WO2005123082A1 - Composition anti-hyperlipemie - Google Patents

Composition anti-hyperlipemie Download PDF

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Publication number
WO2005123082A1
WO2005123082A1 PCT/CN2005/000870 CN2005000870W WO2005123082A1 WO 2005123082 A1 WO2005123082 A1 WO 2005123082A1 CN 2005000870 W CN2005000870 W CN 2005000870W WO 2005123082 A1 WO2005123082 A1 WO 2005123082A1
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Prior art keywords
rosuvastatin
group
aximus
acyclomus
rosuvastatin calcium
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PCT/CN2005/000870
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English (en)
Chinese (zh)
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Zhiquan Zhao
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Lunan Pharmaceutical Group Corporation
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Publication of WO2005123082A1 publication Critical patent/WO2005123082A1/fr

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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • 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

  • composition for treating dyslipidemia Composition for treating dyslipidemia
  • 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.
  • 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.
  • 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).
  • LDL-C Low-density lipoprotein cholesterol
  • 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.
  • the dose of patients who did not reach the target doubled all patients in the experimental group were well tolerated [ ' ] .
  • rosuvastatin has such powerful advantages, its adverse reactions are more serious than those of other statins.
  • rosuvastatin can also impair renal function in some patients (no similar adverse effects have been observed with other statins).
  • the recommended dosage is from 5 mg to 10 mg, and the maximum dose does not exceed 40 mg.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • rosuvastatin 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.
  • composition for treating hyperlipidemia 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.
  • 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.
  • 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.
  • composition of the present invention 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.
  • 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.
  • disintegrants such as sodium carboxymethyl starch, hydroxypropy
  • 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.
  • 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.
  • atorvastatin in the present invention may be any pharmaceutically acceptable salt, or any pharmaceutically acceptable ester or solvate of atorvastatin. detailed description:
  • Example 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 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.
  • 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.
  • a double-layer sheet is obtained by pressing the above two components a and b using a double-layer tablet press.
  • Example 2
  • 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
  • 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.
  • a two-layer sheet is obtained by pressing the two components a and b above using a double-layer tablet press.
  • 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.
  • the two components a and b above are punched by a double-layer tablet machine to obtain a double-layer sheet.
  • 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
  • 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.
  • 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 ⁇ 1000 dry, 16 mesh sieve whole thousand granules, dry granules add prescription amount of behenyl glycerol ⁇ 15
  • 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.
  • 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.
  • 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 45 ⁇ and discharged.
  • Blank pill core 250g 7% PVP solution (solvent is 90% ethanol) 200g
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 45 ⁇ and discharged.
  • 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.
  • Preparation process Pellets containing acyclomus prepared in a are poured into the lower hopper. ⁇ 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 50 ⁇ , and discharged.
  • 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.
  • 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.
  • 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.
  • Preparation method Mix with 1% CMC just before use to prepare the concentration required for the test.
  • Preparation method Mix with 1% CMC before use.
  • 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.
  • Age is 9 to 10 weeks. Weight 180-220g. male.
  • 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.
  • 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.
  • 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.
  • 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] .
  • the common human doses described above are converted into rat doses of about 0.5-1.5 mg / kg.
  • the rosuvastatin calcium dose (calculated as free acid, Same below) Set to 5, 10, 20, 40mg / kg o 5.2 group settings
  • normal animals are divided into: (1) the normal control group; (6) the aximus 100 mg / kg group; (7) the aximus 200 mg / kg group
  • 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 Sul
  • 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.
  • 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).
  • TC total cholesterol
  • 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.
  • 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
  • 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.
  • 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.
  • the total cholesterol, triglyceride, and low-density lipoprotein cholesterol were significantly decreased in each group of acyclomus and rosuvastatin calcium (Table 2).
  • 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.
  • 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.
  • test drug, animal and rat hyperlipidemia model were prepared as in Example 10.
  • model rats are randomly divided into:
  • TC Serum total cholesterol
  • TG triglycerides
  • LDL-C low density lipoprotein cholesterol
  • HDL-L high density lipoprotein cholesterol
  • 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.

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Abstract

L'invention concerne une composition anti-hyperlipémie contenant de l'acipimox et de la rosuvastatine, ou leurs sels, leurs esters et leurs solvates. La proportion en poids est (15/100):1, de préférence (40/100):1, de préférence 60:1. L'acipimox peut être utilisé combiné à de la rosuvastatine, dans une action synergétique, l'effet d'anti-hyperlipémie étant meilleur que celui de la combinaison d'acipimox et de lovastatine.
PCT/CN2005/000870 2004-06-16 2005-06-16 Composition anti-hyperlipemie WO2005123082A1 (fr)

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CNA200410047858XA CN1709257A (zh) 2004-06-16 2004-06-16 治疗高血脂症的组合物

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007119085A1 (fr) * 2006-04-13 2007-10-25 Egis Gyógyszergyár Nyilvánosan Mukodo Reszvenytársaság Sel de zinc de rosuvastatine
WO2009047577A1 (fr) * 2007-10-12 2009-04-16 EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság Procédé de préparation de sel de rosuvastatine zinc
WO2010128346A3 (fr) * 2009-05-07 2011-01-13 Egis Gyógyszergyár Nyilvánosan Mukodo Reszvenytársaság Sels de rosuvastatine et leur procédé de préparation
WO2012073054A2 (fr) 2010-11-29 2012-06-07 Egis Gyógyszergyár Nyilvánosan Múködó Részvény-Társaság Procédé de préparation de sels de rosuvastatine

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CN101385731B (zh) * 2007-09-10 2010-12-15 鲁南制药集团股份有限公司 治疗高脂血症的渗透泵控释制剂组合物及其制备方法

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CN1457786A (zh) * 2003-04-30 2003-11-26 鲁南制药股份有限公司 治疗高血脂症的组合物

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CN1457786A (zh) * 2003-04-30 2003-11-26 鲁南制药股份有限公司 治疗高血脂症的组合物

Cited By (8)

* Cited by examiner, † Cited by third party
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WO2007119085A1 (fr) * 2006-04-13 2007-10-25 Egis Gyógyszergyár Nyilvánosan Mukodo Reszvenytársaság Sel de zinc de rosuvastatine
JP2009533412A (ja) * 2006-04-13 2009-09-17 エギシュ ヂョヂセルヂャール ニルヴァーノサン ミケデ レースヴェーニタールササーグ ロスバスタチン亜鉛塩
US20090306117A1 (en) * 2006-04-13 2009-12-10 Vago Pal Rosuvastatin zinc salt
EA016141B1 (ru) * 2006-04-13 2012-02-28 Эгиш Дьёдьсердьяр Ньильваношан Мюкёдё Ресвеньтаршашаг Цинковая соль розувастатина
US9174945B2 (en) 2006-04-13 2015-11-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Rosuvastatin zinc salt
WO2009047577A1 (fr) * 2007-10-12 2009-04-16 EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság Procédé de préparation de sel de rosuvastatine zinc
WO2010128346A3 (fr) * 2009-05-07 2011-01-13 Egis Gyógyszergyár Nyilvánosan Mukodo Reszvenytársaság Sels de rosuvastatine et leur procédé de préparation
WO2012073054A2 (fr) 2010-11-29 2012-06-07 Egis Gyógyszergyár Nyilvánosan Múködó Részvény-Társaság Procédé de préparation de sels de rosuvastatine

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