US20040265372A1 - Soft tablet containing high molecular weight cellulosics - Google Patents

Soft tablet containing high molecular weight cellulosics Download PDF

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Publication number
US20040265372A1
US20040265372A1 US10/607,766 US60776603A US2004265372A1 US 20040265372 A1 US20040265372 A1 US 20040265372A1 US 60776603 A US60776603 A US 60776603A US 2004265372 A1 US2004265372 A1 US 2004265372A1
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United States
Prior art keywords
dosage form
percent
mixtures
group
active ingredient
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Abandoned
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US10/607,766
Inventor
David Wynn
Nick Parikh
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Johnson and Johnson Consumer Inc
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McNeil PPC Inc
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Publication date
Application filed by McNeil PPC Inc filed Critical McNeil PPC Inc
Priority to US10/607,766 priority Critical patent/US20040265372A1/en
Assigned to MCNEIL-PPC, INC. reassignment MCNEIL-PPC, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PARIKH, NICK, WYNN, DAVID
Priority to ES04253843.9T priority patent/ES2539268T3/en
Priority to CA 2472432 priority patent/CA2472432C/en
Priority to EP04253843.9A priority patent/EP1491184B1/en
Publication of US20040265372A1 publication Critical patent/US20040265372A1/en
Priority to US12/638,070 priority patent/US8496969B2/en
Abandoned legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • 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]

Definitions

  • the present invention relates to an immediate release, chewable or disintegrable tablet comprising a blend of active ingredient and high molecular weight cellulosics, having exceptionally good mouthfeel and stability.
  • compositions intended for oral administration are typically provided in solid dosage forms such as, for example, tablets, capsules, pills, lozenges, or granules. Tablets are swallowed whole, chewed in the mouth, or dissolved in the oral cavity. Chewable or disintegrable tablets are often employed in the administration of pharmaceuticals where it is impractical to provide a tablet for swallowing whole, such as, for example, with pediatric and geriatric patients.
  • Alternative texture masking agents include polyalkylene glycols.
  • U.S. Pat. No. 4,882,154 discloses chewable dosage forms wherein the pharmaceutical ingredient is pre-coated with, for example, a polyalkylene glycol having a molecular weight of less than 3700.
  • WO 00/30617 discloses a taste masked drug particle having an active inner core, a polyethylene oxide layer covering the core, and an outer taste masking layer.
  • these texture masking processes disadvantageously require one or more coating steps, which not only makes them less economical but also increases production cycle time.
  • Another technique for texture masking an agent involves the blending of low-viscosity hydroxyalkylcellulose and high-viscosity hydroxyalkylcellulose with calcium powder, then granulating the blend into pelletizable granules in order to improve the mouth feel of the resulting calcium-containing dosage forms. See, e.g., Japanese Patent Application 5[1993]-306229.
  • U.S. Pat. No. 6,432,442 discloses the use of a gelatin matrix and an optional hydrocolloid as another technique for providing a soft, chewable delivery system. Because these “gummi” or confectionary systems also contain water in an amount of from about 10 to 30 percent by weight of the final product, they disadvantageously possess certain limitations with respect to shelf-life, packaging, and storage conditions. Additionally, it is economically more beneficial to produce other dosage forms such as, for example, compressed tablets, due to their simplicity of processing.
  • This invention relates to an immediate release dosage form capable of being chewed or disintegrated in the oral cavity prior to swallowing, comprising, consisting of, and/or consisting essentially of
  • a matrix comprising, based upon the total weight of the dosage form, from about 0.1 percent to about 25 percent of hydroxyalkylcellulose having a weight average molecular weight of from about 60,000 to about 5,000,000 and/or a viscosity of from about 3,000 mPa.S to about 150,000 mpa.s in a 2% aqueous solution.
  • This invention further relates to an immediate release dosage form capable of being chewed or disintegrated in the oral cavity prior to swallowing, comprising, consisting of, and/or consisting essentially of
  • a matrix comprising, based upon the total weight of the dosage form, from about 0.1 percent to about 25 percent of hydroxyalkylcellulose having a weight average molecular weight of from about 60,000 to about 5,000,000 and/or a viscosity of from about 3,000 mPa.S to about 150,000 mpa.s in a 2% aqueous solution,
  • the term “dosage form” applies to any solid, semi-solid, or liquid composition designed to contain a specific pre-determined amount or “dose” of a certain ingredient, for example an active ingredient as defined below.
  • Dosage forms may include, but are not limited to: a) pharmaceutical drug delivery systems, including those for oral administration, buccal administration, or mucosal delivery; or b) compositions for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorants, and the like.
  • the solid dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the GI tract of a mammal.
  • the dosage forms of the present invention are typically considered to be solid; however, they may contain liquid or semi-solid components.
  • Suitable “solid dosage forms” of the present invention include, but are not limited to, tablets, e.g. caplets; capsules; sachets; and the like.
  • One suitable solid dosage form is a chewable or orally disintegratable tablet.
  • immediate release shall mean that the dissolution of the dosage form conforms to USP specifications for immediate release tablets containing the particular active ingredient employed.
  • USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophen contained in the dosage form is released therefrom within 30 minutes after dosing
  • USP 24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm at least 80% of the ibuprofen contained in the dosage form is released therefrom within 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856 (1999).
  • the term, “good mouth feel” shall mean that the dosage form becomes a slippery, gel-like mass capable of suspending gritty particles during mastication.
  • high weight average molecular weight hydroxyalkylcellulose it is meant a hydroxyalkylcellulose having a) weight average molecular weight between about 60,000 to about 5,000,000, e.g. from about 140,000 to about 1,150,000; and/orb) a viscosity between about 3,000 mPa.s to about 150,000 mPa.s in a 2% aqueous solution, e.g., from about 4,000 mPa.s to about 100,000 mPa.s in a 2% aqueous solution.
  • the dosage form of the present invention may be made from a composition comprising one or more active ingredients and, based upon the total weight of the dosage form, from about 0.1 percent to about 25.0 percent, e.g. from about 0.5 percent to about 10.0 percent, of a hydroxyalkylcellulose having a high weight average molecular weight in the matrix.
  • hydroxyalkylcellulose having a high weight average molecular weight in the matrix shall refer to such a hydroxyalkylcellulose that is present in the final dosage form but is not contained in the active ingredient powder or the granulated active ingredient particles or crystals per se.
  • the granulated active ingredient particles are substantially free of high weight average molecular weight hydroxyalkylcellulose.
  • substantially free of high weight average molecular weight hydroxyalkylcellulose shall mean that the granulated particles contain, based upon the total weight of the particles, less than about 1%, e.g., less than about 0.1% or less than about 0.01% of high weight average molecular weight hydroxyalkylcellulose.
  • Suitable active ingredients include pharmaceuticals, minerals, vitamins, other nutraceuticals, and mixtures thereof.
  • suitable pharmaceuticals include analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, diuretics, expectorants, gastrointestinal agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep aids, urinary tract agents and mixtures thereof.
  • Suitable gastrointestinal agents include stimulant laxatives, such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists, such as famotadine, ranitidine, cimetadine; proton pump inhibitors; gastrointestinal cytoprotectives, such as sucraflate and misoprostol; gastrointestinal prokinetics, such as Prucalopride, antibiotics for H.
  • stimulant laxatives such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof
  • H2 receptor antagonists such as famotadine, ranitidine, cimetadine
  • proton pump inhibitors such
  • pylori such as clarithromycin, amoxicillin, tetracycline, and metronidazole; antidiarrheals, such as diphenoxylate and loperamide; glycopyrrolate; antiemetics, such as ondansetron, analgesics, such as mesalamine.
  • the active agent may be selected from bisacodyl, famotadine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • the active agent may be selected from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • the active agent may be selected from pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • Suitable polydimethylsiloxanes which include, but are not limited to dimethicone and simethicone, are those disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each is expressly incorporated herein by reference.
  • simethicone refers to the broader class of polydimethylsiloxanes, including but not limited to simethicone and dimethicone.
  • the active ingredient(s) are present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, it is well known in the art that various factors must be considered that include, but are not limited to the particular active ingredient being administered, the bioavailability characteristics of the active ingredient, the dose regime, and the age and weight of the patient.
  • the amount of active ingredient contained in the dosage form is, based upon the total weight of the dosage form, from about 0.25 percent to about 70 percent, e.g., from about 0.5 percent to about 25 percent or from about 10 percent to about 50 percent.
  • the active ingredient can be in the form of a fine powder, granule, or large crystal, and typically has an average particle size from about 20 microns to about 1000 microns, e.g., from about 50 microns to about 700 microns or from about 100 microns to about 500 microns.
  • one or more active ingredients are contained in particles having an average size from about 150 to about 400 microns.
  • the active ingredient may be in any form within the particles, for example as a fine powder dispersed throughout a matrix of inactive ingredients, or in crystalline or amorphous form, layered onto an inert seed particle.
  • a coated particle containing the active ingredient coated with a taste masking agent is employed.
  • “Coated particle,” as used herein, refers to a solid active ingredient in the form of a crystal or particle, an agglomerate of individual particles, or a granuled particle, which has been encapsulated with a taste masking agent, either by film coating method known in the art or by other known processes such as coaccervation.
  • acetaminophen particles that have been encapsulated with ethylcellulose or other polymers via coaccervation may be used in the present invention.
  • Such coaccervation-encapsulated acetaminophen may be purchased commercially from Eurand America, Inc. Vandalia, Ohio, or from Circa Inc., Dayton, Ohio.
  • Other commercially available taste masked active ingredients may also be employed.
  • Suitable taste masking coatings are described in, for example, U.S. Pat. Nos. 6,471,991, 4,851,226, 5,075,114, and 5,489,436, which are all incorporated by reference herein.
  • Suitable taste masking agents include, but are not limited to cellulose acetate, ethylcellulose, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride), which is commercially available from Rohm Pharma under the tradename, “EUDRAGIT”, hydroxypropyl methylcelluiose, hydroxypropyl cellulose, hydroxyethyl cellulose, and mixtures thereof.
  • the taste masking agent may be comprised of a mixture of a) at least one solubilizable polymer selected from the group consisting of enteric polymers, reverse enteric polymers, water soluble polymers, and copolymers and mixtures thereof; and b) and at least one insoluble film forming polymer.
  • solubilizable polymer shall mean a polymer that swells or dissolves in a certain medium and can be dispersed at the molecular level to form a homogeneous dispersion therein. The medium may resemble conditions that could exist in the gastrointestinal tract of a human.
  • the solubilizable polymer may be soluble in a water medium (e.g.
  • solubilizable polymer may be soluble in an aqueous medium having a certain pH range, such as at a pH less than 5 (e.g. reverse enteric polymers) or such as at a pH of 5.5 or greater (e.g. enteric polymers).
  • the enteric polymer may be selected from any one of a variety of known enteric polymers, such as shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, polyvinylacetate phthalate, and polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename, “EUDRAGIT S” polymers, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename, “EUDRAGIT L” polymers. Combinations of enteric polymers may also be used.
  • enteric polymers such as shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, polyvinylacetate phthalate, and polymethacrylate-based polymers such as poly(methacryl
  • the enteric polymer is selected from non-acrylate compounds, specifically hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and polyvinylacetate phthalate.
  • Non-acrylates are preferred because acrylate polymers tend to become tacky and agglomerate at high temperature. Cellulose polymers are more heat stable than acrylate polymers.
  • acrylate polymers are known to have a characteristic, slightly unpleasant taste, whereas cellulose polymers have a more neutral taste profile.
  • Suitable reverse enteric polymers include, but are not limited to methylaminoethyl-methacrylate and neutral methacrylic acid esters available from Rohm Pharma GmbH, Germany under the tradename, “EUDRAGITTM E 100.”
  • suitable water soluble polymers include, but are not limited to hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohols, and sodium carboxymethylcellulose.
  • the insoluble film forming polymer may be selected from a number of known compounds, including cellulose acetate, cellulose acetate butyrate, cellulose triacetate, ethylcellulose, neutral ester co-polymer of ethyl acylate and methyl methacrylate, which is commercially available from Rohm Pharma under the tradename, “EUDRAGIT NE”, and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, which is commercially available from Rohm Pharma under the tradename, “EUDRAGIT RS”.
  • One or more than one insoluble film forming polymer may be used.
  • the insoluble film forming polymer is impermeable and does not swell in an aqueous environment. More preferably, the insoluble film forming polymer is selected from cellulose acetate and ethylcellulose.
  • the weight ratio of solubilizable polymer to insoluble film forming polymer in the polymeric coating is preferably in the range of about 5:95 to about 80:20, more preferably about 40:60 to about 70:30.
  • COAT POLYMER POLYMER SYSTEM LEVEL 1 RATIO 2 Cellulose acetate/PVP 5-60% 90/10 to 60/40 Cellulose acetate Butyrate/PVP 5-60% 90/10 to 60/40 Cellulose acetate/HPC 5-60% 90/10 to 50/50 Cellulose acetate/HPMCP 5-60% 90/10 to 50/50 Cellulose acetate Butryate/HPC 5-60% 90/10 to 50/50 Cellulose acetate/EUDRAGIT E100 8-60% ALL RATIOS Cellulose acetate Butryate/EUDRAGIT E 8-60% ALL RATIOS 100 Ethyl cellulose/PVP 8-60% 90/10 to 60/40 Ethyl cellulose/HPC 8-60% 90/10 to 50/50 Ethyl cellulose/EUDRAGIT E 100 8-60% ALL RATIOS HPC 10-60% NA HEC 10-60% NA EUDRAGIT E 100 10-60%
  • the taste masking polymers may also optionally be combined with a surfactant.
  • Suitable surfactants include both ionic and non-ionic materials from both synthetic and natural origins, including but not limited to lecithin, glyceryl esters, sugar esters, polysorbates, mono and diglycerides of fatty acids, propylene glycol esters, sucrose fatty acid esters, polyoxyethylene derivatives of sorbitan fatty acid esters, and mixtures thereof.
  • useful polysorbates include sorbitan trioleate, sorbitan monopalmitate, sorbitan monolaurate, propylene glycol monolaurate, glycerol monostearate, diglycerol monostearate, glycerol lactyl-palmitate.
  • Lactic acid derivatives include sodium stearoyl lactylate and calcium stearoyl lactylate.
  • the dried taste masking coating comprises about 53 wt % hydroxypropyl methylcellulose phthalate (“hypromellose phthalate”), about 43 wt % cellulose acetate, and about 4 wt % polysorbate.
  • the taste masking coating may be coated directly onto the pure active ingredient core or may be coated on to a granulated particle core containing the active ingredient, such that the core is substantially covered.
  • substantially covered shall mean at least about 95%, e.g. about 99% of the exterior surface of the core is covered with the subject coating.
  • the taste masking coating is preferably applied to the active ingredient, or a granulated particle containing the active ingredient, in the form of a solution using conventional fluidized bed technology, such as Wurster coating or rotor coating. These coating operations are further described in Leiberman, et al., 3 Pharmaceutical Dosage Forms 138-150 (1990), which is hereby incorporated by reference.
  • organic solvents may be used to prepare the solution of the taste masking coating.
  • Useful solvents include any of the pharmaceutically suitable organic solvents such as acetone, methanol, ethanol, isopropanol; aqueous solvents such as water; and mixtures thereof.
  • the proportion of the taste masking coating in the solvent solution will be within the range of about 5 to about 20, e.g. from about 8 to about 15, weight percent, depending on the solvent and other similar considerations.
  • One suitable solvent mixture includes acetone and water at a ratio from about 85:15 to about 95:5.
  • the thickness of the taste masking coating on the active ingredient-containing core is typically from about 1 micron to about 20 microns, e.g. from about 2 microns to about 15 microns or from about 4 to about 9 microns.
  • Particles coated with a taste masking coating in a dried state, generally contain the taste masking coating in an amount, based upon the total weight of particle and the taste masking coating, from about 1 percent to about 50 percent, e.g. from about 15 percent to about 25 percent.
  • the exact proportions of the coating to the active ingredient can vary depending upon, for example, the level of tastemasking required and whether a sustained or immediate release of the active ingredient is desired. Increased amounts of the taste masking coating tend to provide a sustained release effect and enhanced taste masking.
  • the active ingredient will constitute from about 5 to about 90 weight percent of the particle, with the remainder being the binder or filler.
  • Suitable binders for the granulated particles include polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and other pharmaceutically acceptable polymers.
  • Fillers suitable for use in such granulated particles include lactose, confectioner's sugar, mannitol, dextrose, fructose, other pharmaceutically acceptable saccharide and microcrystalline cellulose.
  • the active ingredient may be combined with a matrix comprising a high weight average molecular weight hydroxyalkylcellulose, wherein the high weight average molecular weight hydroxyalkylcellulose is present in the matrix in an amount, based upon the total weight of the dosage form, from about 0.1 percent to about 25 percent, e.g. from about 0.5 percent to about 10 percent.
  • the average particle size of the high weight average molecular weight hydroxyalkylcellulose may vary from about 1 micron to about 500 microns, e.g., from about 150 microns to about 400 microns or from about 200 microns to about 300 microns.
  • hydroxyalkylcelluloses that have average molecular weights in the lower end of the range of “high weight average molecular weight” hydroxyalkylcelluloses as defined herein, as well as to employ the lowest level of such hydroxyalkylcelluloses that may yield the desired mouthfeel for the selected active ingredient.
  • Hydroxyalkylcellulose shall mean cellulose derivatives that are substituted with a hydroxyalkyl group, wherein the alkyl group contains from about 1 to about 10 carbons.
  • suitable high molecular weight hydroxyalkylcelluloses include, but are not limited to, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, and the like.
  • the hydroxyalkylcellulose is hydroxypropylcellulose and/or hydroxypropylmethylcellulose.
  • Suitable hydroxypropylmethylcelluloses include those available from Dow Chemical Corporation under the tradenames, “HPMC K4M,” “HPMC K15M,” and “HPMC K100M.”
  • suitable hydroxypropylcelluloses include those available from Hercules, Inc. under the tradenames, “Klucel® H(CS) and “Klucel® M”.
  • the matrix may optionally contain other conventional, pharmaceutically acceptable auxiliary ingredients, such as fillers, conventional dry binders, sweeteners, disintegrants, and lubricants such as, for example, stearic acid, magnesium stearate, and mixtures thereof.
  • auxiliary ingredients such as fillers, conventional dry binders, sweeteners, disintegrants, and lubricants such as, for example, stearic acid, magnesium stearate, and mixtures thereof.
  • Suitable fillers include water-disintegratable, compressible carbohydrates such as, for example, sugars, sugar alcohols, starch hydrolysates, and mixtures thereof.
  • suitable sugars include, but are not limited to dextrose, sucrose, maltose, and lactose.
  • suitable sugar alcohols include, but are not limited to mannitol, sorbitol, maltitol, xylitol, and erythritol.
  • suitable starch hydrolysates include, but are not limited to, dextrins and maltodextrins.
  • the water-disintegratable, compressible carbohydrate may be selected from dextrose monohydrate, mannitol, sorbitol, xylitol, and mixtures thereof.
  • a water-disintegratable compressible carbohydrate is employed as a filler, it is typically present at a level from, based upon the total weight of the dosage form, from about 40 to about 90 percent, e.g. from about 50 to about 80 percent.
  • the matrix may also incorporate pharmaceutically acceptable adjuvants, including, for example, preservatives, flavors such as, for example, orange and/or vanilla, acidulants, glidants, surfactants, and coloring agents such as, for example, FD&C yellow.
  • the matrix preferably comprises no more than, based upon the total weight of the dosage form, about 25 weight % of such optional auxiliary ingredients.
  • the dosage form may be made in any manner, and for tablet dosage forms, a variety of tableting methods are known in the art.
  • Conventional methods for tablet production include direct compression (“dry blending”), dry granulation followed by compression, and wet granulation followed by drying and compression.
  • Other methods include the use of compacting roller technology such as a chilsonator or drop roller, or molding, casting, or extrusion technologies. All of these methods are well known in the art, and are described in detail in, for example, Lachman, et al., The Theory and Practice of Industrial Pharmacy , Chapter 11, (3 rd Ed. 1986), which is incorporated by reference herein.
  • a blend of the active ingredient which may optionally be coated with a tastemasking coating, hydroxyalkylcellulose, and any other appropriate optional ingredients are directly compacted.
  • a pre-determined volume of particles from the blend is filled into a die cavity of a rotary tablet press, which continuously rotates as part of a “die table” from the filling position to a compaction position.
  • the particles are compacted between an upper punch and a lower punch to an ejection position, at which the resulting tablet is pushed from the die cavity by the lower punch and guided to an ejection chute by a stationary “take-off” bar.
  • the tableting method is carried out such that the resulting tablet is relatively soft.
  • the hardness of a “soft” tablet produced in accordance with the present invention is up to about 15 kiloponds per square centimeter (kp/cm 2 ), i.e., e.g., from about 1 kp/cm 2 to 8 kp/cm 2 or from about 2 kp/cm 2 to 6 kp/cm 2 .
  • Hardness is a term used in the art to describe the diametrical breaking strength as measured by conventional pharmaceutical hardness testing equipment, such as a Schleuniger Hardness Tester.
  • tablette hardness testing is found in Leiberman et al., Pharmaceutical Dosage Forms—Tablets , Volume 2, 2 nd ed., Marcel Dekker Inc., 1990, pp. 213-217, 327-329, which is incorporated by reference herein.
  • the tablet of the present invention advantageously has acceptable friability. Friability levels are typically less than about 2%, e.g. less than about 1%, or less than about 0.5%. A discussion of tablet friability is presented in USP 23 (1995) ⁇ 1216>p. 1981.
  • the dosage form of the present invention typically has a moisture content of not more than about 5 percent, as measured by weight loss on drying at 105° C. in a moisture analyzer, such as that available from Arizona Instruments under the tradename, “Computrac Max 2000.”
  • the increase in viscosity will depend upon several factors such as, for example, the amount and molecular weight of such hydroxyalkylcellulose used and the amount and type of active ingredient, generally the use of about 0.1 percent to about 25.0 percent of a 60,000 to about 5,000,000 MW hydroxyalkylcellulose based upon the total weight of the dosage form, will result in a viscosity increase during tablet mastication that is similar to that obtained using gums, but without the drying sensation and without the subsequent excessive slimy or gummy feel imparted by using conventional agents.
  • a coating solution was prepared by dispersing cellulose acetate, hypromellose phthalate (HPMCP-50), and polysorbate-80 in a solvent consisting of 90% acetone and 10% water under ambient conditions, so that the finished solution contained 10% of the coating materials.
  • the relative amounts of coating materials were, based upon the total weight percent of the final coating,
  • Ibuprofen USP powder was combined with colloidal silicon dioxide and microcrystalline cellulose to form the following ibuprofen pre-mixture: Component Weight Percent* Colloidal silicon dioxide 0.27% microcrystalline cellulose** 1.04% Ibuprofen USP 98.71%
  • Granulation solution A simethicone emulsion available from Dow Corning Company under the tradename, “30% Simethicone Emulsion USP Q7-2587” was added to an 8% solids hydroxypropylmethylcellulose aqueous solution under ambient conditions to form the following granulating solution: Component Weight Percent* Simethicone emulsion 0.10% Hydroxypropylmethylcellulose** 7.90% Water 92.00%
  • Ibuprofen Granules The ibuprofen mixture was then granulated to a larger particle sizes of approximately 206 ⁇ m by first spraying the granulating solution thereon at a rate of about 1200 g/min under product temperature conditions of about 19° C. using a Model GRG 600 fluid bed granulator available from Glatt, Inc. and then subsequently drying the sprayed ibuprofen at a product temperature of 23° C.
  • the final dried, ibuprofen granules had the following formulation Component Weight Percent* Ibuprofen 95.7% hydroxypropylmethylcellulose 3.01% colloidal silicon dioxide 0.25% microcrystalline cellulose 1.00% simethicone emulsion 0.04%
  • the resulting ibuprofen granules were then coated with the taste-masking solution described in Example 1 at a rate of bout 375 g/min in a Wurster fluid bed coating unit under product temperature conditions of about 29° C.
  • the resulting coated ibuprofen granules contained, based upon the total dry weight of the ibuprofen granules and the tastemasking coating, about 25% of the taste-masking coating.
  • the colorant, flavor, sucralose NF, acidulant, high molecular weight hydroxypropylmethylcellulose) and crospovidone NF were sieved through a 40 mesh screen to form an excipient blend.
  • the lubricant was then sieved through a 40 mesh screen, added to the total resulting mixture, and manually blended until the final mixture was homogenous.
  • the final mixture was then compressed into 800 mg chewable tablets using 1 ⁇ 2′′ diameter flat faced tooling to a thickness of 0.219′′ inches and a hardness of 5.2 kp. under ambient conditions.

Abstract

The invention relates to an immediate release tablet capable of being chewed or disintegrated in the oral cavity, which comprises a pharmaceutically active ingredient having an optional tastemasking coating, and a matrix comprising hydroxyalkylcellulose having a weight average molecular weight of from about 60,000 to about 5,000,000. The tablet possesses exceptionally good mouthfeel and stability.

Description

    BACKGROUND OF THE INVENTION
  • 1. Field of the Invention [0001]
  • The present invention relates to an immediate release, chewable or disintegrable tablet comprising a blend of active ingredient and high molecular weight cellulosics, having exceptionally good mouthfeel and stability. [0002]
  • 2. Background of the Invention [0003]
  • Pharmaceuticals intended for oral administration are typically provided in solid dosage forms such as, for example, tablets, capsules, pills, lozenges, or granules. Tablets are swallowed whole, chewed in the mouth, or dissolved in the oral cavity. Chewable or disintegrable tablets are often employed in the administration of pharmaceuticals where it is impractical to provide a tablet for swallowing whole, such as, for example, with pediatric and geriatric patients. [0004]
  • Workers in the field continue to try to improve the flavor and mouthfeel of chewable tablets and other comestibles by adding agents, such as gums, thereto. See, e.g., U.S. Pat. No. 4,818,539 and WO 88/06893. In order to effectively texture mask such dosage forms, it is necessary to blend a high level of gum with the active agent. Disadvantageously, during mastication such forms become pasty and initially cause a significant drying phase in the mouth. [0005]
  • Alternative texture masking agents include polyalkylene glycols. For instance, U.S. Pat. No. 4,882,154 discloses chewable dosage forms wherein the pharmaceutical ingredient is pre-coated with, for example, a polyalkylene glycol having a molecular weight of less than 3700. Further, WO 00/30617 discloses a taste masked drug particle having an active inner core, a polyethylene oxide layer covering the core, and an outer taste masking layer. However, these texture masking processes disadvantageously require one or more coating steps, which not only makes them less economical but also increases production cycle time. [0006]
  • Another technique for texture masking an agent involves the blending of low-viscosity hydroxyalkylcellulose and high-viscosity hydroxyalkylcellulose with calcium powder, then granulating the blend into pelletizable granules in order to improve the mouth feel of the resulting calcium-containing dosage forms. See, e.g., Japanese Patent Application 5[1993]-306229. [0007]
  • U.S. Pat. No. 6,432,442 discloses the use of a gelatin matrix and an optional hydrocolloid as another technique for providing a soft, chewable delivery system. Because these “gummi” or confectionary systems also contain water in an amount of from about 10 to 30 percent by weight of the final product, they disadvantageously possess certain limitations with respect to shelf-life, packaging, and storage conditions. Additionally, it is economically more beneficial to produce other dosage forms such as, for example, compressed tablets, due to their simplicity of processing. [0008]
  • It would be desirable to have a chewable or disintegrable, texture masked, immediate release dosage form, and in particular a chewable or disintegrable compressed tablet, that could be suitable for use with active agents having large particle sizes, e.g. those in excess of 100 microns. [0009]
  • SUMMARY OF THE INVENTION
  • This invention relates to an immediate release dosage form capable of being chewed or disintegrated in the oral cavity prior to swallowing, comprising, consisting of, and/or consisting essentially of [0010]
  • a. a plurality of particles comprising a pharmaceutically active ingredient, said particles having a particle size of about 150 μm to about 400 μm; and [0011]
  • b. a matrix comprising, based upon the total weight of the dosage form, from about 0.1 percent to about 25 percent of hydroxyalkylcellulose having a weight average molecular weight of from about 60,000 to about 5,000,000 and/or a viscosity of from about 3,000 mPa.S to about 150,000 mpa.s in a 2% aqueous solution. [0012]
  • This invention further relates to an immediate release dosage form capable of being chewed or disintegrated in the oral cavity prior to swallowing, comprising, consisting of, and/or consisting essentially of [0013]
  • a. a plurality of particles comprising a pharmaceutically active ingredient; and [0014]
  • b. a matrix comprising, based upon the total weight of the dosage form, from about 0.1 percent to about 25 percent of hydroxyalkylcellulose having a weight average molecular weight of from about 60,000 to about 5,000,000 and/or a viscosity of from about 3,000 mPa.S to about 150,000 mpa.s in a 2% aqueous solution, [0015]
  • wherein the pharmaceutically active ingredient is coated with a taste masking coating.[0016]
  • DETAILED DESCRIPTION OF THE INVENTION
  • As used herein, the term “dosage form” applies to any solid, semi-solid, or liquid composition designed to contain a specific pre-determined amount or “dose” of a certain ingredient, for example an active ingredient as defined below. Dosage forms may include, but are not limited to: a) pharmaceutical drug delivery systems, including those for oral administration, buccal administration, or mucosal delivery; or b) compositions for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorants, and the like. In one embodiment, the solid dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the GI tract of a mammal. The dosage forms of the present invention are typically considered to be solid; however, they may contain liquid or semi-solid components. Suitable “solid dosage forms” of the present invention include, but are not limited to, tablets, e.g. caplets; capsules; sachets; and the like. One suitable solid dosage form is a chewable or orally disintegratable tablet. [0017]
  • As used herein, the term “immediate release” shall mean that the dissolution of the dosage form conforms to USP specifications for immediate release tablets containing the particular active ingredient employed. For example, for acetaminophen tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophen contained in the dosage form is released therefrom within 30 minutes after dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm at least 80% of the ibuprofen contained in the dosage form is released therefrom within 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856 (1999). The term, “good mouth feel” shall mean that the dosage form becomes a slippery, gel-like mass capable of suspending gritty particles during mastication. [0018]
  • By “high weight average molecular weight hydroxyalkylcellulose,” it is meant a hydroxyalkylcellulose having a) weight average molecular weight between about 60,000 to about 5,000,000, e.g. from about 140,000 to about 1,150,000; and/orb) a viscosity between about 3,000 mPa.s to about 150,000 mPa.s in a 2% aqueous solution, e.g., from about 4,000 mPa.s to about 100,000 mPa.s in a 2% aqueous solution. [0019]
  • The dosage form of the present invention may be made from a composition comprising one or more active ingredients and, based upon the total weight of the dosage form, from about 0.1 percent to about 25.0 percent, e.g. from about 0.5 percent to about 10.0 percent, of a hydroxyalkylcellulose having a high weight average molecular weight in the matrix. [0020]
  • The phrase “hydroxyalkylcellulose having a high weight average molecular weight in the matrix,” as used herein, shall refer to such a hydroxyalkylcellulose that is present in the final dosage form but is not contained in the active ingredient powder or the granulated active ingredient particles or crystals per se. In one embodiment, the granulated active ingredient particles are substantially free of high weight average molecular weight hydroxyalkylcellulose. As used herein, “substantially free of high weight average molecular weight hydroxyalkylcellulose” shall mean that the granulated particles contain, based upon the total weight of the particles, less than about 1%, e.g., less than about 0.1% or less than about 0.01% of high weight average molecular weight hydroxyalkylcellulose. [0021]
  • Suitable active ingredients include pharmaceuticals, minerals, vitamins, other nutraceuticals, and mixtures thereof. Suitable pharmaceuticals include analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, diuretics, expectorants, gastrointestinal agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep aids, urinary tract agents and mixtures thereof. [0022]
  • Examples of suitable gastrointestinal agents include stimulant laxatives, such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists, such as famotadine, ranitidine, cimetadine; proton pump inhibitors; gastrointestinal cytoprotectives, such as sucraflate and misoprostol; gastrointestinal prokinetics, such as Prucalopride, antibiotics for [0023] H. pylori, such as clarithromycin, amoxicillin, tetracycline, and metronidazole; antidiarrheals, such as diphenoxylate and loperamide; glycopyrrolate; antiemetics, such as ondansetron, analgesics, such as mesalamine.
  • In one embodiment, the active agent may be selected from bisacodyl, famotadine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. [0024]
  • In another embodiment, the active agent may be selected from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. [0025]
  • In another embodiment, the active agent may be selected from pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. [0026]
  • Examples of suitable polydimethylsiloxanes, which include, but are not limited to dimethicone and simethicone, are those disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each is expressly incorporated herein by reference. As used herein, the term “simethicone” refers to the broader class of polydimethylsiloxanes, including but not limited to simethicone and dimethicone. [0027]
  • The active ingredient(s) are present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, it is well known in the art that various factors must be considered that include, but are not limited to the particular active ingredient being administered, the bioavailability characteristics of the active ingredient, the dose regime, and the age and weight of the patient. [0028]
  • In one embodiment, the amount of active ingredient contained in the dosage form is, based upon the total weight of the dosage form, from about 0.25 percent to about 70 percent, e.g., from about 0.5 percent to about 25 percent or from about 10 percent to about 50 percent. [0029]
  • The active ingredient can be in the form of a fine powder, granule, or large crystal, and typically has an average particle size from about 20 microns to about 1000 microns, e.g., from about 50 microns to about 700 microns or from about 100 microns to about 500 microns. In one embodiment, one or more active ingredients are contained in particles having an average size from about 150 to about 400 microns. The active ingredient may be in any form within the particles, for example as a fine powder dispersed throughout a matrix of inactive ingredients, or in crystalline or amorphous form, layered onto an inert seed particle. [0030]
  • If the active ingredient has an objectionable taste, a coated particle containing the active ingredient coated with a taste masking agent is employed. “Coated particle,” as used herein, refers to a solid active ingredient in the form of a crystal or particle, an agglomerate of individual particles, or a granuled particle, which has been encapsulated with a taste masking agent, either by film coating method known in the art or by other known processes such as coaccervation. For example, acetaminophen particles that have been encapsulated with ethylcellulose or other polymers via coaccervation may be used in the present invention. Such coaccervation-encapsulated acetaminophen may be purchased commercially from Eurand America, Inc. Vandalia, Ohio, or from Circa Inc., Dayton, Ohio. Other commercially available taste masked active ingredients may also be employed. [0031]
  • Suitable taste masking coatings are described in, for example, U.S. Pat. Nos. 6,471,991, 4,851,226, 5,075,114, and 5,489,436, which are all incorporated by reference herein. [0032]
  • Examples of suitable taste masking agents include, but are not limited to cellulose acetate, ethylcellulose, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride), which is commercially available from Rohm Pharma under the tradename, “EUDRAGIT”, hydroxypropyl methylcelluiose, hydroxypropyl cellulose, hydroxyethyl cellulose, and mixtures thereof. [0033]
  • In certain embodiments, the taste masking agent may be comprised of a mixture of a) at least one solubilizable polymer selected from the group consisting of enteric polymers, reverse enteric polymers, water soluble polymers, and copolymers and mixtures thereof; and b) and at least one insoluble film forming polymer. “Solubilizable polymer” as used herein, shall mean a polymer that swells or dissolves in a certain medium and can be dispersed at the molecular level to form a homogeneous dispersion therein. The medium may resemble conditions that could exist in the gastrointestinal tract of a human. For example, the solubilizable polymer may be soluble in a water medium (e.g. water soluble polymers). Alternatively the solubilizable polymer may be soluble in an aqueous medium having a certain pH range, such as at a pH less than 5 (e.g. reverse enteric polymers) or such as at a pH of 5.5 or greater (e.g. enteric polymers). [0034]
  • The enteric polymer may be selected from any one of a variety of known enteric polymers, such as shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, polyvinylacetate phthalate, and polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename, “EUDRAGIT S” polymers, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename, “EUDRAGIT L” polymers. Combinations of enteric polymers may also be used. [0035]
  • In one embodiment, the enteric polymer is selected from non-acrylate compounds, specifically hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and polyvinylacetate phthalate. Non-acrylates are preferred because acrylate polymers tend to become tacky and agglomerate at high temperature. Cellulose polymers are more heat stable than acrylate polymers. In addition, acrylate polymers are known to have a characteristic, slightly unpleasant taste, whereas cellulose polymers have a more neutral taste profile. [0036]
  • Examples of suitable reverse enteric polymers include, but are not limited to methylaminoethyl-methacrylate and neutral methacrylic acid esters available from Rohm Pharma GmbH, Germany under the tradename, “EUDRAGIT™ E 100.” Examples of suitable water soluble polymers include, but are not limited to hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohols, and sodium carboxymethylcellulose. [0037]
  • The insoluble film forming polymer may be selected from a number of known compounds, including cellulose acetate, cellulose acetate butyrate, cellulose triacetate, ethylcellulose, neutral ester co-polymer of ethyl acylate and methyl methacrylate, which is commercially available from Rohm Pharma under the tradename, “EUDRAGIT NE”, and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, which is commercially available from Rohm Pharma under the tradename, “EUDRAGIT RS”. One or more than one insoluble film forming polymer may be used. Preferably, the insoluble film forming polymer is impermeable and does not swell in an aqueous environment. More preferably, the insoluble film forming polymer is selected from cellulose acetate and ethylcellulose. [0038]
  • The weight ratio of solubilizable polymer to insoluble film forming polymer in the polymeric coating is preferably in the range of about 5:95 to about 80:20, more preferably about 40:60 to about 70:30. [0039]
  • Other examples of suitable taste masking coatings are provided in the following table: [0040]
    COAT POLYMER
    POLYMER SYSTEM LEVEL1 RATIO2
    Cellulose acetate/PVP  5-60% 90/10 to 60/40
    Cellulose acetate Butyrate/PVP  5-60% 90/10 to 60/40
    Cellulose acetate/HPC  5-60% 90/10 to 50/50
    Cellulose acetate/HPMCP  5-60% 90/10 to 50/50
    Cellulose acetate Butryate/HPC  5-60% 90/10 to 50/50
    Cellulose acetate/EUDRAGIT E100  8-60% ALL RATIOS
    Cellulose acetate Butryate/EUDRAGIT E  8-60% ALL RATIOS
    100
    Ethyl cellulose/PVP  8-60% 90/10 to 60/40
    Ethyl cellulose/HPC  8-60% 90/10 to 50/50
    Ethyl cellulose/EUDRAGIT E 100  8-60% ALL RATIOS
    HPC 10-60% NA
    HEC 10-60% NA
    EUDRAGIT E 100 10-60% NA
    HPMC 10-60% NA
    HEC/HPMC 10-60% ALL RATIOS
    HPC/HPMC 10-60% ALL RATIOS
    HEC/HPC 10-60% ALL RATIOS
    2-vinyl pyridine styrene co-polymer 10-60% NA
    CA/2-vps  8-60% ALL RATIOS
    CAB/2-vps  8-60% ALL RATIOS
    Ethyl cellulose/2-vps  8-60% ALL RATIOS
    Cellulose triacetate/PVP  8-60% 90/10 to 60/40
    Cellulose triacetate/HPC  8-60% 90/10 to 50/50
    Cellulose triacetate/EUDRAGIT E 100  8-60% ALL RATIOS
  • The taste masking polymers may also optionally be combined with a surfactant. Suitable surfactants include both ionic and non-ionic materials from both synthetic and natural origins, including but not limited to lecithin, glyceryl esters, sugar esters, polysorbates, mono and diglycerides of fatty acids, propylene glycol esters, sucrose fatty acid esters, polyoxyethylene derivatives of sorbitan fatty acid esters, and mixtures thereof. Examples of useful polysorbates include sorbitan trioleate, sorbitan monopalmitate, sorbitan monolaurate, propylene glycol monolaurate, glycerol monostearate, diglycerol monostearate, glycerol lactyl-palmitate. Lactic acid derivatives include sodium stearoyl lactylate and calcium stearoyl lactylate. When a surfactant is present in the taste masking coating, the level of surfactant is present in an amount, based upon the total weight of the taste masking coating layer, from about 2% to about 10%. [0041]
  • In one embodiment, the dried taste masking coating comprises about 53 wt % hydroxypropyl methylcellulose phthalate (“hypromellose phthalate”), about 43 wt % cellulose acetate, and about 4 wt % polysorbate. [0042]
  • The taste masking coating may be coated directly onto the pure active ingredient core or may be coated on to a granulated particle core containing the active ingredient, such that the core is substantially covered. As used herein, “substantially covered” shall mean at least about 95%, e.g. about 99% of the exterior surface of the core is covered with the subject coating. [0043]
  • The taste masking coating is preferably applied to the active ingredient, or a granulated particle containing the active ingredient, in the form of a solution using conventional fluidized bed technology, such as Wurster coating or rotor coating. These coating operations are further described in Leiberman, et al., 3 [0044] Pharmaceutical Dosage Forms 138-150 (1990), which is hereby incorporated by reference.
  • A wide variety of organic solvents may be used to prepare the solution of the taste masking coating. Useful solvents include any of the pharmaceutically suitable organic solvents such as acetone, methanol, ethanol, isopropanol; aqueous solvents such as water; and mixtures thereof. Generally, the proportion of the taste masking coating in the solvent solution will be within the range of about 5 to about 20, e.g. from about 8 to about 15, weight percent, depending on the solvent and other similar considerations. One suitable solvent mixture includes acetone and water at a ratio from about 85:15 to about 95:5. [0045]
  • When a fluidized bed coating operation is used, air, which may be heated, passes through a bed of the active ingredient solids to fluidize them, and the solution of the taste masking composition is sprayed onto the fluidized bed and thereby coats the active. The air passing through the bed dried the coating onto the active ingredient, so that a dry coated granule is obtained. [0046]
  • The thickness of the taste masking coating on the active ingredient-containing core is typically from about 1 micron to about 20 microns, e.g. from about 2 microns to about 15 microns or from about 4 to about 9 microns. [0047]
  • Particles coated with a taste masking coating, in a dried state, generally contain the taste masking coating in an amount, based upon the total weight of particle and the taste masking coating, from about 1 percent to about 50 percent, e.g. from about 15 percent to about 25 percent. The exact proportions of the coating to the active ingredient can vary depending upon, for example, the level of tastemasking required and whether a sustained or immediate release of the active ingredient is desired. Increased amounts of the taste masking coating tend to provide a sustained release effect and enhanced taste masking. [0048]
  • In embodiments employing a granulated particle, such as a rotogranulated particle, the active ingredient will constitute from about 5 to about 90 weight percent of the particle, with the remainder being the binder or filler. Suitable binders for the granulated particles include polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and other pharmaceutically acceptable polymers. Fillers suitable for use in such granulated particles include lactose, confectioner's sugar, mannitol, dextrose, fructose, other pharmaceutically acceptable saccharide and microcrystalline cellulose. [0049]
  • According to the dosage form of the present invention, the active ingredient may be combined with a matrix comprising a high weight average molecular weight hydroxyalkylcellulose, wherein the high weight average molecular weight hydroxyalkylcellulose is present in the matrix in an amount, based upon the total weight of the dosage form, from about 0.1 percent to about 25 percent, e.g. from about 0.5 percent to about 10 percent. The average particle size of the high weight average molecular weight hydroxyalkylcellulose may vary from about 1 micron to about 500 microns, e.g., from about 150 microns to about 400 microns or from about 200 microns to about 300 microns. [0050]
  • For optimal dissolution results, it is preferable to employ such hydroxyalkylcelluloses that have average molecular weights in the lower end of the range of “high weight average molecular weight” hydroxyalkylcelluloses as defined herein, as well as to employ the lowest level of such hydroxyalkylcelluloses that may yield the desired mouthfeel for the selected active ingredient. [0051]
  • “Hydroxyalkylcellulose,” as used herein shall mean cellulose derivatives that are substituted with a hydroxyalkyl group, wherein the alkyl group contains from about 1 to about 10 carbons. Examples of suitable high molecular weight hydroxyalkylcelluloses include, but are not limited to, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, and the like. In one embodiment, the hydroxyalkylcellulose is hydroxypropylcellulose and/or hydroxypropylmethylcellulose. [0052]
  • Examples of suitable hydroxypropylmethylcelluloses include those available from Dow Chemical Corporation under the tradenames, “HPMC K4M,” “HPMC K15M,” and “HPMC K100M.” Examples of suitable hydroxypropylcelluloses include those available from Hercules, Inc. under the tradenames, “Klucel® H(CS) and “Klucel® M”. [0053]
  • The matrix may optionally contain other conventional, pharmaceutically acceptable auxiliary ingredients, such as fillers, conventional dry binders, sweeteners, disintegrants, and lubricants such as, for example, stearic acid, magnesium stearate, and mixtures thereof. [0054]
  • Suitable fillers include water-disintegratable, compressible carbohydrates such as, for example, sugars, sugar alcohols, starch hydrolysates, and mixtures thereof. Examples of suitable sugars include, but are not limited to dextrose, sucrose, maltose, and lactose. Examples of suitable sugar alcohols include, but are not limited to mannitol, sorbitol, maltitol, xylitol, and erythritol. Examples of suitable starch hydrolysates include, but are not limited to, dextrins and maltodextrins. [0055]
  • In one embodiment, the water-disintegratable, compressible carbohydrate may be selected from dextrose monohydrate, mannitol, sorbitol, xylitol, and mixtures thereof. In embodiments in which a water-disintegratable compressible carbohydrate is employed as a filler, it is typically present at a level from, based upon the total weight of the dosage form, from about 40 to about 90 percent, e.g. from about 50 to about 80 percent. [0056]
  • The matrix may also incorporate pharmaceutically acceptable adjuvants, including, for example, preservatives, flavors such as, for example, orange and/or vanilla, acidulants, glidants, surfactants, and coloring agents such as, for example, FD&C yellow. However, the matrix preferably comprises no more than, based upon the total weight of the dosage form, about 25 weight % of such optional auxiliary ingredients. [0057]
  • The dosage form may be made in any manner, and for tablet dosage forms, a variety of tableting methods are known in the art. Conventional methods for tablet production include direct compression (“dry blending”), dry granulation followed by compression, and wet granulation followed by drying and compression. Other methods include the use of compacting roller technology such as a chilsonator or drop roller, or molding, casting, or extrusion technologies. All of these methods are well known in the art, and are described in detail in, for example, Lachman, et al., [0058] The Theory and Practice of Industrial Pharmacy, Chapter 11, (3rd Ed. 1986), which is incorporated by reference herein.
  • In the direct compression tableting method, a blend of the active ingredient, which may optionally be coated with a tastemasking coating, hydroxyalkylcellulose, and any other appropriate optional ingredients are directly compacted. After all ingredients are blended together, a pre-determined volume of particles from the blend is filled into a die cavity of a rotary tablet press, which continuously rotates as part of a “die table” from the filling position to a compaction position. The particles are compacted between an upper punch and a lower punch to an ejection position, at which the resulting tablet is pushed from the die cavity by the lower punch and guided to an ejection chute by a stationary “take-off” bar. [0059]
  • In one embodiment, the tableting method is carried out such that the resulting tablet is relatively soft. The hardness of a “soft” tablet produced in accordance with the present invention is up to about 15 kiloponds per square centimeter (kp/cm[0060] 2), i.e., e.g., from about 1 kp/cm2 to 8 kp/cm2 or from about 2 kp/cm2 to 6 kp/cm2. Hardness is a term used in the art to describe the diametrical breaking strength as measured by conventional pharmaceutical hardness testing equipment, such as a Schleuniger Hardness Tester. In order to compare values across differently-sized tablets, the breaking strength is normalized for the area of the break (which may be approximated as tablet diameter times thickness). This normalized value, expressed in kp/cm2, is sometimes referred in the art as “tablet tensile strength.” A general discussion of tablet hardness testing is found in Leiberman et al., Pharmaceutical Dosage Forms—Tablets, Volume 2, 2nd ed., Marcel Dekker Inc., 1990, pp. 213-217, 327-329, which is incorporated by reference herein.
  • The tablet of the present invention advantageously has acceptable friability. Friability levels are typically less than about 2%, e.g. less than about 1%, or less than about 0.5%. A discussion of tablet friability is presented in USP 23 (1995)<1216>p. 1981. [0061]
  • The dosage form of the present invention typically has a moisture content of not more than about 5 percent, as measured by weight loss on drying at 105° C. in a moisture analyzer, such as that available from Arizona Instruments under the tradename, “Computrac Max 2000.”[0062]
  • We have unexpectedly found that the addition of high weight average molecular weight hydroxyalkylcellulose to the matrix results in a dosage form that delivers a good mouthfeel through a rapid viscosity build without an initial intense drying sensation of the mouth and without a subsequent excessive slimy or gummy feel during mastication. Although the increase in viscosity will depend upon several factors such as, for example, the amount and molecular weight of such hydroxyalkylcellulose used and the amount and type of active ingredient, generally the use of about 0.1 percent to about 25.0 percent of a 60,000 to about 5,000,000 MW hydroxyalkylcellulose based upon the total weight of the dosage form, will result in a viscosity increase during tablet mastication that is similar to that obtained using gums, but without the drying sensation and without the subsequent excessive slimy or gummy feel imparted by using conventional agents. [0063]
  • Specific embodiments of the present invention are illustrated by way of the following examples. This invention is not confined to the specific limitations set forth in these examples, but rather to the scope of the appended claims. Unless otherwise stated, the percentages and ratios given below are by weight. [0064]
  • EXAMPLES Example 1 Preparation of Tastemasking Coating Solution
  • A coating solution was prepared by dispersing cellulose acetate, hypromellose phthalate (HPMCP-50), and polysorbate-80 in a solvent consisting of 90% acetone and 10% water under ambient conditions, so that the finished solution contained 10% of the coating materials. The relative amounts of coating materials were, based upon the total weight percent of the final coating, [0065]
  • Cellulose acetate . . . 43% [0066]
  • HPMCP-50* . . . 53% [0067]
  • Polysorbate-80 . . . 4% [0068]
  • *available from Shin-Etsu, Inc. [0069]
  • Example 2 Preparation of Coated Active Ingredient
  • Preparation of Ibuprofen Pre-Mixture: Ibuprofen USP powder was combined with colloidal silicon dioxide and microcrystalline cellulose to form the following ibuprofen pre-mixture: [0070]
    Component Weight Percent*
    Colloidal silicon dioxide  0.27%
    microcrystalline cellulose**  1.04%
    Ibuprofen USP 98.71%
  • Preparation of Granulation solution: A simethicone emulsion available from Dow Corning Company under the tradename, “30% Simethicone Emulsion USP Q7-2587” was added to an 8% solids hydroxypropylmethylcellulose aqueous solution under ambient conditions to form the following granulating solution: [0071]
    Component Weight Percent*
    Simethicone emulsion 0.10%
    Hydroxypropylmethylcellulose** 7.90%
    Water 92.00%
  • Preparation of Ibuprofen Granules: The ibuprofen mixture was then granulated to a larger particle sizes of approximately 206 μm by first spraying the granulating solution thereon at a rate of about 1200 g/min under product temperature conditions of about 19° C. using a Model GRG 600 fluid bed granulator available from Glatt, Inc. and then subsequently drying the sprayed ibuprofen at a product temperature of 23° C. [0072]
  • The final dried, ibuprofen granules had the following formulation [0073]
    Component Weight Percent*
    Ibuprofen 95.7%
    hydroxypropylmethylcellulose 3.01%
    colloidal silicon dioxide 0.25%
    microcrystalline cellulose 1.00%
    simethicone emulsion 0.04%
  • The resulting ibuprofen granules were then coated with the taste-masking solution described in Example 1 at a rate of bout 375 g/min in a Wurster fluid bed coating unit under product temperature conditions of about 29° C. The resulting coated ibuprofen granules contained, based upon the total dry weight of the ibuprofen granules and the tastemasking coating, about 25% of the taste-masking coating. [0074]
  • Example 3 Production of Hydroxyalkylcellulose Tablet and Mouthfeel Evaluation Thereof
  • A batch of tablets having the formulation set forth in Table A below was made and then taste tested for mouthfeel and texture during mastication. [0075]
    TABLE A
    Mg/
    Ingredient Tradename Supplier tablet %/batch
    Flavor 10.64 1.33
    Microcrystalline Cellulose Avicel 40.00 5.00
    Mannitol 417.81 52.23
    Sucralose McNEIL - 2.64 0.33
    PPC, Inc.
    Crospovidone - NF Polyplasdone ISP Corp. 8.00 1.00
    Colorant 1.36 0.17
    72% Coated Ibuprofen* 278.55 34.82
    Lubricant - magnesium 5.00 0.63
    stearate
    Acidulant - citric acid 4.00 0.50
    High MW hydroxypropyl- HPMC K4M Dow 32.00 4.00
    methylcellulose Chemical
    Corp.
    TOTAL 800.00 100.0
  • Preparation of Tablets: [0076]
  • In one container, the colorant, flavor, sucralose NF, acidulant, high molecular weight hydroxypropylmethylcellulose) and crospovidone NF were sieved through a 40 mesh screen to form an excipient blend. [0077]
  • The mannitol was then sieved through a 40 mesh screen and added to the blend. [0078]
  • The coated ibuprofen was then sieved through a 20 mesh screen and added to the blend. [0079]
  • The resulting blend was then manually blended in a plastic blender until the mixture was homogenous. [0080]
  • The lubricant was then sieved through a 40 mesh screen, added to the total resulting mixture, and manually blended until the final mixture was homogenous. The final mixture was then compressed into 800 mg chewable tablets using ½″ diameter flat faced tooling to a thickness of 0.219″ inches and a hardness of 5.2 kp. under ambient conditions. [0081]
  • This procedure was repeated, but with the omission of the high molecular weight hydroxypropylmethylcellulose ingredient. [0082]
  • Samples of the resulting tablets were evaluated by a laboratory panel in a blinded study for grittiness during mastication. The results of the evaluation demonstrated that the high weight average molecular weight hydroxyalkylcellulose-containing tablets had significantly less of a grittiness feel in the mouth in comparison to those tablets lacking the high weight average molecular weight hydroxyalkylcellulose. [0083]

Claims (23)

We claim:
1. An immediate release dosage form capable of being chewed or disintegrated in the oral cavity prior to swallowing, comprised of:
a. a plurality of particles comprising a pharmaceutically active ingredient; and
b. a matrix comprising, based upon the total weight of the dosage form, from about 0.1 percent to about 25 percent of a hydroxyalkylcellulose having a weight average molecular weight of from about 60,000 to about 5,000,000 and/or a viscosity of from about 3,000 mPa.S to about 150,000 mPa.s in a 2% aqueous solution,
wherein the pharmaceutically active ingredient is coated with a taste masking coating.
2. The dosage form of claim 1, wherein the hydroxyalkylcellulose is a hydroxypropylcellulose having a weight average molecular weight of from about 140,000 to about 1,150,000.
3. The dosage form of claim 1, wherein the hydroxyalkylcellulose is a hydroxypropylmethylcellulose having a viscosity of from about 3,000 mPa.S to about 150,000 mPa.s in a 2% aqueous solution.
4. The dosage form of claim 1, wherein the matrix further comprises a water-disintegratable, compressible carbohydrate selected from the group consisting of dextrose monohydrate, mannitol, sorbitol, xylitol, and mixtures thereof.
5. The dosage form of claim 1, wherein the pharmaceutically active ingredient is selected from the group consisting of acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
6. The dosage form of claim 1, wherein the pharmaceutically active ingredient is selected from the group consisting of pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
7. The dosage form of claim 1, wherein the dosage form is a tablet.
8. The dosage form of claim 1, wherein the dosage form is comprised of, based upon the total weight of the dosage form,
a. from greater than about 0.25 percent and less than about 70 percent of the coated particles comprising the pharmaceutically active ingredient, said coated particles comprising, based upon the total weight of the coated particles, from greater than about 1 percent and less than about 50 percent of the taste masking coating; and
b. from greater than about 0.5 percent and less than about 10 percent of the hydroxyalkylcellulose in the matrix.
9. The dosage form of claim 8, wherein the taste masking coating is comprised of:
a) at least one solubilizable polymer; and
b) at least one insoluble film forming polymer.
10. The dosage form of claim 9, wherein the solubilizable polymer is selected from the group consisting of enteric polymers, reverse enteric polymers, water soluble polymers, and mixtures and copolymers thereof.
11. The dosage form of claim 10, wherein the enteric polymers are selected from the group consisting of shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, polyvinylacetate phthalate, polymethacrylate-based polymers and mixtures and copolymers thereof.
12. The dosage form of claim 10, wherein the enteric polymers are selected from the group consisting of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, polyvinylacetate phthalate, and mixtures thereof.
13. The dosage form of claim 10, wherein the reverse enteric polymers are methylaminoethyl-methacrylate and/or neutral methacrylic acid esters.
14. The dosage form of claim 10, wherein the water soluble polymers are selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohols, sodium carboxymethylcellulose, and mixtures thereof.
15. The dosage form of claim 10 wherein the insoluble polymers are selected from the group consisting of cellulose acetate, cellulose acetate butyrate, cellulose triacetate, ethylcellulose, neutral ester co-polymer of ethyl acylate and methyl methacrylate, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) in a ratio of 1:2:0.1, and mixtures and copolymers thereof.
16. The dosage form of claim 9, wherein the taste masking coating is comprised of:
a. a first polymer selected from the group consisting of cellulose acetate and/or cellulose acetate butyrate; and
b. a second polymer selected from the group consisting of enteric polymers, reverse enteric polymers, water soluble polymers, and mixtures and copolymers thereof,
wherein the weight ratio of the second polymer to the first polymer is within the range of about 5:95 to about 80:20.
17. The dosage form of claim 9, wherein the hydroxyalkylcellulose is selected from the group consisting of hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, and mixtures thereof.
18. The dosage form of claim 9, wherein the hydroxyalkylcellulose is hydroxypropylcellulose and/or hydroxypropylmethylcellulose.
19. The dosage form of claim 9, wherein the dosage form is a tablet of manufactured by a direct compression or dry granulation process.
20. The dosage form of claim 9, wherein said dosage form meets USP dissolution requirements for immediate release forms of said pharmaceutically active ingredient.
21. The dosage form of claim 9, which has a moisture content of not more than about 5 percent as measured by weight loss on drying at 105 degrees Celsius.
22. An immediate release dosage form capable of being chewed or disintegrated in the oral cavity prior to swallowing, comprised of:
a. a plurality of coated particles comprising, based upon the total weight of the dosage form, from greater than about 12 percent and less than about 40 percent of a pharmaceutically active ingredient selected from the group consisting of acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof, said coated particles further comprising, based upon the total weight of the coated particles, from greater than about 5 percent and less than about 30 percent of a taste masking coating comprised of cellulose acetate, hydroxymethylcellulose phthalate, and polysorbate-80 at a ratio of 43:53:4, wherein the taste masking coating substantially covers the active ingredient; and
b. a matrix comprising, based upon the total weight of the dosage form, from about 0.5 percent to about 10.0 percent of hydroxypropylmethylcellulose and/or hydroxypropylcellulose having a weight average molecular weight of from about 60,000 to about 5,000,000 and/or a viscosity of from about 3,000 mPa.S to about 150,000 mPa.s in a 2% aqueous solution.
23. The immediate release dosage form of claim 22, wherein the matrix further comprises a water-disintegratable, compressible carbohydrate selected from the group consisting of dextrose monohydrate, mannitol, sorbitol, xylitol, and mixtures thereof.
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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050019396A1 (en) * 2003-07-25 2005-01-27 Galen (Chemicals) Limited Doxycycline metal complex in a solid dosage form
WO2006058022A1 (en) 2004-11-24 2006-06-01 Medpointe Healthcare Inc. Compositions comprising azelastine and methods of use thereof
US20080181932A1 (en) * 2007-01-30 2008-07-31 Drugtech Corporation Compositions for oral delivery of pharmaceuticals
US20080226733A1 (en) * 2007-03-14 2008-09-18 Drugtech Corporation Spatial arrangement of particles in a drinking device for oral delivery of pharmaceuticals
US20080311202A1 (en) * 2005-12-16 2008-12-18 Julia Schulze Nahrup Pharmaceutical Composition Containing Donepezil Hydrochloride, Tablets Produced Therefrom and Methods for Producing the Same
WO2010144865A2 (en) 2009-06-12 2010-12-16 Meritage Pharma, Inc. Methods for treating gastrointestinal disorders
US20120283291A1 (en) * 2004-10-19 2012-11-08 Krka, Tovarna Zdravil D.D., Novo Mesto Solid pharmaceutical composition comprising donepezil hydrochloride
US8637540B2 (en) 2003-11-26 2014-01-28 Acura Pharmaceuticals Compositions for deterring abuse of opioid containing dosage forms
US8758816B2 (en) 2004-11-24 2014-06-24 Meda Pharmaceuticals Inc. Compositions comprising azelastine and methods of use thereof
US8901113B2 (en) 2009-09-30 2014-12-02 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US9101636B2 (en) 2012-11-30 2015-08-11 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US9180104B2 (en) * 2013-03-13 2015-11-10 Tris Pharma, Inc. Benzonatate modified release solid tablets and capsules
CN105188677A (en) * 2013-03-13 2015-12-23 特瑞斯制药股份有限公司 Benzonatate modified release solid tablets and capsules
WO2016033424A1 (en) 2014-08-29 2016-03-03 Genzyme Corporation Methods for the prevention and treatment of major adverse cardiovascular events using compounds that modulate apolipoprotein b
WO2016134846A1 (en) 2015-02-27 2016-09-01 Rottapharm Ltd. Composition for the treatment of acne
WO2017008909A1 (en) 2015-07-16 2017-01-19 Rottapharm S. P. A. Oral formulation comprising berberine and morus alba extract
US9616029B2 (en) 2014-03-26 2017-04-11 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release coated reservoir solid dosage form
WO2017115745A1 (en) * 2015-12-28 2017-07-06 エスエス製薬株式会社 Compacted pharmaceutical preparation
US10064817B2 (en) 2004-11-24 2018-09-04 Meda Pharmaceuticals Inc. Compositions comprising azelastine and methods of use thereof
US10117831B2 (en) 2015-12-19 2018-11-06 First Time Us Generics Llc Soft chew pharmaceutical formulations
US11103581B2 (en) 2015-08-31 2021-08-31 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US11413296B2 (en) 2005-11-12 2022-08-16 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US11633361B2 (en) 2015-12-19 2023-04-25 First Time Us Generics Llc Soft chew pharmaceutical formulations

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2316433A1 (en) * 2009-10-22 2011-05-04 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Orally disintegrating tablets of flurbiprofen
EP2506836B1 (en) * 2009-12-02 2018-02-14 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
FR2999426B1 (en) 2012-12-13 2015-01-02 Flamel Tech Sa MULTIPARTICULAR ORAL FORM WITH IMMEDIATE RELEASE OF AT LEAST ONE ACTIVE COMPOUND, INCLUDING MILL RESISTANT MIXED PARTICLES.
GB2581132B (en) 2019-01-28 2022-06-01 Reckitt Benckiser Health Ltd Novel composition
IT202100016310A1 (en) * 2021-06-22 2022-12-22 Alaia Idea S R L Method for making tablets

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4835187A (en) * 1987-06-15 1989-05-30 American Home Products Corporation Spray dried ibuprofen
US4851232A (en) * 1987-02-13 1989-07-25 Alza Corporation Drug delivery system with means for obtaining desirable in vivo release rate pattern
US5489436A (en) * 1991-06-14 1996-02-06 Mcneil-Ppc, Inc. Taste mask coatings for preparation of chewable pharmaceutical tablets
US5532244A (en) * 1994-06-16 1996-07-02 Eli Lilly And Company Potentiation of drug response
US5637313A (en) * 1994-12-16 1997-06-10 Watson Laboratories, Inc. Chewable dosage forms
US5789393A (en) * 1991-03-01 1998-08-04 The Board Of Regents Of The University Of Michgan Pharmaceutical compositions and uses of water-soluble, high-viscosity grade cellulose ethers
US5876759A (en) * 1993-07-27 1999-03-02 Mcneil-Ppc, Inc. Rapidly disintegrating pharmaceutical dosage form and process for preparation thereof
US20020031552A1 (en) * 2000-06-30 2002-03-14 Mcteigue Daniel Teste masked pharmaceutical particles
US20020122823A1 (en) * 2000-12-29 2002-09-05 Bunick Frank J. Soft tablet containing dextrose monohydrate
US6451345B1 (en) * 2000-01-20 2002-09-17 Eurand Pharmaceuticals Ltd. Functional coating of linezolid microcapsules for taste-masking and associated formulation for oral administration
US6576260B2 (en) * 1999-08-31 2003-06-10 Gruenenthal Gmbh Sustained-release form of administration containing tramadol saccharinate

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4818539A (en) * 1985-02-05 1989-04-04 Warner-Lambert Company Ingestible aggregate and delivery system prepared therefrom
US4882154A (en) * 1985-12-20 1989-11-21 Warner Lambert Co. Confectionery delivery system for mineral supplements
DK130287D0 (en) 1987-03-13 1987-03-13 Benzon As Alfred ORAL PREPARATION
US4851226A (en) * 1987-11-16 1989-07-25 Mcneil Consumer Products Company Chewable medicament tablet containing means for taste masking
JP2663556B2 (en) 1988-09-30 1997-10-15 スズキ株式会社 Valve train for 4-cycle multi-cylinder engine
US4906478A (en) * 1988-12-12 1990-03-06 Valentine Enterprises, Inc. Simethicone/calcium silicate composition
US5275822A (en) * 1989-10-19 1994-01-04 Valentine Enterprises, Inc. Defoaming composition
IT1238072B (en) * 1990-01-19 1993-07-03 Sclavo Spa PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS FOR ORAL ADMINISTRATION OF CALCITONIN
US5075114A (en) * 1990-05-23 1991-12-24 Mcneil-Ppc, Inc. Taste masking and sustained release coatings for pharmaceuticals
US5336486A (en) * 1991-03-28 1994-08-09 Theratech, Inc. Appetite control method
JP2995226B2 (en) 1992-03-03 1999-12-27 日本ワイスレダリー株式会社 Chewable tablets containing calcium
FR2707486B1 (en) 1993-07-16 1995-08-18 Oreal Process for permanent deformation of keratin materials.
US5593696A (en) * 1994-11-21 1997-01-14 Mcneil-Ppc, Inc. Stabilized composition of famotidine and sucralfate for treatment of gastrointestinal disorders
US5879393A (en) * 1997-05-21 1999-03-09 Smith & Nephew, Inc. Trial femoral prosthesis for use in knee joint replacement surgery
US6103260A (en) * 1997-07-17 2000-08-15 Mcneil-Ppc, Inc. Simethicone/anhydrous calcium phosphate compositions
US6432442B1 (en) * 1998-02-23 2002-08-13 Mcneil-Ppc, Inc. Chewable product
US6368625B1 (en) * 1998-08-12 2002-04-09 Cima Labs Inc. Orally disintegrable tablet forming a viscous slurry
US6270790B1 (en) * 1998-08-18 2001-08-07 Mxneil-Ppc, Inc. Soft, convex shaped chewable tablets having reduced friability
US6117451A (en) * 1998-08-25 2000-09-12 Pharmalogix, Inc. Direct compression metformin hydrochloride tablets
JP2002530322A (en) 1998-11-25 2002-09-17 シーマ・ラブス・インコーポレイテッド Taste masking rapid release coating system
FR2811571B1 (en) * 2000-07-11 2002-10-11 Flamel Tech Sa ORAL PHARMACEUTICAL COMPOSITION FOR CONTROLLED RELEASE AND SUSTAINED ABSORPTION OF AN ACTIVE INGREDIENT
US20040265373A1 (en) * 2003-06-27 2004-12-30 David Wynn Soft tablet containing high molecular weight cellulosics

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4851232A (en) * 1987-02-13 1989-07-25 Alza Corporation Drug delivery system with means for obtaining desirable in vivo release rate pattern
US4835187A (en) * 1987-06-15 1989-05-30 American Home Products Corporation Spray dried ibuprofen
US5789393A (en) * 1991-03-01 1998-08-04 The Board Of Regents Of The University Of Michgan Pharmaceutical compositions and uses of water-soluble, high-viscosity grade cellulose ethers
US5489436A (en) * 1991-06-14 1996-02-06 Mcneil-Ppc, Inc. Taste mask coatings for preparation of chewable pharmaceutical tablets
US5876759A (en) * 1993-07-27 1999-03-02 Mcneil-Ppc, Inc. Rapidly disintegrating pharmaceutical dosage form and process for preparation thereof
US5532244A (en) * 1994-06-16 1996-07-02 Eli Lilly And Company Potentiation of drug response
US5637313A (en) * 1994-12-16 1997-06-10 Watson Laboratories, Inc. Chewable dosage forms
US6576260B2 (en) * 1999-08-31 2003-06-10 Gruenenthal Gmbh Sustained-release form of administration containing tramadol saccharinate
US6451345B1 (en) * 2000-01-20 2002-09-17 Eurand Pharmaceuticals Ltd. Functional coating of linezolid microcapsules for taste-masking and associated formulation for oral administration
US20020031552A1 (en) * 2000-06-30 2002-03-14 Mcteigue Daniel Teste masked pharmaceutical particles
US20020122823A1 (en) * 2000-12-29 2002-09-05 Bunick Frank J. Soft tablet containing dextrose monohydrate

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8415331B2 (en) 2003-07-25 2013-04-09 Warner Chilcott Company, Llc Doxycycline metal complex in a solid dosage form
US7485319B2 (en) 2003-07-25 2009-02-03 Warner Chilcott Company, Inc. Doxycycline metal complex in a solid dosage form
US20050019396A1 (en) * 2003-07-25 2005-01-27 Galen (Chemicals) Limited Doxycycline metal complex in a solid dosage form
US20110171299A1 (en) * 2003-07-25 2011-07-14 Warner Chilcott Company, Inc. Doxycycline metal complex in a solid dosage form
US8822489B2 (en) 2003-11-26 2014-09-02 Acura Pharmaceuticals Abuse deterrent compositions and methods of making same
US8637540B2 (en) 2003-11-26 2014-01-28 Acura Pharmaceuticals Compositions for deterring abuse of opioid containing dosage forms
US9492443B2 (en) 2003-11-26 2016-11-15 Acura Pharmaceuticals, Inc. Abuse deterrent compositions and methods of making same
US20120283291A1 (en) * 2004-10-19 2012-11-08 Krka, Tovarna Zdravil D.D., Novo Mesto Solid pharmaceutical composition comprising donepezil hydrochloride
EP2377557A2 (en) 2004-11-24 2011-10-19 MedPointe Healthcare Inc. Compositions comprising azelastine and methods of use thereof
US8071073B2 (en) 2004-11-24 2011-12-06 Meda Pharmaceuticals Inc. Compositions comprising azelastine and methods of use thereof
EP2486942A1 (en) 2004-11-24 2012-08-15 Meda Pharmaceuticals Inc. Compositions comprising azelastine and methods of use thereof
US8758816B2 (en) 2004-11-24 2014-06-24 Meda Pharmaceuticals Inc. Compositions comprising azelastine and methods of use thereof
EP2522365A1 (en) 2004-11-24 2012-11-14 Meda Pharmaceuticals Inc. Compositions comprising azelastine and methods of use thereof
US9919050B2 (en) 2004-11-24 2018-03-20 Meda Pharmaceuticals Inc. Compositions comprising azelastine
US8518919B2 (en) 2004-11-24 2013-08-27 Meda Pharmaceuticals Inc. Compositions comprising azelastine and methods of use thereof
US10064817B2 (en) 2004-11-24 2018-09-04 Meda Pharmaceuticals Inc. Compositions comprising azelastine and methods of use thereof
WO2006058022A1 (en) 2004-11-24 2006-06-01 Medpointe Healthcare Inc. Compositions comprising azelastine and methods of use thereof
US11413296B2 (en) 2005-11-12 2022-08-16 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US8992976B2 (en) * 2005-12-16 2015-03-31 Ratiopharm, Gmbh Pharmaceutical composition containing donepezil hydrochloride, tablets produced therefrom and methods for producing the same
US20080311202A1 (en) * 2005-12-16 2008-12-18 Julia Schulze Nahrup Pharmaceutical Composition Containing Donepezil Hydrochloride, Tablets Produced Therefrom and Methods for Producing the Same
US20080181932A1 (en) * 2007-01-30 2008-07-31 Drugtech Corporation Compositions for oral delivery of pharmaceuticals
US20080226733A1 (en) * 2007-03-14 2008-09-18 Drugtech Corporation Spatial arrangement of particles in a drinking device for oral delivery of pharmaceuticals
US8679541B2 (en) 2007-03-14 2014-03-25 Particle Dynamics International, Llc Spatial arrangement of particles in a drinking device for oral delivery of pharmaceuticals
US9339475B2 (en) 2007-03-14 2016-05-17 Particle Dynamics International, Llc Spatial arrangement of particles in a drinking device for oral delivery of pharmaceuticals
WO2010144865A2 (en) 2009-06-12 2010-12-16 Meritage Pharma, Inc. Methods for treating gastrointestinal disorders
US8901113B2 (en) 2009-09-30 2014-12-02 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US10155044B2 (en) 2009-09-30 2018-12-18 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US9101636B2 (en) 2012-11-30 2015-08-11 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US10441657B2 (en) 2012-11-30 2019-10-15 Abuse Deterrent Pharmaceuticals, Llc Methods and compositions for self-regulated release of active pharmaceutical ingredient
US10688184B2 (en) 2012-11-30 2020-06-23 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US9320796B2 (en) 2012-11-30 2016-04-26 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US11857629B2 (en) 2012-11-30 2024-01-02 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
CN105188677A (en) * 2013-03-13 2015-12-23 特瑞斯制药股份有限公司 Benzonatate modified release solid tablets and capsules
US9408823B2 (en) 2013-03-13 2016-08-09 Tris Pharma, Inc. Benzonatate modified release solid tablets and capsules
US11890267B2 (en) 2013-03-13 2024-02-06 Tris Pharma Inc Benzonatate modified release solid tablets and capsules
US9180104B2 (en) * 2013-03-13 2015-11-10 Tris Pharma, Inc. Benzonatate modified release solid tablets and capsules
US20180200221A1 (en) * 2013-03-13 2018-07-19 Tris Pharma Inc. Benzonatate modified release solid tablets and capsules
US9867797B2 (en) 2013-03-13 2018-01-16 Tris Pharma Inc Benzonatate modified release solid tablets and capsules
US11241411B2 (en) * 2013-03-13 2022-02-08 Tris Pharma, Inc. Benzonatate modified release solid tablets and capsules
US9616029B2 (en) 2014-03-26 2017-04-11 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release coated reservoir solid dosage form
US9980917B2 (en) 2014-03-26 2018-05-29 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release coated reservoir solid dosage form
WO2016033424A1 (en) 2014-08-29 2016-03-03 Genzyme Corporation Methods for the prevention and treatment of major adverse cardiovascular events using compounds that modulate apolipoprotein b
WO2016134846A1 (en) 2015-02-27 2016-09-01 Rottapharm Ltd. Composition for the treatment of acne
WO2017008909A1 (en) 2015-07-16 2017-01-19 Rottapharm S. P. A. Oral formulation comprising berberine and morus alba extract
US11103581B2 (en) 2015-08-31 2021-08-31 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US10117831B2 (en) 2015-12-19 2018-11-06 First Time Us Generics Llc Soft chew pharmaceutical formulations
US11633361B2 (en) 2015-12-19 2023-04-25 First Time Us Generics Llc Soft chew pharmaceutical formulations
RU2744270C2 (en) * 2015-12-28 2021-03-04 ЭсЭсПи КО., ЛТД., ДЖАПАН Compressed pharmaceutical product
JPWO2017115745A1 (en) * 2015-12-28 2018-10-18 エスエス製薬株式会社 Compression molding
WO2017115745A1 (en) * 2015-12-28 2017-07-06 エスエス製薬株式会社 Compacted pharmaceutical preparation

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US8496969B2 (en) 2013-07-30
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US20100092555A1 (en) 2010-04-15
EP1491184B1 (en) 2015-04-01

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