CN103705484B - Stable atorvastatin calcium tablet and preparation methods thereof - Google Patents
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- CN103705484B CN103705484B CN201410003088.2A CN201410003088A CN103705484B CN 103705484 B CN103705484 B CN 103705484B CN 201410003088 A CN201410003088 A CN 201410003088A CN 103705484 B CN103705484 B CN 103705484B
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Abstract
The invention provides a stable atorvastatin calcium tablet which comprises a tablet core and a thin film coating, wherein the tablet core consists of atorvastatin calcium, filler, a disintegrating agent, a lubricant and a proper amount of a compound stabilizer, and the thin film coating contains a stabilizer. The invention further provides multiple preparation methods of the stable atorvastatin calcium tablet. The preparation methods comprise a wet granulation tabletting method, and the thin film coating is a water phase coating. The product is good in quality and high in stability, and the stable atorvastatin calcium tablet has the characteristics of simple process and suit for production on a scale.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to a kind of stable atorvastatin and preparation method thereof.
Background technology
Atorvastatin is statins antilipemic drugs, the low-density lipoprotein cholesterol level of hypercholesterolemiapatients patients can be reduced, for the treatment of hypercholesterolemia, coronary heart disease, within 1991, atorvastatin was invented by Warner-Lambert AG Safnern of the U.S., in Initial Public Offering in 1997.Chemistry [R-(the R by name of Atorvastatin calcium, R)]-2-(4-fluorophenyl)-β, beta-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(aniline) carbonyl]-1-hydrogen-pyrroles-1-enanthic acid calcium trihydrate, molecular formula is (C
33h
34fN
2o
5)
2ca3H
2o, structural formula is as follows:
Atorvastatin is 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase competitive inhibitor.HMG-CoA reductase is the rate-limiting enzyme that 3-hydroxy-3-methylglutaryl-coenzyme A transforms to mevalonic acid, and mevalonic acid is sterin comprises the precursor of cholesterol.Containing a phenyl ring and azacyclo-in atorvastatin molecular structure, enter in human body and do not need metabolism namely to have biological activity.Atorvastatin reduces serum TC, TG and LDL-C by suppressing Hepatic HMG-CoA Reductase and upregulating hepatocyte cell ldl receptor, also has slight rising effect, thus play Regulation serum lipids to HDL-C.
Cardiovascular disease is one of disease that harm humans health (particularly person in middle and old age) is the most common, the most serious, and dyslipidemia is the important risk factor of atherosclerosis, coronary heart disease and other cardiovascular and cerebrovascular diseases.Atorvastatin is as a kind of HMG-CoA reductase inhibitor, in occupation of very consequence in blood lipid-lowering medicine, have the following advantages compared with the medicine of other Statins: (1) effect for reducing fat is stronger: have many experiments to compare the curative effect of various dose atorvastatin and other several statinses simultaneously, find that the effect of atorvastatin is strong compared with other Statins.Wherein CURV ES test compares the curative effect of all statinses first, find that atorvastatin is strong compared with the simvastatin of Isodose, pravastatin, lovastatin, fluvastatin effect, it is the highest that blood fat reduces the ratio reaching U.S.'s Cholesterol Education Program (NCEP) therapeutic goal value.The most attractive is atorvastatin and angiopoiesis comparative study (AvERT), result confirms that positive lipid-lowering therapy at least with through Intradermal coronary angioplasty has same effect in the generation of prevention patients with coronary heart disease heart ischemia sexual behavior part.(2) untoward reaction is few: atorvastatin can be well tolerated, and untoward reaction mostly is slight and transient.
But Atorvastatin calcium is atomic water-soluble, especially almost insoluble or insoluble in pH4.0 and following water.In addition, Atorvastatin calcium is to the sensitivity such as wet, hot, and especially unstable in sour environment, Atorvastatin calcium is degraded into lactone.Conventional adjuvant such as microcrystalline Cellulose, hyprolose etc. all can cause the degraded of Atorvastatin calcium.Although preparing in atorvastatin process the measure that have employed some and control, still existence and stability is poor for the atorvastatin of at present listing, the problem such as related substance rising in storage.
Patent 201210498971.4 discloses a kind of atorvastatin agent and preparation method thereof, adopts wet granule compression tablet.This patent is added with the calcium carbonate of 22.01% as filler, and is surrounded by film-coat, and be added with polyoxyethylene sorbitan monoleate as stripping promoter, calcium carbonate wherein can play Stabilization simultaneously, but still can not solve the problem that in storage process, related substance raises completely.
Patent 200480016391.0 discloses the stable compositions of atorvastatin utilizing wet granulation to prepare, and containing the alkaline-earth metal salt additives and the disintegrating agent that are less than 5%, and adopts volatility alkali to make wetting agent alkalize.But 5% alkali salt is not enough to the alkaline environment controlling tablet, namely the volatility of volatility alkali reduces its effect to stability, can only tolerate the baking temperature of 40 DEG C in drying process, namely 60 DEG C of dry related substances significantly raise, and its atorvastatin lactone is still higher.
Therefore, how atorvastatin being prepared into the product that stripping property is good, stability is high is the problem that field of medicaments technical staff puts forth effort to solve.
Summary of the invention
In view of the deficiencies in the prior art, the invention is intended to provide a kind of stable atorvastatin and preparation method thereof, this tablet is stablized conventional filler, disintegrating agent, and its wet granular can tolerate the temperature drying of 80 DEG C, stable in preparation, storage, and dissolution is good.
Embodiment of the present invention is as follows for achieving the above object:
Stable atorvastatin of the present invention, be made up of label and film-coat, label comprises the following component by mass percentage: Atorvastatin calcium counts 5% ~ 20% with atorvastatin, filler 15% ~ 60%, disintegrating agent 5% ~ 20%, stabilizing agent 1 is 25% ~ 45%, stabilizing agent 2(regulates wetting agent pH value to be 8.0 ~ 11.0), magnesium stearate 0.5% ~ 1%, film-coat comprises following component: film-coat powder is 1% ~ 4% of label weight, and stabilizing agent is 1% ~ 10% of film-coat grain weight amount.
The content of described Atorvastatin calcium counts 6.6%-~ 13% with atorvastatin.
Described filler is the combination of a kind of in lactose, microcrystalline Cellulose, mannitol, sorbitol, pregelatinized Starch or any two kinds, and preferred lactose and microcrystalline Cellulose combinationally use, and consumption is 33% ~ 50%.
Described disintegrating agent be in cross-linking sodium carboxymethyl cellulose, hyprolose, carboxymethylstach sodium, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone any one, preferred cross-linking sodium carboxymethyl cellulose, consumption is 10 ~ 15%.
Described stabilizing agent 1 is the one in the alkalescence materials such as calcium carbonate, magnesium oxide, sodium bicarbonate, preferred calcium carbonate; Stabilizing agent 2 is that in the fixedness alkali such as sodium hydroxide, calcium hydroxide, potassium hydroxide, trometamol, any one is as adjustment wetting agent, and preferred sodium hydroxide, regulates pH to be 9.0 ~ 10.0.
Can also binding agent be added in described label, binding agent be in polyvidone, hyprolose, hypromellose any one.
Described film-coat powder is stomach dissolution type film-coat powder, and as macromolecular materials such as hypromellose, Polyethylene Glycol, polyvidones, film-coat powder is added with modified form composition, and described modified form composition is plasticizer, opacifier.
In described coating stabilizing agent be stabilizing agent 1, stabilizing agent 2 or wherein combine.
The atorvastatin prepared by said method, every sheet contains Atorvastatin calcium in the content of atorvastatin for 10mg, 20mg, 40mg, 80mg.
Described stable atorvastatin, any prior art can be adopted to be prepared, and the product prepared all conforms to quality requirements.
Owing to have employed technique scheme, the technological progress obtained is:
Atorvastatin prepared by the present invention, in wet granule compression tablet process, adopt 80 DEG C of dryings, related substance, content are showed no change; Finished product not only masks uncomfortable taste, and related substance is few, and stability is high, and stripping is complete; In influence factor's test, to light, heat, wet and stablize; Accelerated test 6 months, related substance slightly increases, but lactone is lower than 0.17%, is obviously better than comparative examples preparation, and comparative examples preparation lactone is all higher than 0.2%.Product prepared by the present invention, in representative four kinds of dissolution mediums, all has good stripping; Long-term room-temperature keeps sample 12 months, and related substance, content have no change, and stripping is complete.
Detailed description of the invention
Below by way of specific embodiment, the present invention is further illustrated, but and mean never in any form and limit the invention.In the following example, method therefor is conventional method if no special instructions.
According to component described in table 1, embodiment 1 ~ 7 has prepared multiple atorvastatin, unit for often prepare 1000 atorvastatins add the grams of each component.Atorvastatin calcium in atorvastatin every 1000 add 10g, 20g, 40g, 80g time, what prepare respectively is the product of 10mg, 20mg, 40mg, 80mg specification.
Table 1 embodiment 1 ~ 7 atorvastatin component (1000)
Embodiment preparation method:
(1) embodiment 1,3,4 preparation method: Atorvastatin calcium, filler, disintegrating agent, stabilizing agent 1, binding agent mix, and add water (regulating pH with stabilizing agent 2) soft material processed, granulate, 80 DEG C of dryings, granulate, adds magnesium stearate and always mixes, tabletting.Film-coat powder, stabilizing agent 1(or regulate pH with stabilizing agent 2), pure water stirs evenly, coating, to obtain final product.
(2) embodiment 2 preparation method: filler, 50% disintegrating agent, stabilizing agent mix, hypromellose adds pure water and dissolves, regulates pH with stabilizing agent 2, adding Atorvastatin calcium suspendible is binding agent soft material, granulate, 80 DEG C of dryings, granulate, adds remaining disintegrating agent, magnesium stearate always mixes, tabletting.Film-coat powder, stabilizing agent (or pH adjusting agent), pure water stir evenly, and coating, to obtain final product.
(3) embodiment 5 ~ 7 preparation method: Atorvastatin calcium, filler, disintegrating agent, binding agent mix, and add water (regulating pH with stabilizing agent 2) soft material processed, granulate, 80 DEG C of dryings, granulate, adds magnesium stearate and always mixes, tabletting.Film-coat powder, stabilizing agent (or pH adjusting agent), pure water stir evenly, and coating, to obtain final product.
Study on influencing factors is carried out to the atorvastatin prepared by embodiment 1 ~ 7, carries out influence factor's stability test according to " Chinese Pharmacopoeia " two version relevant regulations in 2010.
The situation of the character when atorvastatin high temperature of table 2 prepared by embodiment 1 ~ 7, high humidity, illumination 10 days, lactone impurity, total assorted, content and stripping.
Table 2
Influence factor's experimental result shows, the content of atorvastatin, related substance prepared by embodiment 1 ~ 7 do not have significant change, illustrates that it is good at high temperature, high humidity, illumination condition stability inferior.
Show through accelerated stability test and long-term stable experiment, atorvastatin long-time stability prepared by the present embodiment are good, meet the relevant regulations of 2010 editions " Chinese Pharmacopoeias ", and dissolution are all greater than 95%, impurity level meets European Pharmacopoeia regulation, maximum list assorted≤0.2%.
Accelerated stability test the results are shown in Table 3, and long-term stable experiment the results are shown in Table 4.
Table 3
Table 4
Comparative examples
Conventionally, inventor has prepared controlled trial product according to the component of table 5.Table 5 list control experiment prepare respectively 1000 atorvastatins add the grams of each component.Comparative examples 1 is the method according to patent 201210498971.4, adds a kind of stabilizing agent calcium carbonate, and stabilizing agent calcium carbonate consumption is 22%, coating, the product of preparation.Comparative examples 2 is the method according to patent 200480016391.0, and stabilizing agent is alkaline-earth metal is 4.7%, adds volatility alkali, without stabilizing agent in film-coat in wetting agent.Comparative examples 3 is according to patent 200480016391.0 method, stabilizing agent alkaline-earth metal 4.7%, the product of preparation.Comparative examples 4 be stabilizing agent calcium carbonate consumption close to 30%, dry powder sheeting, coating, the product of preparation.Comparative examples 5 for not add stabilizing agent, dry powder sheeting, coating, the product of preparation.
Table 5
Comparative examples preparation method:
(1) comparative examples 1: Atorvastatin calcium, filler, disintegrating agent, stabilizing agent, binding agent mix, and add water soft material processed, granulate, 40 DEG C of dryings, granulate, adds magnesium stearate and always mixes, tabletting, coating, to obtain final product.
(2) comparative examples 2: Atorvastatin calcium, filler, disintegrating agent, stabilizing agent, binding agent mix, and add 0.1% ammonia soft material, granulate, 40 DEG C of dryings, granulate, adds magnesium stearate and always mixes, tabletting, coating, to obtain final product.
(3) comparative examples 3: with comparative examples 1.
(4) comparative examples 4: Atorvastatin calcium, filler, disintegrating agent, stabilizing agent, binding agent, magnesium stearate mix, and tabletting, coating, to obtain final product.
(5) comparative examples 5: Atorvastatin calcium, filler, disintegrating agent, binding agent, magnesium stearate mix, and tabletting, coating, to obtain final product.
Atorvastatin prepared by comparative examples 1 ~ 5 is carried out Study on influencing factors, carries out influence factor's stability test according to " Chinese Pharmacopoeia " two version relevant regulations in 2010.
The situation of the character when atorvastatin high temperature of table 6 prepared by comparative examples 1 ~ 5, high humidity, illumination 10 days, lactone impurity, total assorted, content and stripping.
Table 6
Result shows, atorvastatin prepared by comparative examples, and under high temperature, high humidity and illumination, lactone impurity, the related substance such as total assorted raise obviously.
Show through accelerated stability test and long-term stable experiment, atorvastatin long-time stability prepared by comparative examples are poor.
Accelerated stability test the results are shown in Table 7, and long-term stable experiment the results are shown in Table 8.
Table 7
Table 8
Can be found out by above result, compared with prior art, atorvastatin prepared by the present invention is placed 10 days under high temperature, high humidity and illumination condition, and accelerated stability test and long-term stable experiment time, there is lower impurity content, as can be seen here, the atorvastatin stability prepared by the present invention is better than prior art products.
Claims (5)
1. a stable atorvastatin, is made up of label and film-coat, it is characterized in that:
1) the sheet core component of this sheet consists of, wherein by mass percentage:
Atorvastatin calcium 5% ~ 20%,
Filler 15% ~ 60%,
Disintegrating agent 5% ~ 20%,
Stabilizing agent 1
25% ~ 45%,
Stabilizing agent 2 regulates wetting agent pH value to be 8.0 ~ 11.0,
Magnesium stearate 0.5% ~ 1%,
Binding agent;
Filler is wherein the combination of a kind of in lactose, microcrystalline Cellulose, mannitol, sorbitol, pregelatinized Starch or any two kinds; Disintegrating agent is wherein one in cross-linking sodium carboxymethyl cellulose, carboxymethylstach sodium, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone or any two kinds of combinations; Stabilizing agent 1 be wherein in calcium carbonate, magnesium oxide, sodium bicarbonate any one; Stabilizing agent 2 be in sodium hydroxide, calcium hydroxide, potassium hydroxide, trometamol any one; Binding agent be wherein in polyvidone, hyprolose or hypromellose any one;
2) film-coat comprises following component:
1% ~ 4% of film-coat powder label weight,
1% ~ 10% of stabilizing agent film-coat grain weight amount;
Stabilizing agent is stabilizing agent 1, stabilizing agent 2 or wherein combine, stabilizing agent 1 be wherein in calcium carbonate, magnesium oxide, sodium bicarbonate any one; Stabilizing agent 2 be in sodium hydroxide, calcium hydroxide, potassium hydroxide, trometamol any one.
2. stable atorvastatin according to claim 1, the content of Atorvastatin calcium is 6.6 ~ 13%.
3. stable atorvastatin according to claim 1, described film-coat powder is stomach dissolution type film-coat powder.
4. stable atorvastatin according to claim 1, wherein film-coat powder is added with modified form composition, and described modified form composition is plasticizer, opacifier.
5. the stable atorvastatin according to claim arbitrary in Claims 1-4, every sheet contains Atorvastatin calcium in the content of atorvastatin for 10mg, 20mg, 40mg, 80mg.
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| CN104069078B (en) * | 2014-05-22 | 2019-06-11 | 西藏九瑞健康股份有限公司 | Atorvastatin calcium medicine compound and preparation method thereof |
| CN104644600A (en) * | 2015-01-27 | 2015-05-27 | 北京罗诺强施医药技术研发中心有限公司 | Coating tablet of statin medicines and preparation method |
| CN105343024B (en) * | 2015-11-05 | 2018-03-30 | 石家庄市华新药业有限责任公司 | A kind of atorvastatin agent and preparation method thereof |
| CN106420645A (en) * | 2016-11-24 | 2017-02-22 | 浙江新东港药业股份有限公司 | Calcium tablet containing atorvastatin and preparation method |
| CN113546050B (en) * | 2021-07-07 | 2022-11-29 | 海南锦瑞制药有限公司 | Atorvastatin calcium tablet and preparation method thereof |
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| CN1630510A (en) * | 2001-03-14 | 2005-06-22 | 莱克制药与化学公司 | Atorvastatin calcium in a pharmaceutical form, composition thereof, and pharmaceutical formulation comprising atorvastatin calcium |
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| EP0680320B1 (en) * | 1993-01-19 | 1999-04-14 | Warner-Lambert Company | Stable oral ci-981 formulation and process of preparing same |
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| CN1630510A (en) * | 2001-03-14 | 2005-06-22 | 莱克制药与化学公司 | Atorvastatin calcium in a pharmaceutical form, composition thereof, and pharmaceutical formulation comprising atorvastatin calcium |
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