WO2005123082A1

WO2005123082A1 - An anti-hyperlipemia composition

Info

Publication number: WO2005123082A1
Application number: PCT/CN2005/000870
Authority: WO
Inventors: Zhiquan Zhao
Original assignee: Lunan Pharmaceutical Group Corporation
Priority date: 2004-06-16
Filing date: 2005-06-16
Publication date: 2005-12-29
Also published as: CN1709257A

Abstract

The present invention offers an anti-hyperlipemia composition, containing Acipimox and Rosuvastatin, or their salts, esters and solvates. The proportion by weight is (15-100):1, preferably (40-100):1, more preferably 60:1. Acipimox can be used in combination with Rosuvastatin in synergistic action, the effect of anti-hyperlipemia is better than the combination of Acipimox and Lovastatin.

Description

治疗髙血脂症的组合物 Composition for treating dyslipidemia

技术领域 Technical field

本发明涉及一种新的治疗高血脂症的组合物，它含有阿昔莫司与罗苏伐他汀或罗苏伐他汀可药用的盐、酯或溶剂化物。背景技术： The present invention relates to a novel composition for treating hyperlipidemia, which contains acyclovir and rosuvastatin or a pharmaceutically acceptable salt, ester or solvate of rosuvastatin. Background technique:

罗苏伐他汀（Rosuvastatin ) 是国内外进行了广泛研究并已在多国上市的 HMG-CoA 还原酶抑制剂，它通过在体内选择性地抑制胆固醇合成过程中的限速酶 HMG-CoA 还原酶，使胆固醇的合成减少，也使低密度脂蛋白受体合成增加，主要作用部位在肝脏，结果使血胆固醇和低密度脂蛋白胆固醇水平降低，由此对动脉粥样硬化和冠心病的防治产生作用。本品还降低血清甘油三酯水平和增高血高密度脂蛋白水平。罗苏伐他汀有 5、 10、 20和 40mg的片剂。在临床试验中，多数病人服用 5 或 10mg 的开始剂量就达到了国家胆固醇教育计划（National Cholesterol Education Program)推荐的目标 LDL-C水平。 20mg剂量可以作为胆固醇水平非常高的病人的初始剂量，而 40mg的剂量仅应在 20mg剂量治疗疗效不足时使用。 Shepherd 教授最近完成了一项他汀类药物降脂作用比较的临床试验，用药 8周的结果显示：罗苏伐他汀 10mg ( n=539) LDL- C达标率为 80%, 而阿托伐他汀 10mg (n=529 ) 达标率为 63% (P<0. 001 )，阿托伐他汀 20mg (n=925 ) LDL-C达标率为 74% ( Ρ〈0· 01 )。 Jones PH的研究显示：罗苏伐他汀 10mg降低 LDL- C46%，而阿托伐他汀从 10mg递增到 20mg、 40mg， LDL-C分别降低 37% ( P<0. 001 ), 43%和 48%；辛伐他汀从 10mg递增到 20mg、 40mg, LDL-C分别降低 28%、 35%和 39% ( P值均〈0. 001 ); 普伐他汀从 10mg递增到 20mg、 40mg, 降低 LDL- C分别为 20%、 24%和 30% (P值均 <0. 001 )。 Brown WV等将罗苏伐他汀的降脂活性和安全性与普伐他汀和辛伐他汀进行了 52 周的临床随机双盲对照研究，结果表明，在用药 12周后，罗苏伐他汀 5mg和 10mg剂量组的低密度脂蛋白胆固醇 ( LDL-C)分别下降了 39. 1%和 47. 4%，与普伐他汀 20mg组（下降 26. 5%) 和辛伐他汀 20mg组（下降 34. 6%) 有显著差异（P<0. 05 )。用药 52周后，罗苏伐他汀 5mg和 lOmg组达到美国国家胆固醇教育计划推荐 LDL-C目标的比率分别为 88%和 87. 5%, 而普伐他汀组仅为 60%，辛伐他汀组为 72. 5%, (在后 40周，未达目标的患者剂量加倍）所有实验组患者均耐受良好 ^['^]。纵然罗苏伐他汀有着如此强效的优势, 但其不良反应和其它他汀类药物相比较要严重一些，在上市之前的临床试验中，大剂量（80mg) 组有 7例患者发生了危及生命的横纹肌溶解症，因此当时其安全性就受到过质疑。上市前临床试验中还发现，罗苏伐他汀还可损害一些患者的肾功能（未观察到其他他汀类有类似不良反应）。最终， FDA因考虑到罗苏伐他汀的优势（药效稍强于其他他汀类）而批准其上市，但建议服用剂量从 5mg〜10mg开始，最大剂量不超过 40mg。 Rosuvastatin is an HMG-CoA reductase inhibitor that has been extensively studied at home and abroad and has been marketed in many countries. It selectively inhibits the rate-limiting enzyme HMG-CoA reductase in the process of cholesterol synthesis in the body. Reduce cholesterol synthesis and increase LDL receptor synthesis. The main site of action is in the liver. As a result, blood cholesterol and low density lipoprotein cholesterol levels are reduced, which has an effect on the prevention and treatment of atherosclerosis and coronary heart disease. . This product also reduces serum triglyceride levels and increases blood high density lipoprotein levels. Rosuvastatin is available in 5, 10, 20 and 40 mg tablets. In clinical trials, most patients took a starting dose of 5 or 10 mg to reach the target LDL-C level recommended by the National Cholesterol Education Program. The 20 mg dose can be used as an initial dose for patients with very high cholesterol levels, while the 40 mg dose should only be used when the 20 mg dose is ineffective. Professor Shepherd recently completed a clinical trial comparing the lipid-lowering effects of statins. The results of 8 weeks of medication showed that the rosuvastatin 10mg (n = 539) LDL-C compliance rate was 80%, while atorvastatin 10mg (n = 529) The compliance rate was 63% (P <0.01), and the atorvastatin 20mg (n = 925) LDL-C compliance rate was 74% (P <0.01). Jones PH research shows that 10 mg of rosuvastatin reduces LDL-C by 46%, while atorvastatin increases from 10 mg to 20 mg and 40 mg, and LDL-C decreases by 37% (P <0.01), 43% and 48%, respectively. ; Simvastatin increased from 10mg to 20mg, 40mg, LDL-C decreased by 28%, 35%, and 39%, respectively (P values <0.01); Pravastatin increased from 10mg to 20mg, 40mg, decreased LDL-C They are 20%, 24%, and 30% (all P values are <0.001). Brown WV et al. Conducted a 52-week randomized, double-blind, controlled trial of rosuvastatin and lipid-lowering activity and safety of rosuvastatin with pravastatin and simvastatin. The results showed that after 12 weeks of treatment, rosuvastatin 5 mg and Low-density lipoprotein cholesterol (LDL-C) in the 10mg dose group decreased by 39.1% and 47.4%, compared with the pravastatin 20mg group (down 26.5%) and the simvastatin 20mg group (down 34. 6%) were significantly different (P <0.05). After 52 weeks of medication, the ratios of the rosuvastatin 5mg and 10mg groups meeting the LDL-C targets recommended by the US National Cholesterol Education Program were 88% and 87.5%, respectively, compared to only 60% in the pravastatin group and simvastatin group. At 72.5%, (in the next 40 weeks, the dose of patients who did not reach the target doubled) all patients in the experimental group were well tolerated ^[ ' ^] . Although rosuvastatin has such powerful advantages, its adverse reactions are more serious than those of other statins. In clinical trials before marketing, 7 patients in the high-dose (80mg) group experienced life-threatening Rhabdomyolysis, its safety was questioned at that time. Pre-marketing clinical trials have also found that rosuvastatin can also impair renal function in some patients (no similar adverse effects have been observed with other statins). In the end, the FDA approved the marketing of rosuvastatin due to its advantages (slightly stronger than other statins). However, the recommended dosage is from 5 mg to 10 mg, and the maximum dose does not exceed 40 mg.

阿昔莫司（Acipimox) 是一种人工合成的烟酸衍生物，该药口服后吸收迅速，服后 2小时内血浆浓度即达高峰，半衰期为 2小时。阿昔莫司与血浆蛋白结合，几乎不变地从尿中排出，主要作用于脂肪组织，抑制脂肪组织释放非酯化脂肪酸，减少 TG、 VLDL及 LDL的生成。并通过激活脂蛋白脂肪酶，加速 VLDL的降解，通过抑制肝脂肪酶而增高血桨 HDL水平。阿昔莫司是一种安全、有效及易耐受的血脂调节药，尤其适用于血清 TG水平明显升高、 1¾1^~(：水平明显低下， TC水平轻度上升或正常的糖尿病患者。 Acipimox is a synthetic nicotinic acid derivative, which is absorbed quickly after oral administration. The plasma concentration reaches a peak within 2 hours after taking it, and the half-life is 2 hours. Acyclomus binds to plasma proteins and is excreted from the urine almost unchanged. It mainly acts on adipose tissue and inhibits the release of non-esterified fatty acids from adipose tissue. Less generation of TG, VLDL and LDL. It also accelerates the degradation of VLDL by activating lipoprotein lipase, and increases the HDL level of blood paddle by inhibiting liver lipase. Aximolimus is a safe, effective, and tolerable lipid-lowering drug, especially for diabetic patients with significantly elevated serum TG levels, significantly lower levels, slightly elevated TC levels, or normal.

目前，该领域的研究趋势是将两种不同作用机制的血脂调节药制成复方制剂，可以发挥协同作用，同时减少毒副作用。 At present, the research trend in this field is to make two lipid-modulating drugs with different mechanisms of action into a compound preparation, which can exert a synergistic effect while reducing toxic and side effects.

欧洲专利申请 EP0373507公开了 HMG-CoA还原酶抑制剂普伐他汀、洛伐他汀、 velostatin分别为 5mg、 10 mg、 20 mg、 40 mg和烟酸 500mg的组合物的制备，但没有公开其有益效果及最佳配比的实验数据，更没有涉及阿昔莫司与罗苏伐他汀组合物及最佳配比。 European patent application EP0373507 discloses the preparation of HMG-CoA reductase inhibitors pravastatin, lovastatin, and velostatin at 5 mg, 10 mg, 20 mg, 40 mg, and 500 mg of niacin, but does not disclose its beneficial effects And the experimental data of the best ratio, it did not involve the composition of acyclovir and rosuvastatin and the optimal ratio.

《洛伐他汀和烟酸肌醇单用和合用治疗高血脂症的比较》，发表于《心血管病学进展》 1996年第 17卷第六期，公开洛伐他汀和烟酸肌醇合用治疗高血脂症；《普伐他汀和烟酸肌醇单用和合用治疗高血脂症的疗效观察》，发表于《中国动脉硬化杂志》 1997年，第 5卷第 3期，公开普伐他汀和烟酸肌醇合用治疗高血脂症。二者均未涉及阿昔莫司与罗苏伐他汀的组合物及最佳配比。 "Comparison of lovastatin and inositol nicotinate alone and in combination for the treatment of hyperlipidemia", published in "Advances in Cardiovascular Diseases", Vol. 17, Issue 6, 1996. Hyperlipidemia; "Therapeutic effects of pravastatin and inositol nicotinate alone and in combination in the treatment of hyperlipidemia", published in "Chinese Journal of Arteriosclerosis" 1997, Vol. 5 No. 3, published pravastatin and tobacco Combination of inositol in the treatment of hyperlipidemia. Neither involves the composition of acyclovir and rosuvastatin and the optimal ratio.

美国专利 US5260305A公开了 HMG-CoA还原酶抑制剂普伐他汀和烟酸及其衍生物的组合物，具体公开了规格为普伐他汀 5mg、 10 mg, 20 mg, 40 mg和阿昔莫司 750mg 的组合物的制备，但没有公开其有益效果及最佳配比的实验数据，更没有涉及阿昔莫司和罗苏伐他汀组合物及最佳配比。发明内容 US patent US5260305A discloses a composition of HMG-CoA reductase inhibitor pravastatin and nicotinic acid and its derivatives, specifically disclosing specifications of pravastatin 5mg, 10 mg, 20 mg, 40 mg and aximus 750mg The preparation of the composition, but did not disclose its beneficial effects and experimental data of the optimal ratio, let alone the aximus and rosuvastatin composition and the optimal ratio. Summary of the invention

本发明的目的是通过一系列科学的筛选实验，提供一种新的治疗高脂血症的药物组合物，其优点是作用强、毒副作用低和使用方便。本药物组合物含有一定比例的阿昔莫司和罗苏伐他汀或阿昔莫司和罗苏伐他汀可药用的盐、酯或溶剂化物，由于两种药物作用机制不同，组成组合物后降脂作用将更加全面，并且两类药物合用有协同作用，其降脂作用明显优于相同剂量的单方；虽然罗苏伐他汀有着较强大的降脂效果，但大剂量的罗苏伐他汀存在发生可危机生命的横紋肌溶解症的风险，通过阿昔莫司伍用，显著降低了组合物中罗苏伐他汀的用量，使组合物在有效降低血脂水平的同时，大大降低了罗苏伐他汀的用药风险性，同时本组合物一日只需用药一次，用药方便，这将大大提高患者的用药依从性。 The object of the present invention is to provide a new pharmaceutical composition for treating hyperlipidemia through a series of scientific screening experiments, which has the advantages of strong action, low toxic and side effects and convenient use. The pharmaceutical composition contains a certain proportion of acyclovir and rosuvastatin or a pharmaceutically acceptable salt, ester, or solvate of acyclomus and rosuvastatin. Due to the different mechanisms of action of the two drugs, after the composition is composed, The lipid-lowering effect will be more comprehensive, and the combination of the two drugs has a synergistic effect, and its lipid-lowering effect is significantly better than that of the same dose of the single side. Although rosuvastatin has a strong lipid-lowering effect, a large amount of rosuvastatin exists The risk of life-threatening rhabdomyolysis is significantly reduced by the amount of rosuvastatin in the composition through the use of aximolimus, which enables the composition to effectively reduce blood lipid levels while greatly reducing rosulmostat The risk of medication of vastatin, meanwhile, the composition only needs to be administered once a day, which is convenient for administration, which will greatly improve the compliance of patients.

此外，通过对本发明的组合物与背景技术中的 US5260305A和 CN1425374A的组合物进行比较研究，在实验中意外地发现，阿昔莫司与罗苏伐他汀的联合使用在降低血清总胆固醇、血清甘油三酯和低密度脂蛋白胆固醇方面不仅存在着明显的协同性作用，而且与阿昔莫司和普伐他汀的联合使用、阿昔莫司和洛伐他汀的联合使用相比较，降脂效果更为明显，在升高高密度脂蛋白胆固醇方面，也有着比较明显的优势。 In addition, through a comparative study of the composition of the present invention and the composition of US5260305A and CN1425374A in the background art, it was unexpectedly found in the experiment that the combined use of acyclovir and rosuvastatin reduced the total serum cholesterol and serum glycerol. Not only are there significant synergistic effects in the triesters and low-density lipoprotein cholesterol, but the lipid-lowering effect is more significant when compared with the combined use of acyclovir and pravastatin For obvious reasons, it also has obvious advantages in raising high-density lipoprotein cholesterol.

本发明提供的治疗高血脂症的组合物包括两种活性成分，第一个活性成分为阿昔莫司，第二个活性成分选自罗苏伐他汀、或其可药用的盐、酯或溶剂化物。罗苏伐他汀可药用的盐为合适的罗苏伐他汀生理可接受盐，包括衍生自无机的和有机的碱所形成的盐，其可为钠盐、钙盐、钾盐、镁盐、锌盐、铁盐。所述的罗苏伐他汀可药用的酯为合适的罗苏伐他汀生理可接受的酯，包括衍生自脂肪醇、芳香醇、杂环醇所形成的酯，可为甲酯、乙酯、烯丙酯、苯酯。 The composition for treating hyperlipidemia provided by the present invention includes two active ingredients, the first active ingredient is aximus, and the second active ingredient is selected from rosuvastatin, or a pharmaceutically acceptable salt, ester or Solvate. Rosuvastatin pharmaceutically acceptable salts are suitable rosuvastatin physiologically acceptable salts, including those derived from inorganic and organic The salt formed by the base may be a sodium salt, a calcium salt, a potassium salt, a magnesium salt, a zinc salt, or an iron salt. The pharmaceutically acceptable esters of rosuvastatin are suitable rosuvastatin physiologically acceptable esters, including esters derived from fatty alcohols, aromatic alcohols, and heterocyclic alcohols, and may be methyl esters, ethyl esters, Allyl ester, phenyl ester.

本发明以罗苏伐他汀钙为例对两种活性成分的重量比进行筛选，综合考虑它们对高血脂模型大鼠降脂活性和不良反应的程度，可以认为阿昔莫司和罗苏伐他汀（以游离酸计，下同）的重量比在 15-100: 1范围内具有较好的降脂效果和较轻微的不良反应，优选的比例是 40-100: 1，进一步优选的比例是 60: 1；其中阿昔莫司优选做成缓释部分。该组合物的药物制剂的剂型，包括片剂、胶囊、颗粒剂、丸剂、滴丸等固体制剂。 In the present invention, rosuvastatin calcium is used as an example to screen the weight ratio of two active ingredients, and comprehensively considering the degree of their lipid-lowering activity and adverse reactions on hyperlipidemia model rats, it can be considered that aximus and rosuvastatin (Based on free acid, the same applies hereinafter) the weight ratio in the range of 15-100: 1 has a better lipid-lowering effect and minor adverse reactions, the preferred ratio is 40-100: 1, and the more preferred ratio is 60 : 1; Among them, aximus is preferably made into a sustained release part. The dosage form of the pharmaceutical preparation of the composition includes solid preparations such as tablets, capsules, granules, pills, and pills.

本发明的组合物在制成固体制剂，如片剂或胶囊时，为达到持久的治疗效果，优选地将有效量的阿昔莫司制成缓释部分，再与有效量的罗苏伐他汀钙共同制成缓释制剂，如缓释片、.缓释胶囊等。相应地，可药用的辅料包括稀释剂，如淀粉、乳糖、甘露醇、预胶化淀粉、糊精、微晶纤维素；崩解剂，如羧甲基淀粉钠、羟丙基淀粉、低取代羟丙基纤维素、羧甲基纤维素钠；缓释剂，如乙基纤维素、羟丙基甲基纤维素 -4M、羟丙基甲基纤维素- 15M;优特奇 RS-100、 RL100、 RS30D、 RL30D、 NE30D, 以及苏丽丝（乙基纤维素的水分散体）粘合剂，如聚乙烯吡咯垸酮，交联聚乙烯吡咯烷酮，润滑剂，如硬脂酸镁、滑石粉、微粉硅胶等。 When the composition of the present invention is made into a solid preparation, such as a tablet or a capsule, in order to achieve a long-lasting therapeutic effect, an effective amount of acyclovir is preferably made into a sustained-release portion, and then an effective amount of rosuvastatin Calcium is jointly made into a sustained-release preparation, such as a sustained-release tablet, a sustained-release capsule, and the like. Accordingly, pharmaceutically acceptable excipients include diluents such as starch, lactose, mannitol, pregelatinized starch, dextrin, and microcrystalline cellulose; disintegrants such as sodium carboxymethyl starch, hydroxypropyl starch, low Substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose; slow-release agents, such as ethyl cellulose, hydroxypropyl methyl cellulose-4M, hydroxypropyl methyl cellulose-15M; Youteqi RS-100 , RL100, RS30D, RL30D, NE30D, and Su Lisi (aqueous dispersion of ethyl cellulose) binders, such as polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, lubricants, such as magnesium stearate, talc, Micronized silica gel and so on.

本发明的组合物通过药理方面的研究工作，表明当用本发明的组合物时，尤其是采用优选的配比时，与单独应用有效量的阿昔莫司或罗苏伐他汀时相比，本发明的组合物给出令人吃惊的更好效果，同时毒性没有增加，在达到相同降脂效果的情况下，两类药物伍用大大降低了每种药物的使用剂量，这就显著降低了阿昔莫司的不良反应和罗苏伐他汀的用药风险。本发明的组合物可以每日 1-2次给药，优选为每日一次。 The pharmacological research work of the composition of the present invention shows that when the composition of the present invention is used, especially when the preferred formulation ratio is used, compared with when an effective amount of acyclovir or rosuvastatin is used alone, The composition of the present invention gives a surprisingly better effect, while the toxicity is not increased. Under the condition that the same lipid-lowering effect is achieved, the use of the two types of drugs greatly reduces the dosage of each drug, which significantly reduces Adverse effects of acyclovir and risk of rosuvastatin administration. The composition of the present invention can be administered 1-2 times a day, preferably once a day.

另外，我们在筛选实验中发现，本发明组合物中罗苏伐他汀的药理活性与其所成的盐、酯或溶剂化物关系很小，其降脂活性的大小主要与罗苏伐他汀游离酸的量相关。所以本发明中阿托伐他汀可以为任何一种可以药用的盐，也可以为任何一种阿托伐他汀可以药用的酯，或者溶剂化物。具体实施方式： In addition, we found in the screening experiment that the pharmacological activity of rosuvastatin in the composition of the present invention has a small relationship with the salt, ester or solvate formed by it, and the magnitude of its lipid-lowering activity is mainly related to that of rosuvastatin free acid. Quantity related. Therefore, atorvastatin in the present invention may be any pharmaceutically acceptable salt, or any pharmaceutically acceptable ester or solvate of atorvastatin. detailed description:

现通过如下实施例进一步说明本发明的内容，但本发明的应用范围不局限于下列实施例。实施例 1 The content of the present invention is further described by the following examples, but the application scope of the present invention is not limited to the following examples. Example 1

阿昔莫司 200g Aximus 200g

乳糖 30g 30g lactose

羧甲基淀粉钠 30g Sodium Carboxymethyl Starch 30g

微晶纤维素 18g Microcrystalline cellulose 18g

6%PVP的无水乙醇溶液 lOOg 6% PVP anhydrous ethanol solution 100g

硬脂酸镁 2g 制备工艺：阿昔莫司过 100目筛，乳糖、羧甲基淀粉钠、微晶纤维素过 80目筛，称取处方量的阿昔莫司和乳糖、羧甲基淀粉钠、微晶纤维素混合均匀，加入 6%PVP 无水乙醇溶液适量制粒， 6CTC干燥， 16目筛整干颗粒，干颗粒中加入处方量的硬脂罗苏伐他汀钙（其重量以游离酸计，下同） 5g 2g magnesium stearate Preparation process: Axioximus is passed through a 100-mesh sieve, lactose, sodium carboxymethyl starch, and microcrystalline cellulose are passed through an 80-mesh sieve, and a prescribed amount of aximus, lactose, sodium carboxymethyl starch, and microcrystalline fiber are weighed. Mix evenly, add 6% PVP anhydrous ethanol solution to granulate, dry at 6CTC, sieve the dry granules with 16 mesh, add the prescribed amount of calcium stearyl rosuvastatin calcium (the weight is based on free acid, the same below) ) 5g

羟丙基纤维素 15g Hydroxypropyl cellulose 15g

预胶化淀粉 10g Pregelatinized starch 10g

6%PVP的无水乙醇溶液 30g 6% PVP anhydrous ethanol solution 30g

山榆酸甘油酯 lg Glyceryl behenate lg

制备工艺：罗苏伐他汀钙过 100目筛，羟丙基纤维素、预胶化淀粉过 80目筛，称取处方量的罗苏伐他汀钙和羟丙基纤维素、预胶化淀粉混合均匀，加入 6%PVP的无水乙醇溶液适量制粒， 6CTC干燥， 16目筛整干颗粒，千颗粒中加入处方量的山榆酸甘油酯。 Preparation process: Rosuvastatin calcium is passed through a 100 mesh sieve, hydroxypropyl cellulose and pregelatinized starch are passed through an 80 mesh sieve, and a prescribed amount of rosuvastatin calcium is mixed with hydroxypropyl cellulose and pregelatinized starch. Evenly, add an appropriate amount of 6% PVP anhydrous ethanol to granulate, dry at 6CTC, and sieve the dry granules with a 16-mesh sieve. Add the prescribed amount of glyceryl behenate to the thousand granules.

c、将上述 a, b两种组分采用双层压片机冲压片即得双层片。实施例 2 c. A double-layer sheet is obtained by pressing the above two components a and b using a double-layer tablet press. Example 2

阿昔莫司 200g Aximus 200g

乳糖 30g 30g lactose

羧甲基淀粉钠 30g Sodium Carboxymethyl Starch 30g

微晶纤维素 18g Microcrystalline cellulose 18g

6%PVP的无水乙醇溶液 lOOg 6% PVP anhydrous ethanol solution 100g

硬脂酸镁 2g Magnesium stearate 2g

制备工艺：阿昔莫司过 100目筛，乳糖、羧甲基淀粉钠、微晶纤维素过 80目筛，称取处方量的阿昔莫司和乳糖、羧甲基淀粉钠、微晶纤维素混合均匀，加入 6%PVP 无水乙醇溶液适量制粒， 60°C干燥， 16目筛整干颗粒，干颗粒中加入处方量的硬脂 b、罗苏伐他汀钙 10g Preparation process: Axioximus is passed through a 100-mesh sieve, lactose, sodium carboxymethyl starch, and microcrystalline cellulose are passed through an 80-mesh sieve, and a prescribed amount of aximus, lactose, sodium carboxymethyl starch, and microcrystalline fiber are weighed. Mix evenly, add 6% PVP absolute ethanol solution to granulate, dry at 60 ° C, sieve the dry granules with 16 mesh, add the prescribed amount of stearin b and rosuvastatin calcium 10g to the dry granules

羟丙基纤维素 30g ' Hydroxypropyl cellulose 30g ''

预胶化淀粉 20g Pregelatinized starch 20g

6%PVP的无水乙醇溶液 50g 6% PVP anhydrous ethanol solution 50g

山榆酸甘油酯 2g Glyceryl behenate 2g

制备工艺：罗苏伐他汀钙过 100目筛，羟丙基纤维素、预胶化淀粉过 80目筛，称取处方量的罗苏伐他汀钙和羟丙基纤维素、预胶化淀粉混合均匀，加入 6%PVP的无水乙醇溶液适量制粒， 60°C干燥， 16目筛整干颗粒，干颗粒中加入处方量的山榆酸甘油酯。 Preparation process: Rosuvastatin calcium is passed through a 100 mesh sieve, hydroxypropyl cellulose and pregelatinized starch are passed through an 80 mesh sieve, and a prescribed amount of rosuvastatin calcium is mixed with hydroxypropyl cellulose and pregelatinized starch. Evenly, add 6% PVP anhydrous ethanol solution to granulate, dry at 60 ° C, sieve the dry granules with a 16 mesh sieve, and add the prescribed amount of glyceryl behenate to the dry granules.

c、将上述 a， b两种组分采用双层压片机冲压片即得双层片。 c. A two-layer sheet is obtained by pressing the two components a and b above using a double-layer tablet press.

实施例 3 Example 3

a、阿昔莫司 300g a. Acyclomus 300g

羟丙基甲基纤维素- 4M 40g 微晶纤维素 30g Hydroxypropyl Methyl Cellulose-4M 40g Microcrystalline cellulose 30g

8%PVP的无水乙醇溶液 150g 8% PVP in anhydrous ethanol solution 150g

硬酯酸镁 2g Magnesium stearate 2g

制各工艺：阿昔莫司过 100目筛，羟丙基纤维素 - 4M、微晶纤维素过 80目筛，称取处方量的阿昔莫司和羟丙基纤维素 -4M、微晶纤维素混合均匀，加入 8%PVP无水乙醇溶液适量制粒， 60°C干燥， 16目筛整干颗粒，干颗粒中加入处方量的硬脂酸锾。 b、罗苏伐他汀钙 5g Processes: Aximus sieved through a 100 mesh sieve, hydroxypropyl cellulose-4M, microcrystalline cellulose sieved through an 80 mesh sieve, and the prescribed amount of aximus and hydroxypropyl cellulose-4M, microcrystalline The cellulose is mixed uniformly, and an appropriate amount of 8% PVP absolute ethanol solution is added to granulate, dried at 60 ° C, and the dry granules are sieved with a 16 mesh sieve. The dry granules are added with a prescribed amount of rhenium stearate. b. Rosuvastatin calcium 5g

羧甲基纤维素钠 30g Carboxymethylcellulose sodium 30g

乳糖 20g 20g lactose

6%PVP的 95%乙醇溶液 50g 6% PVP in 95% ethanol solution 50g

硬酯酸镁 2g Magnesium stearate 2g

制备工艺：罗苏伐他汀钙过 100目筛，羧甲基纤维素钠、乳糖过 80目筛，称取处方量的罗苏伐他汀钙和羧甲基纤维素钠、乳糖混合均匀，加入 6%PVP的 95%乙醇溶液适量制粒， 6CTC干燥， 16目筛整干颗粒，干颗粒中加入处方量的硬脂酸镁。 c、将上述 a, b两种组分采用双层压片机冲压即得双层片。实施例 4 Preparation process: Rosuvastatin calcium is passed through a 100-mesh sieve, carboxymethylcellulose sodium and lactose are passed through an 80-mesh sieve, and a prescribed amount of rosuvastatin calcium is mixed with sodium carboxymethylcellulose and lactose. A proper amount of 95% ethanol solution of% PVP was granulated, dried at 6CTC, and the dry granules were sieved with a 16-mesh sieve. A prescribed amount of magnesium stearate was added to the dry granules. c. The two components a and b above are punched by a double-layer tablet machine to obtain a double-layer sheet. Example 4

a、阿昔莫司 500g a. Aximus 500g

甘露醇 10g Mannitol 10g

乳糖 40g 40g lactose

微晶纤维素 20g Microcrystalline cellulose 20g

6%PVP的 95%乙醇溶液 120g 6% PVP in 95% ethanol solution 120g

硬酯酸镁 2g Magnesium stearate 2g

制备工艺：阿昔莫司过 100目筛，甘露醇、乳糖、微晶纤维素过 80目筛，称取处方量的阿昔莫司和甘露醇、乳糖、微晶纤维素混合均匀，加入 6%PVP的 95%乙醇溶液适量制粒， 60Ό干燥， 16目筛整干颗粒，干颗粒中加入处方量的硬脂酸镁。 b、罗苏伐他汀钙 5g Preparation process: Aximus is passed through a 100-mesh sieve, mannitol, lactose, and microcrystalline cellulose are passed through an 80-mesh sieve. The prescribed amount of aximus and mannitol, lactose, and microcrystalline cellulose are mixed uniformly. The appropriate amount of 95% ethanol solution of% PVP was granulated, dried at 60 ° C, and the dried granules were sieved with a 16-mesh sieve. The prescribed amount of magnesium stearate was added to the dried granules. b. Rosuvastatin calcium 5g

预胶化淀粉 50g Pregelatinized starch 50g

甘露醇 50g Mannitol 50g

6%PVP的 95%乙醇溶液 100g 6% PVP in 95% ethanol solution 100g

微粉硅胶 5g Micro powder silicone 5g

制备工艺：罗苏伐他汀钙过 100目筛，预胶化淀粉、甘露醇过 80目筛，称取处方量的罗苏伐他汀钙和预胶化淀粉、甘露醇混合均匀，按等量递加法与罗苏伐他汀混勾后，加入 6%PVP的 95%乙醇溶液适量制粒， 60°C干燥， 16目筛整干颗粒，千颗粒中加入处方量的硬脂酸镁。 Preparation process: Rosuvastatin calcium is passed through a 100-mesh sieve, pregelatinized starch and mannitol are passed through an 80-mesh sieve, and a prescribed amount of rosuvastatin calcium is premixed with pregelatinized starch and mannitol. After the addition and mixing with rosuvastatin, add 6% PVP in 95% ethanol solution to granulate, dry at 60 ° C, sieve the dry granules with a 16 mesh sieve, and add the prescribed amount of magnesium stearate to the thousand granules.

c、将上述 a, b两种组分采用双层压片机冲压即得双层片。实施例 5 c. The two components a and b above are punched by a double-layer tablet machine to obtain a double-layer sheet. Example 5

a、阿昔莫司 500g 乳糖 30g a. Aximus 500g 30g lactose

羟丙基甲基纤维素- 15M 20g Hydroxypropyl Methyl Cellulose-15M 20g

8%PVP的 95%乙醇溶液 150g 8% PVP in 95% ethanol solution 150g

山榆酸甘油酯 2g Glyceryl behenate 2g

制备工艺：阿昔莫司过 100 目筛，乳糖、羟丙基.甲基纤维素 -15M过 80 目筛，称取处方量的阿昔莫司和乳糖、羟丙基甲基纤维素- 15M混合均勾，加入 8%PVP的 95% 乙醇溶液适量制粒， 60Ό千燥， 16目筛整千颗粒，干颗粒中加入处方量的山榆酸甘油酉 ¹⁵ Preparation process: Axioximus sieved through a 100-mesh sieve, lactose and hydroxypropyl. Methylcellulose-15M passed through an 80-mesh sieve, and a prescribed amount of axioxime and lactose and hydroxypropyl methylcellulose-15M were weighed. Mix evenly, add 8% PVP in 95% ethanol solution to make granules, 60 燥 1000 dry, 16 mesh sieve whole thousand granules, dry granules add prescription amount of behenyl glycerol 酉¹⁵

b、罗苏伐他汀钙 b. Rosuvastatin calcium

羟丙基纤维素 Hydroxypropyl cellulose

糊精 Dextrin

6%PVP的 95%乙醇溶液 6% PVP in 95% ethanol solution

滑石粉 Talcum powder

制备工艺：罗苏伐他汀钙过 100目筛，羟丙基纤维素、糊精过 80目筛，称取处方量的罗苏伐他汀钙和羟丙基纤维素、糊精混合均匀，加入 6%PVP的 95%乙醇溶液适量制粒， 60°C干燥， 16目筛整干颗粒，干颗粒中加入处方量的滑石粉。 Preparation process: Rosuvastatin calcium is passed through a 100-mesh sieve, hydroxypropyl cellulose and dextrin are passed through an 80-mesh sieve, a prescribed amount of rosuvastatin calcium is mixed with hydroxypropyl cellulose and dextrin, and 6 is added. A proper amount of 95% ethanol solution of% PVP was granulated, dried at 60 ° C, and the dry granules were sieved with a 16-mesh sieve. A prescribed amount of talc was added to the dry granules.

c、将上述 a, b两种组分采用双层压片机冲压即得双层片。实施例 6 c. The two components a and b above are punched by a double-layer tablet machine to obtain a double-layer sheet. Example 6

a、阿昔莫司 200g a. Aximus 200g

空白丸芯 250g Blank pill core 250g

7%PVP溶液（溶剂为 90%乙醇） 200g 7% PVP solution (solvent is 90% ethanol) 200g

制备工艺：将阿昔莫司过 120目筛，处方量称取，倒入下料斗中。开造粒包衣机（台湾元成机械厂），入风压力 0. 5bar，入风温度 30°C，喷枪压力（CYL) 3bar, 雾化压力（CAP1 ) 0. 8bar, 倒入空白丸芯，造粒，下料速度 4rpm，蠕泵 12%，转盘转速 145rpm，喷 7%PVP溶液（溶剂为 90%乙醇）。造粒结束， 50Ό烘千，出料。 b、罗苏伐他汀钙 5g Preparation process: Axioximus is sieved through a 120-mesh sieve, the prescription amount is weighed, and poured into a lower hopper. Open granulation coating machine (Taiwan Yuancheng Machinery Factory), inlet air pressure 0.5 bar, inlet air temperature 30 ° C, spray gun pressure (CYL) 3 bar, atomization pressure (CAP1) 0.8 bar, pour into blank pellet core , Granulation, feeding speed 4 rpm, 12% peristaltic pump, 145 rpm rotation speed, spray 7% PVP solution (solvent is 90% ethanol). After the granulation is finished, it is baked at 50 ° C and discharged. b. Rosuvastatin calcium 5g

空白丸芯 90g Blank Pill Core 90g

7%PVP溶液（溶剂为 90%乙醇） 50g 7% PVP solution (solvent is 90% ethanol) 50g

制备工艺：将罗苏伐他汀钙过 120目筛，处方量称取，倒入下料斗中。开造粒包衣机，入风压力 0. 5bar，入风温度 30°C， CYL3bar, CAP1 0. 8bar, 倒入空白丸芯，造粒，下料速度 4rpm, 蠕泵 6%，转盘转速 160 rpm，喷 7%PVP溶液（溶剂为 90% 乙醇）。造粒结束， 45Ό烘干，出料。 Preparation process: The rosuvastatin calcium is sieved through a 120-mesh sieve, the prescription amount is weighed, and poured into the lower hopper. Open granulation coating machine, inlet air pressure 0.5 bar, inlet air temperature 30 ° C, CYL3bar, CAP1 0.8 bar, pour into blank pellet core, granulate, feed speed 4rpm, peristaltic pump 6%, turntable speed 160 rpm, spray 7% PVP solution (solvent is 90% ethanol). After the granulation is finished, it is dried at 45Ό and discharged.

c、将 a和 b制得的小丸采用硬胶囊药物填充机按照每两粒胶囊中含阿昔莫司与罗苏伐他汀钙的重量分别为 200mg和 30mg进行填充，即可。实施例 7 c. Fill the pellets prepared by a and b with a hard capsule medicine filling machine according to the weight of 200 mg and 30 mg of aximus and rosuvastatin calcium in each two capsules, respectively. Example 7

a、阿昔莫司 300g a. Acyclomus 300g

空白丸芯 250g 7%PVP溶液（溶剂为 90%乙醇） 200g Blank pill core 250g 7% PVP solution (solvent is 90% ethanol) 200g

制备工艺：将阿昔莫司过 120目筛，处方量称取，倒入下料斗中。开造粒包衣机，入风压力 0. 5bar，入风温度 30°C， CYL3bar， CAP1 0. 8bar，倒入空白丸芯，造粒，下料速度 4rpm，蠕泵 12%，转盘转速 145 rpm, 喷 7%PVP溶液（溶剂为 90% 乙醇）。造粒结束， 50°C烘干，出料。 Preparation process: Axioximus is sieved through a 120-mesh sieve, the prescription amount is weighed, and poured into a lower hopper. Open granulation coating machine, inlet air pressure 0.5 bar, inlet air temperature 30 ° C, CYL3bar, CAP1 0.8 bar, pour into blank pellet core, granulate, feed speed 4rpm, peristaltic pump 12%, turntable speed 145 rpm, spray 7% PVP solution (solvent is 90% ethanol). After granulation, dry at 50 ° C and discharge.

b、 a中制得的含阿昔莫司小丸 aximus pill-containing pellets prepared in b, a

Surelease 90g Surelease 90g

滑石粉 lg Talcum powder lg

纯水 50g Pure water 50g

制备工艺：将 a中制得的含阿昔莫司小丸倒入转盘，开造粒包衣机，入风压力 l. Obar, 入风温度 30°C， CYL3bar, CAP1 1. 5bar, 蠕泵 5%，转盘转速 180 rpm, 喷入 Surelease的纯水溶液。包衣结束， 50°C烘干，出料。 Preparation process: Pour the aximolimus-containing pellets prepared in a into a turntable, open a granulating coating machine, and enter the air pressure l. Obar, the air temperature 30 ° C, CYL3bar, CAP1 1. 5bar, peristaltic pump 5 %, The rotating speed of the turntable is 180 rpm, and the pure aqueous solution of Surelease is sprayed. After coating, dry at 50 ° C and discharge.

c、按照实施例 5中 b的要求制得罗苏伐他汀钙小丸，与本例 b中制得的阿昔莫司小丸采用硬胶囊药物填充机按照每两粒胶囊中含阿昔莫司与罗苏伐他汀钙的重量分别为 300mg和 30rag进行填充，即可。实施例 8 c. Rosuvastatin calcium pellets were prepared according to the requirement of b in Example 5, and the aximus pill obtained in this example b was filled with a hard capsule medicine filling machine according to each two capsules containing aximus and The weight of rosuvastatin calcium is 300 mg and 30 rag, respectively. Example 8

阿昔莫司 200g Aximus 200g

空白丸芯 200g Blank pill core 200g

制备工艺：将阿昔莫司过 120目筛，处方量称取，倒入下料斗中。开造粒包衣机，入风压力 0. 5bar，入风温度 30°C， CYL3bar， CAP1 0. 8bar, 倒入空白丸芯，造粒，下料速度 4rpm，蠕泵 12%，转盘转速 165 rpm，喷入 7%PVP溶液（溶剂为 90% 乙醇）。造粒结束， 5CTC烘干，出料。 Preparation process: Axioximus is sieved through a 120-mesh sieve, the prescription amount is weighed, and poured into a lower hopper. Open granulating coating machine, inlet air pressure 0.5 bar, inlet air temperature 30 ° C, CYL3bar, CAP1 0.8 bar, pour into blank pellet core, granulate, feed speed 4rpm, peristaltic pump 12%, turntable speed 165 rpm, spray 7% PVP solution (solvent is 90% ethanol). After granulation, 5CTC is dried and discharged.

b、罗苏伐他汀钙 20g b. Rosuvastatin calcium 20g

空白丸芯 150g Blank Pill Core 150g

7%PVP溶液（溶剂为 90%乙醇） 150g 7% PVP solution (solvent is 90% ethanol) 150g

制备工艺：将罗苏伐他汀钙过 120目筛，处方量称取，倒入下料斗中。开造粒包衣机，入风压力 0. 5bar，入风温度 30°C， CYL3bar, CAP1 0. 8bar，倒入空白丸芯，下料速度 4rpm，蠕泵 12%，转盘转速 120 rpm, 喷入 7%PVP溶液（溶剂为 90% 乙醇）。造粒结束， 45Ό烘干，出料。 Preparation process: The rosuvastatin calcium is sieved through a 120-mesh sieve, the prescription amount is weighed, and poured into the lower hopper. Open granulation coating machine, inlet air pressure 0.5 bar, inlet air temperature 30 ° C, CYL3bar, CAP1 0.8 bar, pour into blank pellet core, feed speed 4rpm, peristaltic pump 12%, turntable speed 120 rpm, spray Add 7% PVP solution (solvent is 90% ethanol). After the granulation is finished, it is dried at 45Ό and discharged.

c、将 a与 b制得的小丸采用硬胶囊药物填充机按照每两粒胶囊中含阿昔莫司与罗苏伐他汀钙的重量分别为 200mg和 40mg进行填充，即可。实施例 9 c. Fill the pellets prepared by a and b with a hard capsule medicine filling machine according to the weight of 200 mg and 40 mg of aximus and rosuvastatin calcium in each two capsules, respectively. Example 9

a、阿昔莫司 300g a. Acyclomus 300g

空白丸芯 300g Blank Pill Core 300g

制备工艺：将阿昔莫司过 120目筛，处方量称取，倒入下料斗中。开造粒包衣机，入风压力 0. 5bar，入风温度 30°C , CYL3bar, CAP1 0. 8bar，倒入空白丸芯，造粒，下料速度 4rpm, 蠕泵 12%，转盘转速 145 rpm，喷入 7%PVP溶液（溶剂为 90% 乙醇）。造粒结束， 50°C烘干，出料。 Preparation process: Axioximus is sieved through a 120-mesh sieve, the prescription amount is weighed, and poured into a lower hopper. Granulated coating Machine, inlet air pressure 0.5 bar, inlet air temperature 30 ° C, CYL3bar, CAP1 0.8 bar, pour into blank pellet core, granulate, feed speed 4rpm, peristaltic pump 12%, turntable speed 145 rpm, spray into 7 % PVP solution (solvent is 90% ethanol). After granulation, dry at 50 ° C and discharge.

乙基纤维素 Ethyl cellulose

硬脂酸 Stearic acid

聚乙二醇 -6000 Polyethylene glycol -6000

滑石粉 Talcum powder

95%乙醇 95% ethanol

制备工艺：将 a中制得的含阿昔莫司小丸倒入下料斗中。幵造粒包衣机，入风温度 30°C，入风压力 0. 5bar，入风温度 30°C， CYL3bar, CAP1 1. Obar，蠕泵 6%，转盘转速 175 rpm，喷入乙基纤维素、硬脂酸和聚乙二醇- 6000的 95%乙醇溶液。包衣结束， 50Ό烘干，出料。 Preparation process: Pellets containing acyclomus prepared in a are poured into the lower hopper.幵 Granulation coating machine, inlet air temperature 30 ° C, inlet air pressure 0.5 bar, inlet air temperature 30 ° C, CYL3bar, CAP1 1. Obar, peristaltic pump 6%, turntable speed 175 rpm, spraying ethyl fiber 95% ethanol solution of vegan, stearic acid and polyethylene glycol-6000. The coating is finished, dried at 50Ό, and discharged.

c、罗苏伐他汀钙 20g c. Rosuvastatin calcium 20g

空白丸芯 150g Blank Pill Core 150g

制备工艺：将罗苏伐他汀钙过 120目筛, 处方量称取，倒入下料斗中，开造粒包衣机，入风压力 0. 5bar，入风温度 30'C , CYL3bar, CAP1 0. 8bar, 倒入空白丸芯，造粒。下料速度 4rpm，蠕泵 12%，转盘转速 120rpm，喷入 7%PVP溶液（溶剂为 90%乙醇）。造粒结束， 45°C烘千，出料。 Preparation process: Pass rosuvastatin calcium through a 120 mesh sieve, weigh the prescription amount, pour it into the lower hopper, open the granulation coating machine, the inlet pressure is 0.5 bar, the inlet temperature is 30'C, CYL3bar, CAP1 0 8bar, pour into blank pellet cores and granulate. Feeding speed is 4 rpm, peristaltic pump is 12%, turntable speed is 120 rpm, and 7% PVP solution is sprayed (solvent is 90% ethanol). After the granulation is finished, it is baked at 45 ° C and discharged.

d、将 b与 c制得的小丸采用硬胶囊药物填充机按照每两粒胶囊中含阿昔莫司与罗苏伐他汀钙的重量分别为 300mg和 40mg进行填充，即可。实施例 10 阿昔莫司和罗苏伐他汀钙复方对大鼠高脂血症降脂效果的配比筛选本试验目的在于通过筛选确定毒性低、作用强和使用方便的阿昔莫司和罗苏伐他汀钙复方制剂配伍组成。采用正常 Wistar大鼠或高脂饲料致大鼠高脂血症模型。受试品阿昔莫司为鲁南制药股份有限公司生产，罗苏伐他汀钙由 AstraZeneca公司生产。结果发现，饲以高脂饲料 14天后，大鼠血清中总胆固醇、甘油三酯和低密度脂蛋白胆固醇均明显升高，形成高脂血症模型。给模型大鼠灌服阿昔莫司（100〜 500mg/kg) 和（或）罗苏伐他汀钙（5〜40mg/kg) 14天后，血清中总胆固醇、甘油三酯、低密度脂蛋白胆固醇均明显下降，高密度脂蛋白胆固醇升高。单用其中一种药或两药伍用，其效果随剂量递增加强。 d. Fill the pellets prepared by b and c with a hard capsule medicine filling machine according to the weight of 300 mg and 40 mg of acyclomus and rosuvastatin calcium in each two capsules, respectively. Example 10 Proportion screening of acyclomus and rosuvastatin calcium compound for hyperlipidemia in rats The purpose of this test is to determine the low-toxicity, strong effect and easy-to-use aximus and Luo by screening Compatible composition of suvastatin calcium compound preparation. A model of hyperlipidemia induced by normal Wistar rats or high-fat diets was used. The test product aximus was produced by Lunan Pharmaceutical Co., Ltd. and rosuvastatin calcium was produced by AstraZeneca. It was found that after 14 days of high-fat diet, total cholesterol, triglycerides, and low-density lipoprotein cholesterol in the serum of the rats were significantly increased, forming a hyperlipidemia model. Model rats were given acyclomus (100 ~ 500mg / kg) and / or rosuvastatin calcium (5 ~ 40mg / kg) for 14 days. Total cholesterol, triglyceride, low-density lipoprotein cholesterol in serum Both were significantly reduced and HDL cholesterol increased. With one or two drugs alone, the effect increases with increasing dose.

结果表明，阿昔莫司和罗苏伐他汀钙伍用对高脂饲料所致的大鼠高脂血症有明显治疗作用，效果与两种药物的剂量相关。从药效和毒性两方面分析，罗苏伐他汀钙 5mg/kg和阿昔莫司 300mg/kg伍用效果较好。 The results show that acyclovir and rosuvastatin calcium have a significant therapeutic effect on hyperlipidemia in rats caused by high-fat diets, and the effect is related to the dose of the two drugs. From the analysis of efficacy and toxicity, rosuvastatin calcium 5mg / kg and acyclomus 300mg / kg have better effects.

1 试验目的 1 Test purpose

通过筛选确定阿昔莫司和罗苏伐他汀钙复方制剂组成，以达到复方制剂毒副作用低、作用全面和增强、使用方便（如每日 1次用药）之目.的。在上述实验基础上按有关要求，进行复方制剂的量效关系和多组份相互影响的试验，为申报开发复方制剂提供实验依据。 Screening to determine the composition of acyclomus and rosuvastatin calcium compound preparations to achieve toxic side effects of the compound preparations Use low, comprehensive and enhanced, easy to use (such as once a day medication). Based on the above experiments, according to relevant requirements, the dose-effect relationship of the compound preparation and the interaction of multiple components are tested to provide an experimental basis for applying for the development of the compound preparation.

2 受试药物 2 Test drugs

2. 1 阿昔莫司 (Acipimox) 2.1 Acipimox

批号： 0307002 Lot number: 0307002

纯度：大于 99. 7% Purity: greater than 99.7%

生产单位：鲁南制药股份有限公司 Production unit: Lunan Pharmaceutical Co., Ltd.

保存条件：阴凉干燥处保存，有效期 1年半。 Storage conditions: Store in a cool and dry place, valid for one and a half years.

配制方法：临用前用 1%CMC混匀，配成试验所需浓度。 Preparation method: Mix with 1% CMC just before use to prepare the concentration required for the test.

2. 2 罗苏伐他汀（Rosuvastatin) 2.2 Rosuvastatin

批号： 030205 Batch number: 030205

纯度：大于 99. 0% Purity: greater than 99.0%

生产单位：阿斯利康公司 Production unit: AstraZeneca

保存条件：阴凉干燥处保存，有效期 2年。 Storage conditions: Store in a cool and dry place, valid for 2 years.

配制方法：临用前用 1%CMC混勾，配成试验所需浓度。 Preparation method: Mix with 1% CMC before use.

3 实验动物 3 Experimental animals

3. 1 品系和来源 3.1 strains and sources

Wistar大鼠，军事医学科学院医学实验动物中心繁殖，实验动物质量许可证号为医动字 D01- 3039。 Wistar rats are bred by the Medical Experimental Animal Center of the Academy of Military Medical Sciences, and the quality permit number for experimental animals is medical action word D01-3039.

3. 2 体重和性别 3.2 weight and sex

年龄为 9周〜 10周。体重 180- 220g。雄性。 Age is 9 to 10 weeks. Weight 180-220g. male.

3. 3饲养条件 3. 3 feeding conditions

动物实验室空气定时排风、光照良好，常温。每笼饲养 5只动物，饲以本院实验动物中心专门为大鼠配制的膨化饲料，自由饮水。动物实验条件合格证号为医动字 D01-2051。试验开始前，观察动物进食、活动及粪便等 1周，选择健康动物进入试验。 The animal laboratory air is regularly ventilated, the light is good, and the room temperature is normal. Five animals were raised in each cage, and they were fed with puffed feed specially prepared for rats by the Experimental Animal Center of the hospital, and had free access to water. The certificate of animal experiment conditions is D01-2051. Before the start of the test, observe the animals' food, activities, and feces for one week, and select healthy animals to enter the test.

4 大鼠高脂血症模型制备^[2] 4 Preparation of rat hyperlipidemia model ^[2]

' 大鼠高脂血症模型采用高脂伺料致高脂血症法。高脂词料配方如下：基础饲料 87. 3%、胆固醇 2%、猪油 10%、甲基硫氧嘧啶 0. 2%、猪胆盐 0. 5%，各成分保证混合均匀。连续 2周。给药期间隔天给予高脂饲料，其余时间给予正常饲料。 'The rat model of hyperlipidemia uses hyperlipidemia to induce hyperlipidemia. The high-fat corpus formula is as follows: basic feed 87.3%, cholesterol 2%, lard 10%, methylthiouracil 0.2%, pig bile salt 0.5%, and the ingredients are guaranteed to mix evenly. 2 consecutive weeks. High-fat feed was given at intervals of the administration period, and normal feed was given the rest.

5 阿昔莫司和罗苏伐他汀钙对正常大鼠血脂的影响 ^[2] 5 Effect of acyclomus and rosuvastatin calcium on blood lipids in normal rats ^[2]

5. 1 剂量选择 5. 1 dose selection

临床上阿昔莫司剂量为 250mg/次 (按人体重 60 kg计算，上述剂量为 4. 2mg/kg), 2〜3次 I日，每日量最大不超过 1200mg ^M。按体表面积为单位的剂量等效原则推算，上述人常用剂量换算成大鼠剂量约为 50mg/kg/day。结合文献报道 ^[:'^]，加之本试验采用 1次 /日给药方法，故在本试验中阿昔莫司剂量设为 100、 200、 300、 500mg/kg。 Clinically, the dose of acyclovir is 250 mg / time (calculated based on human body weight of 60 kg, the above dose is 4.2 mg / kg), 2 to 3 times a day, the maximum daily amount does not exceed 1200 mg ^M. Calculated according to the principle of dose equivalent in terms of body surface area, The usual human doses are converted into rat doses of about 50 mg / kg / day. Combining with the literature reports ^[: ' ^] , plus this test uses the once-daily administration method, so in this test the dose of acyclovir is set to 100, 200, 300, 500 mg / kg.

临床上罗苏伐他汀的剂量为 5〜20mg/次（按人体重 60 kg 计算，上述剂量为 0.1-0.3mg/kg), 1次 /日，每日量最大不超过 40mg^[3]。按体表面积为单位的剂量等效原则推算，上述人常用剂量换算成大鼠剂量约为 0.5-1.5mg/kg，结合文献报道，将本试验中罗苏伐他汀钙剂量（以游离酸计，下同）设为 5、 10、 20、 40mg/kg_o 5.2 组别设置 Clinically, the dose of rosuvastatin is 5 ~ 20mg / time (calculated based on the human body weight of 60 kg, the above dose is 0.1-0.3mg / kg), once a day, and the maximum daily dose does not exceed 40mg ^[3] . Calculated according to the principle of dose equivalence in terms of body surface area, the common human doses described above are converted into rat doses of about 0.5-1.5 mg / kg. Combined with literature reports, the rosuvastatin calcium dose (calculated as free acid, Same below) Set to 5, 10, 20, 40mg / kg _o 5.2 group settings

依据上述剂量设置，按血清总胆固醇水平均衡原则，把正常动物按照随机原则分为： (1) 正常对照组； (6) 阿昔莫司 100mg/kg组； (7) 阿昔莫司 200mg/kg组； According to the above dose setting, according to the principle of equalization of serum total cholesterol levels, normal animals are divided into: (1) the normal control group; (6) the aximus 100 mg / kg group; (7) the aximus 200 mg / kg group

(8)阿昔莫司 300mg/kg组； (9)阿昔莫司 500mg/kg组； (10)罗苏伐他汀钙 5mg/kg 组；（11) 罗苏伐他汀钙 lOmg/kg组；（12) 罗苏伐他汀钙 20mg/kg组；（13) 罗苏伐他汀钙 40mg/kg组； (14) 阿昔莫司 200mg/kg和罗苏伐他汀钙 5mg/kg组； (15) 阿昔莫司 200mg/kg和罗苏伐他汀钙 10mg/kg组；（16) 阿昔莫司 200 mg/kg和罗苏伐他汀钙 20 mg/kg组； (17) 阿昔莫司 200 mg/kg和罗苏伐他汀钙 40 mg/kg组； (18) 阿昔莫司 300 mg/kg和罗苏伐他汀钙 5 mg/kg组； (19) 阿昔莫司 300 mg/kg和罗苏伐他汀钙 10 mg/kg组； (20) 阿昔莫司 300 mg/kg和罗苏伐他汀钙 20 mg/kg组（21) 阿昔莫司 500 mg/kg和罗苏伐他汀钙 10 mg/kg组。每组 6只，雄性。 (8) acyclomus 300mg / kg group; (9) acyclomus 500mg / kg group; (10) rosuvastatin calcium 5mg / kg group; (11) rosuvastatin calcium 10mg / kg group; (12) rosuvastatin calcium 20mg / kg group; (13) rosuvastatin calcium 40mg / kg group; (14) acyclovir 200mg / kg and rosuvastatin calcium 5mg / kg group; (15) Acyclomus 200mg / kg and Rosuvastatin calcium 10mg / kg group; (16) Aximus 200mg / kg and Rosuvastatin calcium 20 mg / kg group; (17) Aximus 200mg / kg / kg and rosuvastatin calcium 40 mg / kg group; (18) acyclomus 300 mg / kg and rosuvastatin calcium 5 mg / kg group; (19) acyclovir 300 mg / kg and roma Sulvastatin calcium 10 mg / kg group; (20) acyclomus 300 mg / kg and rosuvastatin calcium 20 mg / kg group (21) acyclomus 500 mg / kg and rosuvastatin calcium 10 mg / kg group. There are 6 males in each group.

5.4 给药 5.4 Administration

临床给药途径为口服，故本试验采用灌胃法给药，连续灌胃 4天。灌胃均在动物进食后进行。每天 1次。给药体积为 0.3ml/100g体重。 14:00〜16:00给药。 The clinical route of administration is oral. Therefore, this experiment was administered by gavage for 4 consecutive days. Gavage was performed after the animals had eaten. Once a day. The administration volume was 0.3 ml / 100 g body weight. From 14:00 to 16:00.

5.5检测指标 5.5 detection indicators

血清化学指标包括总胆固醇 (TC)、丙氨酸氨基转移酶 (ALT)、肌酸激酶（CK)、甘油三酯 (TG)、低密度脂蛋白胆固醇（LDL-C)、高密度脂蛋白胆固醇 (HDL-L)。其中丙氨酸氨基转移酶 (ALT)、肌酸激酶（CK)检测试剂采用北京中生生物工程高技术公司产品，用 SABA/18全自动生化分析仪测定；其余试剂采用日本罗氏试剂公司产品，用曰立 7020自动生化分析仪测定。测定方法参照试剂说明书取血样前禁食 16小时。 Serum chemical indicators include total cholesterol (TC), alanine aminotransferase (ALT), creatine kinase (CK), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-L). Among them, the alanine aminotransferase (ALT) and creatine kinase (CK) detection reagents were produced by Beijing Zhongsheng Bioengineering High-tech Co., Ltd. and determined by SABA / 18 automatic biochemical analyzer; the remaining reagents were produced by Japanese Roche reagent company. Determined with Yueli 7020 automatic biochemical analyzer. For the determination method, refer to the reagent instructions. Fast for 16 hours before taking blood samples.

6 阿昔莫司和罗苏伐他汀钙对模型大鼠血脂的影响 6 Effect of acyclomus and rosuvastatin calcium on blood lipids in model rats

6.1 剂量依据 6.1 Dosage basis

同正常大鼠实验。 Experiment with normal rats.

6.2 组别设置 6.2 Group settings

依据上述剂量设置，按血清总胆固醇水平均衡原则，把正常动物按照随机原则分为：（1) 正常对照组；（2)模型对照组；（3) 阿昔莫司 150mg/kg组；（4) 阿昔莫司 200mg/kg组； (5) 阿昔莫司 300mg/kg组； (6) 阿昔莫司 400mg/kg组； (7) 阿昔莫司 500mg/kg组；（8) 罗苏伐他汀钙 5mg/kg组；（9) 罗苏伐他汀钙 lOmg/kg组； (10) 罗苏伐他汀钙 20mg/kg组；（11) 罗苏伐他汀钙 40mg/kg组；（12) 阿昔莫司 150mg/kg和罗苏伐他汀钙 10mg/kg组； (13) 阿昔莫司 200mg/kg和罗苏伐他汀钙 10mg/kg组； (14) 阿昔莫司 300 mg/kg和罗苏伐他汀钙 5 mg/kg组； (15) 阿昔莫司 300 mg/kg和罗苏伐他汀钙 10 mg/kg组；（16) 阿昔莫司 300 mg/kg和罗苏伐他汀钙 20 mg/kg组；（17) 阿昔莫司 400 mg/kg和罗苏伐他汀钙 5 mg/kg组（18) 阿昔莫司 500 mg/kg和罗苏伐他汀钙 5 mg/kg组。每组 10只，雄性。 According to the above dose setting, according to the principle of equalization of serum total cholesterol levels, normal animals are divided into: (1) normal control group; (2) model control group; (3) aximus 150mg / kg group; (4) ) Aximus 200mg / kg group; (5) Aximus 300mg / kg group; (6) Aximus 400mg / kg group; (7) Aximus 500mg / kg group; (8) Luo Sovastatin calcium 5mg / kg group; (9) rosuvastatin calcium 10mg / kg group; (10) rosuvastatin calcium 20mg / kg group; (11) rosuvastatin calcium 40mg / kg group; (12) ) Acyclomus 150mg / kg and rosuvastatin calcium 10mg / kg group; (13) Aximus 200mg / kg and rosuvastatin calcium 10mg / kg group; (14) Acyclomus 300 mg / kg kg and rosuvastatin calcium 5 mg / kg group; (15) acyclomus 300 mg / kg and rosuvastatin calcium 10 mg / kg group; (16) acyclovir 300 mg / kg and rosuvast Vatar 20 mg / kg group; (17) 400 mg / kg of acyclomus and 5 mg / kg of rosuvastatin calcium (18) 500 mg / kg of acyclomus and 5 mg / kg of rosuvastatin calcium kg group. There are 10 males in each group.

6.3 给药 6.3 Administration

临床给药途径为口服，故本试验采用灌胃法给药， <连续灌胃 14天。灌胃均在动物进食后进行。每天 1次。给药体积为 0.3ml/100g体重。 The clinical route of administration is oral, so this experiment was administered by gavage for <14 consecutive days. Gavage was performed after the animals had eaten. Once a day. The administration volume was 0.3 ml / 100 g body weight.

6.4检测指标 6.4 Testing indicators

同正常大鼠实验。 Experiment with normal rats.

7 试验结果 7 Test results

7.1 阿昔莫司和罗苏伐他汀钙对正常大鼠血脂的影响 7.1 Effects of Acyclomus and Rosuvastatin Calcium on Blood Lipids in Normal Rats

正常大鼠给药 4天后，阿昔莫司、罗苏伐他汀钙和联合用药组的总胆固醇和低密度脂蛋白胆固醇均有所降低，高密度脂蛋白胆固醇升高 (表 1)。给药后血清甘油三酯略有下降，但无统计学差异。联合用药组的效果优于单药。阿昔莫司和罗苏伐他汀钙及配伍对正常大鼠血脂的影响 Four days after administration in normal rats, total and low-density lipoprotein cholesterol were reduced, and high-density lipoprotein cholesterol was increased in the acyclovir, rosuvastatin calcium, and combination groups (Table 1). After administration, serum triglycerides decreased slightly, but there was no statistical difference. The effect of the combined drug group was better than that of the single drug. Effects of acoximus and rosuvastatin calcium and their compatibility on blood lipids in normal rats

高密度脂蛋白胆固总胆固醇甘油三酯低密度脂蛋白胆固醇组别醇 High-density lipoprotein cholesterol total cholesterol triglyceride low-density lipoprotein cholesterol group alcohol

(mmol/L) (mmol/L) (mmol/L) (mmol / L) (mmol / L) (mmol / L)

(raraol/L) 正斜照 2. 07 + 0. 28 0. 88±0. 56 0. 44 + 0. 10 0. 83 ±0. 09 阿昔莫司 15Qng/kg 1. 68 + 0. 27* 0. 80±0. 27 0. 39±0. 08 0. 86 + 0. 19 阿昔莫司 200mgkg 1. 73±0. 22 0. 75±0. 19 0. 37±0. 06 0. 92 + 0. 22 阿昔莫司 300n¾kg 1. 52 + 0. 21* 0. 73土 0. 12 0. 36±0. 04 0. 95±0. 26 阿昔莫司 400mgkg 1. 69 + 0. 31 0. 66±0, 35 0. 38 + 0. 16 0. 91±0. 32 阿昔莫司 500mgkg 1. 63±0. 27* 0. 50±0, 20 0. 33+0. 08 1. 03 + 0. 30 划娜丐 5m&kg 2. 00±0. 11 0. 73 + 0. 32 0. 39±0. 09 1. 11±0. 37 罗苏伐他汀钙 1. 92±0. 37 0. 68±0. 08 0. 36±0. 10 1. 10 + 0. 14* (raraol / L) Positive oblique 2.07 + 0. 28 0. 88 ± 0. 56 0. 44 + 0. 10 0. 83 ± 0. 09 Aximus 15Qng / kg 1. 68 + 0. 27 * 0. 80 ± 0. 27 0. 39 ± 0. 08 0. 86 + 0. 19 aximus 200mgkg 1. 73 ± 0. 22 0. 75 ± 0. 19 0. 37 ± 0. 06 0. 92 + 0. 22 aximus 300 n¾ kg 1. 52 + 0. 21 * 0. 73 soil 0. 12 0. 36 ± 0. 04 0. 95 ± 0. 26 aximus 400 mgkg 1. 69 + 0. 31 0. 66 ± 0, 35 0. 38 + 0. 16 0. 91 ± 0. 32 Aximus 500mgkg 1. 63 ± 0. 27 * 0. 50 ± 0, 20 0. 33 + 0. 08 1 03 + 0. 30 5m & kg 2. 00 ± 0. 11 0. 73 + 0. 32 0. 39 ± 0. 09 1. 11 ± 0. 37 Rosuvastatin calcium 1. 92 ± 0. 37 0. 68 ± 0. 08 0. 36 ± 0. 10 1. 10 + 0. 14 *

10tngkg 10tngkg

罗苏伐他汀钙 1. 83+0. 26 0. 67±0. 20 0. 32 + 0. 10 1. 06±0. 19Rosuvastatin calcium 1.83 + 0. 26 0. 67 ± 0. 20 0. 32 + 0. 10 1. 06 ± 0. 19

20mg/kg 20mg / kg

罗苏伐他汀钙 1. 73 + 0. 33 0. 60±0. 21 0. 35+0. 22 1. 05 + 0. 47Rosuvastatin calcium 1.73 + 0.33 0. 60 ± 0. 21 0. 35 + 0. 22 1. 05 + 0.47

40mg kg 40mg kg

阿 150 10 mg kg 1. 49 ±0. 31" 0. 65 + 0. 22 0. 37 + 0. 20 1. 02 + 0. 33 阿 200 10 mg/kg 1. 47±0· 28" 0. 63±0. 19 0. 30±0. 15 0. 93±0. 29 阿 300 5 mg/kg 1. 38±0. 27" 0. 53 + 0. 22 0. 32±0. 11 1. 07 + 0. 31 阿 300 10 mg/kg 1. 50 ±0. 38* 0. 56 + 0. 13 0. 29±0. 10 1. 20+0. 34 阿 300 20 mg kg 1. 60±0. 28* 0. 45±0. 21 0. 35 + 0. 05" 1. 35 + 0. 35* 阿 400 5 mg/kg 1. 41±0. 23** 0. 61 + 0. 21 0. 34±0. 15 0. 95+0. 32 阿 500 5 mg/kg 1. 56±0. 61 0. 56±0. 37 0. 31 + 0. 13 1. 21±0. 43 与正常对照组比较, *Ρ<0.05, **Ρ<0.01 7.2 阿昔莫司和罗苏伐他汀钙对模型大鼠血脂的影响 A 150 10 mg kg 1. 49 ± 0. 31 "0. 65 + 0. 22 0. 37 + 0. 20 1. 02 + 0. 33 A 200 10 mg / kg 1. 47 ± 0 · 28" 0. 63 ± 0. 19 0. 30 ± 0. 15 0. 93 ± 0. 29 A 300 5 mg / kg 1. 38 ± 0. 27 "0. 53 + 0. 22 0. 32 ± 0. 11 1. 07 + 0. 31 A 300 10 mg / kg 1. 50 ± 0. 38 * 0. 56 + 0. 13 0. 29 ± 0. 10 1. 20 + 0. 34 A 300 20 mg kg 1. 60 ± 0. 28 * 0. 45 ± 0. 21 0. 35 + 0. 05 "1. 35 + 0. 35 * Ah 400 5 mg / kg 1. 41 ± 0. 23 ** 0. 61 + 0. 21 0. 34 ± 0. 15 0. 95 + 0. 32 500 500 mg / kg 1. 56 ± 0. 61 0. 56 ± 0. 37 0. 31 + 0. 13 1. 21 ± 0. 43 Compared with the normal control group , * P <0.05, ** P <0.01 7.2 Effect of acyclomus and rosuvastatin calcium on blood lipids in model rats

大鼠词以高脂饲料 14天后分组给药。阿昔莫司的剂量从 100〜500mg/kg，罗苏伐他汀钙的剂量从 5〜40mg/kg，组成联合用药组。给药 14天后，与模型对照组比较，阿昔莫司和罗苏伐他汀钙各剂量组血清总胆固醇、甘油三酯、低密度脂蛋白胆固醇均显著下降（表 2)。 Rat words were given in groups on a high-fat diet 14 days later. The dose of acyclovir is from 100 to 500 mg / kg, and the dose of rosuvastatin calcium is from 5 to 40 mg / kg. After 14 days of administration, compared with the model control group, the total cholesterol, triglyceride, and low-density lipoprotein cholesterol were significantly decreased in each group of acyclomus and rosuvastatin calcium (Table 2).

部分阿昔莫司剂量组及与罗苏伐他汀钙联合用药组大鼠血清丙氨酸氨基转移酶升高，高剂量组升高幅度大（表 3)。各组大鼠血清中肌酸激酶活性变化趋势与血清丙氨酸氨基转移酶相似。因此在复方中应尽可能降低罗苏伐他汀钙的剂量，以阿昔莫司 300mg/kg和罗苏 O伐他汀钙 5mg/k_g剂量配伍较好，对血清中肌酸激酶与血清丙氨酸氨基转移酶活性的影响较小。表 2 阿昔莫司和罗苏伐他汀及复方对模型大鼠血脂的影响血清总胆固醇血清甘油三酯 The serum alanine aminotransferase of rats in some of the acyclomus dose group and the combination with rosuvastatin calcium group increased, and the increase in the high dose group was large (Table 3). The trend of creatine kinase activity in serum of rats in each group was similar to that of serum alanine aminotransferase. Therefore, the dose of rosuvastatin calcium should be reduced as much as possible in the compound. It is better to use acyclovir 300mg / kg and rosuvastatin calcium 5mg / k _g . The serum creatine kinase and serum alanine The effect of acid aminotransferase activity is small. Table 2 Effects of acyclomus and rosuvastatin and their compounds on blood lipids in model rats Total serum cholesterol Triglycerides

组别 Group

(mmol/L) (mmol/L) (mmol/L) 正缠 1.96±0· 30 0.73 ±0.13 0.50±0.13 1.18±0· 22 (mmol / L) (mmol / L) (mmol / L) 1.96 ± 0 · 30 0.73 ± 0.13 0.50 ± 0.13 1.18 ± 0 · 22

¾ '醒 5.80 ±0.33™ 2.87 ±0.34™ 3.38±0· 11** 0.99±0.13 阿昔莫司 150 m^kg 5.42±0.82 2.53 ±0.20 3.18 ±0.46 0.97±0· 17 阿昔莫司 200 mgkg 5.21 ±0.52* 2.51±0.12 3.03 ±0.48 0.99 ±0.22 阿昔莫司 300 mg kg 5.11 ±0.49*** 2.33 ±0.21* 2.94±0.33*** 1.10±0· 25 阿昔莫司 400 rag/kg 5.02±0.44^w 2.23 ±0.18** 2.85 ±0.40*" 1.17±0.3 阿昔莫司 500 nig/kg 4.98 ±0.50™ 2.28±0· ΐΓ* 2.83 ±0.38*" 1.19±0.36" 磨丁钙 4.57±0.45 2.20±0· 15 2.96 ±0.61 0.94 ±0.14¾ 'Wake up 5.80 ± 0.33 ™ 2.87 ± 0.34 ™ 3.38 ± 0 · 11 ** 0.99 ± 0.13 aximus 150 m ^ kg 5.42 ± 0.82 2.53 ± 0.20 3.18 ± 0.46 0.97 ± 0 · 17 aximus 200 mgkg 5.21 ± 0.52 * 2.51 ± 0.12 3.03 ± 0.48 0.99 ± 0.22 Aximus 300 mg kg 5.11 ± 0.49 *** 2.33 ± 0.21 * 2.94 ± 0.33 *** 1.10 ± 0 · 25 Aximus 400 rag / kg 5.02 ± 0.44 ^w 2.23 ± 0.18 ** 2.85 ± 0.40 * "1.17 ± 0.3 Acoximus 500 nig / kg 4.98 ± 0.50 ™ 2.28 ± 0 · ΐΓ * 2.83 ± 0.38 *" 1.19 ± 0.36 "Milled calcium 4.57 ± 0.45 2.20 ± 0 · 15 2.96 ± 0.61 0.94 ± 0.14

5 mg kg 5 mg kg

罗苏伐細丐 4.16±0.43*" 2.10±0.20 2.77 ±0.59* 0·98±0.15Rosuveau 4.16 ± 0.43 * "2.10 ± 0.20 2.77 ± 0.59 * 0 · 98 ± 0.15

10 rag/kg 10 rag / kg

频划鎮 3.93±0.3 1.81±0.4Γ* 2.60±0.26*" 1.17±0.31Frequency planning town 3.93 ± 0.3 1.81 ± 0.4Γ * 2.60 ± 0.26 * "1.17 ± 0.31

20 mg/kg 20 mg / kg

罗苏伐他汀鈣 3.56 ±0.36*" 1.77±0.10 2.55 ±0.45*** 1.20 ±0.27**Rosuvastatin calcium 3.56 ± 0.36 * "1.77 ± 0.10 2.55 ± 0.45 *** 1.20 ± 0.27 **

40 mg kg 40 mg kg

阿 150罗苏 10 mg/kg 2.81 ±0.33" 1.27 ±0.36"* 1.12 ±0.27*** 1.80±0.29** 阿 200 10 mg/kg 2.78±0·4(Γ 1·23±0· 46*" 1.10±0.25** 1.88±0· 37** 阿 300 5 mg kg 2.70 ±0.25" 1.20±0.32" 1.05 ±0.15" 1.75 ±0.34*" 阿 300 10 mgkg 2.55±0,3广 1.13±0.2广 0.92 ±0.24*" 1·99±0· 25" 阿 300 20 rag/kg 2.50 ±0.54" 1·05±0· 23^w 0.94 ±0.13™ 2·01±0.26*" 阿 400罗苏 5 mg/kg 2.75 ±0.35*" 1.21±0.23" 1.11±0.2广 1.79±0.32**** 阿 500 5 mg/kg 2.68±0.28** 1.17土 0.15" 1.08±0.25"* 1.73±0.3Γ* 注：与正常对照组比较， #tt#P<0.001；与模型对照组比较， *P<0.05, **P<0.01, ***P<0.001 表 3 阿昔莫司和罗苏伐他汀钙及复方对模型大鼠血清丙氨酸氨基转移酶 A 150 Luo Su 10 mg / kg 2.81 ± 0.33 "1.27 ± 0.36" * 1.12 ± 0.27 *** 1.80 ± 0.29 ** A 200 10 mg / kg 2.78 ± 0 · 4 (Γ 1 · 23 ± 0 · 46 * " 1.10 ± 0.25 ** 1.88 ± 0 · 37 ** A 300 5 mg kg 2.70 ± 0.25 "1.20 ± 0.32" 1.05 ± 0.15 "1.75 ± 0.34 *" A 300 10 mgkg 2.55 ± 0, 3 and 1.13 ± 0.2 and 0.92 ± 0.24 * "1 · 99 ± 0 · 25" Ah 300 20 rag / kg 2.50 ± 0.54 "1 · 05 ± 0 · 23 ^w 0.94 ± 0.13 ™ 2 · 01 ± 0.26 *" Ah 400 Luo Su 5 mg / kg 2.75 ± 0.35 * "1.21 ± 0.23" 1.11 ± 0.2 wide 1.79 ± 0.32 **** 500 500 mg / kg 2.68 ± 0.28 ** 1.17 soil 0.15 "1.08 ± 0.25" * 1.73 ± 0.3Γ * Note: Compared with normal control group , # Tt # P <0.001; compared with the model control group, * P <0.05, ** P <0.01, *** P <0.001 Table 3 Calcium and simvastatin and rosuvastatin calcium and the compound on serum alanine aminotransferase in model rats

和肌酸激酶的影响丙氨酸氨基转移酶肌酸激酶 And creatine kinase effects alanine aminotransferase creatine kinase

组另 ij Group another ij

(U/L) (U / L)

正常对照组 527.9± 138.8 509.2土 184.6^W Normal control group 527.9 ± 138.8 509.2 ± 184.6 ^W

模型細组 683.5±257.6 267.2 ±78.5 Model subgroup 683.5 ± 257.6 267.2 ± 78.5

阿昔莫司 150 mg/kg 591.6± 128.8 259.2 ±134.0 Aximus 150 mg / kg 591.6 ± 128.8 259.2 ± 134.0

阿昔莫司 200 mg/kg 613.8±131.2 264.2± 129.6 Aximus 200 mg / kg 613.8 ± 131.2 264.2 ± 129.6

阿昔莫司 300 mg/kg 636.8 ±229.3 272.8 ±86.0 Aximus 300 mg / kg 636.8 ± 229.3 272.8 ± 86.0

阿昔莫司 400 mg/kg 566.1±265.7 322.5 ±135.6 Acyclomus 400 mg / kg 566.1 ± 265.7 322.5 ± 135.6

阿昔莫司 500 mg/kg 766.1±215.3 309.3± 115.4 Acyclomus 500 mg / kg 766.1 ± 215.3 309.3 ± 115.4

罗苏 5 mg/kg 524.1±233.8 243.6± 112.5 Luo Su 5 mg / kg 524.1 ± 233.8 243.6 ± 112.5

o o

罗苏 10 mg/kg 951.4±312.9* 569.4 ±129.0 Luosu 10 mg / kg 951.4 ± 312.9 * 569.4 ± 129.0

罗苏 20 rag/kg 1562.7±613.6" 1481.2±338.8" Luo Su 20 rag / kg 1562.7 ± 613.6 "1481.2 ± 338.8"

罗苏 40 mg/kg 1808.0±855.9" 1543.2 ±1395.2" Luo Su 40 mg / kg 1808.0 ± 855.9 "1543.2 ± 1395.2"

阿 150罗苏 10 mg/kg 821.7± 165.8 311.2± 169.5 A 150 Luo Su 10 mg / kg 821.7 ± 165.8 311.2 ± 169.5

阿 200罗苏 10 mg/kg 819.3 ±178.2 308.4± 175.2 A 200 Rosue 10 mg / kg 819.3 ± 178.2 308.4 ± 175.2

阿 300罗苏 5 mg/kg 548.8± 186.8 269.6± 106.3 A 300 Luo Su 5 mg / kg 548.8 ± 186.8 269.6 ± 106.3

阿 300罗苏 10 mg/kg 950.3 ±620· 6 749.1±318. Γ A 300 Luo Su 10 mg / kg 950.3 ± 620 · 6 749.1 ± 318. Γ

阿 300罗苏 20 mg/kg 1381.3±678.0* 1031.5 ±749.2"* A 300 Rosue 20 mg / kg 1381.3 ± 678.0 * 1031.5 ± 749.2 "*

阿 400罗苏 5 mg/kg 516.8 ±189.6 235.3 ±97.8 A 400 Luo Su 5 mg / kg 516.8 ± 189.6 235.3 ± 97.8

阿 500罗苏 5 mg/kg 551.9± 115.5' 258.4 ±107.0 A 500 Rosue 5 mg / kg 551.9 ± 115.5 '258.4 ± 107.0

注：与模型对照组比较， *P<0.05, **P<0.01, ***P<0.001 Note: Compared with the model control group, * P <0.05, ** P <0.01, *** P <0.001

8 结论 8 Conclusion

阿昔莫司和罗苏伐他汀钙伍用对高脂饲料所致的大鼠高脂血症有明显治疗作用，降脂效果与两种药物的剂量相关，我们在试验种发现，当阿昔莫司与罗苏伐他汀的剂量配比在 15:1— 100:1的范围内时，各剂量组均取得了很好的协同性作用，本发明所找到的阿昔莫司与罗苏伐他汀的配比范围与 CN03122340.0 所公开的阿昔莫司和罗苏伐他汀 10:1 的比例在降低血清总胆固醇和升高血清高密度胆固醇方面更具有优势。同时我们结合阿昔莫司和罗苏伐他汀钙复方对模型大鼠血清丙氨酸氨基转移酶和肌酸激酶的升高（不良反应），发现，当阿昔莫司与罗苏伐他汀的比例小于 15:1时，虽然也能够取得一定的协同性降血脂效应，但是，在各剂量组给药时，要么由于给药总量太低，不能够取得理想的降脂效果，要么由于罗苏伐他汀的给药量过高，不良反应增强。当罗苏伐他汀的用药量为 5mg/kg时，血清丙氨酸氨基转移酶和肌酸激酶的活性与模型对照组相比较没有区别，当用量大于 10 mg/kg Βΐ，血清丙氨酸氨基转移酶和肌酸激酶随着给药量的增加迅速升高。当阿昔莫司和罗苏伐他汀的用量配比大于 100:1时，由于罗苏伐他汀的用量过小，不能够取得显著的协同性作用。阿昔莫司 300mg/kg和罗苏伐他汀钙 5mg/kg剂量伍用效果显著，同时又无明显的毒性作用。综合考虑降血脂效果和不良反应的程度，阿昔莫司与罗苏伐他汀的重量比在 40- 100 : 1的范围内，有更好的效果和更低的不良反应。此外，本试验结果发现，较高剂量的阿昔莫司每日给药. 1次也有显著的降血 '脂作用，且毒性小，这为阿昔莫司和罗苏伐他汀钙组成复方，实现每日给药 1次提供了实验依据。实施例 11 Acyclomus and rosuvastatin calcium have a significant therapeutic effect on hyperlipidemia in rats caused by high-fat diets. The lipid-lowering effect is related to the dose of the two drugs. We found in the experimental species that when When the dose ratio of Moss to Rosuvastatin is in the range of 15: 1 to 100: 1, each dose group has achieved a good synergistic effect. The aximus and Rosuvava found in the present invention The ratio of statin to the ratio of 10: 1 of acyclomus and rosuvastatin disclosed in CN03122340.0 is more advantageous in reducing total cholesterol and increasing high-density cholesterol. At the same time, we combined the increase of acyclovir calcium and rosuvastatin calcium on serum alanine aminotransferase and creatine kinase (adverse reactions) in model rats. We found that when When the ratio is less than 15: 1, although a certain synergistic hypolipidemic effect can also be obtained, when the dose is administered, either the total amount of administration is too low to achieve the desired lipid-lowering effect, or Suvastatin is administered at too high a level and adverse reactions are enhanced. When the amount of rosuvastatin was 5 mg / kg, the activities of serum alanine aminotransferase and creatine kinase were not different from those of the model control group. When the amount of rosuvastatin was greater than 10 mg / kg βΐ, the serum alanine amino Transferase and creatine kinase increased rapidly with increasing doses. When the dosage ratio of acyclomus and rosuvastatin is greater than 100: 1, because the amount of rosuvastatin is too small, significant synergy cannot be achieved Role. Acyclovir 300mg / kg and Rosuvastatin Calcium 5mg / kg doses have a significant effect without any significant toxicity. Taking into account the effect of lowering blood lipids and the degree of adverse reactions, the weight ratio of acyclovir and rosuvastatin is in the range of 40-100: 1, which has better effects and lower adverse reactions. In addition, the results of this test found that a higher dose of aximolimus was administered daily. It also had a significant blood-lowering effect and low toxicity once. This was a compound consisting of aximuslim and rosuvastatin calcium. The realization of once-daily administration provided experimental basis. Example 11

阿昔莫司和罗苏伐他汀联合使用与阿昔莫司和普伐他汀、阿昔莫司和洛伐他汀联合使用的降脂效果比较 Comparison of lipid-lowering effects of acyclovir and rosuvastatin combined with acyclovir and pravastatin, acyclovir and lovastatin

我们根据实施例 10所筛选到的阿昔莫司罗苏伐他汀的配比与 US5260305A和 CN1425374A所公开的组合物进行了比较研究，在实验中意外发现，并通过大量的动物实验验证了阿昔莫司罗苏伐他汀联合使用在降低血清总胆固醇、血清甘油三酯和低密度脂蛋白胆固醇方面不仅存在着明显的协同性作用，而且与阿昔莫司普伐他汀联合使用、阿昔莫司洛伐他汀联合使用相比较，有着显著的差异，降脂效果更为明显，在升高高密度脂蛋白胆固醇方面，也有着比较明显的优势。 We conducted a comparative study of the composition of aximuslot and rosuvastatin screened in Example 10 with the compositions disclosed in US5260305A and CN1425374A, which was unexpectedly found in the experiments, and was verified by a large number of animal experiments. Not only the synergistic effect of the combined use of moxiprosum and statvastatin in reducing serum total cholesterol, serum triglycerides and low-density lipoprotein cholesterol, but also in combination with acyclovir pravastatin Compared with the combined use of lovastatin, there are significant differences, the lipid-lowering effect is more obvious, and it also has obvious advantages in raising high-density lipoprotein cholesterol.

11. 1 受试药物、动物、大鼠高脂血症模型制备同实施例 10。 11.1 The test drug, animal and rat hyperlipidemia model were prepared as in Example 10.

11. 2组别设置 11. 2 group settings

按血清总胆固醇水平均衡原则，将模型大鼠随机分为： According to the principle of balance of serum total cholesterol levels, model rats are randomly divided into:

正常对照组； Normal control group

模型对照组； Model control group

阿昔莫司 300mg/kg普伐他汀 20mg/kg组； Acyclovir 300mg / kg pravastatin 20mg / kg group;

阿昔莫司 300mg/kg洛伐他汀 10mg/kg组； Acyclovir 300mg / kg lovastatin 10mg / kg group;

阿昔莫司 200mg/kg罗苏伐他汀 10mg/kg组； Aximus 200mg / kg rosuvastatin 10mg / kg group;

阿昔莫司 300mg/kg罗苏伐他汀 5mg/kg组； Acyclovir 300mg / kg rosuvastatin 5mg / kg group;

阿昔莫司 300mg/kg罗苏伐他汀 lOmg/kg组； Acyclomus 300mg / kg rosuvastatin 10mg / kg group;

阿昔莫司 300mg/kg罗苏伐他汀 20mg/kg组； Acyclovir 300mg / kg rosuvastatin 20mg / kg group;

阿昔莫司 400mg/kg罗苏伐他汀 5mg/kg组； Acyclomus 400mg / kg rosuvastatin 5mg / kg group;

阿昔莫司 500mg/kg罗苏伐他汀 5mg/kg组。 Acyclovir 500mg / kg Rosuvastatin 5mg / kg group.

11. 3给药 11. 3 Administration

同实施例 10中的 6. 3。 Same as 6.3 in Example 10.

11. 4检测指标 11. 4 detection indicators

血清总胆固醇 (TC)、甘油三酯 (TG)、低密度脂蛋白胆固醇（LDL-C)、高密度脂蛋白胆固醇 (HDL- L)。 Serum total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-L).

11. 5实验结果 11. 5 Experimental results

大鼠词以高脂词料 14天后分组给药。给药 14天后，阿昔莫司罗苏伐他汀各剂量组在降低血清总胆固醇、血清甘油三酯和低密度脂蛋白胆固醇方面与阿昔莫司 300mg/kg普伐他汀 20mg/kg组、阿昔莫司 300mg/kg洛伐他汀 10mg/kg组相比较，有着显著的差异；在升高高密度脂蛋白胆固醇方面，也有着比较明显的优势。我们的试验结果充分证明阿昔莫司和罗苏伐他汀联合使用在降低血脂方面具有意想不到的效果，阿昔莫司和罗苏伐他汀不仅取得了显著的协同性作用，而且和现有技术公开的阿昔莫司与洛伐他汀，阿昔莫司与普伐他汀的联合使用更具有优势。具体结果见表 5。阿昔莫司罗苏伐他汀联合使用与阿昔莫司普伐他汀、 Rat words were given in groups of 14 days after the high-fat word. After 14 days of administration, each dose group of acyclovir and sovastatin reduced serum total cholesterol, serum triglyceride, and low-density lipoprotein cholesterol with acyclomus 300 mg / kg and pravastatin 20 mg / kg group. Compared with the group of xylimox 300mg / kg and lovastatin 10mg / kg, there are significant differences; in terms of raising high-density lipoprotein cholesterol, there are also obvious advantages. The results of our trials fully demonstrate the unexpected use of acyclovir and rosuvastatin in lowering blood lipids Effect, not only achieved significant synergistic effects of acyclovir and rosuvastatin, but also the combined use of aximus and lovastatin, aximus and pravastatin disclosed in the prior art Advantage. The specific results are shown in Table 5. Aximuspril and rosuvastatin are used in combination with aximusprivastatin,

阿昔莫司洛伐他汀联合使用降脂效果比较 Comparison of lipid-lowering effects of acyclovir and lovastatin

血清总胆固醇血清甘油三酯低雄 aas醇敲劍鍾围组别 Serum total cholesterol serum triglyceride

〇 (mmol/L) (mmol/L) 〇 (mmol / L) (mmol / L)

正就廳 1. 96±0· 30 0. 73±0. 13 0. 50 ±0. 13 1. 18±0. 22 In the hall 1. 96 ± 0 · 30 0. 73 ± 0. 13 0. 50 ± 0. 13 1. 18 ± 0. 22

5. 80±0. 33™ 2. 87 ±0. 34™ 3. 38 ±0. 11" 0. 99 ±0. 13 阿 150 10mg/kg 2. 81 ±0. 33*"** 1. 27±0· 36**** 1. 12 ±0. 27*"** 1. 80±0. 29*"** 阿 20Cl0ra^kg 2. 78±0, 43™** 1. 23 ±0. 46"*** 1. 10±0. 25*"** 1. 88 ±0. 37™** 阿 300罗苏 5 rag/kg 2. 70±0· 25**** 1. 20±0. 32"*** 1. 05±0· 15 1. 75 ±0. 34™** 阿 300罗苏 10 rag/kg 2. 55土 0. 31*"** 1. 03±0. 2广" 0. 92 ±0. 24**** 1. 99 ±0. 25™*** 阿 300 20 mg/kg 2. 50 ±0. 54"*** 1. 05±0. 23*"** 0. 94±0· 13"*** 2. 01 ±0. 26"*** 阿 400 5 mg kg 2. 75 ±0. 35**** 1· 21±0. 23"** 1. 11±0. 21 1. 79±0· 32·** 阿 500 5 mg kg 2. 68±0. 28"*** 1. 17 ±0. 15™** 1. 08±0. 25"** 1. 73±0· 31™** 阿 300+ 普伐 5. 80 ± 0. 33 ™ 2. 87 ± 0. 34 ™ 3. 38 ± 0. 11 "0. 99 ± 0. 13 Ah 150 10mg / kg 2. 81 ± 0. 33 *" ** 1. 27 ± 0 · 36 **** 1. 12 ± 0. 27 * "** 1. 80 ± 0. 29 *" ** 20Cl0ra ^ kg 2. 78 ± 0, 43 ™ ** 1. 23 ± 0. 46 "*** 1. 10 ± 0. 25 *" ** 1. 88 ± 0. 37 ™ ** A 300 Rosso 5 rag / kg 2. 70 ± 0 · 25 **** 1. 20 ± 0 32 "*** 1. 05 ± 0 · 15 1. 75 ± 0. 34 ™ ** A 300 Rosso 10 rag / kg 2. 55 soil 0. 31 *" ** 1. 03 ± 0. 2 "0. 92 ± 0. 24 **** 1. 99 ± 0. 25 ™ *** A 300 20 mg / kg 2. 50 ± 0. 54" *** 1. 05 ± 0. 23 * "* * 0. 94 ± 0 · 13 "*** 2. 01 ± 0. 26" *** 400 5 mg kg 2. 75 ± 0. 35 **** 1 · 21 ± 0. 23 "** 1 11 ± 0. 21 1. 79 ± 0 · 32 · ** A 500 5 mg kg 2. 68 ± 0. 28 "*** 1. 17 ± 0. 15 ™ ** 1. 08 ± 0. 25" ** 1. 73 ± 0 · 31 ™ ** A 300+ general cutting

3. 95 ±0. 39** 1. 73 ±0· 25" 2. 19±0. 29"* 1. 22±0. 23* 3. 95 ± 0. 39 ** 1. 73 ± 0 · 25 "2. 19 ± 0. 29" * 1. 22 ± 0. 23 *

20mg/kg 20mg / kg

阿 300+ 洛伐 300+ lovar

3. 81 ±0. 64** 1. 69±0· 26" 2. 35 ±0. 32*" 1. 31 ±0. 38" 10mg/kg 注：与正常对照组比较，漏 P<0. 001; 与模型对照组比较， **P<0. 01 , ***P<0. 001； 3 3. 81 ± 0. 64 ** 1. 69 ± 0 · 26 "2. 35 ± 0. 32 *" 1. 31 ± 0. 38 "10mg / kg Note: Compared with the normal control group, the leakage P <0. 001; Compared with the model control group, ** P <0. 01, *** P <0. 001; 3

o 与阿昔 300+普伐 20mg/kg组和阿昔 300+洛伐 lOrag/kg组相比较， *P<0. 05, **P<0. 01 , ***Ρ<0. 001 ο 参考文献 o Compared with Axi 300+ Prava 20mg / kg group and Axi 300+ Lova lOrag / kg group, * P <0. 05, ** P <0. 01, *** P <0. 001 ο references

[1] Brown WV, Bays HE et al， Efficacy and safety of rosuvastatin compared with pravastatin and simvaststin in patients with hypercholesterolemia: a randomized, double— bl ined, 52-week trial. [1] Brown WV, Bays HE et al, Efficacy and safety of rosuvastatin compared with pravastatin and simvaststin in patients with hypercholesterolemia: a randomized, double— bl ined, 52-week trial.

[2] 徐叔云，卞如濂，陈修主编.药理学实验方法学（第三版），人民卫生出版社出版， 2002年 1月， 1201-1202 [2] Xu Shuyun, Wu Ruyi, Chen Xiu, eds. Experimental Pharmacology Methodology (Third Edition), published by People's Medical Publishing House, January 2002, 1201-1202

[3] 0LBETAM (acipimox) 说明书（Pharmacia, New Zealand) [3] 0LBETAM (acipimox) Instructions (Pharmacia, New Zealand)

[4] Al-Shurbaji A, et al. The effect of Acipimox on triacylglycerol metabolism in rat. Scand J Clin Lab Invest, 1990, 50 (2) : 203-208 [4] Al-Shurbaji A, et al. The effect of Acipimox on triacylglycerol metabolism in rat. Scand J Clin Lab Invest, 1990, 50 (2): 203-208

[5] Crestor (Rosuvastatin) 说明书 [5] Crestor (Rosuvastatin) instruction manual

Claims

权利要求 Rights request

1. 一种治疗高血脂症的组合物，其特征在于，所述组合物包括： A composition for treating hyperlipidemia, characterized in that the composition comprises:

a) 第一个活性成分：阿昔莫司； a) the first active ingredient: aximus;

b) 第二个活性成分：罗苏伐他汀或其可药用的盐、酯或溶剂化物；第一个活性成分和第二个活性成分（以游离酸计）的比例为 15— 100 : 1。 b) the second active ingredient: rosuvastatin or a pharmaceutically acceptable salt, ester or solvate thereof; the ratio of the first active ingredient to the second active ingredient (calculated as free acid) is 15-100: 1 .

2. 按照权利要求 1 所述的组合物，其特征在于，所述的罗苏伐他汀可以药用的盐为钠盐、钙盐、钾盐、镁盐、锌盐、铁盐。 2. The composition according to claim 1, wherein the pharmaceutically acceptable salts of rosuvastatin are sodium salt, calcium salt, potassium salt, magnesium salt, zinc salt, and iron salt.

3. 按照权利要求 1 所述的组合物，其特征在于，所述的罗苏伐他汀可药用的酯为脂肪醇、芳香醇、杂环醇所形成的酯。 3. The composition according to claim 1, wherein the pharmaceutically acceptable ester of rosuvastatin is an ester formed from a fatty alcohol, an aromatic alcohol, and a heterocyclic alcohol.

4. 按照权利要求 3所述的组合物，其特征在于，所述可药用的酯为罗苏伐他汀的甲酯、乙酯、烯丙酯、苯酯。 The composition according to claim 3, wherein the pharmaceutically acceptable ester is methyl ester, ethyl ester, allyl ester, or phenyl ester of rosuvastatin.

5. 按照权利要求 1-4之一所述的组合物，其特征在于，阿昔莫司与罗苏伐他汀（以游离酸计）的重量比是 40〜100： 1。 5. The composition according to any one of claims 1-4, wherein the weight ratio of acyclomus to rosuvastatin (calculated as free acid) is 40 to 100: 1.

6. 按照权利要求 5所述的组合物，其特征在于，阿昔莫司与罗苏伐他汀（以游离酸计）的重量比是 60: 1。 6. The composition according to claim 5, characterized in that the weight ratio of acyclomus to rosuvastatin (calculated as free acid) is 60: 1.

7. 按照权利要求 1-6之一所述的组合物，其特征在于，所述组合物为片剂、胶囊剂、颗粒剂、丸剂或滴丸。 The composition according to any one of claims 1 to 6, wherein the composition is a tablet, a capsule, a granule, a pill, or a drip pill.