CN1921839A - Stable sustained-release oral dosage forms of gabapentin and process for preparation thereof - Google Patents
Stable sustained-release oral dosage forms of gabapentin and process for preparation thereof Download PDFInfo
- Publication number
- CN1921839A CN1921839A CNA2005800059536A CN200580005953A CN1921839A CN 1921839 A CN1921839 A CN 1921839A CN A2005800059536 A CNA2005800059536 A CN A2005800059536A CN 200580005953 A CN200580005953 A CN 200580005953A CN 1921839 A CN1921839 A CN 1921839A
- Authority
- CN
- China
- Prior art keywords
- granule
- rate control
- gabapentin
- component
- tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 title claims abstract description 170
- 229960002870 gabapentin Drugs 0.000 title claims abstract description 85
- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000013268 sustained release Methods 0.000 title claims abstract description 27
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title abstract description 34
- 239000006186 oral dosage form Substances 0.000 title abstract description 4
- 206010015037 epilepsy Diseases 0.000 claims abstract description 8
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims abstract description 6
- 239000008187 granular material Substances 0.000 claims description 124
- 229920000642 polymer Polymers 0.000 claims description 91
- 239000000203 mixture Substances 0.000 claims description 75
- -1 Poly(ethylene oxide) Polymers 0.000 claims description 50
- 150000003951 lactams Chemical class 0.000 claims description 50
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 37
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 37
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 37
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 17
- 229930195725 Mannitol Natural products 0.000 claims description 15
- 229920001577 copolymer Polymers 0.000 claims description 15
- 239000000594 mannitol Substances 0.000 claims description 15
- 235000010355 mannitol Nutrition 0.000 claims description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- 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 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 239000002245 particle Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 11
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 11
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 11
- 229920002472 Starch Polymers 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
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- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- 238000005469 granulation Methods 0.000 claims description 7
- 230000003179 granulation Effects 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 229920002907 Guar gum Polymers 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 6
- 239000000665 guar gum Substances 0.000 claims description 6
- 235000010417 guar gum Nutrition 0.000 claims description 6
- 229960002154 guar gum Drugs 0.000 claims description 6
- 239000000230 xanthan gum Substances 0.000 claims description 6
- 229920001285 xanthan gum Polymers 0.000 claims description 6
- 235000010493 xanthan gum Nutrition 0.000 claims description 6
- 229940082509 xanthan gum Drugs 0.000 claims description 6
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 235000010981 methylcellulose Nutrition 0.000 claims description 5
- 238000005453 pelletization Methods 0.000 claims description 5
- 239000002002 slurry Substances 0.000 claims description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- 241001597008 Nomeidae Species 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 4
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- 239000005995 Aluminium silicate Substances 0.000 claims description 3
- 229920002261 Corn starch Polymers 0.000 claims description 3
- 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 claims description 3
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- 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 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- 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 claims description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 229940072056 alginate Drugs 0.000 claims description 3
- 235000010443 alginic acid Nutrition 0.000 claims description 3
- 229920000615 alginic acid Polymers 0.000 claims description 3
- 235000012211 aluminium silicate Nutrition 0.000 claims description 3
- 239000001506 calcium phosphate Substances 0.000 claims description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 3
- 235000011010 calcium phosphates Nutrition 0.000 claims description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- 235000011132 calcium sulphate Nutrition 0.000 claims description 3
- 229920002301 cellulose acetate Polymers 0.000 claims description 3
- 239000008120 corn starch Substances 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 3
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 3
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 229920003179 starch-based polymer Polymers 0.000 claims description 3
- 239000004628 starch-based polymer Substances 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- 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 claims description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 3
- 239000008158 vegetable oil Substances 0.000 claims description 3
- 238000005550 wet granulation Methods 0.000 claims description 3
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 3
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 239000003826 tablet Substances 0.000 description 35
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 33
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- 239000002552 dosage form Substances 0.000 description 12
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 11
- 229960000502 poloxamer Drugs 0.000 description 11
- 229920001983 poloxamer Polymers 0.000 description 11
- 238000012216 screening Methods 0.000 description 10
- 239000002671 adjuvant Substances 0.000 description 9
- 238000003860 storage Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229920003091 Methocel™ Polymers 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229960002900 methylcellulose Drugs 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- QGQXAMBOYWULFX-LZWSPWQCSA-N 2-morpholin-4-ylethyl (e)-6-(4,6-dihydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound OC=1C=2C(=O)OCC=2C(C)=C(O)C=1C\C=C(/C)CCC(=O)OCCN1CCOCC1 QGQXAMBOYWULFX-LZWSPWQCSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
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- 239000012736 aqueous medium Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000037058 blood plasma level Effects 0.000 description 1
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- 235000010980 cellulose Nutrition 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- AVKNGPAMCBSNSO-UHFFFAOYSA-N cyclohexylmethanamine Chemical compound NCC1CCCCC1 AVKNGPAMCBSNSO-UHFFFAOYSA-N 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000008383 extra-granule composition Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
- A61K9/20—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
- 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
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- 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
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/2027—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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to stable sustained-release oral dosage forms of gabapentin, processes for preparation thereof, and uses thereof in treating epilepsy or post herpetic neuralgia.
Description
Invention field
The present invention relates to stable sustained-release oral dosage forms, its preparation method and the application in epilepsy or postherpetic neuralgia thereof of gabapentin.
Background of invention
When a kind of human pharmaceutical dosage form of design, wish that this medicine shows its maximum curative effect and minimum side effect.But the dosage form adjustment dosage regimen or the change bioavailability parameter that have medicament slow release by design only reduce on minimum level ground, even do not eliminate the more inherent side effect of medicine.If but medicine is easy to degraded, and is formed with toxic byproduct in time, or exists in dosage form owing to having isolating incompatibility, its consumption can be harmful to patient's health.Various pharmacopeia require dosage forms do not contain these deleterious catabolites or, if present, should be in the safety allowed band.
Gabapentin (1-(amino methyl) cyclohexane extraction acetic acid) is the gamma-amino acid analog of effectively treating epilepsy.Gabapentin be used for auxiliary treatment epilepsy adult patient with without the extensive partial seizure of Secondary cases.Gabapentin also has been approved for the treatment neuropathic pain in some countries.
Report that between preparation and storage life, gabapentin changes into lactam compound (impurity A).In containing the preparation of gabapentin, also see the formation of this lactams.Between the storage life, the reason that lactams forms in the gabapentin formulation also is the result of the catalytic effect of used adjuvant in the preparation.The toxicity that lactams had surpasses gabapentin itself.Report that gabapentin is to the fatal dose (LD of mice
50) be 8,000 mg/kg, and the fatal dose of corresponding lactams is 300 mg/kg.Therefore, for safety, this catabolite that must may form with these impurity with during the storage of pharmaceutical compositions is reduced to minimum.
U.S. Patent number 6,054,482 have listed the pharmaceutic adjuvant with the gabapentin incompatibility, and to the stability of gabapentin without any the obvious adjuvant of influence.Comprise hydroxypropyl emthylcellulose in the catalog of compatible adjuvant.But when gabapentin and hydroxypropyl emthylcellulose preparation, observing lactams content increases, and makes preparation store the camber instability.
Commonly used and the incompatibility that be easy to obtain pharmaceutic adjuvant, especially rate control polymer of gabapentin and some has limited the quantity of compatible adjuvant, makes to be difficult to develop the gabapentin stable sustained-release dosage form with required release characteristic.Need a kind of method, so that the obtained adjuvant of greater number is suitable for preparing the stable sustained-release dosage form of gabapentin.Consider that unstability and the half-life thereof of gabapentin in dosage form is short, should design a kind of slow release formulation of gabapentin, it between the storage life be stable, lactams content is low and the treatment effective plasma level level of gabapentin was provided in time expand.This stable slow release formulation of gabapentin not only provides the gabapentin treatment of secured fashion, other advantage also is provided, has for example kept the stable blood plasma level of gabapentin and reduce total daily dose and make administration frequency be reduced to the probability of every day 1 or 2 times.
Summary of the invention
This paper provides the gabapentin stable sustained-release sheet that comprises component and the outer component of granule in the granule, and component comprises gabapentin and one or more rate control polymers randomly in the granule; The outer component of granule comprises one or more rate control polymers, and wherein, when this tablet was preserved about 3 months under about 40 ℃ and about 75% relative humidity, lactams content was no more than 0.4% of gabapentin weight.The outer rate control polymer of rate control polymer and one or more granules can be identical or different in one or more granules.
The example of stable sustained-release sheet comprises one or more following features.For example, component can comprise one or more rate control polymers in the granule.One or more rate control polymers in one or more rate control polymers in the granule in the component (being rate control polymer in one or more granules) and the outer component of granule (being the outer rate control polymers of one or more granules) account for the 5-80% of tablet weight together.One or more rate control polymers in the granule in the component account for the 0-50% of particle weight, and one or more rate control polymers in the outer component of granule account for the 5-80% of tablet weight.
In the granule or the outer rate control polymer of granule can be following one or more: polyvinylpyrrolidone and derivant thereof; Cellulosic polymer; Vinyl acetate co-polymer; Alginate; Xanthan gum; Guar gum; Starch-based polymer; Poly(ethylene oxide); Methacrylic acid copolymer; Maleic anhydride/methyl ethylene ether copolymer or derivatives thereof; Ethyl cellulose; Cellulose acetate; Methacrylate; Acrylate copolymer or copolymer; High molecular weight polyvinyl alcohol; Wax; Or their mixture.
Cellulosic polymer can be following one or more: hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methylcellulose or its mixture.In some embodiments, slow releasing tablet contains hydroxypropyl emthylcellulose, and its viscosity is about 100-100,000cps, and viscosity is about 15,000cps, even be about 4000cps.In other embodiments, slow releasing tablet contains hydroxypropyl cellulose, and its viscosity is about 7-30,000cps, and viscosity is about 1000-15000cps, even is about 4000cps.
Slow releasing tablet also can comprise one or more other pharmaceutic adjuvants, for example diluent, lubricant, fluidizer, binding agent or its mixture.Diluent can be following one or more: Icing Sugar, calcium phosphate, calcium sulfate, microcrystalline Cellulose, lactose, mannitol, Kaolin, dried starch, sorbitol or its mixture.Lubricant can be following one or more: Pulvis Talci, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate or its mixture.Fluidizer can be following one or more: Pulvis Talci, silicon dioxide, corn starch or its mixture.Binding agent can be following one or more: polyvinylpyrrolidone, polyvinylpyrrolidone//vinyl acetate copolymer, xanthan gum, guar gum, cellulose gum (for example, carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose), gelatin, starch pregelatinized starch or their mixture.
In another general aspect, the preparation method of gabapentin stable sustained-release sheet is provided, this method may further comprise the steps: will contain gabapentin, one or more pharmaceutic adjuvants and randomly the mixture and the granulation liquid of one or more rate control polymers carry out pelletize, to form component in the granule; With component drying in the granule, sieve grain, and mix with the formation admixture with the outer rate control polymer of one or more granules, and this admixture compacting is in blocks.When this tablet was preserved about 3 months under about 40 ℃ and about 75% relative humidity, the lactams content of this stable sustained-release sheet was no more than 0.4% of gabapentin weight.Randomly the outer rate control polymer of rate control polymer and one or more granules can be identical or different in one or more granules.
The embodiment of this method can comprise one or more following features.For example, can prepare component in the granule of tablet described herein by wet granulation or non-slurry pelletizing.Can carry out non-slurry pelletizing by compacting or precompressed.
In another general aspect, the preparation method of gabapentin stable sustained-release sheet is provided, this method may further comprise the steps: with gabapentin, one or more pharmaceutic adjuvants and randomly one or more rate control polymers mix to form mixture; Compacting or precompressed mixture are to form compacts (compact) or precompressed body (slug); Screening (sizing) compacts or precompressed body are to form granule; This granule and the outer rate control polymer of one or more granules are mixed with the formation admixture, and with this admixture compacting in flakes.When this tablet was preserved about 3 months under about 40 ℃ and about 75% relative humidity, the lactams content of this stable sustained-release sheet was no more than 0.4% of gabapentin weight.Randomly the outer rate control polymer of rate control polymer and one or more granules can be identical or different in one or more granules.
In another general aspect, the method of treatment epilepsy or postherpetic neuralgia is provided, this method comprises the patient's gabapentin stable sustained-release sheet that needs treatment, this stable sustained-release sheet comprises component and the outer component of granule in the granule, component comprises the gabapentin for the treatment of effective dose and one or more rate control polymers randomly in the granule, the outer component of granule comprises one or more rate control polymers, wherein, when this tablet is preserved about 3 months under about 40 ℃ and about 75% relative humidity, lactams content is no more than 0.4% of gabapentin weight, and randomly the outer rate control polymer of rate control polymer and one or more granules can be identical or different in one or more granules.
On the other hand, provide tablet by the preparation of following method: will comprise gabapentin, one or more pharmaceutic adjuvants and randomly in one or more granules mixture and the granulation liquid of rate control polymer carry out pelletize, with component in the formation granule; With component drying in the granule, sieve grain, and mix with the formation admixture with the outer rate control polymer of one or more granules, and this admixture compacting is in blocks.
On the other hand, provide tablet by the preparation of following method: with gabapentin, one or more pharmaceutic adjuvants and randomly in one or more granules rate control polymer mix to form mixture; Compacting or precompressed mixture are to form compacts or precompressed body; Screening compacts or precompressed body are to form granule; This granule and the outer rate control polymer of one or more granules are mixed with the formation admixture, and with this admixture compacting in flakes.
Detailed Description Of The Invention
Be surprised to find that for given rate control polymer, the stability of gabapentin sheet is subjected in the granule and the influence of the amount of the rate control polymer that granule exists outward.Specifically, when the amount of rate control polymer in the component in the granule reduced, stability improved.
Methods described herein provide motility and have enlarged the quantity of the suitable pharmaceutic adjuvant that can be used for preparing gabapentin stable sustained-release sheet.When outside the dosage form granule, using a part of rate control polymer,, can adopt general and the inconsistent rate control polymer of gabapentin prepares stable composition according to methods described herein.This method economy and carrying out easily prepares the stable sustained-release sheet of gabapentin, the stable sustained-release tablet of preparation can provide gabapentin treatment effective plasma level level for up to about 24 hours.Granule can be by wet granulation or non-slurry pelletizing preparation.
Can adopt general and gabapentin inconsistent adjuvant, especially rate control polymer in the gabapentin compositions, and not damage the stability of gabapentin.This can add one or more rate control polymers outward by granule, or the remainder that adds the part of one or more rate control polymers in the granule and add one or more rate control polymers outside granule assigns to realize.All compare as the preparation of component in the granule with all rate control polymers, this method can obtain stability-enhanced gabapentin compositions.In addition, methods described herein and tablet can obtain the gabapentin compositions that lactams content reduces.
Therefore, in one embodiment, particulate preparation process is as follows: mix gabapentin, other pharmaceutic adjuvant and randomly one or more rate control polymers to form admixture this admixture and granulation liquid are carried out pelletize, with component in the formation granule; Component in dry this granule; Component in the screening granule; Component in the granule is mixed with one or more rate control polymers and the outer adjuvant of one or more extra granules; And compacting in flakes.
In another embodiment, particulate preparation process is as follows: mix gabapentin, other pharmaceutic adjuvant and randomly a part of rate control polymer to form admixture; Compacting or this admixture of precompressed; Screening; Mix with one or more rate control polymers and the outer adjuvant of other extra granule; And compacting in flakes.
Stability condition defined herein comprises the tolerance of about ± 2 ℃ of temperature and the tolerance of relative humidity about ± 5%.
Gabapentin can free alkali, hydrated form (for example, monohydrate) or its any other pharmaceutically acceptable salt exist.Gabapentin accounts for the 100-1200mg of tablet weight.
Rate control polymer can be hydrophilic or hydrophobic polymer; Especially suitable is swollen polymer in aqueous medium.Amount with respect to the polymer of gabapentin in the tablet depends on required drug release rate, also depends on the polymer that exists in the preparation or the type and the molecular weight of other adjuvant.Rate control polymer can the granule interpolymer and the form of the outer polymer of granule have (promptly in granule component or granule outside in the component), or can be only with granule outward the form of polymer exist.Rate control polymer can be identical or different in the granule or outside the granule.The amount of rate control polymer depends on used type in the granule, also depends on and the inconsistent degree of gabapentin.In general, the total amount of rate control polymer in the dosage form (being the amount of interior rate control polymer of granule and the outer rate control polymer of granule) can be about 5-80% of tablet weight, preferably is about 10-70%, is more preferably the 15-60% of tablet weight.The amount of rate control polymer is about the 0-50% of particle weight or tablet weight in the granule, and the amount of the outer polymer of granule is about the 5-80% of tablet weight.
The example of suitable rate control polymer (in the granule or outside the granule) comprising: polyvinylpyrrolidone (PVP) and derivant thereof (for example, the mixture of copolyvidone, PVP and polyvinyl acetate such as Kollidon SR); Cellulosic polymer (for example, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methylcellulose); Vinyl acetate co-polymer; Polysaccharide (for example, alginate, xanthan gum, guar gum etc.); Starch, starch-based polymer or its mixture; Poly(ethylene oxide), methacrylic acid copolymer; Maleic anhydride/ethylene methacrylic ether copolymer; Perhaps their derivant or mixture.Especially suitable rate control polymer is hydroxypropyl emthylcellulose, hydroxypropyl cellulose or its mixture.
Hydroxypropyl emthylcellulose can have different viscosity, and for example, viscosity is about 100-100,000cps, even be about 4000-15,000cps.The hydroxypropyl emthylcellulose of adequate types is the hydroxypropyl emthylcellulose of being sold with trade name METHOCEL by Dow Chemical Co., for example, and METHOCEL K4MCR, METHOCEL K15MCR and METHOCEL K100MCR.Hydroxypropyl cellulose also can have different viscosity, as the hydroxypropyl cellulose that Aqualon sells with trade name KLUCEL and Japanese Nippon Soda Co.Ltd sells.Suitable hydroxypropyl cellulose comprises that viscosity is about 7-30, and 000cps is about 1000-15,000cps, even be about 4000-15, the hydroxypropyl cellulose of 000cps.Except above-mentioned points, rate control polymer also comprises cellulose derivative (for example, ethyl cellulose or cellulose acetate), methacrylate, acrylate copolymer or copolymer, high molecular weight polyvinyl alcohol or wax (for example, fatty acid or glycerol).
Slow release gabapentin slow releasing tablet described herein also can comprise one or more other extra additives or pharmaceutic adjuvant such as diluent, lubricant, binding agent, fluidizer etc.
Suitable diluent comprise following one or more: Icing Sugar, calcium phosphate, calcium sulfate, microcrystalline Cellulose, lactose, mannitol, Kaolin, dried starch, sorbitol etc., or their mixture.
Examples of suitable lubricants comprise following one or more: Pulvis Talci, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate or their mixture.
Suitable fluidizer comprise following one or more: Pulvis Talci, silicon dioxide, corn starch or their mixture.
Suitable bonding comprise following one or more: polyvinylpyrrolidone, polyvinylpyrrolidone//vinyl acetate copolymer; Xanthan gum, guar gum; Cellulose ether (for example, carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose or its mixture); Gelatin, the starch or derivatives thereof; Or their mixture.
Suitable granulation liquid comprises, for example, below one or more: water, ethanol, isopropyl alcohol, acetone, dichloromethane etc., or their mixture.
Suitable bonding may be dissolved in the suitable granulation liquid, uses with the solution/dispersion form.
The method for preparing gabapentin stable sustained-release sheet may further comprise the steps:
1. will comprise gabapentin and randomly mixture and one or more binder solution/dispersions of one or more rate control polymers carry out pelletize, to form granule (being component in the granule);
2. dried particles (be granule in component), with granule (be granule in component) and one or more rate control polymers and one or more other pharmaceutic adjuvants (for example, one or more diluent, lubricant, fluidizer, binding agent or their mixture) mix with the formation admixture, and by suitable method with this admixture compacting in flakes.
The method for preparing gabapentin stable sustained-release sheet may further comprise the steps:
1. the mixture and the hydroxypropyl cellulose solution/dispersion that will comprise gabapentin and hydroxypropyl cellulose are carried out pelletize, to form granule (being component in the granule);
2. dried particles, with granule and hydroxypropyl emthylcellulose or hydroxypropyl cellulose and one or more other pharmaceutic adjuvants (for example, one or more diluent, lubricant, fluidizer, binding agent or their mixture) mix with the formation admixture, and by suitable method with this admixture compacting in flakes.
Also available one or more non-rate control polymers, for example the OPADRY of Colorcon sale carries out coating to tablet, and is attractive in appearance to give.This coating can account for about 2% of tablet weight.
Can be used for of preparation gabapentin stable sustained-release sheet described herein,, for example, treatment suffers from the patient of epilepsy or postherpetic neuralgia.
This paper has also considered to treat the method for epilepsy or postherpetic neuralgia in the patient, this method comprises one or more gabapentin stable sustained-release sheets described herein of patient that need treatment.
Though described the present invention with the specific embodiment, some improve and the equivalent form of value it will be apparent to those skilled in the art that, and are included in the scope of the present invention.
Preparation described herein is stablized the method for gabapentin tablets and also can be illustrated by the following examples, limits the scope of the invention but should not be construed as.
Embodiment
The following examples have been described the method for compositions of the listed embodiment 1-8 of preparation table 1.
Embodiment 1 and 2
Gabapentin is mixed with a part of hydroxypropyl cellulose, and with the second portion hydroxypropyl cellulose pelletize that is dissolved in the pure water.With particle drying, sieve, and mix with the outer hydroxypropyl emthylcellulose of granule, mannitol, copolyvidone, poloxamer, magnesium stearate and Pulvis Talci, and compacting (embodiment 1) in blocks; Or mix, and compacting (embodiment 2) in flakes with hydroxypropyl emthylcellulose, hydroxypropyl cellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and Pulvis Talci
Embodiment 3 and 4
Gabapentin is mixed with the first hydroxypropyl cellulose, and with the second portion hydroxypropyl cellulose pelletize that is dissolved in isopropyl alcohol/dichloromethane mixed liquor.With particle drying, screening mix with hydroxypropyl cellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and the Pulvis Talci of the outer part of granule, and compacting in flakes.
Embodiment 5
Gabapentin is mixed with a part of hydroxypropyl cellulose, and with the hydroxypropyl cellulose pelletize that is dissolved in the remainder in the pure water.With particle drying, screening mixes with mannitol, copolyvidone, poloxamer, magnesium stearate and Pulvis Talci, and compacting in flakes.
Embodiment 6
Gabapentin is mixed with a part of hydroxypropyl emthylcellulose, and with the remainder hydroxypropyl emthylcellulose pelletize that is dissolved in the pure water.With particle drying, screening mixes with mannitol, copolyvidone, poloxamer, magnesium stearate and Pulvis Talci, and compacting in flakes.
Embodiment 7
Gabapentin is mixed with a part of hydroxypropyl emthylcellulose, and with the remainder hydroxypropyl emthylcellulose pelletize that is dissolved in the pure water.With particle drying, screening mix with the outer hydroxypropyl emthylcellulose of granule, mannitol, copolyvidone, poloxamer, magnesium stearate and Pulvis Talci, and compacting in flakes.
Embodiment 8
Gabapentin is mixed with a part of hydroxypropyl cellulose, and with the remainder hydroxypropyl cellulose pelletize that is dissolved in the isopropyl alcohol.With particle drying, mix with hydroxypropyl emthylcellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and Pulvis Talci, and compacting in flakes.
Embodiment 9
Gabapentin is mixed with a part of hydroxypropyl cellulose, and with the second portion hydroxypropyl cellulose pelletize that is dissolved in the isopropyl alcohol.With particle drying, screening mixes with hydroxypropyl emthylcellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and Pulvis Talci, and compacting in flakes.
Embodiment 10
Gabapentin is mixed with a part of hydroxypropyl cellulose, and with the second portion hydroxypropyl cellulose pelletize that is dissolved in the isopropyl alcohol.With particle drying, screening mix with hydroxypropyl emthylcellulose and the outside branch of hydroxy propyl cellulose crude granule, mannitol, copolyvidone, poloxamer, magnesium stearate and Pulvis Talci, and compacting in flakes.
Table 1: the composition of embodiment 1-8 preparation
| Composition | Quality (mg) | |||||||||
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 | Embodiment 9 | Embodiment 10 | |
| In the granule | ||||||||||
| Gabapentin | 900 | 900 | 900 | 900 | 900 | 900 | 900 | 900 | 650 | 450 |
| Hydroxypropyl cellulose | 39 | 39 | 128 | 55 | 265 | -- | -- | 55 | 36.7 | 27.5 |
| Hydroxypropyl emthylcellulose | -- | -- | -- | -- | -- | 100 | 50 | -- | -- | -- |
| Outside the granule | ||||||||||
| Hydroxypropyl emthylcellulose | 100 | 100 | -- | -- | -- | -- | 50 | 225 | 150 | 112.5 |
| Hydroxypropyl cellulose | -- | 50 | 150 | 225 | -- | -- | -- | -- | -- | 50 |
| Mannitol | 161.5 | 111.5 | 10.5 | 10.5 | 15.5 | 81 | 81 | 10.5 | 13.7 | 10.26 |
| Copolyvidone | 12 | 12 | 12 | 12 | 12 | 12 | 12 | 12 | 8 | 6 |
| Poloxamer | 15 | 15 | 15 | 15 | 15 | 12 | 12 | 15 | 10 | 7.5 |
| Magnesium stearate | 20 | 20 | 20 | 20 | 20 | 15 | 15 | 20 | 13.3 | 10 |
| Pulvis Talci | 22.5 | 22.5 | 22.5 | 22.5 | 22.5 | 15 | 15 | 22.5 | 15 | 11.25 |
| Total amount | 1270 | 1270 | 1258 | 1260 | 1250 | 1135 | 1135 | 1260 | 846.7 | 685 |
Table 2: the composition of embodiment A-G preparation
| Composition | Quality (mg) | ||||||
| A | B | C | D | E | F | G | |
| In the granule | |||||||
| Gabapentin | 900 | 900 | 900 | 900 | 900 | 900 | 900 |
| Hydroxypropyl cellulose | -- | 39 | 100 | 100 | 120 | 20 | 120 |
| Hydroxypropyl emthylcellulose | 100 | 100 | -- | -- | -- | -- | -- |
| Mannitol | 81 | 37 | -- | -- | -- | -- | -- |
| Outside the granule | |||||||
| Hydroxypropyl emthylcellulose | -- | -- | -- | -- | -- | 100 | -- |
| Mannitol | -- | -- | 83.73 | 95.73 | 60.5 | 60.5 | 60.5 |
| Copolyvidone | 12 | 8 | 12 | -- | 12 | 12 | 12 |
| Poloxamer | 12 | 10 | 12 | 12 | 15 | 15 | 15 |
| Magnesium stearate | 15 | 10 | 15 | 15 | 20 | 20 | 20 |
| Pulvis Talci | 15 | 10 | 15 | 15 | 22.5 | 22.5 | 22.5 |
| Total amount | 1135 | 775 | 1137.7 | 1137.7 | 1150 | 1150 | 1150 |
Stability test
The basic goal of accelerated stability test be guarantee stand to store, the expection of transportation and administration stress after, product is still safe and effective when giving the patient.At least before effect duration, the content that product should keep not containing toxicity material and active component should require consistent with sign.Under the normal storage condition, the real-time stabilization test of dosage form was several years.Store under the acceleration environment of temperature and relative humidity, dosage form can provide the general situation about dosage form stability in the reality use.For estimating stability of formulation in a short time, we have studied in the HDPE bottle of sealing, and 60 ℃, the lactams that produces in the preparation when 75% relative humidity (RH) stores 14 days down and 40 ℃, 75%RH store the dependency between the lactams of generation in 3 months down.Listed the composition of the embodiment A-G that under these conditions of storage, tests in the table 2.60 ℃, 75%RH store 14 days down, and the content of lactams is about 0-1.5 in the preparation, and 40 ℃, 75%RH store 3 months down, and the content of lactams is about 1.4 in the preparation.Employing under these two kinds of conditions of storage in the preparation dependency of lactams content represent two kinds of dependencys under the stability condition, by following linear equation (R is described
2=0.9706):
y＝0.6797x+0.0515
Wherein, the lactams content that y=40 ℃/75%RH produced in following 3 months, the lactams content that x=60 ℃/75%RH produced in following 14 days.By above-mentioned dependency, the lactams of pointing out 60 ℃, 75%RH to store 0.5%w/w in 14 days preparations down is equivalent to the lactams that 40 ℃, 75%RH store 0.4%w/w in 3 months preparations down.
When the preparation of embodiment 1-8 is stored 3 months under 40 ℃, 75% relative humidity, the content of finding lactams in these preparations meets the dependency equation, promptly according to above-mentioned definite dependency, the lactams content of measuring when these preparations store 14 days under 60 ℃, 75%RH can effectively be predicted the lactams content when same preparation stores 3 months under 40 ℃, 75%RH.Stability data shows that when the rate control polymer granule interior was divided minimizing, the stability of gabapentin formulation significantly increased.
The embodiment 1,2 and 8 tablets that contain the outer hydroxypropyl emthylcellulose of granule are more stable than the embodiment 6 and 7 tablets that contain hydroxypropyl emthylcellulose in the granule.The initial lactams content of embodiment 1,2 and 8 tablets is about 0.025% (w/w), lactams content was about 0.25-0.36% (w/w) after 60 ℃, 75%RH stored 14 days down, observe lactams content after 40 ℃, 75%RH store 3 months down and be about 0.20-0.25% (w/w), the lactams content of prediction is about 0.22-0.30% (w/w).The initial lactams content of embodiment 6 and 7 tablets is about 0.030-0.040% (w/w), lactams content was about 1.00-1.47% (w/w) after 60 ℃, 75%RH stored 14 days down, observe lactams content after 40 ℃, 75%RH store 3 months down and be about 0.75-0.95% (w/w), the lactams content of prediction is about 0.73-1.05% (w/w).
And, contain in the granule more stable than embodiment 5 tablets that only contain hydroxypropyl cellulose in the granule with the embodiment 3 and 4 tablets of the outer hydroxypropyl cellulose of granule.The initial lactams content of embodiment 3 and 4 tablets is about 0.040% (w/w), lactams content was about 0.17-0.21% (w/w) after 60 ℃, 75%RH stored 14 days down, observe lactams content after 40 ℃, 75%RH store 3 months down and be about 0.12-0.16% (w/w), the lactams content of prediction is about 0.16-0.19% (w/w).The initial lactams content of embodiment 5 tablets is about 0.040% (w/w), lactams content was about 0.74% (w/w) after 60 ℃, 75%RH stored 14 days down, observe lactams content after 40 ℃, 75%RH store 3 months down and be about 0.51% (w/w), the lactams content of prediction is about 0.55% (w/w).
Contain in the granule more stable than embodiment 6 tablets that only contain hydroxypropyl emthylcellulose in the granule with embodiment 7 tablets of the outer hydroxypropyl emthylcellulose of granule.The initial lactams content of embodiment 7 tablets is about 0.030% (w/w), lactams content was about 1.00% (w/w) after 60 ℃, 75%RH stored 14 days down, observe lactams content after 40 ℃, 75%RH store 3 months down and be about 0.75% (w/w), the lactams content of prediction is about 0.73% (w/w).The initial lactams content of embodiment 5 tablets is about 0.040% (w/w), lactams content was about 1.47% (w/w) after 60 ℃, 75%RH stored 14 days down, observe lactams content after 40 ℃, 75%RH store 3 months down and be about 0.94% (w/w), the lactams content of prediction is about 1.05% (w/w).
Though described the present invention with the specific embodiment, some improves and the equivalent form of value will be conspicuous to those skilled in the art, and these improve and the equivalent form of value comprises within the scope of the invention.
Claims (28)
1. the stable sustained-release sheet of a gabapentin, described stable sustained-release sheet comprises:
Contain gabapentin and component in the granule of one or more rate control polymers randomly; With
The outer component of granule that contains one or more rate control polymers,
Wherein, when described tablet was preserved about 3 months under about 40 ℃ and about 75% relative humidity, lactams content was no more than 0.4% of gabapentin weight.
2. stable sustained-release sheet as claimed in claim 1 is characterized in that, one or more rate control polymers in the outer component of one or more rate control polymers in the granule in the component and granule are identical or different.
3. stable sustained-release sheet as claimed in claim 1 is characterized in that, component comprises one or more rate control polymers in the described granule.
4. slow releasing tablet as claimed in claim 1 is characterized in that, one or more rate control polymers in the outer component of one or more rate control polymers in the granule in the component and granule account for about 5-80% of tablet weight together.
5. slow releasing tablet as claimed in claim 4 is characterized in that, one or more rate control polymers in the granule in the component account for about 0-50% of particle weight, and one or more rate control polymers in the outer component of granule account for about 5-80% of tablet weight
6. slow releasing tablet as claimed in claim 1 is characterized in that, described rate control polymer is selected from: polyvinylpyrrolidone and derivant thereof; Cellulosic polymer; Vinyl acetate co-polymer; Alginate; Xanthan gum; Guar gum; Starch; Starch-based polymer; Poly(ethylene oxide); Methacrylic acid copolymer; Maleic anhydride/methyl ethylene ether copolymer or derivatives thereof; Ethyl cellulose; Cellulose acetate; Methacrylate; Acrylate copolymer or copolymer; High molecular weight polyvinyl alcohol; Wax; Or their mixture.
7. slow releasing tablet as claimed in claim 5 is characterized in that, described cellulosic polymer is hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methylcellulose or their mixture.
8. slow releasing tablet as claimed in claim 6 is characterized in that the viscosity of described hydroxypropyl emthylcellulose is about 100-100,000cps.
9. slow releasing tablet as claimed in claim 7 is characterized in that the viscosity of described hydroxypropyl emthylcellulose is about 15,000cps.
10. slow releasing tablet as claimed in claim 7 is characterized in that the viscosity of described hydroxypropyl emthylcellulose is about 4000cps.
11. slow releasing tablet as claimed in claim 6 is characterized in that, the viscosity of described hydroxypropyl cellulose is about 7-30,000cps.
12. slow releasing tablet as claimed in claim 10 is characterized in that, the viscosity of described hydroxypropyl cellulose is about 1000-15000cps.
13. slow releasing tablet as claimed in claim 11 is characterized in that, the viscosity of described hydroxypropyl cellulose is about 4000cps.
14. slow releasing tablet as claimed in claim 1 is characterized in that, described slow releasing tablet also comprises one or more other pharmaceutic adjuvants.
15. slow releasing tablet as claimed in claim 13 is characterized in that, described one or more other pharmaceutic adjuvants are selected from: diluent, lubricant, fluidizer, binding agent or their mixture.
16. slow releasing tablet as claimed in claim 14 is characterized in that, described diluent is selected from: Icing Sugar, calcium phosphate, calcium sulfate, microcrystalline Cellulose, lactose, mannitol, Kaolin, dried starch, sorbitol or their mixture.
17. slow releasing tablet as claimed in claim 14 is characterized in that, described lubricant is selected from: Pulvis Talci, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate or their mixture.
18. slow releasing tablet as claimed in claim 14 is characterized in that, described fluidizer is selected from: Pulvis Talci, silicon dioxide, corn starch or their mixture.
19. slow releasing tablet as claimed in claim 14, it is characterized in that described binding agent is selected from: polyvinylpyrrolidone, polyvinylpyrrolidone//vinyl acetate copolymer, xanthan gum, guar gum, cellulose gum, gelatin, starch pregelatinized starch or their mixture.
20. a method for preparing gabapentin stable sustained-release sheet said method comprising the steps of:
A. will contain gabapentin, one or more pharmaceutic adjuvants and randomly in one or more granules mixture and the granulation liquid of rate control polymer carry out pelletize, with component in the formation granule;
B. with component drying in the granule, sieve grain, and mix with the formation admixture with the outer rate control polymer of one or more granules, and
C. in flakes with described admixture compacting.
21. method as claimed in claim 19 is characterized in that, the outer rate control polymer of rate control polymer and one or more granules is identical or different in described randomly one or more granules.
22. method as claimed in claim 19 is characterized in that, prepares component in the granule by wet granulation.
23. method as claimed in claim 19 is characterized in that, prepares component in the granule by non-slurry pelletizing.
24. method as claimed in claim 22 is characterized in that, carries out non-slurry pelletizing by compacting or precompressed.
25. a method for preparing gabapentin stable sustained-release sheet said method comprising the steps of:
A. with gabapentin, one or more pharmaceutic adjuvants and randomly in one or more granules rate control polymer mix, to form mixture;
B. compacting or precompressed mixture are to form compacts or precompressed body;
C. sieve compacts or precompressed body to form granule;
D. the outer rate control polymer of described granule and one or more granules is mixed to form admixture; And
E. in flakes with described admixture compacting.
26. a method for the treatment of epilepsy or postherpetic neuralgia, described method comprise that the patient who needs treatment comprises the gabapentin stable sustained-release sheet of following composition:
Contain the treatment effective dose gabapentin and the interior component of granule of one or more rate control polymers randomly; With
The outer component of granule that contains one or more rate control polymers,
Wherein, when described tablet was preserved about 3 months under about 40 ℃ and about 75% relative humidity, lactams content was no more than 0.4% of gabapentin weight.
27. a tablet, described tablet is prepared by the method that comprises following steps:
A. will comprise gabapentin, one or more pharmaceutic adjuvants and randomly in one or more granules mixture and the granulation liquid of rate control polymer carry out pelletize, with component in the formation granule;
B. with component drying in the granule, sieve grain, and mix with the formation admixture with the outer rate control polymer of one or more granules, and
C. in flakes with described admixture compacting.
28. a tablet, described tablet is prepared by the method that comprises following steps:
A. with gabapentin, one or more pharmaceutic adjuvants and randomly in one or more granules rate control polymer mix to form mixture;
B. compacting or precompressed mixture are to form compacts or precompressed body;
C. sieve compacts or precompressed body to form granule;
D. the outer rate control polymer of described granule and one or more granules is mixed to form admixture; And
E. in flakes with described admixture compacting.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN83/DEL/2004 | 2004-01-19 | ||
| IN83DE2004 | 2004-01-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1921839A true CN1921839A (en) | 2007-02-28 |
Family
ID=34856866
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800059536A Pending CN1921839A (en) | 2004-01-19 | 2005-01-17 | Stable sustained-release oral dosage forms of gabapentin and process for preparation thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1921839A (en) |
| WO (1) | WO2005077332A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104352460A (en) * | 2014-10-21 | 2015-02-18 | 齐宏 | Gabapentin tablet and preparation method thereof |
| CN106333927A (en) * | 2015-07-08 | 2017-01-18 | 昆山龙灯瑞迪制药有限公司 | Modified-release nicergoline composition |
| CN110917164A (en) * | 2019-12-17 | 2020-03-27 | 南京康川济医药科技有限公司 | Milopalin besylate sustained-release tablets and preparation method thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006077492A1 (en) * | 2005-01-24 | 2006-07-27 | Ranbaxy Laboratories Limited | Sustained release oral dosage forms of gabapentin |
| US8703191B2 (en) * | 2006-07-25 | 2014-04-22 | Intelgenx Corp. | Controlled-release pharmaceutical tablets |
| US10610528B2 (en) | 2009-12-08 | 2020-04-07 | Intelgenx Corp. | Solid oral film dosage forms and methods for making same |
| US20110136815A1 (en) | 2009-12-08 | 2011-06-09 | Horst Zerbe | Solid oral film dosage forms and methods for making same |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU769038B2 (en) * | 1998-05-15 | 2004-01-15 | Warner-Lambert Company Llc | Gamma-aminobutyric acid derivatives containing, solid compositions and process for preparing the same |
| TWI312285B (en) * | 2001-10-25 | 2009-07-21 | Depomed Inc | Methods of treatment using a gastric retained gabapentin dosage |
| AU2003232398A1 (en) * | 2002-06-07 | 2003-12-22 | Ranbaxy Laboratories Limited | Sustained release oral dosage forms of gabapentin |
| WO2005046566A2 (en) * | 2003-08-04 | 2005-05-26 | Sun Pharmaceutical Industries Limited | Stable gabapentin containing composition |
| WO2005020978A1 (en) * | 2003-09-03 | 2005-03-10 | Ranbaxy Laboratories Limited | Sustained release oral tablets of gabapentin and process for their preparation |
-
2005
- 2005-01-17 WO PCT/IB2005/000093 patent/WO2005077332A2/en active Application Filing
- 2005-01-17 CN CNA2005800059536A patent/CN1921839A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104352460A (en) * | 2014-10-21 | 2015-02-18 | 齐宏 | Gabapentin tablet and preparation method thereof |
| CN106333927A (en) * | 2015-07-08 | 2017-01-18 | 昆山龙灯瑞迪制药有限公司 | Modified-release nicergoline composition |
| CN110917164A (en) * | 2019-12-17 | 2020-03-27 | 南京康川济医药科技有限公司 | Milopalin besylate sustained-release tablets and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005077332A2 (en) | 2005-08-25 |
| WO2005077332A3 (en) | 2006-07-27 |
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