CN117771195A - Highly stable nicorandil composition and preparation method thereof - Google Patents
Highly stable nicorandil composition and preparation method thereof Download PDFInfo
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- CN117771195A CN117771195A CN202311786588.3A CN202311786588A CN117771195A CN 117771195 A CN117771195 A CN 117771195A CN 202311786588 A CN202311786588 A CN 202311786588A CN 117771195 A CN117771195 A CN 117771195A
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- 239000000203 mixture Substances 0.000 title claims abstract description 76
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 229960002497 nicorandil Drugs 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title abstract description 32
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 57
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 57
- 239000000945 filler Substances 0.000 claims abstract description 53
- 239000000314 lubricant Substances 0.000 claims abstract description 39
- 239000000463 material Substances 0.000 claims abstract description 38
- 239000004480 active ingredient Substances 0.000 claims abstract description 36
- 238000002156 mixing Methods 0.000 claims abstract description 26
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000002245 particle Substances 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 24
- 239000003381 stabilizer Substances 0.000 claims description 24
- 238000005507 spraying Methods 0.000 claims description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000007884 disintegrant Substances 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 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 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000008101 lactose Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 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 11
- 229930195725 Mannitol Natural products 0.000 claims description 11
- 239000000594 mannitol Substances 0.000 claims description 11
- 235000010355 mannitol Nutrition 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 229920002261 Corn starch Polymers 0.000 claims description 9
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 9
- 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 9
- 239000008120 corn starch Substances 0.000 claims description 9
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 9
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 235000021355 Stearic acid Nutrition 0.000 claims description 8
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 8
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 8
- 239000008117 stearic acid Substances 0.000 claims description 8
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 7
- 235000013539 calcium stearate Nutrition 0.000 claims description 7
- 239000008116 calcium stearate 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
- 235000019359 magnesium stearate Nutrition 0.000 claims description 7
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 7
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 7
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- 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 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 2
- 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 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940083542 sodium Drugs 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 1
- 239000011575 calcium Substances 0.000 claims 1
- 229910052791 calcium Inorganic materials 0.000 claims 1
- 238000004806 packaging method and process Methods 0.000 abstract description 13
- 230000009286 beneficial effect Effects 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000007613 environmental effect Effects 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 14
- 239000002274 desiccant Substances 0.000 description 9
- 238000011835 investigation Methods 0.000 description 6
- VRAIHTAYLFXSJJ-UHFFFAOYSA-N alumane Chemical compound [AlH3].[AlH3] VRAIHTAYLFXSJJ-UHFFFAOYSA-N 0.000 description 5
- 206010002383 Angina Pectoris Diseases 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 238000007907 direct compression Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- -1 nitrate compound Chemical class 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000005022 packaging material Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000004036 potassium channel stimulating agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of medicines, and provides a highly stable nicorandil composition and a preparation method thereof. The composition comprises a component A, polyethylene glycol and other pharmaceutically acceptable auxiliary materials; the component A is an active ingredient or a mixture of at least one selected from a filler, a disintegrating agent and a lubricant and the active ingredient; the active ingredient is nicorandil or pharmaceutically acceptable salt thereof. The preparation method of the composition comprises the following steps: granulating the component A and the polyethylene glycol by adopting a fluidized bed, then mixing with other pharmaceutically acceptable auxiliary materials, and tabletting to obtain the composition. The composition has the advantages of good stability, safety, environmental protection, low cost, simple packaging mode, simple prescription and simple preparation method, and is beneficial to industrialized production.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a highly stable nicorandil composition and a preparation method thereof.
Background
Nicorandil is a drug used to treat angina pectoris. The nicorandil tablet is used as the first potassium channel opener for clinic, is proved to be capable of obviously reducing total cause death, reducing cardiovascular events and improving long-term prognosis of angina patients in two large clinical studies (IONA (the role of nicorandil in angina pectoris treatment) and JCDA (Japanese coronary heart disease study)), and is a brand new choice of angina pectoris treatment.
Because nicorandil is a nitrate compound and is easy to degrade under the damp-heat condition, nicorandil is extremely unstable in a conventional preparation, so that the nicorandil raw material medicine or the preparation needs to avoid contacting with high temperature and high humidity in the preparation or storage process, and a desiccant is additionally added to the packaging of the nicorandil tablets on the market at present, and the degradation rate of the nicorandil tablets is slowed down by controlling moisture. The national drug administration 2017, 10-12, will be Chugai Pharmaceutical co., ltd. The name of the original research imported nicorandil tablet commodity: the SIGMART 5mg specification is listed as a reference preparation, and the packaging mode adopts pillow type packaging (aluminum plastic bubble cap + desiccant + moisture-proof bag), and the packaging has two defects: firstly, the packaging mode is complex, the use of a drying agent is increased, the production cost is increased, and the commercial production is not facilitated. Secondly, once the pillow type package is opened, the dampproofing effect of drier loses efficacy, and long-time placement easily influences the stability of product, influences the quality of product.
Patent CN85109190a (japanese former patent in china) discloses a method for preparing a stable pharmaceutical formulation containing an active ingredient of nicorandil locus. The stable formulation is produced by mixing nicorandil, one or more finely divided saccharides and one or more powdered organic acids. The fine-pulverized saccharides are required to have an average particle size of not more than 10. Mu.m, and although this patent can improve the stability of the drug to some extent, the stability is still unsatisfactory, and the fine-pulverized saccharides are required to be pulverized by a jet mill, and the particle size is extremely severe and the production cost is high. Few commercial manufacturers capable of achieving the particle size are available and are expensive.
Patent CN115429763a discloses a nicorandil tablet and a preparation method thereof, the method comprises the steps of freeze-drying the nicorandil tablet, the moisture content after drying is required to be lower than 0.5%, the method can improve the stability of products to a certain extent, but the freeze-vacuum drying method is long in drying time and complicated in steps, and the dried tablet is required to be packaged in a vacuum drying oven, so that the difficulty of production is increased, and the commercial production is not facilitated.
The patent CN115317456A discloses a nicorandil composition and a preparation method, wherein the composition comprises nicorandil, alkali metal salt of carboxymethyl cellulose, lactose, sodium dodecyl sulfate and hydrogenated vegetable oil, the sample preparation is carried out through a wet granulation process, the prepared wet particles are dried through a fluidized bed, and then atomized, added with hydrogenated vegetable oil solution, dried, granulated and always mixed and tableted.
Patent CN115282123 a discloses a method for preparing a stable nicorandil preparation, which is to grind higher alcohol into higher alcohol mixed powder and prepare the nicorandil preparation by a direct tabletting method, and the method can improve the stability of the medicine to a certain extent, but the packaging mode still needs additional drying agent and moisture-proof bag. The granularity of the stabilizer stearyl alcohol and the filler is controlled too finely, industrialization is difficult, dust is produced in the processes of grinding, sieving, mixing, direct pressing and the like in the production process, the protection of production workers is not facilitated, and the method is not suitable for commercial production.
Therefore, the stability of the commercialized nicorandil tablet is improved, the packaging mode and the production process are simplified, and the problem to be solved is urgent for the present nicorandil preparation.
Disclosure of Invention
In order to solve the technical problems, the invention provides the following technical scheme.
In a first aspect, the present invention provides a composition.
A composition, comprising: component A, stabilizer and other pharmaceutically acceptable auxiliary materials; the component A is an active ingredient or a mixture of at least one selected from a filler, a disintegrating agent and a lubricant and the active ingredient; the active ingredient is nicorandil or pharmaceutically acceptable salt thereof; the stabilizer is polyethylene glycol.
In some embodiments, the composition is a tablet, and the method of making the composition comprises: dissolving a stabilizer with a solvent to obtain a stabilizer solution, granulating the component A and the stabilizer solution by adopting a fluidized bed, mixing with other pharmaceutically acceptable auxiliary materials, and tabletting to obtain the composition.
In some embodiments, the solvent comprises one or more of methanol, ethanol, isopropanol, n-butanol, dichloromethane, chloroform, dimethyl sulfoxide, chloroform, or acetone, among others.
In some embodiments, the polyethylene glycol has a molecular weight of greater than or equal to 1000. In some embodiments, the polyethylene glycol has a molecular weight of 1000 to 10000. In some embodiments, the polyethylene glycol has a molecular weight of 3000-8000. In some embodiments, the polyethylene glycol has a molecular weight of 3000 to 5000. In some embodiments, the polyethylene glycol has a molecular weight of 4000. The use of polyethylene glycol of the molecular weight provided by the present invention is more advantageous in improving the stability of the resulting composition, wherein the preferred polyethylene glycol has a molecular weight of 1000-8000. In some embodiments, the polyethylene glycol has a molecular weight of 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, or 10000.
In some embodiments, the other pharmaceutically acceptable excipients include at least one of a filler, a disintegrant, and a lubricant.
In some embodiments, the component a is an active ingredient and the other pharmaceutically acceptable excipients include at least one of a filler, a disintegrant, and a lubricant. In some embodiments, component a is a mixture of filler, disintegrant, and active ingredient, and the other pharmaceutically acceptable excipients include filler and lubricant.
In some embodiments, the filler in the other pharmaceutically acceptable excipients or the filler in component a is each independently selected from at least one of lactose, mannitol, sorbitol, microcrystalline cellulose, corn starch, sucrose, and dibasic calcium phosphate. In some embodiments, the filler in the other pharmaceutically acceptable adjuvant is mannitol. In some embodiments, the filler in component a is lactose.
In some embodiments, the disintegrant in the other pharmaceutically acceptable excipients or the disintegrant in the component a is each independently selected from at least one of carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose. In some embodiments, the disintegrant in component a is croscarmellose sodium.
In some embodiments, the lubricant in the other pharmaceutically acceptable excipients or the lubricant in component a is each independently selected from at least one of calcium stearate, zinc stearate, magnesium stearate, stearic acid, talc, sodium stearyl fumarate.
In some embodiments, the active ingredient is present in an amount of 5.0wt% to 10.0wt% based on the total mass of the composition.
In some embodiments, the polyethylene glycol is present in an amount of 0.5wt% to 5.0wt% based on the total mass of the composition.
In some embodiments, the filler is present in the additional pharmaceutically acceptable excipients in an amount of 30.0wt% to 90.0wt% based on the total mass of the composition. In some embodiments, the filler is present in the additional pharmaceutically acceptable excipients in an amount of 30.0wt%, 31.0wt%, 31.5wt%, 32.0wt%, 32.5wt%, 33.0wt%, 33.5wt%, 34.0wt%, 34.5wt%, 35.0wt%, 35.5wt%, 36.0wt%, 36.5wt%, 37.0wt%, 37.5wt%, 38.0wt%, 38.5wt%, 39.0wt%, 40.0wt%, 41.0wt%, 42.0wt%, 45.0wt%, 50.0wt%, 55.0wt%, 60.0wt%, 65.0wt%, 70.0wt%, 75.0wt%, 80.0wt%, 81.0wt%, 82.0wt%, 83.0wt%, 83.5wt%, 84.0wt%, 84.5wt%, 85.0wt%, or 90.0wt%, based on the total mass of the composition.
In some embodiments, the filler is present in component a in an amount of 0 to 70.0wt%, based on the total mass of the composition. In some embodiments, the filler is present in component a in an amount of 0, 10.0wt%, 15.0wt%, 20.0wt%, 25.0wt%, 30.0wt%, 35.0wt%, 40.0wt%, 45.0wt%, 46.0wt%, 47.0wt%, 48.0wt%, 49.0wt%, 49.5wt%, 50.0wt%, 50.5wt%, 51.0wt%, 52.0wt%, 53.0wt%, 54.0wt%, 55.0wt%, 60.0wt%, 70.0wt% or 70.0wt% based on the total mass of the composition. In some embodiments, the filler is present in component a in an amount of 0 to 50.0wt%, based on the total mass of the composition.
In some embodiments, the disintegrant is present in the additional pharmaceutically acceptable excipients in an amount of 0 to 5.0wt%, based on the total mass of the composition. In some embodiments, the disintegrant is present in the additional pharmaceutically acceptable excipients in an amount of 0, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, or 5.0wt% based on the total mass of the composition.
In some embodiments, the disintegrant is present in component a in an amount of 0 to 5.0wt%, based on the total mass of the composition. In some embodiments, the disintegrant is present in component a in an amount of 0, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, or 5.0wt% based on the total mass of the composition.
In some embodiments, the lubricant is present in the additional pharmaceutically acceptable excipients in an amount of 0.5wt% to 5.0wt% based on the total mass of the composition. In some embodiments, the amount of lubricant in the additional pharmaceutically acceptable excipients is 0.5wt%, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, or 5.0wt%, based on the total mass of the composition.
In some embodiments, the amount of lubricant in component a is from 0 to 1.0wt%, based on the total mass of the composition. In some embodiments, the amount of lubricant in component a is 0, 0.5wt%, or 1.0wt%, based on the total mass of the composition.
In some embodiments, the composition comprises: component A, polyethylene glycol and other pharmaceutically acceptable auxiliary materials; the component A is an active ingredient; the active ingredient is nicorandil or pharmaceutically acceptable salt thereof; the other pharmaceutically acceptable auxiliary materials are filler, disintegrating agent and lubricant; the filler is at least one of lactose, corn starch or mannitol; the disintegrating agent is croscarmellose sodium; the lubricant is at least one of calcium stearate, zinc stearate, magnesium stearate, stearic acid, talcum powder and sodium stearyl fumarate; the active ingredient is present in an amount of 5.0wt% to 10.0wt% (e.g., 5.0wt%, 5.5wt%, 6.0wt%, 6.5wt%, 7.0wt%, 7.5wt%, 8.0wt%, 8.5wt%, 9.0wt%, 9.5wt%, or 10.0 wt%) based on the total mass of the composition; the polyethylene glycol is present in an amount of 2.0wt% to 5.0wt% (e.g., 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, or 5.0 wt%); the filler is present in an amount of 80.0wt% to 85.0wt% (e.g., 80.0wt%, 80.5wt%, 81.0wt%, 81.5wt%, 82.0wt%, 82.5wt%, 83.0wt%, 83.5wt%, 84.0wt%, 84.5wt%, or 85.0 wt%); the disintegrant is present in an amount of 2.0wt% to 5.0wt% (e.g., 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, or 5.0 wt%); the lubricant is present in an amount of 0.5wt% to 5.0wt% (e.g., 0.5wt%, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, or 5.0 wt%).
In some embodiments, the composition comprises: component A, polyethylene glycol and other pharmaceutically acceptable auxiliary materials; the component A is an active ingredient; the active ingredient is nicorandil or pharmaceutically acceptable salt thereof; the other pharmaceutically acceptable auxiliary materials are filler, disintegrating agent and lubricant; the filler is at least one of lactose, corn starch or mannitol; the disintegrating agent is croscarmellose sodium; the lubricant is at least one of calcium stearate, zinc stearate, magnesium stearate, stearic acid, talcum powder and sodium stearyl fumarate; the content of the active ingredient is 5.0 to 10.0 weight percent calculated by the total mass of the composition; the content of the polyethylene glycol is 3.0wt%; the filler content was 83.5wt%; the content of the disintegrating agent is 3.0wt%; the lubricant is present in an amount of 0.5wt% to 5.0wt% (e.g., 0.5wt%, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, or 5.0 wt%).
In some embodiments, the composition comprises: component A, polyethylene glycol and other pharmaceutically acceptable auxiliary materials; the component A is a mixture of at least one selected from a filler and a disintegrating agent and an active ingredient; the active ingredient is nicorandil or pharmaceutically acceptable salt thereof; the other pharmaceutically acceptable auxiliary materials comprise a filler and a lubricant; the filler in the component A is at least one of lactose, corn starch or mannitol; the disintegrating agent in the component A is croscarmellose sodium; the other pharmaceutically acceptable filler is at least one of lactose, corn starch or mannitol; the lubricant in the other pharmaceutically acceptable auxiliary materials is at least one of calcium stearate, zinc stearate, magnesium stearate, stearic acid, talcum powder and sodium stearyl fumarate; the active ingredient is present in an amount of 5.0wt% to 10.0wt% (e.g., 5.0wt%, 5.5wt%, 6.0wt%, 6.5wt%, 7.0wt%, 7.5wt%, 8.0wt%, 8.5wt%, 9.0wt%, 9.5wt%, or 10.0 wt%) based on the total mass of the composition; the polyethylene glycol is present in an amount of 0.5wt% to 5.0wt% (e.g., 0.5wt%, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, or 5.0 wt%); the filler content in component a is 30.0wt% to 50.0wt% (e.g., 30.0wt%, 30.5wt%, 31.0wt%, 31.5wt%, 32.0wt%, 32.5wt%, 33.0wt%, 33.5wt%, 34.0wt%, 34.5wt%, 35.0wt%, 35.5wt%, 36.0wt%, 36.5wt%, 37.0wt%, 37.5wt%, 38.0wt%, 38.5wt%, 39.0wt%, 39.5wt%, 40.0wt%, 40.5wt%, 41.0wt%, 41.5wt%, 42.0wt%, 42.5wt%, 43.0wt%, 43.5wt%, 44.0wt%, 44.5wt%, 45.0wt%, 45.5wt%, 46.0wt%, 46.5wt%, 47.0wt%, 47.5wt%, 48.0wt%, 48.5, 49.0wt%, 49.5wt%, or 50.0wt%; the disintegrant is present in component a in an amount of 2.0wt% to 5.0wt% (e.g., 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, or 5.0 wt%); the other pharmaceutically acceptable filler is present in an amount of 30.0wt% to 40.0wt% (e.g., 30.0wt%, 30.5wt%, 31.0wt%, 31.5wt%, 32.0wt%, 32.5wt%, 33.0wt%, 33.5wt%, 34.0wt%, 34.5wt%, 35.0wt%, 35.5wt%, 36.0wt%, 36.5wt%, 37.0wt%, 37.5wt%, 38.0wt%, 38.5wt%, 39.0wt%, 39.5wt%, or 40.0 wt%); the other pharmaceutically acceptable lubricant is present in an amount of 0.5wt% to 5.0wt% (e.g., 0.5wt%, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, or 5.0 wt%).
In some embodiments, the dosage form of the composition is a tablet.
In a second aspect, the present invention provides a method of preparing the composition of the first aspect.
A method of preparing the composition of the first aspect, comprising:
(1) Mixing polyethylene glycol with a solvent to obtain a polyethylene glycol solution;
(2) Granulating the component A and the polyethylene glycol solution obtained in the step (1) in a fluidized bed to obtain dry granules;
(3) Mixing the dry particles obtained in the step (2) with other pharmaceutically acceptable auxiliary materials to obtain total mixed particles;
(4) Tabletting the total mixed particles obtained in the step (3) to obtain the composition.
In some embodiments, the component a is an active ingredient, and the other pharmaceutically acceptable excipients include at least one of a filler, a disintegrant, and a lubricant; the method comprises the following steps:
(a) Mixing polyethylene glycol with a solvent to obtain a polyethylene glycol solution;
(b) Granulating nicorandil or pharmaceutically acceptable salt thereof with the polyethylene glycol solution obtained in the step (a) in a fluidized bed to obtain dry granules;
(c) Mixing the dry particles obtained in the step (b) with other pharmaceutically acceptable auxiliary materials to obtain total mixed particles;
(d) Tabletting the total mixed particles obtained in the step (c) to obtain the composition.
In some embodiments, the component a is a mixture of filler, disintegrant, and active ingredient, and the other pharmaceutically acceptable excipients include filler and lubricant; the method comprises the following steps:
(i) Mixing polyethylene glycol with a solvent to obtain a polyethylene glycol solution;
(ii) Granulating the component A and the polyethylene glycol solution obtained in the step (i) in a fluidized bed to obtain dry granules;
(iii) Mixing the dry particles obtained in the step (ii) with other pharmaceutically acceptable auxiliary materials to obtain total mixed particles;
(iv) Tabletting the total mixed particles obtained in step (iii) to obtain the composition.
In some embodiments, the solvent comprises one or more of methanol, ethanol, isopropanol, n-butanol, dichloromethane, chloroform, dimethyl sulfoxide, chloroform, or acetone, among others.
In some embodiments, the granulating of step (2) comprises controlling the temperature of component a to 25 ℃ to 40 ℃, adding the polyethylene glycol solution obtained in step (1) by bottom spraying, top spraying or side spraying, drying, and granulating.
In some embodiments, the granulating of step (b) comprises controlling the temperature of the nicorandil or pharmaceutically acceptable salt thereof at 25 ℃ to 40 ℃, adding the polyethylene glycol solution obtained in step (a) by bottom spraying, top spraying or side spraying, drying, and granulating.
In some embodiments, the granulating of step (ii) comprises controlling the temperature of component a to 25 ℃ to 40 ℃, adding the polyethylene glycol solution obtained in step (i) by bottom spraying, top spraying or side spraying, drying, and granulating.
Advantageous effects
Compared with the prior art, one embodiment of the invention at least comprises the following beneficial effects:
(1) Compared with polyethylene glycol with other molecular weights, the polyethylene glycol with the molecular weight provided by the invention is more beneficial to improving the stability of the obtained nicorandil tablet.
(2) Compared with other preparation processes (such as a direct compression process), the preparation method (fluidized bed granulation) provided by the invention is more beneficial to improving the stability of the obtained nicorandil tablet.
(3) Compared with the nicorandil tablet in the prior art, the nicorandil tablet provided by the invention has better stability.
(4) The nicorandil tablet provided by the invention has excellent stability, the stability of the product can be ensured only by using the conventional aluminum packaging material, the extra use of a drying agent is avoided, the risk of miseating of the drying agent and the pollution to the environment are reduced, and the safety and the effectiveness of the medication of patients are ensured.
(5) The nicorandil tablet provided by the invention is safe and environment-friendly, low in cost, simple in packaging mode, simple in prescription and simple in preparation method, and is beneficial to industrial production.
Definition of terms:
in the context of the present invention, all numbers disclosed herein are approximations, whether or not the word "about" or "about" is used. Based on the numbers disclosed, there is a possibility that the values of each number may differ by less than + -10% or a reasonable difference as recognized by those skilled in the art, such as + -1%, + -2%, + -3%, + -4%, or + -5%.
In the invention, the normal temperature or the room temperature represents the ambient temperature and can be 20-30 ℃; in some embodiments, 22 ℃ to 28 ℃; in some embodiments, 24 ℃ to 26 ℃; in some embodiments, 25 ℃.
The terms "above," "below," "within," and the like are to be construed as including the present number, e.g., two or more means ≡two.
The term "and/or" is understood to mean any one of the selectable items or a combination of any two or more of the selectable items.
The term "% vol" means volume percent.
The term "wt%" represents mass percent.
The term "multiple" means a number of 2 or more, for example 2, 3, 4 or 5, etc.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means 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 present invention. In this specification, schematic representations of the above terms are not necessarily directed 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, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
Detailed Description
The following examples are further illustrative of the invention and are not intended to limit the scope of the invention.
All technical terms used herein have the same meaning as commonly understood by one skilled in the art to which the present invention pertains. As used herein, "and"/"or" includes any and all combinations of one or more of the associated listed items.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
Example 1-example 3:
prescription: see table 1.
Table 1: prescriptions of examples 1-3
The preparation method comprises the following steps:
(1) Dissolving a prescribed amount of stabilizer with a proper amount of absolute ethyl alcohol to obtain a stabilizer solution, wherein the content of the stabilizer in the stabilizer solution is 2.5wt%;
(2) Mixing nicorandil, lactose and croscarmellose sodium with a prescription amount to obtain a component A, placing the component A in a fluidized bed, controlling the temperature of the component A material to be 25-40 ℃, adding the stabilizer solution obtained in the atomization step (1) into the component A, and drying and granulating after the liquid adding and spraying are finished to obtain dry particles;
(3) Uniformly mixing the dry particles obtained in the step (2) with mannitol and stearic acid with a prescribed amount to obtain total mixed particles, and sampling and detecting the mixing uniformity of the total mixed particles (the result is shown in Table 6);
(4) Tabletting and then conventional aluminum-aluminum blister packaging.
Example 4 to example 6
Prescription: see table 2.
Table 2: prescriptions of example 4-example 6
Preparation method
(1) Dissolving a prescribed amount of stabilizer with a proper amount of absolute ethyl alcohol to obtain a stabilizer solution, wherein the content of the stabilizer in the stabilizer solution is 2.5wt%;
(2) Placing a prescription amount of nicorandil into a fluidized bed, controlling the temperature of the nicorandil material to be 25-40 ℃, atomizing the stabilizer solution obtained in the step (1) into the nicorandil, and drying and granulating after the liquid adding and spraying are finished to obtain dry particles;
(3) Uniformly mixing the dry particles obtained in the step (2) with a prescribed amount of filler, a disintegrating agent and a lubricant to obtain total mixed particles, and sampling and detecting the mixing uniformity of the total mixed particles (the result is shown in Table 6);
(4) Tabletting and then conventional aluminum-aluminum blister packaging.
Example 7-example 10
Prescription: see table 3.
Table 3: example 7-prescriptions of example 10
The preparation method comprises the following steps: the procedure is as in example 2.
Example 11, example 12, comparative example 1-comparative example 3: examination of the stabilizers
Prescription: see Table 4
Table 4: prescriptions for example 11, example 12, comparative example 1-comparative example 3
The preparation method comprises the following steps: the procedure is as in example 2.
Comparative example 6: investigation of the preparation method
Prescription: the recipe of example 2 was followed.
The preparation method comprises the following steps:
(1) The components are measured according to the prescription and mixed to obtain total mixed particles, and the mixing uniformity of the total mixed particles is sampled and detected (the result is shown in Table 6);
(2) Tabletting and then conventional aluminum-aluminum blister packaging.
Comparative example 7-comparative example 8: investigation of the stabilizer content
Prescription: see table 5.
Table 5: investigation prescription of stabilizer content
The preparation method is the same as that of example 2.
Test example 1: mixing uniformity of total mixed particles
The total mixed particles of the above examples or comparative examples were taken respectively, and the mixing uniformity was examined, and the results are shown in Table 6.
Table 6: mixing uniformity results
| Sample lot number | Average content (%) | RSD(％) |
| Example 1 | 98.5 | 1.6 |
| Example 2 | 100.7 | 1.1 |
| Example 3 | 97.8 | 2.0 |
| Example 4 | 102.3 | 1.9 |
| Example 5 | 99.2 | 2.4 |
| Example 6 | 100.6 | 2.3 |
| Example 7 | 98.3 | 1.5 |
| Example 8 | 99.6 | 1.7 |
| Example 9 | 102.7 | 2.3 |
| Example 10 | 99.1 | 1.8 |
| Example 11 | 100.3 | 0.9 |
| Example 12 | 99.2 | 1.2 |
| Comparative example 1 | 99.8 | 3.1 |
| Comparative example 2 | 98.9 | 1.5 |
| Comparative example 3 | 101.2 | 2.0 |
| Comparative example 4 | 100.1 | 1.1 |
| Comparative example 5 | 99.2 | 1.4 |
| Comparative example 6 | 101.2 | 2.8 |
| Comparative example 7 | 99.7 | 0.7 |
| Comparative example 8 | 100.3 | 1.2 |
Test example 2: stability investigation
The sample of the above example, comparative example, commercial reference preparation SIGMART aluminum-plastic panel package, commercial reference preparation SIGMART aluminum-aluminum panel package (the commercial aluminum-plastic panel package is taken out and placed in an aluminum-aluminum panel package) and commercial reference preparation SIGMART pillow package sample (pillow package is a panel package + a desiccant + a moisture-proof bag) were taken respectively, and placed under an acceleration condition (40 ℃ C., 75% RH) for 6 months, and the content of the sample and the related substances were measured at 0 month, 3 months and 6 months, and the specific results are shown in tables 7 and 8.
Table 7: stability investigation of content results
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Table 8: stability investigation of related substance results
Conclusion:
(1) Compared with polyethylene glycol with other molecular weights, the polyethylene glycol with the molecular weight provided by the invention is more beneficial to improving the stability of the obtained nicorandil tablet.
(2) Compared with other preparation processes (such as a direct compression process), the preparation method (fluidized bed granulation) provided by the invention is more beneficial to improving the stability of the obtained nicorandil tablet.
(3) Compared with the nicorandil tablet in the prior art, the nicorandil tablet provided by the invention has better stability.
(4) The nicorandil tablet provided by the invention has excellent stability, the stability of the product can be ensured only by using the conventional aluminum packaging material, the extra use of a drying agent is avoided, the risk of miseating of the drying agent and the pollution to the environment are reduced, and the safety and the effectiveness of the medication of patients are ensured.
(5) The nicorandil tablet provided by the invention is safe and environment-friendly, low in cost, simple in packaging mode, simple in prescription and simple in preparation method, and is beneficial to industrial production.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A composition, comprising: component A, stabilizer and other pharmaceutically acceptable auxiliary materials; the component A is an active ingredient or a mixture of at least one selected from a filler, a disintegrating agent and a lubricant and the active ingredient; the active ingredient is nicorandil or pharmaceutically acceptable salt thereof; the stabilizer is polyethylene glycol.
2. The composition of claim 1, which is a tablet, the method of making the composition comprising: dissolving a stabilizer with a solvent to obtain a stabilizer solution, granulating the component A and the stabilizer solution by adopting a fluidized bed, mixing with other pharmaceutically acceptable auxiliary materials, and tabletting to obtain the composition;
optionally, the solvent comprises one or more of methanol, ethanol, isopropanol, n-butanol, dichloromethane, chloroform, dimethyl sulfoxide, chloroform, acetone, or the like.
3. The composition according to any one of claims 1-2, the polyethylene glycol having a molecular weight of ≡1000; or alternatively
The molecular weight of the polyethylene glycol is 1000-10000; or alternatively
The molecular weight of the polyethylene glycol is 1000-8000; or alternatively
The molecular weight of the polyethylene glycol is 3000-5000; or alternatively
The molecular weight of the polyethylene glycol is 4000.
4. A composition according to any one of claims 1 to 3, wherein the other pharmaceutically acceptable excipients comprise at least one of a filler, a disintegrant and a lubricant; and/or
The component A is an active ingredient, and the other pharmaceutically acceptable auxiliary materials comprise at least one of a filler, a disintegrating agent and a lubricant; or the component A is a mixture of a filler, a disintegrating agent and an active ingredient, and the other pharmaceutically acceptable auxiliary materials comprise a filler and a lubricant; and/or
The filler in the other pharmaceutically acceptable auxiliary materials or the filler in the component A is respectively and independently selected from at least one of lactose, mannitol, sorbitol, microcrystalline cellulose, corn starch, sucrose and calcium hydrophosphate; and/or
The disintegrating agent in the other pharmaceutically acceptable auxiliary materials or the disintegrating agent in the component A is respectively and independently selected from at least one of carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose; and/or
The lubricant in the other pharmaceutically acceptable auxiliary materials or the lubricant in the component A is respectively and independently selected from at least one of calcium stearate, zinc stearate, magnesium stearate, stearic acid, talcum powder and sodium stearyl fumarate.
5. The composition according to any one of claims 1 to 4, wherein the active ingredient is present in an amount of 5.0 to 10.0wt%, calculated on the total mass of the composition; and/or
The content of the polyethylene glycol is 0.5 to 5.0 weight percent calculated by the total mass of the composition; and/or
The content of the filler in the other pharmaceutically acceptable auxiliary materials is 30.0-90.0 wt% calculated by the total mass of the composition; and/or
The filler content in component A is 0-70.0wt% or 0-50.0wt%, calculated on the total mass of the composition; and/or
The content of the disintegrating agent in the other pharmaceutically acceptable auxiliary materials is 0-5.0wt% calculated by the total mass of the composition; and/or
The content of disintegrant in the component A is 0 to 5.0wt% based on the total mass of the composition; and/or
The content of the lubricant in the other pharmaceutically acceptable auxiliary materials is 0.5-5.0 wt% calculated by the total mass of the composition; and/or
The content of the lubricant in the component A is 0 to 1.0wt% based on the total mass of the composition.
6. The composition according to any one of claims 1-5, comprising: component A, polyethylene glycol and other pharmaceutically acceptable auxiliary materials; the component A is an active ingredient; the active ingredient is nicorandil or pharmaceutically acceptable salt thereof; the other pharmaceutically acceptable auxiliary materials are filler, disintegrating agent and lubricant; the filler is at least one of lactose, corn starch or mannitol; the disintegrating agent is croscarmellose sodium; the lubricant is at least one of calcium stearate, zinc stearate, magnesium stearate, stearic acid, talcum powder and sodium stearyl fumarate; the content of the active ingredient is 5.0 to 10.0 weight percent calculated by the total mass of the composition; the content of the polyethylene glycol is 2.0-5.0 wt%; the content of the filler is 80.0-85.0 wt%; the content of the disintegrating agent is 2.0-5.0 wt%; the content of the lubricant is 0.5-5.0 wt%.
7. The composition according to any one of claims 1-5, comprising: component A, polyethylene glycol and other pharmaceutically acceptable auxiliary materials; the component A is a mixture of at least one selected from a filler and a disintegrating agent and an active ingredient; the active ingredient is nicorandil or pharmaceutically acceptable salt thereof; the other pharmaceutically acceptable auxiliary materials comprise a filler and a lubricant; the filler in the component A is at least one of lactose, corn starch or mannitol; the disintegrating agent in the component A is croscarmellose sodium; the other pharmaceutically acceptable filler is at least one of lactose, corn starch or mannitol; the lubricant in the other pharmaceutically acceptable auxiliary materials is at least one of calcium stearate, zinc stearate, magnesium stearate, stearic acid, talcum powder and sodium stearyl fumarate; the content of the active ingredient is 5.0 to 10.0 weight percent calculated by the total mass of the composition; the content of the polyethylene glycol is 0.5-5.0 wt%; the content of the filler in the component A is 30.0-50.0 wt%; the content of the disintegrating agent in the component A is 2.0-5.0 wt%; the content of the other pharmaceutically acceptable filler is 30.0wt% to 40.0wt%; the content of the other pharmaceutically acceptable lubricants is 0.5-5.0 wt%.
8. A method of preparing the composition of any one of claims 1-7, comprising:
(1) Mixing polyethylene glycol with a solvent to obtain a polyethylene glycol solution;
(2) Granulating the component A and the polyethylene glycol solution obtained in the step (1) in a fluidized bed to obtain dry granules;
(3) Mixing the dry particles obtained in the step (2) with other pharmaceutically acceptable auxiliary materials to obtain total mixed particles;
(4) Tabletting the total mixed particles obtained in the step (3) to obtain the composition;
or,
the component A is an active ingredient, and the other pharmaceutically acceptable auxiliary materials comprise at least one of a filler, a disintegrating agent and a lubricant; the method comprises the following steps:
(a) Mixing polyethylene glycol with a solvent to obtain a polyethylene glycol solution;
(b) Granulating the active ingredient and the polyethylene glycol solution obtained in the step (a) in a fluidized bed to obtain dry granules;
(c) Mixing the dry particles obtained in the step (b) with other pharmaceutically acceptable auxiliary materials to obtain total mixed particles;
(d) Tabletting the total mixed particles obtained in the step (c) to obtain the composition;
or alternatively
The component A is a mixture of a filler, a disintegrating agent and an active ingredient, and the other pharmaceutically acceptable auxiliary materials comprise a filler and a lubricant; the method comprises the following steps:
(i) Mixing polyethylene glycol with a solvent to obtain a polyethylene glycol solution;
(ii) Granulating the component A and the polyethylene glycol solution obtained in the step (i) in a fluidized bed to obtain dry granules;
(iii) Mixing the dry particles obtained in the step (ii) with other pharmaceutically acceptable auxiliary materials to obtain total mixed particles;
(iv) Tabletting the total mixed particles obtained in step (iii) to obtain the composition.
9. The method of claim 8, wherein the solvent comprises one or more of methanol, ethanol, isopropanol, n-butanol, methylene chloride, chloroform, dimethyl sulfoxide, chloroform, or acetone.
10. The process according to any one of claims 8 to 9, wherein the granulating of step (2) comprises controlling the temperature of component a to 25 ℃ to 40 ℃, adding the polyethylene glycol solution obtained in step (1) by bottom spraying, top spraying or side spraying, drying, and granulating; or alternatively
The granulating of the step (b) comprises the steps of controlling the temperature of the nicorandil or pharmaceutically acceptable salt thereof to be 25-40 ℃, adding the polyethylene glycol solution obtained in the step (a) through bottom spraying, top spraying or side spraying, drying and granulating; or alternatively
The granulating of the step (ii) comprises the steps of controlling the temperature of the component A to be 25-40 ℃, adding the polyethylene glycol solution obtained in the step (i) through bottom spraying, top spraying or side spraying, drying and granulating.
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