WO2005011666A1 - Stable sustained release oral dosage form of gabapentin - Google Patents
Stable sustained release oral dosage form of gabapentin Download PDFInfo
- Publication number
- WO2005011666A1 WO2005011666A1 PCT/IB2004/051408 IB2004051408W WO2005011666A1 WO 2005011666 A1 WO2005011666 A1 WO 2005011666A1 IB 2004051408 W IB2004051408 W IB 2004051408W WO 2005011666 A1 WO2005011666 A1 WO 2005011666A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- gabapentin
- sustained release
- gum
- tablet
- release tablet
- Prior art date
Links
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 title claims abstract description 130
- 229960002870 gabapentin Drugs 0.000 title claims abstract description 65
- 238000013268 sustained release Methods 0.000 title abstract description 8
- 239000012730 sustained-release form Substances 0.000 title abstract description 8
- 239000006186 oral dosage form Substances 0.000 title abstract description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 29
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 29
- 239000007939 sustained release tablet Substances 0.000 claims abstract description 29
- 239000008187 granular material Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 27
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 25
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 25
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 25
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 24
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 24
- 229940124531 pharmaceutical excipient Drugs 0.000 claims abstract description 20
- 150000004676 glycans Chemical class 0.000 claims abstract description 15
- 229920000642 polymer Polymers 0.000 claims abstract description 15
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 15
- 239000005017 polysaccharide Substances 0.000 claims abstract description 15
- 239000003826 tablet Substances 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 16
- 150000003951 lactams Chemical class 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 10
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 10
- 229920002907 Guar gum Polymers 0.000 claims description 8
- 235000010417 guar gum Nutrition 0.000 claims description 8
- 239000000665 guar gum Substances 0.000 claims description 8
- 229960002154 guar gum Drugs 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 8
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- 229920001615 Tragacanth Polymers 0.000 claims description 5
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- 239000000205 acacia gum Substances 0.000 claims description 5
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- 206010015037 epilepsy Diseases 0.000 claims description 5
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- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
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- 238000001035 drying Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 208000004296 neuralgia Diseases 0.000 claims description 3
- 208000021722 neuropathic pain Diseases 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 abstract description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229920001903 high density polyethylene Polymers 0.000 description 3
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- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
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- 239000008213 purified water Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920003082 Povidone K 90 Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- -1 lactam compound Chemical class 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
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- 235000010981 methylcellulose Nutrition 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 238000004513 sizing Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920003085 Kollidon® CL Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- CGWVBPMMLKULCR-UHFFFAOYSA-N acetic acid;cyclohexylmethanamine Chemical compound CC(O)=O.NCC1CCCCC1 CGWVBPMMLKULCR-UHFFFAOYSA-N 0.000 description 1
- 238000011360 adjunctive therapy Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
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- 230000001627 detrimental effect Effects 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; 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
- A61K9/2072—Pills, 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
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Definitions
- the present invention relates to stable sustained release oral dosage forms of gabapentin and methods for making these dosage forms.
- Gabapentin (l-(aminomethyl)cyclohexaneacetic acid) is a #-amino acid analogue effective in the treatment of epilepsy. Gabapentin is indicated as an adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults with epilepsy. Gabapentin has also been approved for neuropathic pain in some countries.
- Gabapentin has been reported to convert to a toxic lactam compound during preparation and storage. This lactam formation is also seen in formulations containing gabapentin. The lactam formation in formulation during storage is apparently a result of the catalytic effects of the excipients used. The lactam has toxicity, which exceeds that of gabapentin itself.
- the lethal dose (LD ) of gabapentin in mice has been reported to be 8,000 mg/kg while that of the corresponding lactam is 300 mg/kg. Consequently, these impurities and the potential formation of such decomposition products during storage of pharmaceutical compositions must be reduced to a minimum for reasons of safety.
- a stable sustained release tablet prepared from granules.
- the granules include gabapentin; one or more hydrophilic rate- controlling polymers selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone and its derivatives, and polysaccharide gum; and, optionally, one or more pharmaceutical excipients.
- Embodiments of the sustained release tablet may include one or more of the following features.
- the lactam content of the tablet may not exceed 0.6% by weight of gabapentin when stored for three months at 40°C and 75% relative humidity.
- the tablet may provide therapeutically effective plasma levels of gabapentin for up to about 24 hours.
- the sustained release tablet may have a dissolution profile measured in a USP type II dissolution apparatus, at 50 rpm, at a temperature of 37 ⁇ 0.5°C in 900ml of 0.06N hydrochloric acid of at least 90% of the gabapentin being released in a time between 4 hours and 12 hours. More particularly, at least 90% of the gabapentin may be released in a time between 8 hours and 12 hours.
- the gabapentin may make up from about 100 mg to about l,200mg by weight of the tablet.
- the hydroxypropylcellulose may have a viscosity of between about 7 cps and about 30,000 cps.
- the hydroxypropylcellulose may have a viscosity of between about 4,000 cps and about 15,000 cps.
- the polyvinylpyrrolidone derivative may be selected from crospovidone, copolyvidone and physical mixtures of polyvinylpyrrolidone and polyvinylacetate.
- the polysaccharide gum may be selected from the group consisting of guar gum, gum arabic, xanthan gum, locust bean gum, gum karaya and gum tragacanth or combinations thereof.
- the pharmaceutical excipients may be selected from diluents, binders, lubricants and glidants.
- the sustained release tablet may be formulated such that the granules do not contain hydroxymethyl propylcellulose.
- the sustained release tablet may further include one or more pharmaceutical excipients mixed with the granules.
- Embodiments of the process may include one or more of the following features.
- the lactam content of the tablet may not exceed 0.6% by weight of gabapentin when stored for three months at 40°C and 75% relative humidity.
- the tablet may provide therapeutically effective plasma levels of gabapentin for up to about 24 hours.
- the sustained release tablet may have a dissolution profile measured in a USP type II dissolution apparatus, at 50 rpm, at a temperature of 37 ⁇ 0.5°C in 900ml of 0.06N hydrochloric acid of at least 90% of the gabapentin being released in a time between 4 hours and 12 hours. More particularly, at least 90% of the gabapentin may be released in a time between 8 hours and 12 hours.
- the gabapentin may make up between about 100 mg and about 1 ,200 mg by weight of the tablet.
- the hydroxypropylcellulose may have a viscosity of between about 7 cps and about 30,000 cps.
- the hydroxypropylcellulose may have a viscosity of between about 4,000 cps and about 15,000 cps.
- the polyvinylpyrrolidone derivative is selected from crospovidone, copolyvidone and physical mixtures of polyvinylpyrrolidone and polyvinylacetate.
- the polysaccharide gum is selected from the group consisting of guar gum, gum arabic, xanthan gum, locust bean gum, gum karaya and gum tragacanth or combinations thereof.
- the other pharmaceutical excipients are selected from diluents, binders, lubricants and glidant.
- the process may further include granulating one or more pharmaceutical excipients with the mixture of gabapentin and one or more hydrophilic rate-controlling polymers.
- a method of treating a medical condition includes providing an oral pharmaceutical sustained release tablet prepared from granules comprising gabapentin, one or more hydrophilic rate controlling polymers selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone and its derivatives, and polysaccharide gum and optionally one or more pharmaceutical excipients.
- Embodiments of the method of treating may include one or more of the following features or those described above.
- the medical condition may be one or both of epilepsy and neuropathic pain.
- sustained release gabapentin tablets can be prepared using hydrophilic polymers selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone and its derivatives, and polysaccharide gums and one or more pharmaceutically acceptable excipients.
- hydrophilic polymers selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone and its derivatives, and polysaccharide gums and one or more pharmaceutically acceptable excipients.
- these sustained release tablets of gabapentin are believed to be capable of maintaining plasma levels of gabapentin in a therapeutic range over an extended time period for up to about 24 hours. This can be accomplished, for example, by varying the concentration of polymers within the granules and possibly outside the granules.
- the stability conditions as defined herein include tolerance of ⁇ 2 ° C in temperature and a tolerance of ⁇ 5% in relative humidity.
- Gabapentin may be present as a free base, hydrated form such as monohydrate or any other pharmaceutically acceptable salts thereof. Gabapentin may comprise from about 100 mg to about 1200 mg by weight of the tablet.
- Hydroxypropylcellulose as used herein, can be of different viscosity grades such as sold by Aqualon under the brand name of Klucel® and also by Nippon Soda Co. Ltd, Japan. Suitable grades are those having viscosity of from about 7 to about 30,000 cps. Especially suitable among these hydroxypropylcelluloses are those having viscosity of 4000 to about 30,000 cps. Typically the amount of hydroxypropylcellulose can be from about 3% to about 40%, particularly from about 5% to about 30% and more particularly from about 5% to about 25% by weight of granules.
- Polyvinylpyrrolidone or PVP refers to a polymer containing N-vinylpyrrolidone as the monomeric unit and is known to the pharmaceutical industry under a variety of designations including povidone, polyvidone, polyvidonum, polyvidonum soluble, and poly(l-vinyl-2-pyrrolidone).
- Cross-linked polyvinylpyrrolidone known as crospovidone available as Kollidon CL and Kollidon CL-M is also included.
- the polyvinylpyrrolidone derivatives include among others the copolymer of N- vinyl-2-pyrrolidone and vinyl acetate which is known as copolyvidon, copolyvidone, and copolyvidonum.
- Polyvinylpyrrolidone and polyvinyl acetate are also included. These mixtures can be in a ratio such as, but not limited to, 20:80 (PVP: polyvinylacetate) like Kollidon SR. It is apparent that other derivatives of polyvinylpyrrolidone known to those skilled in the art can also be used. Polyvinylpyrrolidone is available in a wide range of molecular weights. Particularly suitable are grades having molecular weights between about 8,000 to about 1,300,000 such as Plasdone K-90, Plasdone K-90D. Typically the amount of polyvinylpyrrolidone and its derivatives can be from about 3% to about 40%, particularly from about 3% to about 30% by weight of granules.
- Polysaccharide gums may be selected from the group consisting of guar gum, gum arabic, xanthan gum, locust bean gum, gum karaya and gum tragacanth. Particularly suitable is guar gum. Typically the amount of polysaccharide gum can be from about 3% to about 80%), particularly from about 3% to about 70% and more particularly from about 3% to about 60% by weight of the granules.
- the other pharmaceutical excipients are selected from the group consisting of diluents, binders, lubricants and glidants.
- Suitable diluents include powdered sugar, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, kaolin, dry starch, sorbitol, etc.
- Suitable binders include polyvinylpyirolidone and its derivatives; xanthan gum, guar gum; cellulose ethers such as carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose (extragranularly only, not intra- granularly), hydroxypropyl cellulose, ethyl cellulose; gelatin, starch and its derivatives.
- the granulating liquid can be, but is not limited to, water, ethanol, isopropyl alcohol, acetone, dichloromethane and the like.
- the binder can be dissolved in the granulating liquid and used as a solution.
- Lubricants can be talc, stearic acid, vegetable oil, calcium stearate, zinc stearate and magnesium stearate and glidants include talc, silicon dioxide and cornstarch.
- stable gabapentin sustained release tablets may be prepared by
- [36] Blending gabapentin with hydrophilic rate-controlling polymer(s) like hydroxypropylcellulose, polyvinylpyrrolidone and its derivatives or polysaccharide gum and other pharmaceutical excipients (but not HPMC) in a mixer. 2. Granulating the blend of step (1) with a granulating liquid or a binder solution. 3. Drying and sizing the granules. 4. Mixing the sized granules with other pharmaceutical excipients and compressing into tablet.
- hydrophilic rate-controlling polymer(s) like hydroxypropylcellulose, polyvinylpyrrolidone and its derivatives or polysaccharide gum and other pharmaceutical excipients (but not HPMC) in a mixer. 2. Granulating the blend of step (1) with a granulating liquid or a binder solution. 3. Drying and sizing the granules. 4. Mixing the sized granules with other pharmaceutical excipients and compressing into tablet.
- stable gabapentin sustained release tablets may be prepared by following the steps of
- Tablets can additionally be coated with non-rate-controlling polymer(s) compositions like Opadry® sold by Colorcon to impart aesthetic appeal.
- a coating may comprise about 2% by weight of the tablet.
- Stable gabapentin sustained release tablets and process for the preparation thereof described herein is further illustrated by the following examples but these should not be construed as limiting the scope of the invention.
Abstract
Description
Claims
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PCT/IB2004/051408 WO2005011666A1 (en) | 2003-08-05 | 2004-08-05 | Stable sustained release oral dosage form of gabapentin |
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Cited By (8)
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---|---|---|---|---|
WO2006077492A1 (en) * | 2005-01-24 | 2006-07-27 | Ranbaxy Laboratories Limited | Sustained release oral dosage forms of gabapentin |
WO2006113568A2 (en) * | 2005-04-19 | 2006-10-26 | Alza Corporation | Controlled delivery dosage form of tramadol and gabapentin |
KR100715354B1 (en) | 2005-08-30 | 2007-05-08 | 주식회사 대웅제약 | A stable gabapentin formulation suppressing production of impurities and preparation process thereof |
WO2007086694A1 (en) * | 2006-01-27 | 2007-08-02 | Cj Cheiljedang Corporation | Zaltoprofen-containing sustained release tablet and process for the preparation thereof |
FR2897267A1 (en) * | 2006-02-16 | 2007-08-17 | Flamel Technologies Sa | MULTIMICROPARTICULAR PHARMACEUTICAL FORMS FOR PER OS ADMINISTRATION |
WO2011042793A1 (en) * | 2009-10-06 | 2011-04-14 | Micro Labs Limited | Stabilized pharmaceutical composition comprising gabapentin with minimum levels of pharmaceutically acceptable inert excipients |
US20150147405A1 (en) * | 2012-04-10 | 2015-05-28 | Alpina Laudanum Institute Of Phytopharmaceutical Science Ag | Wet granulation process and granulate material comprising arabic gum |
US20170216212A1 (en) * | 2007-11-23 | 2017-08-03 | Gruenenthal Gmbh | Tapentadol compositions |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102688216A (en) * | 2012-04-16 | 2012-09-26 | 杭州天诚药业有限公司 | Gabapentin tablet and preparation method thereof |
CN110583654A (en) * | 2019-09-18 | 2019-12-20 | 北京农学院 | Plant source nematicide |
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WO2003103634A1 (en) * | 2002-06-07 | 2003-12-18 | Ranbaxy Laboratories Limited | Sustained release oral dosage forms of gabapentin |
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2004
- 2004-08-05 CN CNA2004800224971A patent/CN1832736A/en active Pending
- 2004-08-05 WO PCT/IB2004/051408 patent/WO2005011666A1/en active Application Filing
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US6294198B1 (en) * | 1999-08-24 | 2001-09-25 | Purepac Pharmaceutical Co. | Pharmaceutical tablet formulation containing gabapentin with improved physical and chemical characteristics and method of making the same |
US20030008004A1 (en) * | 1999-08-24 | 2003-01-09 | Zalman Vilkov | Pharmaceutical tablet formulation containing gabapentin with improved physical and chemical characteristics and method of making the same |
US20020091159A1 (en) * | 2000-09-26 | 2002-07-11 | Spiridon Spireas | Stable solid dosage forms of amino acids and processes for producing same |
WO2003103634A1 (en) * | 2002-06-07 | 2003-12-18 | Ranbaxy Laboratories Limited | Sustained release oral dosage forms of gabapentin |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2006077492A1 (en) * | 2005-01-24 | 2006-07-27 | Ranbaxy Laboratories Limited | Sustained release oral dosage forms of gabapentin |
WO2006113568A2 (en) * | 2005-04-19 | 2006-10-26 | Alza Corporation | Controlled delivery dosage form of tramadol and gabapentin |
WO2006113568A3 (en) * | 2005-04-19 | 2007-04-05 | Alza Corp | Controlled delivery dosage form of tramadol and gabapentin |
KR100715354B1 (en) | 2005-08-30 | 2007-05-08 | 주식회사 대웅제약 | A stable gabapentin formulation suppressing production of impurities and preparation process thereof |
WO2007086694A1 (en) * | 2006-01-27 | 2007-08-02 | Cj Cheiljedang Corporation | Zaltoprofen-containing sustained release tablet and process for the preparation thereof |
WO2007093642A2 (en) * | 2006-02-16 | 2007-08-23 | Flamel Technologies | Microparticulate pharmaceutical forms resistant to immediate release of the active principle in the presence of alcohol |
FR2897267A1 (en) * | 2006-02-16 | 2007-08-17 | Flamel Technologies Sa | MULTIMICROPARTICULAR PHARMACEUTICAL FORMS FOR PER OS ADMINISTRATION |
WO2007093642A3 (en) * | 2006-02-16 | 2007-10-04 | Flamel Tech Sa | Microparticulate pharmaceutical forms resistant to immediate release of the active principle in the presence of alcohol |
JP2009526825A (en) * | 2006-02-16 | 2009-07-23 | フラメル・テクノロジーズ | Multiparticulate pharmaceutical formulation for oral administration |
US20170216212A1 (en) * | 2007-11-23 | 2017-08-03 | Gruenenthal Gmbh | Tapentadol compositions |
WO2011042793A1 (en) * | 2009-10-06 | 2011-04-14 | Micro Labs Limited | Stabilized pharmaceutical composition comprising gabapentin with minimum levels of pharmaceutically acceptable inert excipients |
US20150147405A1 (en) * | 2012-04-10 | 2015-05-28 | Alpina Laudanum Institute Of Phytopharmaceutical Science Ag | Wet granulation process and granulate material comprising arabic gum |
US10092518B2 (en) * | 2012-04-10 | 2018-10-09 | Alpina Laudanum Institute Of Phytopharmaceutical Sciences Ag | Wet granulation process and granulate material comprising Arabic gum |
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CN1832736A (en) | 2006-09-13 |
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