WO2012147099A1 - Pharmaceutical compositions of levodopa, carbidopa and entacapone - Google Patents
Pharmaceutical compositions of levodopa, carbidopa and entacapone Download PDFInfo
- Publication number
- WO2012147099A1 WO2012147099A1 PCT/IN2012/000276 IN2012000276W WO2012147099A1 WO 2012147099 A1 WO2012147099 A1 WO 2012147099A1 IN 2012000276 W IN2012000276 W IN 2012000276W WO 2012147099 A1 WO2012147099 A1 WO 2012147099A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- entacapone
- levodopa
- carbidopa
- pharmaceutically acceptable
- hydrates
- Prior art date
Links
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 title claims abstract description 95
- 229960003337 entacapone Drugs 0.000 title claims abstract description 94
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical group OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 title claims abstract description 88
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 229960004502 levodopa Drugs 0.000 title claims abstract description 88
- 229960004205 carbidopa Drugs 0.000 title claims abstract description 75
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 39
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 109
- QTAOMKOIBXZKND-PPHPATTJSA-N carbidopa Chemical compound O.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 QTAOMKOIBXZKND-PPHPATTJSA-N 0.000 claims abstract description 87
- 150000003839 salts Chemical class 0.000 claims abstract description 70
- 150000004677 hydrates Chemical class 0.000 claims abstract description 68
- 239000008187 granular material Substances 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 18
- 239000011230 binding agent Substances 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 9
- 239000011248 coating agent Substances 0.000 claims description 6
- 238000000576 coating method Methods 0.000 claims description 6
- 230000001050 lubricating effect Effects 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000003801 milling Methods 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 239000003826 tablet Substances 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 12
- 239000008108 microcrystalline cellulose Substances 0.000 description 12
- 229940016286 microcrystalline cellulose Drugs 0.000 description 12
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 239000003381 stabilizer Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 235000015165 citric acid Nutrition 0.000 description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 6
- 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 description 6
- IVTMXOXVAHXCHI-YXLMWLKOSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;(2s)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 IVTMXOXVAHXCHI-YXLMWLKOSA-N 0.000 description 5
- 229960000913 crospovidone Drugs 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 5
- 229910002012 Aerosil® Inorganic materials 0.000 description 4
- 102000006378 Catechol O-methyltransferase Human genes 0.000 description 4
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000007888 film coating Substances 0.000 description 4
- 238000009501 film coating Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- -1 aromatic amino acid Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 235000012501 ammonium carbonate Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 235000011083 sodium citrates Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229940075564 anhydrous dibasic sodium phosphate Drugs 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 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
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 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
- 229920001429 chelating resin Polymers 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- MQRJBSHKWOFOGF-UHFFFAOYSA-L disodium;carbonate;hydrate Chemical compound O.[Na+].[Na+].[O-]C([O-])=O MQRJBSHKWOFOGF-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- GYPZFDNQZCSGND-UHFFFAOYSA-N propanoic acid;hydrate Chemical compound O.CCC(O)=O GYPZFDNQZCSGND-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940076133 sodium carbonate monohydrate Drugs 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 229940083608 sodium hydroxide Drugs 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 229940103422 stalevo Drugs 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 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
- 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
- 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
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/275—Nitriles; Isonitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
Definitions
- the present invention relates to the pharmaceutical composition
- the pharmaceutical composition comprising Levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and the process for preparing the same.
- Levodopa an aromatic amino acid
- Carbidopa an inhibitor of aromatic amino acid decarboxylation
- Carbidopa is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (-)-L-(a-hydrazino-(a-methyl-P-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is Ci 0 Hl 4 N 2 O 4 H 2 O, and its structural formula is
- Levodopa and carbidopa are most commonly used drugs in the treatment of the Parkinson's disease.
- Levodopa and carbidopa are commercially available as a combination with the trade name SINMET in the dosage form of tablets and marketed by Merck Sharp & Dohme limited in UK.
- Entacapone an inhibitor of catechol-O-methyltransferase (COMT)
- COMT catechol-O-methyltransferase
- the chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2- propenamide. Its empirical formula is C 14H15N3O5 and its structural formula is
- Entacapone is described in the European patent EP0444899 Bl as a Catechol-O- methyl- transferase (COMT) inhibitor.
- the publication further discloses that for the treatment of the Parkinson's disease, entacapone is given with levodopa, in each of its own composition or combined in one composition.
- the European patent EP1 1 12065 B 1 describes an oral compacted composition comprising a pharmaceutically effective amount of entacapone or a pharmaceutically acceptable salt thereof and a croslinked cellulose derivative.
- Entacapone is commercially available with the trade name COMTESS in the dosage form of film coated tablets and marketed by Orion Corporation in UK.
- European Patent EP 1 189608 Bl discloses an oral solid pharmaceutical composition comprising levodopa, carbidopa and entacapone or their pharmaceutically acceptable salts or hydrates thereof wherein the substantial portion of the carbidopa or pharmaceutically acceptable salt or hydrates thereof is separated from entacapone and levodopa or pharmaceutically acceptable salts or hydrates thereof in the tablet.
- the applicants of this patent further states that it is very difficult to adjust the absorption of the three different active agents from one and the same oral solid composition.
- WO2008053297 A2 describes the single oral composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts thereof, where in substantial portion of entacapone or a pharmaceutically acceptable salt or hydrate thereof is separated from the mixture of levodopa and carbidopa or pharmaceutically acceptable salts or hydrates thereof.
- the present formulation poses a challenge to the formulator to formulate the dosage form comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof as the three active ingredients are highly desirable to be released from the oral solid composition , in a manner so as to achieve the targeted ranges of the pharmacokinetic parameters which in turn would ensure optimal therapeutic activity. It is very challenging to achieve the absorption of the three active ingredients to the therapeutic concentration. It is essential to achieve the desired dissolution profile in different pH media to get the desired absorption. So there is a need to develop a stable solid pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates in order to achieve the desired release of the three active ingredients.
- the present invention relates to pharmaceutical composition
- pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and process for preparing the same.
- the Present invention relates to the pharmaceutical composition comprising two discrete portions of the mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof.
- the invention relates to a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the first discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules and the second discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the powder.
- the invention relates to a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the first discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules and the second discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules.
- the invention provides a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the ratio of mixtures levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof in the first discrete portion to the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof present in the second discrete portion is in the range of 0.01 : 1 to 1 :0.01.
- the present invention relates to a process for the preparation of the pharmaceutical composition comprising two discrete portions of mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the said process comprises a) wet granulating the first discrete portion of mixture comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof with atleast one pharmaceutically excipients with a binder solution to form granules, b) drying and optionally milling said granules, c) mixing said granules with the second discrete portion of the mixture comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and atleast one pharmaceutically excipients to form a blend, d) lubricating said blend with atleast one lubricant to form a final blend e) Compressing said final blend to form a tablet
- the present invention further relates to a process of the pharmaceutical composition comprising two discrete portions of mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the said process comprises a) wet granulating the first discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutical salts thereof or hydrates thereof with atleast one pharmaceutically acceptable excipient with a binder solution to form granules, b) wet granulating the second discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof with atleast one pharmaceutically acceptable excipient with a binder solution to form the granules, c) mixing the granules of the first discrete portion granules and second discrete portion granules of step no a and b, d) lubricating the above mixture with
- the present invention relates to pharmaceutical composition
- pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and process for preparing the same.
- discrete portion refers to a quantity of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof being separated from the other mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof.
- the present invention relates to the pharmaceutical composition comprising two discrete portions of the mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof.
- the invention relates to a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the first discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules and the second discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the powder.
- the invention relates to a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the first discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules and the second discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules.
- the invention provides a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the ratio of mixtures levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof in the first discrete portion to the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof present in the second discrete portion is in the range of 0.01 : 1 to 1 :0.01.
- the stabilizer useful in the pharmaceutical composition of the present invention is acidic substance or alkaline substance or mixtures thereof.
- the acidic substances used as the stabilizers in the stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is selected from the group consisting of citric acid, tartaric acid, malic acid and mixtures thereof. Out of these citric acid is most preferred acidic substance used as a stabilizer.
- the alkaline substances used as the stabilizers the stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is selected from the group consisting of sodium carbonate, ammonium carbonate, anhydrous sodium carbonate, sodium carbonate monohydrate, sodium tartrate, sodium potassium tartrate, sodium citrate, sodium hydroxide, calcium acetate, sodium acetate, dibasic sodium phosphate, anhydrous dibasic sodium phosphate, di ammonium hydrogen phosphate, sodium pyrophosphate and mixtures thereof.
- di basic sodium phosphate, sodium citrate, ammonium carbonate and the mixtures thereof are most preferred alkaline substances used as a stabilizer.
- the pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof preferably contains the stabilizer from 0.5% to 10% by .weight of the total solid dosage form. Most preferably, the composition contains the stabilizer from 1 to 5% by weight of the total solid dosage form (e.g. 1 to 5% of the total tablet weight).
- the stabilizer is present in the first discrete portion of the pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof.
- suitable fillers may include one or more of the microcrystalline cellulose and dibasic calcium phosphate.
- the filler used in the stable pharmaceutical composition of levodopa, carbidopa, and entacapone or pharmaceutically acceptable salts or hydrates thereof is microcrystalline cellulose.
- the microcrystalline cellulose is present in the range from about 5%. to 50% w/w of the total pharmaceutical composition. Most preferably the microcrystalline cellulose may be present in the range from about 10% to 30% w/w of the total pharmaceutical composition.
- Microcrystalline cellulose is present both in the first and second discrete portion preferably in the range in the range of 4: 1 and more preferably in the range of 3 : 1.
- Suitable binders may include one or more of povidone, starch, stearic acid, gums, hydroxy propyl methyl cellulose and the like.
- Suitable lubricants may include one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like.
- Suitable disintegrants may include one or more of crospovidone, sodium starch glycolate and Amberlite I P-88.
- the present invention relates to a process for the preparation of the pharmaceutical composition comprising two discrete portions of mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the said process comprises a) wet granulating the first discrete portion of mixture comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof with atleast one pharmaceutically excipients with a binder solution to form granules, b) drying and optionally milling said granules, c) mixing said ⁇ granules with the second discrete portion of the mixture comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and atleast one pharmaceutically excipients to form a blend, d)
- the present invention further relates to a process of the pharmaceutical composition comprising two discrete portions of mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the said process comprises a) wet granulating the first discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutical salts thereof or hydrates thereof with atleast one pharmaceutically acceptable excipient with a binder solution to form granules, b) wet granulating the second discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof with atleast one pharmaceutically acceptable excipient with a binder solution to form the granules, c) mixing the granules of the first discrete portion granules and second discrete portion granules of step no a and b, d) lubricating the above mixture with
- Table- 1 provides the composition of the tablet comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof where all the active ingredients are wet granulated at the same time and compacted into the tablets
- the pharmaceutical composition is prepared by mixing the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone with the microcrystalline cellulose, citric acid, aerosil in ' a double cone blender.
- the blended mixture is wet granulated with the binder solution comprising the hydroxypropyl methyl cellulose in isopropyl alchol and dichloro methane in the rapid mixture granulator.
- the granules are dried in the tray dryer and milled through the sieve #40.
- the granules prepared are mixed with the second discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone, microcrystalline cellulose, crospovidone in a double cone blender and lubricated with magnesium stearate.
- the lubricated blend is compressed into the tablets and further film coated with the film coating solution.
- Table-3 provides the composition of the present invention Table-3
- the pharmaceutical composition is prepared by mixing the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone with the microcrystalline cellulose, citric acid, aerosil in a double cone blender.
- the blended mixture is wet granulated with the binder solution comprising the hydroxypropyl methyl cellulose in purified water in the rapid mixture granulator.
- the granules are dried in the tray dryer and milled through the sieve #40.
- the granules prepared are mixed with the second discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone, microcrystalline cellulose, crospovidone in a double cone blender and lubricated with magnesium stearate.
- the lubricated blend is compressed into the tablets and further film coated with the film coating solution.
- the pharmaceutical composition is prepared by mixing the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone with the microcrystalline cellulose, citric acid, aerosil in a double cone blender.
- the blended mixture is wet granulated with the binder solution comprising the hydroxypropyl methyl cellulose in isopropyl alchol and dichloro methane in the rapid mixture granulator to form the granules of the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone.
- the granules of the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone are dried in the tray dryer and milled through the sieve #40.
- the second discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone with the microcrystalline cellulose and crospovidone is wet granulated with the binder solution comprising the hydroxy propyl methyl cellulose in isopropyl alchol and dichloro methane in the rapid mixture granulator to form the granules of the second discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone.
- the granules of the second discrete portion of the mixture levodopa, carbidopa monohydrate and levodopa are dried in the tray dryer and milled through sieve #60.
- the granules comprising the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone and the granules comprising the second discrete portion of the mixture of the mixture of levodopa, carbidopa monohydrate and entacapone are mixed in the double cone blender and lubricated with the magnesium stearate to form the lubricated blend.
- the above lubricated blend is compressed into the tablets and further film coated with the film coating solution.
- CD Carbidopa
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Abstract
The present invention relates to the pharmaceutical composition comprising two discrete portions of the mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and the process for preparing the same.
Description
PHARMACEUTICAL COMPOSITIONS OF LEVODOPA, CARBIDOPA
AND ENTACAPONE
FIELD OF INVENTION
The present invention relates to the pharmaceutical composition comprising Levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and the process for preparing the same.
BACK GROUND OF THE INVENTION
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-)-L-a- amino- (3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C9H1 1NO4, and its structural formula is
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (-)-L-(a-hydrazino-(a-methyl-P-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is Ci0Hl4N2O4 H2O, and its structural formula is
Levodopa and carbidopa are most commonly used drugs in the treatment of the Parkinson's disease. Levodopa and carbidopa are commercially available as a combination with the trade name SINMET in the dosage form of tablets and marketed by Merck Sharp & Dohme limited in UK.
Entacapone, an inhibitor of catechol-O-methyltransferase (COMT), is a nitro- catechol-structured compound with a molecular weight of 305.3. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2- propenamide. Its empirical formula is C 14H15N3O5 and its structural formula is
Entacapone is described in the European patent EP0444899 Bl as a Catechol-O- methyl- transferase (COMT) inhibitor. The publication further discloses that for the treatment of the Parkinson's disease, entacapone is given with levodopa, in each of its own composition or combined in one composition. The European patent EP1 1 12065 B 1 describes an oral compacted composition comprising a pharmaceutically effective amount of entacapone or a pharmaceutically acceptable salt thereof and a croslinked cellulose derivative. Entacapone is commercially available with the trade name COMTESS in the dosage form of film coated tablets and marketed by Orion Corporation in UK.
In the treatment regimen of Parkinsonism, medicament needs to be taken several times a day to the keep the patient without symptoms. In the regimen where two separate tablets i.e. one containing levodopa and carbidopa, and the other containing
entacapone, is problematic for many patients, such as those with tremor and old age. The patient compliance has been improved by combining these three active ingredients i.e. levodopa, carbidopa and entacapone. Entacapone in combination with carbidopa and levodopa is commercially available with the trade name STALEVO in the dosage form of film coated tablets and marketed by Orion Corporation in UK.
European Patent EP 1 189608 Bl discloses an oral solid pharmaceutical composition comprising levodopa, carbidopa and entacapone or their pharmaceutically acceptable salts or hydrates thereof wherein the substantial portion of the carbidopa or pharmaceutically acceptable salt or hydrates thereof is separated from entacapone and levodopa or pharmaceutically acceptable salts or hydrates thereof in the tablet. The applicants of this patent further states that it is very difficult to adjust the absorption of the three different active agents from one and the same oral solid composition. It states that the applicants have found a particular interesting way to increase the bioavailability of carbidopa from an oral solid composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is to add carbidopa separately for instance by granulating first levodopa and entacapone together and then adding carbidopa to these granules separately. WO2008053297 A2 describes the single oral composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts thereof, where in substantial portion of entacapone or a pharmaceutically acceptable salt or hydrate thereof is separated from the mixture of levodopa and carbidopa or pharmaceutically acceptable salts or hydrates thereof.
The present formulation poses a challenge to the formulator to formulate the dosage form comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof as the three active ingredients are highly desirable to be
released from the oral solid composition , in a manner so as to achieve the targeted ranges of the pharmacokinetic parameters which in turn would ensure optimal therapeutic activity. It is very challenging to achieve the absorption of the three active ingredients to the therapeutic concentration. It is essential to achieve the desired dissolution profile in different pH media to get the desired absorption. So there is a need to develop a stable solid pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates in order to achieve the desired release of the three active ingredients. SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and process for preparing the same.
The Present invention relates to the pharmaceutical composition comprising two discrete portions of the mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof. In further embodiment the invention relates to a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the first discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules and the second discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the powder.
In further embodiment the invention relates to a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the first discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules and the second discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules.
In further embodiment the invention provides a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the ratio of mixtures levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof in the first discrete portion to the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof present in the second discrete portion is in the range of 0.01 : 1 to 1 :0.01.
The present invention relates to a process for the preparation of the pharmaceutical composition comprising two discrete portions of mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the said process comprises a) wet granulating the first discrete portion of mixture comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof with atleast one pharmaceutically excipients with a binder solution to form granules, b) drying and optionally milling said granules, c) mixing said granules with the second discrete portion of the mixture comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and atleast one pharmaceutically excipients to form a blend, d) lubricating said blend with atleast one lubricant to form a final blend e) Compressing said final blend to form a tablet f) and if desired coating the tablet obtained in step e.
The present invention further relates to a process of the pharmaceutical composition comprising two discrete portions of mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the said process comprises a) wet granulating the first discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutical salts thereof or hydrates thereof with atleast one pharmaceutically acceptable excipient with a binder solution to form granules, b) wet granulating the second discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof with atleast one pharmaceutically acceptable excipient with a binder solution to form the granules, c) mixing the granules of the first discrete portion granules and second discrete portion granules of step no a and b, d) lubricating the above mixture with the mixture, e) compressing the said lubricated blend to form the tablet and f) if desired coating the tablet obtained in step e. DETAILED DESCRIPTION
The present invention relates to pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and process for preparing the same.
The term "discrete portion" refers to a quantity of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof being separated from the other mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof.
The present invention relates to the pharmaceutical composition comprising two discrete portions of the mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof.
In further embodiment the invention relates to a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the first discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules and the second discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the powder. In further embodiment the invention relates to a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the first discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules and the second discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of the granules.
In further embodiment the invention provides a pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the ratio of mixtures levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof in the first discrete portion to the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof present in the second discrete portion is in the range of 0.01 : 1 to 1 :0.01.
The stabilizer useful in the pharmaceutical composition of the present invention is acidic substance or alkaline substance or mixtures thereof.
The acidic substances used as the stabilizers in the stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is selected from the group consisting of citric acid, tartaric acid, malic acid and mixtures thereof. Out of these citric acid is most preferred acidic substance used as a stabilizer.
The alkaline substances used as the stabilizers the stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is selected from the group consisting of sodium carbonate, ammonium carbonate, anhydrous sodium carbonate, sodium carbonate monohydrate, sodium tartrate, sodium potassium tartrate, sodium citrate, sodium hydroxide, calcium acetate, sodium acetate, dibasic sodium phosphate, anhydrous dibasic sodium phosphate, di ammonium hydrogen phosphate, sodium pyrophosphate and mixtures thereof. Out of these alkaline substances di basic sodium phosphate, sodium citrate, ammonium carbonate and the mixtures thereof are most preferred alkaline substances used as a stabilizer.
The pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof preferably contains the stabilizer from 0.5% to 10% by .weight of the total solid dosage form. Most preferably, the composition contains the stabilizer from 1 to 5% by weight of the total solid dosage form (e.g. 1 to 5% of the total tablet weight).
The stabilizer is present in the first discrete portion of the pharmaceutical composition of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof.
Suitable fillers may include one or more of the microcrystalline cellulose and dibasic calcium phosphate. The filler used in the stable pharmaceutical composition of levodopa, carbidopa, and entacapone or pharmaceutically acceptable salts or hydrates thereof is microcrystalline cellulose. The microcrystalline cellulose is present in the range from about 5%. to 50% w/w of the total pharmaceutical composition. Most preferably the microcrystalline cellulose may be present in the range from about 10% to 30% w/w of the total pharmaceutical composition. Microcrystalline cellulose is present both in the first and second discrete portion preferably in the range in the range of 4: 1 and more preferably in the range of 3 : 1.
Suitable binders may include one or more of povidone, starch, stearic acid, gums, hydroxy propyl methyl cellulose and the like.
Suitable lubricants may include one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like.
Suitable disintegrants may include one or more of crospovidone, sodium starch glycolate and Amberlite I P-88. The present invention relates to a process for the preparation of the pharmaceutical composition comprising two discrete portions of mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the said process comprises a) wet granulating the first discrete portion of mixture comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof with atleast one pharmaceutically excipients with a binder solution to form granules, b) drying and optionally milling said granules, c) mixing said ^granules with the second discrete portion of the mixture comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and atleast one
pharmaceutically excipients to form a blend, d) lubricating said blend with atleast one lubricant to form a final blend e) Compressing said final blend to form a tablet f) and if desired coating the tablet obtained in step e.
The present invention further relates to a process of the pharmaceutical composition comprising two discrete portions of mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the said process comprises a) wet granulating the first discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutical salts thereof or hydrates thereof with atleast one pharmaceutically acceptable excipient with a binder solution to form granules, b) wet granulating the second discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof with atleast one pharmaceutically acceptable excipient with a binder solution to form the granules, c) mixing the granules of the first discrete portion granules and second discrete portion granules of step no a and b, d) lubricating the above mixture with the mixture, e) compressing the said lubricated blend to form the tablet and f) if desired coating the tablet obtained in step e.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and don't limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example-1
Table- 1 provides the composition of the tablet comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof where all the active ingredients are wet granulated at the same time and compacted into the tablets
Table-1
Procedure: Levodopa, carbidopa monohydrate, entacapone, crospovidone, microcrystalline cellulose, Aerosil and citric acid are mixed in the double cone blender. The above blended material is wet granulated with the binder solution
comprising the hydroxypropyl methyl cellulose in the dichloromethane and isopropyl alcohol in the rapid mixture granulator. The above granules are dried in the tray dryer and milled through the sieve no #40. The above milled granules are lubricated with the magnesium stearate in the double cone blender. The lubricated blend is compressed into tablets and further film coated with the film coating solution.
Example-2
Tabled provides the composition of the present invention
Table-2
Procedure: The pharmaceutical composition is prepared by mixing the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone with the microcrystalline cellulose, citric acid, aerosil in' a double cone blender. The blended mixture is wet granulated with the binder solution comprising the hydroxypropyl methyl cellulose in isopropyl alchol and dichloro methane in the rapid mixture granulator. The granules are dried in the tray dryer and milled through the sieve #40. The granules prepared are mixed with the second discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone, microcrystalline cellulose, crospovidone in a double cone blender and lubricated with magnesium stearate. The lubricated blend is compressed into the tablets and further film coated with the film coating solution.
Example-3
Table-3 provides the composition of the present invention Table-3
Procedure: The pharmaceutical composition is prepared by mixing the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone with the microcrystalline cellulose, citric acid, aerosil in a double cone blender. The blended mixture is wet granulated with the binder solution comprising the hydroxypropyl methyl cellulose in purified water in the rapid mixture granulator. The granules are
dried in the tray dryer and milled through the sieve #40. The granules prepared are mixed with the second discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone, microcrystalline cellulose, crospovidone in a double cone blender and lubricated with magnesium stearate. The lubricated blend is compressed into the tablets and further film coated with the film coating solution.
ExampIe-4 Table-4 provides the composition of the present invention
Table-4
Procedure: The pharmaceutical composition is prepared by mixing the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone with the microcrystalline cellulose, citric acid, aerosil in a double cone blender. The blended mixture is wet granulated with the binder solution comprising the hydroxypropyl methyl cellulose in isopropyl alchol and dichloro methane in the rapid mixture granulator to form the granules of the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone. The granules of the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone are dried in the tray dryer and milled through the sieve #40. The second discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone with the microcrystalline cellulose and crospovidone is wet granulated with the binder solution comprising the hydroxy propyl methyl cellulose in isopropyl alchol and dichloro methane in the rapid mixture granulator to form the granules of the second discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone. The granules of the second discrete portion of the mixture levodopa, carbidopa monohydrate and levodopa are dried in the tray dryer and milled through sieve #60. The granules comprising the first discrete portion of the mixture of levodopa, carbidopa monohydrate and entacapone and the granules comprising the second discrete portion of the mixture of the mixture of levodopa, carbidopa monohydrate and entacapone are mixed in the double cone blender and lubricated with the magnesium stearate to form the lubricated blend. The above lubricated blend is compressed into the tablets and further film coated with the film coating solution.
Example-5:
The Invitro release profile of the example- 1 in comparison with the example-2 was obtained with the following parameters.
Media: O. IN Hcl, pH 5.5 phosphate buffer
Volume: 750ml for O.IN Hcl, 900 ml for pH 5.5 phosphate buffer
Apparatus: USP I (Basket)
Speed: 50 rpm for 0.1N Hcl, 125 rpm for pH 5.5 Phosphate buffer
Table-5
LD: Levodopa
CD: Carbidopa
ENT: Entacapone
The results demonstrate that the release of the three active ingredients from the formulation is more in the example-2 compared with the example-1.
Claims
1. A pharmaceutical composition comprising two discrete portions of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts, or hydrates thereof.
2. A pharmaceutical composition of claim 1 wherein the first discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of granules and the second discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of powder
3; A pharmaceutical composition of claim 1 wherein the first discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of granules and the second discrete • portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the form of granules.
4. A pharmaceutical composition of claim 1 wherein the ratio of first discrete portion mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and the second discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the range of 0.01 : 1 to 1 :0.01.
5. A process for the preparation of the pharmaceutical composition comprising two discrete portions of mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the said process comprises a) wet granulating the first discrete portion of mixture comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof with atleast one pharmaceutically excipients with a binder solution to form granules, b) drying and optionally milling said granules, c) mixing said granules with the second discrete portion of the mixture comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and atleast one pharmaceutically excipients to form a blend, d) lubricating said blend with atleast one lubricant to form a final blend e) Compressing said final blend to form a tablet f) and if desired coating the tablet obtained in step e.
6. A process for preparation of the pharmaceutical composition of claim 5 wherein the ratio of first discrete portion mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and the second discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the range of 0.01 : 1 to 1 :0.01.
7. A process for the pharmaceutical composition comprising two discrete portions of mixtures of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof wherein the said process comprises a) wet granulating the first discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutical salts thereof or hydrates thereof with atleast one pharmaceutically acceptable excipient with a binder solution to form granules, b) wet granulating the second discrete portion of the mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof with atleast one pharmaceutically acceptable excipient with a binder solution to form the granules, c) mixing the granules of the first discrete portion granules and second discrete portion granules of step no a and b, d) lubricating the above mixture with the mixture, e) compressing the said lubricated blend to form the tablet and f) if desired coating the tablet obtained in ste e.
8. A process for preparation of the pharmaceutical composition of claim .7 wherein the ratio of first discrete portion mixture of levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and the second discrete portion of the mixture of the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is in the range of 0.01 : 1 to 1 :0.01.
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IN3559CH2010 | 2011-04-25 |
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PCT/IN2012/000276 WO2012147099A1 (en) | 2011-04-25 | 2012-04-17 | Pharmaceutical compositions of levodopa, carbidopa and entacapone |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016036308A1 (en) | 2014-09-04 | 2016-03-10 | Lobsor Pharmaceuticals Aktiebolag | Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a comt inhibitor and method of administration thereof |
WO2019182506A1 (en) | 2018-03-23 | 2019-09-26 | Lobsor Pharmaceuticals Aktiebolag | Continuous administration of pharmaceutical composition for treatment of neurodegenerative disorders |
US10555922B2 (en) | 2015-09-04 | 2020-02-11 | Lobsor Pharmaceuticals Aktiebolag | Method of treating a dopamine related disorder in a subject by administering levodopa, in combination with a dopamine decarboxylase inhibitor and a catechol-o-methyltransferase inhibitor |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0444899B1 (en) | 1990-02-27 | 1997-02-05 | Orion-Yhtymà Oy | Catechol derivatives, their physiologically acceptable salts, esters and their use in the treatment of tissue damage induced by lipid peroxidation |
WO2001001984A1 (en) * | 1999-06-30 | 2001-01-11 | Orion Corporation | Levodopa / carbidopa / entacapone pharmaceutical preparation |
EP1112065A1 (en) | 1998-09-14 | 2001-07-04 | Orion Corporation | Pharmaceutical composition comprising entacapone or nitecapone as well as a cross-linked cellulose deivative |
US20060222703A1 (en) * | 2005-04-01 | 2006-10-05 | Iprbox Oy | Pharmaceutical composition and preparation method thereof |
WO2008053297A2 (en) | 2006-10-30 | 2008-05-08 | Wockhardt Research Centre | Pharmaceutical compositions comprising entacapone, levodopa, and carbidopa |
US20080118556A1 (en) * | 1998-11-02 | 2008-05-22 | Elan Corporation, Plc | Modified Release of Compositions Containing a Combination of Carbidopa, Levodopa and Entacapone |
WO2010020969A1 (en) * | 2008-08-22 | 2010-02-25 | Wockhardt Research Centre | An extended release pharmaceutical composition of entacapone or salts thereof |
WO2011107653A2 (en) * | 2010-03-04 | 2011-09-09 | Orion Corporation | Method for treating parkinson's disease |
-
2012
- 2012-04-17 WO PCT/IN2012/000276 patent/WO2012147099A1/en active Application Filing
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0444899B1 (en) | 1990-02-27 | 1997-02-05 | Orion-Yhtymà Oy | Catechol derivatives, their physiologically acceptable salts, esters and their use in the treatment of tissue damage induced by lipid peroxidation |
EP1112065A1 (en) | 1998-09-14 | 2001-07-04 | Orion Corporation | Pharmaceutical composition comprising entacapone or nitecapone as well as a cross-linked cellulose deivative |
US20080118556A1 (en) * | 1998-11-02 | 2008-05-22 | Elan Corporation, Plc | Modified Release of Compositions Containing a Combination of Carbidopa, Levodopa and Entacapone |
WO2001001984A1 (en) * | 1999-06-30 | 2001-01-11 | Orion Corporation | Levodopa / carbidopa / entacapone pharmaceutical preparation |
EP1189608B1 (en) | 1999-06-30 | 2003-07-23 | Orion Corporation | Levodopa/carbidopa/entacapone pharmaceutical preparation |
US20060222703A1 (en) * | 2005-04-01 | 2006-10-05 | Iprbox Oy | Pharmaceutical composition and preparation method thereof |
WO2008053297A2 (en) | 2006-10-30 | 2008-05-08 | Wockhardt Research Centre | Pharmaceutical compositions comprising entacapone, levodopa, and carbidopa |
WO2010020969A1 (en) * | 2008-08-22 | 2010-02-25 | Wockhardt Research Centre | An extended release pharmaceutical composition of entacapone or salts thereof |
WO2011107653A2 (en) * | 2010-03-04 | 2011-09-09 | Orion Corporation | Method for treating parkinson's disease |
Non-Patent Citations (1)
Title |
---|
ANONYMOUS: "Ac-Di-Sol TM efficacy in wet granulation", FMC BIOPOLYMER. THE SCIENCE OF FORMULATION., 1 January 2005 (2005-01-01), pages 1 - 3, XP055040327, Retrieved from the Internet <URL:http://www.fmcbiopolymer.com/Portals/bio/Content/Docs/Neutraceuticals/Ac-Di-Sol Efficacy.pdf> [retrieved on 20121008] * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016036308A1 (en) | 2014-09-04 | 2016-03-10 | Lobsor Pharmaceuticals Aktiebolag | Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a comt inhibitor and method of administration thereof |
US10071069B2 (en) | 2014-09-04 | 2018-09-11 | Lobsor Pharmaceuticals Aktiebolag | Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor and method of administration thereof |
US10786472B2 (en) | 2014-09-04 | 2020-09-29 | Lobsor Pharmaceuticals Aktiebolag | Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor and method of administration thereof |
EP3782617A1 (en) | 2014-09-04 | 2021-02-24 | LobSor Pharmaceuticals Aktiebolag | Pharmaceutical gel compositions comprising levodopa, carbidopa and entacapon |
US11413262B2 (en) | 2014-09-04 | 2022-08-16 | Intrance International Ab | Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor and method of administration thereof |
EP4356907A1 (en) | 2014-09-04 | 2024-04-24 | LobSor Pharmaceuticals Aktiebolag | Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a comtinhibitor and method of administration thereof |
US10555922B2 (en) | 2015-09-04 | 2020-02-11 | Lobsor Pharmaceuticals Aktiebolag | Method of treating a dopamine related disorder in a subject by administering levodopa, in combination with a dopamine decarboxylase inhibitor and a catechol-o-methyltransferase inhibitor |
WO2019182506A1 (en) | 2018-03-23 | 2019-09-26 | Lobsor Pharmaceuticals Aktiebolag | Continuous administration of pharmaceutical composition for treatment of neurodegenerative disorders |
US11547689B2 (en) | 2018-03-23 | 2023-01-10 | Intrance International Ab | Continuous administration of pharmaceutical composition for treatment of neurodegenerative disorders |
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