en) * 1989-10-25 1991-06-13 Sanshin Ind Co Ltd Ship propulsion machinery
US5169645A (en) 1989-10-31 1992-12-08 Duquesne University Of The Holy Ghost Directly compressible granules having improved flow properties
US5223266A (en) * 1990-01-24 1993-06-29 Alza Corporation Long-term delivery device with early startup
US5100676A (en) * 1990-02-02 1992-03-31 Biosurface Technology, Inc. Cool storage of cultured epithelial sheets
US4983394A (en) * 1990-05-03 1991-01-08 Warner-Lambert Company Flavor enhancing and medicinal taste masking agent
US4980169A (en) 1990-05-03 1990-12-25 Warner-Lambert Company Flavor enhancing and increasing efficacy of cough drops
US5213738A (en) * 1990-05-15 1993-05-25 L. Perrigo Company Method for making a capsule-shaped tablet
US5089270A (en) * 1990-05-15 1992-02-18 L. Perrigo Company Capsule-shaped tablet
US5075114A (en) 1990-05-23 1991-12-24 Mcneil-Ppc, Inc. Taste masking and sustained release coatings for pharmaceuticals
US5464631A (en) 1990-06-27 1995-11-07 Warner-Lambert Company Encapsulated dosage forms
US5133892A (en) * 1990-10-17 1992-07-28 Lever Brothers Company, Division Of Conopco, Inc. Machine dishwashing detergent tablets
US5503673A (en) * 1990-11-05 1996-04-02 Mcneil-Ppc, Inc Apparatus for dip coating product
US5228916A (en) 1990-11-05 1993-07-20 Mcneil-Ppc, Inc. Apparatus for creating a gelatin coating
US5436026A (en) * 1990-11-05 1995-07-25 Mcneil-Ppc, Inc. Discharge and transfer system for apparatus for gelatin coating tablets
US5538125A (en) * 1990-11-05 1996-07-23 Mcneil-Ppc, Inc. Indexing and feeding systems for apparatus for gelatin coating tablets
US5683719A (en) 1990-11-22 1997-11-04 British Technology Group Limited Controlled release compositions
US5098715A (en) * 1990-12-20 1992-03-24 Burroughs Wellcome Co. Flavored film-coated tablet
US5232706A (en) * 1990-12-31 1993-08-03 Esteve Quimica, S.A. Oral pharmaceutical preparation containing omeprazol
DE4101873C2 (en) * 1991-01-23 1993-12-09 Isis Pharma Gmbh Orally administrable drug form for the treatment of central dopamine deficiency states
US5378475A (en) 1991-02-21 1995-01-03 University Of Kentucky Research Foundation Sustained release drug delivery devices
NZ241613A (en) * 1991-02-27 1993-06-25 Janssen Pharmaceutica Nv Highlighting intagliations in tablets
CA2061520C (en) * 1991-03-27 2003-04-22 Lawrence J. Daher Delivery system for enhanced onset and increased potency
US5286497A (en) * 1991-05-20 1994-02-15 Carderm Capital L.P. Diltiazem formulation
CA2068402C (en) * 1991-06-14 1998-09-22 Michael R. Hoy Taste mask coatings for preparation of chewable pharmaceutical tablets
YU48263B (en) 1991-06-17 1997-09-30 Byk Gulden Lomberg Chemische Fabrik Gmbh. PROCEDURE FOR OBTAINING PANTOPRAZOLE PHARMACEUTICAL PRODUCT
US5252338A (en) * 1991-06-27 1993-10-12 Alza Corporation Therapy delayed
US5314696A (en) * 1991-06-27 1994-05-24 Paulos Manley A Methods for making and administering a blinded oral dosage form and blinded oral dosage form therefor
US5190927A (en) * 1991-07-09 1993-03-02 Merck & Co., Inc. High-glyceryl, low-acetyl gellan gum for non-brittle gels
US5200191A (en) * 1991-09-11 1993-04-06 Banner Gelatin Products Corp. Softgel manufacturing process
US5405617A (en) 1991-11-07 1995-04-11 Mcneil-Ppc, Inc. Aliphatic or fatty acid esters as a solventless carrier for pharmaceuticals
US5407686A (en) * 1991-11-27 1995-04-18 Sidmak Laboratories, Inc. Sustained release composition for oral administration of active ingredient
US5200195A (en) * 1991-12-06 1993-04-06 Alza Corporation Process for improving dosage form delivery kinetics
DK171536B1 (en) 1991-12-06 1996-12-23 Rasmussen Kann Ind As Window with frame of extruded profile items
US5200194A (en) * 1991-12-18 1993-04-06 Alza Corporation Oral osmotic device
GB2284760B (en) 1993-11-23 1998-06-24 Euro Celtique Sa A method of preparing pharmaceutical compositions by melt pelletisation
AU674840B2 (en) * 1992-01-17 1997-01-16 Bpsi Holdings, Inc. Film coatings and film coating compositions based on cellulosic polymers and lactose
US5427614A (en) * 1992-02-14 1995-06-27 Warner-Lambert Company Starch based formulations
US5209746A (en) * 1992-02-18 1993-05-11 Alza Corporation Osmotically driven delivery devices with pulsatile effect
US5221278A (en) * 1992-03-12 1993-06-22 Alza Corporation Osmotically driven delivery device with expandable orifice for pulsatile delivery effect
US5656296A (en) * 1992-04-29 1997-08-12 Warner-Lambert Company Dual control sustained release drug delivery systems and methods for preparing same
US5260068A (en) * 1992-05-04 1993-11-09 Anda Sr Pharmaceuticals Inc. Multiparticulate pulsatile drug delivery system
GR1002332B (en) 1992-05-21 1996-05-16 Mcneil-Ppc Inc. Novel simethicone containing pharmaceutical compositions.
EP0572731A1 (en) 1992-06-01 1993-12-08 The Procter & Gamble Company Chewable preparation containing a decongestant
US5317849A (en) * 1992-08-07 1994-06-07 Sauter Manufacturing Corporation Encapsulation equipment and method
JPH07507564A (en) 1992-09-30 1995-08-24 ファイザー・インク. Articles containing a core and a coating of variable thickness
AU5681294A (en) * 1992-11-30 1994-06-22 Kv Pharmaceutical Company Tastemasked pharmaceutical materials
US5375963A (en) 1993-01-19 1994-12-27 Wohlwend; Clayton E. Multipurpose lifting apparatus
TW272942B (en) * 1993-02-10 1996-03-21 Takeda Pharm Industry Co Ltd
US5391378A (en) 1993-02-22 1995-02-21 Elizabeth-Hata International, Inc. Two-part medicinal tablet and method of manufacture
JP2524955B2 (en) 1993-04-22 1996-08-14 トーワ株式会社 Method and apparatus for resin sealing molding of electronic parts
DE69425453T2 (en) * 1993-04-23 2001-04-12 Novartis Ag Drug delivery device with controlled release
NZ260408A (en) 1993-05-10 1996-05-28 Euro Celtique Sa Controlled release preparation comprising tramadol
JP3054989B2 (en) * 1993-06-19 2000-06-19 八幡 貞男 Insulated expression container
IT1264855B1 (en) * 1993-06-21 1996-10-17 Zambon Spa PHARMACEUTICAL COMPOSITIONS CONTAINING S (+) - 2- (4-ISOBUTYLPHENYL) PROPIONIC ACID SALTS WITH BASIC AMINO ACIDS
ZA944949B (en) 1993-07-12 1995-04-05 Smithkline Beecham Corp Matrix-entrapped beadlet preparation
EP0716597A1 (en) * 1993-08-30 1996-06-19 Warner-Lambert Company Tablet coating based on a melt-spun mixture of a saccharide and apolymer
US5622719A (en) 1993-09-10 1997-04-22 Fuisz Technologies Ltd. Process and apparatus for making rapidly dissolving dosage units and product therefrom
US5518551A (en) * 1993-09-10 1996-05-21 Fuisz Technologies Ltd. Spheroidal crystal sugar and method of making
US5433951A (en) * 1993-10-13 1995-07-18 Bristol-Myers Squibb Company Sustained release formulation containing captopril and method
US5500227A (en) * 1993-11-23 1996-03-19 Euro-Celtique, S.A. Immediate release tablet cores of insoluble drugs having sustained-release coating
DE4341442C2 (en) * 1993-12-04 1998-11-05 Lohmann Therapie Syst Lts Device for the controlled release of active substances and their use
US5458887A (en) * 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation
US6060639A (en) * 1994-03-04 2000-05-09 Mentor Corporation Testicular prosthesis and method of manufacturing and filling
US5453920A (en) * 1994-03-08 1995-09-26 Eubanks; William W. Trouble light having a shroud with see-through opening
US5559110A (en) 1994-03-09 1996-09-24 The Dupont Merck Pharmaceutical Company Pharmaceutical formulations of cyclic urea type compounds
JPH07281423A (en) * 1994-04-07 1995-10-27 Konica Corp Plate making method of printing plate
US5464633A (en) 1994-05-24 1995-11-07 Jagotec Ag Pharmaceutical tablets releasing the active substance after a definite period of time
US6020002A (en) * 1994-06-14 2000-02-01 Fuisz Technologies Ltd. Delivery of controlled-release system(s)
SE9402431D0 (en) * 1994-07-08 1994-07-08 Astra Ab New tablet formulation
DE69535889D1 (en) 1994-07-08 2009-01-02 Astrazeneca Ab Tableted dosage form composed of many individual units
US5788979A (en) * 1994-07-22 1998-08-04 Inflow Dynamics Inc. Biodegradable coating with inhibitory properties for application to biocompatible materials
IT1274034B (en) 1994-07-26 1997-07-14 Applied Pharma Res PHARMACEUTICAL COMPOSITIONS BASED ON RUBBER TO BE CHEWED AND PROCEDURE FOR THEIR PREPARATION
US5849327A (en) 1994-07-29 1998-12-15 Advanced Polymer Systems, Inc. Delivery of drugs to the lower gastrointestinal tract
EP0773866B1 (en) * 1994-08-03 1998-04-08 Gunter Meinhardt Voss Method or producing coated tablets
DE9414065U1 (en) * 1994-08-31 1994-11-03 Roehm Gmbh Thermoplastic plastic for pharmaceutical casings soluble in intestinal juice
DE4431653C2 (en) * 1994-09-06 2000-01-20 Lohmann Therapie Syst Lts Coated tablet for the controlled release of active substances, a process for their preparation and their use
US5733575A (en) * 1994-10-07 1998-03-31 Bpsi Holdings, Inc. Enteric film coating compositions, method of coating therewith, and coated forms
US5614578A (en) * 1994-10-28 1997-03-25 Alza Corporation Injection-molded dosage form
CA2134611C (en) * 1994-10-28 2002-12-24 Richard John Yarwood Process for preparing solid pharmaceutical dosage forms
US5593696A (en) * 1994-11-21 1997-01-14 Mcneil-Ppc, Inc. Stabilized composition of famotidine and sucralfate for treatment of gastrointestinal disorders
US5756123A (en) * 1994-12-01 1998-05-26 Japan Elanco Co., Ltd. Capsule shell
US5626896A (en) * 1994-12-09 1997-05-06 A.E. Staley Manufacturing Co. Method for making liquid-centered jelly candies
US5582838A (en) * 1994-12-22 1996-12-10 Merck & Co., Inc. Controlled release drug suspension delivery device
DE4446468A1 (en) * 1994-12-23 1996-06-27 Basf Ag Process for the production of coated tablets
US6471994B1 (en) * 1995-01-09 2002-10-29 Edward Mendell Co., Inc. Pharmaceutical excipient having improved compressibility
ES2094694B1 (en) * 1995-02-01 1997-12-16 Esteve Quimica Sa NEW PHARMACEUTICALLY STABLE FORMULATION OF A COMPOUND OF BENZMIDAZOLE AND ITS PROCESS OF OBTAINING.
EP0726216B1 (en) * 1995-02-07 1998-09-09 Hermann Kronseder Transporting star wheel for vessels
SE9500478D0 (en) * 1995-02-09 1995-02-09 Astra Ab New pharmaceutical formulation and process
US5736159A (en) * 1995-04-28 1998-04-07 Andrx Pharmaceuticals, Inc. Controlled release formulation for water insoluble drugs in which a passageway is formed in situ
US5827874A (en) 1995-05-05 1998-10-27 Meyer; Hans Methods of treating pain and inflammation with proline
JPH11507292A (en) 1995-05-09 1999-06-29 カラーコン リミテッド Electrostatic painting
DE59601245D1 (en) * 1995-05-13 1999-03-18 Hermann Kronseder Transport star for vessels
US5627971A (en) * 1995-06-01 1997-05-06 Northern Telecom Limited Machine method for determining the eligibility of links in a network
US5578336A (en) * 1995-06-07 1996-11-26 Monte; Woodrow C. Confection carrier for vitamins, enzymes, phytochemicals and ailmentary vegetable compositions and method of making
US5654005A (en) * 1995-06-07 1997-08-05 Andrx Pharmaceuticals, Inc. Controlled release formulation having a preformed passageway
AU718160B2 (en) * 1995-06-09 2000-04-06 R.P. Scherer Corporation Soft gelatin capsules containing particulate material
US5614207A (en) * 1995-06-30 1997-03-25 Mcneil-Ppc, Inc. Dry mouth lozenge
GB9517031D0 (en) 1995-08-19 1995-10-25 Procter & Gamble Confection compositions
JP3463266B2 (en) * 1995-09-21 2003-11-05 ファーマ パス エルエルシー Novel composition containing acid-labile omeparazole and method for producing the same
AUPN605795A0 (en) * 1995-10-19 1995-11-09 F.H. Faulding & Co. Limited Analgesic pharmaceutical composition
DE19539361A1 (en) 1995-10-23 1997-04-24 Basf Ag Process for the preparation of multilayer, solid pharmaceutical forms for oral or rectal administration
IT1279673B1 (en) * 1995-11-07 1997-12-16 Acma Spa EQUIPMENT AND METHOD FOR THE FORMATION OF ORDERED GROUPS OF PRODUCTS TO BE FOOD BY STEP.
US5733578A (en) * 1995-11-15 1998-03-31 Edward Mendell Co., Inc. Directly compressible high load acetaminophen formulations
JP3220373B2 (en) * 1995-11-28 2001-10-22 バイエル薬品株式会社 Long-acting nifedipine preparation
US6489346B1 (en) 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
SE9600071D0 (en) 1996-01-08 1996-01-08 Astra Ab New oral formulation of two active ingredients I
SE9600070D0 (en) 1996-01-08 1996-01-08 Astra Ab New oral pharmaceutical dosage forms
US5879728A (en) * 1996-01-29 1999-03-09 Warner-Lambert Company Chewable confectionary composition and method of preparing same
US6245351B1 (en) * 1996-03-07 2001-06-12 Takeda Chemical Industries, Ltd. Controlled-release composition
US5711691A (en) * 1996-05-13 1998-01-27 Air Packaging Technologies, Inc. Self-closing and self-sealing valve device for use with inflatable structures
US5827535A (en) 1996-06-21 1998-10-27 Banner Pharmacaps, Inc. Graphically impressed softgel and method for making same
US5797898A (en) 1996-07-02 1998-08-25 Massachusetts Institute Of Technology Microchip drug delivery devices
US5916881A (en) * 1996-10-07 1999-06-29 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo High trehalose content syrup
US5807580A (en) 1996-10-30 1998-09-15 Mcneil-Ppc, Inc. Film coated tablet compositions having enhanced disintegration characteristics
US6077539A (en) 1996-11-12 2000-06-20 Pozen, Inc. Treatment of migraine headache
GB9624110D0 (en) * 1996-11-20 1997-01-08 Molins Plc Transferring rod like articles
US5830801A (en) * 1997-01-02 1998-11-03 Motorola, Inc. Resistless methods of gate formation in MOS devices
DE19710213A1 (en) 1997-03-12 1998-09-17 Basf Ag Process for the manufacture of solid combination dosage forms
US6210710B1 (en) * 1997-04-28 2001-04-03 Hercules Incorporated Sustained release polymer blend for pharmaceutical applications
US5837301A (en) 1997-04-28 1998-11-17 Husky Injection Molding Systems Ltd. Injection molding machine having a high speed turret
US6149939A (en) * 1997-05-09 2000-11-21 Strumor; Mathew A. Healthful dissolvable oral tablets, and mini-bars
KR20010012402A (en) * 1997-05-09 2001-02-15 세이지 파마슈티칼스, 인크. Stable oral pharmaceutical dosage forms
WO1999000122A1 (en) * 1997-06-25 1999-01-07 Ipr-Institute For Pharmaceutical Research Ag Method for reducing body weight
US6517866B1 (en) * 1997-07-01 2003-02-11 Pfizer Inc. Sertraline salts and sustained-release dosage forms of sertraline
DE59812488D1 (en) 1997-07-09 2005-02-17 Swiss Caps Rechte & Lizenzen METHOD AND DEVICE FOR PRODUCING A MULTILAYER, PHYSIOLOGICALLY COMPATIBLE PHARMACEUTICAL FORM
US6110499A (en) * 1997-07-24 2000-08-29 Alza Corporation Phenytoin therapy
US5942034A (en) * 1997-07-24 1999-08-24 Bayer Corporation Apparatus for the gelatin coating of medicaments
DE19733505A1 (en) * 1997-08-01 1999-02-04 Knoll Ag Fast acting analgesic
US6096340A (en) * 1997-11-14 2000-08-01 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6602522B1 (en) 1997-11-14 2003-08-05 Andrx Pharmaceuticals L.L.C. Pharmaceutical formulation for acid-labile compounds
US6174548B1 (en) * 1998-08-28 2001-01-16 Andrx Pharmaceuticals, Inc. Omeprazole formulation
WO1999029297A1 (en) * 1997-12-05 1999-06-17 Alza Corporation Osmotic dosage form comprising first and second coats
US6485748B1 (en) * 1997-12-12 2002-11-26 Andrx Pharmaceuticals, Inc. Once daily pharmaceutical tablet having a unitary core
US6022554A (en) * 1997-12-15 2000-02-08 American Home Products Corporation Polymeric microporous film coated subcutaneous implant
KR100775154B1 (en) 1997-12-19 2007-11-12 스미스클라인 비참 코포레이션 Process for Manufacturing Bite-Dispersion Tablets
US6432442B1 (en) 1998-02-23 2002-08-13 Mcneil-Ppc, Inc. Chewable product
US6110500A (en) 1998-03-25 2000-08-29 Temple University Coated tablet with long term parabolic and zero-order release kinetics
US6365185B1 (en) * 1998-03-26 2002-04-02 University Of Cincinnati Self-destructing, controlled release peroral drug delivery system
US6372254B1 (en) * 1998-04-02 2002-04-16 Impax Pharmaceuticals Inc. Press coated, pulsatile drug delivery system suitable for oral administration
US6394094B1 (en) * 1998-05-01 2002-05-28 Enhance Pharmaceuticals, Inc. Method for injection molding manufacture of controlled release devices
US6365183B1 (en) 1998-05-07 2002-04-02 Alza Corporation Method of fabricating a banded prolonged release active agent dosage form
US6544554B1 (en) 1998-05-15 2003-04-08 Chugai Seiyaku Kabushiki Kaisha Regulated release preparations
UA69413C2 (en) * 1998-05-22 2004-09-15 Брістол-Майерс Сквібб Компані Enteric coated pharmaceutical composition, pharmaceutical composition in form of spheroid beads, method for manufacturing pharmaceutical composition
JP2002516848A (en) 1998-06-03 2002-06-11 アルザ・コーポレーション Method and apparatus for providing long-term medication
US6106267A (en) * 1998-06-05 2000-08-22 Aylward; John T. Apparatus for forming a compression-molded product
US6099865A (en) * 1998-07-08 2000-08-08 Fmc Corporation Croscarmellose taste masking
US6103257A (en) * 1998-07-17 2000-08-15 Num-Pop, Inc. System for delivering pharmaceuticals to the buccal mucosa
UA73092C2 (en) * 1998-07-17 2005-06-15 Брістол-Майерс Сквібб Компані Tablets with enteric coating and method for their manufacture
FR2781152B1 (en) * 1998-07-20 2001-07-06 Permatec Tech Ag USE OF ACRYLIC-TYPE POLYMER AS A DISAGGREGING AGENT
DE19834180A1 (en) * 1998-07-29 2000-02-03 Benckiser Nv Composition for use in a dishwasher
US6200590B1 (en) 1998-08-10 2001-03-13 Naphcare, Inc. Controlled, phased-release suppository and its method of production
DE19840256A1 (en) * 1998-09-03 2000-03-09 Basf Ag Widely applicable, continuous method for preparing coated solid dosage forms, comprises extruding mixture of drug and thermoplastic binder then applying coating composition in liquid or vapor form
US5997905A (en) * 1998-09-04 1999-12-07 Mcneil-Ppc Preparation of pharmaceutically active particles
US6174547B1 (en) * 1999-07-14 2001-01-16 Alza Corporation Dosage form comprising liquid formulation
US6602521B1 (en) 1998-09-29 2003-08-05 Impax Pharmaceuticals, Inc. Multiplex drug delivery system suitable for oral administration
JP3449253B2 (en) * 1998-10-29 2003-09-22 シオノギクオリカプス株式会社 Manufacturing method of hard capsule
US6165512A (en) 1998-10-30 2000-12-26 Fuisz Technologies Ltd. Dosage forms containing taste masked active agents
SE9803772D0 (en) 1998-11-05 1998-11-05 Astra Ab Pharmaceutical formulation
US6183681B1 (en) * 1998-12-07 2001-02-06 Centurion International, Inc. Multi-stage insert molding method
EP1029892B1 (en) 1999-02-10 2002-06-05 Dr. Suwelack Skin & Health Care AG Freeze-dried product containing beta-1,3-glucan from Euglena, its preparation and use
US6274162B1 (en) 2000-01-14 2001-08-14 Bpsi Holdings, Inc. Elegant film coating system
US6248361B1 (en) * 1999-02-26 2001-06-19 Integ, Ltd. Water-soluble folic acid compositions
DE19913692A1 (en) * 1999-03-25 2000-09-28 Basf Ag Mechanically stable pharmaceutical dosage forms containing liquid or semi-solid surface-active substances
US6090401A (en) * 1999-03-31 2000-07-18 Mcneil-Ppc, Inc. Stable foam composition
US6248760B1 (en) * 1999-04-14 2001-06-19 Paul C Wilhelmsen Tablet giving rapid release of nicotine for transmucosal administration
JP3716901B2 (en) * 1999-04-14 2005-11-16 シオノギクオリカプス株式会社 Cellulose ether film
DE19925710C2 (en) 1999-06-07 2002-10-10 Byk Gulden Lomberg Chem Fab New preparation and dosage form containing an acid labile proton pump inhibitor
US6375963B1 (en) 1999-06-16 2002-04-23 Michael A. Repka Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof
US6555139B2 (en) * 1999-06-28 2003-04-29 Wockhardt Europe Limited Preparation of micron-size pharmaceutical particles by microfluidization
DE19954420A1 (en) 1999-11-12 2001-05-31 Lohmann Therapie Syst Lts Preparation consisting of a film, foil or wafer-like dosage form with a two-layer structure and integrated labeling
DE19960494A1 (en) * 1999-12-15 2001-06-21 Knoll Ag Device and method for producing solid active substance-containing forms
CA2395231C (en) * 1999-12-23 2006-08-15 Pfizer Products Inc. Hydrogel-driven layered drug dosage form
DE19963569B4 (en) * 1999-12-29 2006-11-16 Reckitt Benckiser N.V. Composition for use in a dishwasher
US6599532B2 (en) * 2000-01-13 2003-07-29 Osmotica Corp. Osmotic device containing alprazolam and an antipsychotic agent
US6627223B2 (en) 2000-02-11 2003-09-30 Eurand Pharmaceuticals Ltd. Timed pulsatile drug delivery systems
FR2807034B1 (en) 2000-03-29 2002-06-14 Roquette Freres MANNITOL POWDER AND PROCESS FOR PRODUCING THE SAME
US6372252B1 (en) * 2000-04-28 2002-04-16 Adams Laboratories, Inc. Guaifenesin sustained release formulation and tablets
GB2362350A (en) 2000-05-11 2001-11-21 Reckitt Benekiser N V Process and press for the production of tablets
US20030086972A1 (en) 2000-08-09 2003-05-08 Appel Leah E. Hydrogel-driven drug dosage form
US6727200B2 (en) * 2000-08-31 2004-04-27 Mra Laboratories, Inc. High dielectric constant very low fired X7R ceramic capacitor, and powder for making
US20020064550A1 (en) 2000-09-07 2002-05-30 Akpharma, Inc. Edible candy compositions and methods of using same
GB0027471D0 (en) * 2000-11-08 2000-12-27 Smithkline Beecham Plc Processes
WO2002066015A1 (en) 2001-02-16 2002-08-29 Bristol-Myers Squibb Pharma Company Use of polyalkylamine polymers in controlled release devices
US20030070584A1 (en) * 2001-05-15 2003-04-17 Cynthia Gulian Dip coating compositions containing cellulose ethers
HUP0401941A3 (en) 2001-07-16 2008-04-28 Astrazeneca Ab Pharmaceutical formulation comprising a proton pomp inhibitor and antacids and process for its preparation
US6558722B2 (en) * 2001-07-18 2003-05-06 Wm. Wrigley Jr. Company Use of powdered gum in making a coating for a confection
GB0120835D0 (en) 2001-08-28 2001-10-17 Smithkline Beecham Plc Process
US20030059466A1 (en) * 2001-09-14 2003-03-27 Pawan Seth Delayed release tablet of venlafaxin
US6767200B2 (en) * 2001-09-28 2004-07-27 Mcneil-Ppc, Inc. Systems, methods and apparatuses for manufacturing dosage forms
EP1438028A1 (en) 2001-09-28 2004-07-21 McNEIL-PPC, INC. Modified release dosage forms
US7323192B2 (en) * 2001-09-28 2008-01-29 Mcneil-Ppc, Inc. Immediate release tablet
US20030066068A1 (en) * 2001-09-28 2003-04-03 Koninklijke Philips Electronics N.V. Individual recommender database using profiles of others
US20040006111A1 (en) 2002-01-25 2004-01-08 Kenneth Widder Transmucosal delivery of proton pump inhibitors
DK1578350T3 (en) 2002-03-26 2009-08-10 Euro Celtique Sa Composition with gel coating with depot effect
EP1764655A3 (en) 2002-06-11 2007-09-19 ASML Netherlands B.V. Lithographic apparatus and device manufacturing method
TW578439B (en) * 2002-10-25 2004-03-01 Ritdisplay Corp Organic light emitting diode and material applied in the organic light emitting diode
US20050008695A1 (en) * 2003-05-21 2005-01-13 Control Delivery Systems, Inc. Compositions and methods for delivering a biologically active agent
US20050074514A1 (en) * 2003-10-02 2005-04-07 Anderson Oliver B. Zero cycle molding systems, methods and apparatuses for manufacturing dosage forms
ES2409347T3 (en) 2004-10-21 2013-06-26 Aptalis Pharmatech, Inc. Pharmaceutical compositions of masked flavor with gastro-soluble porogenic agents

Patent Citations (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4173626A (en) * 1978-12-11 1979-11-06 Merck & Co., Inc. Sustained release indomethacin
US4286497A (en) * 1979-06-18 1981-09-01 Shamah Alfred A Ratchet-securable toggle retainer
US4523021A (en) * 1981-05-12 1985-06-11 Imperial Chemical Industries Plc 1'-Substituted-spiro[pyrrolidine-3,3'-indoline]-2,2',5-triones
US4572833A (en) * 1982-08-13 1986-02-25 A/S Alfred Benzon Method for preparing a pharmaceutical controlled release composition
US4874614A (en) * 1985-03-25 1989-10-17 Abbott Laboratories Pharmaceutical tableting method
US4863742A (en) * 1986-06-20 1989-09-05 Elan Corporation Plc Controlled absorption pharmaceutical composition
US4980170A (en) * 1988-06-30 1990-12-25 Klinge Pharma Gmbh Pharmaceutical formulation as well as a process for its preparation
US4906478A (en) * 1988-12-12 1990-03-06 Valentine Enterprises, Inc. Simethicone/calcium silicate composition
US4984240A (en) * 1988-12-22 1991-01-08 Codex Corporation Distributed switching architecture for communication module redundancy
US5032406A (en) * 1989-02-21 1991-07-16 Norwich Eaton Pharmaceuticals, Inc. Dual-action tablet
US5100675A (en) * 1989-05-03 1992-03-31 Schering Corporation Sustained release tablet comprising loratadine, ibuprofen and pseudoephedrine
US5275822A (en) * 1989-10-19 1994-01-04 Valentine Enterprises, Inc. Defoaming composition
US5229134A (en) * 1989-12-05 1993-07-20 Laboratories Smith Kline & French Pharmaceutical compositions
US5158777A (en) * 1990-02-16 1992-10-27 E. R. Squibb & Sons, Inc. Captopril formulation providing increased duration of activity
US5912013A (en) * 1991-07-23 1999-06-15 Shire Laboratories, Inc. Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine
US5738874A (en) * 1992-09-24 1998-04-14 Jagotec Ag Pharmaceutical tablet capable of liberating one or more drugs at different release rates
US5415868A (en) * 1993-06-09 1995-05-16 L. Perrigo Company Caplets with gelatin cover and process for making same
US5397574A (en) * 1993-10-04 1995-03-14 Andrx Pharmaceuticals, Inc. Controlled release potassium dosage form
US5558879A (en) * 1995-04-28 1996-09-24 Andrx Pharmaceuticals, Inc. Controlled release formulation for water soluble drugs in which a passageway is formed in situ
US5807579A (en) * 1995-11-16 1998-09-15 F.H. Faulding & Co. Limited Pseudoephedrine combination pharmaceutical compositions
US6294200B1 (en) * 1996-02-06 2001-09-25 Jagotec Ag Pharmaceutical tablet suitable to deliver the active substance in subsequent and predeterminable times
US5824338A (en) * 1996-08-19 1998-10-20 L. Perrigo Company Caplet and gelatin covering therefor
US6103260A (en) * 1997-07-17 2000-08-15 Mcneil-Ppc, Inc. Simethicone/anhydrous calcium phosphate compositions
US6322819B1 (en) * 1998-10-21 2001-11-27 Shire Laboratories, Inc. Oral pulsed dose drug delivery system
US6270805B1 (en) * 1998-11-06 2001-08-07 Andrx Pharmaceuticals, Inc. Two pellet controlled release formulation for water soluble drugs which contains an alkaline metal stearate
US20020102309A1 (en) * 1999-09-14 2002-08-01 Jane C. I. Hirsh Controlled release formulation for administration of an anti-inflammatory naphthalene derivative
US20020028240A1 (en) * 2000-04-17 2002-03-07 Toyohiro Sawada Timed-release compression-coated solid composition for oral administration
US20030068367A1 (en) * 2001-09-28 2003-04-10 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US20030070903A1 (en) * 2001-09-28 2003-04-17 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms
US20030086973A1 (en) * 2001-09-28 2003-05-08 Sowden Harry S Systems, methods and apparatuses for manufacturing dosage forms
US20030124183A1 (en) * 2001-09-28 2003-07-03 Sowden Harry S. Systems, methods and apparatuses for manufacturing dosage forms

Cited By (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090149479A1 (en) * 1998-11-02 2009-06-11 Elan Pharma International Limited Dosing regimen
US10369109B2 (en) 2002-06-17 2019-08-06 Grünenthal GmbH Abuse-proofed dosage form
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US8420056B2 (en) 2003-08-06 2013-04-16 Grunenthal Gmbh Abuse-proofed dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
US8192722B2 (en) 2003-08-06 2012-06-05 Grunenthal Gmbh Abuse-proof dosage form
US8309060B2 (en) 2003-08-06 2012-11-13 Grunenthal Gmbh Abuse-proofed dosage form
US8114383B2 (en) 2003-08-06 2012-02-14 Gruenenthal Gmbh Abuse-proofed dosage form
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US8469036B2 (en) 2003-11-07 2013-06-25 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US8627828B2 (en) 2003-11-07 2014-01-14 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US8636011B2 (en) 2003-11-07 2014-01-28 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US10945454B2 (en) 2003-11-07 2021-03-16 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US10098376B2 (en) 2003-11-07 2018-10-16 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US10765140B2 (en) 2003-11-07 2020-09-08 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US8323889B2 (en) 2004-07-01 2012-12-04 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form
US8114384B2 (en) 2004-07-01 2012-02-14 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US10675278B2 (en) 2005-02-04 2020-06-09 Grünenthal GmbH Crush resistant delayed-release dosage forms
US9492391B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9775811B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US9095614B2 (en) 2006-08-25 2015-08-04 Purdue Pharma L.P. Tamper resistant dosage forms
US9101661B2 (en) 2006-08-25 2015-08-11 Purdue Pharma L.P. Tamper resistant dosage forms
US9084816B2 (en) 2006-08-25 2015-07-21 Purdue Pharma L.P. Tamper resistant dosage forms
US9486412B2 (en) 2006-08-25 2016-11-08 Purdue Pharma L.P. Tamper resistant dosage forms
US9486413B2 (en) 2006-08-25 2016-11-08 Purdue Pharma L.P. Tamper resistant dosage forms
US8911719B2 (en) 2006-08-25 2014-12-16 Purdue Pharma Lp Tamper resistant dosage forms
US9492392B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9492390B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9492393B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9492389B2 (en) 2006-08-25 2016-11-15 Purdue Pharma L.P. Tamper resistant dosage forms
US9545380B2 (en) 2006-08-25 2017-01-17 Purdue Pharma L.P. Tamper resistant dosage forms
US11826472B2 (en) 2006-08-25 2023-11-28 Purdue Pharma L.P. Tamper resistant dosage forms
US8894988B2 (en) 2006-08-25 2014-11-25 Purdue Pharma L.P. Tamper resistant dosage forms
US11304909B2 (en) 2006-08-25 2022-04-19 Purdue Pharma L.P. Tamper resistant dosage forms
US11304908B2 (en) 2006-08-25 2022-04-19 Purdue Pharma L.P. Tamper resistant dosage forms
US11904055B2 (en) 2006-08-25 2024-02-20 Purdue Pharma L.P. Tamper resistant dosage forms
US11298322B2 (en) 2006-08-25 2022-04-12 Purdue Pharma L.P. Tamper resistant dosage forms
US10076499B2 (en) 2006-08-25 2018-09-18 Purdue Pharma L.P. Tamper resistant dosage forms
US9763933B2 (en) 2006-08-25 2017-09-19 Purdue Pharma L.P. Tamper resistant dosage forms
US9763886B2 (en) 2006-08-25 2017-09-19 Purdue Pharma L.P. Tamper resistant dosage forms
US9770417B2 (en) 2006-08-25 2017-09-26 Purdue Pharma L.P. Tamper resistant dosage forms
US9770416B2 (en) 2006-08-25 2017-09-26 Purdue Pharma L.P. Tamper resistant dosage forms
US9775810B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US9775812B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US9775808B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US9775809B2 (en) 2006-08-25 2017-10-03 Purdue Pharma L.P. Tamper resistant dosage forms
US9095615B2 (en) 2006-08-25 2015-08-04 Purdue Pharma L.P. Tamper resistant dosage forms
US8894987B2 (en) 2006-08-25 2014-11-25 William H. McKenna Tamper resistant dosage forms
US8846086B2 (en) 2006-08-25 2014-09-30 Purdue Pharma L.P. Tamper resistant dosage forms
US8834925B2 (en) 2006-08-25 2014-09-16 Purdue Pharma L.P. Tamper resistant dosage forms
US8821929B2 (en) 2006-08-25 2014-09-02 Purdue Pharma L.P. Tamper resistant dosage forms
US8815289B2 (en) 2006-08-25 2014-08-26 Purdue Pharma L.P. Tamper resistant dosage forms
US10076498B2 (en) 2006-08-25 2018-09-18 Purdue Pharma L.P. Tamper resistant dosage forms
US8895061B2 (en) 2007-03-02 2014-11-25 Meda Pharmaceuticals Inc. Compositions comprising carisoprodol and methods of use thereof
US20100189782A1 (en) * 2007-03-02 2010-07-29 Gul Balwani Compositions Comprising Carisoprodol and Methods of Use Thereof
US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
WO2009036287A1 (en) * 2007-09-12 2009-03-19 Elan Pharma International Limited Dosing regimen
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
US8383152B2 (en) 2008-01-25 2013-02-26 Gruenenthal Gmbh Pharmaceutical dosage form
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10493033B2 (en) 2009-07-22 2019-12-03 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US9579285B2 (en) 2010-02-03 2017-02-28 Gruenenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10864164B2 (en) 2011-07-29 2020-12-15 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations

Also Published As

Publication number Publication date
EP1429724B1 (en) 2013-11-06
CN1596102A (en) 2005-03-16
CA2446760A1 (en) 2003-04-03
US20040241236A1 (en) 2004-12-02
US7968120B2 (en) 2011-06-28
NO20032362D0 (en) 2003-05-26
BR0206062A (en) 2004-01-13
HUP0401686A2 (en) 2004-11-29
BR0213593A (en) 2004-08-31
PL369134A1 (en) 2005-04-18
US20030232083A1 (en) 2003-12-18
KR20040045026A (en) 2004-05-31
WO2003026630A1 (en) 2003-04-03
NO20032363D0 (en) 2003-05-26
JP2005529059A (en) 2005-09-29
NO20041613L (en) 2004-04-20
KR20040037206A (en) 2004-05-04
KR20040045031A (en) 2004-05-31
DE60239945D1 (en) 2011-06-16
MXPA04002973A (en) 2005-06-20
JP2005509604A (en) 2005-04-14
US20090155372A1 (en) 2009-06-18
CN1607945A (en) 2005-04-20
EP1438028A1 (en) 2004-07-21
WO2003026612A2 (en) 2003-04-03
WO2003026626A2 (en) 2003-04-03
CA2461684A1 (en) 2003-04-03
DE60228281D1 (en) 2008-09-25
CA2461870A1 (en) 2003-04-03
CA2461659C (en) 2010-12-07
CA2461865A1 (en) 2003-04-03
JP2005509605A (en) 2005-04-14
EP1438030A2 (en) 2004-07-21
CA2461354C (en) 2010-04-27
WO2003026625A1 (en) 2003-04-03
JP2005511515A (en) 2005-04-28
CN100408029C (en) 2008-08-06
CA2461354A1 (en) 2003-04-03
CN1638740A (en) 2005-07-13
WO2003026612A3 (en) 2003-06-26
JP2005508326A (en) 2005-03-31
EP1438018B1 (en) 2010-08-11
KR20040045032A (en) 2004-05-31
US20030235616A1 (en) 2003-12-25
KR20040037208A (en) 2004-05-04
US20040241208A1 (en) 2004-12-02
CN1592610A (en) 2005-03-09
BR0213591A (en) 2004-08-31
JP2005508327A (en) 2005-03-31
DE60237294D1 (en) 2010-09-23
MXPA04002884A (en) 2005-06-20
US20030232082A1 (en) 2003-12-18
JP2005535558A (en) 2005-11-24
MXPA04002974A (en) 2005-06-20
WO2003026615A3 (en) 2003-07-31
KR20040066094A (en) 2004-07-23
KR20040045034A (en) 2004-05-31
US20080305150A1 (en) 2008-12-11
ES2295427T3 (en) 2008-04-16
MXPA04002981A (en) 2005-06-20
US20030219484A1 (en) 2003-11-27
DE60223269D1 (en) 2007-12-13
EP1429746B1 (en) 2008-08-13
JP2005508329A (en) 2005-03-31
EP1429738B1 (en) 2007-10-31
MXPA04002891A (en) 2005-06-20
NO20032364L (en) 2003-07-25
EP1429724A1 (en) 2004-06-23
CA2461616A1 (en) 2003-04-03
NO20032364D0 (en) 2003-05-26
US20040170750A1 (en) 2004-09-02
CA2461653A1 (en) 2003-04-03
MXPA04002976A (en) 2005-06-20
WO2003026613A1 (en) 2003-04-03
NZ532096A (en) 2006-10-27
MXPA04002978A (en) 2005-06-20
CA2446759A1 (en) 2003-04-03
WO2003026625A9 (en) 2004-05-06
US20050266084A1 (en) 2005-12-01
ATE507823T1 (en) 2011-05-15
CN1596104A (en) 2005-03-16
BR0212950A (en) 2004-10-26
US20040062804A1 (en) 2004-04-01
PT1429738E (en) 2007-12-14
MXPA04002975A (en) 2005-06-20
US8545887B2 (en) 2013-10-01
MXPA04002980A (en) 2005-06-20
MXPA04002977A (en) 2005-06-20
EP1438018A1 (en) 2004-07-21
WO2003026624A9 (en) 2004-05-06
EP1432404A1 (en) 2004-06-30
CN1596101A (en) 2005-03-16
US7416738B2 (en) 2008-08-26
KR20040037203A (en) 2004-05-04
BR0213588A (en) 2004-08-31
EP1429738A2 (en) 2004-06-23
NO20032362L (en) 2003-07-14
ES2311073T3 (en) 2009-02-01
ATE476957T1 (en) 2010-08-15
BR0212951A (en) 2004-10-26
KR20040045030A (en) 2004-05-31
KR20040037207A (en) 2004-05-04
EP1429737A1 (en) 2004-06-23
KR20040045033A (en) 2004-05-31
WO2003026627A1 (en) 2003-04-03
WO2003026628A2 (en) 2003-04-03
JP2005508328A (en) 2005-03-31
US20040018327A1 (en) 2004-01-29
WO2003026614A9 (en) 2004-02-26
EP1429745A2 (en) 2004-06-23
NZ532097A (en) 2006-02-24
AU2002330164A1 (en) 2003-04-07
US20050019407A1 (en) 2005-01-27
MXPA04002979A (en) 2005-06-20
WO2003026624A1 (en) 2003-04-03
WO2003026628A3 (en) 2003-05-01
CA2447984A1 (en) 2003-04-03
CO5570655A2 (en) 2005-10-31
WO2003026614A1 (en) 2003-04-03
NZ532568A (en) 2005-07-29
CA2461659A1 (en) 2003-04-03
BR0212921A (en) 2004-10-13
BR0212946A (en) 2004-10-26
EP1429746A2 (en) 2004-06-23
CN1592611A (en) 2005-03-09
CN1592612A (en) 2005-03-09
CN100364515C (en) 2008-01-30
US7972624B2 (en) 2011-07-05
CA2461656A1 (en) 2003-04-03
BR0213589A (en) 2004-08-31
JP2005508330A (en) 2005-03-31
NO20032363L (en) 2003-07-23
US20040213849A1 (en) 2004-10-28
ATE376826T1 (en) 2007-11-15
EP1429743A1 (en) 2004-06-23
EP1463489A1 (en) 2004-10-06
ATE404179T1 (en) 2008-08-15
CN1596100A (en) 2005-03-16
EP1429742B1 (en) 2011-05-04
WO2003026615A2 (en) 2003-04-03
WO2003026616A1 (en) 2003-04-03
WO2003026629A2 (en) 2003-04-03
HUP0401686A3 (en) 2008-04-28
WO2003026626A3 (en) 2003-10-16
CA2461682A1 (en) 2003-04-03
MXPA04002992A (en) 2005-06-20
DE60223269T2 (en) 2008-08-21
BR0206061A (en) 2004-01-13
US7635490B2 (en) 2009-12-22
CN1592613A (en) 2005-03-09
BR0206086A (en) 2003-12-23
WO2003026629A3 (en) 2004-03-04
HK1072902A1 (en) 2005-09-16
EP1429742A2 (en) 2004-06-23
ES2444549T3 (en) 2014-02-25
JP2005508325A (en) 2005-03-31

Similar Documents

Publication Publication Date Title
EP1429742B1 (en) Modified release dosage forms
US20090186082A1 (en) Method of manufacturing modified release dosage forms
CA2499882C (en) Modified release dosage form with two cores
US20030228368A1 (en) Edible solid composition and dosage form
CA2500312A1 (en) Modified release dosage form
AU2002337772A1 (en) Modified release dosage forms

Legal Events

Date Code Title Description
AS Assignment

Owner name: MCNEIL-PPC, INC., NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LEE, DER-YANG;LE, SHUN-POR;PARIKH, NARENDRA;AND OTHERS;REEL/FRAME:015299/0975;SIGNING DATES FROM 20040331 TO 20040426

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION