CN115282123A - Preparation method of stable nicorandil preparation - Google Patents
Preparation method of stable nicorandil preparation Download PDFInfo
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- CN115282123A CN115282123A CN202211109086.2A CN202211109086A CN115282123A CN 115282123 A CN115282123 A CN 115282123A CN 202211109086 A CN202211109086 A CN 202211109086A CN 115282123 A CN115282123 A CN 115282123A
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- nicorandil
- preparation
- higher alcohol
- preparing
- stable
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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 117
- 229960002497 nicorandil Drugs 0.000 title claims abstract description 117
- 238000002360 preparation method Methods 0.000 title claims abstract description 95
- 239000000203 mixture Substances 0.000 claims abstract description 54
- 238000000034 method Methods 0.000 claims abstract description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 35
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000000945 filler Substances 0.000 claims abstract description 25
- 239000011812 mixed powder Substances 0.000 claims abstract description 24
- 239000002245 particle Substances 0.000 claims abstract description 23
- 238000000227 grinding Methods 0.000 claims abstract description 14
- 239000000314 lubricant Substances 0.000 claims abstract description 12
- 238000009472 formulation Methods 0.000 claims abstract description 11
- 239000007884 disintegrant Substances 0.000 claims abstract description 10
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 7
- 229960004977 anhydrous lactose Drugs 0.000 claims abstract description 7
- 229920002261 Corn starch Polymers 0.000 claims abstract description 5
- 239000008120 corn starch Substances 0.000 claims abstract description 5
- 229920000168 Microcrystalline cellulose Polymers 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
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 4
- 229940099112 cornstarch Drugs 0.000 claims abstract 2
- 239000004570 mortar (masonry) Substances 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 10
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 4
- 235000013539 calcium stearate Nutrition 0.000 claims description 4
- 239000008116 calcium stearate Substances 0.000 claims description 4
- 238000007907 direct compression Methods 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims 1
- 239000004067 bulking agent Substances 0.000 claims 1
- 229910052791 calcium Inorganic materials 0.000 claims 1
- 239000011575 calcium Substances 0.000 claims 1
- 239000001768 carboxy methyl cellulose Substances 0.000 claims 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 15
- 239000000463 material Substances 0.000 abstract description 8
- 231100000331 toxic Toxicity 0.000 abstract description 8
- 230000002588 toxic effect Effects 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 6
- 150000001298 alcohols Chemical class 0.000 abstract 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 17
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000005303 weighing Methods 0.000 description 10
- 239000012535 impurity Substances 0.000 description 6
- 235000010355 mannitol Nutrition 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 206010002383 Angina Pectoris Diseases 0.000 description 3
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GOVWOKSKFSBNGD-UHFFFAOYSA-N Ethopabate Chemical compound CCOC1=CC(NC(C)=O)=CC=C1C(=O)OC GOVWOKSKFSBNGD-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 229940093501 ethopabate Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—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
-
- 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
-
- 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
-
- 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
- A61P9/10—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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process for the preparation of a stable nicorandil formulation comprising: grinding the higher alcohol into higher alcohol mixed powder, and preparing the nicorandil preparation from the nicorandil, the disintegrant, the lubricant, the filler and the higher alcohol mixed powder by a direct tabletting method; the filler comprises at least one of anhydrous lactose, microcrystalline cellulose and corn starch, and the particle size of the filler ranges from 20 micrometers to 400 micrometers, so that the active drug is more uniformly distributed in other auxiliary materials; the higher alcohols include stearyl alcohol, which is used to improve the stability of nicorandil formulations. The invention aims to improve the stability of nicorandil while the nicorandil preparation is convenient to prepare, so that the nicorandil can keep the medicinal activity in a wet and hot environment, reduce the toxic and side effects and ensure the safety and the effectiveness of the medication of patients.
Description
Technical Field
The invention belongs to the technical field of nicorandil preparations, and particularly relates to a preparation method of a stable nicorandil preparation.
Background
The nicorandil is a nitric acid ethopabate chemical name, belongs to nitrate compounds, is a potassium ion channel opener which is firstly used for ATP sensitivity clinically, has obvious effects on unique angina pectoris such as spasm type angina pectoris, labor force type angina and the like, can effectively reduce the occurrence rate of cardiovascular events, and can also play an obvious role in improving the prognosis of patients with coronary heart disease; at present, the medicine becomes the first choice medicine for treating coronary heart disease, so that the preparation of the medicine is concerned widely.
For example: patent application with publication number CN87100285A discloses a method for improving the stability of nicorandil tablet by adding a saturated higher fatty acid or a saturated higher fatty alcohol which is solid at room temperature to a proper dosage form, but the preparation is prepared by a wet granulation process, the process is complicated, and the stability of the preparation still needs to be improved.
Patent application publication No. CN1980644A discloses a process for preparing a composition by adding a lubricant, which is a higher saturated aliphatic acid and its salt and/or saturated higher alcohol, which is solid at ordinary temperature, to the composition, wherein the process for preparing the composition is simple by direct compression, but the stability of the composition is slightly poor and the composition is stored at a temperature lower than 25 ℃.
Patent application publication No. CN85109190A discloses a method for improving the stability of nicorandil tablets using finely pulverized sugar and a powdery organic acid as an excipient, but this method requires that the sugar as an excipient must be air-pulverized to have an average particle diameter of less than 10 μm, and the uniformity and stability of the active ingredient of the resulting tablets are not completely satisfactory.
Patent application publication No. CN1839836A discloses a method for producing nicorandil tablets by direct compression of powder or dry granulation tableting or blank granulation, which can prevent nicorandil from being degraded by moisture and heat, but the content of active ingredients in the nicorandil preparation prepared by this method is reduced to 85 to 87% when it is left alone for 4 weeks at 40 ℃ at 75% RH, and thus the method cannot completely solve the problem of poor stability of the nicorandil preparation.
Patent application with publication number CN203075205U discloses a nicorandil preparation packaging combination, which aims to improve the stability of nicorandil during storage, transportation and use, but the packaging combination is complex and high in cost, and is not suitable for commercial use.
Therefore, according to the patent application, the existing nicorandil preparation is not convenient and fast to prepare, and the chemical properties of nicorandil in the preparation process are extremely unstable and are easily affected by a tabletting process and a damp-heat environment, so that the pharmaceutical activity is reduced, the toxic and side effects are increased, and the safety of the administration of a patient and the effectiveness of the preparation cannot be guaranteed.
Disclosure of Invention
The invention aims to provide a preparation method of a stable nicorandil preparation, so that the preparation is convenient to prepare, the stability of nicorandil is improved, the nicorandil can keep the activity of the drug in wet and hot environments, the toxic and side effects are reduced, and the safety and the effectiveness of the drug administration of patients are guaranteed.
A method for preparing a stable nicorandil preparation, which comprises the following steps: grinding the higher alcohol into higher alcohol mixed powder, and preparing the nicorandil preparation from the nicorandil, the disintegrant, the lubricant, the filler and the higher alcohol mixed powder by a direct tabletting method.
By adopting the technical scheme, the direct tabletting process is simpler, granulation and drying are not needed, and the influence of moisture and heat on the stability of nicorandil in the production process is avoided.
Preferably, the filler comprises at least one of anhydrous lactose, microcrystalline fiber, and corn starch.
Preferably, the filler has a particle size in the range of 20 μm to 400 μm.
By adopting the technical scheme, the active medicament is likely to be unevenly distributed in the auxiliary material by adopting a direct tabletting method, so that the product quality is influenced, the active medicament is more evenly distributed in other auxiliary materials by controlling the particle size range of the filler, the active medicament comprises nicorandil, and the other auxiliary materials comprise a disintegrating agent, a lubricating agent, a filling agent and higher alcohol mixed powder.
Preferably, the higher alcohol comprises octadecanol, which is used to improve the stability of the nicorandil formulation.
By adopting the technical scheme, in order to enable the nicorandil preparation to be more stable, octadecanol is added into the prescription to inhibit the degradation of nicorandil, so that the nicorandil can also keep the medicinal activity in the wet and hot environment, the toxic and side effects are reduced, and the safety and the effectiveness of the medication of patients are ensured.
Preferably, the disintegrant comprises carboxymethylcellulose calcium.
Preferably, the lubricant comprises calcium stearate.
Preferably, the higher alcohol is present in an amount of at least 0.5% of the total amount of the nicorandil preparation.
Preferably, the method comprises the steps of putting the higher alcohol into a mortar for grinding, filtering by using a 40-mesh screen to obtain higher alcohol mixed powder, mixing the nicorandil, the disintegrant, the lubricant, the filler and the higher alcohol mixed powder to prepare a mixture, and tabletting the mixture by using a tabletting machine to prepare the nicorandil preparation.
Preferably, the nicorandil accounts for 10 mass percent, the disintegrant accounts for 5 mass percent, the lubricant accounts for 1.5 to 4 mass percent, the filler accounts for 79 to 82 mass percent, and the higher alcohol mixed powder accounts for 1.5 mass percent.
The beneficial effects of the invention are:
firstly, the invention uses a direct tabletting method, is convenient to prepare, does not need granulation and drying, and avoids the influence of moisture and heat on the stability of nicorandil in the production process;
secondly, the particle size range of the filler is 20-400 microns, and the active medicament is unevenly distributed in the auxiliary material by adopting a direct tabletting method, so that the active medicament is more evenly distributed in other auxiliary materials by controlling the particle size range of the filler, the active medicament comprises nicorandil, and the other auxiliary materials comprise disintegrant, lubricant, filler and higher alcohol mixed powder;
thirdly, the octodecyl alcohol is added to inhibit the degradation of the nicorandil, so that the nicorandil preparation is more stable, the nicorandil can also keep the pharmaceutical activity in the wet and hot environment, the toxic and side effects are reduced, and the safety and the effectiveness of the drug for patients are ensured;
the invention can improve the stability of nicorandil while the preparation of the nicorandil preparation is convenient and fast due to the combined action of the three points, so that the nicorandil can keep the medicinal activity in the wet and hot environment, reduce the toxic and side effects and ensure the safety and the effectiveness of the administration of patients.
Detailed Description
Example 1
A method for preparing a stable nicorandil preparation, the formula of which is shown in the following table 1:
TABLE 1
The preparation steps are as follows: (1) The filler has a particle size of 20-400 μm, preferably 20-160 μm; (2) Grinding octadecanol in a mortar, and filtering with a 40-mesh screen to obtain higher alcohol mixed powder; (3) Weighing the components according to the table 1, placing the components in a self-sealing bag for mixing to prepare a mixture, detecting the content uniformity of the mixture, and tabletting the mixture by a tabletting machine to prepare the nicorandil preparation, wherein each nicorandil preparation weighs 50mg and each nicorandil preparation contains 5mg of nicorandil, and the content uniformity result refers to the table 11.
Example 2
A method for preparing a stable nicorandil preparation, the formula of which is shown in the following table 2:
TABLE 2
The preparation method comprises the following steps: (1) The filler has a particle size range of 20 μm to 400 μm, preferably anhydrous lactose having a particle size of 100 μm to 250 μm; (2) Grinding octadecanol in a mortar, and filtering with a 40-mesh screen to obtain higher alcohol mixed powder; (3) Weighing the components according to the table 2, placing the components in a hopper mixer, mixing the components to prepare a mixture, detecting the content uniformity of the mixture, and referring to the table 11 for the content uniformity result, and then tabletting the mixture through a tabletting machine to prepare nicorandil preparations, wherein each nicorandil preparation weighs 50mg, and each nicorandil preparation contains 5mg of nicorandil.
Example 3
A method for preparing a stable nicorandil preparation, which has the formula shown in the following table 3:
TABLE 3
The preparation method comprises the following steps: (1) The filler has a particle size range of 20 μm to 400 μm, preferably anhydrous lactose having a particle size of 50 μm to 200 μm; (2) Grinding octadecanol in a mortar, and filtering the mixture by using a 40-mesh screen to obtain higher alcohol mixed powder; (3) Weighing the components according to the table 3, placing the components in a hopper mixer, mixing the components to prepare a mixture, detecting the content uniformity of the mixture, and referring to the table 11 for the content uniformity result, and then tabletting the mixture through a tabletting machine to prepare nicorandil preparations, wherein each nicorandil preparation weighs 50mg, and each nicorandil preparation contains 5mg of nicorandil.
Example 4
A method for preparing a stable nicorandil preparation, the formula of which is shown in the following table 4:
TABLE 4
The preparation method comprises the following steps: (1) The filler has a particle size in the range of 20 μm to 400 μm, preferably anhydrous lactose having a particle size in the range of 200 μm to 400 μm; (2) Grinding octadecanol in a mortar, and filtering with a 40-mesh screen to obtain higher alcohol mixed powder; (3) Weighing the components according to the table 4, placing the components in a hopper mixer to mix to prepare a mixture, detecting the content uniformity of the mixture, and referring to the table 11 for the content uniformity result, then tabletting and forming the mixture by a tabletting machine to prepare the nicorandil preparation, wherein each nicorandil preparation weighs 50mg, and each nicorandil preparation contains 5mg of nicorandil.
Example 5
A method for preparing a stable nicorandil preparation, the formula of which is shown in the following table 5:
TABLE 5
The preparation steps are as follows: (1) The filler has a particle size range of 20 μm to 400 μm, preferably anhydrous lactose having a particle size of 100 μm to 400 μm; (2) Grinding octadecanol in a mortar, and filtering the mixture by using a 40-mesh screen to obtain higher alcohol mixed powder; (3) Weighing the components according to the table 5, placing the components in a hopper mixer, mixing the components to prepare a mixture, detecting the content uniformity of the mixture, and referring to the table 11 for the content uniformity result, and then tabletting the mixture through a tabletting machine to prepare the nicorandil preparation, wherein each nicorandil preparation weighs 50mg, and each nicorandil preparation contains 5mg of nicorandil.
Example 6
A method for preparing a stable nicorandil preparation, the formula of which is shown in the following table 6:
TABLE 6
The preparation steps are as follows: (1) The filler has a particle size range of 20 μm to 400 μm, preferably 20 μm to 250 μm; (2) Grinding octadecanol in a mortar, and filtering with a 40-mesh screen to obtain higher alcohol mixed powder; (3) Weighing the components according to the table 6, placing the components in a hopper mixer to mix to prepare a mixture, detecting the content uniformity of the mixture, and referring to the table 11 for the content uniformity result, then tabletting and forming the mixture by a tabletting machine to prepare the nicorandil preparation, wherein each nicorandil preparation weighs 50mg, and each nicorandil preparation contains 5mg of nicorandil.
Example 7
A method for preparing a stable nicorandil preparation, the formula of which is shown in the following table 7:
TABLE 7
The preparation method comprises the following steps: (1) Microcrystalline cellulose having a filler particle size in the range of 20 μm to 400 μm, preferably 20 μm to 250 μm; (2) Placing octadecanol into a mortar for grinding, filtering by using a 40-mesh screen to obtain higher alcohol mixed powder, (3) weighing the components according to the table 7, placing the components into a hopper mixer for mixing to prepare a mixture, detecting the content uniformity of the mixture, referring to the table 11 for the content uniformity result, and then tabletting the mixture by using a tabletting machine to prepare the nicorandil preparation, wherein the weight of each nicorandil preparation is 50mg, and each nicorandil preparation contains 5mg of nicorandil.
Example 8
A method for preparing a stable nicorandil preparation, the formula of which is shown in the following table 8:
TABLE 8
The preparation method comprises the following steps: (1) Microcrystalline cellulose having a filler particle size in the range of 20 μm to 400 μm, preferably 200 μm to 400 μm; (2) Grinding octadecanol in a mortar, and filtering with a 40-mesh screen to obtain higher alcohol mixed powder; (3) Weighing the components according to the table 8, placing the components in a hopper mixer to mix to prepare a mixture, detecting the content uniformity of the mixture, and referring to the table 11 for the content uniformity result, then tabletting and forming the mixture by a tabletting machine to prepare the nicorandil preparation, wherein each nicorandil preparation weighs 50mg, and each nicorandil preparation contains 5mg of nicorandil.
Comparative example 1
A method for preparing a nicorandil preparation on the market, the formula of which is shown in the following table 9:
TABLE 9
The preparation method comprises the following steps: (1) Pulverizing mannitol with gas flow for 5min to obtain a powder with average particle size of less than 10 μm, preferably particle size D90 of 9.5 μm; (2) Grinding octadecanol in a mortar, and filtering the mixture by using a 40-mesh screen to obtain higher alcohol mixed powder; (3) Weighing the components according to the table 9, placing the components in a hopper mixer, mixing the components to prepare a mixture, detecting the content uniformity of the mixture, referring to the table 11 for content uniformity results, and then tabletting the mixture through a tabletting machine to prepare the nicorandil preparation.
Comparative example 2
A method for preparing a nicorandil preparation on the market, the formula of which is shown in the following table 10:
TABLE 10
The preparation method comprises the following steps: (1) Pulverizing D-mannitol for 5min, weighing 50g of pulverized D-mannitol, adding 10g of purified water, mixing, sieving with 40 mesh sieve, drying at 50 deg.C for 30min, and sieving with 40 mesh sieve to obtain D-mannitol granules; (2) Grinding octadecanol in a mortar, and filtering with a 40-mesh screen to obtain higher alcohol mixed powder; (3) Nicorandil, corn starch, D-mannitol particles, octadecanol, carboxymethylcellulose calcium and calcium stearate are weighed according to the table 10, the Nicorandil, the corn starch, the D-mannitol particles, the octadecanol, the carboxymethylcellulose calcium and the calcium stearate are placed in a self-sealing bag to be mixed to prepare a mixture, the content uniformity of the mixture is detected, the content uniformity result refers to the table 11, and then the mixture is tableted and formed through a tablet machine to prepare the Nicorandil preparation.
The content uniformity of the mixtures of examples 1 to 8 and comparative examples 1 to 2 was characterized by the average content and RSD, and the results are shown in the following table 11:
TABLE 11
| Number of | Average content (%) | RSD(％) |
| Example 1 | 102.89 | 2.3 |
| Example 2 | 96.60 | 1.1 |
| Example 3 | 97.66 | 1.7 |
| Example 4 | 97.02 | 2.1 |
| Example 5 | 98.45 | 2.6 |
| Example 6 | 97.1 | 2.9 |
| Example 7 | 96.98 | 1.3 |
| Example 8 | 101.68 | 2.1 |
| Comparative example 1 | 107.94 | 8.7 |
| Comparative example 2 | 95.61 | 24.3 |
The RSD value of the nicorandil preparation prepared by the invention is less than 3 percent, the mixing is more uniform, and the direct powder tabletting process which is simple and can avoid the influence of moisture and heat is favorably adopted.
Taking examples 1-8, reference preparation and commercially available nicorandil preparation as comparative examples 3-7 to prepare samples, and testing the effective component content and total impurity content of the samples after the samples are exposed and placed for 30 days under the conditions of 40 ℃ and 75% RH, the specifications of the reference preparation and the comparative examples 3-7 are shown in Table 12, and the testing results are shown in the following Table 13:
TABLE 12
| Number of | Specification of |
| Reference formulation | 5mg |
| Comparative example 3 | 5mg |
| Comparative example 4 | 5mg |
| Comparative example 5 | 5mg |
| Comparative example 6 | 5mg |
| Comparative example 7 | 5mg |
Watch 13
The content of the effective components of the nicorandil preparation prepared by the invention can reach more than 60 percent after being exposed and placed for 30 days under the conditions of 40 ℃ and 75 percent RH, the total impurity content is lower than 30 percent and can reach 17.26 percent; compared with the comparative examples 3-7, the content of the active ingredients is lower than 50%, and the total impurity content exceeds 40%, which shows that the nicorandil preparation prepared by the invention is more stable, the nicorandil can keep the pharmaceutical activity in the wet and hot environments, the toxic and side effects are reduced, and the safety and the effectiveness of the administration of patients are guaranteed.
Taking examples 1-8, reference preparation, and commercially available nicorandil preparation as comparative examples 3-7, preparing samples, testing the effective component content and total impurity content of the samples after the samples are placed in a package for 6 months under the conditions of 40 ℃,75% RH, and the specifications of the reference preparation and the comparative examples 3-7 are shown in Table 12, and the package materials of examples 1-8 comprise: PVC/PE/PVDC composite hard sheet, aluminum foil, desiccant, moisture-proof bag, reference preparation and the packaging materials of comparative examples 3-7 include: the test results of the aluminum-plastic panel, the desiccant and the moisture-proof bag are shown in the following table 14:
TABLE 14
The content of the effective components of the nicorandil preparation prepared by the invention can reach more than 90 percent after being packaged and placed for 6 months under the conditions of 40 ℃ and 75 percent RH, the total impurity content is less than 2 percent and can reach 0.56 percent; compared with the comparative examples 3-7, the content of the active ingredients is lower than 77%, the total impurity content exceeds 19%, and can reach 35.69%, which shows that the nicorandil preparation prepared by the invention is more stable, the nicorandil can keep the drug activity in the wet and hot environments, the toxic and side effects are reduced, and the safety and the effectiveness of the drug administration of patients are guaranteed.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described above, or equivalents may be substituted for elements thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A process for the preparation of a stable nicorandil formulation comprising: grinding the higher alcohol into higher alcohol mixed powder, and preparing the nicorandil preparation from the nicorandil, the disintegrant, the lubricant, the filler and the higher alcohol mixed powder by a direct tabletting method.
2. The method of preparing a stable nicorandil formulation according to claim 1, wherein the filler comprises at least one of anhydrous lactose, microcrystalline cellulose, corn starch.
3. The method of preparing a stable nicorandil formulation as claimed in claim 2, wherein the particle size of the bulking agent is in the range of 20 μm to 400 μm.
4. The method of preparing a stable nicorandil formulation as claimed in claim 1, wherein the higher alcohol comprises octadecanol, which is used to improve the stability of nicorandil formulation.
5. The method of preparing a stable nicorandil formulation as claimed in claim 1, wherein the disintegrant comprises calcium carboxymethylcellulose.
6. The method of preparing a stable nicorandil formulation as claimed in claim 1, wherein the lubricant comprises calcium stearate.
7. The method of preparing a stable nicorandil preparation according to claim 4, wherein the content of the higher alcohol is at least 0.5% of the total amount of the nicorandil preparation.
8. The method for preparing the stable nicorandil preparation according to claim 1, wherein the higher alcohol is ground in a mortar, and filtered through a 40-mesh screen to obtain a higher alcohol mixed powder, and the direct compression method comprises the steps of mixing nicorandil, a disintegrant, a lubricant, a filler and the higher alcohol mixed powder to prepare a mixture, and compressing the mixture by a tablet press to form the nicorandil preparation.
9. The method for preparing a stable nicorandil preparation according to any one of claims 1 to 8, wherein the nicorandil is 10% by mass, the disintegrant is 5% by mass, the lubricant is 1.5 to 4% by mass, the filler is 79 to 82% by mass, and the higher alcohol mixed powder is 1.5% by mass.
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Citations (2)
| 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 |
| CN87100285A (en) * | 1986-01-17 | 1987-08-19 | 中外制药株式会社 | Produce the method for stable nicorandil preparation |
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Patent Citations (2)
| 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 |
| CN87100285A (en) * | 1986-01-17 | 1987-08-19 | 中外制药株式会社 | Produce the method for stable nicorandil preparation |
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