US20050089568A1 - Melt-extruded orally administrable opioid formulations - Google Patents

Melt-extruded orally administrable opioid formulations Download PDF

Info

Publication number
US20050089568A1
US20050089568A1 US10/664,602 US66460203A US2005089568A1 US 20050089568 A1 US20050089568 A1 US 20050089568A1 US 66460203 A US66460203 A US 66460203A US 2005089568 A1 US2005089568 A1 US 2005089568A1
Authority
US
United States
Prior art keywords
hours
formulation
opioid
release
active agent
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
US10/664,602
Inventor
Benjamin Oshlack
Mark Chasin
Hua-pin Huang
David Sackler
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.)
Purdue Pharma LP
Original Assignee
Euro Celtique SA
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23306123&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20050089568(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Euro Celtique SA filed Critical Euro Celtique SA
Priority to US10/664,602 priority Critical patent/US20050089568A1/en
Assigned to EURO-CELTIQUE, S.A. reassignment EURO-CELTIQUE, S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SACKLER, DAVID, CHASIN, MARK, HUANG, HUA-PIN, OSHLACK, BENJAMIN
Publication of US20050089568A1 publication Critical patent/US20050089568A1/en
Assigned to PURDUE PHARMA L.P. reassignment PURDUE PHARMA L.P. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: EURO-CELTIQUE S.A.
Priority to US12/722,974 priority patent/US20100172974A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic 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
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic 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
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/2072Pills, 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
    • 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
    • A61K9/2095Tabletting 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
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29BPREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
    • B29B9/00Making granules
    • B29B9/02Making granules by dividing preformed material
    • B29B9/06Making granules by dividing preformed material in the form of filamentary material, e.g. combined with extrusion
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present invention relates to the use of melt extrusion technology in the production of bioavailable sustained-release matrix pharmaceutical formulations.
  • melt extrusion has been used in the production of immediate release formulations.
  • compositions which provide for controlled release of pharmacologically active substances contained in the compositions after oral administration to humans and animals.
  • Such slow release compositions are used to delay absorption of a medicament until it has reached certain portions of the alimentary tract.
  • sustained-release of a medicament in the alimentary tract further maintains a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered.
  • sustained release formulations including specially coated tablets, coated tablets and capsules wherein the slow release of the active medicament is brought about through selective breakdown of the coating of the preparation or through compounding with a special matrix to affect the release of a drug.
  • Some sustained release formulations provide for related sequential release of a single dose of an active compound at predetermined periods after administration.
  • sustained-release preparations It is the intent of all sustained-release preparations to provide a longer period of pharmacologic response after the administration of the drug and is ordinarily experienced after the administration of the rapid release dosage forms. Such longer periods of response provide for many inherent therapeutic benefits that are not achieved with corresponding short acting, immediate release preparations. This is especially true in the treatment of cancer patients or other patients in need of treatment for the alleviation of moderate to severe pain, where blood levels of an opioid analgesic medicament must be maintained at a therapeutically effective level to provide pain relief.
  • compositions providing the sustained-release of an active compound from a carrier is basically concerned with the release of the active substance into the physiologic fluid of the alimentary tract.
  • the mere presence of an active substance in the gastrointestinal fluids does not, by itself, insure bioavailability.
  • the active drug substance In order to be absorbed, the active drug substance must be in solution.
  • the time required for a given proportion of an active substance from a unit dosage form is determined as the proportion of the amount of active drug substance released from a unit dosage form over a specified time base by a test method conducted under standardized conditions.
  • the physiologic fluids of the gastrointestinal tract are the media for determining dissolution time.
  • the present state of the art recognizes many satisfactory test procedures to measure dissolution time for pharmaceutical compositions, and these test procedures are described in official compendia world wide.
  • the dissolution time determined for a pharmacologically active substance from the specific composition is relatively constant and reproducible.
  • factors affecting the dissolution time are the surface area of the drug substance presented to the dissolution solvent medium, the pH of the solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium.
  • the dissolution concentration of an active drug substance is dynamically modified in its steady state as components are removed from the dissolution medium through absorption across the tissue site. Under physiologic conditions, the saturation level of the dissolved materials is replenished from the dosage form reserve to maintain a relatively uniform and constant dissolution concentration in the solvent medium providing for a steady state absorption.
  • the transport across a tissue absorption site of the gastrointestinal tract is influenced by the Donnan osmotic equilibrium forces on both sides of the membrane since the direction of the driving force is the difference between the concentrations of active substance on either side of the membrane, i.e., the amount dissolved in the gastrointestinal fluids and the amount present in the blood. Since the blood levels are constantly being modified by dilution, circulatory changes, tissue storage, metabolic conversion and systemic excretion, the flow of active materials is directed from the gastrointestinal tract into the blood stream.
  • melt granulation techniques have also been suggested to provide controlled release formulations.
  • melt granulation involves mechanically working an active ingredient in particulate form with one or more suitable binders and/or pharmaceutically acceptable excipients in a mixer until one or more of the binders melts and adheres to the surface of the particulate, eventually building up granules.
  • U.S. Pat. No. 4,957,681 discloses a continuous process for preparing pharmaceutical mixtures having at least two components which are continuously metered.
  • the process includes continuously metering the individual components of the pharmaceutical mixture at a rate of at least 50 g/h on electronic differential metering balances having a metering accuracy of at least ⁇ 5% within time intervals of less than one minute and, additionally, having screw conveyors, thereby obtaining a substantially uniformly metered mixture; and shaping the mixture.
  • Example 1 of the '681 patent is representative of the process.
  • the requisite amounts of a copolymer having a K value of 30 and obtained from 60% of N-vinylpyrrolid-2-one (NVP), stearyl alcohol and theophylline are metered via three metering balances into the hopper of an extruder and extruded.
  • the temperatures of the extruder cylinder consisting of six shots ranged from 30-60° C. and the die is heated to 100° C.
  • the resultant extrudate is then pressed into tablets of the required shape.
  • the '681 patent does not disclose preparation of sustained release opioid pharmaceutical formulations.
  • the polymers used were ethylcellulose, a copolymer of ethyl acrylate and methyl methacrylate containing quaternary ammonium groups, cellulose acetate butyrate, poly(vinyl chloride-co-vinyl acetate) and a copolymer of ethylene and vinyl acetate. In order to lower the extrusion temperature, some plasticizers were used.
  • WO 93/07859 describes drug loaded pellets produced through melt spheronization wherein the therapeutically active agent is blended with various excipoients and binders; the formulation is fed to an extruder where it is heated and extruded at a speed of about 0.05 to 10 mm/sec. at approximately 60-180° C. The extrudate is then cut into pieces in a pelletizer and subsequently fed to a spheronizer for uniform pellet formation.
  • sustained-release oral opioid analgesic formulations may be prepared utilizing melt extrusion techniques to provide bioavailable unit dose products which provide analgesia in a patient for, e.g., 8-24 hours.
  • the invention is also related in part to a new melt-extruded oral sustained-release dosage forms which comprise a pharmaceutically acceptable hydrophobic material, a retardant selected from waxes, fatty alcohols, and fatty acids, and a drug.
  • one aspect of the present invention is related to a pharmaceutical extrudate including an opioid analgesic dispersed in a matrix.
  • the extrudate is strand or spaghetti-shaped and has a diameter from about 0.1 to about 5 mm.
  • the extrudate is divided into unit doses of the opioid analgesic for oral administration to a patient, and provides a sustained analgetic effect for 8-24 hours or more.
  • the matrices preferably include a hydrophobic material and a second retardant material (preferably a hydrophobic fusible carrier) which acts to further slow or control the release of the therapeutically active agent when the formulation is exposed to aqueous solutions in-vitro, or exposed to gastic and/or intestinal fluids.
  • a hydrophobic material preferably a hydrophobic fusible carrier
  • the hydrophobic material is selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.
  • the retardant material is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols and mixtures of the same. Examples include beeswax and carnauba wax, stearic acid, and stearyl alcohol). This list is of course not meant to be exclusive.
  • the extrudate may be cut into multiparticulates by any cutting means known in the art.
  • the multiparticulates have a length of from about 0.1 to 5 mm in length.
  • the multiparticulates may then be divided into unit doses such that each individual unit dose includes a dose of opioid analgesic sufficient to provide analgesia to a mammal, preferably a human patient.
  • the unit doses of multiparticulates may then be incorporated into a solid pharmaceutical dosage formulation, e.g. via compression or shaping into tablets, by placing a requisite amount inside a gelatin capsule, or by forming the extruded product into the form of a suppository.
  • the pharmaceutical extrudates of the present invention may be prepared by blending the drug together with all matrix ingredients (hydrophobic material, binder and any additional (optional) excipients), feeding the resultant mixture into an extruder heated to the requisite temperature necessary to soften the mixture sufficiently to render the mixture extrudable; extruding the viscous, heated mass as a spaghetti-like strand; allowing the extrudate to congeal and harden, and then dividing the strand into desired pieces.
  • This may be accomplished, e.g., by cutting the strands into pellets of 1.5 mm diameter and 1.5 mm in length.
  • the extrudate has a diameter of from about 0.1 to about 5 mm and provides sustained release of said opioid analgesic for a time period of from about 8 to about 24 hours.
  • Another aspect of the invention is directed to pharmaceutical dosage forms including the extrudate prepared as outlined above.
  • the extrudate is cut into multiparticulates using any cutting means known in the art, e.g a blade.
  • the multiparticulates are then divided into unit doses containing an effective amount of opioid analgesic to provide analgesia or pain relief in a human patient over the desired dosing interval.
  • the unit dose of multiparticulates may then be incorporated into tablets, e.g. via direct compression, formed into suppositories, or encapsulated by any means known in the art.
  • a method of treating a patient with sustained-release formulations prepared as described above includes administering a dosage form containing the novel extrudate to a patient in need of opioid analgesic therapy.
  • a unit dose is understood to contain an effective amount of the therapeutically active agent to produce pain relief and/or analgesia to the patient.
  • opioid analgesic administered to a patient will vary due to numerous factors; e.g. the specific opioid analgesic(s) being administered, the weight and tolerance of the patient, other therapeutic agents concomitantly being administered, etc.
  • the dosage form in order for a dosage form to be effective for its intended purpose, the dosage form must be bioavailable.
  • bioavailable is defined as the total amount of a drug substance that is absorbed and available to provide the desired therapeutic effect after administration of a unit dosage form.
  • bioavailability of a given dosage form is determined by comparison to a known reference drug product, as commonly determined and accepted by Governmental Regulatory Agencies, such as the United States FDA.
  • bioavailability is defined for purposes of the present invention as the extent to which the drug (e.g., opioid analgesic) is absorbed from the unit dosage form and is available at the site of drug action.
  • drug e.g., opioid analgesic
  • sustained release is defined for purposes of the present invention as the release of the drug (e.g., opioid analgesic) at such a rate that blood (e.g., plasma) levels are maintained within the therapeutic range but below toxic levels over a period of time greater than 8 hours, more preferably for about 12 to about 24 hours, or longer.
  • drug e.g., opioid analgesic
  • blood e.g., plasma
  • unit dose is defined for purposes of the present invention as the total amount of multiparticulates needed to administer a desired dose of therapeutically active agent (e.g., opioid analgesic) to a patient.
  • therapeutically active agent e.g., opioid analgesic
  • extrudates of the present invention preferably permit release of the opioid (or salts thereof) over a sustained period of time in an aqueous medium.
  • aqueous medium is defined for purposes of the present invention as any water-containing medium, e.g. water, pharmaceutically acceptable dissolution medium, gastric fluid and/or intestinal fluid and the like.
  • FIG. 1 is a graph displaying the dissolution results of Examples 1 and 2;
  • FIG. 2 is a graph displaying the dissolution rates of Examples 3-6;
  • FIGS. 3 and 4 are graphs displaying the pH dependency of the dissolution results of Examples 3 and 6 respectively;
  • FIG. 5 is a graph displaying the dissolution results of Examples 7 and 8 vs. Example 6;
  • FIG. 6 is a graph displaying the dissolution results of Examples 9 and 10;
  • FIG. 7 is a graph displaying the dissolution results of Examples 11 and 12;
  • FIG. 8 is a graph displaying the dissolution results of Examples 15 and 16;
  • FIG. 9 is a schematic representation of a system for carrying out the present invention.
  • FIG. 10 is a graph displaying the fed/fast bioavailability results for Example 20.
  • FIG. 11 is a graph displaying the plasma morphine concentrations of Example 21 obtained from administration of the capsules from Example 6 vs. MS Contin®;
  • FIG. 12 is a graph displaying the plasma oxycodone concentrations of Examples 22 obtained from administrating the capsules from Examples 11 and 13 vs. OxyContin®;
  • FIG. 13 is a graphical representation of the plasma oxycodone concentrations of Example 14.
  • FIG. 14 is a graphical representation of the hydromorphone concentrations of Example 24 using the capsules from Example 17 vs. Dilaudud®;
  • FIG. 15 is a graph displaying the plasma hydromorphone concentrations of Example 24 using capsules from Example 18 vs. Dilaudud®;
  • FIG. 16 is a graph of the steady-state plasma hydromorphone concentrations of Example 25 using the capsules of Example 17.
  • FIG. 17 is a graph of the plasma hydromorphone concentrations of Example 26 using the capsules of Example 19.
  • the sustained-release dosage forms comprise an opioid analgesic as the therapeutically active agent.
  • the drug is incorporated into a melt-extruded strand which includes a pharmaceutically acceptable hydrophobic material such as an alkylcellulose or an acrylic polymer or copolymer.
  • a plasticizer for the hydrophobic material in order to reduce the extrusion temperature.
  • the choice of the most suitable plasticizer is made based on its ability to lower the glass transition temperature (Tg) of the polymer.
  • Tg glass transition temperature
  • a hydrophobic fusible carrier (which may also act as a binder) is utilized instead of a plasticizer.
  • the hydrophobic fusible carrier preferably imparts a slower release of the therapeutically active agent from the melt extruded formulation. Any further pharmaceutical excipients known to those skilled in the art may be added as deemed necessary.
  • Another aspect of the invention is directed to improved melt extruded matrices which comprise a hydrophobic material and a fatty binder such as previously specified.
  • a therapeutically active agent is combined with one or more suitable hydrophobic materials and a hydrophobic fusible carrier is extruded to form an extrudate.
  • the extrudate may then be cut into multiparticulates which are subsequently incorporated into sustained release dosage forms.
  • Therapeutically active agents which may be used in accordance with the present invention include both water soluble and water insoluble drugs.
  • therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexachlorpheniramine maleate), analgesics (e.g., aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.), non-steroidal anti-inflammatory agents (e.g., naproxen, diclofenac, indomethacin, ibuprofen, sulindac), anti-emetics (e.g., metoclopramide, methylnaltrexone), anti-epileptics (e.g., phenytoin, meprobamate and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardipine), anti-tussive
  • antacids e.g. atropine, scopolamine
  • antidiabetics e.g., insulin
  • diuretics e.g., ethcrynic acid, bendrofluthiazide
  • anti-hypotensives e.g., propranolol, clonidine
  • antihypertensives e.g, clonidine, methyldopa
  • bronchodilators e.g., albuterol
  • steroids e.g., hydrocortisone, triamicinolone, prednisone
  • antibiotics e.g., tetracycline
  • antihemorrhoidals hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine), as well as salts, hydrates, and
  • the opioid analgesics used in accordance with the present invention include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan,
  • the opioid analgesic is selected from morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, tramadol or mixtures thereof.
  • the sustained-release opioid oral dosage form of the present invention includes hydromorphone as the therapeutically active ingredient in an amount from about 4 to about 64 mg hydromorphone hydrochloride.
  • the dosage form may contain molar equivalent amounts of other hydromorphone salts or of the hydromorphone base.
  • the opioid analgesic is other than hydromorphone, the dosage form contains an appropriate amount to provide a substantially equivalent therapeutic effect.
  • the opioid analgesic comprises morphine
  • the sustained-release oral dosage forms of the present invention include from about 5 mg to about 800 mg morphine, by weight (based on morphine sulfate).
  • the sustained-release oral dosage forms of the present invention include from about 5 mg to about 400 mg oxycodone.
  • the sustained-release oral dosage forms of the invention include from about 50 mg to about 800 mg tramadol by weight, based on the hydrochloride salt.
  • sustained-release dosage forms of the present invention generally achieve and maintain therapeutic levels substantially without significant increases in the intensity and/or degree of concurrent side effects, such as nausea, vomiting or drowsiness, which are often associated with high blood levels of opioid analgesics. There is also evidence to suggest that the use of the present dosage forms leads to a reduced risk of drug addiction.
  • the oral opioid analgesics have been formulated to provide for an increased duration of analgesic.
  • these formulations at comparable daily dosages of conventional immediate-release drug, are associated with a lower incidence in severity of adverse drug reactions and can also be administered at a lower daily dose than conventional oral medication while maintaining pain control.
  • the dosage form may further include one or more additional which may or may not act synergistically with the opioid analgesics of the present invention.
  • additional therapeutically active agents include non-steroidal anti-inflammatory agents, including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clid
  • the additional (non-opioid) therapeutically active agent may be included in controlled release form or in immediate release form.
  • the additional drug may be incorporated into the controlled release matrix along with the opioid; incorporated as a separated controlled release layer or immediate release layer; or may be incorporated as a powder, granulation, etc., in a gelatin capsule with the extrudates of the present invention.
  • the extrudates of the present invention include at least one hydrophobic material.
  • the hydrophobic material will preferably impart sustained release of the opioid analgesic to the final formulation.
  • Preferred hydrophobic materials which may be used in accordance with the present invention include alkylcelluloses such as natural or synthetic celluloses derivatives (e.g. ethylcellulose), acrylic and methacrylic acid polymers and copolymers, shellac, zein, wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof. This list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material which is capable of imparting sustained release of the active agent and which melts (or softens to the extent necessary to be extruded) may be used in accordance with the present invention.
  • the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • the hydrophobic material is selected from materils such as hydroxyalkylcelluoses such as hydroxypropylmethylcellulose and mixtures of the foregoing.
  • the retardant material is preferably a hydrophobic fusible carrier which may comprise one or more water-insoluble wax-like thermoplastic substances possibly mixed with one or more wax-like thermoplastic substances being less hydrophobic than said one or more water-insoluble wax-like substances.
  • the individual wax-like substances in the binder material should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases.
  • Useful water-insoluble wax-like substances may be those with a water-solubility that is lower than about 1:5,000 (w/w).
  • Such hydrophobic fusible carrier materials are preferably water-insoluble with more or less pronounced hydrophilic and/or hydrophobic trends.
  • the retardant materials useful in the invention have a melting point from about 30 to about 200° C., preferably from about 45 to about 90° C.
  • the hydrophobic fusible carrier may comprise natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl stearyl, cetyl or preferbly cetostearyl ICE), fatty acids, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic polymers having hydrocarbon backbones.
  • Suitable waxes include, for example, beeswax, glycowax, castor wax and carnauba wax.
  • a wax-like substance is defined as any material which is normally solid at room temperature and has a melting of from about 30 to about 100° C.
  • Suitable hydrophobic fusible carrier materials which may be used in accordance with the present invention include digestible, long chain (C 8- C 50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and natural and synthetic waxes. Hydrocarbons having a melting point of between 25° and 90° C. are preferred. Of the long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred in certain embodiments.
  • the oral dosage form may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon.
  • a sustained-release matrix may also contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art. The quantities of these additional materials will be sufficient to provide the desired effect to the desired formulation.
  • a sustained-release matrix incorporating melt-extruded multiparticulates may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glildants that are conventional in the pharmaceutical art in amounts up to about 50% by weight of the particulate if desired.
  • Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), incorporated by reference herein.
  • a process for the preparation of a solid, sustained-release oral dosage form according to the present invention comprising incorporating opioids or a salt thereof in a sustained-release melt-extruded matrix.
  • Incorporation in the matrix may be effected, for example, blending the opioid analgesic, together with at least one hydrophobic material and preferably the additional retardantmaterial (hydrophobic fusible carrier) to obtain a homogeneous mixture.
  • the homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude the same.
  • the resulting homogeneous mixture is then extruded, e.g., using a twin-screw extruder, to form strands.
  • the extrudate is preferably cooled and cut into multiparticulates by any means known in the art.
  • Thee strands are cooled and cut into multiparticulates.
  • the multiparticulates are then divided into unit doses.
  • the extrudate preferably has a diameter of from about 0.1 to about 5 mm and provides sustained release of the therapeutically active agent for a time period of from about 8 to about 24 hours.
  • An optional process for preparing the melt extrusions, multiparticulates and unit doses of the present invention includes directly metering into an extruder a water-insoluble retardant, a therapeutically active agent, and an optional binder; heating said homogenous mixture; extruding said homogenous mixture to thereby form strands; cooling said strands containing said homogencous mixture; and cutting said strands into particles having a size from about 0.1 to to about 12 mm; and dividing said particles into unit doses.
  • a relatively continuous manufacturing procedure is realized.
  • the diameter of the extruder aperture or exit port can also be adjusted to vary the thickness of the extruded strands.
  • the exit part of the extruder need not be round; it can be oblong, rectangular, etc.
  • the exiting strands can be reduced to particles using a hot wire cutter, guillotine, etc.
  • melt extruded multiparticulate system can be, for example, in the form of granules, spheroids or pellets depending uponthe extruder exit orifice.
  • melt-extruded multiparticulate(s)” and “melt-extruded multiparticulate system(s)” and “melt-extruded particles” shall refer to a plurality of units, preferably within a range of similar size and/or shape and containing one or more active agents and one or more excipients, preferably including a retardant as described herein.
  • melt-extruded multiparticulates will be of a range of from about 0.1 to about 12 mm in length and have a diameter of from about 0.1 to about 5 mm.
  • melt-extruded multiparticulates can be any geometricalshape within this size range such as beads, microspheres, seeds, pellets, etc.
  • a particular advantage provided by the invention is the preparation of sustained-release melt-extruded multiparticulate formulations which do not require further processing, e.g., the extrudate may simply be cut into desired lengths and divided into unit doses of the therapeutically active agent without the need of a spheronization step.
  • oral dosage forms are prepared to include an effective amount of melt-extruded multiparticulates within a capsule.
  • a plurality of the melt-extruded multiparticulates may be placed in a gelatin capsule in an amount sufficient to provide an effective sustained-release dose when ingested and contacted by gastric fluid.
  • a suitable amount of the multiparticulate extrudate is compressed into an oral tablet using conventional tableting equipment using standard techniques.
  • Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980), incorporated by reference herein.
  • the extrudate can be shaped into tablets as set forlh in U.S. Pat. No. 4,957,681 (Klimesch, et. al.), describcd in additional detail above and hereby incorporated by reference.
  • the extrudate can be shaped into suppositories containing a unit dose of the therapeutically active agent. This may be accomplished using techniques and equipment well known to those skilled in the art.
  • the sustainedrelease melt-extruded multiparticulate systems or tablets can be coated, or the gelatin capsule can be further coated, with a sustained-release coating comprising one of the hydrophobic materials described above.
  • a sustained-release coating comprising one of the hydrophobic materials described above.
  • Such coatings preferably include a sufficient amount of hydrophobic material to obtain a weight gain level from about 2 to about 30 percent, although the overcoat may be greater depending upon the physical properties of the particular opioid analgesic compound utilized and the desired release rate, among other things.
  • the hydrophobic polymer comprising the sustained-release coating is a pharmaceutically acceptable acrylic polymer, such as those described hereinabove.
  • the solvent which is used for the hydrophobic material in the coating may be any pharmaceutically acceptable solvent, including water, methanol, ethanol, methlyene chloride and mixtures thereof.
  • the unit dosage forms of the present invention may further include combinations of melt-extruded multiparticulates containing one or more of the therapeutically active agents disclosed above before being encapsulated. Furthermore, the unit dosage forms can also include an amount of an immediate release therapeutically active agent for prompt therapeutic effetc.
  • the immediate release therapeutically active agent may be incorporated, e.g., as separate pellets within a gelatin capsule, or may be coated on the surface of the compressed tablet which has been prepared from the multiparticulate extrudate as set forth above.
  • the controlled-release formulations of the present invention slowly release the therapeutically active agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids.
  • the controlled-release profile of the melt-extruded formulations of the invention can be altered, for example, by varying the amount of retardant, i.e., hydrophobic polymer, by varying the amount of plasticizer relative to hydrophobic polymer, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.
  • the sustained-release dosage forms of the present invention preferably release the therapeutically active agent at a rate that is independent of pH, e.g., between pH 1.6 and 7.2.
  • the formulations can be designed to provide a pH-dependent release of the therapeutically active agent.
  • the melt extruded material is prepared without the inclusion pf the therapeutically active agent, which is added thereafter to the extrudate.
  • Such formulations typically will have the therapeutically active agent blended together with the extruded matrix material, and then the mixture would be tabletted in order to provide a slow release formulation.
  • Such formulations may be advantageous, for example, when the therapeutically active agent included in the formulation is sensitive to temperatures needed for softening the hydrophobic material and/or the retardant material.
  • the invention is directed to sustained-release oral opioid formulations which are administrable on a once-a-day basis, and which are prepared from the melt extrudates described herein.
  • sustained-release oral opioid formulations which are administrable on a once-a-day basis, and which are prepared from the melt extrudates described herein.
  • Such dosage forms will provide an in-vitro release (when assessed by the USP Paddle or Basket Method at 100 prm at 900 ml aqueouss buffer (pH between 1.6 and 7.2) at 37° C.
  • Such formulations may further be characterized by a peak plasma level at from about 2 to about 8 hours after oral adminitration, and preferably from about 4 to about 6 hours after administration.
  • Such formulations are further characterized by a W 50 from about 4 to about 12 hours.
  • the oral 24 hour sustained-release opioid dosage form provides a rapid rate of initial rise in the plasma concentration of the opioid after oral administration, such that the peak plasma level obtained in-vivo occurs from about 2 to about 8 hours after oral administration, and/or the absorption half-life is from about 1 to about 3 hours after oral administration (in the fasted state). More preferably in this embodiment the absorption half-life is 1-6 hours and possibly 1-3 hours after oral administration (in the fasted state).
  • Such formulations provide an in-vitro dissolution under the conditions specified above, from about 12.5 to about 42.5% opioid released after one hour, from about 25 to about 65% opioid released after 2 hours, from about 45 to about 85% opioid released after 4 hours, and greater than about 60% opioid released after 8 hours, by weight.
  • Typlical melt extrusion systems capable of carrying-out the present invention include a suitable extruder drive motor having variable speed and constant torque control, start-stop controls, and ammeter.
  • the system will include a temperature control console which includes temperature sensors, cooling means and temperature indicators throughout the length of the extruder.
  • the system will include an extruder such as twin-screw extruder which consists of two counter-rotating intermeshing screws enclosed within a cylinder or barrel having an aperture or die at the exit thereof.
  • the feed materials enter through a feed hopper and is moved through the barrel by the screws and is forced through the die into strands which are thereafter conveyed such as by a continuous movable belt to allow for cooling and being directed to a pelletizer or other suitable device to render the extruded ropes into the multiparticulate system.
  • the pelletizer can consist of rollers, fixed knife, rotating cutter and the like. Suitable instruments and systems are available from distributors such as C.W. Brabender Instruments, Inc. of South Hackensack, N.J. Other suitable apparatus will be apparent to those of ordinary skill in the art.
  • a further aspect of the invention is related to the preparation of melt extruded multiparticulates as set forth) above in a manner which controls the amount of air included in the extruded product.
  • the amount of air included in the extrudate it has been surprisingly found that the release rate of the therapeutically active agent from the, e.g., multiparticulate extrudate, can be altered significantly.
  • the pH dependecy of the extruded product can be altered as well.
  • the melt extruded product is prepared in a manner which substantially excludes air during the extrusion phase of the process.
  • This may be accomplished, for example, by using a Leistritz extruder having a vacuum attachment.
  • extruded multiparticulates prepared according to the invention using the Leistritz extruder under vacuum provides a melt-extruded product having different physical characteristics.
  • the extrudate is substantially non-porous when magnified, e.g., using a scanning electron microscope whichr provides an SEM (scanning electron micrograph).
  • roller knife to an appropriate speed (e.g., to 3-100 ft/min and 100-800 rpm). Cut the congealed strands to the desired size (e.g., 3-5 mm in diameter, 0.3-5 mm in length.
  • chlorpheniramine maleate controlled release pellets were prepared according to the above manufacturingprocedure using ethylcellulose and an acrylic polymer (Eudragit RSPO), respectively as the retardant.
  • the formulations are set forth in Tables 1 and 2 below. The dissolution of these formulations is set forth in FIG. 1 .
  • Drug release rate from ethylcellulose pellets (prepared at 105° C.) is significantly slower than that from Eudragit RSPO pellets (prepared at 85° C.).
  • Ex. 3 The excipients used in Ex. 2 were employed to make morphine sulfate controlled release pellets. TABLE 3 EX. 3 Composition Amt. (mg) per Capsule Morphine Sulfate 60 Eudragit RSPO 42 Stearic Acid 18 Total 120
  • the drug release rate of Example 3 was slower than expected especially during later hours of the dissolution.
  • Examples 4-5 were prepared in accordance with Example 3 above. To increase the drug dissolution rate during later hours, varying amounts of Eudragit L-100 were incorporated in the formulation. The drug dissolution rate increases with increasing amount of Eudragit L-100 in the formulation.
  • the morphine sulfate capsule formulation are set forth in tables 4-6 below: TABLE 4 EX. 4 Composition Amt. (mg) per Capsule Morphine Sulfate 60 Eudragit RSPO 38.4 Eudragit L-100 3.6 Stearic Acid 18 Total 120
  • a sustained release morphine sulfate formulation was prepared having the ingredients listed in Table 6 below: TABLE 6 Percentage Ingredients Amt(mg)/Capsule in Formula Morphine Sulfate 60 50 Eudragit RSPO 36 30 Eudragit L-100 6 5 Stearic Acid 18 15 Total 120 100
  • Example 6 The formulation of Example 6 was prepared as follows:
  • the twin screw extruder is consisted of a pair of counterrotating screws and a barrel block equipped with heating/cooling zones. The extrudate is delivered to a pelletizer through a conveyor belt and cut into pellets of the desirable size.
  • Example 6 The capsules of Example 6 were found to have the following dissolution results: Time (hr) 1 2 4 8 12 18 24 Mean % dissolved 16 33 52 72 84 95 102
  • the drug dissolution rate obtained from the product of Ex. 3 showed a significant pH dependency.
  • the release rate was slower in SIF (simulated intestinal fluid) than in SGF (simulated gastric fluid).
  • Oxycodone HCl once-a-day capsules were produced with the following formula using the technology describced in Example 6. The formulation is set forth in Table 13 below. TABLE 13 Percentage Ingredients Amt(mg)/Capsule in Formula Oxycodone HCl 20 25 Eudragit RSPO 39 48.75 Eudragit L-100 3 3.75 Stearic Acid 18 22.5 Total 80 100
  • pellet manufacturing procedure is the same as described in Example 6. However, 80 mg of pellets were encapsulated to contain 20 mg of oxycodone HCL.
  • Ex. 15-16 The formula used in Ex. 6 was applied to hydromorphone hydrochloride. Due to the higher potency of hydromorphone, only 8 mg of drug was used. The missing 52 mg was replaced by 52 mg of talc (Ex. 16) or 52 mg of excipients (Ex. 15). The results are shown in FIG. 8 . TABLE 15 EX. 15 Composition Amt. (mg) per Capsule Hydromorphone Hydrochloride 8 Eudragit RSPO 67.2 Eudragit L-100 11.2 Stearic Acid 33.6 Total 120
  • pellet manufacturing procedure is the same as described in Example 6. However, pellets of 1.0 mm in diameter and 1.0 mm in length were prepared. Each capsule holds 80 mg of pellets and contains 8 mg of hydromorphone HCL.
  • Hydromorphone HCl once-a-day capsules were produced with the formula set forth in 18 below as the second example of the technology described in Example 6.
  • Hydromorphone HCl once-a-day capsules were produced with the following formula according to the method described Example 6. TABLE 19 Percentage Ingredients Amt(mg)/Capsule in Formula Hydromorphone HCL 8 10 Eudragit RSPO 41.5 51.9 Eudragit L-100 8.5 10.6 Stearic Acid 22 27.5 Total 80 100
  • Example 3 a bioavailability study was undertaken. Fourteen subjects were given the morphine sulfate formulations of Example 3. The results are provided in Table 20 below in FIG. 10 . TABLE 20 Group AUC Cmax Tmax Example 3 Fasted 230 15.7 2.1 Example 3 Fed 213 14.0 3.2
  • the formulation is an ideal candidate for an extended release or once-a-day product without a food effect.
  • a bioavailability study of morphine capsules of Example 6 was conducted in 12 normal male volunteers. Capsules of 60 mg in strength were administered either with or without food in a single dose, two-way crossover study. Blood samples were taken periodically and assayed for morphine concentrations using gas chromatography with mass detection (G/MS). From the data, the following pharmacokinetic parameters were calculated and are indicated in Table 21 below. TABLE 21 AUC, Treatment n ⁇ hr/ml Cmax, n/ml Tmax, hr Fasted 228 15.7 2.1 Fed 210 14.0 3.2
  • Example 6 When compared to the typical blood levels of MS Contin®, a single dose twice-a-day marketed morphine sulfate 30 mg tablets, in the fasted state, it can be ssen that the capsules of Example 6 are suitable for once daily administration. At the 24th hour the blood levels are well above MS-Contin and within the therapeutic range ( FIG. 11 ).
  • a bioavailability study of oxycodone capsules of examples 11 and 13 was conducted in 10 normal male volunteers. Capsules of example 13 were administered either with ot without food. Capsules of example 11 were administered without food. The study was conducted in a single dose, four-way crossover design. Blood samples were taken periodically and assayed for oxycodone concentrations using gas chromatography with mass detection (G/MS).
  • G/MS gas chromatography with mass detection
  • a bioavailability study of oxycodone controlled release tablets of example 14 was conducted in 25 normal volunteers. These tablets were administered either with or without foo. The study was conducted in a single dose, randomized crossover design. Blood samples were taken periodically and assayed for oxycodone concentrations using gas chromatography with mass detection (GC/MS). The plasma oxycodone concentration versus time curves are shown in FIG. 13 .
  • GC/MS gas chromatography with mass detection
  • a bioavailability study of hydromorphone capsules of Examples 17 and 18 was conducted using a single dose, five-way crossover study in 12 normal male volunteers. The subjects received either 8 mg of Dilaudid tablet (immediate release) or 8 mg of HH-MEM capsules. Dilaudid tablets were administered after an overnight fast. MEM capsules were administered with or without food. Blood samples were taken periodically and assayed for hydromorphone concentrations using gas chromatography with mass detection (G/MS). From the data, the following pharmacokinetic parameters were calculated.
  • G/MS gas chromatography with mass detection
  • Example 17 looks ideal.
  • the data of Example 17 is shown graphically in FIG. 14 and the data of Example 18 is shown graphically in FIG. 15 .
  • Example 17 is an ideal product for once-a-day administration for either single dose or multiple dose administration.
  • the twin screw extruder is consisted of a pair of counterrotating screws and a barrel block equipped with heating/cooling zones. The stranded extrudate is congealed on a conveyor belt and cut into pellets of the desirable size.
  • the pellets were milled into granules through a suitable screen.
  • the granulation was blended with talc and magnesium stearate.
  • the mixture was then compressed into capsule-shaped tablets.
  • Example 27 The manufacturing method and dissolution method are the same as described in Example 27. Additional dissolution media used include pH 1.2 simulated gastric fluid (SGF) without enzyme, pH 7.5 simulated intestinal fluid (SIF) without enzyme, and pH 4 phosphate buffer.
  • SGF simulated gastric fluid
  • SIF simulated intestinal fluid

Abstract

Bioavailable sustained release oral opioid analgesic dosage forms, comprising a plurality of multiparticulates produced via melt extrusion techniques are disclosed.

Description

    BACKGROUND OF THE INVENTION
  • The present invention relates to the use of melt extrusion technology in the production of bioavailable sustained-release matrix pharmaceutical formulations. Previously, melt extrusion has been used in the production of immediate release formulations.
  • It is known in the pharmaceutical art to prepare compositions which provide for controlled release of pharmacologically active substances contained in the compositions after oral administration to humans and animals. Such slow release compositions are used to delay absorption of a medicament until it has reached certain portions of the alimentary tract. Such sustained-release of a medicament in the alimentary tract further maintains a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered.
  • Different methods of preparing controlled release pharmaceutical dosage forms have been suggested. For example, direct compression techniques, wet granulation techniques, encapsulation techniques and the like have been proposed to deliver pharmaceutically active ingredients to the alimentary tract over extended periods.
  • Additionally, various types of sustained release formulations are known in the art, including specially coated tablets, coated tablets and capsules wherein the slow release of the active medicament is brought about through selective breakdown of the coating of the preparation or through compounding with a special matrix to affect the release of a drug. Some sustained release formulations provide for related sequential release of a single dose of an active compound at predetermined periods after administration.
  • It is the intent of all sustained-release preparations to provide a longer period of pharmacologic response after the administration of the drug and is ordinarily experienced after the administration of the rapid release dosage forms. Such longer periods of response provide for many inherent therapeutic benefits that are not achieved with corresponding short acting, immediate release preparations. This is especially true in the treatment of cancer patients or other patients in need of treatment for the alleviation of moderate to severe pain, where blood levels of an opioid analgesic medicament must be maintained at a therapeutically effective level to provide pain relief. Unless conventional rapid acting drug therapy is carefully administered at frequent intervals to maintain effective steady state blood levels of the drug, peaks and valleys in the blood level of the active drug occur because of the rapid absorption, systemic excretion of the compound and through metabolic inactivation, thereby producing special problems maintenance of analgesic efficacy.
  • The prior art teaching of the preparation and use of compositions providing the sustained-release of an active compound from a carrier is basically concerned with the release of the active substance into the physiologic fluid of the alimentary tract. However, it is generally recognized that the mere presence of an active substance in the gastrointestinal fluids does not, by itself, insure bioavailability.
  • In order to be absorbed, the active drug substance must be in solution. The time required for a given proportion of an active substance from a unit dosage form is determined as the proportion of the amount of active drug substance released from a unit dosage form over a specified time base by a test method conducted under standardized conditions. The physiologic fluids of the gastrointestinal tract are the media for determining dissolution time. The present state of the art recognizes many satisfactory test procedures to measure dissolution time for pharmaceutical compositions, and these test procedures are described in official compendia world wide.
  • Although there are many diverse factors which influence the dissolution of drug substance from its carrier, the dissolution time determined for a pharmacologically active substance from the specific composition is relatively constant and reproducible. Among the different factors affecting the dissolution time are the surface area of the drug substance presented to the dissolution solvent medium, the pH of the solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium. Thus, the dissolution concentration of an active drug substance is dynamically modified in its steady state as components are removed from the dissolution medium through absorption across the tissue site. Under physiologic conditions, the saturation level of the dissolved materials is replenished from the dosage form reserve to maintain a relatively uniform and constant dissolution concentration in the solvent medium providing for a steady state absorption.
  • The transport across a tissue absorption site of the gastrointestinal tract is influenced by the Donnan osmotic equilibrium forces on both sides of the membrane since the direction of the driving force is the difference between the concentrations of active substance on either side of the membrane, i.e., the amount dissolved in the gastrointestinal fluids and the amount present in the blood. Since the blood levels are constantly being modified by dilution, circulatory changes, tissue storage, metabolic conversion and systemic excretion, the flow of active materials is directed from the gastrointestinal tract into the blood stream.
  • Notwithstanding the diverse factors influencing both dissolution and absorption of a drug substance, a strong correlation has been established between the in-vitro dissolution time determined for a dosage form and (in-vivo) bioavailability. The dissolution time and the bioavailability determined for a composition are two of the most significant fundamental characteristics for consideration when evaluating sustained-release compositions.
  • Melt granulation techniques have also been suggested to provide controlled release formulations. Generally, melt granulation involves mechanically working an active ingredient in particulate form with one or more suitable binders and/or pharmaceutically acceptable excipients in a mixer until one or more of the binders melts and adheres to the surface of the particulate, eventually building up granules.
  • U.S. Pat. No. 4,957,681 (Klimesch), et. al.) discloses a continuous process for preparing pharmaceutical mixtures having at least two components which are continuously metered. The process includes continuously metering the individual components of the pharmaceutical mixture at a rate of at least 50 g/h on electronic differential metering balances having a metering accuracy of at least ±5% within time intervals of less than one minute and, additionally, having screw conveyors, thereby obtaining a substantially uniformly metered mixture; and shaping the mixture. Example 1 of the '681 patent is representative of the process. The requisite amounts of a copolymer having a K value of 30 and obtained from 60% of N-vinylpyrrolid-2-one (NVP), stearyl alcohol and theophylline are metered via three metering balances into the hopper of an extruder and extruded. The temperatures of the extruder cylinder consisting of six shots ranged from 30-60° C. and the die is heated to 100° C. The resultant extrudate is then pressed into tablets of the required shape. The '681 patent does not disclose preparation of sustained release opioid pharmaceutical formulations.
  • N. Follonier., et al., Hot-Melt Extruded Pellets for the Sustained Release of Highly Dosed Freely Soluble Drugs, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 18 (1991) describes certain diltiazem hydrochloride formulations prepared using hot-melt screw-extrusion to obtain sustained-release pellets to be filled into hard gelatin capsules. The polymers used were ethylcellulose, a copolymer of ethyl acrylate and methyl methacrylate containing quaternary ammonium groups, cellulose acetate butyrate, poly(vinyl chloride-co-vinyl acetate) and a copolymer of ethylene and vinyl acetate. In order to lower the extrusion temperature, some plasticizers were used.
  • WO 93/07859 describes drug loaded pellets produced through melt spheronization wherein the therapeutically active agent is blended with various excipoients and binders; the formulation is fed to an extruder where it is heated and extruded at a speed of about 0.05 to 10 mm/sec. at approximately 60-180° C. The extrudate is then cut into pieces in a pelletizer and subsequently fed to a spheronizer for uniform pellet formation.
  • Despite the foregoing advances and the various techniques for preparing sustained release formulations available in the pharmaceutical art, there is a need in the art for an orally administrable opioid formulation which would provide an extended duration of effect which is also easy to prepare, e.g via melt-granulation techniques.
  • OBJECTS AND SUMMARY OF THE INVENTION
  • It is therefore an object of the present invention to provide sustained-release pharmaceutical formulations suitable for oral administration and methods for preparing the same utilizing melt-extrusion techniques.
  • It is also an object of the present invention to provide improved methods for producing pharmaceutical extrudates containing opioid analgesics and pharmaceutical acceptable hydrophobic materials via melt extrusion techniques.
  • It is a further object of the present invention to provide a sustained-release melt extruded multi-particulate formulation which need not be spheronized in order to obtain a final dosage form.
  • It is also an object of the present invention to provide methods of treatment for human patients in need of opioid analgesic therapy using dosage forms prepared in accordance with the methods disclosed herein.
  • In accordance with the above objects and others which will be apparent from the further reading of the specification and of the appended claims, the present invention is related in part to the surprising discovery that sustained-release oral opioid analgesic formulations may be prepared utilizing melt extrusion techniques to provide bioavailable unit dose products which provide analgesia in a patient for, e.g., 8-24 hours.
  • The invention is also related in part to a new melt-extruded oral sustained-release dosage forms which comprise a pharmaceutically acceptable hydrophobic material, a retardant selected from waxes, fatty alcohols, and fatty acids, and a drug.
  • More particularly, one aspect of the present invention is related to a pharmaceutical extrudate including an opioid analgesic dispersed in a matrix. Preferably, the extrudate is strand or spaghetti-shaped and has a diameter from about 0.1 to about 5 mm. The extrudate is divided into unit doses of the opioid analgesic for oral administration to a patient, and provides a sustained analgetic effect for 8-24 hours or more.
  • The matrices preferably include a hydrophobic material and a second retardant material (preferably a hydrophobic fusible carrier) which acts to further slow or control the release of the therapeutically active agent when the formulation is exposed to aqueous solutions in-vitro, or exposed to gastic and/or intestinal fluids.
  • Preferably, the hydrophobic material is selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.
  • The retardant material (hydrophobic fusible carrier) is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols and mixtures of the same. Examples include beeswax and carnauba wax, stearic acid, and stearyl alcohol). This list is of course not meant to be exclusive.
  • The extrudate may be cut into multiparticulates by any cutting means known in the art. Preferably, the multiparticulates have a length of from about 0.1 to 5 mm in length. The multiparticulates may then be divided into unit doses such that each individual unit dose includes a dose of opioid analgesic sufficient to provide analgesia to a mammal, preferably a human patient.
  • The unit doses of multiparticulates may then be incorporated into a solid pharmaceutical dosage formulation, e.g. via compression or shaping into tablets, by placing a requisite amount inside a gelatin capsule, or by forming the extruded product into the form of a suppository.
  • The pharmaceutical extrudates of the present invention may be prepared by blending the drug together with all matrix ingredients (hydrophobic material, binder and any additional (optional) excipients), feeding the resultant mixture into an extruder heated to the requisite temperature necessary to soften the mixture sufficiently to render the mixture extrudable; extruding the viscous, heated mass as a spaghetti-like strand; allowing the extrudate to congeal and harden, and then dividing the strand into desired pieces. This may be accomplished, e.g., by cutting the strands into pellets of 1.5 mm diameter and 1.5 mm in length. Preferably, the extrudate has a diameter of from about 0.1 to about 5 mm and provides sustained release of said opioid analgesic for a time period of from about 8 to about 24 hours.
  • Another aspect of the invention is directed to pharmaceutical dosage forms including the extrudate prepared as outlined above. The extrudate is cut into multiparticulates using any cutting means known in the art, e.g a blade. The multiparticulates are then divided into unit doses containing an effective amount of opioid analgesic to provide analgesia or pain relief in a human patient over the desired dosing interval. The unit dose of multiparticulates may then be incorporated into tablets, e.g. via direct compression, formed into suppositories, or encapsulated by any means known in the art.
  • In yet a further aspect of the invention, there is provided a method of treating a patient with sustained-release formulations prepared as described above. This method includes administering a dosage form containing the novel extrudate to a patient in need of opioid analgesic therapy. For purposes of the present invention, a unit dose is understood to contain an effective amount of the therapeutically active agent to produce pain relief and/or analgesia to the patient. One skilled in the art will recognize that the dose of opioid analgesic administered to a patient will vary due to numerous factors; e.g. the specific opioid analgesic(s) being administered, the weight and tolerance of the patient, other therapeutic agents concomitantly being administered, etc.
  • As mentioned above, in order for a dosage form to be effective for its intended purpose, the dosage form must be bioavailable. For purposes of the present invention, the term “bioavailable” is defined as the total amount of a drug substance that is absorbed and available to provide the desired therapeutic effect after administration of a unit dosage form. Generally, the bioavailability of a given dosage form is determined by comparison to a known reference drug product, as commonly determined and accepted by Governmental Regulatory Agencies, such as the United States FDA.
  • The term “bioavailability” is defined for purposes of the present invention as the extent to which the drug (e.g., opioid analgesic) is absorbed from the unit dosage form and is available at the site of drug action.
  • The terms “sustained release”, “extended duration”, and “controlled release” are defined for purposes of the present invention as the release of the drug (e.g., opioid analgesic) at such a rate that blood (e.g., plasma) levels are maintained within the therapeutic range but below toxic levels over a period of time greater than 8 hours, more preferably for about 12 to about 24 hours, or longer.
  • The term “unit dose” is defined for purposes of the present invention as the total amount of multiparticulates needed to administer a desired dose of therapeutically active agent (e.g., opioid analgesic) to a patient.
  • The extrudates of the present invention preferably permit release of the opioid (or salts thereof) over a sustained period of time in an aqueous medium. The term “Aqueous medium” is defined for purposes of the present invention as any water-containing medium, e.g. water, pharmaceutically acceptable dissolution medium, gastric fluid and/or intestinal fluid and the like.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • The following drawing is illustrative of an embodiment of the invention and is not meant to limit the scope of the invention as encompassed by the claims.
  • FIG. 1 is a graph displaying the dissolution results of Examples 1 and 2;
  • FIG. 2 is a graph displaying the dissolution rates of Examples 3-6;
  • FIGS. 3 and 4 are graphs displaying the pH dependency of the dissolution results of Examples 3 and 6 respectively;
  • FIG. 5 is a graph displaying the dissolution results of Examples 7 and 8 vs. Example 6;
  • FIG. 6 is a graph displaying the dissolution results of Examples 9 and 10;
  • FIG. 7 is a graph displaying the dissolution results of Examples 11 and 12;
  • FIG. 8 is a graph displaying the dissolution results of Examples 15 and 16;
  • FIG. 9 is a schematic representation of a system for carrying out the present invention;
  • FIG. 10 is a graph displaying the fed/fast bioavailability results for Example 20;
  • FIG. 11 is a graph displaying the plasma morphine concentrations of Example 21 obtained from administration of the capsules from Example 6 vs. MS Contin®;
  • FIG. 12 is a graph displaying the plasma oxycodone concentrations of Examples 22 obtained from administrating the capsules from Examples 11 and 13 vs. OxyContin®;
  • FIG. 13 is a graphical representation of the plasma oxycodone concentrations of Example 14;
  • FIG. 14 is a graphical representation of the hydromorphone concentrations of Example 24 using the capsules from Example 17 vs. Dilaudud®;
  • FIG. 15 is a graph displaying the plasma hydromorphone concentrations of Example 24 using capsules from Example 18 vs. Dilaudud®;
  • FIG. 16 is a graph of the steady-state plasma hydromorphone concentrations of Example 25 using the capsules of Example 17; and
  • FIG. 17 is a graph of the plasma hydromorphone concentrations of Example 26 using the capsules of Example 19.
  • DETAILED DESCRIPTION
  • In one aspect of the invention, the sustained-release dosage forms comprise an opioid analgesic as the therapeutically active agent. In such formulations, the drug is incorporated into a melt-extruded strand which includes a pharmaceutically acceptable hydrophobic material such as an alkylcellulose or an acrylic polymer or copolymer. In certain embodiments, it is preferably to further add to the blend a plasticizer for the hydrophobic material in order to reduce the extrusion temperature. The choice of the most suitable plasticizer is made based on its ability to lower the glass transition temperature (Tg) of the polymer. In preferred alternative embodiments, a hydrophobic fusible carrier (which may also act as a binder) is utilized instead of a plasticizer. The hydrophobic fusible carrier preferably imparts a slower release of the therapeutically active agent from the melt extruded formulation. Any further pharmaceutical excipients known to those skilled in the art may be added as deemed necessary.
  • Another aspect of the invention is directed to improved melt extruded matrices which comprise a hydrophobic material and a fatty binder such as previously specified. In accordance therewith, a therapeutically active agent is combined with one or more suitable hydrophobic materials and a hydrophobic fusible carrier is extruded to form an extrudate. The extrudate may then be cut into multiparticulates which are subsequently incorporated into sustained release dosage forms.
  • Therapeutically Active Agents
  • Therapeutically active agents which may be used in accordance with the present invention include both water soluble and water insoluble drugs. Examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexachlorpheniramine maleate), analgesics (e.g., aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.), non-steroidal anti-inflammatory agents (e.g., naproxen, diclofenac, indomethacin, ibuprofen, sulindac), anti-emetics (e.g., metoclopramide, methylnaltrexone), anti-epileptics (e.g., phenytoin, meprobamate and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardipine), anti-tussive agents and expectorants (e.g., codeine phosphate), anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g. atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethcrynic acid, bendrofluthiazide), anti-hypotensives (e.g., propranolol, clonidine), antihypertensives (e.g, clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamicinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine), as well as salts, hydrates, and solvates of the same.
  • In embodiments of the invention directed to opioid analgesics, the opioid analgesics used in accordance with the present invention include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, salts thereof, mixtures of any of the foregoing, mixed mu-agonists/antagonists, mu-antagonist combinations, and the like. The opioid analgesic may be in the form of the free base, or in the form of a pharmaceutically acceptable salt, or in the form of a pharmaceutically acceptable complex.
  • In certain preferred embodiments, the opioid analgesic is selected from morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, tramadol or mixtures thereof.
  • In one preferred embodiment the sustained-release opioid oral dosage form of the present invention includes hydromorphone as the therapeutically active ingredient in an amount from about 4 to about 64 mg hydromorphone hydrochloride. Alternatively, the dosage form may contain molar equivalent amounts of other hydromorphone salts or of the hydromorphone base. In other preferred embodiments where the opioid analgesic is other than hydromorphone, the dosage form contains an appropriate amount to provide a substantially equivalent therapeutic effect. For example, when the opioid analgesic comprises morphine, the sustained-release oral dosage forms of the present invention include from about 5 mg to about 800 mg morphine, by weight (based on morphine sulfate). When the opioid analgesic comprises oxycodone, the sustained-release oral dosage forms of the present invention include from about 5 mg to about 400 mg oxycodone. When the opioid analgesic is tramadol, the sustained-release oral dosage forms of the invention include from about 50 mg to about 800 mg tramadol by weight, based on the hydrochloride salt.
  • The sustained-release dosage forms of the present invention generally achieve and maintain therapeutic levels substantially without significant increases in the intensity and/or degree of concurrent side effects, such as nausea, vomiting or drowsiness, which are often associated with high blood levels of opioid analgesics. There is also evidence to suggest that the use of the present dosage forms leads to a reduced risk of drug addiction.
  • In the present invention, the oral opioid analgesics have been formulated to provide for an increased duration of analgesic. Surprisingly, these formulations, at comparable daily dosages of conventional immediate-release drug, are associated with a lower incidence in severity of adverse drug reactions and can also be administered at a lower daily dose than conventional oral medication while maintaining pain control.
  • When the therapeutically active agent included in the dosage forms of the present invention is an opioid analgesic, the dosage form may further include one or more additional which may or may not act synergistically with the opioid analgesics of the present invention. Examples of such additional therapeutically active agents include non-steroidal anti-inflammatory agents, including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the like. Other suitable additional drugs which may be included in the dosage forms of the present invention include acetaminophen, aspirin, salicylate-derived analgesics and antipyretics or salts thereof, and other non-opioid analgesics.
  • The additional (non-opioid) therapeutically active agent may be included in controlled release form or in immediate release form. The additional drug may be incorporated into the controlled release matrix along with the opioid; incorporated as a separated controlled release layer or immediate release layer; or may be incorporated as a powder, granulation, etc., in a gelatin capsule with the extrudates of the present invention.
  • Matrix Ingredients
  • The extrudates of the present invention include at least one hydrophobic material. The hydrophobic material will preferably impart sustained release of the opioid analgesic to the final formulation. Preferred hydrophobic materials which may be used in accordance with the present invention include alkylcelluloses such as natural or synthetic celluloses derivatives (e.g. ethylcellulose), acrylic and methacrylic acid polymers and copolymers, shellac, zein, wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof. This list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material which is capable of imparting sustained release of the active agent and which melts (or softens to the extent necessary to be extruded) may be used in accordance with the present invention.
  • In certain preferred embodients of the present invention, the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. In other embodiments, the hydrophobic material is selected from materils such as hydroxyalkylcelluoses such as hydroxypropylmethylcellulose and mixtures of the foregoing.
  • The retardant material is preferably a hydrophobic fusible carrier which may comprise one or more water-insoluble wax-like thermoplastic substances possibly mixed with one or more wax-like thermoplastic substances being less hydrophobic than said one or more water-insoluble wax-like substances. In order to achieve constant release, the individual wax-like substances in the binder material should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases.
  • Useful water-insoluble wax-like substances may be those with a water-solubility that is lower than about 1:5,000 (w/w).
  • Such hydrophobic fusible carrier materials are preferably water-insoluble with more or less pronounced hydrophilic and/or hydrophobic trends. Preferably, the retardant materials useful in the invention have a melting point from about 30 to about 200° C., preferably from about 45 to about 90° C. Specifically, the hydrophobic fusible carrier may comprise natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl stearyl, cetyl or preferbly cetostearyl alcool), fatty acids, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic polymers having hydrocarbon backbones. Suitable waxes include, for example, beeswax, glycowax, castor wax and carnauba wax. For purposes of the present invention, a wax-like substance is defined as any material which is normally solid at room temperature and has a melting of from about 30 to about 100° C.
  • Suitable hydrophobic fusible carrier materials which may be used in accordance with the present invention include digestible, long chain (C8-C50, especially C12-C40), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and natural and synthetic waxes. Hydrocarbons having a melting point of between 25° and 90° C. are preferred. Of the long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred in certain embodiments. The oral dosage form may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon.
  • In addition to the above ingredients, a sustained-release matrix may also contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art. The quantities of these additional materials will be sufficient to provide the desired effect to the desired formulation. In addition to the above ingredients, a sustained-release matrix incorporating melt-extruded multiparticulates may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glildants that are conventional in the pharmaceutical art in amounts up to about 50% by weight of the particulate if desired. Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), incorporated by reference herein.
  • In order to facilitate the the reparation of a solid, sustained-release oral dosage form according to this invention there is provided, in a further aspect of the present invention, a process for the preparation of a solid, sustained-release oral dosage form according to the present invention comprising incorporating opioids or a salt thereof in a sustained-release melt-extruded matrix. Incorporation in the matrix may be effected, for example, blending the opioid analgesic, together with at least one hydrophobic material and preferably the additional retardantmaterial (hydrophobic fusible carrier) to obtain a homogeneous mixture. The homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude the same. The resulting homogeneous mixture is then extruded, e.g., using a twin-screw extruder, to form strands. The extrudate is preferably cooled and cut into multiparticulates by any means known in the art. Thee strands are cooled and cut into multiparticulates. The multiparticulates are then divided into unit doses. The extrudate preferably has a diameter of from about 0.1 to about 5 mm and provides sustained release of the therapeutically active agent for a time period of from about 8 to about 24 hours.
  • An optional process for preparing the melt extrusions, multiparticulates and unit doses of the present invention includes directly metering into an extruder a water-insoluble retardant, a therapeutically active agent, and an optional binder; heating said homogenous mixture; extruding said homogenous mixture to thereby form strands; cooling said strands containing said homogencous mixture; and cutting said strands into particles having a size from about 0.1 to to about 12 mm; and dividing said particles into unit doses. In this aspect of the invention, a relatively continuous manufacturing procedure is realized.
  • The diameter of the extruder aperture or exit port can also be adjusted to vary the thickness of the extruded strands. Furthermore, the exit part of the extruder need not be round; it can be oblong, rectangular, etc. The exiting strands can be reduced to particles using a hot wire cutter, guillotine, etc.
  • The melt extruded multiparticulate system can be, for example, in the form of granules, spheroids or pellets depending uponthe extruder exit orifice. For purposes of the present invention, the terms “melt-extruded multiparticulate(s)” and “melt-extruded multiparticulate system(s)” and “melt-extruded particles” shall refer to a plurality of units, preferably within a range of similar size and/or shape and containing one or more active agents and one or more excipients, preferably including a retardant as described herein. In this regard, the melt-extruded multiparticulates will be of a range of from about 0.1 to about 12 mm in length and have a diameter of from about 0.1 to about 5 mm. In adition, it is to be understood that the melt-extruded multiparticulates can be any geometricalshape within this size range such as beads, microspheres, seeds, pellets, etc.
  • A particular advantage provided by the invention is the preparation of sustained-release melt-extruded multiparticulate formulations which do not require further processing, e.g., the extrudate may simply be cut into desired lengths and divided into unit doses of the therapeutically active agent without the need of a spheronization step.
  • In one preferred embodiment, oral dosage forms are prepared to include an effective amount of melt-extruded multiparticulates within a capsule. For example, a plurality of the melt-extruded multiparticulates may be placed in a gelatin capsule in an amount sufficient to provide an effective sustained-release dose when ingested and contacted by gastric fluid.
  • In another perferred embodiment, a suitable amount of the multiparticulate extrudate is compressed into an oral tablet using conventional tableting equipment using standard techniques. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980), incorporated by reference herein.
  • In yet another preferred embodiment, the extrudate can be shaped into tablets as set forlh in U.S. Pat. No. 4,957,681 (Klimesch, et. al.), describcd in additional detail above and hereby incorporated by reference.
  • In yet a further embodiment, the extrudate can be shaped into suppositories containing a unit dose of the therapeutically active agent. This may be accomplished using techniques and equipment well known to those skilled in the art.
  • Optionally, the sustainedrelease melt-extruded multiparticulate systems or tablets can be coated, or the gelatin capsule can be further coated, with a sustained-release coating comprising one of the hydrophobic materials described above. Such coatings preferably include a sufficient amount of hydrophobic material to obtain a weight gain level from about 2 to about 30 percent, although the overcoat may be greater depending upon the physical properties of the particular opioid analgesic compound utilized and the desired release rate, among other things. In certain preferred embodiments of the present invention, the hydrophobic polymer comprising the sustained-release coating is a pharmaceutically acceptable acrylic polymer, such as those described hereinabove. The solvent which is used for the hydrophobic material in the coating may be any pharmaceutically acceptable solvent, including water, methanol, ethanol, methlyene chloride and mixtures thereof. The unit dosage forms of the present invention may further include combinations of melt-extruded multiparticulates containing one or more of the therapeutically active agents disclosed above before being encapsulated. Furthermore, the unit dosage forms can also include an amount of an immediate release therapeutically active agent for prompt therapeutic effetc. The immediate release therapeutically active agent may be incorporated, e.g., as separate pellets within a gelatin capsule, or may be coated on the surface of the compressed tablet which has been prepared from the multiparticulate extrudate as set forth above.
  • The controlled-release formulations of the present invention slowly release the therapeutically active agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled-release profile of the melt-extruded formulations of the invention can be altered, for example, by varying the amount of retardant, i.e., hydrophobic polymer, by varying the amount of plasticizer relative to hydrophobic polymer, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc. In certain embodiments of the invention, the the sustained-release dosage forms of the present invention preferably release the therapeutically active agent at a rate that is independent of pH, e.g., between pH 1.6 and 7.2. In other embodiments, the formulations can be designed to provide a pH-dependent release of the therapeutically active agent.
  • In other embodiments of the invention, the melt extruded material is prepared without the inclusion pf the therapeutically active agent, which is added thereafter to the extrudate. Such formulations typically will have the therapeutically active agent blended together with the extruded matrix material, and then the mixture would be tabletted in order to provide a slow release formulation. Such formulations may be advantageous, for example, when the therapeutically active agent included in the formulation is sensitive to temperatures needed for softening the hydrophobic material and/or the retardant material.
  • In certain preferred embodiments, the invention is directed to sustained-release oral opioid formulations which are administrable on a once-a-day basis, and which are prepared from the melt extrudates described herein. Such dosage forms will provide an in-vitro release (when assessed by the USP Paddle or Basket Method at 100 prm at 900 ml aqueouss buffer (pH between 1.6 and 7.2) at 37° C. from about 1 to about 42.5% opioid released after one hour, from about 5 to about 65% opioid released after 2 hours, from about 15 to about 85% opioid released after 4 hours, from about 20 to about 90% opioid released after 6 hours, from about 35 to about 95% opioid released after 12 hours, from about 45 to about 100% opioid released after 18 hours, and from about 55 to about 100% opioid released after 24 hours, by weight. Such formulations may further be characterized by a peak plasma level at from about 2 to about 8 hours after oral adminitration, and preferably from about 4 to about 6 hours after administration. Such formulations are further characterized by a W50 from about 4 to about 12 hours.
  • In certain preferred embodiments, the oral 24 hour sustained-release opioid dosage form provides a rapid rate of initial rise in the plasma concentration of the opioid after oral administration, such that the peak plasma level obtained in-vivo occurs from about 2 to about 8 hours after oral administration, and/or the absorption half-life is from about 1 to about 3 hours after oral administration (in the fasted state). More preferably in this embodiment the absorption half-life is 1-6 hours and possibly 1-3 hours after oral administration (in the fasted state). Such formulations provide an in-vitro dissolution under the conditions specified above, from about 12.5 to about 42.5% opioid released after one hour, from about 25 to about 65% opioid released after 2 hours, from about 45 to about 85% opioid released after 4 hours, and greater than about 60% opioid released after 8 hours, by weight.
  • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.
  • Melt-Extrusion Techniques
  • Typlical melt extrusion systems capable of carrying-out the present invention include a suitable extruder drive motor having variable speed and constant torque control, start-stop controls, and ammeter. In additioin, the system will include a temperature control console which includes temperature sensors, cooling means and temperature indicators throughout the length of the extruder. In addition, the system will include an extruder such as twin-screw extruder which consists of two counter-rotating intermeshing screws enclosed within a cylinder or barrel having an aperture or die at the exit thereof. The feed materials enter through a feed hopper and is moved through the barrel by the screws and is forced through the die into strands which are thereafter conveyed such as by a continuous movable belt to allow for cooling and being directed to a pelletizer or other suitable device to render the extruded ropes into the multiparticulate system. The pelletizer can consist of rollers, fixed knife, rotating cutter and the like. Suitable instruments and systems are available from distributors such as C.W. Brabender Instruments, Inc. of South Hackensack, N.J. Other suitable apparatus will be apparent to those of ordinary skill in the art.
  • A further aspect of the invention is related to the preparation of melt extruded multiparticulates as set forth) above in a manner which controls the amount of air included in the extruded product. By controlling the amount of air included in the extrudate, it has been surprisingly found that the release rate of the therapeutically active agent from the, e.g., multiparticulate extrudate, can be altered significantly. In certain embodiments, it has been surprisingly found that the pH dependecy of the extruded product can be altered as well.
  • Thus, in a further aspect of the invention, the melt extruded product is prepared in a manner which substantially excludes air during the extrusion phase of the process. This may be accomplished, for example, by using a Leistritz extruder having a vacuum attachment. It has been surprisingly found that extruded multiparticulates prepared according to the invention using the Leistritz extruder under vacuum provides a melt-extruded product having different physical characteristics. In particular, the extrudate is substantially non-porous when magnified, e.g., using a scanning electron microscope whichr provides an SEM (scanning electron micrograph). Contrary to conventional thought, it has been found that such substantially non-porous formulations provide a faster release of the therapeutically active agent, relative to the same formulation prepared without vacuum. SEMs of the multiparticulates prepared using an extruder under vacuum appear very smooth, and the multiparticulates tend to be more robust than those multiparticulates prepared without vacuum. It has been observed that in at least certain formulations, the use of extrusion under vacuum provides an extruded multiparticulate product which is more pH-dependent than its counterpart formulation prepared without vacuum.
  • General Pellet Manufacturing Procedure
  • The following technique was used to manufacture the extrudate and multiparticulates for Examples 1-26:
  • Blend the required amount of drug, hydrophobic material and binder along with any additional excipients.
  • Charge a powder feeder with the proper amount of drug/excipient blend.
  • Set temperatures of extruder heating zones to the required temperature, depending on the formulation. Typically, the temperature should be set at about 83° C. Wait until the corresponding heating zones reach steady temperatures. Set the extruder screw rotation speed to 20 rpm. Start the feeder, the conveyor and the pelletizer. After the excipients are melted and the drug is embedded in the molten mixture, the resultant viscous mass is extruded as spaghetti-like strands. The diameter of the extruder aperture can be adjusted to vary the thickness of the resulting strand.
  • Set the conveyor belt speed to an appropriate speed (e.g., 3-100 ft/min). Allow the extruded semisolid strands to be congealed and/or hardened while transported to the pelletizer on the conveyor belt. Additional cooling devices may be needed to ensure proper congealing. (The conveyor belt may not be needed to cool the strand, if the material congeals rapidly enough.)
  • Set the roller knife to an appropriate speed (e.g., to 3-100 ft/min and 100-800 rpm). Cut the congealed strands to the desired size (e.g., 3-5 mm in diameter, 0.3-5 mm in length.
  • Collect the pellet product.
  • Fill a desired weight of pellets into hard gelatin capsules to obtain an appropriate doses of the drug.
  • Dissolution Method
  • The following dissolution method was used to obtain dissolution profiles for the dosage forms of Examples 1-25:
  • (USP II Paddle at 100 rpm at 37° C.)
  • Media—1st hour in 700 ml simulated gastric fluid (SGF), pH 1.2 without enzyme
      • thereafter, 900 ml simulated intestinal fluid (SIF), pH 7.5 without enzyme
  • Using HPLC procedures for assay
  • The followifg examples illustrate various aspects of the present invention. They are not meant to be construed to limit the claims in any manner whatsoever.
  • EXAMPLES 1-2 Controlled Release Chlorpheniramine Formulations
  • In these examples, chlorpheniramine maleate controlled release pellets were prepared according to the above manufacturingprocedure using ethylcellulose and an acrylic polymer (Eudragit RSPO), respectively as the retardant. The formulations are set forth in Tables 1 and 2 below. The dissolution of these formulations is set forth in FIG. 1. Drug release rate from ethylcellulose pellets (prepared at 105° C.) is significantly slower than that from Eudragit RSPO pellets (prepared at 85° C.).
    TABLE 1
    EX. 1
    Composition Amt. (mg) per Capsule
    Chlorpheniramine Maleate
     60
    Ethyl Cellulose  84
    Stearic Acid  36
    Total 180
  • TABLE 2
    EX. 2
    Composition Amt. (mg) per Capsule
    Chlorpheniramine Maleate
     60
    Eudragit RSPO  84
    Stearic Acid  36
    Total 180
  • EXAMPLES 3-6 Controlled Release Morphine Formulations
  • Ex. 3 The excipients used in Ex. 2 were employed to make morphine sulfate controlled release pellets.
    TABLE 3
    EX. 3
    Composition Amt. (mg) per Capsule
    Morphine Sulfate
     60
    Eudragit RSPO  42
    Stearic Acid  18
    Total 120
  • The drug release rate of Example 3 was slower than expected especially during later hours of the dissolution.
  • Ex. 4-5 Examples 4-5 were prepared in accordance with Example 3 above. To increase the drug dissolution rate during later hours, varying amounts of Eudragit L-100 were incorporated in the formulation. The drug dissolution rate increases with increasing amount of Eudragit L-100 in the formulation. The morphine sulfate capsule formulation are set forth in tables 4-6 below:
    TABLE 4
    EX. 4
    Composition Amt. (mg) per Capsule
    Morphine Sulfate
    60
    Eudragit RSPO 38.4
    Eudragit L-100 3.6
    Stearic Acid 18
    Total 120
  • TABLE 5
    EX. 5
    Composition Amt. (mg) per Capsule
    Morphine Sulfate
    60
    Eudragit RSPO 33.6
    Eudragit L-100 8.4
    Stearic Acid 18
    Total 120
  • Ex. 6. A sustained release morphine sulfate formulation was prepared having the ingredients listed in Table 6 below:
    TABLE 6
    Percentage
    Ingredients Amt(mg)/Capsule in Formula
    Morphine Sulfate
     60  50
    Eudragit RSPO  36  30
    Eudragit L-100  6  5
    Stearic Acid  18  15
    Total 120 100
  • The formulation of Example 6 was prepared as follows:
  • Pellet Manufacture
  • a. Extruder system description—The twin screw extruder is consisted of a pair of counterrotating screws and a barrel block equipped with heating/cooling zones. The extrudate is delivered to a pelletizer through a conveyor belt and cut into pellets of the desirable size.
  • b. Manufacturing procedure
    • 1. Blend the drug and all the excipients in a proper mixer.
    • 2. Place the mixture in a powder feeder.
    • 3. Set temperatures of the extruder heating zones to approximately 83° C.
    • 4. Set the extruder screw rotation speed to 20 rpm.
    • 5. Start the feeder, the conveyor and the pelletizer.
    • 6. After the excipients are melted and the drug embedded in the molten mixture, the viscous mass is extruded as spaghetti-like strands.
    • 7. The extrudate is congealed and hardened while being delivered to the pelletizer on the conveyor belt.
    • 8. The roller knife of the pelletizer cuts the strands into pellets of 1.5 mm in diameter and 1.5 mm in length.
  • Encapsulation
  • After the pellets were manufactured, 120 mg of pellets are encapsulated in size #2 hard gelatin capsules, rendering capules containing 60 mg of morphine sufate. These capsules were then tested using the following dissolution methodology:
  • The capsules of Example 6 were found to have the following dissolution results:
    Time (hr)
    1 2 4 8 12 18 24
    Mean % dissolved 16 33 52 72 84 95 102
  • As seen in FIG. 3, the drug dissolution rate obtained from the product of Ex. 3 showed a significant pH dependency. The release rate was slower in SIF (simulated intestinal fluid) than in SGF (simulated gastric fluid).
  • In FIG. 4, it can be seen that due to the addition of Eudragit L-100, the drug dissolution rate obtained from Ex. 6 was less pH dependent. The drug release rate was faster in SIF during later hours of dissolution which is desirable for complete bioavailability.
  • EXAMPLES 7-8
  • As demonstrated in FIG. 5, with proper choice of plasticizers, the drug release rate from the formula containing Eudragit L-100 can be reduced. This may be necessary to achieve desirable plasma drug concentration profiles after oral administration of the pellets.
    TABLE 7
    EX. 7
    Composition Amt. (mg) per Capsule
    Morphine Sulfate
    60
    Eudragit RSPO 33.6
    Eudragit L-100 8.4
    Stearic Acid 9
    Diethyl Phthalate 9
    Total 120
  • TABLE 8
    EX. 8
    Composition Amt. (mg) per Capsule
    Morphine Sulfate
    60
    Eudragit RSPO 33.6
    Eudragit L-100 8.4
    Stearic Acid 9
    Tributyl Citrate 9
    Total 120
  • EXAMPLES 9-10
  • A different polymer/wax combination was used as an alternative formulation. As seen in FIG. 6, the drug dissolution rate from ethylcellulose/polyvinyl acetate phthalate was somewhat faster.
    TABLE 9
    EX. 9
    Composition Amt. (mg) per Capsule
    Morphine Sulfate
    60
    Ethyl Cellulose 38.4
    Polyvinyl Acetate Phthalate 3.6
    Stearic Acid 18
    Total 120
  • TABLE 10
    EX. 10
    Composition Amt. (mg) per Capsule
    Morphine Sulfate
    60
    Ethyl Cellulose 34.8
    Polyvinyl Acetate Phthalate 7.2
    Stearic Acid 18
    Total 120
  • EXAMPLES 11-14 Controlled Release Oxycodone Formulations
  • The formula used in Ex. 6 was applied to oxycodone hydrochloride. Due to the higher potency of oxycodone, only 20 mg of drug was used. The missing 40 mg was replaced by 40 mg of talc (Ex. 12). No replacement was used in Ex. 11. When tested in only SGF or SIF, the use of Eudragit L causes the formulation to become less pH dependent. The results are shown in FIG. 7.
    TABLE 11
    Percentage
    Ingredients Amt(mg)/Capsule in Formula
    Oxycodone HCL
    20 25
    Eudragit RSPO 36 45
    Eudragit L-100 6 7.5
    Stearic Acid 18 22.5
    Total 80 100
  • The pellet manufacturing procedure and the dissolution method are the same as described in Example 6.
  • The above capsules were found to have the dissolution results set forth in Table 11a below:
    TABLE 11a
    Time (hr)
    1 2 4 8 12 18 24
    Mean % dissolved 14 29 45 66 81 94 101
  • TABLE 12
    EX. 12
    Composition Amt. (mg) per Capsule
    Oxycodone Hydrochloride
    20
    Eudragit RSPO 36
    Eudragit L-100 6
    Stearic Acid 18
    Talc 40
    Total 120
  • Ex. 13 Oxycodone HCl once-a-day capsules were produced with the following formula using the technology describced in Example 6. The formulation is set forth in Table 13 below.
    TABLE 13
    Percentage
    Ingredients Amt(mg)/Capsule in Formula
    Oxycodone HCl
    20 25
    Eudragit RSPO 39 48.75
    Eudragit L-100 3 3.75
    Stearic Acid 18 22.5
    Total 80 100
  • The pellet manufacturing procedure is the same as described in Example 6. However, 80 mg of pellets were encapsulated to contain 20 mg of oxycodone HCL.
  • The above capsules were tested using the following dissolution methodology:
    • 1. Apparatus—USP type II (paddle), 100 rpm at 37° C.
    • 2. Media—Either 900 ml simulated gastric fluid (SGF), pH 1.2 without enzyme; or 900 ml simulated intestinal fluid (SIF), pH 7.5 without enzyme.
    • 3. Analytical method—High performance liquid chromatography.
  • The dissolution results are set forth in Table 13a below:
    TABLE 13a
    Time (hr)
    1 2 4 8 12 18 24
    Mean % dissolved (SGF) 13 20 29 41 51 62 71
    Mean % dissolved (SIF) 14 21 31 44 57 68 80
  • Ex. 14 To prepare an oxycodone HCl controlled release tablet which would dissolve preferentially in a lower pH, the following formula is used:
    TABLE 14
    Ingredients Amt(mg)/Tablet Percentage in Formula
    Oxycodone HCl
    40 30.8
    Eudragit RS30D (solid) 14 10.8
    Spray Dried Lactose 35.25 27.1
    PVP 5 3.9
    Triacetin 2 1.5
    Stearyl Alcohol 25 19.2
    Talc 2.5 1.9
    Magnesium Stearate 1.25 0.9
    Film Coat 5 3.9
    Total 130 100
  • Total Manufacture
    • 1. Mix Eudragit RS30D (suspension) and Triacetin for 5 minutes.
    • 2. Place spray dried lactose, oxycodone HCl, PVP, in a fluid bed drier.
    • 3. Spray the ssuspension onto the powders under fluidization.
    • 4. Pass the granulation through a Comil to reduce lumps.
    • 5. Melt stearyl alcohol at 70° C.
    • 6. Incorporate the molten stearyl alcohol into the dry granulation in a Collete Mixer.
    • 7. Transfer the waxed granulation to a cooling tray and allow the granulation to congeal.
    • 8. Pass the granulation through a Comil.
    • 9. Mix the waxed granulation with talc and magnesium stearate in a Collete Mixer.
    • 10. Compress the lubricated granulation into tablets using a rotary tablet press.
    • 11. Film coat the tablets.
  • These tablets were then tested using the following dissolution methodology described in Example 13.
  • The above tablets were found to have the following dissolution results:
    TABLE 14a
    Time (hr)
    1 2 4 8 12
    Mean % dissolved SGF 39 53 70 90 99
    Mean % dissolved SIF 35 48 65 83 93
  • EXAMPLES 15-19 Controlled Release Hydromorphone Formulations
  • Ex. 15-16 The formula used in Ex. 6 was applied to hydromorphone hydrochloride. Due to the higher potency of hydromorphone, only 8 mg of drug was used. The missing 52 mg was replaced by 52 mg of talc (Ex. 16) or 52 mg of excipients (Ex. 15). The results are shown in FIG. 8.
    TABLE 15
    EX. 15
    Composition Amt. (mg) per Capsule
    Hydromorphone Hydrochloride
    8
    Eudragit RSPO 67.2
    Eudragit L-100 11.2
    Stearic Acid 33.6
    Total 120
  • TABLE 16
    EX. 16
    Composition Amt. (mg) per Capsule
    Hydromorphone Hydrochloride
    8
    Eudragit RSPO 36
    Eudragit L-100 6
    Stearic Acid 18
    Talc 52
    Total 120
  • Ex. 17 1 Hydromorphone HCl once-a-day capsules were produced with the formula set forth in Table 17 below using the technology described in Example 6.
    TABLE 17
    Percentage
    Ingredients Amt(mg)/Capsule in Formula
    Hydromorphone HCL
    8 10
    Eudragit RSPO 53 66.25
    Stearyl Alcohol 19 23.75
    Total 80 100
  • The pellet manufacturing procedure is the same as described in Example 6. However, pellets of 1.0 mm in diameter and 1.0 mm in length were prepared. Each capsule holds 80 mg of pellets and contains 8 mg of hydromorphone HCL.
  • The above capsules were tested using the dissolution methodology described in Example 6.
  • The above capsules were found to have the dissolution results set forth in Table 17a below:
    TABLE 17a
    Time (hr)
    1 2 4 8 12 18 24
    Mean % dissolved 17 28 32 45 56 69 82
  • Ex. 18 Hydromorphone HCl once-a-day capsules were produced with the formula set forth in 18 below as the second example of the technology described in Example 6.
    TABLE 18
    Percentage
    Ingredients Amt(mg)/Capsule in Formula
    Hydromorphone HCl
    8 10
    Eudragit RSPO 48 60
    Stearyl Alcohol 24 30
    Total 80 100
  • The pellet manufacturing procedure and the dissolution method are the same as described in Example 6.
  • The above capsules were found to have the dissolution results set forth in Table 18a below:
    TABLE 18a
    Time (hr)
    1 2 4 8 12 18 24
    Mean % dissolved 23 29 40 56 69 84 96
  • Ex. 19 Hydromorphone HCl once-a-day capsules were produced with the following formula according to the method described Example 6.
    TABLE 19
    Percentage
    Ingredients Amt(mg)/Capsule in Formula
    Hydromorphone HCL
    8 10
    Eudragit RSPO 41.5 51.9
    Eudragit L-100 8.5 10.6
    Stearic Acid 22 27.5
    Total 80 100
  • The manufacturing procedure of the pellets and the dissolution method are the same as described in Example 6.
  • The above capsules were found to have the following dissolution results.
    TABLE 19a
    Time (hr)
    1 2 4 8 12 18 24
    Mean % dissolved 4 14 36 52 64 75 84
  • EXAMPLE 20
  • In this Example, a bioavailability study was undertaken. Fourteen subjects were given the morphine sulfate formulations of Example 3. The results are provided in Table 20 below in FIG. 10.
    TABLE 20
    Group AUC Cmax Tmax
    Example 3 Fasted 230 15.7 2.1
    Example 3 Fed 213 14.0 3.2
  • From the above data, it can be seen that the formulation is an ideal candidate for an extended release or once-a-day product without a food effect.
  • EXAMPLE 21 Bioavailability of Morphine Sulfate Melt Extrusiuon Multiparticulate 60 Mg Capsules
  • A bioavailability study of morphine capsules of Example 6 was conducted in 12 normal male volunteers. Capsules of 60 mg in strength were administered either with or without food in a single dose, two-way crossover study. Blood samples were taken periodically and assayed for morphine concentrations using gas chromatography with mass detection (G/MS). From the data, the following pharmacokinetic parameters were calculated and are indicated in Table 21 below.
    TABLE 21
    AUC,
    Treatment n · hr/ml Cmax, n/ml Tmax, hr
    Fasted 228 15.7 2.1
    Fed 210 14.0 3.2
  • When compared to the typical blood levels of MS Contin®, a single dose twice-a-day marketed morphine sulfate 30 mg tablets, in the fasted state, it can be ssen that the capsules of Example 6 are suitable for once daily administration. At the 24th hour the blood levels are well above MS-Contin and within the therapeutic range (FIG. 11).
  • EXAMPLE 22 Bioavailability of OXY-MEM 20 Mg Capsules
  • A bioavailability study of oxycodone capsules of examples 11 and 13 was conducted in 10 normal male volunteers. Capsules of example 13 were administered either with ot without food. Capsules of example 11 were administered without food. The study was conducted in a single dose, four-way crossover design. Blood samples were taken periodically and assayed for oxycodone concentrations using gas chromatography with mass detection (G/MS).
  • From the data, the following pharmacokinetic parameters were calculated as set forth in Table 22 below:
    TABLE 22
    AUC,
    Treatment n · hr/ml Cmax, n/ml Tmax, hr
    Example 13, fasted 207 9.7 5.3
    Example 13, fed 261 14.8 6.4
    Example 11, fasted 244 12.9 6.0
    Oxycontin, fasted 249 20.8 3.2
  • From the above data, it can be concluded that both Examples 11 and 13, but particularly Example 13, are suitable for once daily administration. This is shown graphically in FIG. 12.
  • EXAMPLE 23 Bioavailability of Example 14 Tablets
  • A bioavailability study of oxycodone controlled release tablets of example 14 was conducted in 25 normal volunteers. These tablets were administered either with or without foo. The study was conducted in a single dose, randomized crossover design. Blood samples were taken periodically and assayed for oxycodone concentrations using gas chromatography with mass detection (GC/MS). The plasma oxycodone concentration versus time curves are shown in FIG. 13.
  • From the data, the following pharmacokinetic parameters were calculated.
    TABLE 23
    Treatment AUC, ng · hr/ml Cmax, ng/ml Tmax, hr
    Example 14, fasted 422 39.3 3.1
    Example 14, fed 416 35.3 4.8
  • Surprisingly, it was found that the controlled release oxycodone HCl preparation, which dissolved preferentially in low pH, does not show substantial food effect. From the Cmax data, it can be seen that there is no significant change in blood oxycodone levels when the drug was taken with food than without food (35.3/39.3=0.09). From the AUC (area under the curve) data, it appears that the amount of drug absorbed with or without food is similar (416/422=0.986).
  • EXAMPLE 24 Bioavailability of HH-MEM 8 Mg Capsules
  • A bioavailability study of hydromorphone capsules of Examples 17 and 18 was conducted using a single dose, five-way crossover study in 12 normal male volunteers. The subjects received either 8 mg of Dilaudid tablet (immediate release) or 8 mg of HH-MEM capsules. Dilaudid tablets were administered after an overnight fast. MEM capsules were administered with or without food. Blood samples were taken periodically and assayed for hydromorphone concentrations using gas chromatography with mass detection (G/MS). From the data, the following pharmacokinetic parameters were calculated.
    TABLE 24
    AUC,
    Treatment n · hr/ml Cmax, n/ml Tmax, hr
    Example 17, fasted 19.00 0.72 6.8
    Example 17, fed 20.10 0.75 2.4
    Example 18, fasted 19.23 0.76 3.9
    Example 18, fed 21.47 0.93 1.9
    Dilaudid, fasted 14.55 3.69 0.7
  • From the data, both formulations 17 and 18 would be suitable for once-a-day administration both not having a food effect, and in fact Example 17 looks ideal. The data of Example 17 is shown graphically in FIG. 14 and the data of Example 18 is shown graphically in FIG. 15.
  • EXAMPLE 25 Steady State Bioavailability of HH-MEM 8 Mg Capsules
  • To assess steady state plasma levels and the effect of food on hydromorphone, a single dose, two-way crossover study was conducted in 12 normal male volunteers. The subjects received either 4 mg of Dilaudid (immediate release) every 6 hours or 16 mg of the capsules according to Example 17 every 24 hours. Venous blood samples were taken at predetermined time points. The plasma hydromorphone concentrations were quantitated using gas chromatography with mass detection (G/MS).
  • From the data from day 4, the following pharmacokinetic parameters were calculated and set forth in Table 25 below.
    TABLE 25
    AUC, Cmax,
    Treatment n · hr/ml n/ml Cmin, n/ml Tmax, hr
    Example 17 36.08 2.15 1.49 5.8
    Dilaudid 33.53 3.44 0.94 1.6
  • The results are shown graphically in FIG. 16. From this data it can be seen that Example 17 is an ideal product for once-a-day administration for either single dose or multiple dose administration.
  • EXAMPLE 26 Bioavailability of HH-MEM 8 Mg capsules
  • To assess bioavailability and effect of food on hydromorphone MEM capsules, a single dose. three-way crossover study was conducted in 12 normal male volunteers. The subjects received either 8 mg of Dilaudid tablet *immediate release) or 8 mg of HH-MEM (Example 19) Dilaudid tablets were administered after an overnight fast. MEM capsules were administered with our without food. Venous blood samples were taken at predetermined at time points. The plasma hydromorphone concentrations were quantitated using gas chromatography with mass detection (G/MS).
  • From the data, the following pharmacokinetic parameters were calculated and are st forth in Table 26 below.
    TABLE 26
    AUC, Cmax,
    Treatment n · hr/ml n/ml Tmax, hr
    Example 19, fasted 15.83 0.52 5.6
    Example 19, fed 16.55 0.65 4.1
    Dilaudid, fasted 16.54 3.15 0.8
  • From the above data it can be cconcluded that a once-a-day Hydromorphone product can be produced using other ingredients than are used for Examples 17 and 18. This data is shown graphically in FIG. 17.
  • EXAMPLE 27 Tramadol HCl 200 Mg SR Tablet
  • The following formula is used to prepare melt extrusion granulation and tablet.
    TABLE 27
    Percentage
    Ingredients Amt(mg)/Tablet in Formula
    Tramadol HCl 200 53.4
    Eudragit RSPO 74 19.8
    Tributyl Citrate 14.8 4.0
    Stearyl Alcohol 74 19.8
    Talc 7.4 2.0
    Magnesium Stearate 3.8 1.0
    Total 374 100
  • Granulation Manufacture
  • a. Extruder system description—The twin screw extruder is consisted of a pair of counterrotating screws and a barrel block equipped with heating/cooling zones. The stranded extrudate is congealed on a conveyor belt and cut into pellets of the desirable size.
  • b. Manufacturing procedure
    • 1. Blend the drug and all the excipients in a proper mixer.
    • 2. Place the mixture in a powder feeder.
    • 3. Set temperatures of the extruder heating zones to approximately 65° C.
    • 4. Set the extruder screw rotation speed to 40 rpm.
    • 5. Start the feeder and the conveyor.
    • 6. After the excipients are melted and the drug embedded in the molten mixture, the viscous mass is extruded as spaghetti-like strands.
    • 7. The extrudate is congealed and hardened while being carried away on a conveyor belt.
    • 8. The stranded extrudate was cut into pellets of 2 mm in diameter and 2-8 cm in length.
  • Tableting
  • The pellets were milled into granules through a suitable screen. The granulation was blended with talc and magnesium stearate. The mixture was then compressed into capsule-shaped tablets.
  • Dissolution Method
    • 1. Apparatus—USP Type II (paddle), 100 rpm at 37° C.
    • 2. The tablet was placed in a tablet sinker clip and immersed in each vessel.
    • 3. Media—900 ml pH 6.5 phosphate buffer.
    • 4. Analytical method—High performance liquid chromatography.
  • The above tablets were found to have the following dissolution results:
    TABLE 27a
    Time (hr)
    1 2 4 8 12 18 24
    Mean % dissolved 24 33 45 61 71 82 88
  • EXAMPLE 28 Tramadol HCl 200 Mg SR Tablet
  • The following formula is used to prepare melt extrusion granulation and tablet with a slower dissolution profile than Example 27.
    TABLE 28
    Percentage
    Ingredients Amt(mg)/Tablet in Formula
    Tramadol HCl 200 44.1
    Ethyl cellulose 110 24.3
    Tributyl Citrate 22 4.9
    Stearyl Alcohol 110 14.3
    Talc 7.4 1.6
    Magnesium Stearate 3.4 0.8
    Total 453.2 100
  • The manufacturing method and dissolution method are the same as described in Example 27. Additional dissolution media used include pH 1.2 simulated gastric fluid (SGF) without enzyme, pH 7.5 simulated intestinal fluid (SIF) without enzyme, and pH 4 phosphate buffer.
  • The above tablets were found to have the following dissolution results:
    TABLE 28a
    Time (hr)
    1 2 4 8 12 18 24
    Mean % dissolved SGF 18 26 35 49 59 70 80
    pH4 17 25 34 49 60 73 83
    pH6.5 17 23 33 46 57 70 81
    SIF 17 23 32 45 56 68 78
  • The results show that the dissolution profiles of Tramadol SR tablets in media of different pH values are similar. Based on our experience with similar formula of other opiates, a formula which demonstrates pH independent dissolution profile would provide a consistent drug release profile in vivo without food effect.
  • The examples provided above are not meant to be exclusive. Many other variations of the present invention would be obvious to those skilled in the art, and are contemplated to be within the scope of the appended claims.

Claims (24)

1. A sustained-release pharmaceutical formulation, comprising a melt-extruded blend of a therapeutically active agent, one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polylners and copolrmers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof; and one or more hydrophobic fusible carriers which provide a further retardant effect and selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said hydrophobic fusible carrier having a melting point from 30 to 200° C., said melt-extruded blend divided into a unit dose containing an effective amount of said therapeutically active agent to render a desired therapeutic effect and providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours.
2. The formulation of claim 1, wherein said extrudate comprises a strand-shaped matrix cut into into multiparticulates having a length of from about 0.1 to about 5 mm in length.
3. The formulation of claim 1, wherein said extrudate has a diameter of from about 0.1 to about 5 mm.
4. The formulation of claim 1, wherein said therapeutically active agent is an opioid analgesic.
5. The formulation of claim 4, wherein said opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, salts thereof and mixtures thereof.
6. The extrudate of claim 1, wherein said opioid analgesic is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine tramadol and mixtures thereof.
7. The formulation of claim 2, wherein a unit dose comprising an effective amount of said multiparticulates to render a therapeutic effect is contained within a gelatin capsule.
8. The formulation of claim 2, wherein a unit dose comprising an effective amount of said multiparticulates to render a therapeutic effect is compressed into a tablet.
9. The formulation of claim 8, wherein said therapeutically active agent is tramadol.
10. The formulation of claim 7 wherein said therapeutically active agent is an opioid analgesic selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone dihydrocodeine, dihydromorphine, tramadol and mixtures thereof.
11. The formulation of claim 10, which provides an in-vitro release (when assessed by the USP Paddle or Basket Method at 100 prm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C. from about 1 to about 42.5% opioid released after one hour, from about 5 to about 65% opioid released after 2 hours, from about 15 to about 85% opioid released after 4 hours, from about 20 to about 90% opioid released after 6 hours, from about 35 to about 95% opioid released after 12 hours, from about 45 to about 100% opioid released after 18 hours, and from about 55 to about 100% opioid released after 24 hours, by weight.
12. The formulation of claim 10, which provides a peak plasma level at from about 2 to about 8 hours after oral administration, and preferably from about 4 to about 6 hours after administration.
13. The formulation of claim 10, which provides a W50 from about 4 to about 12 hours.
14. The formulation of claim 10, which provides a rapid rate of initial rise in the plasma concentration of the opioid after oral administration, such that the peak plasma level obtained in-vivo occurs from about 2 to about 8 hours after oral administration.
15. The formulation of claim 10, which provides a rapid rate of initial rise in the plasma concentration of the opioid after oral administration, such that the absorption half-life is from about 1 to 8 hours after oral administration (in the fasted state).
16. The formulation of claim 10, which provides an in-vitro release (when assessed by the USP Paddle or Basket Method at 100 arm it 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C. from about 12.5 to about 42.5% opioid released after one hour, from about 25 to about 65% opioid released after 2 hours, from about 45 to about 85% opioid released after 4 hours, and greater than about 60% opioid released after 8 hours, by weight.
17. The formulation of claim 1, wjerein said extruded blend is substantially non-porous.
18. A method of preparing a sustained-release pharmaceutical extrudate suitable for oral administration, comprising:
blending a therapeutically active agent together with (1) a hydrophobic material selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof and (2) a hydrophobic fusible carrier selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, said retardant material having a melting point between 30-200° C. and being included in an amount sufficient to further slow the release of the therapeutically active agent,
heating said blend to a temperature sufficient to soften the mixture sufficiently to extrude the same;
extruding said heated mixture as a strand having a diameter of from 0.1-3 mm;
cooling said strand; and
dividing said strand to form non-spheroidal multi-particulates of said extrudate having a length from 0.1-5 mm; and
dividing said non-spheroidal multi-particulates into unit doses containing an effective amount of said therapeutically active agent, said unit dose providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours.
19. The method of claim 18, wherein said therapeutically active agent is an opioid analgesic is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, salts thereof and mixtures thereof.
20. The method of claim 18, further comprising containing said unit dose of said multiparticulates with a gelatine capsule.
21. The method of claim 18, further comprising compressing said unit dose of multi-particulates into a tablet.
22. The method of claim 18m further comprising extruding said heated mixture under vacuum conditions to provide a substantially non-porous extrudate.
23. A sustained-release pharmaceutical formulation, comprising a melt-extruded blend of an opioid analgesic and one or more hydrophobic materials selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof; said melt-extruded blend divided into a unit dose containing an effective amount of said therapeutically active agent to render a desired therapeutic effect and providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours.
24. The extrudate of claim 23, wherein said opioid analgesic is selected from the groups consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine, tramadol and mixtures thereof.
US10/664,602 1994-11-04 2003-09-16 Melt-extruded orally administrable opioid formulations Abandoned US20050089568A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/664,602 US20050089568A1 (en) 1994-11-04 2003-09-16 Melt-extruded orally administrable opioid formulations
US12/722,974 US20100172974A1 (en) 1994-11-04 2010-03-12 Melt-extruded orally administrable opioid formulations

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US08/334,209 US5965161A (en) 1994-11-04 1994-11-04 Extruded multi-particulates
PCT/US1995/014745 WO1996014058A1 (en) 1994-11-04 1995-11-03 Melt-extruded orally administrable opioid formulations
US08/833,948 US5958452A (en) 1994-11-04 1997-04-10 Extruded orally administrable opioid formulations
US09/360,056 US6261599B1 (en) 1994-11-04 1999-07-23 Melt-extruded orally administrable opioid formulations
US09/777,616 US6743442B2 (en) 1994-11-04 2001-02-06 Melt-extruded orally administrable opioid formulations
US10/664,602 US20050089568A1 (en) 1994-11-04 2003-09-16 Melt-extruded orally administrable opioid formulations

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US09/360,056 Continuation US6261599B1 (en) 1994-11-04 1999-07-23 Melt-extruded orally administrable opioid formulations
US09/777,616 Continuation US6743442B2 (en) 1994-11-04 2001-02-06 Melt-extruded orally administrable opioid formulations

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US7655105A Continuation 1994-11-04 2005-03-09

Publications (1)

Publication Number Publication Date
US20050089568A1 true US20050089568A1 (en) 2005-04-28

Family

ID=23306123

Family Applications (11)

Application Number Title Priority Date Filing Date
US08/334,209 Expired - Lifetime US5965161A (en) 1994-11-04 1994-11-04 Extruded multi-particulates
US08/833,948 Expired - Lifetime US5958452A (en) 1994-11-04 1997-04-10 Extruded orally administrable opioid formulations
US09/358,828 Expired - Lifetime US6335033B2 (en) 1994-11-04 1999-07-22 Melt-extrusion multiparticulates
US09/360,056 Expired - Lifetime US6261599B1 (en) 1994-11-04 1999-07-23 Melt-extruded orally administrable opioid formulations
US09/777,616 Expired - Fee Related US6743442B2 (en) 1994-11-04 2001-02-06 Melt-extruded orally administrable opioid formulations
US10/038,867 Expired - Fee Related US6706281B2 (en) 1994-11-04 2002-01-02 Melt-extrusion multiparticulates
US10/664,602 Abandoned US20050089568A1 (en) 1994-11-04 2003-09-16 Melt-extruded orally administrable opioid formulations
US10/690,389 Abandoned US20040081694A1 (en) 1994-11-04 2003-10-21 Melt-extruded orally administrable opioid formulations
US10/745,950 Expired - Fee Related US7510727B2 (en) 1994-11-04 2003-12-23 Melt-extrusion multiparticulates
US12/372,460 Abandoned US20090148517A1 (en) 1994-11-04 2009-02-17 Melt-extrusion multiparticulates
US12/722,974 Abandoned US20100172974A1 (en) 1994-11-04 2010-03-12 Melt-extruded orally administrable opioid formulations

Family Applications Before (6)

Application Number Title Priority Date Filing Date
US08/334,209 Expired - Lifetime US5965161A (en) 1994-11-04 1994-11-04 Extruded multi-particulates
US08/833,948 Expired - Lifetime US5958452A (en) 1994-11-04 1997-04-10 Extruded orally administrable opioid formulations
US09/358,828 Expired - Lifetime US6335033B2 (en) 1994-11-04 1999-07-22 Melt-extrusion multiparticulates
US09/360,056 Expired - Lifetime US6261599B1 (en) 1994-11-04 1999-07-23 Melt-extruded orally administrable opioid formulations
US09/777,616 Expired - Fee Related US6743442B2 (en) 1994-11-04 2001-02-06 Melt-extruded orally administrable opioid formulations
US10/038,867 Expired - Fee Related US6706281B2 (en) 1994-11-04 2002-01-02 Melt-extrusion multiparticulates

Family Applications After (4)

Application Number Title Priority Date Filing Date
US10/690,389 Abandoned US20040081694A1 (en) 1994-11-04 2003-10-21 Melt-extruded orally administrable opioid formulations
US10/745,950 Expired - Fee Related US7510727B2 (en) 1994-11-04 2003-12-23 Melt-extrusion multiparticulates
US12/372,460 Abandoned US20090148517A1 (en) 1994-11-04 2009-02-17 Melt-extrusion multiparticulates
US12/722,974 Abandoned US20100172974A1 (en) 1994-11-04 2010-03-12 Melt-extruded orally administrable opioid formulations

Country Status (17)

Country Link
US (11) US5965161A (en)
EP (7) EP1741426B1 (en)
JP (1) JP3186064B2 (en)
KR (1) KR100232945B1 (en)
AT (5) ATE452627T1 (en)
AU (1) AU705894B2 (en)
CA (1) CA2204180C (en)
DE (5) DE69535767D1 (en)
DK (5) DK1449530T3 (en)
ES (5) ES2282757T3 (en)
HK (3) HK1069110A1 (en)
HU (1) HUT77626A (en)
IL (5) IL142413A (en)
PT (5) PT1449531E (en)
TW (1) TW425288B (en)
WO (1) WO1996014058A1 (en)
ZA (1) ZA959367B (en)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040013697A1 (en) * 2000-05-30 2004-01-22 Gunther Berndl Self-emulsifying active substance formulation and use of this formulation
US20060165790A1 (en) * 2003-06-27 2006-07-27 Malcolm Walden Multiparticulates
KR100656019B1 (en) * 2005-10-20 2006-12-08 현대자동차주식회사 New polyimide-co-polybenzimidazole and polymer electrolytes membrane using them
US20070048376A1 (en) * 2005-08-24 2007-03-01 Penwest Pharmaceuticals Co. Sustained release formulations of nalbuphine
US20070185145A1 (en) * 2006-02-03 2007-08-09 Royds Robert B Pharmaceutical composition containing a central opioid agonist, a central opioid antagonist, and a peripheral opioid antagonist, and method for making the same
US20080069891A1 (en) * 2006-09-15 2008-03-20 Cima Labs, Inc. Abuse resistant drug formulation
US20090022798A1 (en) * 2007-07-20 2009-01-22 Abbott Gmbh & Co. Kg Formulations of nonopioid and confined opioid analgesics
US20090317355A1 (en) * 2006-01-21 2009-12-24 Abbott Gmbh & Co. Kg, Abuse resistant melt extruded formulation having reduced alcohol interaction
US20100172989A1 (en) * 2006-01-21 2010-07-08 Abbott Laboratories Abuse resistant melt extruded formulation having reduced alcohol interaction
US7811604B1 (en) 2005-11-14 2010-10-12 Barr Laboratories, Inc. Non-effervescent, orally disintegrating solid pharmaceutical dosage forms comprising clozapine and methods of making and using the same
US20110015216A1 (en) * 2003-08-28 2011-01-20 Abbott Laboratories Solid Pharmaceutical Dosage Form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
US8765175B2 (en) 2005-08-24 2014-07-01 Endo Pharmaceuticals Inc Sustained release formulation of nalbuphine
US8927025B2 (en) 2010-05-11 2015-01-06 Cima Labs Inc. Alcohol-resistant metoprolol-containing extended-release oral dosage forms
US8951555B1 (en) 2000-10-30 2015-02-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8975273B2 (en) 1999-10-29 2015-03-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9226907B2 (en) 2008-02-01 2016-01-05 Abbvie Inc. Extended release hydrocodone acetaminophen and related methods and uses thereof
US9259872B2 (en) 2004-08-31 2016-02-16 Euro-Celtique S.A. Multiparticulates
US9707224B2 (en) 2013-10-31 2017-07-18 Cima Labs Inc. Immediate release abuse-deterrent granulated dosage forms
US9861629B1 (en) 2015-10-07 2018-01-09 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10335375B2 (en) 2017-05-30 2019-07-02 Patheon Softgels, Inc. Anti-overingestion abuse deterrent compositions
US10335405B1 (en) 2016-05-04 2019-07-02 Patheon Softgels, Inc. Non-burst releasing pharmaceutical composition
US11324707B2 (en) 2019-05-07 2022-05-10 Clexio Biosciences Ltd. Abuse-deterrent dosage forms containing esketamine

Families Citing this family (306)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5266331A (en) * 1991-11-27 1993-11-30 Euroceltique, S.A. Controlled release oxycodone compositions
US5958459A (en) * 1991-12-24 1999-09-28 Purdue Pharma L.P. Opioid formulations having extended controlled released
US5968551A (en) * 1991-12-24 1999-10-19 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US5478577A (en) * 1993-11-23 1995-12-26 Euroceltique, S.A. Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level
US20080075781A1 (en) * 1992-11-25 2008-03-27 Purdue Pharma Lp Controlled release oxycodone compositions
NZ260408A (en) 1993-05-10 1996-05-28 Euro Celtique Sa Controlled release preparation comprising tramadol
US20070275062A1 (en) * 1993-06-18 2007-11-29 Benjamin Oshlack Controlled release oxycodone compositions
US5914131A (en) * 1994-07-07 1999-06-22 Alza Corporation Hydromorphone therapy
GB9422154D0 (en) 1994-11-03 1994-12-21 Euro Celtique Sa Pharmaceutical compositions and method of producing the same
US20020006438A1 (en) * 1998-09-25 2002-01-17 Benjamin Oshlack Sustained release hydromorphone formulations exhibiting bimodal characteristics
US5965161A (en) * 1994-11-04 1999-10-12 Euro-Celtique, S.A. Extruded multi-particulates
DE19531277A1 (en) * 1995-08-25 1997-02-27 Basf Ag Use of lipids as an aid in the production of solid dosage forms by the melt extrusion process
GB9519363D0 (en) 1995-09-22 1995-11-22 Euro Celtique Sa Pharmaceutical formulation
DE19539360A1 (en) * 1995-10-23 1997-04-24 Basf Ag Process for the production of solid dosage forms
GB9614902D0 (en) * 1996-07-16 1996-09-04 Rhodes John Sustained release composition
JPH1050306A (en) * 1996-07-31 1998-02-20 Toyota Autom Loom Works Ltd Manufacture of hydrogen storage alloy electrode
EP1342548B1 (en) * 1996-10-28 2015-12-23 General Mills, Inc. Embedding and encapsulation of controlled release particles and encapsulated product
DE69730982T2 (en) * 1996-10-28 2005-09-01 General Mills, Inc., Minneapolis Encapsulation and encapsulation of particles for controlled release
BE1010803A3 (en) * 1996-12-16 1999-02-02 Therabel Research Sa Tablets pharmaceutical sustained release tramadol a basic and their preparation.
US5968547A (en) 1997-02-24 1999-10-19 Euro-Celtique, S.A. Method of providing sustained analgesia with buprenorphine
WO1999001111A1 (en) 1997-07-02 1999-01-14 Euro-Celtique, S.A. Stabilized sustained release tramadol formulations
DE19733505A1 (en) * 1997-08-01 1999-02-04 Knoll Ag Fast acting analgesic
RS49982B (en) * 1997-09-17 2008-09-29 Euro-Celtique S.A., Synergistic analgesic combination of opioid analgesic and cyclooxygenase-2 inhibitor
US20030158220A1 (en) * 1997-11-03 2003-08-21 Foss Joseph F. Use of methylnaltrexone and related compounds to treat chronic opioid use side effects
US6274591B1 (en) * 1997-11-03 2001-08-14 Joseph F. Foss Use of methylnaltrexone and related compounds
US6559158B1 (en) * 1997-11-03 2003-05-06 Ur Labs, Inc. Use of methylnaltrexone and related compounds to treat chronic opioid use side affects
CN1204890C (en) * 1997-12-22 2005-06-08 欧罗赛铁克股份有限公司 Method for preventing abuse of opioid dosage forms
AU773642C (en) 1997-12-22 2006-04-06 Mundipharma Pty Limited Opioid agonist/antagonist combinations
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
US8524277B2 (en) 1998-03-06 2013-09-03 Alza Corporation Extended release dosage form
US6074689A (en) * 1998-03-10 2000-06-13 Immucell Corporation Colonic delivery of protein or peptide compositions
DE69941212D1 (en) 1998-03-23 2009-09-17 Gen Mills Inc PLASTERING COMPONENTS IN EDIBLE PRODUCTS
AR018321A1 (en) * 1998-03-26 2001-11-14 Alza Corp A DOSAGE FORM OF PROLONGED LIBERATION THAT INCLUDES OXIBUTININE AND THE USES OF OXIBUTININE AND THE DOSAGE FORM OF PROLONGED LIBERATION.
SA99191255B1 (en) 1998-11-30 2006-11-25 جي دي سيرل اند كو celecoxib compounds
DE19859636A1 (en) * 1998-12-23 2000-06-29 Hexal Ag Controlled release pharmaceutical composition with tilidine mesylate as active ingredient
US7429407B2 (en) * 1998-12-30 2008-09-30 Aeromatic Fielder Ag Process for coating small bodies, including tablets
EP1140033B1 (en) * 1999-01-14 2005-10-12 Amcol International Corporation Improved controlled release compositions
DE19918325A1 (en) 1999-04-22 2000-10-26 Euro Celtique Sa Extruded drug dosage form, e.g. granulate for tableting, comprising an active agent in a polysaccharide-containing matrix, giving a release profile which is controllable by extrusion conditions and/or the inclusion of additives
FR2795326B1 (en) * 1999-06-28 2001-08-31 Adir SOLID THERMOFORMABLE PHARMACEUTICAL COMPOSITION WITH CONTROLLED RELEASE
US20030236236A1 (en) * 1999-06-30 2003-12-25 Feng-Jing Chen Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
DE19940944B4 (en) * 1999-08-31 2006-10-12 Grünenthal GmbH Retarded, oral, pharmaceutical dosage forms
DE19943501A1 (en) * 1999-09-10 2001-03-15 Basf Ag Underwater granulation of melts containing active ingredients
US6500463B1 (en) 1999-10-01 2002-12-31 General Mills, Inc. Encapsulation of sensitive components into a matrix to obtain discrete shelf-stable particles
US6491953B1 (en) 2000-01-07 2002-12-10 Amcol International Corporation Controlled release compositions and method
US6953593B2 (en) * 2000-02-01 2005-10-11 Lipoprotein Technologies, Inc. Sustained-release microencapsulated delivery system
PT2092936E (en) 2000-02-08 2013-06-20 Euro Celtique Sa Tamper-resistant oral opioid agonist formulations
NZ521034A (en) * 2000-02-28 2004-08-27 Vectura Ltd Improvements in or relating to the delivery of oral drugs
US6436453B1 (en) 2000-06-16 2002-08-20 General Mills, Inc. Production of oil encapsulated minerals and vitamins in a glassy matrix
US6468568B1 (en) 2000-06-16 2002-10-22 General Mills, Inc. Oligosaccharide encapsulated mineral and vitamin ingredients
FR2818552B1 (en) * 2000-12-26 2003-02-07 Servier Lab SOLID THERMOFORMABLE PHARMACEUTICAL COMPOSITIONS FOR THE CONTROLLED RELEASE OF IVABRADINE
FR2818549B1 (en) * 2000-12-26 2003-02-07 Servier Lab SOLID THERMOFORMABLE PHARMACEUTICAL COMPOSITION FOR THE CONTROLLED RELEASE OF TRIMETAZIDINE
FR2818550B1 (en) * 2000-12-26 2003-02-07 Servier Lab SOLID THERMOFORMABLE PHARMACEUTICAL COMPOSITION FOR THE CONTROLLED RELEASE OF PERINDOPRIL
EP1386251A4 (en) * 2001-03-02 2005-11-23 Euro Celtique Sa Method and apparatus for compounding individualized dosage forms
WO2002072064A2 (en) * 2001-03-09 2002-09-19 Dow Global Technologies Inc. Granular composition comprising an active compound and a cellulose ether and the use thereof
US7858118B2 (en) * 2001-04-11 2010-12-28 Galephar Pharmaceutical Research, Inc. Extended release composition containing Tramadol
UA81224C2 (en) * 2001-05-02 2007-12-25 Euro Celtic S A Dosage form of oxycodone and use thereof
US20110104214A1 (en) 2004-04-15 2011-05-05 Purdue Pharma L.P. Once-a-day oxycodone formulations
CA2446550C (en) 2001-05-11 2012-03-06 Endo Pharmaceuticals, Inc. Abuse-resistant controlled-release opioid dosage form
US20030070584A1 (en) 2001-05-15 2003-04-17 Cynthia Gulian Dip coating compositions containing cellulose ethers
AUPR510001A0 (en) * 2001-05-18 2001-06-14 Jupitar Pty Ltd Formulation and method
JP4310605B2 (en) 2001-05-25 2009-08-12 大塚製薬株式会社 Pharmaceutical composition
US20030022909A1 (en) * 2001-06-05 2003-01-30 University Of Chicago Use of methylnaltrexone to treat immune suppression
GB0113841D0 (en) * 2001-06-07 2001-08-01 Boots Co Plc Therapeutic agents
US7968119B2 (en) * 2001-06-26 2011-06-28 Farrell John J Tamper-proof narcotic delivery system
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
WO2003004032A1 (en) * 2001-07-06 2003-01-16 Endo Pharmaceuticals, Inc. Oral administration of 6-hydroxy-oxymorphone for use as an analgesic
PL207748B1 (en) * 2001-07-06 2011-01-31 Penwest Pharmaceuticals Company Sustained release formulations of oxymorphone
DE60230632D1 (en) 2001-07-18 2009-02-12 Euro Celtique Sa PHARMACEUTICAL COMBINATIONS OF OXYCODONE AND NALOXONE
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
US7157103B2 (en) * 2001-08-06 2007-01-02 Euro-Celtique S.A. Pharmaceutical formulation containing irritant
DE60232417D1 (en) 2001-08-06 2009-07-02 Euro Celtique Sa OPIOID AGONIST FORMULATIONS WITH FREEZER AND SEQUESTRATED ANTAGONIST
WO2003013433A2 (en) 2001-08-06 2003-02-20 Euro-Celtique S.A. Sequestered antagonist formulations
US20030044458A1 (en) * 2001-08-06 2003-03-06 Curtis Wright Oral dosage form comprising a therapeutic agent and an adverse-effect agent
DE10141650C1 (en) 2001-08-24 2002-11-28 Lohmann Therapie Syst Lts Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate
EP1429744A1 (en) 2001-09-21 2004-06-23 Egalet A/S Morphine polymer release system
US20040234602A1 (en) 2001-09-21 2004-11-25 Gina Fischer Polymer release system
JP2005523876A (en) * 2001-09-26 2005-08-11 ペンウェスト ファーマシューティカルズ カンパニー Opioid formulations with reduced potential for abuse
US8309118B2 (en) 2001-09-28 2012-11-13 Mcneil-Ppc, Inc. Film forming compositions containing sucralose
US7491407B2 (en) * 2001-10-31 2009-02-17 North Carolina State University Fiber-based nano drug delivery systems (NDDS)
HRP20020124A2 (en) * 2002-02-11 2003-10-31 Pliva D D Sustained/controlled release solid formulation as a novel drug delivery system with reduced risk of dose dumping
US20050182056A9 (en) * 2002-02-21 2005-08-18 Seth Pawan Modified release formulations of at least one form of tramadol
US8128957B1 (en) 2002-02-21 2012-03-06 Valeant International (Barbados) Srl Modified release compositions of at least one form of tramadol
DE10208344A1 (en) * 2002-02-27 2003-09-04 Roehm Gmbh Melt extrusion of active ingredient salts
CN102813654A (en) 2002-04-05 2012-12-12 欧洲凯尔蒂克公司 Matrix for sustained, invariant and independent release of active compounds
WO2003090717A1 (en) * 2002-04-23 2003-11-06 Nanotherapeutics, Inc Process of forming and modifying particles and compositions produced thereby
EP1513497A2 (en) * 2002-05-31 2005-03-16 Alza Corporation Dosage forms and compositions for osmotic delivery of variable dosages of oxycodone
US7776314B2 (en) 2002-06-17 2010-08-17 Grunenthal Gmbh Abuse-proofed dosage system
GB0214013D0 (en) * 2002-06-18 2002-07-31 Euro Celtique Sa Pharmaceutical product
JP4694207B2 (en) * 2002-07-05 2011-06-08 コルジウム ファーマシューティカル, インコーポレイテッド Abuse deterrent pharmaceutical compositions for opioids and other drugs
US10004729B2 (en) 2002-07-05 2018-06-26 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
US8557291B2 (en) * 2002-07-05 2013-10-15 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
US8840928B2 (en) * 2002-07-05 2014-09-23 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
ES2677769T3 (en) * 2002-09-20 2018-08-06 Alpharma Pharmaceuticals Llc Sequestering subunit and related compositions and procedures
US20050020613A1 (en) * 2002-09-20 2005-01-27 Alpharma, Inc. Sustained release opioid formulations and method of use
US20090162431A1 (en) * 2002-09-21 2009-06-25 Shuyi Zhang Sustained release formulations containing acetaminophen and tramadol
WO2004026262A2 (en) 2002-09-23 2004-04-01 Verion, Inc. Abuse-resistant pharmaceutical compositions
US8487002B2 (en) * 2002-10-25 2013-07-16 Paladin Labs Inc. Controlled-release compositions
TWI319713B (en) * 2002-10-25 2010-01-21 Sustained-release tramadol formulations with 24-hour efficacy
ES2553136T3 (en) 2002-12-13 2015-12-04 Durect Corporation Oral drug delivery system comprising high viscosity liquid vehicle materials
US20040115287A1 (en) * 2002-12-17 2004-06-17 Lipocine, Inc. Hydrophobic active agent compositions and methods
DE10300325A1 (en) 2003-01-09 2004-07-22 Hexal Ag Granules with oily substance, manufacturing process and tablet
CN100500130C (en) * 2003-01-23 2009-06-17 株式会社太平洋 Sustained-release preparations and method for producing the same
US7136656B2 (en) * 2003-03-20 2006-11-14 Interdigital Technology Corporation Method of fast dynamic channel allocation call admission control for radio link addition in radio resource management
DE602004031096D1 (en) 2003-03-26 2011-03-03 Egalet As MORPHINE SYSTEM WITH CONTROLLED RELEASE
CA2520321A1 (en) * 2003-04-04 2004-10-14 Pharmacia Corporation Oral extended release compressed tablets of multiparticulates
EP2368553B1 (en) 2003-04-08 2014-12-31 Progenics Pharmaceuticals, Inc. Pharmaceutical formulations containing methylnaltrexone
US20040202717A1 (en) 2003-04-08 2004-10-14 Mehta Atul M. Abuse-resistant oral dosage forms and method of use thereof
JP2006522819A (en) * 2003-04-08 2006-10-05 プロジェニックス ファーマシューティカルズ,インコーポレーテッド Combination therapy of constipation combined with laxatives and peripheral opioid antagonists
BRPI0409128A (en) * 2003-04-08 2006-03-28 Progenics Pharm Inc use of peripheral opioid antagonists, especially methylnaltrexone to treat irritable bowel syndrome
EP1615625A4 (en) 2003-04-21 2010-12-15 Euro Celtique Sa Tamper resistant dosage form comprising co-extruded, adverse agent particles and process of making same
MY135852A (en) * 2003-04-21 2008-07-31 Euro Celtique Sa Pharmaceutical products
TWI357815B (en) * 2003-06-27 2012-02-11 Euro Celtique Sa Multiparticulates
DE102004020220A1 (en) * 2004-04-22 2005-11-10 Grünenthal GmbH Process for the preparation of a secured against misuse, solid dosage form
DE10336400A1 (en) 2003-08-06 2005-03-24 Grünenthal GmbH Anti-abuse dosage form
JP4939217B2 (en) * 2003-08-06 2012-05-23 グリューネンタ−ル・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Abuse prevention dosage form
DE102004032051A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Process for the preparation of a secured against misuse, solid dosage form
US20070048228A1 (en) 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
DE10361596A1 (en) * 2003-12-24 2005-09-29 Grünenthal GmbH Process for producing an anti-abuse dosage form
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
DE102005005446A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Break-resistant dosage forms with sustained release
US20060172006A1 (en) * 2003-10-10 2006-08-03 Vincent Lenaerts Sustained-release tramadol formulations with 24-hour clinical efficacy
US20050089558A1 (en) * 2003-10-28 2005-04-28 Alamo Pharmaceuticals, Llc Compositions and methods for the co-formulation and administration of tramadol and propoxyphene
CA2547773A1 (en) * 2003-12-04 2005-06-16 Pfizer Products Inc. Spray-congeal process using an extruder for preparing multiparticulate azithromycin compositions containing preferably a poloxamer and a glyceride
WO2005053639A2 (en) * 2003-12-04 2005-06-16 Pfizer Products Inc. Controlled release multiparticulates formed with dissolution enhancers
AU2004294817B2 (en) 2003-12-04 2007-01-25 Pfizer Products Inc. Method for making pharmaceutical multiparticulates
BRPI0417348A (en) 2003-12-04 2007-03-13 Pfizer Prod Inc spray gelatinization process using an extruder for preparing multiparticulate crystalline drug compositions preferably containing a poloxamer and a glyceride
WO2005053652A1 (en) 2003-12-04 2005-06-16 Pfizer Products Inc. Multiparticulate crystalline drug compositions containing a poloxamer and a glyceride
US6984403B2 (en) 2003-12-04 2006-01-10 Pfizer Inc. Azithromycin dosage forms with reduced side effects
EP1694304A2 (en) * 2003-12-04 2006-08-30 Pfizer Products Inc. Azithromycin multiparticulate dosage forms by liquid-based processes
EP1691786A1 (en) * 2003-12-04 2006-08-23 Pfizer Products Inc. Multiparticulate compositions with improved stability
US8883204B2 (en) * 2003-12-09 2014-11-11 Purdue Pharma L.P. Tamper resistant co-extruded dosage form containing an active agent and an adverse agent and process of making same
DE602004005076T2 (en) * 2003-12-09 2007-11-15 Euro-Celtique S.A. CO-EXTRUDED SAFETY DOSAGE FORM WITH AN ACTIVE AGENT AND AN ADVERSE AGENT AND METHOD OF MANUFACTURING THEREOF
GB0403098D0 (en) * 2004-02-12 2004-03-17 Euro Celtique Sa Extrusion
GB0403100D0 (en) * 2004-02-12 2004-03-17 Euro Celtique Sa Particulates
GB0501638D0 (en) * 2005-01-28 2005-03-02 Euro Celtique Sa Particulates
TWI350762B (en) * 2004-02-12 2011-10-21 Euro Celtique Sa Particulates
DE602005012244D1 (en) * 2004-03-30 2009-02-26 Euro Celtique Sa MANIPULATION SAFE DOSING FORM WITH AN ADSORBEN AND AN ADVERSE MEDIUM
EP1604666A1 (en) 2004-06-08 2005-12-14 Euro-Celtique S.A. Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD)
EP1604667A1 (en) * 2004-06-08 2005-12-14 Euro-Celtique S.A. Opioids for the treatment of the restless leg syndrome
EP3326617A1 (en) * 2004-06-12 2018-05-30 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
DE102004032049A1 (en) * 2004-07-01 2006-01-19 Grünenthal GmbH Anti-abuse, oral dosage form
AR049562A1 (en) * 2004-07-01 2006-08-16 Gruenenthal Gmbh ORAL PHARMACEUTICAL FORMS, WITH CONTROLLED OPIOID RELEASE, PROTECTED AGAINST ABUSE AND PROCEDURE FOR PREPARATION
CA2572928A1 (en) * 2004-07-22 2006-02-26 Amorepacific Corporation Sustained-release preparations containing topiramate and the producing method thereof
KR20070048272A (en) * 2004-09-01 2007-05-08 유로-셀띠끄 소시에떼 아노님 Opioid dosage forms having dose proportional steady state cave and auc and less than dose proportional single dose cmax
TWI436991B (en) 2004-11-22 2014-05-11 Euro Celtique Sa Methods for purifying trans-(-)-△9-tetrahydrocannabinol and trans-(+)-△9-tetrahydrocannabinol
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.
TWI432196B (en) * 2005-01-18 2014-04-01 Euro Celtique Sa Method of treating visceral pain
EP1845989A1 (en) * 2005-01-20 2007-10-24 Progenics Pharmaceuticals, Inc. Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction
EP2319499A1 (en) * 2005-01-28 2011-05-11 Euro-Celtique S.A. Alcohol resistant dosage forms
DE102005005449A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Process for producing an anti-abuse dosage form
EP1702558A1 (en) 2005-02-28 2006-09-20 Euro-Celtique S.A. Method and device for the assessment of bowel function
EP1695700A1 (en) * 2005-02-28 2006-08-30 Euro-Celtique S.A. Dosage form containing oxycodone and naloxone
US9662325B2 (en) 2005-03-07 2017-05-30 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
WO2006096626A2 (en) 2005-03-07 2006-09-14 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US8518962B2 (en) 2005-03-07 2013-08-27 The University Of Chicago Use of opioid antagonists
US8524731B2 (en) 2005-03-07 2013-09-03 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US20090023778A1 (en) * 2005-04-28 2009-01-22 Eisai R&D Management Co., Ltd. Composition Containing Anti-Dementia Drug
GB0509276D0 (en) * 2005-05-06 2005-06-15 Univ Cranfield Synthetic receptor
CN101166517B (en) * 2005-05-10 2012-01-04 诺瓦提斯公司 Extrusion process for making compositions with poorly compressible therapeutic compounds
US20100152299A1 (en) * 2005-05-10 2010-06-17 Madhav Vasanthavada Process for making compositions with poorly compressible therapeutic compounds
AU2011224098B2 (en) * 2005-05-10 2013-10-31 Novartis Ag Extrusion process for making compositions with poorly compressible therapeutic compounds
US20060286148A1 (en) * 2005-05-18 2006-12-21 Ppd, Inc. Method of forming implants
AR057035A1 (en) 2005-05-25 2007-11-14 Progenics Pharm Inc SYNTHESIS OF (R) -N-METHYLNTREXONE, PHARMACEUTICAL COMPOSITIONS AND USES
AR057325A1 (en) 2005-05-25 2007-11-28 Progenics Pharm Inc SYNTHESIS OF (S) -N-METHYLNTREXONE, PHARMACEUTICAL COMPOSITIONS AND USES
US20080194611A1 (en) * 2005-06-03 2008-08-14 Alverdy John C Modulation of Cell Barrier Dysfunction
ES2344313T3 (en) * 2005-06-09 2010-08-24 Euro-Celtique S.A. PHARMACEUTICAL COMPOSITIONS OF A NEUROACTIVE STEROID AND USES OF THE SAME.
TWI366460B (en) 2005-06-16 2012-06-21 Euro Celtique Sa Cannabinoid active pharmaceutical ingredient for improved dosage forms
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
DK1931346T3 (en) 2005-09-09 2012-10-22 Angelini Labopharm Llc Trazodone composition for once daily administration
CA2623237C (en) * 2005-09-23 2013-07-09 F. Hoffmann-La Roche Ag Novel dosage formulation
US20070160960A1 (en) * 2005-10-21 2007-07-12 Laser Shot, Inc. System and method for calculating a projectile impact coordinates
US7803413B2 (en) 2005-10-31 2010-09-28 General Mills Ip Holdings Ii, Llc. Encapsulation of readily oxidizable components
PL116330U1 (en) * 2005-10-31 2007-04-02 Alza Corp Method for the reduction of alcohol provoked rapid increase in the released dose of the orally administered opioide with prolonged liberation
GB2431875A (en) * 2005-10-31 2007-05-09 Alza Corp Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms
CN1957909B (en) * 2005-10-31 2013-09-11 阿尔扎公司 Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms
WO2008134071A1 (en) 2007-04-26 2008-11-06 Theraquest Biosciences, Inc. Multimodal abuse resistant extended release formulations
US20090082466A1 (en) * 2006-01-27 2009-03-26 Najib Babul Abuse Resistant and Extended Release Formulations and Method of Use Thereof
US8329744B2 (en) 2005-11-02 2012-12-11 Relmada Therapeutics, Inc. Methods of preventing the serotonin syndrome and compositions for use thereof
WO2007056142A2 (en) * 2005-11-02 2007-05-18 Theraquest Biosciences, Llc Methods of preventing the serotonin syndrome and compositions for use therefor
EP1810678A1 (en) 2006-01-19 2007-07-25 Holger Lars Hermann Use of morphine and naloxone for drug substitution
JP2009523833A (en) * 2006-01-21 2009-06-25 アボット ゲーエムベーハー ウント カンパニー カーゲー Formulations and methods for drug delivery
US20070190141A1 (en) * 2006-02-16 2007-08-16 Aaron Dely Extended release opiate composition
US20070212414A1 (en) * 2006-03-08 2007-09-13 Penwest Pharmaceuticals Co. Ethanol-resistant sustained release formulations
FI20060501L (en) * 2006-05-22 2007-11-23 Biohit Oyj Composition and method for binding acetaldehyde in the stomach
EP1859788A1 (en) * 2006-05-24 2007-11-28 Abbott GmbH & Co. KG Production of enveloped pharmaceutical dosage forms
SI2484346T1 (en) 2006-06-19 2017-05-31 Alpharma Pharmaceuticals Llc Pharmaceutical compositions
AU2007275034A1 (en) * 2006-07-21 2008-01-24 Lab International Srl Hydrophilic abuse deterrent delivery system
SA07280459B1 (en) 2006-08-25 2011-07-20 بيورديو فارما إل. بي. Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic
US8128460B2 (en) * 2006-09-14 2012-03-06 The Material Works, Ltd. Method of producing rust inhibitive sheet metal through scale removal with a slurry blasting descaling cell
US20080081067A1 (en) * 2006-10-03 2008-04-03 Gupta Manishkumar Sustained release pharmaceutical compositions of venlafaxine and process for preparation thereof
ES2524556T3 (en) 2006-10-09 2014-12-10 Charleston Laboratories, Inc. Pharmaceutical compositions
DE102007009243A1 (en) * 2007-02-22 2008-09-18 Evonik Röhm Gmbh Pellets with a drug matrix and a polymer coating, and a method for producing the pellets
DE102007009242A1 (en) 2007-02-22 2008-09-18 Evonik Röhm Gmbh Pellets with enteric-coated matix
DE102007011485A1 (en) 2007-03-07 2008-09-11 Grünenthal GmbH Dosage form with more difficult abuse
GB2447898B (en) * 2007-03-24 2011-08-17 Reckitt Benckiser Healthcare A tablet having improved stability with at least two actives
JP5461386B2 (en) 2007-03-29 2014-04-02 プロジェニックス ファーマシューティカルズ,インコーポレーテッド Peripheral opioid receptor antagonists and uses thereof
ES2540551T3 (en) 2007-03-29 2015-07-10 Wyeth Llc Peripheral opioid receptor antagonists and uses thereof
MX351611B (en) 2007-03-29 2017-10-20 Wyeth Llc Crystal forms of (r) -n-methylnaltrexone bromide and uses thereof.
DE102007025858A1 (en) * 2007-06-01 2008-12-04 Grünenthal GmbH Process for the preparation of a medicament dosage form
EP2155167A2 (en) 2007-06-04 2010-02-24 Egalet A/S Controlled release pharmaceutical compositions for prolonged effect
DE102007026550A1 (en) * 2007-06-08 2008-12-11 Bayer Healthcare Ag Extrudates with improved taste masking
US20090124650A1 (en) * 2007-06-21 2009-05-14 Endo Pharmaceuticals, Inc. Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instructions on Effects of Alcohol
WO2009032246A2 (en) 2007-09-03 2009-03-12 Nanotherapeutics, Inc. Particulate compositions for delivery of poorly soluble drugs
JP4879351B2 (en) 2007-10-19 2012-02-22 大塚製薬株式会社 Pharmaceutical solid formulation
AU2008335809A1 (en) 2007-12-06 2009-06-18 Durect Corporation Methods useful for the treatment of pain, arthritic conditions, or inflammation associated with a chronic condition
EP2224808A4 (en) * 2007-12-17 2013-11-27 Alpharma Pharmaceuticals Llc Pharmaceutical composition
US20100151014A1 (en) * 2008-12-16 2010-06-17 Alpharma Pharmaceuticals, Llc Pharmaceutical composition
US8623418B2 (en) 2007-12-17 2014-01-07 Alpharma Pharmaceuticals Llc Pharmaceutical composition
EP3090743A1 (en) 2008-01-09 2016-11-09 Charleston Laboratories, Inc. Pharmaceutical compositions for treating headache and eliminating nausea
TW200950776A (en) * 2008-01-24 2009-12-16 Abbott Gmbh & Co Kg Abuse resistant melt extruded formulation having reduced alcohol interaction
RU2493830C2 (en) 2008-01-25 2013-09-27 Грюненталь Гмбх Drug form
US20090246276A1 (en) * 2008-01-28 2009-10-01 Graham Jackson Pharmaceutical Compositions
EP2730578A1 (en) 2008-02-06 2014-05-14 Progenics Pharmaceuticals, Inc. Preparation and use of (r),(r)-2,2'-bis-methylnal trexone
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
EP2278966B1 (en) 2008-03-21 2019-10-09 The University of Chicago Treatment with opioid antagonists and mtor inhibitors
CN102014846A (en) * 2008-04-30 2011-04-13 诺瓦提斯公司 Continuous process for making pharmaceutical compositions
BRPI0912014A2 (en) 2008-05-09 2019-03-06 Grünenthal GmbH A process for preparing an intermediate powder formulation and a final solid dosage form using a spray freeze step
EP2309987B1 (en) * 2008-07-03 2012-08-29 Novartis AG Melt granulation process
RU2478388C2 (en) * 2008-07-07 2013-04-10 Еуро-Селтик С.А. Pharmaceutical composition, containing opioid antagonist for treatment of urinary retention
US9192578B2 (en) * 2008-08-20 2015-11-24 Board Of Regents, The University Of Texas System Hot-melt extrusion of modified release multi-particulates
AU2009289464B2 (en) 2008-09-04 2015-12-10 Farnam Companies, Inc. Chewable sustained release formulations
BRPI0913724B8 (en) * 2008-09-18 2021-05-25 Purdue Pharma Lp extended release dosage forms comprising naltrexone and poly (e-caprolactone) and their preparation
CA2676881C (en) 2008-09-30 2017-04-25 Wyeth Peripheral opioid receptor antagonists and uses thereof
US20100260844A1 (en) 2008-11-03 2010-10-14 Scicinski Jan J Oral pharmaceutical dosage forms
WO2010078486A2 (en) 2008-12-31 2010-07-08 Upsher-Smith Laboratories, Inc. Opioid-containing oral pharmaceutical compositions and methods
US11304960B2 (en) 2009-01-08 2022-04-19 Chandrashekar Giliyar Steroidal compositions
WO2010089132A1 (en) 2009-02-06 2010-08-12 Egalet A/S Immediate release composition resistant to abuse by intake of alcohol
SI2405915T1 (en) 2009-03-10 2019-03-29 Euro-Celtique S.A. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
GB0909680D0 (en) 2009-06-05 2009-07-22 Euro Celtique Sa Dosage form
US9743228B2 (en) 2009-06-22 2017-08-22 Qualcomm Incorporated Transport of LCS-related messages for LTE access
WO2010149169A2 (en) 2009-06-24 2010-12-29 Egalet A/S Controlled release formulations
CA2767576C (en) 2009-07-08 2020-03-10 Charleston Laboratories Inc. Pharmaceutical compositions comprising an antiemetic and an opioid analgesic
JP2012533585A (en) 2009-07-22 2012-12-27 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Tamper-resistant dosage forms for oxidation-sensitive opioids
BR112012001547A2 (en) 2009-07-22 2016-03-08 Gruenenthal Gmbh hot melt extruded pharmaceutical dosage form
US20110052685A1 (en) * 2009-08-31 2011-03-03 Depomed, Inc. Gastric retentive pharmaceutical compositions for immediate and extended release of acetaminophen
BR112012008317A2 (en) 2009-09-17 2016-03-22 Upsher Smith Lab Inc sustained release product comprising a combination of a non-opioid amine and a non-steroidal anti-inflammatory drug
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
US8597681B2 (en) 2009-12-22 2013-12-03 Mallinckrodt Llc Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans
US9198861B2 (en) 2009-12-22 2015-12-01 Mallinckrodt Llc Methods of producing stabilized solid dosage pharmaceutical compositions containing morphinans
CN102821757B (en) * 2010-02-03 2016-01-20 格吕伦塔尔有限公司 By extrusion mechanism for powdery medicine compositions
DE112011101605T5 (en) 2010-05-10 2013-04-25 Euro-Celtique S.A. A pharmaceutical composition comprising hydromorphone and naloxone
JP5840201B2 (en) 2010-05-10 2016-01-06 ユーロ−セルティーク エス.エイ. Combination of granules loaded with active agent and additional active agent
KR20130030261A (en) 2010-05-10 2013-03-26 유로-셀티큐 에스.에이. Manufacturing of active-free granules and tablets comprising the same
WO2012028319A1 (en) 2010-09-02 2012-03-08 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
WO2012028318A1 (en) 2010-09-02 2012-03-08 Grünenthal GmbH Tamper resistant dosage form comprising an anionic polymer
JP2013537915A (en) * 2010-09-24 2013-10-07 キューアールエックスファーマ リミテッド Opioid controlled release formulations
US20180153904A1 (en) 2010-11-30 2018-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
GB201020895D0 (en) * 2010-12-09 2011-01-26 Euro Celtique Sa Dosage form
US20120148675A1 (en) 2010-12-10 2012-06-14 Basawaraj Chickmath Testosterone undecanoate compositions
CN104873455B (en) 2010-12-22 2023-09-12 普渡制药公司 Coated Tamper Resistant Controlled Release Dosage Forms
US9233073B2 (en) 2010-12-23 2016-01-12 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
US8858963B1 (en) 2011-05-17 2014-10-14 Mallinckrodt Llc Tamper resistant composition comprising hydrocodone and acetaminophen for rapid onset and extended duration of analgesia
US8741885B1 (en) 2011-05-17 2014-06-03 Mallinckrodt Llc Gastric retentive extended release pharmaceutical compositions
US9050335B1 (en) 2011-05-17 2015-06-09 Mallinckrodt Llc Pharmaceutical compositions for extended release of oxycodone and acetaminophen resulting in a quick onset and prolonged period of analgesia
AT511581A1 (en) 2011-05-26 2012-12-15 G L Pharma Gmbh ORAL RETARDANT FORMULATION
US8758826B2 (en) * 2011-07-05 2014-06-24 Wet Inc. Cannabinoid receptor binding agents, compositions, and methods
CN103857386A (en) 2011-07-29 2014-06-11 格吕伦塔尔有限公司 Tamper-resistant tablet providing immediate drug release
BR112014002022A2 (en) 2011-07-29 2017-02-21 Gruenenthal Gmbh tamper-resistant tablet providing immediate drug release
CA2847611A1 (en) * 2011-09-16 2013-03-21 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
CN105749294A (en) * 2011-10-26 2016-07-13 凯姆制药公司 Benzoic Acid, Benzoic Acid Derivatives And Heteroaryl Carboxylic Acid Conjugates Of Hydromorphone, Prodrugs, Methods Of Making And Use Thereof
US20130225697A1 (en) 2012-02-28 2013-08-29 Grunenthal Gmbh Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
WO2013128276A2 (en) * 2012-03-02 2013-09-06 Rhodes Pharmaceuticals L.P. Tamper resistant immediate release formulations
EA201491875A1 (en) 2012-04-17 2015-04-30 Пурдью Фарма Л.П. SYSTEMS AND METHODS OF TREATMENT OF OPIOID-INDUCED PHARMACEUTICAL PHARMACODYNAMIC RESPONSE
AU2013248351B2 (en) 2012-04-18 2018-04-26 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
KR20150059167A (en) 2012-07-06 2015-05-29 에갈렛 리미티드 Abuse deterrent pharmaceutical compositions for controlled release
WO2014011830A1 (en) 2012-07-12 2014-01-16 Mallinckrodt Llc Extended release, abuse deterrent pharmaceutical compositions
US10702453B2 (en) 2012-11-14 2020-07-07 Xerox Corporation Method and system for printing personalized medication
KR101659983B1 (en) 2012-12-31 2016-09-26 주식회사 삼양바이오팜 Melt-extruded release controlled pharmaceutical composition and oral dosage form comprising the same
IN2012CH05549A (en) * 2012-12-31 2015-07-03 Aizant Drug Res Solution Private Ltd
EA201500742A1 (en) 2013-02-05 2015-12-30 Пердью Фарма Л.П. PHARMACEUTICAL COMPOSITIONS PROTECTED FROM NON-GOAL USE
CN105120659A (en) 2013-03-15 2015-12-02 度瑞公司 Compositions with a rheological modifier to reduce dissolution variability
US10751287B2 (en) 2013-03-15 2020-08-25 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
MX2015016254A (en) 2013-05-29 2016-04-20 Gruenenthal Gmbh Tamper resistant dosage form with bimodal release profile.
BR112015026549A2 (en) 2013-05-29 2017-07-25 Gruenenthal Gmbh tamper-proof dosage form containing one or more particles
AU2014289187B2 (en) 2013-07-12 2019-07-11 Grunenthal Gmbh Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
JP2016525138A (en) 2013-07-23 2016-08-22 ユーロ−セルティーク エス.エイ. Oxycodone and naloxone combination for use in the treatment of pain in patients suffering from diseases that cause pain and intestinal dysbiosis and / or diseases that increase the risk for intestinal bacterial transfer
JP6539274B2 (en) 2013-08-12 2019-07-03 ファーマシューティカル マニュファクチュアリング リサーチ サービシズ,インコーポレーテッド Extruded immediate release abuse deterrent pills
UA116405C2 (en) 2013-11-13 2018-03-12 Євро-Селтік С.А. Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome
CA2931553C (en) 2013-11-26 2022-01-18 Grunenthal Gmbh Preparation of a powdery pharmaceutical composition by means of cryo-milling
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
MX2016014738A (en) 2014-05-12 2017-03-06 Gruenenthal Gmbh Tamper resistant immediate release capsule formulation comprising tapentadol.
WO2015181059A1 (en) 2014-05-26 2015-12-03 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
ES2809458T3 (en) 2014-07-17 2021-03-04 Pharmaceutical Manufacturing Res Services Inc Liquid filled, abuse deterrent and immediate release dosage form
US20170246187A1 (en) 2014-08-28 2017-08-31 Lipocine Inc. (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE
US9498485B2 (en) 2014-08-28 2016-11-22 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
CH710097A2 (en) 2014-09-12 2016-03-15 Chemspeed Technologies Ag Method and apparatus for the production of an extrudate.
US9849124B2 (en) 2014-10-17 2017-12-26 Purdue Pharma L.P. Systems and methods for treating an opioid-induced adverse pharmacodynamic response
CA3002137A1 (en) 2014-10-17 2016-04-21 Salix Pharmaceuticals, Inc. Use of methylnaltrexone to attenuate tumor progression
AU2015336065A1 (en) 2014-10-20 2017-05-04 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
NZ731586A (en) 2014-12-02 2018-06-29 Kempharm Inc Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of oxymorphone, prodrugs, methods of making and use thereof
AU2016251854A1 (en) 2015-04-24 2017-10-19 Grunenthal Gmbh Tamper-resistant dosage form with immediate release and resistance against solvent extraction
JP2018526414A (en) 2015-09-10 2018-09-13 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Protection against oral overdose with abuse-inhibiting immediate release formulations
JP2019507181A (en) 2016-03-04 2019-03-14 チャールストン ラボラトリーズ,インコーポレイテッド Pharmaceutical composition
WO2017172406A1 (en) 2016-03-31 2017-10-05 Mallinckrodt Llc Extended release, abuse deterrent dosage forms
WO2017222575A1 (en) 2016-06-23 2017-12-28 Collegium Pharmaceutical, Inc. Process of making more stable abuse-deterrent oral formulations
US11559530B2 (en) 2016-11-28 2023-01-24 Lipocine Inc. Oral testosterone undecanoate therapy
WO2019087084A1 (en) 2017-11-02 2019-05-09 Eman Biodiscoveries Sd. Bhd. Extract of orthosiphon stamineus, formulations, and uses thereof
CN110755396B (en) * 2019-12-06 2022-04-08 北京悦康科创医药科技股份有限公司 Ibuprofen sustained-release pellet and preparation method thereof
EP4119129A4 (en) * 2020-03-11 2024-01-24 Sawai Seiyaku Kk Granules and preparation using same
CN113080436B (en) * 2021-04-08 2024-03-01 南京纽邦生物科技有限公司 Gamma-aminobutyric acid dry suspension and preparation method thereof

Citations (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2738303A (en) * 1952-07-18 1956-03-13 Smith Kline French Lab Sympathomimetic preparation
US3065143A (en) * 1960-04-19 1962-11-20 Richardson Merrell Inc Sustained release tablet
US3652589A (en) * 1967-07-27 1972-03-28 Gruenenthal Chemie 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols
US3714350A (en) * 1969-03-10 1973-01-30 Mobil Oil Corp Phosphoryl and thiophosphoryl pyrones as insecticides
US3830934A (en) * 1967-07-27 1974-08-20 Gruenenthal Chemie Analgesic and antitussive compositions and methods
US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3880991A (en) * 1969-03-24 1975-04-29 Brook David E Polymeric article for dispensing drugs
US3950508A (en) * 1972-05-10 1976-04-13 Laboratoires Servier Process for obtaining pharmaceutical sustained releases
US3965256A (en) * 1972-05-16 1976-06-22 Synergistics Slow release pharmaceutical compositions
US3974157A (en) * 1974-03-04 1976-08-10 Pennwalt Corporation 1-(Amino-alkyl)-2-aryl-cyclohexane alcohols and esters
US4013784A (en) * 1973-12-06 1977-03-22 Peter Speiser Delayed release pharmaceutical preparations
US4076798A (en) * 1975-05-29 1978-02-28 American Cyanamid Company High molecular weight polyester resin, the method of making the same and the use thereof as a pharmaceutical composition
US4132753A (en) * 1965-02-12 1979-01-02 American Cyanamid Company Process for preparing oral sustained release granules
US4173417A (en) * 1977-04-15 1979-11-06 Hpm Corporation Extrusion apparatus and method
US4230687A (en) * 1978-05-30 1980-10-28 Griffith Laboratories U.S.A., Inc. Encapsulation of active agents as microdispersions in homogeneous natural polymeric matrices
US4259314A (en) * 1979-12-10 1981-03-31 Hans Lowey Method and composition for the preparation of controlled long-acting pharmaceuticals
US4265875A (en) * 1976-07-23 1981-05-05 Inveresk Research International Controlled release suppositories
US4310483A (en) * 1978-08-15 1982-01-12 Ciba-Geigy Corporation Thermal tumbling granulation
US4343789A (en) * 1979-07-05 1982-08-10 Yamanouchi Pharmaceutical Co., Ltd. Sustained release pharmaceutical composition of solid medical material
US4344431A (en) * 1969-03-24 1982-08-17 University Of Delaware Polymeric article for dispensing drugs
US4346709A (en) * 1980-11-10 1982-08-31 Alza Corporation Drug delivery devices comprising erodible polymer and erosion rate modifier
US4366172A (en) * 1977-09-29 1982-12-28 The Upjohn Company 4-Amino-cyclohexanols, their pharmaceutical compositions and methods of use
US4374082A (en) * 1981-08-18 1983-02-15 Richard Hochschild Method for making a pharmaceutical and/or nutritional dosage form
US4380534A (en) * 1980-04-07 1983-04-19 Yamanouchi Pharmaceutical Co., Ltd. Solid drug preparations
USRE33093E (en) * 1986-06-16 1989-10-17 Johnson & Johnson Consumer Products, Inc. Bioadhesive extruded film for intra-oral drug delivery and process
US5958452A (en) * 1994-11-04 1999-09-28 Euro-Celtique, S.A. Extruded orally administrable opioid formulations

Family Cites Families (196)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US33093A (en) * 1861-08-20 Improvement in potato-diggers
US2743303A (en) * 1955-04-01 1956-04-24 Du Pont Process for the preparation of 1, 1, 4, 4-tetrafluorobutadiene 1, 3 from acetylene and tetrafluoroethylene
GB1357737A (en) * 1970-10-09 1974-06-26 Arpic Sa Sustained release pharmaceutical compositions
GB1405088A (en) 1971-06-03 1975-09-03 Mundipharma Ag Slow release formulation
US4450150A (en) * 1973-05-17 1984-05-22 Arthur D. Little, Inc. Biodegradable, implantable drug delivery depots, and method for preparing and using the same
DE2426811A1 (en) 1974-06-04 1976-01-08 Klinge Co Chem Pharm Fab PROCESS FOR THE MANUFACTURING OF RETARD TABLETS
DE2426812A1 (en) 1974-06-04 1976-01-02 Klinge Co Chem Pharm Fab PROCESS FOR THE MANUFACTURING OF GRANULES
DE2439538C3 (en) 1974-08-17 1980-07-17 Ludwig Heumann & Co Gmbh, 8500 Nuernberg Process for the manufacture of orally administered drugs with delayed release of action
DE2549740A1 (en) 1975-11-17 1977-05-18 Sandoz Ag NEW GALENIC FORMS AND METHODS FOR THEIR PRODUCTION
US4406883A (en) * 1976-07-23 1983-09-27 Merrell Dow Pharmaceuticals Inc. Controlled release suppositories consisting essentially of a linear polymer particularly, polyvinyl pyrrolidones
CH637014A5 (en) 1978-09-29 1983-07-15 Sandoz Ag METHOD FOR PRODUCING SUPPOSITORIES.
DE2923279B1 (en) 1979-06-08 1980-11-20 Kali Chemie Pharma Gmbh Process for the production of pancreatin pellets
US4309405A (en) * 1979-08-09 1982-01-05 American Home Products Corporation Sustained release pharmaceutical compositions
IE49324B1 (en) 1979-12-19 1985-09-18 Euro Celtique Sa Controlled release compositions
US4457933A (en) * 1980-01-24 1984-07-03 Bristol-Myers Company Prevention of analgesic abuse
DE3024416C2 (en) 1980-06-28 1982-04-15 Gödecke AG, 1000 Berlin Process for the production of medicaments with sustained release of active substances
JPS57171428A (en) * 1981-04-13 1982-10-22 Sankyo Co Ltd Preparation of coated solid preparation
DE3124983A1 (en) 1981-06-25 1983-01-20 Meditest Inst Fuer Medizinisch ORAL ADMINISTRATIVE FORMS
US4366159A (en) * 1981-09-08 1982-12-28 Michael Richard Magruder Nalbuphine-narcotic analgesic composition and method of producing analgesia
US4369172A (en) 1981-12-18 1983-01-18 Forest Laboratories Inc. Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose
US4987136A (en) * 1982-03-16 1991-01-22 The Rockefeller University Method for controlling gastrointestinal dysmotility
US4389393A (en) 1982-03-26 1983-06-21 Forest Laboratories, Inc. Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose
US4421736A (en) * 1982-05-20 1983-12-20 Merrel Dow Pharmaceuticals Inc. Sustained release diethylpropion compositions
US4443428A (en) 1982-06-21 1984-04-17 Euroceltique, S.A. Extended action controlled release compositions
AU1873783A (en) 1982-10-08 1984-04-12 Verex Laboratories Inc. Constant release formulation
US4469613A (en) * 1983-02-23 1984-09-04 International Flavors & Fragrances Inc. Detergent bar containing poly(epsilon caprolactone) and aromatizing agent
US4882167A (en) * 1983-05-31 1989-11-21 Jang Choong Gook Dry direct compression compositions for controlled release dosage forms
JPS6013838A (en) * 1983-07-04 1985-01-24 Mitsui Petrochem Ind Ltd Polypropylene composition
US4917899A (en) * 1983-12-22 1990-04-17 Elan Corporation Plc Controlled absorption diltiazem formulation
EP0147780A3 (en) 1984-01-03 1987-03-11 Merck & Co. Inc. Drug delivery device
EP0152379A3 (en) 1984-02-15 1986-10-29 Ciba-Geigy Ag Process for preparing pharmaceutical compositions containing unilamellar liposomes
GB8405112D0 (en) * 1984-02-28 1984-04-04 Akzo Nv Anti-arrhythmic amino-alcohols
US4649042A (en) * 1984-05-31 1987-03-10 Eli Lilly And Company Rumen delivery device
US4629621A (en) * 1984-07-23 1986-12-16 Zetachron, Inc. Erodible matrix for sustained release bioactive composition
US4894234A (en) * 1984-10-05 1990-01-16 Sharma Shri C Novel drug delivery system for antiarrhythmics
EP0189861A3 (en) 1985-01-26 1988-02-17 Showa Denko Kabushiki Kaisha Percutaneous absorption accelerator for ionic water-soluble medicine
US4772475A (en) 1985-03-08 1988-09-20 Yamanouchi Pharmaceutical Co., Ltd. Controlled-release multiple units pharmaceutical formulation
US4720384A (en) * 1985-05-03 1988-01-19 E. I. Du Pont De Nemours And Company Manufacture of hollow fine tubular drug delivery systems
FR2581541B1 (en) * 1985-05-09 1988-05-20 Rhone Poulenc Sante NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE EXTENDED RELEASE OF AN ACTIVE INGREDIENT AND THEIR PREPARATION METHOD
GB8514665D0 (en) * 1985-06-11 1985-07-10 Eroceltique Sa Oral pharmaceutical composition
JPS61293911A (en) * 1985-06-24 1986-12-24 Teisan Seiyaku Kk Sustained release preparation
DE3524003A1 (en) * 1985-07-04 1987-01-08 Heumann Ludwig & Co Gmbh MEDICINE GRANULES WITH DELAYED ACTIVE SUBSTANCE RELEASE AND METHOD FOR THE PRODUCTION THEREOF
FR2585246A1 (en) 1985-07-26 1987-01-30 Cortial PROCESS FOR OBTAINING SOLID PHARMACEUTICAL FORMS WITH PROLONGED RELEASE
GB8521350D0 (en) * 1985-08-28 1985-10-02 Euro Celtique Sa Analgesic composition
DE3685091D1 (en) * 1985-11-08 1992-06-04 Ici Plc DEVICE AND METHOD FOR SHAPING EXTRUDED PARTICLES.
US4778676A (en) * 1985-12-20 1988-10-18 Warner-Lambert Company Confectionery delivery system for actives
US4879108A (en) * 1985-12-20 1989-11-07 Warner-Lambert Company Confectionery delivery system for antipyretics
US4882153A (en) * 1985-12-20 1989-11-21 Warner Lambert Co. Confectionery delivery system for antitussives
US4882155A (en) * 1985-12-20 1989-11-21 Warner Lambert Co. Confectionery delivery system for antiarrhythmics
US4882159A (en) * 1985-12-20 1989-11-21 Warner Lambert Co. Confectionery delivery system for appetite suppressants
US4882151A (en) * 1985-12-20 1989-11-21 Warner Lambert Co. Confectionery delivery system for antihistimines
US4882152A (en) * 1985-12-20 1989-11-21 Yang Robert K Confectionery delivery system for laxatives, vitamins and antacids
US4882156A (en) * 1985-12-20 1989-11-21 Warner Lambert Co. Confectionery delivery system for expectorants
US4882157A (en) * 1985-12-20 1989-11-21 Yang Robert K Confectionery delivery system for anti-cholesterolemics
US4940665A (en) 1985-12-27 1990-07-10 Showa Denko K. K. Method for granulation of enzyme
DE3602370A1 (en) 1986-01-27 1987-08-06 Chrubasik Sigrun Use of analgesics by inhalation
DE3602360A1 (en) 1986-01-27 1987-07-30 Krupp Polysius Ag SIDE SCRATCHER FOR SCHUETTGUTHALDE
US4764378A (en) * 1986-02-10 1988-08-16 Zetachron, Inc. Buccal drug dosage form
GB2186485B (en) * 1986-02-13 1988-09-07 Ethical Pharma Ltd Slow release formulation
US4994227A (en) * 1986-03-10 1991-02-19 American Cyanamid Company Method for the preparation of sustained released bolus formulation
DE3610878A1 (en) 1986-04-01 1987-10-08 Boehringer Ingelheim Kg PELLET SHAPES
DE3612212A1 (en) * 1986-04-11 1987-10-15 Basf Ag METHOD FOR PRODUCING SOLID PHARMACEUTICAL FORMS
DE3612211A1 (en) 1986-04-11 1987-10-15 Basf Ag CONTINUOUS TABLET METHOD
US4820523A (en) 1986-04-15 1989-04-11 Warner-Lambert Company Pharmaceutical composition
GB8613688D0 (en) 1986-06-05 1986-07-09 Euro Celtique Sa Pharmaceutical composition
GB8613689D0 (en) 1986-06-05 1986-07-09 Euro Celtique Sa Pharmaceutical composition
EP0249347B1 (en) 1986-06-10 1994-06-29 Euroceltique S.A. Controlled release dihydrocodeine composition
DE3623193A1 (en) 1986-07-10 1988-01-14 Gruenenthal Gmbh NEW COMPOUNDS, THIS MEDICINAL PRODUCT AND METHOD FOR THE PRODUCTION THEREOF
US4970075A (en) * 1986-07-18 1990-11-13 Euroceltique, S.A. Controlled release bases for pharmaceuticals
JPH0816066B2 (en) 1986-07-18 1996-02-21 エーザイ株式会社 Long-acting drug
US4861598A (en) * 1986-07-18 1989-08-29 Euroceltique, S.A. Controlled release bases for pharmaceuticals
US4760094A (en) 1986-10-21 1988-07-26 American Home Products Corporation (Del.) Spray dried acetaminophen
GB8626098D0 (en) 1986-10-31 1986-12-03 Euro Celtique Sa Controlled release hydromorphone composition
IE873172L (en) 1986-12-29 1988-06-29 Harvard College Continuous process for producing a comestible tablet
US5026560A (en) * 1987-01-29 1991-06-25 Takeda Chemical Industries, Ltd. Spherical granules having core and their production
ZA882783B (en) 1987-06-10 1988-10-20 Warner-Lambert Company Process for preparing a pharmaceutical composition
DE3721721C1 (en) * 1987-07-01 1988-06-09 Hoechst Ag Process for coating granules
GB8717168D0 (en) 1987-07-21 1987-08-26 Roussel Lab Ltd Controlled-release device
FR2618329B1 (en) 1987-07-22 1997-03-28 Dow Corning Sa METHOD OF MANUFACTURING A RING CAPABLE OF ENSURING THE RELEASE OF A THERAPEUTIC AGENT, AND RING MANUFACTURED BY THIS METHOD
US5049394A (en) * 1987-09-11 1991-09-17 E. R. Squibb & Sons, Inc. Pharmaceutical composition containing high drug load and method for preparing same
US4959208A (en) * 1987-10-19 1990-09-25 Ppg Industries, Inc. Active agent delivery device
US5418154A (en) * 1987-11-17 1995-05-23 Brown University Research Foundation Method of preparing elongated seamless capsules containing biological material
SE463450B (en) 1987-12-11 1990-11-26 Nemo Ivarson DEVICE FOR MIXING, KNOWLEDGE AND EXTRUSION OF PRODUCTS MADE OF SCIENCE AND POWDER
EP0327295A3 (en) 1988-02-01 1989-09-06 F.H. FAULDING & CO. LTD. Tetracycline dosage form
US4842761A (en) * 1988-03-23 1989-06-27 International Flavors & Fragrances, Inc. Compositions and methods for controlled release of fragrance-bearing substances
DE3812567A1 (en) 1988-04-15 1989-10-26 Basf Ag METHOD FOR PRODUCING PHARMACEUTICAL MIXTURES
DE3812799A1 (en) 1988-04-16 1989-10-26 Sanol Arznei Schwarz Gmbh ORGANIC PREPARATION FOR THE PURPOSES OF AN ACTUATED ACTIVE INGREDIENTS AND METHOD OF PREPARING THEM
US5472710A (en) 1988-04-16 1995-12-05 Schwarz Pharma Ag Pharmaceutical preparation to be administered orally with controlled release of active substance and method for its manufacture
JP2681373B2 (en) 1988-07-18 1997-11-26 塩野義製薬株式会社 Method for manufacturing sustained-release preparation
DE3827061C1 (en) * 1988-08-10 1990-02-15 Deutsche Gelatine-Fabriken Stoess & Co Gmbh, 6930 Eberbach, De
US4925675A (en) * 1988-08-19 1990-05-15 Himedics, Inc. Erythromycin microencapsulated granules
GB8820327D0 (en) 1988-08-26 1988-09-28 May & Baker Ltd New compositions of matter
DE3830353A1 (en) * 1988-09-07 1990-03-15 Basf Ag METHOD FOR THE CONTINUOUS PRODUCTION OF SOLID PHARMACEUTICAL FORMS
DE3830355A1 (en) 1988-09-07 1990-03-15 Basf Ag METHOD FOR PRODUCING PHARMACEUTICAL TABLETS
DE68916497T2 (en) 1988-09-30 1994-11-17 Rhone Poulenc Rorer Ltd Pharmaceutical granules.
US5178868A (en) * 1988-10-26 1993-01-12 Kabi Pharmacia Aktiebolaq Dosage form
JP2893191B2 (en) * 1988-11-08 1999-05-17 武田薬品工業株式会社 Controlled release matrix agent
AU645003B2 (en) 1988-11-08 1994-01-06 Takeda Chemical Industries Ltd. Sustained release preparations
IL92343A0 (en) * 1988-12-20 1990-07-26 Gist Brocades Nv Granulate for multiparticulate controlled release oral compositions,their preparation and oral pharmaceutical compositions containing them
EP0376331A3 (en) * 1988-12-29 1991-03-13 Asahi Kogaku Kogyo Kabushiki Kaisha Slow release drug delivery granules and process for production thereof
US5330766A (en) * 1989-01-06 1994-07-19 F. H. Faulding & Co. Limited Sustained release pharmaceutical composition
US5202128A (en) * 1989-01-06 1993-04-13 F. H. Faulding & Co. Limited Sustained release pharmaceutical composition
CA2007055A1 (en) 1989-01-06 1990-07-06 Garth Boehm Theophylline dosage form
US5196203A (en) * 1989-01-06 1993-03-23 F. H. Faulding & Co. Limited Theophylline dosage form
CA2007181C (en) 1989-01-06 1998-11-24 Angelo Mario Morella Sustained release pharmaceutical composition
US5013306A (en) * 1989-01-18 1991-05-07 Becton, Dickinson And Company Anti-infective and antithrombogenic medical articles and method for their preparation
US5165952A (en) 1989-01-18 1992-11-24 Becton, Dickinson And Company Anti-infective and antithrombogenic medical articles and method for their preparation
FR2642420B1 (en) 1989-01-27 1991-09-06 Valpan Sa Labo Pharma NEW FORMAL RELEASE GALENIC FORM CONTAINING A COMBINATION OF FERROUS SALTS, SUCCINIC ACID AND ASCORBIC ACID
US5007790A (en) * 1989-04-11 1991-04-16 Depomed Systems, Inc. Sustained-release oral drug dosage form
US5126145A (en) * 1989-04-13 1992-06-30 Upsher Smith Laboratories Inc Controlled release tablet containing water soluble medicament
US5229148A (en) * 1989-04-19 1993-07-20 Wm. Wrigley Jr. Company Method of combining active ingredients with polyvinyl acetates
US5133974A (en) * 1989-05-05 1992-07-28 Kv Pharmaceutical Company Extended release pharmaceutical formulations
US4967486A (en) * 1989-06-19 1990-11-06 Glatt Gmbh Microwave assisted fluidized bed processor
DK161743C (en) * 1989-07-03 1992-02-17 Niro Atomizer As PROCEDURE AND APPARATUS FOR AGGLOMERATION OF A POWDER-SHAPED MATERIAL
DE415693T1 (en) 1989-08-28 1991-10-17 Arizona Technology Development Corp., Tucson, Ariz., Us COMPOSITION AND METHOD FOR SELECTIVELY REINFORCING THE OPIATE EFFECT AND REDUCING OPIATE TOLERANCE AND DEPENDENCY.
EP0418596A3 (en) * 1989-09-21 1991-10-23 American Cyanamid Company Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form
DK469989D0 (en) * 1989-09-22 1989-09-22 Bukh Meditec PHARMACEUTICAL PREPARATION
US5169645A (en) * 1989-10-31 1992-12-08 Duquesne University Of The Holy Ghost Directly compressible granules having improved flow properties
IL96311A (en) 1989-12-01 1995-05-26 Abbott Lab Sustained-release drug dosage units
DE4000571C1 (en) 1990-01-10 1991-06-06 Herbert 7853 Steinen De Huettlin
US5296266A (en) 1990-02-22 1994-03-22 Seiko Epson Corporation Method of preparing microcapsule
JP3191948B2 (en) 1990-04-12 2001-07-23 塩野義製薬株式会社 Coated preparation and method for producing the same
ES2081477T3 (en) * 1990-04-24 1996-03-16 Teijin Ltd PATCH.
IE65045B1 (en) 1990-04-28 1995-10-04 Takeda Chemical Industries Ltd Granulated preparations and method of producing the same
US5183690A (en) * 1990-06-25 1993-02-02 The United States Of America, As Represented By The Secretary Of Agriculture Starch encapsulation of biologically active agents by a continuous process
CA2065301C (en) 1990-06-25 2001-10-16 Shigeru Kawashima Crystalline mixture solid containing maltitol and a process for preparing it
HU208495B (en) 1990-06-27 1993-11-29 Alkaloida Vegyeszeti Gyar Process for producing retarde pharmaceutical compositions
FR2663818B1 (en) 1990-06-29 1993-07-09 Rhone Poulenc Nutrition Animale PROCESS FOR THE PREPARATION OF GRANULES OF ACTIVE PRINCIPLES BY EXTRUSION.
GB2246514B (en) 1990-08-01 1993-12-15 Scras Sustained release pharmaceutical compositions and the preparation of particles for use therein
US5035509A (en) * 1990-08-13 1991-07-30 Hpm Corporation Multi-channel extrusion screw with a zig-zag undercut barrier
EP0472502B1 (en) 1990-08-24 1995-05-31 Spirig Ag Pharmazeutische Präparate Process for obtaining granules
JP2875611B2 (en) * 1990-08-29 1999-03-31 エーザイ株式会社 Topical formulation containing calcium silicate
US5102668A (en) * 1990-10-05 1992-04-07 Kingaform Technology, Inc. Sustained release pharmaceutical preparation using diffusion barriers whose permeabilities change in response to changing pH
DE4031881C2 (en) 1990-10-08 1994-02-24 Sanol Arznei Schwarz Gmbh Solvent-free, oral sustained-release pharmaceutical preparation and process for its preparation
SE9003296L (en) * 1990-10-16 1992-04-17 Kabi Pharmacia Ab PROCEDURE SHOULD FORMULATE MEDICINAL PRODUCTS
GB2248842A (en) 1990-10-16 1992-04-22 American Cyanamid Co Film-forming polymer compositions
US5271934A (en) * 1990-10-22 1993-12-21 Revlon Consumer Products Corporation Encapsulated antiperspirant salts and deodorant/antiperspirants
FR2670398B1 (en) 1990-12-14 1995-02-17 Roquette Freres DIRECTLY COMPRESSIBLE POWDER COMPOSITION AND PROCESS FOR OBTAINING SAME.
US5240400A (en) * 1990-12-17 1993-08-31 Fuji Paudal Kabushiki Kaisha Screw-type extrusion granulating apparatus, especially for producing very fine granules
JPH0622669B2 (en) 1990-12-17 1994-03-30 不二パウダル株式会社 Pre-extrusion screw type extrusion granulator
US5403593A (en) 1991-03-04 1995-04-04 Sandoz Ltd. Melt granulated compositions for preparing sustained release dosage forms
US5273758A (en) * 1991-03-18 1993-12-28 Sandoz Ltd. Directly compressible polyethylene oxide vehicle for preparing therapeutic dosage forms
US5132142A (en) * 1991-03-19 1992-07-21 Glatt Gmbh Apparatus and method for producing pellets by layering power onto particles
IT1245891B (en) 1991-04-12 1994-10-25 Alfa Wassermann Spa CONTROLLED RELEASE PHARMACEUTICAL FORMULATIONS FOR ORAL USE GAS RESISTANT CONTAINING BILE ACIDS AND THEIR SALTS.
DK0580860T4 (en) 1991-04-16 2005-03-21 Nippon Shinyaku Co Ltd Process for preparing a solid dispersion
TW209174B (en) * 1991-04-19 1993-07-11 Takeda Pharm Industry Co Ltd
US5380535A (en) 1991-05-28 1995-01-10 Geyer; Robert P. Chewable drug-delivery compositions and methods for preparing the same
DK116591D0 (en) * 1991-06-17 1991-06-17 Ferring Farma Lab PROCEDURE FOR THE PREPARATION OF SUPPOSITORIES BY COMPRESSION AND SUPPOSITIONS OBTAINED BY THE PROCEDURE
DE4120760A1 (en) * 1991-06-24 1993-03-04 3 M Medica Gmbh CARRIER SYSTEMS FOR MEDICINAL PRODUCTS
US5330768A (en) * 1991-07-05 1994-07-19 Massachusetts Institute Of Technology Controlled drug delivery using polymer/pluronic blends
IT1251153B (en) 1991-08-06 1995-05-04 Vectorpharma Int SOLID PHARMACEUTICAL COMPOSITIONS FOR ORAL ADMINISTRATION HAVING PROHIBITED GASTRIC RESIDENCE
DE4127665A1 (en) 1991-08-22 1993-02-25 Beiersdorf Ag GALENIC MATRIX
US5340581A (en) 1991-08-23 1994-08-23 Gillette Canada, Inc. Sustained-release matrices for dental application
DK0534628T3 (en) 1991-09-06 1996-12-09 Mcneilab Inc Preparations containing a tramadol material and any one of codeine, oxycodone or hydrocodone, and use thereof
RU2121346C1 (en) * 1991-09-06 1998-11-10 МакНейлэб, Инк. Composition containing substance tramadol and acetaminophen and a method of treatment using thereof
US5215758A (en) 1991-09-11 1993-06-01 Euroceltique, S.A. Controlled release matrix suppository for pharmaceuticals
GB9121204D0 (en) 1991-10-04 1991-11-20 Euro Celtique Sa Medicament
US5288502A (en) * 1991-10-16 1994-02-22 The University Of Texas System Preparation and uses of multi-phase microspheres
WO1993007859A1 (en) * 1991-10-23 1993-04-29 Warner-Lambert Company Novel pharmaceutical pellets and process for their production
AU661723B2 (en) 1991-10-30 1995-08-03 Mcneilab, Inc. Composition comprising a tramadol material and a non-steroidal anti-inflammatory drug
US5162117A (en) * 1991-11-22 1992-11-10 Schering Corporation Controlled release flutamide composition
DE4138513A1 (en) 1991-11-23 1993-05-27 Basf Ag SOLID PHARMACEUTICAL RETARD FORM
US5266331A (en) 1991-11-27 1993-11-30 Euroceltique, S.A. Controlled release oxycodone compositions
EP0615438B1 (en) 1991-12-05 1996-07-24 Mallinckrodt Veterinary, Inc. A carbohydrate glass matrix for the sustained release of a therapeutic agent
US5478577A (en) 1993-11-23 1995-12-26 Euroceltique, S.A. Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level
US5472712A (en) * 1991-12-24 1995-12-05 Euroceltique, S.A. Controlled-release formulations coated with aqueous dispersions of ethylcellulose
GB2281204A (en) 1993-07-27 1995-03-01 Euro Celtique Sa Sustained release morphine compositions
US5580578A (en) * 1992-01-27 1996-12-03 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
GB2284760B (en) 1993-11-23 1998-06-24 Euro Celtique Sa A method of preparing pharmaceutical compositions by melt pelletisation
US5167964A (en) * 1992-02-14 1992-12-01 Warner-Lambert Company Semi-enteric drug delivery systems and methods for preparing same
JP3623805B2 (en) * 1992-02-20 2005-02-23 ユーロセルテイツク・エス・アー Hydromorphone spheroid modified release formulation
GB9203689D0 (en) * 1992-02-20 1992-04-08 Euro Celtique Sa Pharmaceutical composition
ZA932272B (en) * 1992-03-30 1993-10-19 Alza Corp Viscous suspensions of controlled-release drug particles
US5262172A (en) * 1992-06-19 1993-11-16 Digestive Care Inc. Compositions of gastric acid-resistant microspheres containing buffered bile acids
US5234697A (en) * 1992-06-22 1993-08-10 Digestive Care Inc. Compositions of gastric acid-resistant microspheres containing salts of bile acids
US5429825A (en) 1992-06-26 1995-07-04 Mcneil-Ppc, Inc. Rotomelt granulation
US5350584A (en) 1992-06-26 1994-09-27 Merck & Co., Inc. Spheronization process using charged resins
DE4227385A1 (en) 1992-08-19 1994-02-24 Kali Chemie Pharma Gmbh Pancreatin micropellets
DE69332291T2 (en) 1992-10-16 2003-07-31 Nippon Shinyaku Co Ltd METHOD FOR PRODUCING WAX MATRICES
DE4236408A1 (en) 1992-10-28 1994-05-05 Siemens Ag Switchable damping device
DE4236752A1 (en) 1992-10-30 1994-05-05 Asta Medica Ag Combination preparation of flupirtine and morphine for the treatment of pain and for avoiding morphine addiction
NZ260408A (en) 1993-05-10 1996-05-28 Euro Celtique Sa Controlled release preparation comprising tramadol
IT1265074B1 (en) 1993-05-18 1996-10-30 Istituto Biochimico Italiano SLOW-RELEASE PHARMACEUTICAL COMPOSITION CONTAINING A BILIARY ACID AS THE ACTIVE SUBSTANCE
IL109944A (en) 1993-07-01 1998-12-06 Euro Celtique Sa Sustained release dosage unit forms containing morphine and a method of preparing these sustained release dosage unit forms
IL110014A (en) 1993-07-01 1999-11-30 Euro Celtique Sa Solid controlled-release oral dosage forms of opioid analgesics
DE4325465B4 (en) * 1993-07-29 2004-03-04 Zenz, Michael, Prof. Dr.med. Oral pharmaceutical preparation for pain therapy
DE4329794C2 (en) 1993-09-03 1997-09-18 Gruenenthal Gmbh Tramadol salt-containing drugs with delayed release
HU218673B (en) 1993-10-07 2000-10-28 Euroceltique S.A. Controlled release pharmaceutical composition for orally administration comprising opioid analgesic and process for producing its
US5476528A (en) 1993-12-20 1995-12-19 Tennessee Valley Authority System for improving material release profiles
JP3224931B2 (en) 1994-01-12 2001-11-05 株式会社日本製鋼所 Twin screw extruder
US5395626A (en) 1994-03-23 1995-03-07 Ortho Pharmaceutical Corporation Multilayered controlled release pharmaceutical dosage form
DE4413350A1 (en) 1994-04-18 1995-10-19 Basf Ag Retard matrix pellets and process for their production
DE4418837A1 (en) 1994-05-30 1995-12-07 Bayer Ag Thermal granulation process
US5567439A (en) 1994-06-14 1996-10-22 Fuisz Technologies Ltd. Delivery of controlled-release systems(s)
US6706284B2 (en) * 2001-03-15 2004-03-16 Yamanouchi Pharmaceutical Co., Ltd. Bitterness-reduced oral pharmaceutical composition
DE60232417D1 (en) * 2001-08-06 2009-07-02 Euro Celtique Sa OPIOID AGONIST FORMULATIONS WITH FREEZER AND SEQUESTRATED ANTAGONIST

Patent Citations (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2738303A (en) * 1952-07-18 1956-03-13 Smith Kline French Lab Sympathomimetic preparation
US3065143A (en) * 1960-04-19 1962-11-20 Richardson Merrell Inc Sustained release tablet
US4132753A (en) * 1965-02-12 1979-01-02 American Cyanamid Company Process for preparing oral sustained release granules
US3652589A (en) * 1967-07-27 1972-03-28 Gruenenthal Chemie 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols
US3830934A (en) * 1967-07-27 1974-08-20 Gruenenthal Chemie Analgesic and antitussive compositions and methods
US3714350A (en) * 1969-03-10 1973-01-30 Mobil Oil Corp Phosphoryl and thiophosphoryl pyrones as insecticides
US3880991A (en) * 1969-03-24 1975-04-29 Brook David E Polymeric article for dispensing drugs
US4344431A (en) * 1969-03-24 1982-08-17 University Of Delaware Polymeric article for dispensing drugs
US3950508A (en) * 1972-05-10 1976-04-13 Laboratoires Servier Process for obtaining pharmaceutical sustained releases
US3965256A (en) * 1972-05-16 1976-06-22 Synergistics Slow release pharmaceutical compositions
US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US4013784A (en) * 1973-12-06 1977-03-22 Peter Speiser Delayed release pharmaceutical preparations
US3974157A (en) * 1974-03-04 1976-08-10 Pennwalt Corporation 1-(Amino-alkyl)-2-aryl-cyclohexane alcohols and esters
US4076798A (en) * 1975-05-29 1978-02-28 American Cyanamid Company High molecular weight polyester resin, the method of making the same and the use thereof as a pharmaceutical composition
US4292300A (en) * 1976-07-23 1981-09-29 Inveresk Research International Controlled release suppositories
US4265875A (en) * 1976-07-23 1981-05-05 Inveresk Research International Controlled release suppositories
US4173417A (en) * 1977-04-15 1979-11-06 Hpm Corporation Extrusion apparatus and method
US4366172A (en) * 1977-09-29 1982-12-28 The Upjohn Company 4-Amino-cyclohexanols, their pharmaceutical compositions and methods of use
US4230687A (en) * 1978-05-30 1980-10-28 Griffith Laboratories U.S.A., Inc. Encapsulation of active agents as microdispersions in homogeneous natural polymeric matrices
US4310483A (en) * 1978-08-15 1982-01-12 Ciba-Geigy Corporation Thermal tumbling granulation
US4343789A (en) * 1979-07-05 1982-08-10 Yamanouchi Pharmaceutical Co., Ltd. Sustained release pharmaceutical composition of solid medical material
US4259314A (en) * 1979-12-10 1981-03-31 Hans Lowey Method and composition for the preparation of controlled long-acting pharmaceuticals
US4380534A (en) * 1980-04-07 1983-04-19 Yamanouchi Pharmaceutical Co., Ltd. Solid drug preparations
US4346709A (en) * 1980-11-10 1982-08-31 Alza Corporation Drug delivery devices comprising erodible polymer and erosion rate modifier
US4374082A (en) * 1981-08-18 1983-02-15 Richard Hochschild Method for making a pharmaceutical and/or nutritional dosage form
USRE33093E (en) * 1986-06-16 1989-10-17 Johnson & Johnson Consumer Products, Inc. Bioadhesive extruded film for intra-oral drug delivery and process
US5958452A (en) * 1994-11-04 1999-09-28 Euro-Celtique, S.A. Extruded orally administrable opioid formulations

Cited By (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9278074B2 (en) 1999-10-29 2016-03-08 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9669024B2 (en) 1999-10-29 2017-06-06 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9669022B2 (en) 1999-10-29 2017-06-06 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9320717B2 (en) 1999-10-29 2016-04-26 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9675611B1 (en) 1999-10-29 2017-06-13 Purdue Pharma L.P. Methods of providing analgesia
US9056107B1 (en) 1999-10-29 2015-06-16 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8975273B2 (en) 1999-10-29 2015-03-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10076516B2 (en) 1999-10-29 2018-09-18 Purdue Pharma L.P. Methods of manufacturing oral dosage forms
US8980291B2 (en) 1999-10-29 2015-03-17 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
US20040013697A1 (en) * 2000-05-30 2004-01-22 Gunther Berndl Self-emulsifying active substance formulation and use of this formulation
US9289391B2 (en) 2000-10-30 2016-03-22 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9205055B2 (en) 2000-10-30 2015-12-08 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9669023B2 (en) 2000-10-30 2017-06-06 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9682077B2 (en) 2000-10-30 2017-06-20 Purdue Pharma L.P. Methods of providing analgesia
US9572804B2 (en) 2000-10-30 2017-02-21 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9572805B2 (en) 2000-10-30 2017-02-21 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9526724B2 (en) 2000-10-30 2016-12-27 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9517236B2 (en) 2000-10-30 2016-12-13 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9056052B1 (en) 2000-10-30 2015-06-16 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9504681B2 (en) 2000-10-30 2016-11-29 Purdue Pharma L.P. Controlled release hydrocodone formulations
US8951555B1 (en) 2000-10-30 2015-02-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10022368B2 (en) 2000-10-30 2018-07-17 Purdue Pharma L.P. Methods of manufacturing oral formulations
US9023401B1 (en) 2000-10-30 2015-05-05 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9205056B2 (en) 2000-10-30 2015-12-08 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9198863B2 (en) 2000-10-30 2015-12-01 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9060940B2 (en) 2000-10-30 2015-06-23 Purdue Pharma L.P. Controlled release hydrocodone
US20060165790A1 (en) * 2003-06-27 2006-07-27 Malcolm Walden Multiparticulates
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US8333990B2 (en) 2003-08-28 2012-12-18 Abbott Laboratories Solid pharmaceutical dosage form
US8399015B2 (en) 2003-08-28 2013-03-19 Abbvie Inc. Solid pharmaceutical dosage form
US8309613B2 (en) 2003-08-28 2012-11-13 Abbvie Inc. Solid pharmaceutical dosage form
US8691878B2 (en) 2003-08-28 2014-04-08 Abbvie Inc. Solid pharmaceutical dosage form
US20110015216A1 (en) * 2003-08-28 2011-01-20 Abbott Laboratories Solid Pharmaceutical Dosage Form
US9259872B2 (en) 2004-08-31 2016-02-16 Euro-Celtique S.A. Multiparticulates
US8771732B2 (en) 2005-08-24 2014-07-08 Endo Pharmaceuticals Inc Sustained release formulations of nalbuphine
US9351938B2 (en) 2005-08-24 2016-05-31 Endo Pharmaceuticals Inc Sustained release formulation of nalbuphine
US10406106B2 (en) 2005-08-24 2019-09-10 Endo Pharmaceuticals Inc. Sustained release formulations of nalbuphine
US8765175B2 (en) 2005-08-24 2014-07-01 Endo Pharmaceuticals Inc Sustained release formulation of nalbuphine
US10172798B2 (en) 2005-08-24 2019-01-08 Endo Pharmaceuticals Inc. Sustained release formulation of nalbuphine
US20070048376A1 (en) * 2005-08-24 2007-03-01 Penwest Pharmaceuticals Co. Sustained release formulations of nalbuphine
US9186330B2 (en) 2005-08-24 2015-11-17 Endo Pharmaceuticals Inc. Sustained release formulation of nalbuphine
KR100656019B1 (en) * 2005-10-20 2006-12-08 현대자동차주식회사 New polyimide-co-polybenzimidazole and polymer electrolytes membrane using them
US7811604B1 (en) 2005-11-14 2010-10-12 Barr Laboratories, Inc. Non-effervescent, orally disintegrating solid pharmaceutical dosage forms comprising clozapine and methods of making and using the same
US20090317355A1 (en) * 2006-01-21 2009-12-24 Abbott Gmbh & Co. Kg, Abuse resistant melt extruded formulation having reduced alcohol interaction
US20100172989A1 (en) * 2006-01-21 2010-07-08 Abbott Laboratories Abuse resistant melt extruded formulation having reduced alcohol interaction
US20070185145A1 (en) * 2006-02-03 2007-08-09 Royds Robert B Pharmaceutical composition containing a central opioid agonist, a central opioid antagonist, and a peripheral opioid antagonist, and method for making the same
US9216176B2 (en) 2006-09-15 2015-12-22 Cima Labs Inc. Abuse resistant drug formulation
US20080069891A1 (en) * 2006-09-15 2008-03-20 Cima Labs, Inc. Abuse resistant drug formulation
US9572803B2 (en) 2006-09-15 2017-02-21 Cima Labs Inc. Abuse resistant drug formulation
US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
US9974751B2 (en) 2006-09-15 2018-05-22 Cima Labs Inc. Abuse resistant drug formulation
US20090022798A1 (en) * 2007-07-20 2009-01-22 Abbott Gmbh & Co. Kg Formulations of nonopioid and confined opioid analgesics
US9226907B2 (en) 2008-02-01 2016-01-05 Abbvie Inc. Extended release hydrocodone acetaminophen and related methods and uses thereof
US8927025B2 (en) 2010-05-11 2015-01-06 Cima Labs Inc. Alcohol-resistant metoprolol-containing extended-release oral dosage forms
US9707224B2 (en) 2013-10-31 2017-07-18 Cima Labs Inc. Immediate release abuse-deterrent granulated dosage forms
US11844796B2 (en) 2013-10-31 2023-12-19 Clexio Biosciences Ltd. Immediate release abuse-deterrent granulated dosage forms
US9757371B2 (en) 2013-10-31 2017-09-12 Cima Labs Inc. Immediate release abuse-deterrent granulated dosage forms
US11207318B2 (en) 2013-10-31 2021-12-28 Clexio Biosciences Ltd. Immediate release abuse-deterrent granulated dosage forms
US10568881B2 (en) 2013-10-31 2020-02-25 Clexio Biosciences Ltd. Immediate release abuse-deterrent granulated dosage forms
US10478429B2 (en) 2015-10-07 2019-11-19 Patheon Softgels, Inc. Abuse deterrent dosage forms
US9943513B1 (en) 2015-10-07 2018-04-17 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
US9861629B1 (en) 2015-10-07 2018-01-09 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
US10335405B1 (en) 2016-05-04 2019-07-02 Patheon Softgels, Inc. Non-burst releasing pharmaceutical composition
US10335375B2 (en) 2017-05-30 2019-07-02 Patheon Softgels, Inc. Anti-overingestion abuse deterrent compositions
US11324707B2 (en) 2019-05-07 2022-05-10 Clexio Biosciences Ltd. Abuse-deterrent dosage forms containing esketamine

Also Published As

Publication number Publication date
AU705894B2 (en) 1999-06-03
US20040081694A1 (en) 2004-04-29
IL142413A (en) 2004-02-19
EP0785775B1 (en) 2004-01-07
EP1741426B1 (en) 2008-06-04
EP1488786A1 (en) 2004-12-22
EP1741426A3 (en) 2007-02-28
US6335033B2 (en) 2002-01-01
DE69535426D1 (en) 2007-04-26
AU4157096A (en) 1996-05-31
EP0785775A1 (en) 1997-07-30
DE69535445T2 (en) 2008-01-24
EP1449530A2 (en) 2004-08-25
US6261599B1 (en) 2001-07-17
ATE452627T1 (en) 2010-01-15
TW425288B (en) 2001-03-11
EP1449531A3 (en) 2004-09-22
IL129410A (en) 2003-06-24
DE69532415D1 (en) 2004-02-12
HK1059887A1 (en) 2004-07-23
HK1069110A1 (en) 2005-05-13
ES2308675T3 (en) 2008-12-01
EP1449530B1 (en) 2007-03-14
DE69536035D1 (en) 2010-02-04
ES2282757T3 (en) 2007-10-16
DK1348429T3 (en) 2010-04-19
DE69532415T3 (en) 2013-03-28
US20100172974A1 (en) 2010-07-08
CA2204180C (en) 2000-10-31
DK0785775T4 (en) 2013-01-21
DE69535767D1 (en) 2008-07-17
US20010036476A1 (en) 2001-11-01
HK1069109A1 (en) 2005-05-13
PT1449530E (en) 2007-06-04
US5965161A (en) 1999-10-12
ES2214512T3 (en) 2004-09-16
PT1348429E (en) 2010-03-09
IL115871A (en) 1999-08-17
PT785775E (en) 2004-04-30
DK1741426T3 (en) 2008-10-06
US6743442B2 (en) 2004-06-01
US20030026839A1 (en) 2003-02-06
PT1449531E (en) 2007-06-25
ES2338641T3 (en) 2010-05-11
EP1449531B1 (en) 2007-03-28
ES2282756T3 (en) 2007-10-16
US6706281B2 (en) 2004-03-16
KR100232945B1 (en) 1999-12-01
IL159766A0 (en) 2004-06-20
US20090148517A1 (en) 2009-06-11
DK1449531T3 (en) 2007-07-30
EP1348429A2 (en) 2003-10-01
ATE397441T1 (en) 2008-06-15
EP0785775A4 (en) 1998-08-19
US5958452A (en) 1999-09-28
HUT77626A (en) 1998-06-29
US7510727B2 (en) 2009-03-31
WO1996014058A1 (en) 1996-05-17
US20010033865A1 (en) 2001-10-25
EP1348429A3 (en) 2003-11-26
EP1449530A3 (en) 2004-09-22
CA2204180A1 (en) 1996-05-17
EP1741426A2 (en) 2007-01-10
DK1449530T3 (en) 2007-07-02
EP1449531A2 (en) 2004-08-25
IL159766A (en) 2006-06-11
JP3186064B2 (en) 2001-07-11
ZA959367B (en) 1996-06-13
EP2283816A1 (en) 2011-02-16
DE69532415T2 (en) 2004-12-30
US20040185096A1 (en) 2004-09-23
JPH10508608A (en) 1998-08-25
DE69535445D1 (en) 2007-05-10
DE69535426T2 (en) 2007-12-06
ATE356616T1 (en) 2007-04-15
ATE357909T1 (en) 2007-04-15
DK0785775T3 (en) 2004-05-24
EP1348429B1 (en) 2009-12-23
PT1741426E (en) 2008-09-01
IL115871A0 (en) 1996-01-31
ATE257375T1 (en) 2004-01-15
IL129410A0 (en) 2000-02-17
EP0785775B2 (en) 2012-12-05

Similar Documents

Publication Publication Date Title
US6743442B2 (en) Melt-extruded orally administrable opioid formulations
US9603802B2 (en) Extrusion
AU2005282784A1 (en) Opioid dosage forms having dose proportional steady state Cave and AUC and less than dose proportional single dose Cmax
AU747389B2 (en) Melt-extruded orally administrable opioid formulations

Legal Events

Date Code Title Description
AS Assignment

Owner name: EURO-CELTIQUE, S.A., LUXEMBOURG

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:OSHLACK, BENJAMIN;CHASIN, MARK;HUANG, HUA-PIN;AND OTHERS;REEL/FRAME:015182/0693;SIGNING DATES FROM 20031112 TO 20031113

STCB Information on status: application discontinuation

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

AS Assignment

Owner name: PURDUE PHARMA L.P., CONNECTICUT

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:EURO-CELTIQUE S.A.;REEL/FRAME:021217/0075

Effective date: 20080709