CN117547534B - Nicorandil sustained release preparation and preparation method thereof - Google Patents
Nicorandil sustained release preparation and preparation method thereof Download PDFInfo
- Publication number
- CN117547534B CN117547534B CN202311499053.8A CN202311499053A CN117547534B CN 117547534 B CN117547534 B CN 117547534B CN 202311499053 A CN202311499053 A CN 202311499053A CN 117547534 B CN117547534 B CN 117547534B
- Authority
- CN
- China
- Prior art keywords
- nicorandil
- sustained release
- preparation
- release
- release preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 title claims abstract description 83
- 229960002497 nicorandil Drugs 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 50
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 35
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims abstract 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 abstract description 39
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 27
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 27
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 27
- 238000013268 sustained release Methods 0.000 claims abstract description 27
- 239000012730 sustained-release form Substances 0.000 claims abstract description 27
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229940049654 glyceryl behenate Drugs 0.000 claims abstract description 24
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000004359 castor oil Substances 0.000 claims abstract description 20
- 235000019438 castor oil Nutrition 0.000 claims abstract description 20
- 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 abstract description 20
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 239000003085 diluting agent Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 150000007524 organic acids Chemical class 0.000 claims abstract description 8
- 239000002245 particle Substances 0.000 claims abstract description 8
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 4
- 239000000463 material Substances 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 25
- 238000007873 sieving Methods 0.000 claims description 18
- 239000003826 tablet Substances 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 239000000843 powder Substances 0.000 claims description 13
- 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 10
- 229930195725 Mannitol Natural products 0.000 claims description 10
- 238000007907 direct compression Methods 0.000 claims description 10
- 239000000594 mannitol Substances 0.000 claims description 10
- 235000010355 mannitol Nutrition 0.000 claims description 10
- 239000007939 sustained release tablet Substances 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 238000010298 pulverizing process Methods 0.000 claims description 3
- 235000021314 Palmitic acid Nutrition 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 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
- 235000005985 organic acids Nutrition 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 30
- 230000000694 effects Effects 0.000 description 21
- 239000003814 drug Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000008280 blood Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 8
- -1 nitrate compound Chemical class 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- 229920002125 Sokalan® Polymers 0.000 description 4
- 229960001631 carbomer Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000007908 dry granulation Methods 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 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 description 2
- 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 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 102000004257 Potassium Channel Human genes 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 210000002464 muscle smooth vascular Anatomy 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 108020001213 potassium channel Proteins 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinic acid amide Natural products NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910021646 siderite Inorganic materials 0.000 description 1
- 230000036578 sleeping time Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
The invention provides a nicorandil sustained release preparation and a preparation method thereof, wherein the preparation comprises the following raw materials: nicorandil or its salt derivatives, sustained release agent and other pharmaceutically acceptable excipient; the sustained release preparation is characterized in that the sustained release preparation is at least one of glyceryl behenate, stearyl alcohol, hydrogenated castor oil and ethyl cellulose; the other pharmaceutically acceptable excipients at least comprise a diluent selected from at least one of small particle size sugar alcohols, microcrystalline cellulose and organic acids; and the content of the nicorandil is 1-10%, the content of the sustained release agent is 40-80% and the balance is excipient according to 100% of the mass of the nicorandil sustained release preparation. The sustained release preparation can last 24 hours for sustained release and has good stability. Is obviously superior to the sustained release preparation of nicorandil disclosed in the prior patent and the prior commercial preparation of the Xigemai.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a nicorandil sustained-release preparation and a preparation method thereof.
Background
Nicotil is a nitrate compound, is a nitrate derivative of nicotinamide, and mainly has the function of dilating blood vessels. The chemical name is: n- (2-hydroxyethyl) nicotinamide nitrate with a molecular formula of C 8H9N3O4 and CAS number 65141-46-0 has the following structural formula:
The nicorandil has white crystal appearance and special smell. Belongs to BCS III in the biological pharmacy classification system: high solubility and low permeability. Nicorandil is easily dissolved in methanol, ethanol and acetic acid, is dissolved in anhydrous acetic acid, is slightly dissolved in water and is slightly dissolved in diethyl ether, and the equilibrium solubility in water at 37 ℃ is 13.5mg/mL. Nicorandil has a melting point of 92 ℃ (decomposition), pka=3.24±0.01. According to the report of the related literature, the physical stability of nicorandil is poor, the nicorandil is sensitive to temperature and humidity, and the nicorandil is easy to degrade under the conditions of high temperature and high humidity.
Nicotil is mainly used for treating angina pectoris and coronary heart disease, has the characteristics of nitrate medicines, is also a potassium ion channel opener, is the only medicine with a double action mechanism in the cardiovascular system medicines on the market at present, and is also the first potassium ion channel opener for clinical ATP sensitivity. Nicorandil can dilate coronary artery blood vessels, increase blood flow of the coronary artery blood vessels, and relax vascular smooth muscles; nicorandil also can promote the outflow of potassium ions in cells, inhibit the inflow of calcium ions, and increase the permeability of cell membranes to potassium ions, thereby relaxing vascular smooth muscle and vasodilating blood vessels.
The Nicotil preparation on the market at present mainly comprises injection, tablet and freeze-dried powder injection. In 1995, nicorandil tablets were marketed in china, which had poor compliance with medication by patients due to the extremely short half-life of the drug (about 1 h) and the need to be orally administered three times a day. When the medicine is taken, the blood concentration is difficult to reach a steady state due to the influence of individual difference, sleeping time and other factors. When the blood concentration is too high, certain toxic and side effects are easy to generate; when the blood concentration is low, it may not exhibit a good therapeutic effect below the effective therapeutic concentration. Therefore, further development of a nicorandil drug preparation capable of achieving slow release within a certain period of time is needed to reduce peak-valley phenomenon of blood concentration, improve the drug curative effect and reduce toxic and side effects.
The sustained release preparation related to nicorandil is CN1994283A, and the inventor uses a hydrophilic gel skeleton material with higher water content to prepare sustained release tablets so as to achieve the sustained release effect. In the embodiment, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer and other materials are used, but the sustained release effect for 24 hours can not be achieved only by 12 hours. In addition, the preparation process adopted by the inventor is dry granulation and wet granulation, and the invention aims to prepare the nicorandil sustained-release preparation by adopting a powder direct-compression process, has simple process steps and is easier for industrialized amplification. The comparative study of the examples shows that the sustained release preparation of the invention has better drug stability compared with the sustained release preparation of nicorandil prepared in the patent CN 1994283A.
Disclosure of Invention
Therefore, the invention aims to provide the nicorandil sustained-release preparation and the preparation method thereof, the sustained-release effect can reach 24 hours, the sustained-release preparation has good stability, the peak-valley phenomenon of the blood concentration can be reduced, the curative effect of the medicine is improved, and the adverse reaction is alleviated.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a sustained release preparation of nicorandil, which is prepared from the following raw materials: nicorandil or its salt derivatives, sustained release agent and other pharmaceutically acceptable excipient; the sustained release preparation is characterized in that the sustained release preparation is at least one of glyceryl behenate, stearyl alcohol, hydrogenated castor oil and ethyl cellulose; the other pharmaceutically acceptable excipients at least comprise a diluent selected from at least one of small particle size sugar alcohols, microcrystalline cellulose and organic acids; and the content of the nicorandil is 1-10%, the content of the sustained release agent is 40-80% and the balance is excipient according to 100% of the mass of the nicorandil sustained release preparation.
Preferably, the dosage of the slow release agent is 45-80%, more preferably 45-70%; preferably, the slow release agent is selected from at least two of glyceryl behenate, stearyl alcohol, hydrogenated castor oil and ethyl cellulose; further preferably, the slow release agent is at least one of glyceryl behenate, stearyl alcohol, hydrogenated castor oil and ethyl cellulose; and/or the content of the glyceryl behenate in the nicorandil sustained release preparation is 25-35%.
Preferably, in the diluent, the small particle size sugar alcohol is micronized mannitol having a particle size < 100 μm, preferably < 25 μm, further preferably < 10 μm; the organic acid is small molecular organic acid, preferably at least one of fumaric acid, stearic acid and palmitic acid; the weight ratio of the diluent in the nicorandil slow release preparation is 10-50%, preferably 15-30%.
Preferably, the other pharmaceutically acceptable excipients further comprise a lubricant selected from at least one of magnesium stearate, sodium stearyl fumarate; the weight ratio of the lubricant in the nicorandil slow release preparation is 0-2%.
Preferably, the other pharmaceutically acceptable excipients further comprise a glidant selected from at least one of colloidal silicon dioxide, talc; the glidant accounts for 0-2% of the weight of the nicorandil sustained-release preparation.
Preferably, the preparation raw materials comprise the following components in percentage by weight: 1 to 5 percent of nicorandil, 25 to 35 percent of glyceryl behenate, 5 to 10 percent of stearyl alcohol, 15 to 25 percent of ethyl cellulose, 0 to 10 percent of hydrogenated castor oil, 35 to 50 percent of diluent, 1 to 2 percent of lubricant and 1 to 2 percent of glidant.
Preferably, the sustained release formulation is a tablet having a tablet weight of 400mg to 700mg, preferably 600mg to 700mg, most preferably 700mg.
In a second aspect, the invention provides a method for preparing a sustained release tablet of nicorandil, which adopts a powder direct compression process to prepare the sustained release preparation of nicorandil.
Preferably, the preparation method comprises the following steps:
(1) Sieving nicorandil or its salt derivatives with 80 mesh sieve, pulverizing the rest solid adjuvants, sieving with 60 mesh sieve, and collecting materials respectively;
(2) Blending the nicorandil or its salt derivative powder with sustained release agent and other pharmaceutically acceptable excipients, sieving with 40 mesh sieve, collecting material, and tabletting to obtain nicorandil sustained release tablet.
Compared with the prior art, the invention has the following technical effects:
(1) The sustained release preparation for sustained release for 24 hours is prepared from the nicorandil or the salt derivative thereof, at least one of glyceryl behenate, stearyl alcohol, hydrogenated castor oil and ethylcellulose, and excipients such as diluents, is suitable for being orally taken once a day, can reduce peak valley phenomenon of blood concentration, maintain the steady state of blood concentration, improve the curative effect of the medicament, alleviate adverse reaction, increase the medication safety, and improve the medication compliance of patients.
(2) The nicorandil sustained release preparation is obtained by adopting a dry preparation process, has simple procedures and good stability. In addition, the stability test research contrast shows that compared with the sustained release preparation of nicorandil in the patent CN1994283A and the existing commercial preparation of the Xigemai, the sustained release preparation of the nicorandil and the salt derivative thereof has better stability.
Drawings
Fig. 1: release curves of example 13 and comparative examples 5 to 6.
Detailed Description
In the description of the present invention, it is to be noted that the specific conditions are not specified in the examples, and the description is performed under the conventional conditions or the conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The invention will now be described in further detail with reference to the drawings and to specific examples, which are given by way of illustration and not limitation.
In order to better describe the present invention, the chromatographic conditions for the release profile determination and the chromatographic conditions for the relevant material determination are written out.
The test is carried out according to the rule of the second method of the dissolution and release degree determination method of the four general rules 0931 of the edition 2020 of Chinese pharmacopoeia, 900mL of degassed hydrochloric acid solution with the pH of 1.0 is used as a release medium, the temperature of the medium is 37+/-0.5 ℃, and the rotating speed is 75r/min. Sampling 10ml at 1,2, 4, 6, 8, 12, 16 and 24 hours respectively, simultaneously supplementing fresh medium with the same temperature, filtering the sample by a microporous filter membrane with the thickness of 0.45 mu m, measuring the peak area of the filtrate by high performance liquid chromatography, and detecting the wavelength of 254nm; and precisely weighing a proper amount of the reference substance, measuring by the same method, and calculating the accumulated release according to an external standard method.
Examples 1 to 4 and comparative examples 1 to 4
Examples 1 to 4 and comparative examples 1 to 4 each employ glyceryl behenate @888 ATO), stearyl alcohol, ethylcellulose (T10) and hydrogenated castor oil as slow release agent, and adopting powder direct compression preparation process to prepare the nicorandil slow release tablet. The mass percentages of the raw materials of examples 1 to 4 and comparative examples 1 to 4 are shown in Table 1:
Table 1 the mass percentages of the raw materials of examples 1 to 4 and comparative examples 1 to 4
The preparation method comprises the following steps:
(1) Sieving nicorandil with 80 mesh sieve, and glyceryl behenate 888 ATO), stearyl alcohol, ethylcellulose (T10), hydrogenated castor oil, mannitol (if necessary, by pulverizing) by 60 mesh sieve, collecting materials respectively;
(2) Premixing nicorandil with mannitol for 5min; blending other auxiliary materials for 5min, and sieving with a 40-mesh sieve;
(3) Mixing the above materials for 5min, sieving with 40 mesh sieve, collecting materials, and tabletting.
The release curve of the prepared sustained release tablet in 900ml hydrochloric acid with pH of 1.0 is measured by adopting a high performance liquid chromatography method, and the experimental results are shown in table 2.
Table 2 results of the release profile experiments for the different examples 1-4, comparative examples 1-4
As can be seen from Table 2, when the weight of the fixing sheet and the amount of the slow-release framework material are used, glyceryl behenate is used singly888 ATO), stearyl alcohol, ethylcellulose (T10), hydrogenated castor oil as a matrix material, comparative examples 1-4 exhibited a slower slow release effect, and the release medium was difficult to enter the tablet core due to the water insolubility of the auxiliary material itself, resulting in incomplete final release. In examples 1 to 4, water-insoluble ethylcellulose (T10) was used in combination with a waxy skeleton material, which was used to produce an erodible peeling effect in the latter stage, and was released completely at the end of 16 hours to 90% or more. The release curves of the examples and the comparative examples show that glyceryl behenate is used888 ATO), stearyl alcohol, ethylcellulose (T10) and hydrogenated castor oil, and the slow release effect of the composition is superior to that of a prescription which uses one auxiliary material alone.
Examples 5 to 8
Examples 5 to 8 use glyceryl behenate888 ATO), stearyl alcohol and ethyl cellulose (T10) as slow-release skeleton materials, and adopting a powder direct-compression preparation process to prepare the nicorandil slow-release preparation with different tablet weights. The mass percentages of the raw materials in examples 5 to 8 are shown in Table 3:
Table 3 weight percentage of raw materials of examples 5 to 8
The preparation method comprises the following steps:
(1) Sieving nicorandil with 80 mesh sieve, and glyceryl behenate 888 ATO), stearyl alcohol, ethyl cellulose (T10), mannitol (if necessary, crushed) through a 60 mesh screen, and collecting the materials;
(2) Premixing nicorandil with mannitol for 5min; blending other auxiliary materials for 5min, blending for 5min, and sieving with a 40-mesh sieve;
(3) Mixing the above materials for 5min, sieving with 40 mesh sieve, collecting materials, and tabletting.
The release curve of the prepared sustained release tablet in 900ml hydrochloric acid with pH of 1.0 is measured by adopting a high performance liquid chromatography method, and the experimental results are shown in table 4.
Table 4 results of the release profile experiments for the different examples from examples 5 to 8
As is clear from Table 4, the sustained release time was gradually prolonged with increasing tablet weight, and the sustained release time was 12 to 24 hours in the range of 400mg to 700 mg. The analysis is that the slow release materials are all water insoluble, and the diffusion path formed after the dissolution of the raw materials becomes longer along with the increase of the tablet weight, so that the release speed is slowed down. When the tablet weight is 600mg to 700mg, the dissolution rate in 1 hour is reduced to below 20 percent, and the converted dose is about 5mg which is equivalent to the dose of the quick release preparation. This means that the release amount within 1h can reach similar effective dosages of the quick release preparation and exert the drug effect rapidly. In combination, the effect of the tablet weight at 700mg is optimal.
Examples 9 to 11 and comparative example 5
Examples 9 to 11 and comparative example 5 Using glyceryl behenate888 ATO), stearyl alcohol and ethyl cellulose (T10) as slow-release skeleton materials, and adopting a powder direct-compression preparation process to prepare the nicorandil slow-release preparation. The mass percentages of the raw materials of examples 9 to 11 and comparative example 5 are shown in Table 3:
table 5 different compositions in examples 9 to 11 and comparative example 5:
The preparation method comprises the following steps:
(1) Sieving nicorandil with 80 mesh sieve, and glyceryl behenate 888 ATO), stearyl alcohol, ethyl cellulose (T10), mannitol (if necessary, crushed) through a 60 mesh screen, and collecting the materials;
(2) Premixing nicorandil with mannitol for 5min; blending other auxiliary materials for 5min, blending for 5min, and sieving with a 40-mesh sieve;
(3) Mixing the above materials for 5min, sieving with 40 mesh sieve, collecting materials, and tabletting.
The release curve of the prepared sustained release tablet in 900ml hydrochloric acid with pH of 1.0 is measured by adopting a high performance liquid chromatography method, and the experimental results are shown in table 6.
TABLE 6 results of Release Curve experiments for examples 9-11 and comparative example 5
As can be seen from Table 6, glyceryl behenate was used888 ATO), stearyl alcohol and ethylcellulose (T10) can be released about 20% in 1h, the converted dosage is equivalent to the specification of 5mg of the quick-release preparation, the quick-release preparation can achieve the blood concentration similar to the quick-release preparation, and the sustained-release preparation can be released continuously. Comparative example 5 shows a release of 19.3% at 1h, indicating the use of glyceryl behenate @888 ATO), stearyl alcohol and ethyl cellulose (T10) have better hydrophobic effect, delay the time of water dissolution and pore canal formation, and have slower early release. However, the release degree of comparative example 5 is 86.5% in 24 hours, and the release platform is not reached, which shows that the slow release material glyceryl behenate is [ ]888 ATO) was used at 40% with incomplete release.
Examples 12 to 13
Examples 12 to 13 use glyceryl behenate888 ATO), hydrogenated castor oil and ethyl cellulose (T10) as slow-release skeleton material, and adopting a powder direct compression preparation process to prepare the nicorandil slow-release preparation. The mass percentages of the raw materials in examples 12 to 13 are shown in Table 7:
table 7 different compositions in examples 12 to 13:
The preparation method comprises the following steps:
(1) Sieving nicorandil with 80 mesh sieve, and glyceryl behenate 888 ATO), hydrogenated castor oil, ethyl cellulose (T10), mannitol (if necessary crushed) through a 60 mesh screen, and collecting the materials;
(2) Premixing nicorandil with mannitol for 5min; blending other auxiliary materials for 5min, blending for 5min, and sieving with a 40-mesh sieve;
(3) Mixing the above materials for 5min, sieving with 40 mesh sieve, collecting materials, and tabletting.
The release curve of the prepared sustained release tablet in 900ml hydrochloric acid with pH of 1.0 is measured by adopting a high performance liquid chromatography method, and the experimental results are shown in table 8.
TABLE 8 Release Curve test results for different examples from examples 12-13
As can be seen from Table 8, glyceryl behenate was used888 ATO), hydrogenated castor oil, and ethylcellulose (T10) can be released at about 20% in 1h, the converted dose is equivalent to 5mg of the quick-release preparation, which indicates that the quick-release preparation can quickly take effect, achieve similar blood concentration as the quick-release preparation, and can be released continuously. The overall dissolution trend of example 12 was substantially the same as that of example 10, indicating that the same proportions of hydrogenated castor oil and stearyl alcohol had comparable sustained release effects, with no effect on the targeted sustained release. Example 13 Glycerol behenate used was used with a release of 20.0% at 1h888 ATO), hydrogenated castor oil, ethylcellulose (T10) and stearyl alcohol have better hydrophobic effect, the multicomponent compounding delays the time of water dissolution and pore formation, the dissolution rate in the later 12 hours is 73%, and the rest of the medicine can maintain the stable release in the later stage, so that the nicorandil slow release preparation prepared by adopting the powder direct compression process can show good slow release capacity, and the slow release time can reach 24 hours.
Comparative example 6
At present, a slow release preparation patent related to nicorandil is CN1994283A, and the inventor in the patent prepares a slow release tablet by using a hydrophilic gel skeleton material with higher water content so as to achieve a slow release effect. In the embodiment, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer and other materials are used, but the sustained release effect for 24 hours can not be achieved only by 12 hours. Comparative example 6a sustained release formulation of nicorandil was prepared using the method described in patent CN1994283a, the raw material composition is shown in table 9.
Table 9 comparative example 6 of different compositions:
| Composition of the components | Comparative example 6 |
| Nicorandil | 5g |
| Hydroxypropyl methylcellulose | 15g |
| Hydroxypropyl cellulose | 50g |
| Carbomer (carbomer) | 1g |
| Lactose and lactose | 10g |
| Microcrystalline cellulose | 10g |
| Polyethylene glycol 4000 | 30g |
| Magnesium stearate | Proper amount of |
Wherein, comparative example 6 refers to example 1 in patent CN1994283a using a dry granulation process; the release curve of the prepared sustained release tablet in 900mL hydrochloric acid with pH of 1.0 is measured by adopting a high performance liquid chromatography method, and the experimental results are shown in Table 10.
Table 10 results of the release profile experiments for the different comparative examples in comparative example 6
As can be seen from table 10, the sustained release preparation of nicorandil prepared by the method described in patent CN1994283a releases more than 85% of the active ingredient within 8 hours, and the sustained release effect for 24 hours cannot be achieved due to the short half-life period of nicorandil. The release curves of example 16, comparative example 5 and comparative example 6 are shown in fig. 1, and it can be seen that the formulation of example 16 shows a more stable sustained release capability.
Example 14
Stability study
Stability tests were performed on the commercial formulations of siderite, examples 4, 8, 13, comparative examples 4 to 6, and the following procedure were performed: the preparation of example 4, example 8, example 13, comparative example 4 to comparative example 6 and commercial preparation of Xigemai are packaged by adopting aluminum plastic, and are placed for 6 months under the condition of long-term test (25 ℃ +/-2 ℃ and 60%RH+/-10%RH), the main inspection index is related substances, and the stability results are shown in Table 11.
Table 11 stability examination results (unit:%)
Description:
impurity 1 chemical name: pyridine-3-carboxylic acid; the molecular formula: c 6H5NO2
Impurity B chemical name: n- (2-hydroxyethyl) nitostaamine; the molecular formula: c 8H10N2O2
Impurity C chemical name: diethyl nicotinate; the molecular formula: c 18H10N2O2
Impurity D chemical name: 2- (3-pyridine) -2-oxazoline; the molecular formula: c 8H8N2 O
The polymer composition is: ① Impurity 4 chemical name: 3- [ [ (2-nitroxy) ethyl ] aminomethyl ] -1- [2- [ (pyridine-3-carbonyl) amino ] ethyl ] pyridin-1-ium of formula: c 12H27N7O6;
② Impurity 5 chemical name: 3- [ [ (2-nitroxy) ethyl ] carbamoyl ] -1- {2- [ (1- [2- [ (pyridine-3-carbonyl) amino ] ethyl ] pyridin-1-ium of formula: c 12H27N7O6;
③ Impurity 6 chemical name: 3- [ [2- (nitroxy) ethyl ] carbamoyl ] -1- [2- [ (1- [2- [ (1- [2- [ (pyridine-3-carbonyl) amino ] ethyl ] pyridin-1-ium of formula: c 32H36N9O7. (impurity 4, impurity 5, impurity 6 are described in European pharmacopoeia)
As can be seen from Table 11, example 8 has better stability than 300mg when the tablet weight of the nicorandil sustained-release preparation is 700mg, compared with example 4, and is derived from the selected skeleton material glyceryl behenate @888 ATO), stearyl alcohol, hydrogenated castor oil, and ethylcellulose (T10) all exhibit hydrophobic properties that effectively encapsulate nicorandil. Thus, the time of oxidation and hydrolysis of nicorandil is delayed, and the stability of the tablet is improved.
In examples 8 and 13 and comparative example 5, the difference in stability was not significant under the condition of consistent sheet weights, and glyceryl behenate was selected as compared with Xigemai888 ATO), stearyl alcohol, hydrogenated castor oil, and ethylcellulose (T10) can provide better high temperature stability.
The total impurities of comparative example 6 after 6 months of placement are more than 2%, which is because a large amount of hydrophilic gel materials are used in the prescription, and the water content of the materials can accelerate the degradation of nicorandil under the condition of external packing. Meanwhile, the hydrophobic framework material has low water content, can effectively prevent water invasion and improves the stability of a sample.
Therefore, compared with the preparation method of the patent CN1994283A, the preparation method of the sustained-release preparation of the nicorandil and the existing commercial preparation of the Xigemai, the sustained-release preparation of the nicorandil has better stability. In addition, the preparation process adopted by the inventor is dry granulation and wet granulation, and the preparation method adopts a powder direct compression process to prepare the nicorandil sustained release preparation, has simple process steps and is easier for industrialized amplification.
Also, CN85109190a is a patent related to nicorandil stability, and the inventors use one or more small particle size sugar, one or more powdered organic acid and nicorandil to prepare nicorandil preparation after mixing, which has better stability but no good sustained release capability, and the in vitro dissolution release result indicates that the sustained release time is 6h at the most. The nicorandil sustained release preparation of the invention has better sustained release effect in the aspect of in vitro release compared with the nicorandil tablet prepared by the method in the patent CN 85109190A.
In conclusion, a great amount of slow-release materials are researched and studied, and the slow-release preparation of the nicorandil and the salt derivatives thereof can be prepared by adopting a conventional powder direct compression method by using one or more than one of glyceryl behenate, stearyl alcohol, hydrogenated castor oil and ethyl cellulose (T10), wherein the slow-release effect can reach 24 hours and the stability is good.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (5)
1. The nicorandil slow release preparation is characterized in that the preparation raw materials comprise: nicorandil or its salt derivatives, sustained release agent and other pharmaceutically acceptable excipient; the slow release agent is a compound of glyceryl behenate, ethyl cellulose and stearyl alcohol, or a compound of glyceryl behenate, ethyl cellulose, stearyl alcohol and hydrogenated castor oil, and the dosage of the slow release agent is 45-70%; the other pharmaceutically acceptable excipients at least comprise a diluent, a lubricant and a glidant, wherein the diluent is at least one of sugar alcohol with small particle size, microcrystalline cellulose and organic acid, the lubricant is at least one of magnesium stearate and sodium stearyl fumarate, the glidant is at least one of colloidal silicon dioxide and talcum powder,
The preparation raw materials comprise the following components in percentage by weight: 1-5% of nicorandil, 25-35% of glyceryl behenate, 5-10% of stearyl alcohol, 15-25% of ethyl cellulose, 0-10% of hydrogenated castor oil, 10-50% of a diluent, 1-2% of a lubricant and 1-2% of a glidant.
2. The sustained release formulation of nicorandil as claimed in claim 1, wherein in the diluent, the small particle size sugar alcohol is micronized mannitol having a particle size < 100 μm; the organic acid is small molecular organic acid, and is at least one of fumaric acid, stearic acid and palmitic acid.
3. The sustained release formulation of nicorandil as claimed in claim 1 or 2, wherein the sustained release formulation is a tablet having a tablet weight of 400mg to 700mg.
4. A method for preparing a sustained release preparation of nicorandil as claimed in claim 3, wherein the preparation of the sustained release preparation of nicorandil is carried out by adopting a powder direct compression process.
5. The method according to claim 4, comprising:
(1) Sieving nicorandil or its salt derivatives with 80 mesh sieve, pulverizing the rest solid adjuvants, sieving with 60 mesh sieve, and collecting materials respectively;
(2) Blending the nicorandil or its salt derivative powder with sustained release agent and other pharmaceutically acceptable excipients, sieving with 40 mesh sieve, collecting material, and tabletting to obtain nicorandil sustained release tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311499053.8A CN117547534B (en) | 2023-11-10 | Nicorandil sustained release preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311499053.8A CN117547534B (en) | 2023-11-10 | Nicorandil sustained release preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117547534A CN117547534A (en) | 2024-02-13 |
| CN117547534B true CN117547534B (en) | 2024-07-12 |
Family
ID=
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62103018A (en) * | 1985-07-08 | 1987-05-13 | Chugai Pharmaceut Co Ltd | Production of nicorandil preparation |
| US4822808A (en) * | 1986-01-17 | 1989-04-18 | Chugai Seiyaku Kabushiki Kaisha | Method for production of stable nicorandil preparation |
| CN1994283A (en) * | 2005-09-26 | 2007-07-11 | 刘凤鸣 | Sustained-release preparation of nicorandil |
| WO2010005257A2 (en) * | 2008-07-11 | 2010-01-14 | 주식회사 엘지생명과학 | Controlled-release pharmaceutical preparation containing nicorandil |
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62103018A (en) * | 1985-07-08 | 1987-05-13 | Chugai Pharmaceut Co Ltd | Production of nicorandil preparation |
| US4822808A (en) * | 1986-01-17 | 1989-04-18 | Chugai Seiyaku Kabushiki Kaisha | Method for production of stable nicorandil preparation |
| CN1994283A (en) * | 2005-09-26 | 2007-07-11 | 刘凤鸣 | Sustained-release preparation of nicorandil |
| WO2010005257A2 (en) * | 2008-07-11 | 2010-01-14 | 주식회사 엘지생명과학 | Controlled-release pharmaceutical preparation containing nicorandil |
Non-Patent Citations (1)
| Title |
|---|
| 尼可地尔骨架型缓释片的处方优化及体外释药研究;金桂兰等;《中国药房》;20161231;第27卷(第25期);3564-3566 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5775464B2 (en) | Delayed release oral dosage composition containing amorphous CDDO-ME | |
| JP2568202B2 (en) | Controlled release dihydrocodeine composition | |
| CN101267810A (en) | Capsule formulation of pirfenidone and pharmaceutically acceptable excipients | |
| US20230321090A1 (en) | Bromocriptine formulations | |
| CN115518066A (en) | Pharmaceutical composition for treating anticoagulation and application | |
| KR20210125994A (en) | Amorphous Sparsentan Composition | |
| CN101653425B (en) | Arbidol hydrochloride medicament composition dispersible tablets and preparation method thereof | |
| CN116549396A (en) | Solid dispersion containing adefovir, solid dosage form and preparation method | |
| CN117547534B (en) | Nicorandil sustained release preparation and preparation method thereof | |
| CN102008469B (en) | Method for preparing telmisartan amlodipine tablets | |
| CN113633616A (en) | Solid preparation with high bioavailability | |
| CN110623934A (en) | Trimetazidine hydrochloride sustained release tablet and preparation method thereof | |
| CN117547534A (en) | Nicorandil sustained release preparation and preparation method thereof | |
| CN113018271B (en) | Tandospirone pharmaceutical composition and preparation method and application thereof | |
| CN101244068B (en) | Hemsleyadin sustained-release preparation | |
| CN114917213B (en) | Mental disorder therapeutic agent comprising amitriptyline and method for treating mental disorder | |
| EP3936119A1 (en) | Pharmaceutical composition of prolyl hydroxylase inhibitor and preparation method therefor | |
| CN113521020B (en) | A solid dosage form of adefovir containing water soluble acid | |
| CN112516097B (en) | Levamlodipine besylate composition | |
| CN114557976B (en) | Scutellarin sustained release tablet and preparation method thereof | |
| CN116421595B (en) | Dapagliflozin pharmaceutical composition, and preparation method and application thereof | |
| CN114099500B (en) | Edaravone sustained-release pharmaceutical composition, preparation method and application | |
| CN103705489B (en) | Bezafibrate dual-release slow-release capsule medicinal composition | |
| CN114177152A (en) | Digoxin micro tablet and preparation method thereof | |
| WO2023093640A1 (en) | Darolutamide pharmaceutical composition, preparation method therefor and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20240619 Address after: No. 1800 road 214122 Jiangsu Lihu Binhu District City of Wuxi Province Applicant after: Jiangnan University Country or region after: China Address before: 22nd Floor, Wuxi Chamber of Commerce Building, No. 1 Financial 8th Street, Wuxi Economic Development Zone, Jiangsu Province, China, 214111 Applicant before: Jiangsu Novobito New Drug Research and Development Co.,Ltd. Country or region before: China |
|
| GR01 | Patent grant |