WO2006046954A1 - Burst-release polymer composition and dosage forms comprising the same - Google Patents
Burst-release polymer composition and dosage forms comprising the same Download PDFInfo
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- WO2006046954A1 WO2006046954A1 PCT/US2004/035763 US2004035763W WO2006046954A1 WO 2006046954 A1 WO2006046954 A1 WO 2006046954A1 US 2004035763 W US2004035763 W US 2004035763W WO 2006046954 A1 WO2006046954 A1 WO 2006046954A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- compositions comprising a high molecular weight, water soluble polymer having a cloud point from about 20 to about 90° C, and one or more carrageenans.
- the compositions may be conveniently molded into components of pharmaceutical dosage forms, e.g. a shell over a core comprising active ingredient, and as such provide burst release of the active ingredient from the dosage form.
- WO 01/32150 discloses an edible, hardenable coating composition containing micro crystalline cellulose, carrageenan, and at least one of a strengthening polymer, a plasticizer, a surface active agent or a combination thereof.
- the composition provides a prompt, i.e., immediate, release coating for solid dosage forms and is applied by spray coating.
- WO 00/40223 relates to a composition
- a composition comprising hydroxypropylcellulose and at least one anionic polymer such as carboxymethyl ether salts of cellulose, methacrylic acid polymers and copolymers, carboxyvinyl polymers and copolymers, alginic acid salts, pectinic acid salts, pectic acid salts, carrageenan, agar and qarboxylic acid salts of polysaccharides.
- the ratio of hydroxypropylcellulose to anionic polymer is from 1:20 to 20:1.
- the composition is used as an aqueous solution to coat substrates.
- U.S. Patent No. 6,358,525 Bl discloses a pharmaceutical composition containing a medicament and a blend of two components.
- the first component is hydroxypropylcellulose and the second component is at least one other polymer selected from a group that includes carrageenan, agar, and gellan gum.
- the pharmaceutical composition is formed into a tablet that may be coated with a conventional coating material.
- U.S. Patent No. 6,245,356 Bl relates to a sustained release, oral, solid dosage form comprising agglomerated particles of a therapeutically active medicament in amorphous form, a gelling agent, an ionizable gel strength enhancing agent and an inert diluent.
- the gelling agent preferably comprises xanthan gum and locust bean gum, but may alternatively comprise alginates, carrageenan, pectin, and other compounds.
- the ionizable gel strength enhancing agent may be a monovalent or multivalent metal cation.
- the active medicament in amorphous form, gelling agent, ionizable gel strength enhancing agent and an inert diluent are mixed or granulated together and formed into a tablet.
- compositions comprising water soluble polymers are often difficult to use, for example in coating operations, because their viscosity becomes too high, especially with increasing polymer concentrations, or increasing polymer molecular weight. Spraying and molding processes can be particularly difficult. Accordingly, dilute solutions must be used, resulting in lengthy processing times to build up adequate thickness.
- compositions comprising a combination of a high molecular weight, water soluble polymer having a cloud point from about 20 to about 90° C and one or more carrageenans, in certain embodiments with gellan gum and in other embodiments with both gellan gum and a lubricant, may be used as a component of a dosage form, for example as the shell of a dosage form containing active ingredient in an underlying core.
- the high molecular weight, water soluble polymer and the carrageenan can be dispersed in water, along with other ingredients, at a temperature above the cloud point of the high molecular weight, water soluble polymer, leaving the high molecular weight, water soluble polymer undissolved and the viscosity of the dispersion manageable.
- the dispersion flows easily, and sets quickly and strongly at a relatively high temperature due to the presence of the carrageenan.
- Cores containing active ingredient can advantageously be coated with this composition, preferably by molding, to prepare dosage forms that provide a burst release of the active ingredient.
- the invention provides a composition comprising 40 to 95 weight percent of a high molecular weight, water soluble polymer having a cloud point from about 20 to about 90° C, 5 to 25 weight percent carrageenan, and 0.5 to 5 weight percent gellan gum.
- the invention provides a composition consisting essentially of: a) 40 to 95 weight percent of hydroxypropyl methylcellulose having a viscosity from about 80 to about 120,000 mPa s in 2% aqueous solution; b) 5 to 25 weight percent carrageenan, c) 0.5 to 5 weight percent gellan gum; d) up to 10 weight percent potassium chloride; and e) 5 to 20 weight percent of glyceryl monostearate.
- the invention in another embodiment, relates to an aqueous dispersion comprising: a) 8 to 20 weight percent of a high molecular weight, water soluble polymer having a cloud point from about 20 to about 90° C; b) 1 to 3 weight percent carrageenan; c) 0.2 to 1 weight percent gellan gum; and about 80 weight percent water.
- the invention provides an aqueous dispersion consisting essentially of: a) 8 to 20 weight percent of hydroxypropyl methylcellulose having a viscosity from about 80 to about 120,000 mPa s in 2% aqueous splution; b) 1 to 3 weight percent carrageenan; c) 0.2 to 1 weight percent gellan gum; d) up to 2 weight percent of potassium chloride; e) 1 to 5 weight percent of glyceryl monostearate; and f) about 80 weight percent water.
- the invention provides a composition comprising 40 to 95 weight percent of a high molecular weight, water soluble polymer having a cloud point from about 20 to about 90° C, 5 to 40 weight percent of one or more carrageenans, and 0.5 to 30 weight percent lubricant.
- the invention provides a composition consisting essentially of: a) 40 to 95 weight percent of hydroxypropyl methylcellulose having a viscosity from about 80 to about 120,000 mPa s in 2% aqueous solution; b) 5 to 40 weight percent of one or more carrageenans, c) up to 10 weight percent potassium chloride; and d) 5 to 40 weight percent of glyceryl monostearate.
- the invention also provides an aqueous dispersion comprising: a) 8 to 20 weight percent of a high molecular weight, water soluble polymer having a cloud point from about 20 to about 90° C; b) 1 to 5 weight percent of one or more carrageenans; c) 0.1 to 6 weight percent glyceryl monostearate ; and d) about 80 weight percent water.
- the invention further provides an aqueous dispersion consisting essentially of: a) 8 to 20 weight percent of hydroxypropyl methylcellulose having a viscosity from about 80 to about 120,000 mPa s in 2% aqueous solution; b) 1 to 5 weight percent of one or more carrageenans; c) up to 2 weight percent of potassium chloride; d) 0.1 to 6 weight percent of glyceryl monostearate; and e) about 80 weight percent water.
- Figures 1 and 2 depict the percent release of active ingredient versus hours for the dosage forms of Example 1 and Example 2, respectively.
- dosage form applies to any solid object, semi-solid, or liquid composition designed to contain a specific pre-determined amount (dose) of a certain ingredient, for example an active ingredient as defined below.
- Suitable dosage forms may be pharmaceutical drug delivery systems, including those for oral administration, buccal administration, rectal administration, topical or mucosal delivery, or subcutaneous implants, or other implanted drug delivery systems; or compositions for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorants, and the like.
- the dosage forms of the present invention are considered to be solid, however they may contain liquid or semi-solid components.
- the dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the gastro ⁇ intestinal tract of a human.
- Suitable active ingredients for use in this invention include for example pharmaceuticals, minerals, vitamins and other nutraceuticals, oral care agents, flavorants and mixtures thereof.
- Suitable pharmaceuticals include analgesics, anti ⁇ inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, oral contraceptives, diuretics, expectorants, gastrointestinal agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tract agents and mixtures thereof.
- Suitable oral care agents include breath fresheners, tooth whiteners, antimicrobial agents, tooth mineralizers, tooth decay inhibitors, topical anesthetics, mucoprotectants, and the like.
- Suitable flavorants include menthol, peppermint, mint flavors, fruit flavors, chocolate, vanilla, bubblegum flavors, coffee flavors, liqueur flavors and combinations and the like.
- Suitable gastrointestinal agents include antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum sodium carbonate; stimulant laxatives, such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists, such as famotadine, ranitidine, cimetadine, nizatidine; proton pump inhibitors such as omeprazole or lansoprazole; gastrointestinal cytoprotectives, such as sucraflate and misoprostol; gastrointestinal prokinetics, such as prucalopride, antibiotics for H.
- antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum
- pylori such as clarithromycin, amoxicillin, tetracycline, and metronidazole
- antidiarrheals such as diphenoxylate and loperamide
- glycopyrrolate such as glycopyrrolate
- antiemetics such as ondansetron
- analgesics such as mesalamine.
- the active ingredient maybe selected from bisacodyl, famotadine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
- the active ingredient is selected from analgesics, anti ⁇ inflammatories, and antipyretics, e.g. non-steroidal anti-inflammatory drugs (NSAIDs), including propionic acid derivatives, e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acid derivatives, e.g. indomethacin, diclofenac, sulindac, tolmetin, and the like; fenamic acid derivatives, e.g. mefanamic acid, meclofenamic acid, fiufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g.
- NSAIDs non-steroidal anti-inflammatory drugs
- the active ingredient is selected from propionic acid derivative NSAID, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof.
- NSAID e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof.
- the active ingredient may be selected from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
- the active ingredient may be selected from pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
- suitable polydimethylsiloxanes which include, but are not limited to dimethicone and simethicone, are those disclosed in United States Patent Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each is expressly incorporated herein by reference.
- the term "simethicone” refers to the broader class of polydimethylsiloxanes, including but not limited to simethicone and dimethicone.
- the active ingredient or ingredients are present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. Li determining such amounts, the particular active ingredient being administered, the bioavailability characteristics of the active ingredient, the dosing regimen, the age and weight of the patient, and other factors must be considered, as known in the art.
- the dosage form comprises at least about 1 weight percent, preferably, the dosage form comprises at least about 5 weight percent, e.g. at least about 25 weight percent of a combination of one or more active ingredients.
- a core comprises a total of at least about 50 weight percent, e.g. at - least about 70 weight percent, say at least about 80 weight percent (based on the weight of the core) of one or more active ingredients.
- the active ingredient or ingredients may be present in the dosage form in any form.
- the active ingredient may be dispersed at the molecular level, e.g. melted or dissolved, within the dosage form, or maybe in the form of particles, which in turn may be coated or uncoated.
- the particles typically have an average particle size of about 1-2000 microns. In one embodiment, such particles are crystals having an average particle size of about 1-300 microns. In another embodiment, the particles are granules or pellets having an average particle size of about 50-2000 microns, for example about 50-1000 microns, say about 100-800 microns.
- the composition of the invention comprises a combination of a high molecular weight, water soluble polymer, one or more carrageenans, and gellan gum and/or a lubricant such as glyceryl monostearate. It is a solid and is preferably substantially free of pores having a diameter of 0.5 to 5.0 microns. It may be used as a component of a pharmaceutical dosage form, such as the shell of a dosage form, a portion of a shell of a dosage form, the core of a dosage form, a portion of the core of a dosage form, or combined with one or more active ingredients into a dosage form per se in which case it may optionally be coated with conventional coating materials, as well known in the art.
- the high molecular weight, water soluble polymer has a cloud point from about 20 to about 90° C. Preferably, the high molecular weight, water soluble polymer has a cloud point from about 35 to about 70° C.
- the weight average molecular weight of the high molecular weight, water soluble polymer may be in the range of about 1000 to about 2,000,000 g/mole.
- Suitable high molecular weight, water soluble polymers include hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, and mixtures thereof.
- the high molecular weight, water soluble polymer comprises hydroxypropyl cellulose having a weight average molecular weight from about 140,000 to about 1,150,000. In another embodiment, the high molecular weight, water soluble polymer comprises hydroxypropyl methylcellulose having a viscosity from about 80 to about 120,000 mPa s in 2% aqueous solution. In a further embodiment, the high molecular weight, water soluble polymer comprises methylcellulose having a viscosity 'of 4000 mPa s in 2% aqueous solution. In yet another embodiment, the high molecular weight, water soluble polymer comprises polyvinyl alcohol having a weight average molecular weight from about 30,000 to about 200,000.
- the composition also comprises one or more carrageenans.
- the carrageenan is typically present in an amount from about 5 to about 40, or 5 to about 25 weight percent of the composition.
- carrageenans include Kappa, Lambda and Iota carrageenans and combinations thereof.
- the carrageenan comprises a Kappa carrageenan.
- the carrageenan comprises a combination of Kappa and Lambda carrageenans.
- the composition further comprises gellan gum, preferably in the range of about 0.5 to about 5 weight percent of the composition.
- useful gellan gums include unclarif ⁇ ed low acyl, clarified low acyl, and unclarified high acyl gellan gum and combinations thereof.
- the gellan gum comprises unclarified high acyl gellan gum Accordingly, the composition in one embodiment comprises about 40 to about 95 weight percent of a high molecular weight, water soluble polymer having a cloud point from about 20 to about 90° C, 5 to 25 weight percent carrageenan, and 0.5 to 5 weight percent gellan gum.
- the composition consists essentially of a) 40 to 95 weight percent of hydroxypropyl methylcellulose having a viscosity from about 80 to about 120,000 mPa s in 2% aqueous solution; b) 5 to 25 weight percent carrageenan, c) 0.5 to 5 weight percent gellan gum; d) up to 10 weight percent potassium chloride; and e) 5 to 20 weight percent of glyceryl monostearate.
- the composition further comprises a lubricant, preferably in the range of about 0.5 to about 30 weight percent of the composition.
- the lubricant may be, for example, glyceryl monostearate, glyceryl palmitostearate, glycerol monooleate, hydrogenated vegetable oil, type I, magnesium stearate, and talc.
- the lubricant is glyceryl monostearate.
- the composition in one embodiment comprises 40 to 95 weight percent of a high molecular weight, water soluble polymer having a cloud point from about 20 to about 90° C, 5 to 40 weight percent of one or more carrageenans, and 0.5 to 30 weight percent lubricant.
- the composition consists essentially of: a) 40 to 95 weight percent of hydroxypropyl methylcellulose having a viscosity from about 80 to about 120,000 mPa s in 2% aqueous solution; b) 5 to 40 weight percent of one or more carrageenans, c) up to 10 weight percent potassium chloride; and d) 5 to 40 weight percent of glyceryl monostearate.
- composition also comprises active ingredient.
- the level of high molecular weight water soluble polymer in the composition is adjusted downward by the amount of the active ingredient.
- the composition comprises up to about 80 weight percent of at least one active ingredient; about 15 to about 95 weight percent of a high molecular weight, water soluble polymer having a cloud point from about 20 to about 90° C; and about 5 to about 25 weight percent carrageenans.
- the composition whether used as a shell, portion of a shell, i.e. "shell portion," core, core portion, or as a dosage form per se, may comprise other optional ingredients.
- the composition also comprises an inorganic cation. Suitable inorganic cations include pharmaceutically acceptable monovalent, divalent, and trivalent cations.
- the inorganic cation may be selected from the group consisting of potassium cations, calcium cations, and mixtures thereof.
- the composition also comprises a water-insoluble polymer.
- Suitable water-insoluble polymers include of ethyl cellulose, cellulose acetate, cellulose acetate butyrate and mixtures thereof.
- a dosage form according to the invention comprises a core at least partially surrounded by a shell or a shell portion that comprises a high molecular weight, water soluble polymer, carrageenan, and gellan gum and/or a lubricant.
- a shell or a shell portion that comprises a high molecular weight, water soluble polymer, carrageenan, and gellan gum and/or a lubricant.
- Such shell may comprise about 1 to about 75, or about 2 to about 24, or about 5 to about 15, weight percent of the total weight of the dosage form.
- the average thickness of the shell or shell portion may be in the range of about 50 to about 500 microns.
- the shell may completely surround the core, or only partially surround the core. Moreover, only one shell portion may comprise the composition of the invention, as further discussed below.
- a shell comprising a first shell portion and a second shell portion surrounds the core, and the first shell portion comprises the composition of the present invention, while the second shell portion is compositionally different from the first shell portion.
- the weight of said first shell portion may be from about 1 to about 75, e.g. about 1 to about 25, or about 1 to about 10 percent of the weight of the dosage form.
- the second shell portion may comprise any suitable materials, and be applied by any suitable method, for example, those disclosed in U.S. Application Serial Nos. 10/432,488 filed September 28,2002; 10/432,504, filed September 28, 2002; 10/432,812, filed September 28, 2002; and 10/393,610, filed March 21, 2003, the disclosures of which are incorporated herein by reference.
- the core may be any solid form.
- the core may prepared by any suitable method, including for example compression or molding.
- core refers to a material which is at least partially enveloped or surrounded by another material.
- the core is a self-contained unitary object, such as a tablet or capsule.
- the core comprises a solid, for example, the core may be a compressed or molded tablet, hard or soft capsule, suppository, or a confectionery form such as a lozenge, nougat, caramel, fondant, or fat based composition.
- the core or a portion thereof may be in the form of a semi-solid or a liquid in the finished dosage form.
- the core may comprise a liquid filled capsule, or a semisolid fondant material.
- the core comprises a flowable component, such as a plurality of granules or particles, or a liquid
- the core preferably additionally comprises an enveloping component, such as a capsule shell, or a coating, for containing the flowable material.
- the shell or shell portions of the present invention are in direct contact with the enveloping component of the core, which separates the shell from the flowable component of the core.
- the core is a compressed tablet having a hardness from about 2 to about 30 kp/cm 2 , e.g. from about 6 to about 25 kp/cm 2 .
- Hardness is a term used in the art to describe the diametral breaking strength of either the core or the coated solid dosage form as measured by conventional pharmaceutical hardness testing equipment, such as a Schleuniger Hardness Tester. In order to compare values across different size tablets, the breaking strength must be normalized for the area of the break. This normalized value, expressed in kp/cm 2 , is sometimes referred in the art as tablet tensile strength.
- the core may have one of a variety of different shapes.
- the core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, cylinder, sphere, torus, or the like.
- a core has one or more major faces.
- the core surface typically has two opposing major faces formed by contact with the upper and lower punch faces in the compression machine.
- the core surface typically further comprises a "belly-band" located between the two major faces, and formed by contact with the die walls in the compression machine.
- a core may also comprise a multilayer tablet.
- Exemplary core shapes that may be employed include tablet shapes formed from compression tooling shapes described by "The Elizabeth Companies Tablet Design Training Manual” (Elizabeth Carbide Die Co., Inc., p. 7 (McKeesport, Pa.) (incorporated herein by reference).
- the core typically comprises active ingredient and a variety of excipients, depending on the method by which it is made.
- suitable excipients include fillers, binders, disintegrants, lubricants, glidants, and the like, as known in the art.
- a core made by compression may be a single or multi-layer, for example bi- layer, tablet.
- Suitable fillers for use in making the core by compression include water- soluble compressible carbohydrates such as sugars, which include dextrose, sucrose, maltose, and lactose, sugar-alcohols, which include mannitol, sorbitol, maltitol, xylitol, starch hydrolysates, which include dextrins, and maltodextrins, and the like, water insoluble plastically deforming materials such as microcrystalline cellulose or other cellulosic derivatives, water-insoluble brittle fracture materials such as dicalcium phosphate, tricalcium phosphate and the like and mixtures thereof.
- water- soluble compressible carbohydrates such as sugars, which include dextrose, sucrose, maltose, and lactose
- sugar-alcohols which include mannitol, sorbitol, maltitol, xylitol
- starch hydrolysates which include dextrins, and maltodextr
- Suitable binders for making the core by compression include dry binders such as polyvinyl pyrrolidone, hydroxypropylmethylcellulose, and the like; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, starches, and the like; and derivatives and mixtures thereof.
- Suitable disintegrants for making the core by compression include sodium starch glycolate, cross-
- Suitable lubricants for making the core by compression include long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides and waxes.
- Suitable glidants for making the core by compression include colloidal silicon dioxide, and the like.
- the core or a portion thereof may optionally comprise release modifying excipients as known in the art, for example as disclosed in commonly assigned, copending U.S. Application Serial No. 10/432,488, the disclosure of which is incorporated by reference herein.
- Suitable release-modifying excipients for making the core by compression include swellable erodible hydrophillic materials, insoluble edible materials, pH-dependent polymers, and the like.
- Suitable pharmaceutically acceptable adjuvants for making the cores by compression include, preservatives; high intensity sweeteners such as aspartame, acesulfame potassium, sucralose, and saccharin; flavorants; colorants; antioxidants; surfactants; wetting agents; and the like and mixtures thereof.
- a dry blending i.e. direct compression
- wet granulation process may be employed, as known in the art.
- a dry blending (direct compression) method the active ingredient or ingredients, together with the excipients, are blended in a suitable blender, then transferred directly to a compression machine for pressing into tablets.
- a wet granulation method the active ingredient or ingredients, appropriate excipients, and a solution or dispersion of a wet binder (e.g. an aqueous cooked starch paste, or solution of polyvinyl pyrrolidone) are mixed and granulated.
- a wet binder e.g. an aqueous cooked starch paste, or solution of polyvinyl pyrrolidone
- a dry binder may be included among the excipients, and the mixture may be granulated with water or other suitable solvent.
- Suitable apparatuses for wet granulation are known in the art, including low shear, e.g. planetary mixers; high shear mixers; and fluid beds, including rotary fluid beds.
- the resulting granulated material is dried, and optionally dry-blended with further ingredients, e.g. adjuvants and/or excipients such as for example lubricants, colorants, and the like.
- the final dry blend is then suitable for compression.
- Methods for direct compression and wet granulation processes are known in the art, and are described in detail in, for example, Lachman, et al, The Theory and Practice of Industrial Pharmacy, Chapter 11 (3rd ed. 1986).
- the dry-blended, or wet granulated, powder mixture is typically compacted into tablets using a rotary compression machine as known in the art, such as for example those commercially available from Fette America Inc., Rockaway, NJ, or Manesty Machines LTD, Liverpool, UK.
- a rotary compression machine a metered volume of powder is filled into a die cavity, which rotates as part of a "die table" from the filling position to a compaction position where the powder is compacted between an upper and a lower punch to an ejection position where 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 core may be prepared by the compression methods and apparatus described in copending U.S. Patent Application Serial No. 09/966,509, pages 16-27, the disclosure of which is incorporated herein by reference.
- the core is made using a rotary compression module comprising a fill zone, insertion zone, compression zone, ejection zone, and purge zone in a single apparatus having a double row die construction as shown'in Figure 6 of U.S. patent application Serial No. 09/966,509.
- the dies of the compression module are preferably filled using the assistance of a vacuum, with filters located in or near each die.
- the shell may be substantially unitary and continuous, or the shell may comprise multiple portions, e.g. a first shell portion and a second shell portion. In certain embodiments, at least one such shell portion comprises the composition of the invention. Li certain embodiments the shell or shell portions are in direct contact with the core. In certain other embodiments, the shell or shell portions are in direct contact with a subcoating that substantially surrounds the core, hi certain embodiments, the shell or a shell portion may comprise one ore more openings therein.
- the term "substantially conformally” shall mean that the inner surface of the shell has peaks and valleys or indentations and protrusions corresponding substantially inversely to the peaks and valleys of the outer surface of the core.
- the indentations and protrusions typically have a length, width, height or depth in one dimension of greater than 10 microns, say greater than 20 microns, and less than about 30,000 microns, preferably less than about 2000 microns.
- the shell comprises a first shell portion and a second shell portion that are compositionally different.
- a first shell portion comprises the composition of the invention
- a second shell portion is compositionally different from the first shell portion.
- compositionally different means having features that are readily distinguishable by qualitative or quantitative chemical analysis, physical testing, or visual observation.
- the first and second shell portions may contain different ingredients, or different levels of the same ingredients, or the first and second shell portions may have different physical or chemical properties, different functional properties, or be visually distinct. Examples of physical or chemical properties that may be different include hydrophylicity, hydrophobicity, hygroscopicity, elasticity, plasticity, tensile strength, crystallinity, and density.
- Examples of functional properties which may be different include rate and/or extent of dissolution of the material itself or of an active ingredient therefrom, rate of disintegration of the material, permeability to active ingredients, permeability to water or aqueous media, and the like.
- Examples of visual distinctions include size, shape, topography, or other geometric features, color, hue, opacity, and gloss.
- the dosage form of the invention comprises: a) a core containing an active ingredient; b) an optional subcoating that substantially covers the core; and c) a shell comprising first and second shell portions residing on the surface of the subcoating, the first shell portion comprising the composition of the invention.
- substantially covers shall mean at least about 95 percent of the surface area of the core is covered by the subcoating.
- subcoatings are well known in the art and disclosed in, for example, United States Patent Nos. 3,185,626, which is incorporated by reference herein. Any composition suitable for film-coating a tablet may be used as a subcoating according to the present invention. Examples of suitable subcoatings are disclosed in United States Patent Nos. 4,683,256, 4,543,370, 4,643,894, 4,828,841, 4,725,441, 4,802,924, 5,630,871, and 6,274,162, which are all incorporated by reference herein.
- cellulose ethers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxyethylcellulose
- polycarbohydrates such as xanthan gum, starch, and maltodextrin
- plasticizers including for example, glycerin, polyethylene glycol, propylene glycol, dibutyl sebecate, triethyl citrate, vegetable oils such as castor oil, surfactants such as polysorbate-80, sodium lauryl sulfate and dioctyl-sodium sulfosuccinate
- polycarbohydrates pigments, and opacifiers.
- the subcoating comprises from about 2 percent to about 8 percent, e.g. from about 4 percent to about 6 percent of a water-soluble cellulose ether and from about 0.1 percent to about 1 percent, castor oil, as disclosed in detail in United States Patent No. 5,658, 589, which is incorporated by reference herein.
- the subcoating comprises from about 20 percent to about 50 percent, e.g., from about 25 percent to about 40 percent of HPMC; from about 45 percent to about 75 percent, e.g., from about 50 percent to about 70 percent of maltodextrin; and from about 1 percent to about 10 percent, e.g., from about 5 percent to about 10 percent of PEG 400.
- the dried subcoating typically is present in an amount, based upon the dry weight of the core, from about 0 percent to about 5 percent.
- an aqueous dispersion of the composition comprising the high molecular weight, water soluble polymer and carrageenan, along with gellan gum and/or a lubricant, is used to prepare the shell.
- these ingredients are dispersed in water at a temperature above the cloud point of the high molecular weight, water soluble polymer.
- the dispersion is applied to a core, by for example molding, dipping, spraying, or other means.
- the dispersion is applied to the core by molding. Spraying is least preferred.
- the core is cooled, preferably at a relatively high temperature, i.e., above the cloud point of the high molecular weight, water soluble polymer.
- the aqueous dispersion typically comprises about 5 to about 40 weight percent solids. In one embodiment, the aqueous dispersion comprises about 10 to about 30 weight percent solids.
- the high molecular weight, water soluble polymer comprises about 8 to about 20 weight percent of the total weight of the aqueous dispersion.
- the aqueous dispersion comprises about 0 0.5 to about 6 weight percent carrageenan and 0.2 to about 3weight percent gellan gum.
- the aqueous dispersion comprises about 0.5 to about 7 weight percent carrageenan and 0.1 to about 6 weight percent lubricant such as glyceryl monostearate.
- the shell thickness at various locations may be measured using a microscope, for example, an environmental scanning electron microscope, model XL 30 ESEM LaB6, Philips Electronic Instruments Company, Mahwah, WI.
- the shell thickness is measured at 6 different locations on a single dosage form.
- the relative standard deviation (RSD) is calculated as the sample standard deviation, devided by the mean, times 100 as known in the art (i.e. the RSD is the standard deviation expressed as a percentage of the mean).
- the RSD in shell thickness provides an indication of the variation in the thickness of the shell on a single dosage form.
- the relative standard deviation in shell thickness is less than about 40%, e.g less than about 30%, or less than about 20%.
- the shell itself or an outer coating thereon may optionally contain active ingredient.
- active ingredient will be released immediately from the dosage form upon ingestion, or contacting of the dosage form with a liquid medium.
- such active ingredient will be released in a controlled, sustained, prolonged, or extended fashion upon ingestion, or contacting of the dosage form with a liquid medium.
- the core, the shell, or the composition is prepared by molding.
- the core, the shell, or the composition is made from a dispersion as described above optionally comprising active ingredient.
- the dispersion comprises the high molecular weight, water soluble polymer dispersed in a liquid carrier comprising the carrageenan along with the gellan gum and/or lubricant and a liquid plasticizer at a temperature above the cloud point of the high molecular weight polymer and above the gelling temperature of the carrageenan and gellan gum.
- Suitable liquid plasticizers include water, glycerin, propylene glycol, triacetin, triethyl citrate, polyethylene glycol, sorbitol, tribuyl citrate, and mixtures thereof.
- molding is performed via thermal setting molding using • the method and apparatus described in copending U.S. patent application Serial No. 09/966,450, pages 57-63, the disclosure of which is incorporated herein by reference.
- the composition is formed by injecting the dispersion into a molding chamber. The dispersion is cooled and solidifies in the molding chamber into a shaped form (i.e., having the shape of the mold).
- the dispersion may comprise solid particles of the high molecular weight, water-soluble polymer suspended in a liquid carrier comprising the other ingredients (carrageenan, gellan gum and/or lubricant) and the liquid plasticizer, e.g. water.
- the other ingredients are dissolved in the liquid plasticizer.
- molding is performed by thermal cycle molding using the method and apparatus described in copending U.S. patent application Serial No. 09/966,497, pages 27-51, the disclosure of which is incorporated herein by reference.
- Thermal cycle molding is performed by injecting the dispersion into a heated molding chamber.
- the dispersion may comprise the high molecular weight water soluble polymer dispersed in a liquid carrier comprising carrageenan along with gellan gum and/or lubricant and water at a temperature above the cloud point of the high molecular weight polymer and above the gelling temperature of the other polymers.
- the dispersion is cooled and solidifies in the molding chamber into a shaped form (i.e., having the shape of the mold).
- the thermal cycle molding module 200 comprises a rotor 202 around which a plurality of mold units 204 are disposed.
- the thermal cycle molding module includes a reservoir 206 (see Figure 4) for holding dispersion.
- the thermal cycle molding module is provided with a temperature control system for rapidly heating and cooling the mold units.
- Figures 55 and 56 depict the temperature control system 600.
- the mold units may comprise center mold assemblies 212, upper mold assemblies 214, and lower mold assemblies 210, as shown in Figures 26-28, which mate to form mold cavities having a desired shape, for instance of a core or a shell surrounding one or more cores.
- center mold assemblies 212 upper mold assemblies 214, and lower mold assemblies 210, as shown in Figures 26-28, which mate to form mold cavities having a desired shape, for instance of a core or a shell surrounding one or more cores.
- Dispersion which is heated to a flowable state in reservoir 206, is injected into the resulting mold cavities. The temperature of the dispersion is then decreased, hardening the dispersion.
- the mold assemblies open and eject the finished product.
- the shell is applied to the dosage form using a thermal cycle molding apparatus of the general type shown in Figures 28A-C of copending U.S. Application Serial No. 09/966,497 comprising rotatable center mold assemblies 212, lower mold assemblies 210 and upper mold assemblies 214. Cores are continuously fed to the mold assemblies. Dispersion for making the shell, which is heated to a flowable state in reservoir 206, is injected into the mold cavities created by the closed mold assemblies holding the cores. The temperature of the shell dispersion is then decreased, hardening it around the cores. The mold assemblies open and eject the finished dosage forms. Shell coating is performed in two steps, each half of the dosage forms being coated separately as shown in the flow diagram of Figure 28B of copending U.S. Application Serial No. 09/966,939 via rotation of the center mold assembly.
- the compression module of copending U.S. patent application Serial No. 09/966,509, pp. 16-27 may be employed to make the core and the shell is applied to the core using a thermal cycle molding module as described above.
- a transfer device as described in U.S. patent application Serial No. 09/966,414, pp. 51-57, the disclosure of which is incorporated herein by reference, may be used to transfer the cores from the compression module to the thermal cycle molding module.
- Such a transfer device may have the structure shown as 300 in Figure 3 of copending U.S. Application Serial No. 09/966,939. It comprises a plurality of transfer units 304 attached in cantilever fashion to a belt 312 as shown in Figures 68 and 69 of copending U.S. Application Serial No. 09/966,939.
- the transfer device rotates and operates in sync with the compression module and the thermal 5 cycle molding module to which it is coupled.
- Transfer units 304 comprise retainers 330 for holding cores as they travel around the transfer device.
- a liquid carrier for the dispersion is formed from a mixture of carrageenan with gellan gum and/or lubricant and a liquid plasticizer
- the liquid carrier may be a thermoplastic system.
- the mixture can be in a thermoplastic state depending on temperature and pressure.
- the liquid carrier is not a thermoplastic system.
- the shell, core, or the composition of the 5 invention may additionally comprise a water insoluble polymer at a level of up to about 40%, e.g 15% of the weight of the shell, core, or the composition of the invention.
- a water insoluble polymer employed, the weight ratio of high molecular weight water soluble polymer to water insoluble polymer may be from about 99:1 to about 50:50.
- Suitable water insoluble polymers 0 include ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose propionate, and mixtures thereof.
- the dispersion for making cores or the shell by molding may optionally comprise adjuvants or excipients, which may comprise up to about 30% by weight of the dispersion.
- adjuvants or excipients include detackifiers, 5 humectants, surfactants, anti-foaming agents, colorants, flavorants, sweeteners, i opacifiers, and the like.
- the composition typically is preferably substantially free of pores in the diameter range of 0.5 to 5.0 microns, i.e. has a pore volume in the pore diameter range of 0.5 to 5.0 microns of less than about 0.02 cc/g, preferably less than about 0.01 cc/g, more preferably less than about 0.005 cc/g.
- Typical compressed materials have pore volumes in this diameter range of more than about 0.02 cc/g.
- Pore volume, pore diameter and density may be determined using a Quantachrome Instruments PoreMaster 60 mercury intrusion porosimeter and associated computer software program known as "Porowin.” The procedure is documented in the Quantachrome Instruments PoreMaster Operation Manual.
- the PoreMaster determines both pore volume and pore diameter of a solid or powder by forced intrusion of a non- wetting liquid (mercury), which involves evacuation of the sample in a sample cell (penetrometer), filling the cell with mercury to surround the sample with mercury, applying pressure to the sample cell by: (i) compressed air (up to 50 psi maximum); and (ii) a hydraulic (oil) pressure generator (up to 60000 psi maximum). Intruded volume is measured by a change in the capacitance as mercury moves from outside the sample into its pores under applied pressure.
- a non- wetting liquid cury
- the samples remain in sealed packages or as received in the dessicator until analysis.
- the vacuum pump is switched on, the mercury vapor cold trap is filled with liquid nitrogen, the compressed gas supply is regulated at 55 psi., and the instrument is turned on and allowed a warm up time of at least 30 minutes.
- the empty penetrometer cell is assembled as described in the instrument manual and its weight is recorded. The cell is installed in the low pressure station and "evacuation and fill only" is selected from the analysis menu, and the following settings are employed:
- Fine Evacuation rate 10 Coarse Evacuation time: 5 min.
- the cell (filled with mercury) is then removed and weighed.
- the cell is then emptied into the mercury reservoir, and two tablets from each sample are placed in the cell and the cell is reassembled.
- the weight of the cell and sample are then recorded.
- the cell is then installed in the low-pressure station, the low-pressure option is selected from the menu, and the following parameters are set:
- Dosage forms according to the invention preferably provide modified release of at least one active ingredient contained therein.
- modified release means the release of an active ingredient from a dosage form or a portion thereof in other than an immediate release fashion, i.e., other than immediately upon contact of the dosage form or portion thereof with a liquid medium.
- types of modified release include delayed or controlled.
- Types of controlled release include prolonged, sustained, extended, retarded, and the like.
- Modified release profiles that incorporate a delayed release feature include pulsatile, repeat action, and the like.
- suitable mechanisms for achieving modified release of an active ingredient include diffusion, erosion, surface area control via geometry and/or impermeable barriers, and other known mechanisms known.
- the composition of the invention is used as a shell over a core and provides for delayed burst release of at least one active ingredient contained in the underlying core. That is, release of the active ingredient from the dosage form is delayed for a pre-determined time after ingestion by the patient, after which it is promptly released.
- a dosage form according to the invention was made by coating a core (tablet) prepared as set forth in Part A below with Dispersion A as follows.
- ibuprofen and croscarmellose sodium were mixed in a 1 qt. P-K blender for 5 minutes. Magnesium stearate was added to the mixture and mixed for another 5 minutes.
- a Beta press Manesty, Liverpool, UK equipped with round punch and die unit 0.375" in diameter was used to make the core from the ibuprofen final blend. The compressed core weighed 430 mg and contained 404 mg of ibuprofen.
- Dispersion A The following ingredients were used to make Dispersion A:
- a beaker was submersed in an 85°C water bath (Ret digi-visc; Antal-Direct, Wayne, PA). D.I. water was added to the beaker, followed by gellan gum, and the two were mixed with an electric mixer equipped with a propeller style blade until all powder was dispersed. An agitating speed of 1000 rpm was used. The carrageenan powder was added next and then mixed for 15 minutes. The hydroxypropyl methylcellulose powder was added and then mixed for 120 minutes to form Dispersion A in flowable form.
- an 85°C water bath Ret digi-visc; Antal-Direct, Wayne, PA.
- a laboratory scale thermal cycle molding unit was used to apply first and second shell portions made from Dispersion A to the core, and comprised a single mold assembly made from an upper mold assembly portion comprising an upper mold cavity, and a lower mold assembly portion comprising a lower mold cavity.
- the lower mold assembly portion was first cycled to a hot stage at 85°C for 30 seconds.
- Dispersion A was introduced into the lower mold cavity.
- the core from Part A was then inserted into a blank upper mold assembly.
- the blank upper mold assembly portion was mated with the lower mold assembly portion.
- the mold assembly was then cycled to a cold stage at 5°C for 60 seconds to harden the first shell portion.
- the blank mold assembly portion was removed from the lower mold assembly portion.
- the upper mold assembly portion was cycled to a hot stage at 85 0 C for 30 seconds. A further portion of Dispersion A was added to the upper mold cavity.
- the lower mold assembly portion which had been maintained at 5°C, was then mated with the upper mold assembly portion. Both the upper and lower mold assembly portions were cycled to a cold stage at 5 0 C for 90 seconds to harden the second shell portion.
- the lower mold assembly portion was then removed and the finished dosage form, a molded coated core with two halves of the same shell material, was ejected from the upper mold cavity.
- the finished dosage form was dried at ambient room temperature for 12 hours to remove all residual water. The weight gain due to application of the shell (i.e. the difference in weight between the finished dosage form, and the core) was recorded.
- a core (tablet) prepared as set forth in Example 1, Part A was coated with Dispersion B to prepare a dosage form according to the invention as follows.
- Dispersion B The following ingredients were used to make Dispersion B:
- Glyceryl monostearate was dispersed in hot D. I. water and mixed with an electric mixer equipped with a propeller style blade to form a glyceryl monostearate dispersion (20%w/w).
- a beaker was then submersed in an 85°C water bath (Ret digi- vise; Antal-Direct, Wayne, PA).
- D.I. water was added to the beaker.
- Carrageenan powder was added to the beaker and was mixed with an electric mixer equipped with a propeller style blade until all powder was melted. An agitating speed of 1000 rpm was used.
- the hydroxypropyl methylcellulose powder was then added and mixed for 15 minutes.
- the glyceryl monostearate dispersion was added and then mixed for 120 minutes to form Dispersion B in flowable form.
- Dispersion B Application of Dispersion B to the cores:
- a laboratory scale thermal cycle molding unit was used to apply first and second shell portions to the cores as described in Example 1 using Dispersion B, except that both the upper and lower mold assembly portions were cycled to a hot stage at 85°C for 20 seconds and then were cycled to a cold stage at 5°C for 90 seconds to harden the second shell portion.
- the finished dosage form a molded coated core with two halves of the same shell material, was then ejected from the upper mold cavity as in Example 1.
- the finished dosage form was dried at 5O 0 C for 12 hours to remove all residual water.
- the weight gain due to application of the shell i.e. the difference in weight between the finished dosage form, and the core) was recorded.
- AU curves were derived using the following dissolution apparatus: USP Type II apparatus (paddles, 50 RPM). Media: pH 6.8 phosphate buffer at 37°C. Time points: Samples were removed at 0.5, 1, 1.5. 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, and 8 hours to be analyzed for ibuprofen. Dissolution samples were analyzed for ibuprofen versus a standard prepared at the theoretical concentration for 100% released of the compound. Samples were assayed spectrophotometrically using a Gary 50 UV- Visible spectrophotometer at 254 nm for ibuprofen content.
Abstract
Description
Claims
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PCT/US2004/035763 WO2006046954A1 (en) | 2004-10-26 | 2004-10-26 | Burst-release polymer composition and dosage forms comprising the same |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0234670A2 (en) * | 1986-01-18 | 1987-09-02 | The Boots Company PLC | Sustained-release pharmaceutical formulation containing xanthan gum |
EP0622408A1 (en) * | 1993-04-27 | 1994-11-02 | Monsanto Company | Composition and process for gelatin-free soft capsules |
EP0875245A2 (en) * | 1997-04-28 | 1998-11-04 | Hercules Incorporated | Substained release polymer blend matrix for pharmaceutical application |
US20020187190A1 (en) * | 1996-12-17 | 2002-12-12 | Dominique Cade | Polymer film compositions for capsules |
WO2003000293A1 (en) * | 2001-06-21 | 2003-01-03 | Astrazeneca Ab | Pharmaceutical formulation |
US20040129174A1 (en) * | 2001-09-28 | 2004-07-08 | Shun-Por Li | Burst-release polymer composition and dosage forms comprising the same |
-
2004
- 2004-10-26 CA CA002584469A patent/CA2584469A1/en not_active Abandoned
- 2004-10-26 WO PCT/US2004/035763 patent/WO2006046954A1/en active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0234670A2 (en) * | 1986-01-18 | 1987-09-02 | The Boots Company PLC | Sustained-release pharmaceutical formulation containing xanthan gum |
EP0622408A1 (en) * | 1993-04-27 | 1994-11-02 | Monsanto Company | Composition and process for gelatin-free soft capsules |
US20020187190A1 (en) * | 1996-12-17 | 2002-12-12 | Dominique Cade | Polymer film compositions for capsules |
EP0875245A2 (en) * | 1997-04-28 | 1998-11-04 | Hercules Incorporated | Substained release polymer blend matrix for pharmaceutical application |
WO2003000293A1 (en) * | 2001-06-21 | 2003-01-03 | Astrazeneca Ab | Pharmaceutical formulation |
US20040129174A1 (en) * | 2001-09-28 | 2004-07-08 | Shun-Por Li | Burst-release polymer composition and dosage forms comprising the same |
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