CN112741827A - Vigabatrin solid preparation and preparation method thereof - Google Patents
Vigabatrin solid preparation and preparation method thereof Download PDFInfo
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- CN112741827A CN112741827A CN201911055259.5A CN201911055259A CN112741827A CN 112741827 A CN112741827 A CN 112741827A CN 201911055259 A CN201911055259 A CN 201911055259A CN 112741827 A CN112741827 A CN 112741827A
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- vigabatrin
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- parts
- solid preparation
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- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 title claims abstract description 197
- 229960005318 vigabatrin Drugs 0.000 title claims abstract description 196
- 238000002360 preparation method Methods 0.000 title claims abstract description 126
- 239000007787 solid Substances 0.000 title claims abstract description 75
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 159
- 239000012535 impurity Substances 0.000 claims abstract description 56
- 239000000463 material Substances 0.000 claims abstract description 45
- 239000002904 solvent Substances 0.000 claims abstract description 27
- 238000002156 mixing Methods 0.000 claims abstract description 25
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 11
- 238000000576 coating method Methods 0.000 claims description 67
- 239000011248 coating agent Substances 0.000 claims description 65
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 56
- 239000003826 tablet Substances 0.000 claims description 52
- 239000001856 Ethyl cellulose Substances 0.000 claims description 48
- 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 48
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 48
- 229920001249 ethyl cellulose Polymers 0.000 claims description 48
- 229920003081 Povidone K 30 Polymers 0.000 claims description 47
- 229920002472 Starch Polymers 0.000 claims description 42
- 239000008107 starch Substances 0.000 claims description 42
- 235000019698 starch Nutrition 0.000 claims description 42
- 239000000783 alginic acid Substances 0.000 claims description 41
- 235000010443 alginic acid Nutrition 0.000 claims description 41
- 229920000615 alginic acid Polymers 0.000 claims description 41
- 229960001126 alginic acid Drugs 0.000 claims description 41
- 150000004781 alginic acids Chemical class 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 30
- 239000011734 sodium Substances 0.000 claims description 30
- 229910052708 sodium Inorganic materials 0.000 claims description 30
- 235000019359 magnesium stearate Nutrition 0.000 claims description 28
- 239000008187 granular material Substances 0.000 claims description 23
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 20
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 20
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 20
- 239000000314 lubricant Substances 0.000 claims description 17
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 13
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 13
- 229930195725 Mannitol Natural products 0.000 claims description 13
- 239000008101 lactose Substances 0.000 claims description 13
- 239000000594 mannitol Substances 0.000 claims description 13
- 235000010355 mannitol Nutrition 0.000 claims description 13
- 239000000843 powder Substances 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 12
- 238000009472 formulation Methods 0.000 claims description 12
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 11
- 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 11
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 11
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 10
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 7
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 7
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 7
- 238000004806 packaging method and process Methods 0.000 claims description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 235000010356 sorbitol Nutrition 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 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 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 61
- 235000019441 ethanol Nutrition 0.000 description 52
- 239000007941 film coated tablet Substances 0.000 description 44
- 238000007873 sieving Methods 0.000 description 16
- 239000007779 soft material Substances 0.000 description 16
- 239000002994 raw material Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000005303 weighing Methods 0.000 description 14
- 239000007888 film coating Substances 0.000 description 11
- 238000009501 film coating Methods 0.000 description 11
- 239000000080 wetting agent Substances 0.000 description 10
- 238000005520 cutting process Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 229940069328 povidone Drugs 0.000 description 4
- 229940083542 sodium Drugs 0.000 description 4
- 238000005550 wet granulation Methods 0.000 description 4
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 3
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 3
- 208000035977 Rare disease Diseases 0.000 description 3
- 229960002684 aminocaproic acid Drugs 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960004667 ethyl cellulose Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000643 oven drying Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 229940033134 talc Drugs 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- OYVDXEVJHXWJAE-UHFFFAOYSA-N 5-ethenylpyrrolidin-2-one Chemical compound C=CC1CCC(=O)N1 OYVDXEVJHXWJAE-UHFFFAOYSA-N 0.000 description 1
- ANRFTTXEGCYVMQ-UHFFFAOYSA-L C(C=CC(=O)[O-])(=O)[O-].[Na+].C(CCCCCCCCCCCCCCCCC)(=O)O.[Na+] Chemical compound C(C=CC(=O)[O-])(=O)[O-].[Na+].C(CCCCCCCCCCCCCCCCC)(=O)O.[Na+] ANRFTTXEGCYVMQ-UHFFFAOYSA-L 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 208000001654 Drug Resistant Epilepsy Diseases 0.000 description 1
- 206010021750 Infantile Spasms Diseases 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 201000006791 West syndrome Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000007916 tablet composition Substances 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
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of pharmaceutical preparations, and in particular relates to a vigabatrin solid preparation and a preparation method thereof. The preparation method of the vigabatrin solid preparation comprises the following steps: dissolving a binder in a first anhydrous alcohol solvent to obtain a binding solution; mixing the vigabatrin, pharmaceutically acceptable auxiliary materials and the bonding solution, granulating and drying to prepare the vigabatrin solid preparation. Also provides a vigabatrin solid preparation obtained according to the preparation method. The vigabatrin solid preparation or the vigabatrin solid preparation prepared according to the preparation method has good stability and low content of impurity A and total impurities.
Description
Technical Field
The invention relates to the field of medicinal preparations, in particular to a vigabatrin solid preparation and a preparation method thereof.
Background
Epilepsy is a disease characterized by dysfunction of the central nervous system caused by abnormal discharge of recurrent neurons, is one of common diseases and frequently encountered diseases in clinic, and seriously affects the daily life of patients. While the traditional antiepileptic drugs can control most of epilepsy, 20-30% of epilepsy cannot be effectively controlled.
Vigabatrin, chemical name 4-amino-5-hexenoic acid, selectively inhibits gamma-aminobutyric acid (GABA) transaminase, thereby increasing GABA concentration in brain and generating antiepileptic effect. In 2009 vigabatrin was designated by the FDA as an adjunctive therapeutic for the treatment of infantile spasms and locally complex seizures of adult refractory epilepsy, a rare disease drug.
However, the progress of China is slow in the aspect of prevention, treatment and rescue of rare diseases, and a blank exists in the research and development industry of rare diseases medicines in China. Therefore, in order to meet the clinical urgent need of medication and alleviate the problem of difficult medication of patients, the research and invention on the aspect of vigabatrin is necessary.
In consideration of the important therapeutic effect of vigabatrin, the quality control of vigabatrin is very important, and in the prior art, the research on the impurity control of vigabatrin preparation is rarely seen. Therefore, it is necessary to develop a stable aminocaproic acid preparation having a low impurity content.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a vigabatrin solid preparation and a preparation method thereof. The vigabatrin solid preparation has high stability, and the content of the impurity A and the total impurity content are both low.
The vigabatrin solid preparation provided by the invention can improve the stability and reduce the content of impurity A and total impurities by controlling the preparation process of the preparation and carrying out wet granulation by using a bonding solution prepared from an anhydrous alcohol solvent; further, in the coating process with the coating material, an alcohol solution having a low water content, for example, an alcohol solution having a mass concentration of 80% or more, preferably, an anhydrous alcohol solvent is used to prepare a coating solution for coating, thereby avoiding the use of water and reducing the influence of water on the stability of the solid preparation. The vigabatrin solid preparation provided by the method has low impurity content, and after long-time storage, the impurity change is not large, and the stability is good.
Specifically, the invention provides the following technical scheme:
in a first aspect of the present invention, the present invention provides a method for preparing a vigabatrin solid preparation, comprising: dissolving a binder in a first anhydrous alcohol solvent to obtain a binding solution; mixing the vigabatrin, pharmaceutically acceptable auxiliary materials and the bonding solution, granulating and drying to prepare the vigabatrin solid preparation. According to the preparation method of the vigabatrin solid preparation, in the preparation process of the vigabatrin solid preparation, the used bonding solution is prepared by dissolving a bonding agent in a first absolute alcohol solvent, and then the vigabatrin solid preparation is obtained through wet granulation.
According to an embodiment of the present invention, the preparation method of the vigabatrin solid preparation described above may further include the following technical features:
in some embodiments of the invention, the method of preparing further comprises: coating the vigabatrin solid preparation by using a coating solution to obtain a vigabatrin coated preparation, wherein the coating solution is obtained by dissolving a coating material in an alcohol solution with the mass concentration of more than 80%, and preferably is obtained by dissolving the coating material in a second absolute alcohol solvent. In the process of coating the vigabatrin solid preparation by using the coating solution, the lower the water content in the used alcohol solution, the better the stability of the obtained vigabatrin coating preparation, for example, the alcohol solution with the mass concentration of more than 80%, preferably the alcohol solution with the mass concentration of more than 85%, more preferably the alcohol solution with the mass concentration of more than 90%, more preferably the alcohol solution with the mass concentration of more than 95%, and most preferably the second anhydrous alcohol solvent are used to prepare the coating solution.
In some embodiments of the present invention, the alcohol in the first anhydrous alcohol solvent, the second anhydrous alcohol solvent and the alcohol solution with the mass concentration of 80% or more is selected from at least one of C1-C6 straight chain alcohol or branched chain alcohol, preferably at least one of isopropanol, ethanol, propylene glycol, and more preferably ethanol. The solid preparation of the vigabatrin or the vigabatrin coated preparation obtained by using the alcohol solvent to prepare the bonding solution or the coating solution has good stability, and the content of impurities is low after the solid preparation or the vigabatrin coated preparation is placed for a certain time at a high temperature of 60 ℃, so that the content of the impurities is superior to that of a reference preparation.
In some embodiments of the invention, the binder is at least one selected from ethyl cellulose, povidone K30.
In some embodiments of the invention, the binder is ethyl cellulose and povidone K30, the mass ratio of ethyl cellulose to povidone being 3: 2-4: 2, preferably, the mass ratio of the vigabatrin to the adhesive is 60: 3-80: 3. thus, a solid vigabatrin preparation can be obtained by using a wet preparation.
In some embodiments of the invention, the pharmaceutically acceptable excipients include at least one of a filler, a disintegrant, and a lubricant.
In some embodiments of the present invention, the filler is at least one selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sorbitol, starch, pregelatinized starch.
In some embodiments of the present invention, the disintegrant is at least one selected from the group consisting of sodium carboxymethyl starch, calcium carboxymethyl cellulose, crospovidone, and croscarmellose sodium. Sodium carboxymethyl starch is preferred.
In at least some embodiments of the present invention, the lubricant is at least one selected from magnesium stearate, silicon dioxide, sodium lauryl sulfate, talc, sodium stearyl fumarate.
In some embodiments of the present invention, the pharmaceutically acceptable auxiliary material further includes alginic acid, preferably, the alginic acid accounts for 0.05% to 0.3% of the vigabatrin solid preparation, and more preferably, the mass ratio of vigabatrin to the alginic acid is 160: 0.1-20: 0.1.
in a second aspect of the invention, the invention provides a preparation method of a vigabatrin solid preparation, wherein the vigabatrin solid preparation is prepared by wet granulation of a bonding solution dissolved in a first absolute alcohol solvent.
The preparation method of the vigabatrin solid preparation provided by the first aspect or the preparation method of the vigabatrin solid preparation provided by the second aspect can be used for preparing the vigabatrin solid preparation. The prepared vigabatrin solid preparation comprises vigabatrin and pharmaceutically-available auxiliary materials, wherein the pharmaceutically-available auxiliary materials comprise alginic acid. The vigabatrin solid preparation prepared by the method has good stability and low impurity content, and meets the requirement of production and medication.
In a third aspect of the invention, the invention provides a vigabatrin solid preparation, which comprises vigabatrin and pharmaceutically acceptable auxiliary materials, wherein the pharmaceutically acceptable auxiliary materials comprise alginic acid. The vigabatrin solid preparation provided by the invention contains alginic acid and vigabatrin, the alginic acid enhances the stability of the vigabatrin solid preparation, so that the vigabatrin solid preparation has low impurity content, and the impurity content is not greatly changed after the vigabatrin solid preparation is placed through an accelerated experiment. For example, when the vigabatrin solid preparation is placed at 60 ℃ for 30 days without being packaged, the content of the impurity A and the total impurity content are superior to those of a reference preparation, the content of the impurity A is still below 0.3%, and the total impurity content is still below 1.0%.
According to an embodiment of the present invention, the vigabatrin solid preparation described above may further include the following technical features:
in some embodiments of the present invention, the pharmaceutically acceptable excipient further comprises a binder, and the binder is at least one selected from ethyl cellulose and povidone. Preferably, the weight ratio of the ethyl cellulose to the povidone is 3: 2-4: 2.
in some embodiments of the invention, the pharmaceutically acceptable excipient further comprises a disintegrant.
In some embodiments of the invention, the disintegrant is selected from at least one of sodium carboxymethyl starch, calcium carboxymethyl cellulose, crospovidone, and croscarmellose sodium.
In some embodiments of the present invention, the pharmaceutically acceptable excipient further comprises alginic acid, and the alginic acid accounts for 0.05% to 0.3% of the vigabatrin solid preparation. Therefore, the stability of the vigabatrin solid preparation can be improved, the generation of impurities can be reduced, and the disintegration of the vigabatrin solid preparation in vivo can be promoted.
In some embodiments of the invention, the pharmaceutically acceptable excipient further comprises at least one of a filler and a lubricant.
In some embodiments of the present invention, the filler is at least one selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sorbitol, starch, pregelatinized starch. The substances can be used as fillers to improve the performance of the vigabatrin solid preparation and realize the effect of weight increment and capacity increase.
In some embodiments of the invention, the lubricant is at least one selected from magnesium stearate, silicon dioxide, sodium lauryl sulfate, talc, sodium stearyl fumarate.
In some embodiments of the invention, the vigabatrin solid formulation is selected from at least one of the following: (a) the composition comprises 60-80 parts by weight of vigabatrin, 15-35 parts by weight of microcrystalline cellulose, 1-3 parts by weight of sodium carboxymethyl starch, 0.01-0.3 part by weight of alginic acid, 1.5-2.5 parts by weight of ethyl cellulose, 1-2.5 parts by weight of povidone K30 and 1-3 parts by weight of magnesium stearate; (b) the composition comprises 60-80 parts by weight of vigabatrin, 15-35 parts by weight of mannitol, 1-3 parts by weight of sodium carboxymethyl starch, 0.01-0.3 part by weight of alginic acid, 1.5-2.5 parts by weight of ethyl cellulose, 1-2.5 parts by weight of povidone K30 and 1-3 parts by weight of magnesium stearate; (c) the feed additive comprises 60-80 parts by weight of vigabatrin, 15-35 parts by weight of lactose, 1-3 parts by weight of sodium carboxymethyl starch, 0.01-0.3 part by weight of alginic acid, 1.5-2.5 parts by weight of ethyl cellulose, 1-2.5 parts by weight of povidone K30 and 1-3 parts by weight of magnesium stearate; optionally, a coating material may be included. The vigabatrin solid preparation has low impurity content and good stability, and meets the requirements of production and safe medication.
In a fourth aspect of the present invention, the present invention provides a vigabatrin solid preparation, which is prepared according to the preparation method of the first aspect of the present invention or the preparation method of the second aspect of the present invention.
According to an embodiment of the present invention, the vigabatrin solid preparation may further include the following technical features:
in some embodiments of the invention, the solid formulation comprises: 60-80 parts by weight of vigabatrin; 1-2 parts by weight of sodium carboxymethyl starch or croscarmellose sodium; 0.01 to 0.3 parts by weight of alginic acid; 1-3 parts by weight of povidone K30 and/or 1-3 parts by weight of ethyl cellulose; 1-3 parts by weight of magnesium stearate or sodium stearyl fumarate; 10-30 parts by weight of microcrystalline cellulose or mannitol or lactose or starch; optionally, a coating material.
In some embodiments of the invention, the solid formulation comprises: 60-80 parts by weight of vigabatrin; 1.3-1.6 parts by weight of sodium carboxymethyl starch or croscarmellose sodium; 0.05 to 0.3 part by weight of alginic acid; 1.8-2 parts by weight of ethyl cellulose; 1-1.2 parts by weight of povidone K30; 1.2-1.5 parts by weight of magnesium stearate; 10-30 parts by weight of microcrystalline cellulose or mannitol or lactose or starch; optionally, a coating material.
In some embodiments of the present invention, the vigabatrin solid preparation is left at 60 ℃ for 10 days without packaging, and the content of the impurity A is below 0.3%, and the total impurity content is below 1.0%.
In some embodiments of the invention, the content of impurity a is below 0.3% and the total impurity content is below 1.0% when left unpackaged at 60 ℃ for 30 days.
The first anhydrous alcohol and the second anhydrous alcohol both refer to alcohols having a mass concentration of not less than 99.7%.
In some embodiments of the present invention, the solid formulation is selected from at least one of a tablet, a granule, a powder, and a capsule.
Detailed Description
The present invention will be described in detail with reference to the following embodiments, which are illustrative and are not to be construed as limiting the present invention.
The invention provides a vigabatrin solid preparation, which comprises vigabatrin and pharmaceutically-available auxiliary materials, wherein the pharmaceutically-available auxiliary materials comprise alginic acid. The vigabatrin solid preparation provided by the method is placed at 60 ℃ for 30 days without packaging, the content of the impurity A is below 0.3%, and the total impurity content is below 1.0%. For example, the content of the impurity a may be 0.28% or less, 0.25% or less, 0.23% or less, 0.2% or less; the total impurity content may be below 0.9%, below 0.85%, below 0.8%, even below 0.7%. Herein, when referring to the content, unless otherwise specified, it refers to the mass percentage of a certain substance in the total substance. The vigabatrin solid preparation can be prepared into a needed dosage form according to needs, such as tablets, granules, powder or capsules.
For example, in some embodiments of the present invention, the present invention provides a vigabatrin tablet comprising 60 to 80 parts by weight of vigabatrin, 15 to 35 parts by weight of microcrystalline cellulose, 1 to 3 parts by weight of sodium carboxymethyl starch, 0.01 to 0.3 part by weight of alginic acid, 1.5 to 2.5 parts by weight of ethyl cellulose, 1 to 2.5 parts by weight of povidone K30 and 1 to 3 parts by weight of magnesium stearate; optionally, a coating material may be included.
In other embodiments of the present invention, the present invention provides a vigabatrin tablet, comprising 60 to 80 parts by weight of vigabatrin, 15 to 35 parts by weight of mannitol, 1 to 3 parts by weight of sodium carboxymethyl starch, 0.01 to 0.3 part by weight of alginic acid, 1.5 to 2.5 parts by weight of ethyl cellulose, 1 to 2.5 parts by weight of povidone K30 and 1 to 3 parts by weight of magnesium stearate; optionally, a coating material may be included.
In still other embodiments of the present invention, the present invention provides a vigabatrin tablet, comprising vigabatrin 60-80 parts by weight, lactose 15-35 parts by weight, sodium carboxymethyl starch 1-3 parts by weight, alginic acid 0.01-0.3 parts by weight, ethyl cellulose 1.5-2.5 parts by weight, povidone K30 1-2.5 parts by weight, and magnesium stearate 1-3 parts by weight; optionally, a coating material may be included.
In some embodiments of the invention, the solid formulation comprises: 60-80 parts by weight of vigabatrin; 1-2 parts by weight of sodium carboxymethyl starch or croscarmellose sodium; 0.01 to 0.3 parts by weight of alginic acid; 1-3 parts by weight of povidone K30 and/or 1-3 parts by weight of ethyl cellulose; 1-3 parts by weight of magnesium stearate or sodium stearyl fumarate; 10-30 parts by weight of microcrystalline cellulose or mannitol or lactose or starch; optionally, a coating material.
In some embodiments of the invention, the solid formulation comprises: 60-80 parts by weight of vigabatrin; 1.3-1.6 parts by weight of sodium carboxymethyl starch or croscarmellose sodium; 0.05 to 0.3 part by weight of alginic acid; 1.8-2 parts by weight of ethyl cellulose; 1-1.2 parts by weight of povidone K30; 1.2-1.5 parts by weight of magnesium stearate; 10-30 parts by weight of microcrystalline cellulose or mannitol or lactose or starch; optionally, a coating material.
The invention also provides a preparation method of vigabatrin tablets, which comprises the following steps: dissolving a binder in a first anhydrous alcohol solvent to obtain a binding solution; mixing vigabatrin, filler, disintegrating agent (also including alginic acid) and the binding solution, granulating, and oven drying to obtain oven dried granule; mixing and tabletting the dried granules and a lubricant so as to obtain the vigabatrin tablets.
In still other embodiments of the present invention, the present invention provides a method for preparing vigabatrin-coated tablets, the method comprising: dissolving a binder in a first anhydrous alcohol solvent to obtain a binding solution; mixing vigabatrin, filler, disintegrating agent (also including alginic acid) and the binding solution, granulating, and oven drying to obtain oven dried granule; mixing and tabletting the dried granules and a lubricant to obtain vigabatrin tablets; coating the vigabatrin tablets by using a coating solution to obtain vigabatrin coated tablets, wherein the coating solution is obtained by dissolving a coating material in an alcohol solution with the mass concentration of more than 80%, preferably in an alcohol solution with the mass concentration of more than 90%, more preferably in an alcohol solution with the mass concentration of more than 95%, and more preferably in a second anhydrous alcohol solvent.
The alcohol solvent used in the preparation method of the vigabatrin tablet or the vigabatrin coated tablet is at least one selected from isopropanol, ethanol and propylene glycol, preferably ethanol. In at least some embodiments of the invention, the binder is at least one selected from ethylcellulose, povidone. In still other embodiments of the present invention, the disintegrant is at least one selected from the group consisting of sodium carboxymethyl starch, calcium carboxymethyl cellulose, crospovidone, and sodium croscarmellose. In other embodiments of the present invention, the filler is at least one of sodium carboxymethyl starch, mannitol, sorbitol, starch, pregelatinized starch. In other embodiments of the present invention, the lubricant is at least one selected from magnesium stearate and silicon dioxide. The vigabatrin tablet or the coated tablet provided by the method has good stability and low impurity content.
Herein, the anhydrous alcohol is not intended to emphasize that no moisture is contained at all, and as long as the moisture content is small, the alcohol concentration may be high, and specifically, the alcohol concentration may be not less than 99.7% by mass, for example, the first anhydrous alcohol and the second anhydrous alcohol each refer to an alcohol concentration of not less than 99.7% by mass.
The vigabatrin solid preparation provided by the invention can improve the stability and reduce the content of impurity A and total impurities by controlling the preparation process of the preparation and carrying out wet granulation on the bonding solution prepared by taking anhydrous alcohol as a solvent. In addition, in the process of preparing the coating preparation, the influence of water on the stability of the solid preparation is reduced by preparing a coating solution from an alcohol solution with low water content, such as an alcohol solution with a mass concentration of at least 80%. The vigabatrin solid preparation provided by the method has low impurity content, the impurity A content and the total impurity content are superior to those of a reference preparation after the vigabatrin solid preparation is placed for 30 days at the temperature of 60 ℃, the stability is good, and the impurity content is low.
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. The anhydrous alcohol used in the examples was a commercially available alcohol having a mass concentration of not less than 99.7%.
Example 1
Example 1 provides a vigabatrin film-coated tablet and a preparation method thereof, wherein the vigabatrin film-coated tablet has the following components as shown in table 1 below:
TABLE 1 vigabatrin film-coated tablet ingredients
The preparation method of the vigabatrin film-coated tablet comprises the following steps:
(1) weighing ethyl cellulose and povidone K30 according to the weight percentage in the table 1, dissolving the ethyl cellulose and the povidone K30 in absolute ethyl alcohol serving as a wetting agent, and preparing a bonding solution with the mass percentage of 10%.
(2) Weighing the raw materials of vigabatrin, microcrystalline cellulose, sodium carboxymethyl starch and alginic acid according to the table 1, placing the raw materials in a wet mixing granulator, mixing the materials for several minutes until the mixture is uniform, adding the bonding solution containing the ethyl cellulose and the povidone K30, cutting the bonding solution while stirring, and preparing a soft material.
(3) And (3) sieving the prepared soft material with a 24-mesh sieve, granulating, and then putting into an oven at 45 ℃ for drying.
(4) Taking out the dried granules, sieving with a 24-mesh sieve, and grading. The lubricant magnesium stearate in the amount shown in table 1 was then added and mixed for several minutes.
(5) And (4) tabletting the granules mixed in the step (4) to obtain the vigabatrin tablets.
(6) According to the dosage in the table 1, dissolving the coating material Opadry film coating powder in absolute ethyl alcohol to prepare coating liquid with the mass percentage of 11%, and then coating the vigabatrin tablets to obtain the vigabatrin film coated tablets.
Example 2
Example 2 provides a vigabatrin film-coated tablet and a preparation method thereof, wherein the vigabatrin film-coated tablet has the following components as shown in table 2 below:
TABLE 2 vigabatrin film-coated tablet ingredients
The preparation method comprises the following steps:
(1) weighing ethyl cellulose and povidone K30 according to the weight percentage in the table 2, dissolving the ethyl cellulose and the povidone K30 in anhydrous isopropanol serving as a wetting agent, and preparing a bonding solution with the mass percentage of 12%.
(2) Weighing the raw materials of vigabatrin, mannitol, sodium carboxymethyl starch and alginic acid according to the table 2, placing the raw materials in a wet mixing granulator, mixing the materials for several minutes until the mixture is uniform, adding the bonding solution containing the ethyl cellulose and the povidone K30, cutting the mixture while stirring the mixture to prepare a soft material.
(3) And (3) sieving the prepared soft material with a 24-mesh sieve, granulating, and then putting into an oven at 45 ℃ for drying.
(4) Taking out the dried granules, sieving with a 24-mesh sieve, and grading. The lubricant magnesium stearate in the amount shown in table 2 was then added and mixed for several minutes.
(5) And (4) tabletting the granules mixed in the step (4) to obtain the vigabatrin tablets.
(6) According to the dosage in the table 2, the coating material opadry film coating powder is dissolved in anhydrous isopropanol to prepare coating liquid with the mass percentage of 12%, and then the vigabatrin tablets are coated to obtain the vigabatrin film coating tablets.
Example 3
Example 3 provides a vigabatrin film-coated tablet and a preparation method thereof, wherein the vigabatrin film-coated tablet has the following components:
TABLE 3 vigabatrin film-coated tablet ingredients
| 1000 tablets (g) | Weight percent of | |
| Vigabatrin | 500 | 80％ |
| Lactose | 62.5 | 10％ |
| Sodium carboxymethyl starch | 9.69 | 1.55％ |
| Alginic acid | 0.31 | 0.05％ |
| Ethyl cellulose | 12.5 | 2％ |
| Povidone K30 | 6.25 | 1％ |
| Magnesium stearate | 8.75 | 1.4％ |
| Coating film | ||
| Opadry film coating powder | 25 | 4％ |
The preparation method comprises the following steps:
(1) weighing ethyl cellulose and povidone K30 according to the weight percentage in the table 3, dissolving the ethyl cellulose and the povidone K30 in anhydrous isopropanol serving as a wetting agent, and preparing a bonding solution with the mass percentage of 12%.
(2) Weighing the raw materials of vigabatrin, lactose, sodium carboxymethyl starch and alginic acid according to the table 3, placing the raw materials in a wet mixing granulator, mixing the materials for several minutes until the mixture is uniform, adding a binding solution containing ethyl cellulose and povidone K30, cutting the mixture while stirring the mixture to prepare a soft material.
(3) And (3) sieving the prepared soft material with a 24-mesh sieve, granulating, and then putting into an oven at 45 ℃ for drying.
(4) Taking out the dried granules, sieving with a 24-mesh sieve, and grading. The lubricant magnesium stearate in the amount shown in table 3 was then added and mixed for several minutes.
(5) And (4) tabletting the granules mixed in the step (4) to obtain the vigabatrin tablets.
(6) According to the dosage in the table 3, the coating material opadry is dissolved in anhydrous propylene glycol to prepare a coating solution with the mass percentage of 10%, and then the vigabatrin tablets are coated to obtain the vigabatrin film coated tablets.
Example 4
Example 4 provides a vigabatrin film-coated tablet and a preparation method thereof, wherein the vigabatrin film-coated tablet has the following components as shown in table 4 below:
TABLE 4 vigabatrin film-coated tablet ingredients
| 1000 tablets (g) | Weight percent of | |
| Vigabatrin | 500 | 70％ |
| Starch | 142 | 20％ |
| Croscarmellose sodium | 10.71 | 1.5％ |
| Alginic acid | 0.71 | 0.1％ |
| Ethyl cellulose | 13.57 | 1.9％ |
| Povidone K30 | 7.86 | 1.1％ |
| Stearic acid sodium fumarate | 10.00 | 1.4％ |
| Coating film | ||
| Opadry film coating powder | 28.57 | 4％ |
The preparation method of the vigabatrin film-coated tablet comprises the following steps:
(1) weighing ethyl cellulose and povidone K30 according to the weight percentage in the table 4, dissolving the ethyl cellulose and the povidone K30 in absolute ethyl alcohol serving as a wetting agent, and preparing a bonding solution with the mass percentage of 10%.
(2) Weighing the raw materials of vigabatrin, starch, croscarmellose sodium and alginic acid according to table 4, placing in a wet mixing granulator, mixing for several minutes until uniform, then adding the above binding solution containing ethylcellulose and povidone K30, cutting while stirring to prepare a soft material.
(3) And (3) sieving the prepared soft material with a 24-mesh sieve, granulating, and then putting into an oven at 45 ℃ for drying.
(4) Taking out the dried granules, sieving with a 24-mesh sieve, and grading. The lubricant sodium stearyl fumarate, in the amount indicated in Table 4, was then added and mixed for several minutes.
(5) And (4) tabletting the granules mixed in the step (4) to obtain the vigabatrin tablets.
(6) According to the dosage in the table 4, dissolving the coating material Opadry film coating powder in absolute ethyl alcohol to prepare coating liquid with the mass percentage of 11%, and then coating the vigabatrin tablets to obtain the vigabatrin film coated tablets.
Example 5
Example 5 provides a vigabatrin film-coated tablet and a preparation method thereof, wherein the vigabatrin film-coated tablet has the following components:
TABLE 5 vigabatrin film-coated tablet ingredients
| 1000 tablets (g) | Weight percent of | |
| Vigabatrin | 500 | 70％ |
| Microcrystalline cellulose | 142 | 20％ |
| Sodium carboxymethyl starch | 10.71 | 1.5％ |
| Alginic acid | 0.71 | 0.1％ |
| Povidone K30 | 21.43 | 3％ |
| Magnesium stearate | 10.00 | 1.4％ |
| Coating film | ||
| Opadry film coating powder | 28.57 | 4％ |
The preparation method of the vigabatrin film-coated tablet comprises the following steps:
(1) povidone K30 was weighed according to Table 5 and dissolved in a wetting agent, anhydrous ethanol, to make a 10% by weight binding solution.
(2) Weighing the raw materials of vigabatrin, microcrystalline cellulose, sodium carboxymethyl starch and alginic acid according to the table 5, placing the raw materials in a wet mixing granulator, mixing the materials for several minutes until the mixture is uniform, adding the binding solution containing povidone K30, cutting the mixture while stirring the mixture to prepare soft materials.
(3) And (3) sieving the prepared soft material with a 24-mesh sieve, granulating, and then putting into an oven at 45 ℃ for drying.
(4) Taking out the dried granules, sieving with a 24-mesh sieve, and grading. The lubricant magnesium stearate in the amount in table 5 was then added and mixed for several minutes.
(5) And (4) tabletting the granules mixed in the step (4) to obtain the vigabatrin tablets.
(6) According to the dosage in the table 5, dissolving the coating material Opadry film coating powder in absolute ethyl alcohol to prepare coating liquid with the mass percentage of 11%, and then coating the vigabatrin tablets to obtain the vigabatrin film coated tablets.
Example 6
Example 6 provides a vigabatrin film-coated tablet, the composition of which is shown in table 6 below:
TABLE 6 vigabatrin film-coated tablet ingredients
| 1000 tablets (g) | Weight percent of | |
| Vigabatrin | 500g | 70％ |
| Microcrystalline cellulose | 142 | 20％ |
| Sodium carboxymethyl starch | 11.42 | 1.6％ |
| Ethyl cellulose | 13.57 | 1.9％ |
| Povidone K30 | 7.86 | 1.1％ |
| Magnesium stearate | 10.00 | 1.4％ |
| Coating film | ||
| Opadry film coating powder | 28.57 | 4％ |
The preparation method of the vigabatrin film-coated tablet comprises the following steps:
(1) weighing ethyl cellulose and povidone K30 according to the weight percentage in the table 6, dissolving the ethyl cellulose and the povidone K30 in absolute ethyl alcohol serving as a wetting agent, and preparing a bonding solution with the mass percentage of 10%.
(2) Weighing the raw materials of vigabatrin, microcrystalline cellulose and sodium carboxymethyl starch according to the table 6, placing the raw materials in a wet mixing granulator, mixing the materials for several minutes until the mixture is uniform, adding the bonding solution containing the ethyl cellulose and the povidone K30, cutting the bonding solution while stirring the bonding solution to prepare a soft material.
(3) And (3) sieving the prepared soft material with a 24-mesh sieve, granulating, and then putting into an oven at 45 ℃ for drying.
(4) Taking out the dried granules, sieving with a 24-mesh sieve, and grading. The lubricant magnesium stearate in the amount shown in table 6 was then added and mixed for several minutes.
(5) And (4) tabletting the granules mixed in the step (4) to obtain the vigabatrin tablets.
(6) According to the dosage in the table 1, dissolving the coating material Opadry film coating powder in absolute ethyl alcohol to prepare coating liquid with the mass percentage of 11%, and then coating the vigabatrin tablets to obtain the vigabatrin film coated tablets.
Example 7
Example 7 provides a vigabatrin film-coated tablet having the following composition in table 7 below:
TABLE 7 vigabatrin film-coated tablets
| 1000 tablets (g) | Weight percent of | |
| Vigabatrin | 500 | 70％ |
| Microcrystalline cellulose | 142 | 20％ |
| Sodium carboxymethyl starch | 10.71 | 1.5％ |
| Alginic acid | 0.71 | 0.1％ |
| Ethyl cellulose | 12.14 | 1.7％ |
| Povidone K30 | 9.29 | 1.3％ |
| Magnesium stearate | 10.00 | 1.4％ |
| Coating film | ||
| Opadry film coating powder | 28.57 | 4％ |
The vigabatrin film-coated tablets were prepared according to the method of example 1.
Example 8
Example 8 provides a vigabatrin film-coated tablet, the composition of which is shown in table 8 below:
TABLE 8 vigabatrin film-coated tablets
The vigabatrin film-coated tablets were prepared according to the method of example 1.
The vigabatrin film-coated tablets prepared in examples 1 to 8 were left at 60 ℃ without any packaging (i.e., vigabatrin film-coated tablet bare chips), and then sampled for the change of impurity a (5-vinyl-2-pyrrolidone) and total impurity data on days 0, 10 and 30, respectively, and the results are shown in table 9 below. As commercially available
As a comparison of the reference formulations, the reference formulations used in the following examples are the same as those of the present example.
TABLE 9 stability test results of vigabatrin film-coated tablet bare chips prepared in each example
The experimental result shows that, under the condition of no external packaging, after the embodiments 1 to 8 are placed at 60 ℃ for 10 days, the content of the impurity A and the total impurities is not increased much, the stability of the bare chip is good, and the requirements of the quality standard (the limit of related substances is that the amount of the impurity A is not more than 0.3%, and the total amount of the impurity is not more than 1.0%) for the aminocaproic acid tablet in the USP39-NF34 are still met. When the proportion of alginic acid or ethyl cellulose and povidone K30 added into the bare chip is within a certain range, the stability is still good after the bare chip is placed at 60 ℃ for 30 days, the stability is better than that of a reference preparation, and the requirements of the quality standard (the limit of related substances is that the amount of the impurity A is not more than 0.3 percent, and the total amount of the impurity is not more than 1.0 percent) of the aminocaproic acid tablet in USP39-NF34 are still met. However, when the ratio of alginic acid or ethylcellulose, povidone K30, was not added to the bare chips, the stability was significantly deteriorated at the later stage of storage, as shown in examples 4 to 8, which were significantly inferior to examples 1 to 4, when they were left at 60 ℃ for 30 days.
Dissolution tests are carried out on the vigabatrin film-coated tablets prepared in examples 1-8 and are compared with a reference reagent, wherein the dissolution test refers to a second method of 0931 of the four general rules of the national pharmacopoeia 2015 edition as a dissolution detection method, the dissolution rate of 1000ml of water as a dissolution medium and 50 revolutions per minute is measured, and the dissolution rate is measured by using a commercially available method
As reference formulation, the data are shown in table 10 below:
TABLE 10 results of dissolution test
The dissolution results given at different times in table 10 are cumulative dissolution results. Experimental results show that the prepared vigabatrin film-coated tablet has consistent drug release behavior (f2 factor is more than 50) with a reference preparation, and by combining data in Table 10, the dissolution behavior similarity of examples 1-3 and the reference preparation is higher, and f2 factors are more than 60.
Example 9
Referring to the supplementary material components of the vigabatrin film-coated tablet of example 1, example 9 was conducted to study the preparation process of vigabatrin tablets, in which water, 20% ethanol by mass concentration, 50% ethanol by mass concentration, 80% ethanol by mass concentration, 95% ethanol by mass concentration and absolute ethanol were used as wetting agents (here, ethanol with different mass concentrations was prepared by mixing water and ethanol), respectively, during the preparation of vigabatrin tablets, and the stability effect of each wetting agent on the vigabatrin tablets obtained by the preparation was studied. Wherein, the vigabatrin tablet has the following components as shown in the following table 11:
TABLE 11 Divigabatrin tablet composition
| 1000 tablets (g) | Weight percent of | |
| Vigabatrin | 500 | 70％ |
| Microcrystalline cellulose | 142 | 20％ |
| Sodium carboxymethyl starch | 10.71 | 1.5％ |
| Alginic acid | 0.71 | 0.1％ |
| Ethyl cellulose | 13.57 | 1.9％ |
| Povidone K30 | 7.86 | 1.1％ |
| Magnesium stearate | 10.00 | 1.4％ |
The preparation method of the vigabatrin tablets comprises the following steps:
(1) ethyl cellulose and povidone K30 were weighed according to table 11 and dissolved in a wetting agent (water, 20% ethanol by mass, 50% ethanol by mass, 80% ethanol by mass, 95% ethanol by mass, and absolute ethanol, respectively) to prepare a 10% by mass binding solution.
(2) Weighing vigabatrin raw material, microcrystalline cellulose, sodium carboxymethyl starch and alginic acid according to the table 11, placing the materials in a wet mixing granulator, mixing the materials for several minutes until the mixture is uniform, adding the bonding solution containing the ethyl cellulose and the povidone K30 obtained in the step (1), cutting the bonding solution while stirring, and preparing a soft material.
(3) And (3) sieving the prepared soft material with a 24-mesh sieve, granulating, and then putting into an oven at 45 ℃ for drying.
(4) Taking out the dried granules, sieving with a 24-mesh sieve, and grading. The lubricant magnesium stearate in the amount in table 11 was then added and mixed for several minutes.
(5) And (4) tabletting the granules mixed in the step (4) to obtain the vigabatrin tablets.
The prepared tablets were left at 60 ℃ and sampled for 0 day and 10 days, respectively, to determine the changes of the substances, and the results are shown in Table 12 below.
Table 12 vigabatrin tablet impurity variation results
As can be seen from the results given in table 12, the content of impurity a and the content of total impurities were significantly lower over a period of time using an absolute ethanol-dissolving adhesive as a bonding solution than the vigabatrin tablets prepared using an absolute ethanol-dissolving adhesive containing moisture as a bonding solution. It is demonstrated that the addition of moisture during the wet preparation process affects the stability of the solid preparation of vigabatrin, even if the addition of slight moisture, for example, 95% ethanol solution adhesive is used as the binding solution, which has low stability and significantly increased contents of impurity A and total impurities after being placed at an accelerated speed.
Example 10
Referring to the supplementary material components of the vigabatrin film-coated tablet of example 1, example 10 was conducted to study the preparation process of vigabatrin film-coated tablets, in which water, 50% ethanol by mass, 70% ethanol by mass, 80% ethanol by mass, 95% ethanol by mass, and absolute ethanol were used as coating solvents (here, ethanol of different mass concentrations was prepared by mixing water and ethanol), respectively, in the process of coating vigabatrin tablets, and the influence of each coating solvent on the stability of the vigabatrin film-coated tablets obtained was studied. The specific experimental procedure for this example is as follows:
(1) weighing ethyl cellulose and povidone K30 according to the weight percentage in the table 1, dissolving the ethyl cellulose and the povidone K30 in absolute ethyl alcohol serving as a wetting agent, and preparing a bonding solution with the mass percentage of 10%.
(2) Weighing the raw materials of vigabatrin, microcrystalline cellulose, sodium carboxymethyl starch and alginic acid according to the table 1, placing the raw materials in a wet mixing granulator, mixing the materials for several minutes until the mixture is uniform, adding the bonding solution containing the ethyl cellulose and the povidone K30, cutting the bonding solution while stirring, and preparing a soft material.
(3) And (3) sieving the prepared soft material with a 24-mesh sieve, granulating, and then putting into an oven at 45 ℃ for drying.
(4) Taking out the dried granules, sieving with a 24-mesh sieve, and grading. The lubricant magnesium stearate in the amount shown in table 1 was then added and mixed for several minutes.
(5) And (4) tabletting the granules mixed in the step (4) to obtain the vigabatrin tablets.
(6) According to the table 1, the coating material opadry is dissolved in a coating solvent (water, 50% ethanol by mass, 70% ethanol by mass, 80% ethanol by mass, 95% ethanol, and absolute ethanol) to prepare a coating solution with the mass percent of 11%, and then the vigabatrin tablets are coated to obtain the vigabatrin film coated tablets.
The resulting vigabatrin film-coated tablet bare chips (i.e., without any external packaging) were placed at 60 ℃ and sampled for the change of the relevant substances at 0 day and 10 days, respectively, as shown in Table 13 below.
Table 13 results of impurity changes in vigabatrin film coated tablet dies
As can be seen from the results given in table 13, when the coated tablets were prepared using absolute ethanol as a coating solvent, the content of impurity a and the content of total impurities were significantly lower than those of vigabatrin coated tablets prepared using absolute ethanol containing moisture as a coating solvent upon accelerated standing for a certain period of time. It is demonstrated that the addition of water during the coating process also affects the stability of the vigabatrin-coated tablet, and that the stability is not high when using a 70% mass concentration ethanol aqueous solution or a 50% mass concentration ethanol aqueous solution as a coating solvent, which is accelerated to stand, compared to when using ethanol with a mass concentration of 80% or more as a coating solvent.
The terms "first", "second" and "first" are used herein for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "a plurality" means at least two, e.g., two, three, etc., unless specifically limited otherwise.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A preparation method of a vigabatrin solid preparation is characterized by comprising the following steps:
dissolving a binder in a first anhydrous alcohol solvent to obtain a binding solution;
mixing the vigabatrin, pharmaceutically acceptable auxiliary materials and the bonding solution, granulating and drying to prepare the vigabatrin solid preparation.
2. The method of claim 1, further comprising:
coating the vigabatrin solid preparation by using a coating solution to obtain a vigabatrin coated preparation, wherein the coating solution is obtained by dissolving a coating material in an alcohol solution with the mass concentration of more than 80%, and preferably is obtained by dissolving the coating material in a second absolute alcohol solvent.
3. The method according to claim 1 or 2, wherein the alcohol in the first anhydrous alcohol solvent, the second anhydrous alcohol solvent, and the alcohol solution at a mass concentration of 80% or more is independently selected from at least one of C1-C6 linear or branched alcohols, preferably at least one of isopropanol, ethanol, and propylene glycol, and more preferably ethanol.
4. The preparation method according to claim 3, wherein the binder is at least one selected from ethyl cellulose, povidone K30;
preferably ethyl cellulose and povidone K30, wherein the mass ratio of the ethyl cellulose to the povidone K30 is 3: 2-4: 2.
more preferably, the mass ratio of the vigabatrin to the binder is 60: 3-80: 3.
5. the preparation method according to claim 3, wherein the pharmaceutically acceptable auxiliary materials include a disintegrant, a filler, a lubricant;
optionally, the disintegrant is selected from at least one of sodium carboxymethyl starch, calcium carboxymethyl cellulose, crospovidone, and croscarmellose sodium;
the filler is at least one selected from microcrystalline cellulose, mannitol, lactose, sorbitol, starch and pregelatinized starch;
the lubricant is selected from at least one of magnesium stearate, sodium stearyl fumarate, silicon dioxide, talcum powder and sodium dodecyl sulfate.
6. The preparation method according to claim 3, wherein the pharmaceutically acceptable auxiliary materials further comprise alginic acid, preferably, the alginic acid accounts for 0.05% -0.3% of the vigabatrin solid preparation, and more preferably, the mass ratio of vigabatrin to alginic acid is 160: 0.1-20: 0.1.
7. a vigabatrin solid preparation, characterized in that the vigabatrin solid preparation is prepared according to the preparation method of any one of claims 1-6.
8. The vigabatrin solid formulation of claim 7, wherein the solid formulation comprises:
60-80 parts by weight of vigabatrin;
1-2 parts by weight of sodium carboxymethyl starch or croscarmellose sodium;
0.01 to 0.3 parts by weight of alginic acid;
1-3 parts by weight of povidone K30 and/or 1-3 parts by weight of ethyl cellulose;
1-3 parts by weight of magnesium stearate or sodium stearyl fumarate;
10-30 parts by weight of microcrystalline cellulose or mannitol or lactose or starch;
optionally, a coating material may be included as well,
preferably, the solid formulation comprises:
60-80 parts by weight of vigabatrin;
1.3-1.6 parts by weight of sodium carboxymethyl starch or croscarmellose sodium;
0.05 to 0.3 part by weight of alginic acid;
1.8-2 parts by weight of ethyl cellulose;
1-1.2 parts by weight of povidone K30;
1.2-1.5 parts by weight of magnesium stearate;
10-30 parts by weight of microcrystalline cellulose or mannitol or lactose or starch;
optionally, a coating material.
9. The vigabatrin solid preparation according to claim 7, wherein the vigabatrin solid preparation is left for 10 days at 60 ℃ without packaging, the content of impurity A is below 0.3%, the total impurity content is below 1.0%,
preferably, the content of the impurity A is below 0.3 percent and the total impurity content is below 1.0 percent when the product is placed at 60 ℃ for 30 days without being packaged.
10. The vigabatrin solid preparation according to claim 7, wherein the solid preparation is at least one selected from the group consisting of tablets, granules, powders and capsules.
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| CN116120200A (en) * | 2021-11-15 | 2023-05-16 | 武汉武药科技有限公司 | Vigabatrin bulk drug, vigabatrin solid composition and preparation method thereof |
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| CN104922075A (en) * | 2015-05-31 | 2015-09-23 | 黑龙江佰彤儿童药物研究有限公司 | Solid preparation for treating pediatric epilepsy and preparation method thereof |
| CN108014085A (en) * | 2016-11-04 | 2018-05-11 | 武汉武药科技有限公司 | A kind of preparation method and applications of sabril solid composite |
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