CN113616621A - Levodopa and carbidopa controlled release preparation and preparation method thereof - Google Patents
Levodopa and carbidopa controlled release preparation and preparation method thereof Download PDFInfo
- Publication number
- CN113616621A CN113616621A CN202110956705.0A CN202110956705A CN113616621A CN 113616621 A CN113616621 A CN 113616621A CN 202110956705 A CN202110956705 A CN 202110956705A CN 113616621 A CN113616621 A CN 113616621A
- Authority
- CN
- China
- Prior art keywords
- controlled release
- oral solid
- solid formulation
- levodopa
- carbidopa
- 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.)
- Pending
Links
- 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 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title description 9
- 239000003405 delayed action preparation Substances 0.000 title description 2
- 238000013270 controlled release Methods 0.000 claims abstract description 166
- 239000011248 coating agent Substances 0.000 claims abstract description 75
- 238000000576 coating method Methods 0.000 claims abstract description 75
- 239000000203 mixture Substances 0.000 claims abstract description 66
- 238000009472 formulation Methods 0.000 claims abstract description 43
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims abstract description 36
- 239000007787 solid Substances 0.000 claims abstract description 35
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 32
- 229960004502 levodopa Drugs 0.000 claims abstract description 28
- 229960004205 carbidopa Drugs 0.000 claims abstract description 27
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims abstract description 24
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 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 claims abstract description 23
- 239000008185 minitablet Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000011159 matrix material Substances 0.000 claims description 69
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 56
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 52
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 52
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 51
- 229960003943 hypromellose Drugs 0.000 claims description 46
- 230000003111 delayed effect Effects 0.000 claims description 44
- 239000002775 capsule Substances 0.000 claims description 33
- 229920000642 polymer Polymers 0.000 claims description 30
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 21
- 239000008187 granular material Substances 0.000 claims description 21
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 21
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 21
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 21
- 239000006185 dispersion Substances 0.000 claims description 19
- 239000003826 tablet Substances 0.000 claims description 19
- 229920001525 carrageenan Polymers 0.000 claims description 18
- 239000000679 carrageenan Substances 0.000 claims description 18
- 235000010418 carrageenan Nutrition 0.000 claims description 18
- 229940113118 carrageenan Drugs 0.000 claims description 18
- 229920001577 copolymer Polymers 0.000 claims description 18
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 18
- 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 17
- 229930195725 Mannitol Natural products 0.000 claims description 17
- 239000000594 mannitol Substances 0.000 claims description 17
- 235000010355 mannitol Nutrition 0.000 claims description 17
- 229920003081 Povidone K 30 Polymers 0.000 claims description 14
- 239000012752 auxiliary agent Substances 0.000 claims description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 13
- 239000000314 lubricant Substances 0.000 claims description 13
- 239000001069 triethyl citrate Substances 0.000 claims description 13
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 13
- 235000013769 triethyl citrate Nutrition 0.000 claims description 13
- 239000003085 diluting agent Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 239000000454 talc Substances 0.000 claims description 10
- 235000012222 talc Nutrition 0.000 claims description 10
- 229910052623 talc Inorganic materials 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 230000032683 aging Effects 0.000 claims description 8
- 239000001856 Ethyl cellulose Substances 0.000 claims description 7
- 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 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims description 7
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 7
- 229920001249 ethyl cellulose Polymers 0.000 claims description 7
- 229960004667 ethyl cellulose Drugs 0.000 claims description 7
- 229920000609 methyl cellulose Polymers 0.000 claims description 7
- 239000001923 methylcellulose Substances 0.000 claims description 7
- 229960002900 methylcellulose Drugs 0.000 claims description 7
- 235000010981 methylcellulose Nutrition 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 229940069328 povidone Drugs 0.000 claims description 7
- 238000007873 sieving Methods 0.000 claims description 7
- 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 6
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- 239000005434 MCC/mannitol excipient Substances 0.000 claims description 5
- 229920002125 Sokalan® Polymers 0.000 claims description 5
- 229960001631 carbomer Drugs 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 229960001855 mannitol Drugs 0.000 claims description 5
- 229920002261 Corn starch Polymers 0.000 claims description 4
- 239000008120 corn starch Substances 0.000 claims description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- 229960001021 lactose monohydrate Drugs 0.000 claims description 3
- 238000005550 wet granulation Methods 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims 1
- 239000012730 sustained-release form Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 description 27
- 229960004106 citric acid Drugs 0.000 description 12
- 235000015165 citric acid Nutrition 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 239000008186 active pharmaceutical agent Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000008363 phosphate buffer Substances 0.000 description 6
- 238000005507 spraying Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 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 4
- 229960004543 anhydrous citric acid Drugs 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 235000002906 tartaric acid Nutrition 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 238000011978 dissolution method Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 230000003139 buffering effect Effects 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 229940013066 rytary Drugs 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 206010030312 On and off phenomenon Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Images
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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- 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
- 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
-
- 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
-
- 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
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a controlled release oral solid formulation comprising levodopa, carbidopa and a carboxylic acid, comprising a multi-unit mini tablet comprising a controlled release portion and an immediate release coating, and a method for preparing the same. Wherein the controlled release portion comprises a carboxylic acid and a first portion of levodopa and carbidopa and the immediate release coating comprises a second portion of levodopa and carbidopa.
Description
Technical Field
The present invention relates to the field of pharmaceutical manufacturing, and more particularly to a controlled release oral solid formulation comprising a multi-unit mini-tablet of carbidopa and levodopa, said mini-tablet comprising a controlled release portion and an immediate release coating. The invention also relates to a preparation method of the controlled release oral solid preparation containing the multi-unit micro-tablet.
Background
Levodopa and carbidopa are among the drugs for the treatment of parkinsonism, such as parkinson's disease and related disorders.
U.S. patent nos. 7094427, 8377474, 8454998, 8557283, 9089607, 9089608, 9463246, 9533046 disclose a combination of Carbidopa (CD) and Levodopa (LD) that includes immediate release and controlled release components, and the use of carboxylic acids (tartaric acid) other than carbidopa and levodopa to treat dopamine depleted conditions in the brain tissue of a patient. This would provide a method of reducing motor fluctuations in a parkinson's disease patient.
Currently, formulations containing Carbidopa (CD), Levodopa (LD) and tartaric acid are commercially available, for exampleAnd (4) making capsules. The formulation contains 3 different ingredients, mixed and filled in capsules. The 3 components are (a) a controlled release component comprising levodopa, carbidopa, and one or more rate controlling excipients; (b) a carboxylic acid component comprising tartaric acid and one or more rate controlling polymers; and (c) an immediate release component comprising levodopa and carbidopa, wherein the carboxylic acid component of (b) is different from the carbidopa and direct release components of levodopa and the controlled release components of carbidopa and levodopa; the carboxylic acid component is a separate part and is coated with an enteric polymer; the immediate release component (c) and the carboxylic acid component (b) comprise pellets or granules.
The preparation process of the capsule is complex, and enteric-coated pellets containing carbidopa and levodopa and enteric-coated pellets containing tartaric acid are required to be prepared and encapsulated in a gelatin capsule.
At present, a substitute preparation with simple and controllable preparation process and low cost is urgently needed.
Disclosure of Invention
The present invention provides a novel process for the preparation of a controlled release pharmaceutical composition of Carbidopa (CD) and Levodopa (LD) using a Carboxylic Acid (CA), wherein the carboxylic acid is not a controlled release component or a separate component other than an immediate release component, but is contained in a controlled release matrix. The immediate release component, the controlled release component and the carboxylic acid component are composed of a single component in a multi-unit mini-tablet that is filled in a hard capsule shell.
A first aspect of the present invention provides a controlled release oral solid formulation comprising levodopa and carbidopa, said controlled release oral solid formulation comprising a multi-unit mini-tablet, said mini-tablet comprising from the inside to the outside a controlled release portion comprising a carboxylic acid and a first portion of levodopa and carbidopa, and an immediate release coating comprising a second portion of levodopa and carbidopa.
In some preferred embodiments, the immediate release coating is coated over the controlled release portion.
In some preferred embodiments, the controlled release portion comprises a controlled release matrix and a delayed release coating, and the carboxylic acid is located within the controlled release matrix.
In some preferred embodiments, the controlled release matrix comprises levodopa, carbidopa, a carboxylic acid, a first pharmaceutically acceptable auxiliary agent, and a controlled release polymer; preferably, the first pharmaceutically acceptable auxiliary agent is selected from microcrystalline cellulose (e.g. microcrystalline cellulose PH101, PH102, PH103, PH105, PH302), corn starch, mannitol and mixtures thereof; more preferably, the first pharmaceutically acceptable auxiliary agent is microcrystalline cellulose PH101 and mannitol.
In some preferred embodiments, the controlled release matrix comprises ethylcellulose, hypromellose, methylcellulose, povidone, and mixtures thereof; preferably, the controlled release matrix comprises hypromellose.
In some preferred embodiments, the delayed release coating comprises a methacrylic acid-ethyl acrylate copolymerAnd one or more of an aqueous dispersion thereof, triethyl citrate, talc and diethyl phthalate; preferably, the methacrylic acid-ethyl acrylate copolymer and the aqueous dispersion thereof areL100-55、s100、FS30D orL30D-55; more preferably, the delayed release coating is composed of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, triethyl citrate and talc.
In some preferred embodiments, the immediate release coating comprises levodopa, carbidopa, and a second pharmaceutically acceptable auxiliary agent; preferably, the second pharmaceutically acceptable auxiliary agent is mannitol, croscarmellose sodium, povidone K30, magnesium stearate, corn starch, talc, lactose monohydrate, pregelatinized starch and mixtures thereof; more preferably, the immediate release coating is comprised of levodopa, carbidopa, and povidone K30.
In some preferred embodiments, the carboxylic acid is citric acid. More preferably, the controlled release oral formulation comprises 70mg to 120mg of citric acid per unit.
In some preferred embodiments, the controlled release oral solid formulation is a capsule.
In some preferred embodiments, the carboxylic acid and 75% of the levodopa and carbidopa are contained in the controlled release portion, and 25% of the levodopa and carbidopa are coated on the controlled release portion as an immediate release coating.
In some preferred embodiments, the controlled release matrix is prepared with a controlled release polymer; preferably, the controlled release polymer is hypromellose, carrageenan, ethylcellulose, methylcellulose, or carbomer; more preferably, the controlled release polymer is hypromellose K4MCr, hypromellose K100M, or carrageenan Viscarin 109; more preferably, the weight of the hypromellose K4M Cr is 0-16% of the weight of the controlled release matrix, or the weight of the hypromellose K100M is 0-16% of the weight of the controlled release matrix, or the weight of the carrageenan Viscarin109 is 0-3% of the weight of the controlled release matrix; most preferably, the controlled release polymer is hypromellose K4M Cr, 3-7% by weight of the controlled release matrix.
In some preferred embodiments, the controlled release matrix further comprises a diluent, a lubricant, and a binder; preferably, the diluent is microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol, the lubricant is magnesium stearate, and the binder is povidone.
In some preferred embodiments, the size of the controlled release matrix is in the range between 2.0mm and 5.5 mm.
A second aspect of the present invention provides a method for producing the above controlled release oral solid formulation, comprising:
a. sieving and mixing the carboxylic acid, diluent, and first portion of levodopa and carbidopa;
b. adding a binder solution, and performing wet granulation, preferably by using a high-shear wet granulator;
c. drying the obtained granules, and grading;
d. sieving the controlled release polymer and lubricant, mixing with the dried and granulated granules, and tabletting to obtain controlled release matrix;
e. preparing delayed release coating liquid, coating the delayed release coating on the controlled release matrix, and aging;
f. preparing an immediate release coating solution, and coating on the delayed release coating tablet core; and
g. the coated tablet cores are loaded into capsule shells.
In some preferred embodiments, the controlled release matrix comprises 75% levodopa and carbidopa, and the immediate release coating comprises 25% levodopa and carbidopa.
In some preferred embodiments, wherein in step a, the diluent is microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol.
In some preferred embodiments, wherein in step a, the sieving is performed with a 20 mesh screen.
In some preferred embodiments, wherein in step b, the binder solution is povidone K30 solution.
In some preferred embodiments, wherein in step c, size stabilization is performed using a 0.8mm screen.
In some preferred embodiments, wherein the lubricant is magnesium stearate.
In some preferred embodiments, wherein the controlled release polymer is hypromellose, carrageenan, ethylcellulose, methylcellulose, or carbomer; preferably, the controlled release polymer is hypromellose K4M Cr, hypromellose K100M, or carrageenan Viscarin 109; more preferably, the weight of the hypromellose K4M Cr is 0-16% of the weight of the controlled release matrix, or the weight of the hypromellose K100M is 0-16% of the weight of the controlled release matrix, or the weight of the carrageenan Viscarin109 is 0-3% of the weight of the controlled release matrix; most preferably, the controlled release polymer is hypromellose K4M Cr, which is 3-7% by weight of the controlled release matrix.
In some preferred embodiments, wherein in step d, the controlled release polymer has a mesh size of 20 mesh.
In some preferred embodiments, wherein in step d, the lubricant has a mesh size of 60 mesh.
In some preferred embodiments, wherein in step d, the tablet is compressed with a punch having a size between 2.0mm and 5.5 mm.
In some preferred embodiments, wherein in step e, the delayed release coating solution comprises methacrylic acid-ethyl acrylate copolymer and aqueous dispersion thereof, triethyl citrate, talc, and orthophthalic acidOne or more of diethyl dicarboxylate, methacrylic acid-ethyl acrylate copolymer and aqueous dispersions thereof, e.g.L100-55、s100、FS30D orL30D-55; preferably, the delayed release coating is made of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersionL30D-55, triethyl citrate and talcum powder.
In some preferred embodiments, wherein in step e, the concentration of the methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion in the delayed release coating is 8-15% w/w.
In some preferred embodiments, wherein the aging temperature in step e is 40 ℃.
A third aspect of the present invention provides a controlled release oral solid formulation obtained according to the above production method.
Drawings
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the example serve to explain the principles of the invention and not to limit the invention.
FIG. 1 shows the dissolution contrast of levodopa for the home-made product 239-033 prepared in example 3 and the reference formulation RYTARY (20002203A).
FIG. 2 shows the carbidopa dissolution comparison of the home-made product 239-033 prepared in example 3 and the reference formulation RYTARY (20002203A).
Detailed Description
The invention will now be further described by way of the following examples, which are not intended to limit the scope of the invention. It will be appreciated by those skilled in the art that equivalent substitutions for the features of the invention, or corresponding modifications, may be made without departing from the scope of the invention.
In a first aspect of the present invention, there is provided a multi-unit mini-tablet controlled release oral solid formulation, wherein the controlled release oral solid formulation is a capsule, the mini-tablets have a controlled release matrix, a delayed release coating and an immediate release coating in this order from the inside out, and a carboxylic acid is located within the controlled release matrix. Wherein carboxylic acid and 75% of levodopa and carbidopa are contained in a controlled release matrix, and 25% of levodopa and carbidopa are coated as an immediate release coating on the micro-tablets, filled in capsule shells. In some embodiments, the controlled release matrix comprises a carboxylic acid, levodopa, carbidopa, a first pharmaceutically acceptable auxiliary agent, and a controlled release coating.
In some embodiments, the first pharmaceutically acceptable auxiliary agent comprises a diluent, a lubricant, and a binder. Preferably, the diluent is microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol. Preferably, the lubricant is magnesium stearate. Preferably, the binder is povidone.
In some embodiments, the delayed release coating comprises one or more of methacrylic acid-ethyl acrylate copolymer and aqueous dispersions thereof, triethyl citrate, talc, and diethyl phthalate. Methacrylic acid-ethyl acrylate copolymers and aqueous dispersions thereof such as, but not limited to L100-55、s100、FS30D andL30D-55. In a preferred embodiment, the delayed release coating is formed from methacrylic acid-ethyl acrylate copolymers and aqueous dispersions thereofL30D-55, triethyl citrate and talcum powder.
In some embodiments, the immediate release coating comprises levodopa, carbidopa, and a second pharmaceutically acceptable auxiliary agent. In some embodiments, the second pharmaceutically acceptable auxiliary agent is mannitol, croscarmellose sodium, povidone K30, magnesium stearate, corn starch, talc, lactose monohydrate, pregelatinized starch, and mixtures thereof. In a preferred embodiment, the immediate release coating is comprised of levodopa, carbidopa, and povidone K30.
In some embodiments, the controlled release matrix is prepared using a controlled release polymer. In some embodiments, the controlled release polymer is hypromellose, carrageenan, ethylcellulose, methylcellulose, sodium carboxymethyl starch, or carbomer. In preferred embodiments, the controlled release polymer is hypromellose K4M Cr, hypromellose K100M, or carrageenan Viscarin 109. Most preferably, the controlled release polymer hypromellose K4M Cr comprises 0-16% by weight of the controlled release matrix, or hypromellose K100M comprises 0-16% by weight of the controlled release matrix, or carrageenan Viscarin109 comprises 0-3% by weight of the controlled release matrix.
In some embodiments, the carboxylic acid is citric acid. Preferably, each capsule contains 70mg to 120mg of citric acid.
In some embodiments, the mini-sheet has a size in a range between 2.0mm and 5.5 mm.
In a second aspect, the present invention provides a process for preparing the above capsule, comprising:
a. sieving and mixing a carboxylic acid, a diluent, and a first portion of levodopa and carbidopa, preferably the carboxylic acid is citric acid, most preferably the carboxylic acid is 70mg to 120mg citric acid;
b. adding the adhesive solution and granulating; preferably, a high shear wet granulator is used for wet granulation;
c. drying the obtained granules, and grading;
d. sieving the controlled release polymer and lubricant, mixing with the dried and granulated granules, and tabletting to obtain tablet core;
e. preparing delayed release coating liquid, coating the delayed release coating on the tablet core, and aging;
f. preparing immediate release coating liquid, and coating on the delayed release coating tablet core to obtain multi-unit mini tablets; and
g. the multi-unit mini-tablets are loaded into the capsule shells.
Specifically, the invention provides a preparation method of an immediate-release and controlled-release capsule of carbidopa and levodopa, which comprises the following steps:
passing a first portion of carbidopa and levodopa, as well as microcrystalline cellulose, mannitol, and citric acid through a #20 mesh screen into a high shear granulator and mixing; adding the povidone aqueous solution into the mixture and granulating; drying the granules in a fluidised bed and subsequently dry-granulating with a dry granulator equipped with a 0.8mm sieve; the hypromellose was passed through a #20 mesh screen, transferred to a blender with the granules and blended, followed by the incorporation of magnesium stearate which passed through a #60 mesh screen; tabletting the mixture with a 2.0mm round punch to obtain a controlled release matrix; mixing methacrylic acid-ethyl acrylate copolymer and its water dispersion, triethyl citrate and talcum powder to delayed release coating liquid, spraying on controlled release substrate to increase weight, and aging at 40 deg.C; the coating solution of the immediate release coating is prepared by adding povidone, a second part of levodopa and carbidopa into purified water, spraying the mixture onto the coating piece of the delayed release coating, and filling the coating piece into a capsule shell.
A third aspect of the present invention provides a controlled release oral solid formulation prepared according to the above method.
In the following examples, unless otherwise specified, dissolution experiments were performed by referring to the dissolution method of the FDA dissolution database in the united states.
Examples
Example 1
Table 1: materials, types and manufacturers
Controlled release core tablets are prepared by using controlled release polymers with different viscosity grades, such as hypromellose K4M Cr (2663-.
Different concentrations of these controlled release polymers were used: the content of the hydroxypropyl methylcellulose K4M Cr is 0-16% of the weight of the controlled release matrix, the content of the HPMC K100M is 0-16% of the weight of the controlled release matrix, and the content of the carrageenan is 0-3% of the weight of the controlled release matrix.
Example 1-1: the production process using hypromellose comprises the following steps:
carbidopa, levodopa, microcrystalline cellulose PH101, mannitol, and citric acid were passed through a #20 mesh screen, added to a high shear granulator, and mixed. Povidone K30 aqueous solution was added thereto and granulated. After drying the granules in the fluidized bed, they were dry-sized using a dry-sizer equipped with a 0.8mm screen. The hypromellose was passed through a 20 mesh screen, transferred to a blender with the granules and mixed. Magnesium stearate was passed through a #60 mesh screen, added and mixed. The mixture was compressed with a 5.5mm round punch and filled into capsules.
Examples 1 to 2: the production process using carrageenan comprises the following steps:
carbidopa, levodopa, microcrystalline cellulose PH101, mannitol, citric acid and carrageenan are sieved by a 20-mesh sieve, and transferred to a high-shear granulator to be mixed. Povidone K30 aqueous solution was added thereto and granulated. After drying the granules in the fluidized bed, they were dry-sized using a dry-sizer equipped with a 0.8mm screen. The dry whole granules were transferred to a mixer for mixing. Magnesium stearate was passed through a #60 mesh screen, added and mixed. The mixture was compressed with a 5.5mm round punch and filled into capsules.
Table 2: formulation of controlled release matrices for carbidopa and levodopa capsules (percentages being based on total weight of controlled release matrix), compressed using a 5.5mm punch.
Dissolution rate data: the prescription is developed by adopting a dissolution method of the American FDA dissolution database.
Us FDA dissolution database dissolution parameters: pH7.0, 50mM phosphate buffer, basket apparatus, 75 rpm, dissolution medium: 900 ml of
Table 3: dissolution of carbidopa and levodopa capsules (5.5mM controlled release matrix) in 50mM phosphate buffer, pH7.0 (basket apparatus, 75 rpm, dissolution media: 900 ml)
CD-carbidopa; LD-Levodopa
Remarking: the controlled release matrix contained 75% API and the immediate release coating contained 25% API. The controlled release fraction was therefore optimized for comparison with the reference formulation (RLD) by adding the actual% Delayed Release (DR) value of 25%.
And (4) conclusion: f2 in batch 239-. Hypromellose K4M Cr was therefore selected from this study for further optimization studies.
Example 2: strategy for developing 2.0mm controlled release matrix in capsule
Example 2-1: optimization of controlled Release matrices
The controlled release matrix was prepared by tabletting with a 2.0mm punch and hypromellose k4M Cr as the controlled release polymer. Hydroxypropyl methylcellulose K4M Cr with different concentrations is selected for research, the research range is that the hydroxypropyl methylcellulose K4M Cr accounts for 3% -7% of the weight of the controlled release matrix, and the anhydrous citric acid accounts for 90-120 mg/capsule. The details of the specific compositions are given in the following table.
Table 4: formulation of controlled release matrix for capdopa and levodopa capsules pressed with 2.0mm punches
The production process using hypromellose comprises the following steps:
carbidopa, levodopa, microcrystalline cellulose PH101, mannitol, and citric acid were passed through a #20 mesh screen into a high shear granulator and mixed. Povidone K30 aqueous solution was added thereto and granulated. After drying the granules in the fluidized bed, they were dry-sized using a dry-sizer equipped with a 0.8mm screen. The hypromellose was passed through a #20 mesh screen, transferred to a blender with the granules and mixed. Magnesium stearate was sieved through a #60 mesh sieve, added to the mixture of granules and hypromellose and mixed well. The mixture was compressed with a 2.0mm round punch and filled into capsules.
Dissolution rate data: development and evaluation of prescription parameters for controlled release matrices using the dissolution method of the U.S. FDA dissolution database
Us FDA dissolution database dissolution parameters:
pH7.0, 50mM phosphate buffer, basket apparatus, 75 rpm, dissolution medium: 900 ml of
Table 5: dissolution of carbidopa and levodopa capsules (2.0 mM controlled release matrix) in 50mM phosphate buffer, pH7.0 (basket apparatus, 75 rpm, dissolution media: 900 ml)
CD-carbidopa; LD-Levodopa
Remarking: the controlled release matrix contained 75% API. The immediate release coating contained 25% API. Therefore for comparison with RLD, the control release fraction is optimized by adding 25% of the actual release value% Delayed Release (DR).
And (4) conclusion: the dissolution curves of batch Nos. 239-. Thus, the amount of hypromellose K4M Cr was determined to be 5% by weight of the controlled release matrix and the amount of anhydrous citric acid was determined to be 100 mg/capsule, compressed using a 2.0mm punch.
Example 2-2: optimization study of 2.0mm micro-tablet delayed release coating layer in capsule
The delayed release coating was coated on the controlled release substrate prepared in example 2-1 using a delayed release coating solution containing 8-15% w/w of methacrylic acid copolymer. The delayed release coated tablets were filled into capsules and the dissolution profile was examined.
The production process comprises the following steps:
carbidopa, levodopa, microcrystalline cellulose PH101, mannitol, and citric acid were passed through a #20 mesh screen into a high shear granulator and mixed. Povidone K30 aqueous solution was added thereto and granulated. After drying the granules in the fluidized bed, they were dry-sized using a dry-sizer equipped with a 0.8mm screen. The hypromellose was passed through a #20 mesh screen, transferred to a blender with the granules and mixed. Magnesium stearate was passed through a #60 mesh, added and mixed. The mixture was compressed using a 2.0mm round punch. Mixing methacrylic acid-ethyl acrylate copolymer and its water dispersion, triethyl citrate and talcum powder to delayed release coating solution, spraying on controlled release matrix to increase weight, aging at 40 deg.C, filling into capsule, and detecting dissolution curve.
Table 6: prescription composition of 2.0mm punch pressed carbidopa and levodopa capsule delayed release coating coated tablet
Us FDA dissolution database dissolution parameters:
an acid stage: simulated gastric fluid (without enzyme), 900 ml, basket apparatus, 75 rpm
A buffering stage: pH7.0, 50mM phosphate buffer, 900 ml, basket apparatus, 75 rpm
Table 7: dissolution of delayed release coated tablets in simulated gastric fluid and phosphate buffered saline
CD-carbidopa; LD-Levodopa
Remarking: the controlled release matrix contains 75% of the drug substance. The immediate release coating contained 25% API. The actual value of the 25% release% Delayed Release (DR) was therefore added to optimize the controlled release portion for comparison with RLD.
And (4) conclusion: the dissolution profile of batch 239-033 (12% delayed release coated tablet) was found to be satisfactory with a value of F2 greater than 50. Thus, the amount of hypromellose K4M Cr was determined to be 5% by weight of the controlled release matrix, the amount of anhydrous citric acid was determined to be 100 mg/capsule, and the delayed release coating weight gain was 12% by weight of the controlled release matrix.
Example 3: examples of research on immediate release and controlled release capsule formulations
The production process using hypromellose comprises the following steps:
a first portion of carbidopa and levodopa, as well as microcrystalline cellulose PH101, mannitol, and citric acid were passed through a #20 mesh screen into a high shear granulator and mixed. Povidone K30 aqueous solution was added thereto and granulated. After drying the granules in the fluidized bed, they were dry-sized using a dry-sizer equipped with a 0.8mm screen. The hypromellose was passed through a 20 mesh screen, transferred to a blender with the granules and mixed. Magnesium stearate was passed through a #60 mesh, added and mixed. The mixture was compressed using a 2.0mm round punch. Mixing methacrylic acid-ethyl acrylate copolymer and its water dispersion, triethyl citrate and talcum powder to the delayed layer coating solution, spraying onto plain film to increase weight, and aging at 40 deg.C. The immediate release coating solution is prepared by adding povidone K30, a second part of levodopa and carbidopa into purified water, spraying onto delayed release coating tablet, filling into capsule, and detecting dissolution curve. The dissolution curves are shown in fig. 1 and 2.
Table 8: prescription composition of finished product
Us FDA dissolution database dissolution parameters:
an acid stage: simulated gastric fluid (without enzyme), 900 ml, basket apparatus, 75 rpm
A buffering stage: pH7.0, 50mM phosphate buffer, 900 ml, basket apparatus, 75 rpm
Table 9: dissolution of delayed release coated tablet capsules in acid and buffer solutions
CD-carbidopa; LD-Levodopa
And (4) conclusion: the dissolution profile of batch 239-033 (12% delayed release coating) was found to be satisfactory, with a value of F2 of greater than 50. Thus, the amount of hypromellose K4M Cr was determined to be 5% by weight of the controlled release matrix and the amount of anhydrous citric acid was determined to be 100 mg/capsule, compressed using a 2.0mm punch and the delayed release coating layer was coated with a weight gain of 12% by weight of the controlled release matrix.
Claims (28)
1. A controlled release oral solid formulation comprising a multi-unit mini-tablet comprising from inside to outside a controlled release portion comprising a carboxylic acid and a first portion of levodopa and carbidopa and an immediate release coating comprising a second portion of levodopa and carbidopa.
2. The controlled release oral solid formulation of claim 1, wherein the immediate release coating is coated over the controlled release portion.
3. The controlled release oral solid formulation of claim 2, wherein the controlled release portion comprises a controlled release matrix and a delayed release coating, and the carboxylic acid is located within the controlled release matrix.
4. The controlled release oral solid formulation of claim 3, wherein the controlled release matrix comprises levodopa, carbidopa, a carboxylic acid, a first pharmaceutically acceptable auxiliary agent, and a controlled release polymer.
5. The controlled release oral solid formulation according to claim 4, wherein the first pharmaceutically acceptable auxiliary agent is selected from the group consisting of microcrystalline cellulose, such as microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH103, microcrystalline cellulose PH105, microcrystalline cellulose PH 302; preferably, the first pharmaceutically acceptable auxiliary agent is microcrystalline cellulose PH101 and mannitol.
6. The controlled release oral solid formulation according to claim 5, wherein the controlled release matrix comprises ethylcellulose, hypromellose, methylcellulose, povidone, and mixtures thereof; preferably, the controlled release matrix comprises hypromellose.
7. Control according to claim 3A sustained release oral solid formulation, wherein the delayed release coating comprises one or more of methacrylic acid-ethyl acrylate copolymer and aqueous dispersion thereof, triethyl citrate, talc and diethyl phthalate; preferably, the methacrylic acid-ethyl acrylate copolymer and the aqueous dispersion thereof areL100-55、s100、FS30D orL30D-55; more preferably, the delayed release coating is composed of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion, triethyl citrate and talc.
8. The controlled release oral solid formulation of claim 2, wherein the immediate release coating comprises levodopa, carbidopa, and a second pharmaceutically acceptable auxiliary agent.
9. The controlled release oral solid formulation of claim 8, wherein the second pharmaceutically acceptable auxiliary agent is mannitol, croscarmellose sodium, povidone K30, magnesium stearate, corn starch, talc, lactose monohydrate, pregelatinized starch, and mixtures thereof; preferably, the immediate release coating consists of levodopa, carbidopa, and povidone K30.
10. The controlled release oral solid formulation of claim 1, wherein the carboxylic acid is citric acid.
11. The controlled release oral solid formulation of claim 10, wherein each unit of the controlled release oral formulation comprises from 70mg to 120mg of citric acid.
12. The controlled release oral solid formulation of claim 1, wherein the controlled release oral solid formulation is a capsule.
13. The controlled release oral solid formulation of claim 12, wherein the carboxylic acid and 75% of the levodopa and carbidopa are contained in the controlled release portion and 25% of the levodopa and carbidopa are coated onto the controlled release portion as an immediate release coating.
14. The controlled release oral solid formulation of claim 13, wherein the controlled release matrix is prepared with a controlled release polymer; preferably, the controlled release polymer is hypromellose, carrageenan, ethylcellulose, methylcellulose, or carbomer; more preferably, the controlled release polymer is hypromellose K4M Cr, hypromellose K100M, or carrageenan Viscarin 109.
15. The controlled release oral solid formulation according to claim 14, wherein hypromellose K4M Cr is 0-16% by weight of the controlled release matrix, or hypromellose K100M is 0-16% by weight of the controlled release matrix, or carrageenan Viscarin109 is 0-3% by weight of the controlled release matrix.
16. The controlled release oral solid formulation according to claim 15, wherein the controlled release polymer is hypromellose K4M Cr, in an amount of 3-7% by weight of the controlled release matrix.
17. The controlled release oral solid formulation of claim 14, wherein the controlled release matrix further comprises a diluent, a lubricant, and a binder.
18. The controlled release oral solid formulation of claim 17, wherein the diluent is microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol.
19. The controlled release oral solid formulation of claim 17, wherein the lubricant is magnesium stearate.
20. The controlled release oral solid formulation according to claim 17, wherein the binder is povidone.
21. The controlled release oral solid formulation according to any one of claims 12-20, wherein the size of the controlled release matrix is in the range between 2.0mm and 5.5 mm.
22. A method of making a controlled release oral solid formulation, the controlled release oral solid formulation being a capsule comprising a plurality of unit mini-tablets, the mini-tablets comprising a controlled release portion and an immediate release coating outside the controlled release portion, the controlled release portion comprising a controlled release matrix and a delayed release coating, the controlled release matrix comprising a carboxylic acid and a first portion of levodopa and carbidopa, and the immediate release coating comprising a second portion of levodopa and carbidopa, the method comprising:
a. sieving and mixing a carboxylic acid, a diluent, and a first portion of levodopa and carbidopa, preferably the carboxylic acid is citric acid, most preferably the carboxylic acid is 70mg to 120mg citric acid;
b. adding a binder solution, and performing wet granulation, preferably by using a high-shear wet granulator;
c. drying the obtained granules, and grading;
d. sieving the controlled release polymer and lubricant, mixing with the dried and granulated granules, and tabletting to obtain controlled release matrix;
e. preparing delayed release coating liquid, coating the delayed release coating on the controlled release matrix, and aging;
f. preparing an immediate release coating solution, and coating on the delayed release coating tablet core; and
g. the coated tablet cores are loaded into capsule shells.
23. The method of claim 22, wherein the controlled release matrix comprises 75% levodopa and carbidopa and the immediate release coating comprises 25% levodopa and carbidopa.
24. The method according to claim 22, wherein in step a, the diluent is microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol, and is sieved with a 20 mesh sieve; in the step b, the binder solution is povidone K30 solution; in step c, the granules were sized using a 0.8mm mesh.
25. The method of claim 22, wherein the lubricant is magnesium stearate and the controlled release polymer is hypromellose, carrageenan, ethylcellulose, methylcellulose, or carbomer; more preferably, the controlled release polymer is hypromellose K4M Cr, hypromellose K100M, or carrageenan Viscarin 109; preferably, the hydroxypropyl methylcellulose K4M Cr is 0-16% of the weight of the controlled release matrix, or the hydroxypropyl methylcellulose K100M is 0-16% of the weight of the controlled release matrix, or the carrageenan Viscarin109 is 0-3% of the weight of the controlled release matrix; more preferably, the controlled release polymer is hypromellose K4M Cr, which is 3-7% of the weight of the controlled release matrix.
26. The method according to claim 22, wherein in step d, the controlled release polymer has a mesh size of 20 mesh and the lubricant has a mesh size of 60 mesh.
27. The method of claim 22, wherein in step d, the tablet is compressed with a punch having a size between 2.0mm and 5.5 mm.
28. The method of claim 22, wherein in step e, the delayed release coating solution comprises one or more of methacrylic acid-ethyl acrylate copolymers and aqueous dispersions thereof, such as triethyl citrate, talc, and diethyl phthalateL100-55、s100、FS30D orL30D-55; preferably, the delayed release coating is made of methacrylic acid-ethyl acrylate copolymer and its aqueous dispersionL30D-55, triethyl citrate and talcum powder; more preferably, the concentration of the methacrylic acid-ethyl acrylate copolymer and its aqueous dispersion in the coating solution of the delayed release coating is 8 to 15 w/w% and the aging temperature is 40 ℃.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110956705.0A CN113616621A (en) | 2021-08-19 | 2021-08-19 | Levodopa and carbidopa controlled release preparation and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110956705.0A CN113616621A (en) | 2021-08-19 | 2021-08-19 | Levodopa and carbidopa controlled release preparation and preparation method thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113616621A true CN113616621A (en) | 2021-11-09 |
Family
ID=78386754
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110956705.0A Pending CN113616621A (en) | 2021-08-19 | 2021-08-19 | Levodopa and carbidopa controlled release preparation and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113616621A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024120389A1 (en) * | 2022-12-05 | 2024-06-13 | 上海汉都医药科技有限公司 | Delayed timed release pharmaceutical composition, preparation method therefor, and use thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200706182A (en) * | 2005-08-02 | 2007-02-16 | Impax Laboratories Inc | Combination immediate release controlled release levodopa and carbidopa dosage forms |
CN101516351A (en) * | 2005-08-05 | 2009-08-26 | 奥斯莫蒂卡有限公司 | Extended release solid pharmaceutical composition containing carbidopa and levodopa |
CN101910113A (en) * | 2007-12-28 | 2010-12-08 | 怡百克制药公司 | Controlled release formulations of levodopa and uses thereof |
CN101926785A (en) * | 2009-06-18 | 2010-12-29 | 北京科信必成医药科技发展有限公司 | Medicinal controlled release preparation for treating parkinsonism and preparation method thereof |
CN103191094A (en) * | 2013-04-19 | 2013-07-10 | 浙江美华鼎昌医药科技有限公司 | Carbidopa-levodopa controlled release tablet and preparation method of tablet |
CN110996922A (en) * | 2017-06-16 | 2020-04-10 | 卡希夫生物科学有限责任公司 | Gastric retentive dosage forms for sustained drug delivery |
-
2021
- 2021-08-19 CN CN202110956705.0A patent/CN113616621A/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200706182A (en) * | 2005-08-02 | 2007-02-16 | Impax Laboratories Inc | Combination immediate release controlled release levodopa and carbidopa dosage forms |
CN101516351A (en) * | 2005-08-05 | 2009-08-26 | 奥斯莫蒂卡有限公司 | Extended release solid pharmaceutical composition containing carbidopa and levodopa |
CN101910113A (en) * | 2007-12-28 | 2010-12-08 | 怡百克制药公司 | Controlled release formulations of levodopa and uses thereof |
CN101926785A (en) * | 2009-06-18 | 2010-12-29 | 北京科信必成医药科技发展有限公司 | Medicinal controlled release preparation for treating parkinsonism and preparation method thereof |
CN103191094A (en) * | 2013-04-19 | 2013-07-10 | 浙江美华鼎昌医药科技有限公司 | Carbidopa-levodopa controlled release tablet and preparation method of tablet |
CN110996922A (en) * | 2017-06-16 | 2020-04-10 | 卡希夫生物科学有限责任公司 | Gastric retentive dosage forms for sustained drug delivery |
Non-Patent Citations (1)
Title |
---|
上海知了数据系统有限公司组织编写: "《CDR临床用药手册》", 30 June 2020, 中国医药科技出版社 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024120389A1 (en) * | 2022-12-05 | 2024-06-13 | 上海汉都医药科技有限公司 | Delayed timed release pharmaceutical composition, preparation method therefor, and use thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230011269A1 (en) | Pharmaceutical composition comprising a potent inhibitor of urat1 | |
EP1842534B1 (en) | Metoprolol succinate extended release tablets and methods for their preparation | |
JP2005512997A (en) | Tamsulosin tablets | |
WO2011111818A1 (en) | Sustained release type pharmaceutical composition containing mosapride or salt thereof | |
JP2006522099A (en) | Oral sustained-release compressed tablet composed of composite granules | |
NZ201008A (en) | Oral preparations containing dipyridamole and at least 5 molar equivalents of orally acceptable acidic excipient | |
US20090324717A1 (en) | Extended release pharmaceutical formulation of metoprolol and process for its preparation | |
RU2672879C2 (en) | Antitubercular composition comprising rifampicin, isoniazid, ethambutol and pyrazinamide and process for preparation thereof | |
WO1999053905A1 (en) | Multiple-unit sustained release tablets | |
CN103068372B (en) | The pharmaceutical composition of metabotropic glutamate receptor 5 (MGLU5) antagonist | |
JP5545952B2 (en) | Sustained release preparation and method for producing the same | |
EP2533766B1 (en) | Pharmaceutical mini-tablets for sustained release of flecainide acetate | |
US20070092568A1 (en) | Galantamine compositions | |
CN105012301B (en) | The pharmaceutical composition of metabotropic glutamate receptor 5 (MGLU5) antagonist | |
CN113616621A (en) | Levodopa and carbidopa controlled release preparation and preparation method thereof | |
EP4103158A1 (en) | Composition comprising ramipril and indapamide | |
CN108366982A (en) | Eflornithine and sulindac, the combination preparation of fixed dosage | |
WO2018228440A1 (en) | Controlled release febuxostat composition and preparation method therefor | |
CN108066304A (en) | Tamsulosin Orally disintegrating tablet compositions with sustained release performance | |
RU2727721C2 (en) | Sustained-release pharmaceutical composition containing rivastigmine | |
EP3995136A1 (en) | Pharmaceutical composition containing tamsulosin or hydrochloride thereof and preparation method therefor | |
CN112057429B (en) | Lei Xina Deg controlled release pharmaceutical composition | |
JP4614139B2 (en) | Method for producing tamsulosin hydrochloride sustained release tablet and tamsulosin hydrochloride sustained release tablet comprising the same | |
JP2022514040A (en) | Tamsulosin hydrochloride-containing pharmaceutical composition having excellent acid resistance and a method for producing the same. | |
WO2003013480A1 (en) | Improved enteric formulation of fluoxetin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |