WO2018049989A1 - 一种瑞舒伐他汀钙药物组合物及其制备方法 - Google Patents

一种瑞舒伐他汀钙药物组合物及其制备方法 Download PDF

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WO2018049989A1
WO2018049989A1 PCT/CN2017/100106 CN2017100106W WO2018049989A1 WO 2018049989 A1 WO2018049989 A1 WO 2018049989A1 CN 2017100106 W CN2017100106 W CN 2017100106W WO 2018049989 A1 WO2018049989 A1 WO 2018049989A1
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rosuvastatin calcium
pharmaceutical composition
weight ratio
rosuvastatin
calcium
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PCT/CN2017/100106
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English (en)
French (fr)
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李晓强
林巧平
任晋生
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南京先声东元制药有限公司
江苏先声药业有限公司
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Publication of WO2018049989A1 publication Critical patent/WO2018049989A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the technical field of the pharmaceutical preparation of the invention relates to a pharmaceutical composition and a preparation method thereof, in particular to a rosuvastatin calcium pharmaceutical composition and a preparation method thereof.
  • Vascular disease is a type of disease that seriously endangers human health. In recent years, the incidence and mortality of such diseases have increased significantly in both Western and Eastern countries. According to the World Health Organization, about 15 million people worldwide die from cardiovascular and cerebrovascular diseases every year. In China, the incidence of cardiovascular and cerebrovascular diseases is as high as 8%, and the mortality rate is close to 50% of the total mortality rate. On average, every 20 minutes. One person died of cardiovascular and cerebrovascular diseases. Cardiovascular and cerebrovascular diseases are mainly caused by atherosclerosis, and more than 80% of atherosclerosis is caused by hyperlipidemia. According to the survey, among those aged 15-69 who have had blood lipid tests, hyperlipidemia accounts for 40%.
  • Hyperlipidemia refers to a systemic lipid in which serum cholesterol (TC), triglyceride (TG) and/or low-density lipoprotein (LDL) is too high and/or serum high-density lipoprotein (HDL) is too low. Abnormal metabolism.
  • TC serum cholesterol
  • TG triglyceride
  • LDL low-density lipoprotein
  • HDL serum high-density lipoprotein
  • LDL-C serum low-density lipoprotein cholesterol
  • new statin lipid-lowering drugs that have been developed and marketed have been able to effectively reduce serum low-density lipoprotein (LDL-C) blood cholesterol. Since 1994, five landmark large-scale clinical studies have been published.
  • statin lipid-lowering drugs can significantly reduce plasma cholesterol (mainly LDL-C) levels, while significantly reducing coronary heart disease patients and non-crown
  • plasma cholesterol mainly LDL-C
  • Rosuvastatin Calcium was developed for the Japanese salt mine (Japan Shionogi) and was transferred to the British company Zeneca in April 1998 and named rosuvastatin.
  • Phase IIa and phase IIb clinical trials were completed, and Phase III clinical validation was accelerated.
  • AstraZeneca named rosuvastatin as Crestorm.
  • rosuvastatin is not called "super statin"
  • its lipid-lowering effect is very good, it is the most powerful lipid-lowering effect so far. drug. Therefore, the independent research and development of the new statin drug rosuvastatin is of great significance to fill the gap of new drugs in China, promote the health of people in China, and achieve social and economic benefits.
  • rosuvastatin calcium has advantages: (1) rosuvastatin is superior to simvastatin and pravastatin in lowering LDL-C (very low-density lipoprotein cholesterol).
  • rosuvastatin is better than LDL-C and elevated HDL-C Ruvastatin; (3) rosuvastatin is more effective than atorvastatin in treating heterozygous families with genetic hyperlipidemia.
  • rosuvastatin is a novel HMG-CoA reductase inhibitor, which is effective in reducing serum TC and TG. It is stronger than the current application of atorvastatin, pravastatin and simvastatin, but side effects. Not increasing, it is the strongest lipid-lowering drug at present.
  • rosuvastatin calcium bis-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine- 5-yl](3R,5S)-3,5-hydroxyhept-6-enoic acid]calcium salt (2:1), the structural formula is:
  • a stable pharmaceutical composition comprising a statin compound is disclosed in CN1091634A by adding an alkaline medium (such as a carbonate or a salt capable of maintaining the pH of the water-soluble or dispersion of the composition at least 8). Bicarbonate) to achieve stabilization.
  • an alkaline medium such as a carbonate or a salt capable of maintaining the pH of the water-soluble or dispersion of the composition at least 8. Bicarbonate
  • a pharmaceutical composition (compressed under the trade name Crestor) is described in the patent specification of WO 0154668, WO 0154669 or US Pat. No. 6,316,460, according to which a stable drug comprising rosuvastatin calcium cannot be completed by only using a pH-adjuvanting agent.
  • the preparation of the composition but also the presence of a polyvalent metal salt to prevent the formation of lactones and oxidative decomposition products.
  • inorganic salts of polyvalent metals (Ca, mg, Zn, Al, Fe, and combinations thereof) are used as stabilizing additives, such as aluminum silicate, magnesium silicate, calcium orthophosphate, magnesium orthophosphate, and orthophosphoric acid. aluminum.
  • the commercially available (with Crestor as a trade name) drug combination The material contains calcium orthophosphate as a stabilizer. While this method increases the stability of the preparation, it brings about a problem that the magazine content increases rapidly.
  • WO02089788 describes pharmaceutical compositions comprising statins which provide their stability by the addition of an amino sugar such as N-methyl-glucosamine.
  • amino sugars have the advantage that they do not irritate the intestinal mucosa compared to inorganic alkaline earth metal salts.
  • WO0053173 describes a sustained release pharmaceutical composition comprising statin as an active ingredient, wherein the release of the active ingredient in the stomach and the formation of lactone under acidic conditions are prevented by a special 2/18 page gel structure and an enteric coated dosage form.
  • WO0162230 describes a mannitol-based particle in which an active ingredient statin is dissolved in a sodium hydroxide solution and added to the pharmaceutical dosage form together with a granulating solution.
  • WO2008035128 describes a novel pharmaceutical composition comprising amorphous rosuvastatin calcium, wherein magnesium hydroxide and/or calcium acetate or calcium gluconate or calcium glycerophosphate or aluminum hydroxide is used as a stabilizer.
  • CN102860994A describes a rosuvastatin calcium tablet consisting of a core and a coating layer, characterized in that the core is composed of rosuvastatin calcium, lactose, microcrystalline cellulose, a disintegrant and a lubricant.
  • the lactose is spray-dried lactose or granular lactose
  • the microcrystalline cellulose is steam-dried microcrystalline cellulose or spray-dried microcrystalline cellulose.
  • the rosuvastatin calcium composition described in the above literature provides stability by pH control, or addition of a stabilizer, or preparation into a special preparation, the preparation process is cumbersome, the cycle is long, and the cost is high, which is not conducive to large-scale production.
  • the rosuvastatin calcium oral solid preparation prepared according to a conventional method has a cumulative dissolution degree. High, low bioavailability in the body.
  • the larger dose (10-40mg) is prone to fluctuations in the peak-to-valley concentration of blood, such as rhabdomyolysis, proteinuria, nephropathy, and kidney. Adverse reactions such as failure, hepatotoxicity, pharyngitis, headache and flu-like symptoms.
  • the inventors have discovered a new pharmaceutical composition of rosuvastatin calcium by long-term and large-scale experiments, which is prepared, stored, and subjected to high temperature and high light conditions. Lactone degradation products, oxidative degradation products, and photodegradation products are no longer significantly increased, which can ensure the stability of long-term storage, thereby solving the problem that has been plagued by the stability of rosuvastatin calcium preparation.
  • the composition has the advantages of simple prescription, simple process, no special processing equipment, low cost, and the like, thereby playing a more active role in the widespread promotion of the drug in the clinic.
  • the technical problem to be solved by the present invention is to provide a rosuvastatin calcium pharmaceutical composition with good stability, specifically
  • the present invention provides a pharmaceutical composition of rosuvastatin calcium containing rosuvastatin calcium and a stabilizer.
  • the stabilizer of the present invention is selected from the group consisting of ⁇ -cyclodextrin, wherein the weight ratio of rosuvastatin calcium to the stabilizer is Preferred More preferably, it is 1:9.5, 1:10, and 1:10.5.
  • the pharmaceutical composition of the present invention further comprises a filler, the filler is lactose and microcrystalline cellulose, and the weight ratio of the rosuvastatin calcium to lactose is The weight ratio of the rosuvastatin calcium to the microcrystalline cellulose is
  • the weight ratio of the rosuvastatin calcium to the lactose is further preferably 1:3.5, 1:4, and the weight ratio of the rosuvastatin calcium to the microcrystalline cellulose is 1. : 4, 1:3.
  • composition of the present invention further comprising a disintegrant selected from the group consisting of crospovidone, the weight ratio of the rosuvastatin calcium to the disintegrant is Preferred More preferably, it is 10:10.
  • the pharmaceutical composition of the present invention further comprises a glidant, a lubricant and a binder.
  • the glidant is talc
  • the lubricant is magnesium stearate
  • the binder is povidone K30, wherein the weight ratio of rosuvastatin calcium to the flow aid is Preferred
  • the weight ratio of rosuvastatin calcium to lubricant is Preferred
  • the weight ratio of rosuvastatin calcium to the binder is Preferred
  • the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable excipient.
  • a rosuvastatin calcium tablet comprising the pharmaceutical composition described above.
  • the preparation method of the tablet comprises the following steps: the raw materials are respectively passed through a 100 mesh sieve, thoroughly mixed, and compressed.
  • the method of preparation further comprises coating with gastric soluble Opadry.
  • a rosuvastatin calcium tablet provided by the present invention is as follows:
  • the prescription amount of rosuvastatin calcium and the prescription amount ⁇ -cyclodextrin are evenly mixed, and the other auxiliary materials are added to the prescription and fully mixed.
  • the pharmaceutical composition of the present invention can achieve a good stabilizing effect without adding an alkaline substance.
  • the invention achieves the requirement of pharmaceutically stable rosuvastatin calcium which can be prepared for enteral administration, has less dosage of preparation auxiliary materials, and has the advantages of stable color, long storage period and maximum avoidance, rosuvastatin Calcium produces degradation of unrelated substances.
  • Prescription 1 Prescription 2 Prescription 3
  • Prescription 4 Prescription 5
  • Prescription 6 Rosuvastatin calcium 10.4 10.4 10.4 10.4 10.4 --cyclodextrin 104 95 105 104 95 105 lactose 35 50 35 40 40 45
  • Microcrystalline cellulose 35 30 40 40 35 30
  • Cross-linked povidone 8 8 8 6 8 10 Povidone K30 2 2 2 4 3 talcum powder 4 4 4 6 6 3
  • the prescription amount of rosuvastatin calcium and the prescription amount ⁇ -cyclodextrin are evenly mixed. Add the prescription amount of lactose, microcrystalline cellulose, crospovidone and povidone K30, and mix thoroughly. Add the prescribed amount of talc powder, magnesium stearate, and mix well.
  • the above prescription particles have good fluidity, compressibility and friability.
  • the tablets prepared in the examples were respectively placed under high temperature (60 ° C) and strong light (4500 lx) for 10 days, and the contents of related substances (%) were detected at 0, 5, and 10 days respectively.
  • the detection method of related substances may be CN103776939A. The method described in .

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Abstract

本发明涉及一种瑞舒伐他汀钙药物组合物及其制备方法，含有瑞舒伐他汀钙和稳定剂，所述稳定剂选自β-环糊精，所述瑞舒伐他汀钙和稳定剂的重量比为1:8~14。本发明的组合物料稳定性好，适于临床患者的使用。

Description

一种瑞舒伐他汀钙药物组合物及其制备方法 技术领域
本发明药物制剂技术领域，涉及一种药物组合物及其制备方法，具体而言涉及瑞舒伐他汀钙药物组合物及其制备方法。
背景技术
血管疾病是一类严重危害人类健康的疾病，近年来，无论在西方国家还是东方国家，该类疾病的发病率和死亡率都呈明显上升态势。据世界卫生组织统计，全世界每年大约有1500万人死于心脑血管疾病，在我国，心脑血管疾病发生率高达8％，死亡率接近总死亡率的50％；平均每20分钟就有一人因心脑血管疾病而死亡。心脑血管疾病主要根源于动脉粥样硬化，而80％以上的动脉粥样硬化由高脂血症造成。据调查，15-69岁作过血脂检查的人群中，高脂血症者占40％。
高血脂症是指血清中胆固醇(TC)、甘油三酯(TG)和(或)低密度脂蛋白(LDL)过高和(或)血清高密度脂蛋白(HDL)过低的一种全身脂代谢异常。20多年以来，通过冠心病二级和一级预防的诸多临床试验已经证实，降低血清低密度脂蛋白胆固醇(LDL-C)能够显著降低心血管病发病率、病死率及总死亡率。而近年来，相继开发上市的新型他汀类调脂药物，能够有效的降低血清低密度脂蛋白(LDL-C)血胆固醇，从1994年以来，相继发表了5项具有里程碑意义的大规模临床研究(4S、WOSCAPS、CARE、LIPID、AFCAPS/TexsCAPS)，其结果都一致证实：应用他汀类降脂药物能明显降低血浆胆固醇(主要是LDL-C)水平，同时能显著降低冠心病人群和非冠脉事件发生率和冠心病病死率，而不增加非心血管疾病的死亡率。所以，降低LDL-C已成为冠心病防治的重要措施之一。
瑞舒伐他汀钙(RosuvastatinCalcium)为日本盐野义(大阪Shionogi公司)研制开发，1998年4月转让给英国Zeneca公司，并且命名为瑞舒伐他汀。1999年2月在美国完成了该药的I期，IIa期与IIb期临床验证，并加速了III期临床验证。2000年12月AstraZeneca将瑞舒伐他汀的商品名定为Crestortm。从其已有的临床验证结果和与同类产品的比较两方面来看，瑞舒伐他汀都不愧被称为“超级他汀”，其降脂效果非常好，是迄今为止的最强效的降脂药物。因此，自主研发新型他汀药物瑞舒伐他汀，对填补我国新型药物的空白，促进我国人们身体健康水平，取得社会效益和经济效益，都有重大意义。
荷兰莱顿大学医学中心的心血管教授伊斯特·沃尔博士指出，早期临床实验表明：瑞舒伐他汀的不凡之处在于它不仅能降低低密度脂蛋白(LDL)的含量，同时也可使有益于人体的高密度脂蛋白(HDL)的含量增加14％，从而可以使心血管的发病风险降低近50％。相比其它他汀类药物，瑞舒伐他汀钙具有如有优点：(1)瑞舒伐他汀在降低LDL-C(极低密度脂蛋白胆固醇)上的效果优于辛伐他汀和普伐他汀，使更多的病人能够达到期望的LDL-C水平；(2)在治疗IIa或IIb型高脂血症病人时，瑞舒伐他汀的降低LDL-C和升高HDL-C的效果优于阿伐他汀；(3)瑞舒伐他汀在治疗杂合子家庭遗传高脂血症病人的效果强于阿伐他汀。综上所述，瑞舒伐他汀是一个新型的HMG-CoA还原酶抑制剂，对降低血清TC，TG均有效，作用较目前应用的阿伐他汀、普伐他汀、辛伐他汀强，但副作用不增加，是目前最强的降脂新药。
瑞舒伐他汀钙的化学名：双-(E)-7-[4-(4-氟基苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]-嘧啶-5-基](3R，5S)-3，5-羟基庚-6-烯酸]钙盐(2∶1)，结构式为：
Figure PCTCN2017100106-appb-000001
由于瑞舒伐他汀钙分子中庚烯酸链上的β，δ-羟基非常不稳定，尤其是碳-碳双键相邻的羟基很容易被氧化成酮官能团，也能够发生分子内环合生成内酯，因此在较高温度或较高湿度环境中，瑞舒伐他汀钙很容易降解，形成的主要产物为(3R，5S)内酯降解产物和氧化产物，从而给制剂生产和储存造成困难。由此可见，通过处方筛选和制备工艺研究制备一种稳定性强的瑞舒伐他汀钙口服固体制剂显得尤为重要。
CN1091634A中公开了一种含有他汀化合物的稳定药物组合物，该组合物是通过加入一种能够使该组合物的水溶或分散液的pH值至少保持在8的碱性介质(例如碳酸盐或碳酸氢盐)来达到稳定作用。
在WO0154668、WO0154669或US6316460等专利说明书中对市售(以Crestor为商品名)的药物组合物进行了描述，根据这些描述，仅通过用pH辅助化剂不能完成包含瑞舒伐他汀钙的稳定药物组合物的制备，而是还需要存在多价金属盐来防止形成内酯和氧化分解产物。在该药物组合物中，用多价金属(Ca、mg、Zn、Al、Fe及其组合)的无机盐作为稳定添加剂，例如硅酸铝、硅酸镁、正磷酸钙、正磷酸镁和正磷酸铝。所述的市售(以Crestor为商品名)药物组合 物包含正磷酸钙作为稳定剂。这种方法在增加制剂稳定性的同时，却给制剂带来了杂志含量增加较快的问题。
WO02089788描述了包含他汀的药物组合物，通过加入氨基糖(例如N-甲基-葡萄糖胺)来提供其稳定性。根据说明书，与无机碱土金属盐相比，氨基糖的优点为其不会刺激肠粘膜。
WO0053173描述了包含他汀作为活性成分的缓释的药物组合物，其中通过特殊的2/18页凝胶结构和肠包衣剂型来阻止活性成分在胃中释放和酸性条件下的内酯形成。
WO0162230描述了一种甘露醇基颗粒，其中将活性成分他汀类药物溶解于氢氧化钠溶液中并将其与制粒溶液一起加入到所述药物剂型中。
WO2008035128描述了一种包含无定形瑞舒伐他汀钙的新型药物组合物，其中，以氢氧化镁和/或乙酸钙或葡萄酸钙或甘油磷酸钙或氢氧化铝作为稳定剂。
CN102860994A描述了一种瑞舒伐他汀钙片，由片芯和包衣层组成，其特征在于：所述片芯由瑞舒伐他汀钙、乳糖、微晶纤维素、崩解剂和润滑剂组成，所述乳糖为喷雾干燥乳糖或颗粒乳糖，所述微晶纤维素为流通蒸汽干燥微晶纤维素或喷雾干燥微晶纤维素。
上述文献所描述的瑞舒伐他汀钙组合物通过pH控制、或加入稳定剂、或制备成特殊制剂等方式来提供其稳定性，处方工艺繁琐，周期长，成本高，不利于规模化生产。
另外，由于瑞舒伐他汀钙在水中或0.1mol/L盐酸或0.1mol/L氢氧化钠溶液中几乎不溶，因此按照常规方法制备的瑞舒伐他汀钙口服固体制剂，均存在累积溶出度不高，体内生物利用度较低的问题。同时，虽然瑞舒伐他汀钙的降脂作用显著，但是较大剂量(10-40mg)服用时易产生血药浓度的“峰谷”波动，从而发生如横纹肌溶解症、蛋白尿、肾病、肾衰竭、肝毒性、咽炎、头痛和流感样症状等不良反应。
因此，依然有待于找到一种理想的瑞舒伐他汀钙药物组合物，以进一步得到质量良好、稳定性及制造成本优于现有技术的组合物制剂。
根据上述现有技术，需要制备易于配制的包含瑞舒伐他汀钙的稳定的药物组合物。
为了解决上述问题，发明人通过长期大量的试验摸索，令人吃惊的发现了一种新的瑞舒伐他汀钙的药物组合物，该组合物在制备、存储、高温、强光条件下，其内酯降解物，氧化降解物，光照降解物均不再显著增加，能够保证长期贮存的稳定性，从而解决了一直困扰瑞舒伐他汀钙制剂稳定性的问题。同时，该组合物具有处方、工艺简单，无需特殊处理生产设备、成本低廉等优点，从而为该药物在临床中的广泛推广，起到了更为积极的作用。
发明内容
本发明要解决的技术问题是提供一种具有良好稳定性的瑞舒伐他汀钙药物组合物，具体而 言，本发明提供一种瑞舒伐他汀钙的药物组合物，该药物组合物含有瑞舒伐他汀钙和稳定剂。
本发明所述的稳定剂选自β-环糊精，其中瑞舒伐他汀钙和稳定剂的重量比为
Figure PCTCN2017100106-appb-000002
优选为
Figure PCTCN2017100106-appb-000003
进一步优选为1:9.5、1:10、1:10.5。
本发明所述的药物组合物，还进一步含有填充剂，所述填充剂为乳糖和微晶纤维素，所述瑞舒伐他汀钙和乳糖的重量比为
Figure PCTCN2017100106-appb-000004
所述瑞舒伐他汀钙和微晶纤维素的重量比为
Figure PCTCN2017100106-appb-000005
本发明所述的药物组合物，所述瑞舒伐他汀钙和乳糖的重量比进一步优选为为1:3.5、1:4，所述瑞舒伐他汀钙和微晶纤维素的重量比为1:4、1:3。
本发明所述的药物组合物，其进一步包括崩解剂，所述崩解剂选自交联聚维酮，所述瑞舒伐他汀钙和崩解剂的重量比为
Figure PCTCN2017100106-appb-000006
优选为
Figure PCTCN2017100106-appb-000007
进一步优选为10:10。
本发明所述的药物组合物，进一步包括助流剂、润滑剂和粘合剂。所述助流剂为滑石粉，所述润滑剂为硬脂酸镁，所述粘合剂为聚维酮K30，其中，瑞舒伐他汀钙和述助流剂的重量比为
Figure PCTCN2017100106-appb-000008
优选为
Figure PCTCN2017100106-appb-000009
瑞舒伐他汀钙和润滑剂的重量比为
Figure PCTCN2017100106-appb-000010
优选为
Figure PCTCN2017100106-appb-000011
瑞舒伐他汀钙和述粘合剂的重量比为
Figure PCTCN2017100106-appb-000012
优选为
Figure PCTCN2017100106-appb-000013
本发明所述的药物组合物，可以更进一步含有药学上可以接受的辅料。
本发明另一方面提供一种瑞舒伐他汀钙片剂，含有以上所述的药物组合物。该片剂的制备方法，主要步骤包括：原辅料分别过100目筛、充分混匀、压片即得。该制备方法进一步包括利用胃溶性欧巴代进行包衣。
具体而言，本发明提供的一种瑞舒伐他汀钙片剂的制备工艺步骤如下：
(1)原、辅料分别过100目筛，备用。
(2)按上表称取处方量瑞舒伐他汀钙和处方量β‐环糊精混合均匀，加入处方量其他辅料充分混匀。
(3)压片，制得素片。
(4)将处方量胃溶性欧巴代用85％乙醇配制成5％溶液，备用。
(5)取素片，筛去细粉，置包衣锅内，徐徐吹热风至片床温度约40℃，对素片进行包衣，包装，即得。
本发明的药物组合物，不需添加碱性物质即可达到良好的稳定作用。
本发明达到了对药学上稳定的可制备成肠道给药的瑞舒伐他汀钙的要求，制剂辅料用量少，并同时具有颜色稳定、保存期长，最大限度避免了，瑞舒伐他汀钙产生不利相关物质的降解作用。
具体实施方式
实施例1瑞舒伐他汀钙片的制备
处方组成(1000片用量，投料量：g)：
处方 处方1 处方2 处方3 处方4 处方5 处方6
瑞舒伐他汀钙 10.4 10.4 10.4 10.4 10.4 10.4
β-环糊精 104 95 105 104 95 105
乳糖 35 50 35 40 40 45
微晶纤维素 35 30 40 40 35 30
交联聚维酮 8 8 8 6 8 10
聚维酮K30 2 2 2 2 4 3
滑石粉 4 4 4 6 6 3
硬脂酸镁 2 2 2 4 4 2
胃溶性欧巴代 4 4 4 4 3.5 4
制备工艺：
(6)原、辅料分别过100目筛，备用。
(7)按上表称取处方量瑞舒伐他汀钙和处方量β‐环糊精混合均匀，加入处方量乳糖、微晶纤维素、交联聚维酮、聚维酮K30，充分混匀，加入处方量滑石粉、硬脂酸镁，充分混匀。
(8)压片，制得素片。
(9)将处方量胃溶性欧巴代用85％乙醇配制成5％溶液，备用。
(10)取素片，筛去细粉，置包衣锅内，徐徐吹热风至片床温度约40℃，对素片进行包衣，包装，即得。
以上处方颗粒流动性、可压性和素片脆碎度好。
实施例2瑞舒伐他汀钙片的制备
处方组成(1000片用量，投料量：g)：
处方 处方7 处方8 处方9
瑞舒伐他汀钙 10.4 10.4 10.4
β-环糊精 83 50 50
乳糖 50 80 40
微晶纤维素 30 42 40
交联聚维酮 8 8 8
聚维酮K30 2 2 2
滑石粉 4 4 4
硬脂酸镁 2 2 2
胃溶性欧巴代 4 4 4
制备工艺：
(1)原、辅料分别过100目筛，备用。
(2)按上表称取处方量瑞舒伐他汀钙和处方量β‐环糊精混合均匀，加入处方量乳糖、微晶纤维素、交联聚维酮、聚维酮K30，充分混匀，加入处方量滑石粉、硬脂酸镁，充分混匀。
(3)压片，制得素片。
(4)将处方量胃溶性欧巴代用85％乙醇配制成5％溶液，备用。
(5)取素片，筛去细粉，置包衣锅内，徐徐吹热风至片床温度约40℃，对素片进行包衣，包装，即得。
实施例3影响因素试验
将实施例制备得到的片剂分别置高温(60℃)、强光(4500lx)条件下10天，分别于0、5、10天检测有关物质含量(％),有关物质的检测方法可以采用CN103776939A中记载的方法。
检测结果如下表所示：
Figure PCTCN2017100106-appb-000014
Figure PCTCN2017100106-appb-000015
结果表明，本发明的处方取得了显著提升的稳定性。

Claims (11)

  1. 一种瑞舒伐他汀钙的药物组合物，含有瑞舒伐他汀钙和稳定剂，所述稳定剂选自β-环糊精，其特征在于所述瑞舒伐他汀钙和稳定剂的重量比为
    Figure PCTCN2017100106-appb-100001
  2. 权利要求1所述的药物组合物，其特征在于优选所述瑞舒伐他汀钙和稳定剂的重量比为
    Figure PCTCN2017100106-appb-100002
    优选为
    Figure PCTCN2017100106-appb-100003
    更进一步优选为1:9.5、1:10、1:10.5。
  3. 权利要求1所述的药物组合物，其特征在于还含有填充剂，所述填充剂为乳糖和微晶纤维素，所述瑞舒伐他汀钙和乳糖的重量比为
    Figure PCTCN2017100106-appb-100004
    所述瑞舒伐他汀钙和微晶纤维素的重量比为
    Figure PCTCN2017100106-appb-100005
  4. 权利要求3所述的药物组合物，其特征在于所述瑞舒伐他汀钙和乳糖的重量比为1:3.5、1:4。
  5. 权利要求3所述的药物组合物，其特征在于所述瑞舒伐他汀钙和微晶纤维素的重量比为1:4、1:3。
  6. 权利要求1-5所述的药物组合物，其特征在于进一步包括崩解剂，所述崩解剂选自交联聚维酮，所述瑞舒伐他汀钙和崩解剂的重量比为
    Figure PCTCN2017100106-appb-100006
    优选为
    Figure PCTCN2017100106-appb-100007
    进一步优选为10:10。
  7. 权利要求1-6所述的药物组合物，其特征在于进步包括助流剂、润滑剂和粘合剂。
  8. 权利要求1-7所述的药物组合物，其特征在于所述助流剂为滑石粉，所述润滑剂为硬脂酸镁，所述粘合剂为聚维酮K30，其中，瑞舒伐他汀钙和述助流剂的重量比为
    Figure PCTCN2017100106-appb-100008
    优选为
    Figure PCTCN2017100106-appb-100009
    瑞舒伐他汀钙和润滑剂的重量比为
    Figure PCTCN2017100106-appb-100010
    优选为
    Figure PCTCN2017100106-appb-100011
    瑞舒伐他汀钙和述粘合剂的重量比为
    Figure PCTCN2017100106-appb-100012
    优选为
    Figure PCTCN2017100106-appb-100013
  9. 一种瑞舒伐他汀钙片剂，含有权利要求1-8所述的药物组合物。
  10. 权利要求8所述的片剂的制备方法，其特征如下：原辅料分别过100目筛、充分混匀、压片即得。
  11. 权利要求9所述的片剂的制备方法，进一步包括利用胃溶性欧巴代进行包衣。
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CN103860498A (zh) * 2014-03-18 2014-06-18 孙常成 一种瑞舒伐他汀钙分散片及其制备方法

Family Cites Families (1)

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TR200902077A2 (tr) * 2009-03-17 2010-01-21 Sanovel İlaç San.Veti̇c.A.Ş. Stabil rosuvastatin kompozisyonları

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102008477A (zh) * 2010-11-28 2011-04-13 天津市汉康医药生物技术有限公司 一种瑞舒伐他汀钙片药物组合物的制备方法
CN103860498A (zh) * 2014-03-18 2014-06-18 孙常成 一种瑞舒伐他汀钙分散片及其制备方法

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