CN113750073A - Preparation method of high-purity nateglinide capsule - Google Patents
Preparation method of high-purity nateglinide capsule Download PDFInfo
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- CN113750073A CN113750073A CN202111158149.9A CN202111158149A CN113750073A CN 113750073 A CN113750073 A CN 113750073A CN 202111158149 A CN202111158149 A CN 202111158149A CN 113750073 A CN113750073 A CN 113750073A
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- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 title claims abstract description 77
- 229960000698 nateglinide Drugs 0.000 title claims abstract description 72
- 239000002775 capsule Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 239000007908 nanoemulsion Substances 0.000 claims abstract description 27
- 239000006184 cosolvent Substances 0.000 claims abstract description 9
- 239000003085 diluting agent Substances 0.000 claims abstract description 9
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 239000007884 disintegrant Substances 0.000 claims abstract description 8
- 239000013078 crystal Substances 0.000 claims description 34
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 239000007901 soft capsule Substances 0.000 claims description 10
- 238000009210 therapy by ultrasound Methods 0.000 claims description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 239000003921 oil Substances 0.000 claims description 8
- 235000019198 oils Nutrition 0.000 claims description 8
- -1 phenolic aldehyde Chemical class 0.000 claims description 8
- 229960003966 nicotinamide Drugs 0.000 claims description 7
- 235000005152 nicotinamide Nutrition 0.000 claims description 7
- 239000011570 nicotinamide Substances 0.000 claims description 7
- 229920000136 polysorbate Polymers 0.000 claims description 7
- 229950008882 polysorbate Drugs 0.000 claims description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 6
- 125000002091 cationic group Chemical group 0.000 claims description 6
- 239000000839 emulsion Substances 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 229920002401 polyacrylamide Polymers 0.000 claims description 6
- YXGDSBSUTMGHOL-UHFFFAOYSA-N 4-propan-2-ylcyclohexane-1-carbonyl chloride Chemical compound CC(C)C1CCC(C(Cl)=O)CC1 YXGDSBSUTMGHOL-UHFFFAOYSA-N 0.000 claims description 5
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims description 5
- 229930182832 D-phenylalanine Natural products 0.000 claims description 5
- 108010010803 Gelatin Proteins 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- 229960000913 crospovidone Drugs 0.000 claims description 5
- 238000001723 curing Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000008273 gelatin Substances 0.000 claims description 5
- 229920000159 gelatin Polymers 0.000 claims description 5
- 235000019322 gelatine Nutrition 0.000 claims description 5
- 235000011852 gelatine desserts Nutrition 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000004530 micro-emulsion Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 238000003825 pressing Methods 0.000 claims description 5
- 238000010008 shearing Methods 0.000 claims description 5
- PSRQIJMEXPZYEO-UHFFFAOYSA-N 1-cyclohexylpropane-1,2-diol Chemical compound CC(O)C(O)C1CCCCC1 PSRQIJMEXPZYEO-UHFFFAOYSA-N 0.000 claims description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- 229920002785 Croscarmellose sodium 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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 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 4
- 239000010495 camellia oil Substances 0.000 claims description 4
- 239000004359 castor oil Substances 0.000 claims description 4
- 235000019438 castor oil Nutrition 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000004006 olive oil Substances 0.000 claims description 4
- 235000008390 olive oil Nutrition 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- 229940068968 polysorbate 80 Drugs 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 3
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 3
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 3
- 229940113124 polysorbate 60 Drugs 0.000 claims description 3
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 9
- 238000004090 dissolution Methods 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 3
- 230000001737 promoting effect Effects 0.000 abstract description 2
- 238000010521 absorption reaction Methods 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 8
- 239000003472 antidiabetic agent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000008566 D-phenylalanines Chemical class 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 102000016924 KATP Channels Human genes 0.000 description 1
- 108010053914 KATP Channels Proteins 0.000 description 1
- NEAPKZHDYMQZCB-UHFFFAOYSA-N N-[2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]ethyl]-2-oxo-3H-1,3-benzoxazole-6-carboxamide Chemical compound C1CN(CCN1CCNC(=O)C2=CC3=C(C=C2)NC(=O)O3)C4=CN=C(N=C4)NC5CC6=CC=CC=C6C5 NEAPKZHDYMQZCB-UHFFFAOYSA-N 0.000 description 1
- 102000018692 Sulfonylurea Receptors Human genes 0.000 description 1
- 108010091821 Sulfonylurea Receptors Proteins 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- BNYHRGTXRPWASY-UHFFFAOYSA-N nonylsulfonylurea Chemical compound CCCCCCCCCS(=O)(=O)NC(N)=O BNYHRGTXRPWASY-UHFFFAOYSA-N 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a preparation method of a high-purity nateglinide capsule, which comprises the following steps: the preparation method comprises the steps of preparing nateglinide S1H, preparing S2 nano emulsion and preparing a nateglinide S3 capsule, wherein the preparation method comprises the steps of combining and proportioning the raw materials, reasonably selecting a diluent, a cosolvent, an oil phase, an emulsifier, a disintegrant and an agglutinant, promoting the dissolution of the nateglinide, improving the dissolution rate of the nateglinide, uniformly dispersing the medicine, ensuring stable absorption in a human body and improving the bioavailability.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of a high-purity nateglinide capsule.
Background
Nateglinide (trade name: Nateglinide), the content is off-white; the D-phenylalanine derivative belongs to non-sulfonylurea hypoglycemic agents, and has the action mechanism that the D-phenylalanine derivative is mainly combined with a sulfonylurea receptor on an islet B cell to block the opening of an islet cell ATP sensitive potassium channel, so that the cell membrane depolarizes, the calcium channel is opened, and the insulin secretion is promoted; the compound is a new generation of hypoglycemic drugs with amino acid structures, is the first insulin secretion promoting amino acid derivative for treating type 2 diabetes, has a unique structure, is superior to other oral hypoglycemic drugs in chemical and pharmacological aspects, can effectively control postprandial blood sugar level, and has the characteristics of quick response, short action time, cardiovascular side effects, low hypoglycemic incidence rate and the like.
The nateglinide has B, H, S crystal forms, the stability difference of the three crystal forms is large, the nateglinide B is unstable and easy to generate crystal transformation, only the nateglinide H is used for preparation at present, and the nateglinide H is superior to the nateglinide B in the aspects of stability, pharmacology and drug effect. The traditional preparation method is that steam is used as a temperature control means, so that B, H, S various crystal forms, isomers and other impurities are more easily generated, the purity of the obtained product is low, the quality is unstable, and the patent CN109369443A provides a new preparation method of the nateglinide H crystal form, and the dissolution rate is poor; the patent CN102813636B, nateglinide tablet and the preparation method thereof have the disadvantages of poor dissolution rate, difficult water dissolution and low oral bioavailability in the storage process.
Disclosure of Invention
In view of this, the present invention provides a method for preparing high purity nateglinide capsules, which solves the above problems.
The technical scheme of the invention is realized as follows: a preparation method of high-purity nateglinide capsules comprises the following steps: the method comprises the following steps:
preparation of nateglinide form H, S1: condensing trans-4-isopropylcyclohexanecarbonyl chloride and D-phenylalanine to obtain crude nateglinide B crystal, crushing at low temperature to obtain particle seed crystal, adding a crystallizing agent, heating to 35-40 ℃ to guide crystallization, and obtaining white nateglinide H crystal;
s2, preparation of nano emulsion: the nano emulsion comprises the following raw materials in parts by weight: 13-30 parts of H-type nateglinide, 20-25 parts of diluent, 10-15 parts of cosolvent, 3-8 parts of oil phase, 2-4 parts of emulsifier, 1-3 parts of disintegrant and 0.5-1.5 parts of agglutinant;
the preparation method of the nano emulsion comprises the following steps: dissolving H-type nateglinide white crystals obtained in S1 in an alcohol solvent, respectively adding a diluent and a cosolvent, uniformly mixing to obtain a clear liquid, adding an oil phase, an emulsifier, a disintegrant and an agglomerant, mixing at 50-80 ℃, shearing into a microemulsion, and performing ultrasonic treatment to form a nano emulsion, wherein the ultrasonic treatment conditions are as follows: temperature: 35-45 ℃, ultrasonic power: 200-350W, ultrasonic time: 20-80 s;
s3, preparation of nateglinide capsules: and introducing nitrogen into the nano emulsion, reacting at 50-70 ℃ to obtain a content, preparing a soft capsule by using gelatin, water, sorbitol and/or glycerol as capsule wall materials by adopting a mould pressing method, and curing and drying the soft capsule by cold air to obtain the nateglinide capsule.
Further, the temperature of the low temperature in the S1 is 15-20 ℃.
Further, the crystallization agent in the S1 is prepared by mixing water-soluble phenolic aldehyde and nicotinamide in a mass ratio of 0.3-1.6: 1-3, and adding water in a mass-volume ratio of 2-4: 1.
Further, the mass volume ratio g/L of the H-form nateglinide white crystal in the S2 to the alcohol solvent is 1-5: 3, the alcohol solvent is one of methanol, ethanol, benzyl alcohol and glycol.
Further, the diluent in S2 is triethanolamine or n-propyl ester.
Further, the cosolvent in the S2 is polysorbate 80 and/or polysorbate 60.
Further, the oil phase in S2 is one of camellia oil, olive oil, and castor oil.
Further, the emulsifier is one of cyclohexylpropylene glycol, polyethylene glycol and polysorbate 400.
Further, the disintegrating agent is one of croscarmellose sodium, crospovidone and crospovidone.
Further, the agglutinant is cationic polyacrylamide emulsion or acrylic acid.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention crushes the crude product crystal of the nateglinide B type at low temperature, adds a specific crystallizing agent, mixes the water-soluble phenolic aldehyde and the nicotinamide in proportion, and the free phenolic aldehyde molecule and the free amide group can be used as a proton acceptor and a donor to promote the bonding between the molecules of the nateglinide crystal, so that the purity of the separated H type nateglinide white crystal is higher.
(2) Through the combination and proportioning of the raw materials, the diluent, the cosolvent, the oil phase, the emulsifier, the disintegrant and the coagulant are reasonably selected, the dissolution of substances is promoted, the dissolution rate of the nateglinide is improved, the medicine is uniformly dispersed and is stably absorbed by a human body, and the bioavailability is improved.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.
Example 1
A preparation method of high-purity nateglinide capsules comprises the following steps: the method comprises the following steps:
preparation of nateglinide form H, S1: condensing trans-4-isopropyl cyclohexanecarbonyl chloride and D-phenylalanine to obtain crude nateglinide B type crystals, crushing at 15 ℃ to obtain particle seed crystals, adding a crystallizing agent, heating to 35 ℃ to guide crystallization, mixing the crystallizing agent with water-soluble phenol aldehyde and nicotinamide in a mass ratio of 0.3:1, and adding water in a mass-volume ratio of 2:1 to obtain a crystallizing agent, so as to obtain white nateglinide H type crystals;
s2, preparation of nano emulsion: the nano emulsion comprises the following raw materials in parts by weight: 13 parts of nateglinide H, 20 parts of triethanolamine, 8010 parts of polysorbate, 3 parts of camellia oil, 2 parts of cyclohexyl propylene glycol, 1 part of croscarmellose sodium and 0.5 part of cationic polyacrylamide emulsion;
the preparation method of the nano emulsion comprises the following steps: dissolving H-type nateglinide white crystals obtained in S1 in methanol, respectively adding triethanolamine and polysorbate 80, mixing uniformly to obtain clear liquid, adding camellia oil, cyclohexyl propylene glycol, croscarmellose sodium and cationic polyacrylamide emulsion, mixing at 50 ℃, shearing into microemulsion, and performing ultrasonic treatment to form nano emulsion, wherein the ultrasonic treatment conditions are as follows: temperature: 35 ℃, ultrasonic power: 200W, ultrasonic time: 20 s;
s3, preparation of nateglinide capsules: introducing nitrogen into the nano emulsion, reacting at 50 ℃ to obtain a content, preparing a soft capsule by using gelatin, water and sorbitol as capsule materials by a mould pressing method, and curing and drying the soft capsule by cold air to obtain the nateglinide capsule.
Example 2
A preparation method of high-purity nateglinide capsules comprises the following steps: the method comprises the following steps:
preparation of nateglinide form H, S1: condensing trans-4-isopropyl cyclohexanecarbonyl chloride and D-phenylalanine to obtain crude nateglinide B crystal, crushing at low temperature to obtain fine grain seed crystal, adding a crystallizing agent, heating to 40 ℃ to guide crystallization to obtain white nateglinide H crystal, mixing the crystallizing agent with water-soluble phenolic aldehyde and nicotinamide in a mass ratio of 1.6:3, and adding water in a mass-volume ratio of 4: 1;
s2, preparation of nano emulsion: the nano emulsion comprises the following raw materials in parts by weight: 30 parts of nateglinide H, 25 parts of triethanolamine, 0-15 parts of polysorbate 8010-8 parts of castor oil, 4004 parts of polysorbate, 1-3 parts of crosslinked polyvinylpyrrolidone and 1.5 parts of cationic polyacrylamide emulsion;
the preparation method of the nano emulsion comprises the following steps: dissolving the H-type nateglinide white crystal obtained in S1 in an alcohol solvent, respectively adding triethanolamine and polysorbate 80, uniformly mixing to obtain a clear liquid, adding castor oil, polysorbate 400, cross-linked polyvinylpyrrolidone and cationic polyacrylamide emulsion, mixing at 80 ℃, shearing into microemulsion, and performing ultrasonic treatment to form nano emulsion, wherein the ultrasonic treatment conditions are as follows: temperature: 45 ℃, ultrasonic power: 350W, ultrasonic time: 80 s;
s3, preparation of nateglinide capsules: introducing nitrogen into the nano emulsion, reacting at 70 ℃ to obtain a content, preparing a soft capsule by using gelatin, water and sorbitol as capsule materials by a mould pressing method, and curing and drying the soft capsule by cold air to obtain the nateglinide capsule.
Example 3
A preparation method of high-purity nateglinide capsules comprises the following steps: the method comprises the following steps:
preparation of nateglinide form H, S1: condensing trans-4-isopropyl cyclohexanecarbonyl chloride and D-phenylalanine to obtain crude nateglinide B type crystals, crushing at 18 ℃ to obtain particle seed crystals, adding a crystallizing agent, heating to 38 ℃ to guide crystallization to obtain white nateglinide H type crystals, mixing the crystallizing agent with water-soluble phenol aldehyde and nicotinamide in a mass ratio of 0.9:2, and adding water in a mass-volume ratio of 3: 1;
s2, preparation of nano emulsion: the nano emulsion comprises the following raw materials in parts by weight: 18 parts of nateglinide H, 23 parts of n-propyl ester, 6012 parts of polysorbate, 5 parts of olive oil, 3 parts of polyethylene glycol, 2 parts of crospovidone and 1.0 part of acrylic acid;
the preparation method of the nano emulsion comprises the following steps: dissolving the H-type nateglinide white crystal obtained in S1 in an alcohol solvent, respectively adding n-propyl ester and polysorbate 60, uniformly mixing to obtain a clear liquid, adding olive oil, polyethylene glycol, crospovidone and acrylic acid, mixing at 70 ℃, shearing into a microemulsion, and performing ultrasonic treatment to form a nano emulsion, wherein the ultrasonic treatment conditions are as follows: temperature: 40 ℃, ultrasonic power: 320W, ultrasonic time: 60 s;
s3, preparation of nateglinide capsules: introducing nitrogen into the nano emulsion, reacting at 60 ℃ to obtain a content, preparing a soft capsule by using gelatin, water and glycerol as capsule wall materials by adopting a mould pressing method, and curing and drying the soft capsule by cold air to obtain the nateglinide capsule.
Example 4
The difference between the embodiment and the embodiment 3 is that the crystallizing agent of S1 is obtained by mixing water-soluble phenolic aldehyde and nicotinamide with the mass ratio of 0.1:1, and adding water with the mass volume ratio of 3: 1.
Example 5
The difference between the embodiment and the embodiment 3 is that the mass volume ratio g/L of the H-shaped nateglinide white crystals in the S2 to the alcohol solvent is 1-5: 3.
comparative example 1
This comparative example differs from example 3 in that the S1 is not fed with n-pentane to induce crystallization.
Comparative example 2
The comparative example differs from example 3 in that the nanoemulsion comprises the following raw materials in parts by weight: 10 parts of H-type nateglinide, 30 parts of diluent, 8 parts of cosolvent, 10 parts of oil phase, 5 parts of emulsifier, 4 parts of disintegrant and 2 parts of agglutinant.
First, purity determination
The purity of the nateglinide capsules prepared in the examples 1 to 5 and the comparative examples 1 to 2 is detected by High Performance Liquid Chromatography (HPLC), and the detection result is as follows:
as can be seen from the above table, the technical problem that the separation conditions of the H crystal form and the B crystal form are relatively similar is solved by crushing at low temperature and adding the crystallizing agent to guide crystallization by the method of the invention, and a pure H crystal form product is obtained, and the purity is higher under the condition of a certain proportion of the crystallizing agent.
Second, capsule performance test
The capsules of examples 1-5 and comparative examples 1-2 were tested for disintegration time and dissolution, the disintegration time was tested according to the method for testing disintegration time in pharmacopoeia 2020, high performance liquid chromatography was used for measurement, a chromatogram was recorded, the main content of each capsule was calculated by peak area according to an external standard method, and the dissolution of the capsules was calculated by comparison with the labeled amount.
| Disintegration time limit | Dissolution rate% | |
| Example 1 | 6′52″ | 76.58 |
| Example 2 | 6′55″ | 78.38 |
| Example 3 | 6′35″ | 83.62 |
| Example 4 | 7′06″ | 77.25 |
| Example 5 | 7′21″ | 74.50 |
| Comparative example 1 | 9′15″ | 60.35 |
| Comparative example 2 | 8′55″ | 58.25 |
According to the invention, through the combination and proportioning of the raw materials, the dissolution of substances is promoted, the dissolution rate of nateglinide is improved, the disintegrant is scientifically selected, the hygroscopicity is weak, external moisture can be broken up in time before entering the interior during dissolution, and the interference of moisture is reduced.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. A preparation method of high-purity nateglinide capsules is characterized by comprising the following steps: the method comprises the following steps:
preparation of nateglinide form H, S1: condensing trans-4-isopropylcyclohexanecarbonyl chloride and D-phenylalanine to obtain crude nateglinide B crystal, crushing at low temperature to obtain particle seed crystal, adding a crystallizing agent, heating to 35-40 ℃ to guide crystallization, and obtaining white nateglinide H crystal;
s2, preparation of nano emulsion: the nano emulsion comprises the following raw materials in parts by weight: 13-30 parts of H-type nateglinide, 20-25 parts of diluent, 10-15 parts of cosolvent, 3-8 parts of oil phase, 2-4 parts of emulsifier, 1-3 parts of disintegrant and 0.5-1.5 parts of agglutinant;
the preparation method of the nano emulsion comprises the following steps: dissolving H-type nateglinide white crystals obtained in S1 in an alcohol solvent, respectively adding a diluent and a cosolvent, uniformly mixing to obtain a clear liquid, adding an oil phase, an emulsifier, a disintegrant and an agglomerant, mixing at 50-80 ℃, shearing into a microemulsion, and performing ultrasonic treatment to form a nano emulsion, wherein the ultrasonic treatment conditions are as follows: temperature: 35-45 ℃, ultrasonic power: 200-350W, ultrasonic time: 20-80 s;
s3, preparation of nateglinide capsules: and introducing nitrogen into the nano emulsion, reacting at 50-70 ℃ to obtain a content, preparing a soft capsule by using gelatin, water, sorbitol and/or glycerol as capsule wall materials by adopting a mould pressing method, and curing and drying the soft capsule by cold air to obtain the nateglinide capsule.
2. The process for preparing a high purity nateglinide capsule according to claim 1, wherein: the temperature of the low temperature in the S1 is 15-20 ℃.
3. The process for preparing a high purity nateglinide capsule according to claim 1, wherein: the crystallizing agent in the S1 is prepared by mixing water-soluble phenolic aldehyde and nicotinamide in a mass ratio of 0.3-1.6: 1-3, and adding water in a mass-volume ratio of 2-4: 1.
4. The process for preparing a high purity nateglinide capsule according to claim 1, wherein: the mass-to-volume ratio g/L of the H-type nateglinide white crystal in the S2 to the alcohol solvent is 1-5: 3, the alcohol solvent is one of methanol, ethanol, benzyl alcohol and glycol.
5. The process for preparing a high purity nateglinide capsule according to claim 1, wherein: and the diluent in the S2 is triethanolamine or n-propyl ester.
6. The process for preparing a high purity nateglinide capsule according to claim 1, wherein: the cosolvent in the S2 is polysorbate 80 and/or polysorbate 60.
7. The process for preparing a high purity nateglinide capsule according to claim 1, wherein: the oil phase in S2 is one of camellia oil, olive oil and castor oil.
8. The process for preparing a high purity nateglinide capsule according to claim 1, wherein: the emulsifier is one of cyclohexyl propylene glycol, polyethylene glycol and polysorbate 400.
9. The process for preparing a high purity nateglinide capsule according to claim 1, wherein: the disintegrating agent is one of croscarmellose sodium, crospovidone and crospolyvinylpyrrolidone.
10. The process for preparing a high purity nateglinide capsule according to claim 1, wherein: the agglutinant is cationic polyacrylamide emulsion or acrylic acid.
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