WO2005115393A1 - Composition anti-hyperlipemie - Google Patents

Composition anti-hyperlipemie Download PDF

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Publication number
WO2005115393A1
WO2005115393A1 PCT/CN2005/000728 CN2005000728W WO2005115393A1 WO 2005115393 A1 WO2005115393 A1 WO 2005115393A1 CN 2005000728 W CN2005000728 W CN 2005000728W WO 2005115393 A1 WO2005115393 A1 WO 2005115393A1
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Prior art keywords
pitavastatin
pitavastatin calcium
group
acyclomus
calcium
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PCT/CN2005/000728
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English (en)
Chinese (zh)
Inventor
Zhiquan Zhao
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Lunan Pharmaceutical Group Corporation
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Priority to CN200580007179.2A priority Critical patent/CN1929843A/zh
Publication of WO2005115393A1 publication Critical patent/WO2005115393A1/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

  • the present invention relates to a novel composition for treating hyperlipidemia, which comprises the first active ingredient aximus and the second active ingredient pitavastatin calcium or a pharmaceutically acceptable salt, ester or solvate thereof.
  • statins have been well received by people, and their clinical efficacy is superior to other types of lipid-lowering drugs.
  • statins can reduce the incidence and mortality of coronary heart disease, and can slow or even reduce the development of atherosclerotic plaques that have formed.
  • Pitavastatin is the first fully synthetic new lipid-lowering drug such as hydroxyglutaryl coenzyme A (HMG-CoA) reductase inhibitor. It has no pharmacological activity and has direct pharmacological activity.
  • HMG-CoA hydroxyglutaryl coenzyme A reductase inhibitor
  • This product competitively inhibits the rate-limiting enzyme hydroxymethylglutaryl coenzyme A reductase in the process of cholesterol synthesis in the body, which reduces the synthesis of cholesterol, which in turn increases the synthesis of low-density lipoprotein receptors, thereby strengthening the receptor-mediated
  • This product also leads to the decomposition and elimination of low-density lipoprotein cholesterol.
  • This product also inhibits the synthesis of very low-density lipoprotein cholesterol and thus reduces the production of low-density lipoprotein cholesterol.
  • Acipimox is a synthetic nicotinic acid derivative, which can inhibit the decomposition of adipose tissue and reduce the release of free fatty acids from adipose tissue, thereby reducing the synthesis of triglycerides (TG) in the liver.
  • Synthesis of Very Low Density Lipoprotein (VLDL) and Low Density Lipoprotein (LDL) to Make Triglycerides (TG) in Serum And total cholesterol (TC) decreases.
  • VLDL Very Low Density Lipoprotein
  • LDL Low Density Lipoprotein
  • TC Serum And total cholesterol
  • This product can also inhibit liver lipase activity and reduce the breakdown of high density lipoprotein (HDD).
  • the drug is rapidly absorbed orally, and the blood concentration reaches a peak within 2 hours after the drug, and the half-life is 2 hours.
  • aximus may effectively treat hypertriglyceridemia (type IV), hypercholesterolemia (type Ila), and high triglyceride combined with high Cholesterolemia (lib type) is a safe, effective, and well-tolerated lipid-lowering drug.
  • the research trend in this field is to make two lipid-lowering drugs with different mechanisms of action into compound preparations, thereby making the lipid-lowering effect more comprehensive, and at the same time, it can play a synergistic effect, enhance the efficacy, and reduce toxic and side effects.
  • 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 pharmacological experimental data of the optimal ratio, nor did it involve the problem of combined use of pitavastatin and aximus.
  • Chinese patent application CN1425374A discloses aximustine and lovastatin composition, and the disclosed ratio is that the weight ratio of acyclomus and lovastatin is 25-50: 1, and the preferred ratio is 25: 1 or 37.5: 1 However, it did not involve the optimal ratio of aximolimus and pitavastatin compound and corresponding pharmacological experimental data. Summary of the invention
  • the purpose of the present invention is to provide a new pharmaceutical composition for treating hyperlipidemia, which composition contains the first active ingredient aximus and the second active ingredient pitavastatin or a pharmaceutically acceptable salt or ester thereof. Or solvate. Due to the different mechanism of action of the two drugs, the lipid-lowering effect is more comprehensive after the composition is composed, and the two drugs have a synergistic effect, and their lipid-lowering effect is obviously better than that of the same dose of the single prescription. In addition, by rationally selecting the amount of pitavastatin in the composition, the composition can effectively reduce blood lipid levels without significant toxic and side effects. At the same time, the composition only needs to be administered once a day, which is convenient for administration, which will greatly improve patients Medication compliance.
  • the present invention provides a composition for treating hyperlipidemia, the composition includes two active ingredients, the first active ingredient is aximus, the second active ingredient is pitavastatin, or Its pharmaceutically acceptable salts, esters or solvates.
  • Pitavastatin salt is a suitable physiologically acceptable salt of pitavastatin, including salts derived from inorganic and organic bases, which may be sodium, calcium, potassium, magnesium, zinc , Iron salt.
  • the pharmaceutically acceptable esters of pitavastatin are suitable physiologically acceptable esters of pitavastatin, including esters derived from fatty alcohols, aromatic alcohols, and heterocyclic alcohols, such as methyl esters, ethyl esters, and olefins. Propyl ester, phenyl ester.
  • pitavastatin calcium is used as an example to screen the weight ratio of two active ingredients, and acyclovir is obtained through experiments.
  • the weight ratio of sevastat and pitavastatin (based on the free acid, the same below) is 50 to 800: 1, the preferred ratio is 100 to 400: 1, and the more preferred ratio is 200: 1.
  • the dosage form of the pharmaceutical preparation of the composition of the present invention can be prepared according to general preparation methods known in the art, and the content of acyclomus is equivalent to that of the composition.
  • the daily dose is about 200 ⁇ 750mg
  • the content of pitavastatin salt is equivalent to the daily dose of 0.25 ⁇ 2 mg in terms of free acid.
  • Pitavastatin salts include alkali metal salts such as sodium salts and potassium salts, or alkaline earth metal salts such as magnesium and calcium, and sodium salts are preferred.
  • 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 pitavastatin salt is used.
  • sustained-release preparations such as sustained-release tablets, sustained-release capsules, etc.
  • 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; Youtech Qi-100 , RL100, RS30D, RL30D, NE30D, and Surelease (Surelease, 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, hydroxypropyl
  • 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 the application of an effective amount of acyclovir or pitavastatin alone, Surprisingly better results, while the toxicity has not increased, so the safe dosage range is large, the duration of the effect is long, the comprehensive effect is good, and the use is convenient.
  • the composition of the present invention can be administered 1 to 2 times a day, preferably once a day.
  • the composition of the present invention also exhibits better lipid-lowering activity when used in combination with acyclomus and pravastatin, and in combination with acyclomus and lovastatin.
  • pitavastatin can be any pharmaceutically acceptable salt, and can also be any pharmaceutically acceptable ester or solvate of pitavastatin.
  • Example 1 The content of the present invention is further described by the following examples, but the protection 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 protection scope of the present invention is not limited to the following examples.
  • Preparation process Axioximus is sieved through a 120-mesh sieve, the prescription amount is weighed, and poured into a lower hopper. ⁇ Granulation coating machine, inlet air pressure 0.5bar, inlet air temperature 30 ° C, spray gun pressure (CYL) 3bar, atomizing pressure (CAP1) O.Sbar, pour into blank pellet core, granulate, feed speed 4rpm The peristaltic pump is 12%, the speed of the turntable is 145rpm, and the 7% PVP solution is sprayed (the solvent is 90% ethanol). After granulation, dry at 50 ° C and discharge.
  • Preparation process Pass pitavastatin calcium through a 120-mesh sieve, weigh the prescription amount, and pour it into the lower hopper. Open the granulation coating machine, the inlet pressure is 0.5 1 ⁇ 1 ", the inlet temperature is 30 ° ⁇ , ⁇ ] 15 15 ⁇ 1] :, CAP1: 0.8 bar, pour into the blank pellet core, granulate, cut off The speed is 4 rpm, the peristaltic pump is 6%, the rotating speed of the rotary table is 160 rpm, and the 7% PVP solution (solvent is 90% ethanol) is sprayed. After the granulation is finished, it is dried at 45 ° C and discharged.
  • Preparation process Pitavastatin calcium is sieved through a 100-mesh sieve, hydroxypropyl cellulose and pregelatinized starch are sieved through an 80-mesh sieve, and a prescribed amount of pitavastatin calcium, hydroxypropyl cellulose, and pre-gelatinized starch are mixed uniformly.
  • An appropriate amount of 6% PVP absolute ethanol solution was added to granulate, dried at 60 ° C, and the dry granules were sieved with a 16-mesh sieve.
  • a prescribed amount of glyceryl behenate was added to the dry granules.
  • the two components of a and b are punched with a double-layer tablet machine to obtain a double-layer tablet.
  • Each tablet contains acyclomus and pitavastatin calcium (calculated as free acid) in amounts of 200 mg and 1 mg, respectively. .
  • 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 the ingredients evenly, add 6% PVP absolute 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 dry granules.
  • pitavastatin calcium 1.5g (based on pitavastatin free acid)
  • Glyceryl behenate 2g Preparation process: Pitavastatin calcium is sieved through a 100-mesh sieve, hydroxypropyl cellulose and pregelatinized starch are sieved through an 80-mesh sieve, and the prescribed amount of pitavastatin calcium, hydroxypropyl cellulose, and pregelatinized starch are mixed uniformly. Add 6% PVP anhydrous ethanol solution to granulate, dry at 60 ° C, sieve the dry granules with 16 mesh, and add the prescribed amount of glyceryl behenate to the dry granules. c. The two components of a and b are punched with a double-layer tablet machine to obtain a double-layer tablet. Each tablet contains acyclomus and pitavastatin calcium (calculated as free acid) in amounts of 200 mg and 1.5, respectively. mg.
  • Preparation process Aximolimus is passed through a 100-mesh sieve, lactose, sodium carboxymethyl starch, and microcrystalline cellulose are passed through an 80-mesh sieve, 'weigh out the prescribed amount of acyclovir and lactose, sodium carboxymethyl starch, and microcrystalline
  • the cellulose was mixed uniformly, granulated by adding a 6% PVP absolute ethanol solution, dried at 60 ° C, and sieved with 16 meshes to dry the granules. The dry granules were added with a prescribed amount of magnesium stearate.
  • Pitavastatin Calcium Calcium 2g (based on Pitavastatin free acid)
  • Preparation process Axioximus is passed through a 100-mesh sieve, hydroxypropyl cellulose-4M, microcrystalline cellulose is passed through an 80-mesh sieve, and a prescribed amount of aximus, hydroxypropyl cellulose-4M, and microcrystalline fiber are weighed. Mix the ingredients evenly, add 8% 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 magnesium stearate to the dry granules.
  • Preparation process Pitavastatin calcium is passed through a 100-mesh sieve, carboxymethylcellulose sodium and lactose are passed through an 80-mesh sieve, and a prescribed amount of pitavastatin calcium is mixed with sodium carboxymethylcellulose and lactose, and 6% PVP is added. An appropriate amount of 95% ethanol solution was granulated, dried at 60 ° C, and the dried granules were sieved with a 16-mesh sieve. A prescribed amount of magnesium stearate was added to the dried granules.
  • a and b are punched by a double-layer tablet machine to obtain a double-layer tablet.
  • Each tablet contains acyclomus and pitavastatin calcium (calculated as free acid) in amounts of 300 mg and 1 mg, respectively.
  • Preparation process Axioximus is sieved through a 120-mesh sieve, the prescription amount is weighed, and poured into a lower hopper. ⁇ Granulation coating machine, the inlet air pressure is 0.5 1 ⁇ , the inlet air temperature is 30 °. Ya 3 1 ⁇ , CAP1: 0.8 bar, pour into blank pellet core, granulate, feed speed 4ipm, peristaltic pump 12%, turntable speed 145 rpm, spray 7% PVP solution (solvent is 90% ethanol). After the granulation is finished, it is dried at 50 ⁇ and discharged.
  • Preparation process pour the aximus-containing pellets prepared in a into a turntable, open a granulating coating machine, the inlet pressure is 1.0 bar, the inlet temperature is 30 ° C, CYL: 3bar, CAPl: 1.5bar, peristaltic pump 5%, turntable rotating at 180 rpm, sprayed into Surelease's pure aqueous solution. After coating, dry at 50 ° C and discharge.
  • 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 0.5bar, inlet air temperature 30 ° C, CYL: 3bar, CAPl: 0.8bar, pour into blank pellet core, granulate, feed speed 4rpm, peristaltic pump 12%, rotary table speed Spray 7% PVP solution (solvent is 90% ethanol) at 145 rpm. 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 0.5bar, inlet air temperature 30 ° C, CYL: 3bar, CAPl: l.Obar, peristaltic pump 6%, rotary table speed 175 rpm, spray into B 95% ethanol solution of cellulose, stearic acid and polyethylene glycol-6000. After coating, dry at 50 ° C and discharge.
  • Preparation process Pitavastatin calcium is sieved through a 120 mesh sieve, the prescription amount is weighed, poured into the lower hopper, a granulating coating machine is operated, and the inlet pressure is 0.5 1) 01 ', and the inlet temperature is 301 ° C. Ah] ⁇ 3 1331, CAP1: 0.8 bar, pour into blank pill core 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 granulation, drying at 45 ° C, discharging.
  • Preparation process Axioximus 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. Add 6 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.
  • Preparation process Pitavastatin calcium is passed through a 100-mesh sieve, pregelatinized starch, mannitol, and lactose are passed through an 80-mesh sieve.
  • the prescribed amount of pitavastatin calcium and pregelatinized starch, mannitol, and lactose are mixed uniformly.
  • the appropriate amount of 95% ethanol solution of% PVP was granulated, dried at 60 ° C, and the dry granules were sieved with 16 mesh. The dry granules were added with the prescribed amount of magnesium stearate.
  • Preparation process Axioximus is passed through a 100-mesh sieve, lactose and hydroxypropyl methylcellulose-15M are passed through an 80-mesh sieve, and a prescribed amount of aximus is mixed with lactose and hydroxypropylmethylcellulose-15M. Evenly, add 8% PVP in a 95% 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.
  • pitavastatin calcium lg (based on pitavastatin free acid)
  • Preparation process Pitavastatin calcium is passed through a 100-mesh sieve, hydroxypropyl cellulose and dextrin are passed through an 80-mesh sieve, and a prescribed amount of pitavastatin calcium is mixed with hydroxypropyl cellulose and dextrin.
  • PVP's 95% ethanol solution was granulated in an appropriate amount, dried at 60 ° C, and dried with a 16-mesh sieve. The dry granules were added with a prescribed amount of talc.
  • the purpose of this test is to determine the composition of acyclovir and pitavastatin calcium compound preparations with low toxicity, strong effects, and easy use by screening.
  • a hyperlipidemia model was induced in a high-fat corpus, and model rats were continuously infused with acyclovir (100 ⁇ 400mg / kg) and / or pitavastatin calcium (0.25 ⁇ 2mg / kg, with free acid The following doses of pitavastatin calcium are calculated based on pitavastatin free acid) for 14 days.
  • the results showed that acyclovir and pitavastatin calcium have a significant therapeutic effect on hyperlipidemia in rats caused by high-fat words, and the lipid-lowering effect is related to the dose of the two drugs.
  • Aximus 200 Compounds containing ⁇ 400mg / kg and pitavastatin calcium 0.5 ⁇ 2 mg / kg can reduce total serum cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) in rats to varying degrees. , Elevated high-density lipoprotein bile Sterol level (HDL-C). Among them, the combination of acyclovir 300mg / kg and pitavastatin calcium 1.5mg / kg had the most significant effect, showing synergistic effects on TC and LDL-C levels, and alanine amino groups in the serum of hyperlipidemia model rats.
  • TC total serum cholesterol
  • TG triglycerides
  • LDL-C low-density lipoprotein cholesterol
  • HDL-C Elevated high-density lipoprotein bile Sterol level
  • the effects of the levels of transferase and creatine kinase are small, and a compound consisting of 300 mg / kg of aximolimus and 1.5 mg / kg of pitavastatin calcium is preferred. Within the experimental dose range, the combination drug group had no significant effect on serum enzyme activity related to liver and muscle breadth.
  • composition of acyclomus and pitavastatin calcium compound preparations was determined through screening, so as to achieve the purposes of low toxicity, comprehensive and enhanced effects, and convenient use of the compound preparations.
  • Preparation method Mix with 1% sodium carboxymethyl cellulose (CMC) just before use to make up the required concentration for the test.
  • CMC carboxymethyl cellulose
  • Wistar rats are bred by the Medical Experimental Animal Center of the Academy of Military Medical Sciences. The quality permit number of experimental animals is D01-3039. 3.2 Weight and gender
  • the animal laboratory air is regularly ventilated, the light is good, and the room temperature is normal.
  • Five animals were kept in each cage, and they were fed with puffed words specially prepared for rats in the experimental animal center of the hospital, and they were free to drink water.
  • the animal test condition certificate number is D01-2051. Before the test, observe the animals' food, activities, and feces for 1 week, and select healthy animals to enter the test.
  • the rat model of hyperlipidemia uses hyperlipidemia induced by hyperlipidemia.
  • the high-fat serving formula is as follows: basic feed 86.3%, cholesterol 3%, lard 10%, methylthiouracil 0.2%, and pig bile salt 0.5%, to ensure that the ingredients are evenly mixed. 2 consecutive weeks. High-fat feed was given at intervals of the administration period.
  • the dose of acyclovir is 250 mg / time (calculated based on a human body weight of 60 kg, the above dose is 4.2 mg / kg), 2 to 3 times / day, and the daily maximum amount does not exceed 1200 mg [3] .
  • the above commonly used human dose is converted into a rat dose of about 50 mg / kg / day.
  • the dose of acyclovir in this test was set to 100, 200, 300, 400 mg / kg.
  • the dose of pitavastatin calcium is 1-2 mg / time, calculated based on a human body weight of 60 kg.
  • the above dose is 0.165-0.33 mg / kg, once per day, and the maximum daily dose does not exceed 4 mg.
  • the above commonly used doses in humans were converted into rat doses of approximately 0.0425 mg / kg.
  • References reported that the dose of pitavastatin calcium in this trial was set to 0.25, 0.5, 1, 1.5, 2 mg / kg.
  • normal animals were randomly divided into: (1) normal control group; (2) acyclovir 100 mg / kg group; (3) aximus 200 mg / kg group ; (4) acyclomus 300mg / kg group; (5) acyclomus 400mg / kg group; (6) pitavastatin calcium 0.25mg / kg group; (7) pitavastatin calcium 0.5mg / kg group (8) Pitavastatin calcium 1mg / kg group; (9) Pitavastatin calcium 1.5mg / kg group; (10) Pitavastatin calcium 2mg / kg group; (11) Aximus 200mg / kg and Pita Vastatin calcium 0.5mg / kg group; (12) acyclomus 200 mg / kg and pitavastatin calcium 1 mg / kg group; (13) acyclomus 200 mg / kg and pitavastatin calcium 1.5 mg / kg group; (14) acyclomus 200 mg / kg and pitavastatin calcium 1.5 mg / kg group; (14) acyclomus 200
  • the clinical route of administration is oral. Therefore, this test 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.
  • 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 Company and determined by SABA / 18 automatic biochemical analyzer. Measured with Hitachi 7020 automatic biochemical analyzer. For the determination method, refer to the reagent instructions. Fast for 16 hours before taking blood samples.
  • the model rats were randomly divided into: (1) normal control group; (2) model control group; (3) aximus 100mg / kg group; (4) Aximus 200mg / kg group;
  • acyclomus 300mg / kg group (6) acyclomus 400mg / kg group; (7) pitavastatin calcium 0.25mg / kg group; (8) pitavastatin calcium 0.5mg / kg group; (9) pitavastatin calcium 1mg / kg group; (10) pitavastatin calcium 1.5mg / kg group; (11) pitavastatin calcium 2mg / kg group; (12) aximus 200mg / kg and pitava Statin calcium 0.5mg / kg group;
  • the clinical route of administration is oral. Therefore, in this test, the drug was administered by gavage for 14 days. Gavage was performed after the animals had eaten. Once a day. The administration volume was 0.3 ml / 100 g body weight.
  • acyclomus and pitavastatin calcium compound determines the dose of acyclomus and pitavastatin calcium compound: (1) a normal control group; (2) a model control group; (3) a Ximolimus 300mg / kg; (4) Pitavastatin calcium 1.5mg / kg; (5) Aximolimus 300mg / kg and Pitavastatin calcium 1.5mg / kg compound group.
  • the serum total cholesterol levels were measured before grouping, and randomized according to the principle of equilibrium. There are 10 animals in each group.
  • Rats were fed with high-fat ingredients in 14 days.
  • the dosage range of acyclovir is 100 ⁇ 400mg / kg, and the dosage range of pitavastatin calcium is 0.25 ⁇ 2mg / kg.
  • the total cholesterol, triglyceride, and low-density lipoprotein cholesterol in the various dose groups of acyclovir and pitavastatin calcium decreased to varying degrees, and the high-density lipoprotein cholesterol levels Increased.
  • Aximolimus and pitavastatin 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 compound with pitavastatin calcium 0.5 ⁇ 2 mg / kg can reduce total serum cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in rats to varying degrees. Density lipoprotein cholesterol level (HDL-C).
  • acyclovir 300 mg / kg and pitavastatin calcium 1.5 mg / kg had the most significant effect, showing synergistic effects on TC and LDL-C levels, and alanine amino groups in serum of model rats with blood lipids.
  • the effects of transferase and creatine kinase levels are small, and a compound consisting of 300 mg / kg of aximolimus and 1.5 mg / kg of pitavastatin calcium is preferred.
  • the combined drug group had no significant effect on serum enzyme activity related to liver and muscle toxicity.
  • the current clinical use of acyclovir is 3 times / day, and this experiment proves that aximus once / day still has significant hypolipidemic effect and low toxicity. This is aximus and piva
  • the statin calcium composition is only used once a day after the compound provides a reliable experimental basis, which will definitely It is greatly convenient for patients to take, and improves the compliance of patients.
  • test drug, animal and rat hyperlipidemia model were prepared as in Example 9.
  • model rats were randomly divided into-normal control group;
  • TC Serum total cholesterol
  • TG triglycerides
  • LDL-C low density lipoprotein cholesterol
  • HDL-L high density lipoprotein cholesterol
  • Rats were fed with high fat for 14 days. After 14 days of administration, each dose group of aximusprivastatin calcium reduced total serum cholesterol, serum triglycerides, and low-density lipoprotein cholesterol with acyclomus 300mg / kg pravastatin 20mg / kg group. Compared with the 300 mg / k g lovastatin 10 mg / kg group, there is a significant difference; it also has a clear advantage in raising high-density lipoprotein cholesterol. Our test results fully prove that the combined use of acyclovir and pitavastatin has an unexpected effect in lowering blood lipids.
  • Axioximus and pitavastatin have not only achieved significant synergistic effects, but also disclosed with the prior art
  • the combined use of acyclovir and lovastatin, and acyclovir and pravastatin have more advantages.
  • the specific results are shown in Table 4.

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Abstract

L'invention concerne une composition anti-hyperlipémie, contenant de l'Acipimox et de la pitavastatine, ou leurs sels, leurs esters ou leurs solvates. La proportion en poids est de (50-800) :1, de préférence (100-400) :1, en particulier 200 :1. L'Acipimox peut être utilisé en association avec la pitavastatine en action synergique, l'effet de l'anti-hyperlipémie est plus approprié que l'association de l'Acipimox et de l'ovastatine L.
PCT/CN2005/000728 2004-05-25 2005-05-25 Composition anti-hyperlipemie WO2005115393A1 (fr)

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CN200580007179.2A CN1929843A (zh) 2004-05-25 2005-05-25 治疗高血脂症的组合物

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CN200410024204.5 2004-05-25
CN200410024204 2004-05-25

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WO2005115393A1 true WO2005115393A1 (fr) 2005-12-08

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1425374A (zh) * 2003-01-20 2003-06-25 鲁南制药股份有限公司 治疗高血脂症的组合物
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
CN1485037A (zh) * 2002-09-29 2004-03-31 中国人民解放军军事医学科学院附属医 含烟酸和他汀类药物的药物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1485037A (zh) * 2002-09-29 2004-03-31 中国人民解放军军事医学科学院附属医 含烟酸和他汀类药物的药物
CN1425374A (zh) * 2003-01-20 2003-06-25 鲁南制药股份有限公司 治疗高血脂症的组合物
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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