CN114732792A - Nicorandil orally disintegrating tablet and preparation method thereof - Google Patents
Nicorandil orally disintegrating tablet and preparation method thereof Download PDFInfo
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- CN114732792A CN114732792A CN202210307787.0A CN202210307787A CN114732792A CN 114732792 A CN114732792 A CN 114732792A CN 202210307787 A CN202210307787 A CN 202210307787A CN 114732792 A CN114732792 A CN 114732792A
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- nicorandil
- orally disintegrating
- disintegrating tablet
- preparation
- mannitol
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- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 title claims abstract description 118
- 229960002497 nicorandil Drugs 0.000 title claims abstract description 117
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title abstract description 36
- 239000000314 lubricant Substances 0.000 claims abstract description 21
- 239000000945 filler Substances 0.000 claims abstract description 20
- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 10
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims abstract description 10
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 10
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000008117 stearic acid Substances 0.000 claims abstract description 10
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 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 37
- 235000010355 mannitol Nutrition 0.000 claims description 23
- 239000002245 particle Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 14
- 239000013078 crystal Substances 0.000 claims description 12
- 229930195725 Mannitol Natural products 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 150000005846 sugar alcohols Polymers 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 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 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- 229960000913 crospovidone Drugs 0.000 claims description 7
- 239000007884 disintegrant Substances 0.000 claims description 7
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 7
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 7
- 239000000600 sorbitol Substances 0.000 claims description 7
- 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 6
- 239000002994 raw material Substances 0.000 claims description 6
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000004067 bulking agent Substances 0.000 claims 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 14
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- 238000010521 absorption reaction Methods 0.000 abstract description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000005303 weighing Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 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 3
- 206010002383 Angina Pectoris Diseases 0.000 description 3
- 208000019505 Deglutition disease Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 230000000291 postprandial effect Effects 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 102000004257 Potassium Channel Human genes 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
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- 238000002347 injection Methods 0.000 description 2
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- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
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- 210000000214 mouth Anatomy 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical group 0.000 description 2
- 108020001213 potassium channel Proteins 0.000 description 2
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- 238000011160 research Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 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
- 206010003225 Arteriospasm coronary Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000003890 Coronary Vasospasm Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 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 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 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 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 201000011634 coronary artery vasospasm Diseases 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 229940102187 disintegrating oral tablet Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
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- 230000002496 gastric effect Effects 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- 230000004060 metabolic process Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
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- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
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Images
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Diabetes (AREA)
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Abstract
The invention relates to the field of pharmaceutical preparations, in particular to a nicorandil orally disintegrating tablet and a preparation method thereof. The auxiliary materials comprise a disintegrating agent, a filling agent and a lubricating agent, wherein the lubricating agent is stearic acid and/or stearyl alcohol, and the dosage of the lubricating agent is 4-12% based on 100% of the total mass of the nicorandil orally disintegrating tablet. The nicorandil orally disintegrating tablet provided by the invention has the advantages of high quality, good stability effect, rapid disintegration, high bioavailability, small irritation to digestive tract mucosa, more choices in clinical use, convenience in taking and rapid absorption, and can increase the adaptability of patients.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a nicorandil orally disintegrating tablet and a preparation method thereof.
Background
Nicorandil, chemical name is N- (2-hydroxyethyl) nicotinamide nitrate, molecular formula is C8H9N3O4The ATP sensitive potassium ion channel opener is the first ATP sensitive potassium ion channel opener used in clinic. Clinical studies prove that nicorandil is suitable for various types of angina, including exertional angina and spastic angina, and can remarkably reduce the occurrence risk of cardiovascular events and improve prognosis. Nicorandil has the functions of preventing intracellular calcium ion from dissociating, increasing permeability of cell membranes to potassium ions, expanding coronary vessels, continuously increasing coronary blood flow and inhibiting coronary artery spasm, does not influence blood pressure, heart rate, myocardial contractility and myocardial oxygen consumption when expanding the coronary vessels, and also has the functions of inhibiting platelet aggregation and preventing thrombosis.
Orally Disintegrating Tablets (ODT) are a new type of oral dosage form. The preparation can be rapidly disintegrated in oral cavity under anhydrous condition (or only a small amount of water exists), enters digestive tract along with swallowing, is absorbed in oral cavity without mucosa, and has the same absorption and metabolism process as common tablet. Compared with the common preparation, the ODT has the advantages of convenient administration, small irritation to digestive tract mucous membrane, and the like. A significant proportion of elderly or stroke patients have dysphagia (dysphagia), and many have persistent problems. This may lead to reduced patient compliance when such patients are given an oral formulation that must be swallowed intact. Other patients may also suffer from dysphagia as they are common in all age groups and are observed in approximately 35% of the general population and up to 60% of all patients in the institutional care (institutionalized) population and long-term care facilities in approximately 20%.
However, nicorandil has poor stability, needs to be stored below 10 ℃, has activity in a crystal state, is prepared into the rapidly disintegrating oral tablet from nicorandil, is produced and stored at normal temperature, has preparation procedures such as tabletting and the like, has the problem that the active ingredients of the prepared nicorandil are reduced due to easy damage and inactivation of crystal forms in the preparation process, has the risk of instability and failure of the nicorandil, and simultaneously can become unstable along with the storage time, and at present, no related patent of the preparation method of the nicorandil orally disintegrating tablet exists in China.
Disclosure of Invention
In order to solve the technical problems, the invention provides an nicorandil orally disintegrating tablet and a preparation method thereof. The nicorandil orally disintegrating tablet provided by the invention has the advantages of higher quality, good stability effect, fast disintegration, high bioavailability, small irritation to digestive tract mucous membrane, more choices in clinical use, convenience in taking and fast absorption, and increases the adaptability of patients.
According to the first aspect, the nicorandil orally disintegrating tablet provided by the invention comprises raw materials (namely active ingredients and auxiliary materials) including active ingredients nicorandil and a lubricant, wherein the lubricant is stearic acid and/or stearyl alcohol, and the amount of the lubricant is 4-12% based on 100% of the total mass of the nicorandil orally disintegrating tablet.
According to the invention, stearic acid/stearyl alcohol is used as a lubricant in the nicorandil orally disintegrating tablet, the lubricant is easier to break in the tabletting process, so that the integrity of nicorandil crystal grains is protected, and the stability of nicorandil can be effectively improved; furthermore, the reasonable amount (preferably 5-8%) of the lubricant is controlled, the lubricant can play an ideal role as a nicorandil protective agent besides the inherent lubricating effect, and the lubricant with a specific amount is selected, so that the nicorandil protective agent can be matched with nicorandil and other auxiliary materials, and the stability and the comprehensive performance of the nicorandil orally disintegrating tablet are improved.
In addition, the research of the invention further discovers that the particle size of the active ingredient nicorandil added with the active ingredient with the specific particle size is beneficial to maintaining the stability of the nicorandil, and the nicorandil with the particle size can better maintain the crystal grain size of the nicorandil by matching with the specific tabletting pressure, thereby maintaining the stability of the preparation.
Preferably, the particle size D90 of the nicorandil is 100-350 μm, preferably 150-250 μm; and/or the tabletting pressure is 10-15KN, preferably 11-13 KN. The nicorandil orally disintegrating tablet provided by the invention is prepared by mixing the nicorandil with the particle size and auxiliary materials and tabletting under the pressure. For example, the particle size D90 of nicorandil may be 150 μm, 200 μm, 250 μm, 350 μm, etc., and is particularly preferably 200 μm.
The invention adopts the specific particle size and pressure of nicorandil, not only obviously improves the stability, but also can improve the compressibility and the fluidity by further matching with auxiliary materials such as a filling agent and the like, and is particularly beneficial to the nicorandil to finish high-quality and high-stability tabletting under the pressure.
In order to further improve the stability and the comprehensive performance of the preparation, the invention screens the particularly suitable filling agents:
preferably, the filler is a polyol filler comprising D-mannitol and a second polyol; preferably, the second polyhydric sugar alcohol is selected from sorbitol and/or xylitol; more preferably, the D-mannitol is beta and alpha mixed crystal mannitol.
The invention finds that the coordination of D-mannitol and second polyhydric sugar alcohol containing a certain amount can further reduce various related substances and total impurities of the nicorandil orally disintegrating tablet and improve the comprehensive performance such as disintegration, for example, the various related substances and total impurities of the nicorandil orally disintegrating tablet containing the filler are 1/2 times of those containing other fillers such as lactose, and the disintegration time limit of the invention is better. In addition, the crystal form of the D-mannitol has positive influence on the physical and chemical properties of the nicorandil oral rapidly disintegrating tablet preparation such as solubility, stability, density and the like, and can further influence the function and application of the nicorandil oral rapidly disintegrating tablet preparation. Compared with nicorandil oral rapidly disintegrating tablet prepared by delta crystal form mannitol, alpha and beta mixed crystal mannitol have better solubility, stability, density and other physical and chemical properties.
Further preferably, in the filling agent, the mass ratio of the D-mannitol to the second polyhydric sugar alcohol is 2-4: 1, preferably 2.5-3.9: 1, more preferably 3.25-3.85: 1, the Nicorandil orally disintegrating tablet prepared by the method can further improve the stability and improve the mouthfeel of the Nicorandil orally disintegrating tablet by adopting the combination of the D-mannitol and the sorbitol/xylitol according to a certain proportion, and the Nicorandil with the particle size can be conveniently subjected to high-quality tabletting under the tabletting pressure of 10-15 KN.
Further preferably, the mass ratio of the filler to the nicorandil is 5-20: 1; and/or the mass ratio of the filler to the lubricant is 8-18: 1; preferably 9-17: 1. The invention adopts the lubricant and the filler in a specific mass ratio, can obviously improve the compressibility and can further improve the mouthfeel.
Preferably, the raw materials also comprise a disintegrating agent, and the appropriate disintegrating agent screened by the invention is crospovidone and/or carboxymethyl starch sodium, so that the disintegrating property, the stability and the comprehensive performance of the preparation can be improved.
Further preferably, the disintegrant is crospovidone.
According to the invention, researches show that when the disintegrant is crospovidone, the nicorandil orally disintegrating tablet has better stability and disintegration, for example, compared with a scheme of adopting croscarmellose sodium, the total impurity is reduced by about 1/3 and the disintegration time limit is reduced by about 80 percent by adopting the crospovidone.
More preferably, the mass ratio of the disintegrant to the polyalcohol filler is 1:15 to 18, preferably 1:15 to 17.
The nicorandil orally disintegrating tablet has the hardness of 30-70N, the disintegration time is less than 3min, and the preferred disintegration time is less than 60s, such as 15s, 18s, 19s, 20s, 30s, 40s, 50s and 60 s.
Preferably, the nicorandil orally disintegrating tablet has the hardness of 30-70N and the disintegration time of less than 60s, such as 15s, 18s, 19s, 20s, 30s, 40s, 50s and 60 s.
Further preferably, as a preferred embodiment of the invention, more ideal nicorandil stability and comprehensive effect can be realized by adopting specific dosage and composition; the method comprises the following specific steps:
the filler is a mixture of D-mannitol and sorbitol in a mass ratio of 3.5-4: 1.
Preferably, the total amount of the above raw materials is 100 parts.
Preferably, the nicorandil orally disintegrating tablet provided by the invention has the following prescription: 4-12% of nicorandil, 60-65% of D-mannitol, 15-25% of sorbitol, 4-12% of stearic acid and 2-6% of crospovidone.
More preferably, the prescription is as follows: the nicorandil orally disintegrating tablet is prepared from 4-6% of nicorandil, 64-66% of D-mannitol, 16-18% of sorbitol, 7-9% of stearic acid and 4-6% of crospovidone, and has the advantages of remarkably improving the stability and comprehensive performance of the nicorandil orally disintegrating tablet, along with convenient administration, quick disintegration, quick absorption, high bioavailability, small irritation to gastrointestinal mucosa and the like, and contribution to improving the medicine taking experience, adaptability and taste of patients.
Further, the particle size D90 of the nicorandil which is more preferable in the invention is 200 +/-10 μm.
Preferably, the nicorandil orally disintegrating tablet is 5mg or 10mg in terms of active ingredients; the 5mg specification nicorandil orally disintegrating tablet preferably has in vivo bioequivalence with 5mg specification cigumedil tablet.
In a second aspect, the invention provides a preparation method of the nicorandil orally disintegrating tablet, which comprises the following steps: mixing the nicorandil and auxiliary materials, and tabletting to obtain the nicorandil orally disintegrating tablet with high stability.
Preferably, the nicorandil and the auxiliary material are mixed and then tabletted under the pressure of 10-15 KN.
Further preferably, in the preparation method provided by the invention, the nicorandil and the lubricant are preferably mixed firstly, and then the disintegrant and the filler are added and mixed.
Preferably, the nicorandil and the lubricant are mixed for 1-20 min at the rotating speed of 5-15 rpm, and then the disintegrating excipient and the filler are added and continuously mixed for 10-40 min. The nicorandil orally disintegrating tablet with high stability and excellent performances in all aspects can be better prepared by adopting the treatment and the conditions.
The invention has the beneficial effects that: the nicorandil orally disintegrating tablet with high stability and excellent comprehensive performance is obtained by adopting the specific lubricant and the dosage and matching with the active ingredient nicorandil and other auxiliary materials under certain pressure, the product has higher quality, good stability effect, quick disintegration, high bioavailability, small irritation to digestive tract mucosa, provides more choices in clinical use, is convenient to take, quick to absorb and good in taste, and increases the adaptability of patients.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a graph of the nicorandil orally disintegrating tablet and the nicorandil tablet of 5mg on an empty stomach according to the embodiment of the invention;
FIG. 2 is a graph showing the time curve of 5mg postprandial administration of nicorandil orally disintegrating tablets and nicorandil tablets according to the embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and the following embodiments are used for illustrating the present invention and are not intended to limit the scope of the present invention. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products available from normal commercial vendors, not indicated by the manufacturer.
In the examples of the present invention, mannitol (D-mannitol) was alpha and beta mixed crystal mannitol of type 200 SD.
Example 1
The embodiment provides a nicorandil orally disintegrating tablet and a preparation method thereof. The composition of each 1000 nicorandil orally disintegrating tablets comprises the following components:
the particle size D90 of nicorandil is 200 + -10 μm.
The preparation method of the nicorandil orally disintegrating tablet provided by the embodiment is as follows:
1. weighing raw and auxiliary materials according to the prescription amount for later use;
2. adding nicorandil and stearic acid into a hopper mixer, mixing for 10min at the rotating speed of 10rpm, adding the rest of the auxiliary materials into the hopper mixer, continuously mixing for 30min, and discharging;
3. tabletting by adopting a high-speed tabletting machine according to the theoretical tablet weight of 100mg, controlling the main compression pressure (tabletting pressure) to be 11-13 KN, and controlling the hardness of the plain tablets to be 30-50N.
Example 2
The embodiment provides an nicorandil orally disintegrating tablet and a preparation method thereof. The composition of each 1000 nicorandil orally disintegrating tablets comprises:
the particle size D90 of nicorandil is 250 + -10 μm.
The preparation method of the nicorandil orally disintegrating tablet provided by the embodiment is as follows:
1. weighing raw and auxiliary materials according to the prescription amount for later use;
2. adding nicorandil and stearic acid into a hopper mixer, mixing for 10min at the rotating speed of 10rpm, adding the rest of the auxiliary materials into the hopper mixer, continuously mixing for 30min, and discharging;
3. tabletting by adopting a high-speed tabletting machine according to the theoretical tablet weight of 100mg, controlling the main compression pressure to be 11-13 KN, and controlling the hardness of the plain tablets to be 30-50N.
Example 3
The embodiment provides an nicorandil orally disintegrating tablet and a preparation method thereof. The composition of each 1000 nicorandil orally disintegrating tablets comprises the following components:
the particle size D90 of nicorandil is 150 + -10 μm.
The preparation method of the nicorandil orally disintegrating tablet provided by the embodiment is as follows:
1. weighing raw and auxiliary materials according to the prescription amount for later use;
2. adding nicorandil and stearic acid into a hopper mixer, mixing for 10min at the rotating speed of 10rpm, adding the rest of the auxiliary materials into the hopper mixer, continuously mixing for 30min, and discharging;
3. tabletting by adopting a high-speed tabletting machine according to the theoretical tablet weight of 100mg, controlling the main compression pressure to be 11-13 KN, and controlling the hardness of the plain tablets to be 30-50N.
Example 4
The embodiment provides an nicorandil orally disintegrating tablet and a preparation method thereof.
The preparation method is the same as that of the embodiment 1, and the difference is that the main pressure is controlled to be 14-15 KN, and the plain film hardness is 40-60N.
Example 5
The embodiment provides an nicorandil orally disintegrating tablet and a preparation method thereof.
The preparation is identical to example 1, except that stearic acid is replaced by stearyl alcohol.
Comparative example 1
The embodiment provides an nicorandil orally disintegrating tablet and a preparation method thereof.
The preparation method is the same as that of example 1, except that magnesium stearate is selected as the lubricant, the dosage of the lubricant is 1%, and the dosage of mannitol is changed to 72%.
Comparative example 2
The comparative example provides an nicorandil orally disintegrating tablet and a preparation method thereof.
The preparation method is the same as that of example 1, and only the delta crystal form mannitol (model M200) is adopted to replace alpha and beta mixed crystal mannitol.
Comparative example 3
The comparative example provides an nicorandil orally disintegrating tablet and a preparation method thereof.
The preparation was carried out in the same manner as in example 1, except that a particle size D90 of 100. + -. 10 μm was used.
Comparative example 4
The comparative example provides an orally disintegrating nicorandil tablet and a preparation method thereof.
The preparation was carried out in the same manner as in example 1, except that a particle size D90 of 400. + -. 20 μm was used.
Experimental example 1
The related substances are determined by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general regulation 0512).
Solvent: mobile phase A: water-tetrahydrofuran-triethylamine-trifluoroacetic acid (982:10:5: 3).
Test solution: an appropriate amount of the nicorandil oral disintegrating tablet (the same shall apply hereinafter) is taken, dissolved by the mobile phase A and quantitatively diluted to prepare a solution containing about 2mg per 1 ml.
Control solution: taking 1ml of test solution, placing the test solution in a 100ml measuring flask, and diluting the test solution to a scale by using the mobile phase A; precisely measuring 1ml, placing into a 5ml measuring flask, diluting with mobile phase A to scale, and shaking.
System applicability solution: taking a reference substance of nicorandil impurity B, C, D, E, I, J and a proper amount of nicorandil, dissolving by using a mobile phase A, and quantitatively diluting to prepare a solution containing 4 mug of impurity B, E, 10 mug of impurity C, D, J, 40 mug of impurity I and 2mg of nicorandil in each 1 ml.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica filler is used as a filling agent; gradient elution is carried out on a water-tetrahydrofuran-triethylamine-trifluoroacetic acid (982:10:5:3) as a mobile phase A, a water-tetrahydrofuran-triethylamine-trifluoroacetic acid (972:15:5:8) as a mobile phase B and a mobile phase A, B according to the following conditions; the detection wavelength is 254 nm; the flow rate is 1 ml/min; the injection volume was 20. mu.l.
System applicability requirements: in a system applicability solution chromatogram, the peak-appearance sequence is sequentially impurity E, impurity B, impurity C, impurity D, nicorandil, impurity I and impurity J, and the separation degree of each chromatographic peak is in accordance with the specification.
The determination method comprises the following steps: precisely measuring the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording the chromatogram.
And (3) content uniformity determination: taking 1 tablet of the product, placing in a 50ml measuring flask, adding 1ml of water to disintegrate, adding 15ml of water, shaking for 10 minutes, adding water to scale, shaking, filtering, precisely measuring 10ml of the subsequent filtrate, placing in a 50ml measuring flask, adding water to scale, and shaking to obtain a sample solution; taking a proper amount of nicorandil reference substance, precisely weighing, and adding water to prepare a solution containing about 20 mu g of nicorandil per 1ml as a reference substance solution. Measuring absorbance at 262nm wavelength by ultraviolet-spectrophotometry (0401 in the four-part general rule of 2020 edition of Chinese pharmacopoeia), and calculating content and content uniformity (0941 in the four-part general rule of 2020 edition of Chinese pharmacopoeia).
Disintegration time (0921 in the four general rules of the 2020 edition of Chinese pharmacopoeia).
Content determination: measuring by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general regulation 0512).
Test solution: taking 20 tablets of the product, precisely weighing, grinding, taking a proper amount of fine powder (about 20mg equivalent to nicorandil), putting the fine powder into a 50ml measuring flask, adding 30ml of solvent, shaking for 10min, diluting with the solvent to scale, shaking uniformly, filtering, precisely weighing 5ml of subsequent filtrate, putting the subsequent filtrate into a 25ml measuring flask, diluting with the solvent to scale, and shaking uniformly.
Control solution: taking 20mg of a reference substance, placing the reference substance in a 50ml measuring flask, dissolving and diluting the reference substance to the scale mark by using a solvent, precisely measuring 5ml of the reference substance, placing the reference substance in a 25ml measuring flask, diluting the reference substance to the scale mark by using the solvent, and shaking up.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; acetonitrile-water (25:75) is used as a mobile phase; the detection wavelength is 254 nm; the flow rate is 1 ml/min; the injection volume is 20 mul; the solvent was 80% methanol.
The determination method comprises the following steps: precisely measuring 20 μ l of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, recording chromatogram, and calculating according to external standard method by peak area.
And (3) investigating long-term stability test:
samples of the commercial preparations of the examples and the comparative examples are placed at a temperature of 25 +/-2 ℃, are sampled and analyzed after being placed for 0 month, 3 months and 6 months, and the properties, related substances, contents, content uniformity and disintegration time limit of the samples after being placed are measured and calculated, and the results are shown in table 1.
TABLE 1 long term stability results for examples and comparative examples, commercial formulations
Accelerated stability test investigation:
the samples of the examples and the comparative examples are placed at the temperature of 40 +/-2 ℃, are sampled and analyzed after being placed for 0 month, 3 months and 6 months, and the properties, related substances, content uniformity and disintegration time limit of the samples after being placed are measured and calculated, and the results are shown in table 2.
Table 2 examples and comparative examples, commercial formulations accelerated stability results
It can be seen that the substances of the examples according to the invention are superior in stability to the comparative examples and the commercially available formulations, and have a faster disintegration time than the commercially available formulations, and that a particle size of 400 μm has an influence on the mixing uniformity.
TABLE 3 impurity code and chemical Structure
Experimental example 2
In example 1, nicorandil orally disintegrating tablets of 5mg size and a commercially available formulation, xghamel nicorandil tablet (size: 5mg, trade name:
xige mai, manufacturing enterprise: nipro Pharma Corporation kagamisishi Plant) in a single-site, randomized, open, single (fasting/postprandial n ═ 12) oral administration, two-formulation, two-sequence, two-cycle, crossover human bioequivalence test, using the following amounts: orally administered 1 tablet with 240ml warm boiled water. The pharmacokinetic parameters obtained (AUC0-t, AUC0- ∞, Cmax) were statistically analyzed and evaluated 12h after the time of administration. The fasting and postprandial drug time curves of the nicorandil orally disintegrating tablet and the nicorandil tablet with the same specification in figure 1 and figure 2 result in that the two drugs have a living bodyAnd (4) physical equivalence.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. The nicorandil orally disintegrating tablet is characterized in that stearic acid and/or stearyl alcohol are adopted as a lubricant, and the dosage of the lubricant is 4-12% based on 100% of the total mass of the nicorandil orally disintegrating tablet.
2. The nicorandil orally disintegrating tablet according to claim 1, wherein the particle size D90 of nicorandil is 100-350 μm, preferably 150-250 μm; and/or the tabletting pressure is 10-15KN, preferably 11-13 KN.
3. The nicorandil orally disintegrating tablet according to claim 1 or 2, wherein the raw material further comprises a bulking agent, the bulking agent adopts a polyalcohol bulking agent, and the polyalcohol bulking agent is a mixture of D-mannitol and a second polyalcohol alcohol;
preferably, the second polyhydric sugar alcohol is selected from sorbitol and/or xylitol; the D-mannitol is beta and alpha mixed crystal mannitol.
4. The nicorandil orally disintegrating tablet according to claim 3, wherein the mass ratio of D-mannitol to the second polyhydric sugar alcohol in the bulking agent is 2-4: 1.
5. The nicorandil orally disintegrating tablet according to claim 2 or 3, wherein the mass ratio of the bulking agent to the lubricant is 8-18: 1; preferably 9-17: 1.
6. The nicorandil orally disintegrating tablet according to any one of claims 1 to 5, wherein the raw material further comprises a disintegrant, and the disintegrant is crospovidone and/or carboxymethyl starch sodium.
7. The nicorandil orally disintegrating tablet according to claim 6, wherein the mass ratio of the disintegrant to the filler is 1: 15-18.
8. The nicorandil orally disintegrating tablet according to claim 1, which is characterized by comprising the following components in parts by weight:
the filler is a mixture of D-mannitol and sorbitol in a mass ratio of 3.5-4: 1.
9. The nicorandil orally disintegrating tablet according to claim 8, wherein the nicorandil has a particle size D90 of 200 ± 10 μm.
10. The method for preparing the nicorandil orally disintegrating tablet according to any one of claims 1 to 9, wherein the nicorandil and other raw materials are mixed and then tableted, preferably, tableted under a pressure of 10 to 15 KN.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85109190A (en) * | 1984-12-17 | 1986-07-16 | 中外制药株式会社 | Produce the method for stable nicorandil preparation |
| US4822808A (en) * | 1986-01-17 | 1989-04-18 | Chugai Seiyaku Kabushiki Kaisha | Method for production of stable nicorandil preparation |
| WO1999007370A1 (en) * | 1997-08-08 | 1999-02-18 | Biomedica Foscama Industria Chimico-Farmaceutica S.P.A. | Oral solid pharmaceutical compositions containing nicorandil for a modulated release and the process for their preparation |
| US20070190134A1 (en) * | 2004-07-08 | 2007-08-16 | Aventis Pharma S.A. | Compositions containing nicorandil, preparation method and use |
| WO2013125350A1 (en) * | 2012-02-23 | 2013-08-29 | フロイント産業株式会社 | Direct-compression excipient for orally disintegrating tablet and method for producing same, and orally disintegrating tablet |
-
2022
- 2022-03-25 CN CN202210307787.0A patent/CN114732792A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85109190A (en) * | 1984-12-17 | 1986-07-16 | 中外制药株式会社 | Produce the method for stable nicorandil preparation |
| US4822808A (en) * | 1986-01-17 | 1989-04-18 | Chugai Seiyaku Kabushiki Kaisha | Method for production of stable nicorandil preparation |
| WO1999007370A1 (en) * | 1997-08-08 | 1999-02-18 | Biomedica Foscama Industria Chimico-Farmaceutica S.P.A. | Oral solid pharmaceutical compositions containing nicorandil for a modulated release and the process for their preparation |
| US20070190134A1 (en) * | 2004-07-08 | 2007-08-16 | Aventis Pharma S.A. | Compositions containing nicorandil, preparation method and use |
| WO2013125350A1 (en) * | 2012-02-23 | 2013-08-29 | フロイント産業株式会社 | Direct-compression excipient for orally disintegrating tablet and method for producing same, and orally disintegrating tablet |
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