WO2005105095A1 - Combinaison pour le traitement de l'hyperlipidemie - Google Patents

Combinaison pour le traitement de l'hyperlipidemie Download PDF

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Publication number
WO2005105095A1
WO2005105095A1 PCT/CN2005/000608 CN2005000608W WO2005105095A1 WO 2005105095 A1 WO2005105095 A1 WO 2005105095A1 CN 2005000608 W CN2005000608 W CN 2005000608W WO 2005105095 A1 WO2005105095 A1 WO 2005105095A1
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Prior art keywords
atorvastatin calcium
atorvastatin
group
acyclovir
acyclomus
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PCT/CN2005/000608
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English (en)
French (fr)
Inventor
Zhiquan Zhao
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Lunan Pharmaceutical Group Corporation
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Application filed by Lunan Pharmaceutical Group Corporation filed Critical Lunan Pharmaceutical Group Corporation
Priority to JP2007509858A priority Critical patent/JP4741581B2/ja
Priority to US11/587,845 priority patent/US20080207643A1/en
Priority to EP05752335A priority patent/EP1741431B1/en
Publication of WO2005105095A1 publication Critical patent/WO2005105095A1/zh

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a novel composition for treating hyperlipidemia, which contains the first active ingredient aximus
  • Atorvastatin and the second active ingredient Atorvastatin or a pharmaceutically acceptable salt, ester or solvate thereof.
  • statins have been well-received 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.
  • Atorvastatin is a third-generation statin lipid-lowering drug. It is a fully-synthesized glutaryl coenzyme A (HMG-CoA) reductase inhibitor. It was first marketed in the United States as a calcium salt in 1995. . Its chemical name is: R- CR ', R')] -2- (4-fluorophenyl)- ⁇ ⁇ -dihydroxy-5-(1-methylethyl)-3-phenyl-4- [ (Aniline) carbonyl] -1-Hydrro-pyrrole-1-heptanoic acid calcium trihydrate. Structural formula-
  • atorvastatin refers to the above-mentioned calcium salt trihydrate, or atorvastatin calcium, and its dosage / specification is generally based on atorvastatin free acid.
  • China Medical Guide Network www.daoyi.com/drug/html/200009/6000000189670.html
  • HMG-CoA reductase is a rate-limiting enzyme in the cholesterol synthase system, and by inhibiting it, the cholesterol synthesis is reduced.
  • Atorvastatin is the same as pravastatin and has biological activity after oral absorption, while lovastatin and simvastatin are prodrugs and need to be metabolized in vivo to have biological activity. Atorvastatin therefore works faster than lovastatin and simvastatin. This medicine has a stronger inhibitory effect on HMG-CoA reductase than other similar drugs.
  • the 50% inhibitory concentration (IC50) of atorvastatin on HMG-CoA reductase inhibition was 73 nmoLU 1 and 2650 for pravastatin .
  • Atorvastatin 80 mg / d, pravastatin 40 mg / d, and simvastatin 40 mg / d reduced plasma methylvaleric acid (MVA) concentrations by 59%, 32%, and 49%, respectively.
  • a single dose of atorvastatin has a longer duration of HMG-CoA reductase inhibition than other similar drugs.
  • LDL low-density lipoprotein
  • Atorvastatin inhibits HMG-CoA reductase by reducing the cholesterol concentration in plasma and tissue cells, which can stimulate the increase of LDL receptor density in the liver, thereby making plasma low density lipoprotein cholesterol (LDL-C) Clear enhancement.
  • the liver LDL receptor can bind to very low density lipoprotein (VLDL), which increases the degradation of VLDL, which reduces the triglyceride (TG) concentration.
  • VLDL very low density lipoprotein
  • VLDL-C very low density lipoprotein cholesterol
  • Atorvastatin is beneficial for delaying atherosclerotic lesions by lowering blood lipids, reducing lipid infiltration and alveolar cell formation. This medicine can still prevent atherosclerotic plaque rupture.
  • atorvastatin can inhibit vascular smooth muscle proliferation and migration. Animal experiments show that 2.5 mg / kg of the drug can reduce atherosclerotic plaque area in rabbits by 67% (P ⁇ 0.05), but the same dose of lovastatin, pravastatin, and simvastatin have no such effect; It also has the effects of inhibiting platelet activation, reducing blood viscosity, and inhibiting coagulation.
  • Atorvastatin is generally well tolerated, most of the adverse reactions are mild, and patients are better tolerated than lovastatin.
  • Acipimox is a synthetic nicotinic acid derivative that 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.
  • Inhibition of the synthesis of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) reduced the concentrations of triglyceride (TG) and total cholesterol (TC) in serum.
  • VLDL very low-density lipoprotein
  • LDL low-density lipoprotein
  • This product also inhibits liver lipase activity and reduces 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.
  • acyclovir can effectively treat hypertriglyceridemia (type IV), ⁇ cholesterolemia (type Ila), and high triglycerides combined with high cholesterol Anemia (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, so that the lipid-lowering effect is more comprehensive, and at the same time, it can play a synergistic effect, enhance efficacy, and reduce toxic and side effects.
  • U.S. Patent No. 5,260,305A discloses a combination of HMG-CoA reductase inhibitor pravastatin and nicotinic acid and derivatives thereof, 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 best ratio.
  • Chinese patent application CN1425374A discloses aximuslim and lovastatin composition, and the disclosed ratio is that the weight ratio of aximuslim and lovastatin is 25-50: 1, and the preferred ratio is 25: 1 or 37.5: 1 However, it did not cover the optimal ratio of acoximus and atorvastatin compound and corresponding pharmacological experimental data. Summary of the invention
  • the object of the present invention is to provide a new pharmaceutical composition for treating hyperlipidemia, which composition contains the first active ingredient Acipimox and the second active ingredient Atorvastatin or its Medicinal salts, esters or solvates. Due to the different mechanism of action of acyclovir and atorvastatin, the lipid-lowering effect is more comprehensive after the composition is composed, 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 prescription. In addition, by rationally selecting the amount of atorvastatin in the composition, the composition can effectively reduce blood lipid levels without significant toxic and side effects.
  • composition of the present invention only needs to be administered once a day, which is convenient for administration, which will greatly improve Patient compliance.
  • acyclovir and atorvastatin reduced the total serum cholesterol and serum glycerol.
  • the lipid-lowering effect is more significant when compared with the combined use of acyclovir and pravastatin
  • compositions of the present invention is composed of acyclomus and atorvastatin calcium and pharmaceutical excipients, wherein the weight ratio of acyclomus and atorvastatin calcium (based on free acid, the same below) is 10 ⁇ 80: 1, the preferred ratio is 10-30: 1, and a further preferred ratio is 30: 1.
  • the dosage form of the pharmaceutical preparation of the composition including solid preparations such as tablets, capsules, granules, pills, and dripping pills, can be prepared according to general preparation methods known in the art, and the content of aximus is equivalent to that when the composition is administered.
  • the atorvastatin calcium content is equivalent to a daily dose of 5 to 80 mg, of which the daily dose of atorvastatin calcium content is equivalent to 10 to 30 mg.
  • 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 atorvastatin 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; Utopic RS-100 , RL100, RS30D, RL30D, NE30D, and Surelease (Surelease, aqueous dispersion of ethyl cellulose) adhesives, such as polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, lubricants, such as magnesium stearate, talc Powder, micronized silica gel, etc.
  • disintegrants such as sodium carboxymethyl starch, hydroxypropyl star
  • 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 effective amount of acyclovir or atorvastatin alone, It showed a surprisingly better effect without increasing toxicity, so the safe dosage range was large, the duration of the effect was long, the comprehensive effect was good, and the use was convenient.
  • the composition of the present invention can be administered 1-2 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.
  • atorvastatin in the present invention may be any pharmaceutically acceptable salt, that is, a suitable atorvastatin physiologically acceptable salt, including salts formed from inorganic and organic bases, which are sodium salts, Calcium, potassium, magnesium, zinc, iron; or any pharmaceutically acceptable ester of atorvastatin, that is, a suitable physiologically acceptable ester of atorvastatin, including derivatives derived from fatty alcohols,
  • the esters formed by aromatic alcohols and heterocyclic alcohols are methyl esters, ethyl esters, allyl esters, and phenyl esters.
  • Example 1 The following examples further illustrate the composition of the present invention, a preparation method thereof, and a therapeutic effect, but the protection scope of the present invention is not limited to the examples.
  • Example 1 The following examples further illustrate the composition of the present invention, a preparation method thereof, and a therapeutic effect, but the protection scope of the present invention is not limited to the examples.
  • 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, spray gun pressure (CYL) 3bar, atomization pressure (CAP1) 0.8bar, pour into blank pellet core, granulate, feed speed 4rpm, The pump is 12%, the rotating 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.
  • Atorvastatin calcium 5g (calculated as free acid)
  • Preparation process Atorvastatin 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, CYL: 3 bar, CAP1: 0.8 bar, pour into blank pellet core, granulate, feed speed 4rpm, peristaltic pump 6%, turntable Rotate at 160 rpm and spray a 7% P VP solution (solvent is 90% ethanol). After granulation, drying at 45 ° C, discharging.
  • Preparation process Aximolimus 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 acyclovir and lactose, sodium carboxymethyl starch, and microcrystalline fiber are weighed. Mix the ingredients evenly, add 6% PVP anhydrous ethanol solution to granulate, 6 (TC 1000 dry, 16 mesh sieve to dry the granules, and add the prescribed amount of magnesium stearate to the dry granules.
  • Atorvastatin 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 atorvastatin calcium is mixed with hydroxypropyl cellulose and pregelatinized starch. Hook evenly, add 6% PVP anhydrous ethanol solution to granulate, dry at 60 ° C, sieve the dry granules with a 16 mesh sieve, add the prescribed amount of behenyl glycerol c to the dry granules, and mix the above two components a and b.
  • a double-layer tablet was punched to obtain a double-layer tablet. Each tablet contained acyclomus and atorvastatin calcium (calculated as free acid) and weighed 200 mg and 10 mg, respectively.
  • Preparation process Aximolimus 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 acyclovir and lactose, sodium carboxymethyl starch, and microcrystalline fiber are weighed. Mix the ingredients 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 magnesium stearate to the dry granules.
  • Atorvastatin calcium 20g (calculated as free acid)
  • Atorvastatin 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 atorvastatin 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.
  • the two components a and b above are punched with a double-layer tablet machine to obtain a double-layer tablet. Each tablet contains acyclomus and atorvastatin calcium (calculated as free acid). The weight is 200mg. And 20mg.
  • Preparation process Axioximus sieved through a 100-mesh sieve, hydroxypropyl cellulose-4M, microcrystalline cellulose sieved through an 80-mesh sieve, and a prescribed amount of acyclomus and hydroxypropyl cellulose-4M, microcrystalline fiber were weighed. Mix the ingredients uniformly, add 8% PVP absolute ethanol solution to granulate, dry at 60 ⁇ , sieve 16 meshes to dry the granules, and add the prescribed amount of magnesium stearate to the dry granules.
  • Atorvastatin calcium is passed through a 100-mesh sieve, carboxymethylcellulose sodium and lactose are passed through an 80-mesh sieve, and the prescribed amount of atorvastatin calcium is mixed with sodium carboxymethylcellulose and lactose.
  • the appropriate amount of 95% ethanol solution of% PVP was granulated, dried at 60 ° C, and the dry granules were sieved with a 16 mesh sieve. The dry granules were added with a prescribed amount of stearic acid.
  • Preparation process Axioximus is sieved through a 120-mesh sieve, the prescription is weighed, and poured into a lower hopper.
  • Granulation coating machine inlet pressure 0.5 bar, inlet temperature 30 ° C, CYL: 3 bar, CAP1: 0.8 bar, pour into blank pellet core, make Pellets, feeding speed 4rpm, 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 C and discharged.
  • Preparation process Pour the aximolimus-containing pellets prepared in a into a turntable, open a granulating coating machine, the air pressure is 1.0 bar, the air temperature is 30 ° C, CYL: 3bar, CAP1: 1.5bar, worm Pump 5%, turntable 180 rpm, spray into Surelease's pure aqueous solution. After coating, dry at 50 ° C and discharge.
  • Atorvastatin calcium pellets were prepared in accordance with the requirements of b in Example 1, and the aximostat pellets prepared in this example b were filled with a hard capsule drug filling machine according to each two capsules containing aximus and A Filling of atorvastatin calcium (calculated as free acid) is 300mg and 10mg respectively.
  • Preparation process Axioximus is sieved through a 120-mesh sieve, the prescription is weighed, and poured into a lower hopper. Open granulation coating machine, inlet air pressure 0.5bar, inlet air temperature 30 ° C, CYL: 3bar, CAP1: 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, 5CTC is dried and discharged.
  • Preparation process Pellets containing acyclomus prepared in a are poured into a lower hopper. Open granulation coating machine, inlet air temperature 30 ° C, inlet air pressure 0.5bar, inlet air temperature 30 ° C, CYL: 3bar, CAP1: l.Obar, peristaltic pump 6%, The turntable was rotated at 175 rpm, and a 95% ethanol solution of ethyl cellulose, stearic acid, and polyethylene glycol-6000 was sprayed. After coating, dry at 50 ° C and discharge.
  • Atorvastatin calcium 5g (calculated as free acid)
  • Atorvastatin calcium is sieved through a 120-mesh sieve, the prescription amount is weighed, poured into the lower hopper, and the granulation coating machine is operated.
  • the inlet air pressure is 0.5 bar
  • the inlet air temperature is 30 ° C
  • CYL 3 bar
  • CAP1 0.8 bar
  • Feeding speed is 4 rpm
  • peristaltic pump is 12%
  • turntable speed is 120 rpm
  • 7% PVP solution is sprayed (solvent is 90% ethanol). After granulation, drying at 45 ° C, discharging.
  • 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 is mixed with mannitol, lactose, and microcrystalline cellulose.
  • 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.
  • Atorvastatin Calcium 5g (as free acid)
  • Atorvastatin calcium is passed through a 100-mesh sieve, pregelatinized starch, mannitol, and lactose are passed through an 80-mesh sieve. Take the prescribed amount of atorvastatin calcium and pregelatinized starch, mannitol and lactose, mix well, add 6% PVP in 95% ethanol solution to granulate, dry at 60 ° C, sieve 16 meshes to dry the granules, and dry granules Add the prescribed amount of magnesium stearate. c. The two components a and b are punched by a double-layer tablet machine to obtain a double-layer tablet. Each tablet contains aximus and atorvastatin calcium (calculated as free acid). The weight is 400mg and 5mg, respectively. .
  • 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. Homogeneously hook, add 8% PVP in 95% 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.
  • Atorvastatin calcium 10g (based on free acid)
  • Atorvastatin calcium is passed through a 100-mesh sieve, hydroxypropyl cellulose and dextrin are passed through an 80-mesh sieve, and a prescribed amount of atorvastatin calcium is mixed with hydroxypropyl cellulose and dextrin.
  • the two components a and b are punched by a double-layer tablet machine to obtain a double-layer tablet.
  • Each tablet contains acyclomus and atorvastatin calcium (calculated as free acid). The weight is 400mg and 10mg respectively. .
  • the purpose of this test is to determine the composition of acyclovir and atorvastatin calcium compound preparations with low toxicity, strong effect, and convenient use by screening.
  • the hyperlipidemia model of rats was induced by high-fat diet, and model rats were continuously infused with acyclovir (100 ⁇ 400mg / kg) and / or atorvastatin calcium (2.5 ⁇ 30mg / kg, with free acid Plan, the following Dose was calculated based on atorvastatin free acid) for 14 days. It was found that acyclovir and atorvastatin 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.
  • the combination of acyclovir 300 mg / kg and atorvastatin calcium 10 mg / kg has the most significant effect, and a compound consisting of 300 mg / kg and atorvastatin calcium 10 mg / kg is preferred.
  • the combined drug group had no significant effect on serum enzyme activity related to liver and muscle toxicity.
  • composition of acyclomus and atorvastatin calcium compound preparation was determined through screening to achieve the purpose of low toxicity, comprehensive effect and enhanced convenience of the compound preparation.
  • Production unit Lunan Pharmaceutical Co., Ltd. Preparation method: Before use, mix with 1% sodium carboxymethyl cellulose (CMC) to prepare the concentration required for the test.
  • CMC carboxymethyl cellulose
  • Production unit Homemade by Shandong New Times Pharmaceutical Co., Ltd.
  • Preparation method Mix with 1% CMC just before use to prepare the concentration required for the test.
  • 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 word D01-3039.
  • the rat model of hyperlipidemia uses hyperlipidemia induced by hyperlipidemia.
  • the formula of high-fat feed is as follows: basic feed 86.3%, cholesterol 3%, lard 10%, methylthiouracil 0.2%, and pig bile salt 0.5%. 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 the human body weight of 60 kg, the above dose is 4.2 mg / kg), 2 to 3 times / day, and the maximum daily dose does not exceed 1200 mg ra .
  • the above commonly used human dose is converted into a rat dose of about 50 mg / kg / day.
  • the dose of acyclovir in this trial was set to 100, 200, 300, 400 mg / kgo
  • the atorvastatin calcium dose is 10 mg / time (calculated based on human body weight of 60 kg, the above dose is 0.17 mg / kg), once a day, and the maximum daily dose does not exceed 80 mg [4] .
  • the above-mentioned common human dose is converted into a rat dose of about 0.85 mg / kg.
  • the dose of atorvastatin calcium in this trial was set to 2.5, 5, 10, 20, 30 mg / kg.
  • normal animals were randomly divided into: (1) a normal control group; (2) acyclomus 100 mg / kg group; (3) aximus 200 mg / kg group (4) Acyclovir 300mg / kg group; (5) Acyclomus 400mg / kg group; (6) Atorvastatin calcium 2.5mg / kg group; (7) Atorvastatin calcium 5mg / kg Group; (8) atorvastatin calcium 10mg / kg group; (9) atorvastatin calcium 20mg / kg group; (10) atorvastatin calcium 30mg / kg group; (11) acyclovir 200mg / kg kg and atorvastatin calcium 5mg / kg group; (12) Aximus 200mg / kg and Atorvastatin calcium 10mg / kg group; (13) Aximus 200mg / kg and Atorvastatin calcium 20 mg / kg group; (14) Aximus Group 300
  • 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 Co., Ltd. and determined by SABA / 18 automatic biochemical analyzer; the remaining reagents were produced by Japan Roche Reagent Co., Ltd. , Using Hitachi 7020 automatic biochemical analyzer. For the determination method, refer to the reagent instructions. Fast for 16 hours before taking blood samples. 6 Effect of acyclomus and atorvastatin calcium on blood lipid levels in hyperlipidemia rats
  • the model rats were randomly divided into: (1) normal control group; (2) model control group; (3) aximus 100mg / kg group; (4) Acyclomus 200mg / kg group; (5) Aximus 300mg / kg group; (6) Aximus 400mg / kg group; (7) Atorvastatin calcium 2.5mg / kg group; (8) Atorvastatin calcium 5mg / kg group; (9) Atorvastatin calcium 10mg / kg group; (10) Atorvastatin calcium 20mg / kg group; (11) Atorvastatin calcium 30mg / kg group; ( 12) Acyclomus 200mg / kg and Atorvastatin calcium 5mg / kg group; (13) Aximus 200mg / kg and Atorvastatin calcium 10mg / kg group; (14) Aximus 200mg / kg / kg and atorvastatin calcium 20 mg / kg group; (15) acyclovir 300 mg / kg group;
  • the clinical route of administration is oral. Therefore, in this test, gastric administration was used 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.
  • acyclomus and atorvastatin calcium compound determines the dose of acyclomus and atorvastatin calcium compound: (1) the normal control group; (2) the model control group; (3 ) Acyclovir 200mg / kg ; (4) Acyclomus 300mg / kg; (5) Atorvastatin calcium 10mg / kg ; (6) Atorvastatin calcium 20mg / kg; (7) Acyclovir 200mg / kg and atorvastatin calcium 10mg / kg group; (8) aximus 200mg / kg and atorvastatin calcium 20mg / kg group; (9) aximus 300mg / kg And atorvastatin calcium 10mg / k g group.
  • Rats were fed with high-fat diets in groups of 14 days.
  • the dose range of acyclovir is 100 ⁇ 400mg / kg, and the dose range of atorvastatin calcium is 2.5 30mg / kg.
  • the total cholesterol, triglyceride, and low-density lipoprotein cholesterol in the various dose groups of acyclovir and atorvastatin calcium decreased to varying degrees, and the high-density lipoprotein cholesterol levels Have increased, see Table 2
  • acyclomus 200 mg / kg and atorvastatin calcium 10 mg / kg Compared with the model control group, acyclomus 200 mg / kg and atorvastatin calcium 10 mg / kg, acyclovir 200 mg / kg and atorvastatin calcium 20 mg / kg, and acyclovir 300 mg / kg and a
  • the levels of serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol in the three combination groups of atorvastatin calcium 10mg / kg significantly decreased, and the levels of high-density lipoprotein cholesterol increased significantly.
  • the combination group of acyclovir and atorvastatin calcium can significantly reduce the total cholesterol, triglyceride, and low density in the serum of model rats. Lipoprotein cholesterol levels and significantly higher HDL cholesterol levels are shown in Table 4.
  • acyclovir 200mg / kg and atorvastatin calcium 10mg / kg compared with the model control group, acyclovir 200mg / kg and atorvastatin calcium 10mg / kg, acyclovir 200mg / kg and atorvastatin calcium 20mg / kg, and acyclomus 300mg / kg
  • the combination of kg and atorvastatin calcium 10 mg / kg has a significant effect, which can significantly reduce the levels of total serum cholesterol, triglycerides, and low-density lipoprotein cholesterol in rats, and significantly increase high-density lipoprotein cholesterol levels.
  • acyclomus or atorvastatin calcium single group Compared with the same dose of acyclomus or atorvastatin calcium single group, the levels of serum total cholesterol, triglyceride, and low-density lipoprotein cholesterol were significantly reduced in the three combined drug groups, and the levels of high-density lipoprotein cholesterol were significantly reduced. Increased, the three combined drug groups showed a synergistic effect on the above indicators. Among them, the combination of acyclovir 300 mg / kg and atorvastatin calcium 10 mg kg has the most significant effect. Therefore, a compound consisting of 300 mg / kg and atorvastatin calcium 10 mg / kg is preferred. Table 4 Effect of different components of aximus and atorvastatin calcium on hyperlipidemia in rats Total serum cholesterol Triglyceride Low density lipoprotein cholesterol High density lipoprotein cholesterol group
  • Acyclovir and atorvastatin calcium have a significant effect on the treatment of hyperlipidemia in rats caused by hyperlipidemia.
  • the lipid-lowering effect is related to the dose of the two drugs.
  • Atorvastatin calcium 10mg / kg Acyclomus 200mg / kg and Atorvastatin 20mg / kg and Acyclomus 300mg / kg and Atorvastatin 10mg / kg
  • the combination group has a significant effect, which can significantly reduce Rat serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels significantly increased high-density lipoprotein cholesterol levels, and showed synergistic effects on the above indicators.
  • acyclovir 300 mg / kg and atorvastatin calcium calcium 10 mg / kg has the most significant effect, and a compound consisting of 300 mg / kg and atorvastatin calcium 10 mg / kg is preferred.
  • the combined drug group had no significant effect on serum enzyme activity, and it was initially shown that it had no significant toxic effect on liver and striated muscle.
  • the current single-clinical usage of acyclovir is 3 times / day, and this experiment proves that acyclomus once / day still has significant hypolipidemic effect and low toxicity. This is aximus and ator Vastatin calcium is a compound that provides a reliable experimental basis only once a day after administration. This will greatly facilitate the patient's taking and improve patient compliance.
  • test drug, animal and rat hyperlipidemia model were prepared as in Example 9.
  • model rats are randomly divided into:
  • TC Serum total cholesterol
  • TG triglycerides
  • LDL-C low density lipoprotein cholesterol
  • HDL-L high density lipoprotein cholesterol
  • Rats were fed with high-fat diets in groups of 14 days. After 14 days of administration, each dose group of acyclovir atorvastatin calcium reduced serum total cholesterol, serum triglycerides, and low-density lipoprotein cholesterol with acyclomus 300 mg / kg pravastatin 20 mg / kg group, Compared with the acyclomus 300 mg / kg lovastatin 10 mg / kg group, there are significant differences; in terms of raising high-density lipoprotein cholesterol, there are also obvious advantages. Our trial The test results fully prove that the combined use of acyclovir and atorvastatin has an unexpected effect in lowering blood lipids.
  • Aximustor and atorvastatin 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 5.

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Description

治疗高血脂症的组合物 技术领域
本发明涉及一种新的治疗高血脂症的组合物， 其含有第一活性成分阿昔莫司
(Acipimox)和第二活性成分阿托伐他汀 (Atorvastatin)或其可药用盐、 酯或溶剂化物。 背景技术
随着医药科学的不断发展， 人们认识到胆固醇、 脂肪等含量过高是发生心血管疾 病的基本病因， 髙血脂是发生冠心病及高血压的主要危险因素。 因此， 人们开始把血 脂调节药的开发作为防治心血管疾病的重点。 自 20世纪 80年代末起， 降血脂药物大 量推出， 其中他汀类药物受到人们好评， 其临床疗效之佳是其它各类调节血脂药物所 不能相比的。 十多年来， 几个国际大规模冠心病防治试验的完成， 证实他汀类药物可 以降低冠心病的发病率和死亡率， 而且能使已经形成的动脉粥样硬化斑块发展减缓， 甚至减退， 从而打破了冠心病不可逆转的传统观念， 由"他汀"引发的一场血脂革命正 在全球兴起。 目前， 医药界对调脂药在防治心血管疾病方面的作用充满信心， 调脂疗 法将成为 21世纪预防心血管疾病的主要方法。
阿托伐他汀（Atorvastatin)是第三代他汀类调脂药， 是一种全合成的羟甲戊二酰 辅酶 A (HMG- CoA)还原酶抑制剂， 1995年首次在美国以钙盐形式上市。其化学名称为： R- C R' ， R' ) ] -2- (4-氟苯基） - β δ -二羟基- 5- (1-甲基乙基) - 3-苯基 -4- [ (苯 胺)羰基] -1-氢-吡咯- 1-庚酸钙三水合物。 结构式-
Figure imgf000002_0001
分子式： ( C33HM FN205) 2Ca · 3H20
通常所说的阿托伐他汀就是指上述的钙盐三水合物， 或称为阿托伐他汀钙， 其剂 量 /规 格 一 般都 是 按 照 阿 托 伐 他 汀 游 离 酸计 。 中 国 导 医 网 (www.daoyi.com/drug/html/200009/6000000189670.html)对其药效综述如下：
1、 抑制 HMG-CoA还原酶。 HMG-CoA还原酶是胆固醇合成酶系中的限速酶， 通 过对其的抑制作用， 从而使胆固醇合成减少。阿托伐他汀与普伐他汀 (pravastatin)相同， 口服吸收后即有生物活性，而洛伐他汀 (lovastatin)和辛伐他汀 (simvastatin)为前药，需在 体内代谢后才具有生物活性。 因此阿托伐他汀发挥作用比洛伐他汀和辛伐他汀更快。 本药对 HMG-CoA还原酶的抑制作用较其他同类药物强。 阿托伐他汀对 HMG-CoA还 原酶抑制作用的 50%抑制浓度 (IC50)为 73 nmoLU1,而普伐他汀为 2650
Figure imgf000003_0001
。 阿托 伐他汀 80 mg/d,普伐他汀 40 mg/d,辛伐他汀 40 mg/d使血浆甲基二羟戊酸 (MVA)浓度 分别减少 59%, 32%和 49%。 此外， 单剂量阿托伐他汀对 HMG-CoA还原酶抑制作用 的持续时间较其他同类药物长。
2、 增加低密度脂蛋白 (LDL)受体。 阿托伐他汀通过对 HMG-CoA还原酶的抑制作 用使血浆中和组织细胞内胆固醇浓度均降低， 可剌激肝脏内 LDL受体密度增加， 从而 使血浆低密度脂蛋白胆固醇 (LDL-C)清除增强。 肝脏 LDL受体可与极低密度脂蛋白 (VLDL)结合， 使 VLDL降解增加， 从而使甘油三酯 （TG)浓度下降。
3、 抑制极低密度脂蛋白胆固醇 (VLDL-C)合成。 胆固醇是合成 VLDL必需的， 本 药通过使血浆胆固醇浓度降低， 使 VLDL合成和分泌减少。 VLDL是携带和转运 TG 必需的， VLDL-C又是 LDL-C的前体， 故本药可使 TG、 VLDL-C、 LDL-C均降低。
4 抗动脉粥样硬化作用。 阿托伐他汀通过降低血脂、减少脂质浸润和泡沬细胞形成， 对延迟动脉粥样硬化病变有利。 本药尚可防止动脉粥样硬化斑块破裂。 此外， 体外实 验表明阿托伐他汀可抑制血管平滑肌增殖和迁移。动物实验表明， 本药 2.5 mg/kg可使 兔动脉粥样硬化斑块面积减少 67 % ( P < 0.05),而同样剂量的洛伐他汀、 普伐他汀、 辛 伐他汀无此作用； 本药尚有抑制血小板激活、 降低血粘度、 抑制凝血等作用。 临床研 究表明 22例高脂血症病人应用本药 80 mg/d后使血漿粘度降低 10%， 凝血因子 VII的 活性降低 8%， 血栓垸 A2(TXA2)诱发的血小板聚集率降低 11%。 这些作用均对防止动 脉粥样硬化有利。
阿托伐他汀一般耐受性良好， 大部分不良反应轻微， 与洛伐他汀相比， 病人耐受 性更好。
阿昔莫司 （Acipimox)是一种人工合成的烟酸衍生物， 能抑制脂肪组织的分解， 减少游离脂肪酸自脂肪组织释放， 从而降低甘油三酯 （TG)在肝脏中的合成， 并通过 抑制极低密度脂蛋白（VLDL)和低密度脂蛋白（LDL)的合成，使血清中甘油三酯（TG) 和总胆固醇 （TC) 的浓度下降。 本品还可抑制肝脏脂肪酶的活性， 减少高密度脂蛋白 (HDD 的分解。 该药口服吸收迅速， 药后 2小时内血药浓度即达峰值， 半衰期为 2 小时。 该药不与血浆蛋白结合， 不被代谢， 主要以原形经尿排出。 在临床上， 阿昔莫 司可有效治疗高甘油三酯症 （IV型）、 髙胆固醇血症（Ila型） 及高甘油三酯合并高胆 固醇血症（lib型）， 是一种安全、 有效、 耐受性好的调血脂药。
目前，该领域的研究趋势是将两种不同作用机制的调血脂药制成复方制剂，从而使 降脂作用更加全面， 同时还可发挥协同作用， 增强疗效， 减少毒副作用。
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药理实验数据。
中国专利申请 CN1425374A公开了阿昔莫司和洛伐他汀组合物， 公开的比例是阿 昔莫司和洛伐他汀的重量比为 25~50:1，优选的比例是 25:1或 37.5:1，但没有涉及阿昔 莫司和阿托伐他汀复方的最佳配比及相应药理实验数据。 发明内容
本发明的目的在于提供一种新的治疗高脂血症的药物组合物， 该组合物含有第一 活性成分阿昔莫司（Acipimox)和第二活性成分阿托伐他汀 (Atorvastatin)或其可药用盐、 酯或溶剂化物。 由于阿昔莫司和阿托伐他汀的作用机制不同， 组成组合物后降脂作用 更加全面， 并且两药合用有协同作用， 其降脂作用明显优于相同剂量的单方。 此外， 通过合理选择组合物中阿托伐他汀的用量， 使组合物在有效降低血脂水平的同时又无 明显的毒副作用， 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 顺应性。 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， 阿昔莫司与阿托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， 在升髙高密度脂蛋白胆固醇方面， 也有着比较明显的优势。
本发明的组合物之一是由阿昔莫司和阿托伐他汀钙以及药用辅料组成， 其中阿昔 莫司和阿托伐他汀钙 （以游离酸计， 下同） 的重量比为 10~80:1 , 优选的比例的是 10-30:1 , 进一步优选的比例的是 30:1。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， 可以按照本领域公知的一般制剂方法制备， 阿昔莫 司含量相当于在将组合物给药时约 200~750mg 的日剂量， 阿托伐他汀钙含量相当于 5~80 mg的日剂量， 其中优选阿托伐他汀钙含量相当于 10~30 mg的日剂量。
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， 再与有效量的阿托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 （Surelease, 乙基纤维素的水分散体）粘合剂， 如聚乙烯吡咯烷酮， 交联聚乙烯 吡咯垸酮， 润滑剂， 如硬脂酸镁、 滑石粉、 微粉硅胶等。
本发明的组合物通过药理方面的研究工作，表明当采用本发明的组合物，尤其是釆 用优选的配比时， 与单独应用有效量的阿昔莫司或阿托伐他汀钙相比， 显示出令人吃 惊的更佳效果， 同时毒性没有增加， 因而安全剂量范围大， 疗效持续时间长， 综合效 果好， 使用方便。 本发明的组合物可以每日 1-2次给药， 优选为每日 1次。 本发明的 组合物与阿昔莫司和普伐他汀联合使用、 与阿昔莫司和洛伐他汀的联合使用相比， 也 表现出更好的降脂活性。
另外， 我们在筛选实验中发现， 本发明组合物中阿托伐他汀的药理活性与其所成 的盐、 酯或溶剂化物关系很小， 其降脂活性的大小仅与阿托伐他汀游历酸的量有关。 所以本发明中阿托伐他汀可以为任何一种可以药用的盐， 即合适的阿托伐他汀生理可 接受的盐， 包括衍生自无机的和有机的碱所形成的盐， 为钠盐、 钙盐、 钾盐、 镁盐、 锌盐、 铁盐； 也可以为任何一种阿托伐他汀可以药用的酯， 即合适的阿托伐他汀生理 可接受的酯， 包括衍生自脂肪醇、 芳香醇、 杂环醇所形成的酯， 为甲酯、 乙酯、 烯丙 酯、 苯酯。
具体实施方式
现通过如下实施例进一步说明本发明的组合物及其制备方法以及治疗效果， 但本 发明的保护范围并不限于实施例。 实施例 1
a、 阿昔莫司 200g
空白丸芯 250g
7%PVP溶液（溶剂为 90%乙醇） 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 , 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，媢泵 12%， 转盘转速 145rpm， 喷 7%PVP溶液 (溶剂为 90%乙醇）。 造粒结束， 50°C烘干， 出料。
b、 阿托伐他汀钙 5g (以游离酸计）
空白丸芯 30g
7%PVP溶液 （溶剂为 90%乙醇） 30g
制备工艺： 将阿托伐他汀钙过 120目筛， 处方量称取， 倒入下料斗中。 开造粒包 衣机， 入风压力 0.5 bar, 入风温度 30°C， CYL: 3 bar, CAP1 : 0.8 bar, 倒入空白丸 芯，造粒， 下料速度 4rpm，蠕泵 6%， 转盘转速 160 rpm， 喷 7%P VP溶液（溶剂为 90% 乙醇）。 造粒结束， 45°C烘干， 出料。
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阿托伐 他汀钙 （以游离酸计） 的重量分别为 200mg和 5mg进行填充， 即可。 实施例 2
阿昔莫司 200g
乳糖 30g
羧甲基淀粉钠 30g
微晶纤维素 18g
6%PVP的无水乙醇溶液 100g
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， 6(TC千燥， 16目筛整干颗粒， 干颗粒中加入处方量的硬 ¾旨酸镁。 b、 阿托伐他汀钙 10g (以游离酸计） 15g
预胶化淀粉 10g
6%PVP的无水乙醇溶液 30g
山榆酸甘油酯 lg
制备工艺： 阿托伐他汀钙过 100目筛， 羟丙基纤维素、 预胶化淀粉过 80目筛， 称 取处方量的阿托伐他汀钙和羟丙基纤维素、预胶化淀粉混合均勾，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 c、 将上述 a,b两种组分釆用双层压片机冲压片即得双层片， 每片含阿昔莫司与阿托伐 他汀钙 （以游离酸计） 的重量分别为 200mg和 10mg。
实施例 3
阿昔莫司 200g
乳糖 30g
羧甲基淀粉钠 30g
微晶纤维素 ' 18g
6%PVP的无水乙醇溶液 100g
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酸镁。 b、 阿托伐他汀钙 20g (以游离酸计）
羟丙基纤维素 30g
预胶化淀粉 20g
6%PVP的无水乙醇溶液 50g
山榆酸甘油酯 2g
制备工艺： 阿托伐他汀钙过 100目筛， 羟丙基纤维素、 预胶化淀粉过 80目筛， 称 取处方量的阿托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。 c、 将上述 a,b两种组分釆用双层压片机冲压片即得双层片， 每片含阿昔莫司与阿托伐 他汀钙（以游离酸计） 的重量分别为 200mg和 20mg。 实施例 4
a、 阿」昔苜莫吴司司 300g
羟丙基甲基纤维素 -4M 40g
微晶纤维素 30g
8%PVP的无水乙醇溶液 150g
2g
制备工艺： 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， 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、 阿托伐他汀钙 20g (以游离酸计）
羧甲基纤维素钠 30g
乳糖 20g
6%PVP的 95%乙醇溶液 50g
2g
制备工艺： 阿托伐他汀钙过 100目筛， 羧甲基纤维素钠、 乳糖过 80目筛， 称取处 方量的阿托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， 60°C干燥， 16目筛整干颗粒， 干颗粒中加入处方量的硬脂酸僕。
c、 将上述 a,b两种组分采用双层压片机冲压即得双层片， 每片含阿昔莫司与阿托伐他
实施例 5
a、 阿昔莫司 300g
空白丸芯 250g
7%PVP溶液（溶剂为 90%乙醇） 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 0.5 bar, 入风温度 30°C， CYL: 3 bar, CAP1 : 0.8 bar, 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。
b、 a中制得的含阿昔莫司小丸
Surelease 90g
滑石粉 lg
纯水 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， CYL: 3bar， 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。
c、 按照实例 1中 b的要求制得阿托伐他汀钙小丸， 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阿托伐他汀钙 （以游离酸 计） 的重量分别为 300mg和 10mg进行填充， 即可。 实施例 6
a、 阿昔莫司 300g
空白丸芯 300g
7%PVP溶液（溶剂为 90%乙醇） 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， CYL: 3bar， 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， 5CTC烘干， 出料。
b、 a中制得的含阿昔莫司小丸
乙基纤维素 40g
硬脂酸 70g
聚乙二醇 -6000 6g
滑石粉 12g
95%乙醇 lOOOg
制备工艺： 将 a中制得的含阿昔莫司小丸倒入下料斗中。 开造粒包衣机， 入风温 度 30°C， 入风压力 0.5bar， 入风温度 30°C， CYL: 3bar, CAP1 : l.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， 50°C烘干， 出料。
c、 阿托伐他汀钙 5g (以游离酸计）
' 空白丸芯 30g
7%PVP溶液（溶剂为 90%乙醇） 30g
制备工艺： 将阿托伐他汀钙过 120 目筛， 处方量称取， 倒入下料斗中， 开造粒包 衣机， 入风压力 0.5 bar, 入风温度 30°C， CYL: 3 bar, CAP1 : 0.8 bar, 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烘干， 出料。
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阿 托伐他汀钙 （以游离酸计） 的重量分别为 300mg和 5mg进行填充， 即可。 实施例 7
a、 阿昔莫司 400g
甘露醇 10g
乳糖 40g
微晶纤维素 20g
6%PVP的 95%乙醇溶液 120g
硬酯酸镁 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。
阿托伐他汀钙 5g (以游离酸计)
预胶化淀粉 50g
甘露醇 50g
乳糖 40g
6%PVP的 95%乙醇溶液 100g
5g
制备工艺： 阿托伐他汀钙过 100目筛， 预胶化淀粉、 甘露醇、 乳糖过 80目筛， 称 取处方量的阿托伐他汀钙和预胶化淀粉、甘露醇、乳糖混合均匀， 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， 每片含阿昔莫司与阿托伐他 汀钙（以游离酸计） 的重量分别为 400mg和 5mg。 实施例 8
a、 阿昔莫司 400g
乳糖 30g
羟丙基甲基纤维素 -15M 20g
8%PVP的 95%乙醇溶液 150g
山榆酸甘油酯 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， 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。
b、 阿托伐他汀钙 10g (以游离酸计）
羟丙基纤维素 25g
糊精 20g
6%PVP的 95%乙醇溶液 50g
滑石粉 2g
制备工艺： 阿托伐他汀钙过 100目筛， 羟丙基纤维素、 糊精过 80 ·目筛， 称取处方 量的阿托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， 60Ό干燥， 16目筛整千颗粒， 干颗粒中加入处方量的滑石粉。
c、 将上述 a,b两种组分采用双层压片机冲压即得双层片， 每片含阿昔莫司与阿托 伐他汀钙 （以游离酸计） 的重量分别为 400mg和 10mg。
实施例 9 阿昔莫司和阿托伐他汀钙复方治疗大鼠髙血脂症的复方筛选
本试验的目的在于通过筛选确定毒性低、 作用强、 使用方便的阿昔莫司和阿托伐 他汀钙复方制剂的组成。 采用高脂饲料诱发大鼠高脂血症模型， 给模型大鼠连续灌服 阿昔莫司 （100~400mg/kg)和（或） 阿托伐他汀钙（2.5~30mg/kg， 以游离酸计， 下述 剂量均以阿托伐他汀游离酸计） 14天。 结果发现， 阿昔莫司和阿托伐他汀钙伍用对高 脂词料所致的大鼠高脂血症有明显的治疗作用， 降脂效果与两种药物的剂量相关， 阿 昔莫司 200mg/kg和阿托伐他汀钙 10mg/kg、 阿昔莫司 200mg/kg和阿托伐他汀钙 20mg/kg及阿昔莫司 300mg/kg和阿托伐他汀钙 lOmg/kg联合用药组效果显著， 可显著 降低大鼠血清总胆固醇、 甘油三酯、 低密度脂蛋白胆固醇水平， 显著升高髙密度脂蛋 白胆固醇水平， 并对上述指标均表现出协同作用。其中阿昔莫司 300mg/kg和阿托伐他 汀钙 10mg/kg联合用药组效果最显著，优选阿昔莫司 300mg/kg和阿托伐他汀钙 10mg/kg 组成的复方。 在本实验剂量范围内， 联合用药组对与肝脏和肌肉毒性相关的血清酶活 性无明显影响。
1 试验目的
通过筛选确定阿昔莫司和阿托伐他汀钙复方制剂的组成， 以达到复方制剂毒副作 用低、 作用全面和增强、 使用方便之目的。
2 受试药物
2.1 烟酸衍生物
药品名称： 阿昔莫司 （Acipimox)
批 号： 0207002
纯 度： 大于 99.7%
生产单位： 鲁南制药股份有限公司 配制方法： 临用前用 1%羧甲基纤维素钠 （CMC)混匀， 配成试验所需浓度。
2.2他汀类药物
药品名称： 阿托伐他汀钙 （Atorvastatin)
批 号： 031002
纯 度： 大于 99.0%
生产单位： 山东新时代药业有限公司自制
配制方法： 临用前用 1% CMC混匀， 配成试验所需浓度。
3 动物 3.1 品系和来源
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。
3.2体重和性别
年龄 9周〜 10周， 体重 180-220g， 雄性。
3.3饲养条件
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。 4 大鼠高脂血症模型制备 [1]
大鼠高脂血症模型采用高脂饲料致高脂血症法。 高脂饲料配方如下： 基础饲料 86.3%、 胆固醇 3%、 猪油 10%、 甲基硫氧嘧啶 0.2%、 猪胆盐 0.5%， 保证各成分混合 均勾。 连续 2周。 给药期间隔天给予高脂饲料。
5 阿昔莫司和阿托伐他汀钙对正常大鼠血脂水平的影响
5.1 剂量设置依据
临床上阿昔莫司的剂量为 250mg/次（按人体重 60 kg计算，上述剂量为 4.2mg/kg)， 2~3次 /日， 每日量最大不超过 1200mg ra。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 m，将本试验中阿昔莫 司的剂量设定为 100、 200、 300、 400mg/kgo
临床上阿托伐他汀钙的剂量为 10mg/次 （按人体重 60 kg计算， 上述剂量为 0.17mg/kg), 1次 /日， 每日量最大不超过 80mg [4]。 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 0.85mg/kg。 结合文献报道 [5·8]， 将本试验 中阿托伐他汀钙的剂量设定为 2.5、 5、 10、 20 、 30mg/kg。
5.2组别设置
依据上述剂量设置， 按血清总胆固醇水平均衡原则， 将正常动物随机分为： （1 ) 正常对照组； （2) 阿昔莫司 lOOmg/kg组； （3 ) 阿昔莫司 200mg/kg组； （4) 阿昔莫司 300mg/kg组； （5 ) 阿昔莫司 400mg/kg组； （6) 阿托伐他汀钙 2.5mg/kg组； （7) 阿托 伐他汀钙 5mg/kg组； （8) 阿托伐他汀钙 10mg/kg组； （9) 阿托伐他汀钙 20mg/kg组； ( 10)阿托伐他汀钙 30mg/kg组； （11 )阿昔莫司 200mg/kg和阿托伐他汀钙 5mg/kg组； ( 12) 阿昔莫司 200mg/kg和阿托伐他汀钙 lOmg/kg组； （13 ) 阿昔莫司 200 mg/kg和 阿托伐他汀钙 20 mg/kg组； （14)阿昔莫司 300 mg/kg和阿托伐他汀钙 5 mg/kg组； （15 ) 阿昔莫司 300 mg/kg和阿托伐他汀钙 10 mg/kg组； （16)阿昔莫司 300 mg/kg和阿托伐 他汀钙 20 mg/kg组； （17) 阿昔莫司 400 mg/kg和阿托伐他汀钙 5 mg kg组； （18) 阿 昔莫司 400 mg/kg和阿托伐他汀钙 10 mg/kg组。 每组 10只。
5.3 给药
临床拟用的给药途径为口服， 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。
5.4检测指标
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； 其余试剂釆用日本罗氏试剂公司产品， 用 日立 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。 6 阿昔莫司和阿托伐他汀钙对高脂血症大鼠血脂水平的影响
6.1 剂量设置依据
同 5.1正常大鼠实验。
6.2组别设置
依据上述剂量设置， 按血清总胆固醇水平均衡原则， 将模型大鼠随机分为： （1 ) 正常对照组； （2)模型对照组； （3 ) 阿昔莫司 100mg/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)阿托伐他汀钙 2.5mg/kg 组； （8) 阿托伐他汀钙 5mg/kg组； （9) 阿托伐他汀钙 10mg/kg组； （10) 阿托伐他汀 钙 20mg/kg组； （ 11 )阿托伐他汀钙 30mg/kg组； （12)阿昔莫司 200mg/kg和阿托伐他 汀钙 5mg/kg组； （13 ) 阿昔莫司 200mg/kg和阿托伐他汀钙 10mg/kg组； （14) 阿昔莫 司 200 mg/kg和阿托伐他汀钙 20 mg/kg组； （ 15 )阿昔莫司 300 mg/kg和阿托伐他汀钙 5 mg/kg组； （16) 阿昔莫司 300 mg/kg和阿托伐他汀钙 10 mg/kg组； （17) 阿昔莫司 300 mg/kg和阿托伐他汀钙 20 mg/kg组； （18) 阿昔莫司 400 mg/kg和阿托伐他汀钙 5 mg/kg组； （ 19)阿昔莫司 400 mg/kg和阿托伐他汀钙 10 mg/kg组。 每组 10只。
6.3 给药 临床拟用的给药途径为口服， 故本试验釆用灌胃法给药， 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。
6.4检测指标
同 5.4正常大鼠实验。
7 阿昔莫司和阿托伐他汀钙复方不同组分相互影响试验
7.1 组别设置
从疗效较显著的阿昔莫司和阿托伐他汀钙剂量组中， 确定阿昔莫司和阿托伐他汀 钙复方的剂量： （1 ) 正常对照组； （2)模型对照组； （3 ) 阿昔莫司 200mg/kg; (4) 阿 昔莫司 300mg/kg; (5 ) 阿托伐他汀钙 10mg/kg; (6) 阿托伐他汀钙 20mg/kg; (7) 阿 昔莫司 200mg/kg和阿托伐他汀钙 10mg/kg组复方组； （8) 阿昔莫司 200mg/kg和阿托 伐他汀钙 20mg/kg组复方组； （9)阿昔莫司 300mg/kg和阿托伐他汀钙 10mg/kg组复方 组。 每组 10只。 分组前测定血清总胆固醇水平， 按均衡原则随机分组。 每组 10只。 7.2给药和检测指标
同前述 6.3和 5.4。
8 试验结果 ,
8.1 阿昔莫司和阿托伐他汀钙对正常大鼠血脂水平的影响
正常大鼠给药 4天后， 阿昔莫司、 阿托伐他汀钙和联合用药组的总胆固醇、 血清 甘油三酯、 低密度脂蛋白胆固醇均有所降低， 高密度脂蛋白胆固醇水平升高， 见表 1。
表 1 阿昔莫司和阿托伐他汀钙及复方对正常大鼠血脂的影响
血清总胆固醇 血清甘油三酯 低密度脂蛋白胆固 高密度脂蛋白胆 组别
(mmol/L) (mmol/L) 醇（mmol/L) 固醇（mmol/L) 正常对照组 1.74±0.19 0.73±0.25 0.34±0.10 0.95±0.19 阿昔莫司 100mg/kg 1.60±0.35 0.71±0.27 0.32±0.12 0.97±0.16 阿昔莫司 200mg/kg 1.55±0.28 0.69±0.33 0.26±0.11 0.98±0.23 阿昔莫司 300mg/kg 1.51±0.26* 0.63±0.28 0.29±0.11 1.15±0.26 阿昔莫司 400mg kg 1.49±0.28* 0.57±0.36 0.24±0.14 1.18±0.13** 阿托伐他汀钙 2.5mg/kg 1.69±0.33 0.69±0.33 0.30±0.14 0.99±0.11 阿托伐他汀钙 5mg/kg 1.64±0.30 0.67±0.28 0.25±0.16 0.96±0.11 阿托伐他汀钙 IOmg kg 1.52±0.31 0.65±0.33 0.23±0.09* 1.03±0.24 阿托伐他汀钙 20mg kg 1.46±0.24* 0.55±0.16 0.21±0.09* 1.05±0.13 阿托伐他汀钙 30mg kg 1.41±0.29* 0.51±0.18* 0.19±0.12* 1.08±0.18 阿昔 200+阿托 5mg kg 1.53±0.24 0.61±0.33 0.23±0.09* 1.08±0.20 阿昔 200+阿托 10mg/kg 1.47±0.24* 0.49±0.11* 0,19±0.10** 1.15±0.16* 阿昔 200+阿托 20mg/kg 1.38±0.32** 0.46±0.13** 0.17±0.06*** 1.19±0.16** 阿昔 300+阿托 5mg kg 1.46±0.25* 0.63±0.22 0.27±0.06 0.99±0.22 阿昔 300+阿托 IOmg/kg 1.44±0.26* . 0.50±0.06* 0.18±0.12** 1.20±0.15** 阿昔 300+阿托 20mg/kg 1.45±0.27* 0.50±0.17* 0.20±0.09** 1.09±0.24 阿昔 400+阿托 5mg/kg 1.44±0.31* 0.52±0.12* 0.25±0.10 1.03±0.17 阿昔 400+阿托 10mg kg 1.41±0.36* 0.51±0.14* 0.24±0.08* 1.11±0.21 注： 与正常对照组比较， *P<0.05,**P<0.01 8.2阿昔莫司和阿托伐他汀钙对模型大鼠血脂水平的影响
大鼠饲以高脂饲料 14天后分组给药。 阿昔莫司的剂量范围为 100~400mg/kg， 阿 托伐他汀钙的剂量范围为 2.5 30mg/kg， 组成联合用药组。给药 14天后， 与模型对照 组比较， 阿昔莫司和阿托伐他汀钙各剂量组血清总胆固醇、 甘油三酯、 低密度脂蛋白 胆固醇均有不同程度的下降， 高密度脂蛋白胆固醇水平均有所升高， 见表 2
与模型对照组相比， 阿昔莫司 200mg/kg和阿托伐他汀钙 10mg/kg、 阿昔莫司 200mg/kg和阿托伐他汀钙 20mg/kg及阿昔莫司 300mg/kg和阿托伐他汀钙 10mg/kg三 个联合用药组大鼠的血清总胆固醇、甘油三酯、低密度脂蛋白胆固醇水平均显著降低， 高密度脂蛋白胆固醇水平均显著升高。 与相同剂量的阿昔莫司或阿托伐他汀钙单方组 比较， 上述三个联合用药组血清总胆固醇、 甘油三酯、 低密度脂蛋白胆固醇水平均显 著降低， 高密度脂蛋白胆固醇水平均显著升高， 并对上述指标均表现出协同作用。 其 中以阿昔莫司 300mg/kg和阿托伐他汀钙 10mg/kg联合用药组效果最为显著。 表 2 阿昔莫司和阿托伐他汀钙及复方对模型大鼠血脂的影响
Figure imgf000016_0001
注： 与正常对照组比较， 髓 PO.Q01 ; 与模型对照组比较， *P<0.05,**P<0.01 ***P<0.001
8.3 阿昔莫司和阿托伐他汀钙对模型大鼠血清酶活性的影响
本实验通过测定用药 14天后高血脂模型大鼠血清中丙氨酸氨基转移酶和肌酸激酶 的水平， 来评价阿昔莫司和阿托伐他汀钙及复方对模型大鼠肝脏功能和骨骼肌组织的 影响。 结果表明， 与模型对照组相比， 阿昔莫司各剂量（100~400mg/kg)组模型大鼠 血清丙氨酸氨基转移酶和肌酸激酶水平均无显著差异 （P>0.05 ); 阿托伐他汀钙各剂量 (2.5~30mg/kg)组模型大鼠血清中上述指标亦未见显著差异（P>0.05)， 阿托伐他汀钙 和阿昔莫司各联合用药组大鼠血清丙氨酸氨基转移酶和血清肌酸激酶均无明显变化
(P>0.05 ), 见表 3。
表 3阿昔莫司和阿托伐他汀钙及复方对模型大鼠血清丙氨酸氨基转移酶和肌酸激酶的影响
丙氨酸氨基转移酶
组别 肌酸激酶（U L)
(nmol.s_1/L)
正常对照组 639.5±111.3 351.4±144.2 模型对照组 667.9±109.9 373.6±112.4 阿昔莫司 100mg/kg 640.3±117.6 361.4±106.4 阿昔莫司 200mg/kg 645.4±124.9 354.4±110.9 阿昔莫司 300mg/kg 655.5±110.5 380.33±120.1 阿昔莫司 400mg kg 642.8±114.2 377.3±103.4 阿托伐他汀钙 2.5mg/kg 635.0±115.2 364.6±105.9 阿托伐他汀钙 5mg/kg 674.5±132.9 367.7±132.6 阿托伐他汀钙 10mg/kg 650.0±101.8 389.0±119.1 阿托伐他汀钙 20mg/kg 640.6±95.6 378.8±109.3 阿托伐他汀钙 30mg/kg 66.4±117.7 384.2±120.8 阿昔 200+阿托 5mg/kg 653.4±110.5 374.1±101.5 阿昔 200+阿托 10mg/kg 669.7±123.0 353.3±124.6 阿昔 200+阿托 20mg kg 641.6±125.1 367.4±111.4 阿昔 300+阿托 5mg/kg 604.9±132.6 361.9±115.2 阿昔 300+阿托 10mg/kg 647.7±128.2 370.6±130.0 阿昔 300+阿托 20mg/kg 646.6±124.0 372.1±117.3 阿昔 400+阿托 5mg/kg 651.9±136.1 369.4±103.2 阿昔 400+阿托 10mg/kg 647.3±140.6 375.8±119.9
8.4 阿昔莫司和阿托伐他汀钙复方中不同组分相互影响试验
高血脂模型大鼠连续给药 14天后， 与相同剂量的单方相比， 阿昔莫司和阿托伐他 汀钙联合用药组均能明显降低模型大鼠血清中总胆固醇、 甘油三酯、 低密度脂蛋白胆 固醇水平以及明显升高高密度脂蛋白胆固醇水平， 见表 4。
综合分析， 与模型对照组相比， 阿昔莫司 200mg/kg和阿托伐他汀钙 10mg/kg、 阿 昔莫司 200mg/kg和阿托伐他汀钙 20mg/kg及阿昔莫司 300mg/kg和阿托伐他汀钙 lOmg/kg联合用药组效果显著，可显著降低大鼠血清总胆固醇、甘油三酯、低密度脂蛋 白胆固醇水平， 显著升高高密度脂蛋白胆固醇水平。 与相同剂量的阿昔莫司或阿托伐 他汀钙单方组比较， 上述三个联合用药组血清总胆固醇、 甘油三酯、 低密度脂蛋白胆 固醇水平均显著降低， 高密度脂蛋白胆固醇水平均显著升高， 三个联合用药组对上述 指标均表现出协同.作用。其中阿昔莫司 300mg/kg和阿托伐他汀钙 lOmg kg联合用药组 效果最显著， 因此优选阿昔莫司 300mg/kg和阿托伐他汀钙 10mg/kg组成的复方。 表 4 阿昔莫司和阿托伐他汀钙复方中不同组分治疗大鼠高脂血症的效果 血清总胆固醇 血清甘油三酯 低密度脂蛋白胆固醇 高密度脂蛋白胆固 组别
(mmol/L) (mmol/L) (mmol/L) 醇 (mmol/L) 正常对照组 2.09±0.96 0.78±0.18 0.30±0.14 1.26±0.50 模型对照组 12.14i2.24** 2.14±0.50 8.93±1.36 3.18±1.27*** 阿昔莫司 200mg/kg 10.31±1.67 1.79±0.63 7.27±1.83* 4.20±1.10 阿昔莫司 300mg/kg 8.69±1.88** 1.68±0.56 6.96±1.23" 4.54±0.52* 阿托伐他汀钙 10mg/kg 10.20±1.62* 1.56±0.62* 7.30±1.88* 4.46±1.3* 阿托伐他汀钙 20mg/kg 9.65±2.22* 1.47±0.56* 6.80±1.66** 4.51±1.09* 阿昔 200+阿托 lOmg/kg 7.43±1.67***'!|' @@ 0.99±0.22***'!| @ 4.91±1.26***'|!' @@ 5.95±1.07*** π· @ 阿昔 200+阿托 20mg/kg 6.34±1.81*** ι|!·&&& 0.82±0.26***'"' && 4.25±1.63***·Μ· &&
阿昔 300+阿托 10mg/kg 4.82±1.03**— @@@ 0.73±0.23*** ^>@@ 3.95±1.28**— @@@ 6.45±1.07**— @@ 注： 与正常对照组比较， ###Ρ<0. 01 #Ρ<0. 05
与模型对照组比较， *Ρ<0. 05 **Ρ<0. 01, ***Ρ<0. 001
与阿昔莫司 200mg/kg组比较，！！！ P<0. 001,！！ P<0. 01
与阿托伐他汀钙 10mg/kg组比较， @P<0. 05 i@P<0. 01 » SiiP<0. 001
与阿昔莫司 300mg/kg组比较， ' ' "Ρ<0. 001
与阿托伐他汀钙 20mg/kg组比较， &&&P<0. 001, &P<0. 05
9 结论
阿昔莫司和阿托伐他汀钙伍用对高脂伺料所致的大鼠高脂血症有明显的治疗作 用， 降脂效果与两种药物的剂量相关， 阿昔莫司 200mg kg和阿托伐他汀钙 10mg/kg 阿昔莫司 200mg/kg和阿托伐他汀钙 20mg/kg及阿昔莫司 300mg/kg和阿托伐他汀钙 10mg/kg联合用药组效果显著，可显著降低大鼠血清总胆固醇、甘油三酯、低密度脂蛋 白胆固醇水平， 显著升髙高密度脂蛋白胆固醇水平， 并对上述指标均表现出协同作用。 其中阿昔莫司 300mg/kg和阿托伐他汀钙钙 10mg/kg联合用药组效果最显著，优选阿昔 莫司 300mg/kg和阿托伐他汀钙 10mg/kg组成的复方。在本实验剂量范围内， 联合用药 组对血清酶活性无明显影响， 初步表明对肝和横紋肌无明显的毒性作用。 此外， 目前 阿昔莫司单方的临床用法为 3次 /日， 本实验证明， 阿昔莫司 1次 /日仍有显著的降血脂 作用， 且毒性小， 这为阿昔莫司和阿托伐他汀钙组成复方后一日仅用药 1次提供了可 靠的实验依据， 这必将大大方便患者服用， 提高患者的顺应性。 实施例 10
阿昔莫司和阿托伐他汀钙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
我们根据实施例 9所筛选到的阿昔莫司阿托伐他汀的配比与上述专利所公开的组 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阿 托伐他汀钙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。
10.1 受试药物、 动物、 大鼠高脂血症模型制备同实施例 9。
10.2组别设置
按血清总胆固醇水平均衡原则， 将模型大鼠随机分为：
正常对照组；
模型对照组；
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；
阿昔莫司 200mg/kg阿托伐他汀钙 5mg/kg组；
阿昔莫司 200mg/kg阿托伐他汀钙 10mg/kg组；
阿昔莫司 200mg/kg阿托伐他汀钙 20mg kg组；
阿昔莫司 300mg/kg阿托伐他汀钙 5mg/kg组；
阿昔莫司 300mg/kg阿托伐他汀钙 10mg/kg组；
阿昔莫司 300mg/kg阿托伐他汀钙 20mg/kg组；
阿昔莫司 400mg kg阿托伐他汀钙 5mg/kg组；
阿昔莫司 400mg/kg阿托伐他汀钙 10mg/kg组。
10.3给药
同实施例 9中的 6.3。
10.4捡测指标
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)。
10.5实验结果
大鼠饲以高脂饲料 14天后分组给药。 给药 14天后， 阿昔莫司阿托伐他汀钙各剂 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阿托伐他汀联合使用在降低血脂方面具有意想不到的效 果， 阿昔莫司和阿托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。
表 5 阿昔莫司阿托伐他汀钙联合使用与阿昔莫司普伐他汀、
阿昔莫司洛伐他汀联合使用降脂效果比较
Figure imgf000020_0001
注： 与正常对照组比较， ###P<0.001 ; 与模型对照组比较， **P<0.01， ***P<0.001 ;
与阿昔 300+普伐 20mg/kg组和阿昔 300+洛伐 10mg/kg组相比较， *P<0.05， **P<0.01 参考文献
[1] 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] OLBETAM (acipimox) 说明书 （Pharmacia, New Zealand)
[3] Scand J Clin Lab Invest, 1990, 50(2):203-208
[4] 阿托伐他汀钙片使用说明书， http://www.sda.gov.cn， 国家食品药品管理局网站
[5] Clin. Chim. Acta. 2004， 339 ( 1-2)： 189-194
[6] Int. J. Cardiol. 2003,91 ( 1 )： 59-69
[7] Metabolism 2003, 52 (5)： 609-615
[8] Biochim. Biophys. Acta. 2002, 1580 (2-3)： 161-170

Claims

权利要求
1. 一种治疗高血脂症的组合物， 其特征在于， 所述的组合物包括- a) 第一个活性成分： 阿昔莫司；
b) 第二个活性成分： 阿托伐他汀、 或其可药用盐、 酯或溶剂化物。
2. 按照权利要求 1所述的组合物，其特征在于，所述的阿托伐他汀的可药用盐选自钠 盐、 钙盐、 钾盐、 镁盐、 锌盐或铁盐。
3. 按照权利要求 1所述的组合物，其特征在于，所述的阿托伐他汀的可药用酯选自脂 肪醇、 芳香醇、 杂环醇所形成的酯。
4. 按照权利要求 1或 2所述的组合物，其特征在于，所述的第二个活性成分优选为阿 托伐他汀的钙盐。
5. 按照权利要求 1-4之一所述的组合物， 其特征在于，所述第一个活性成分与第二个 活性成分的重量比是（10〜80)： 1。
6. 按照权利要求 5所述的组合物，其特征在于，第一个活性成分与第二个活性成分的 重量比是： ( 10〜30)： 1。
7. 按照权利要求 6所述的组合物，其特征在于，第一个活性成分与第二个活性成分的 重量比是 30: 1。
8. 按照权利要求 1〜7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。
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CN101892276B (zh) * 2010-06-12 2012-11-21 郝志艳 一种阿托伐他汀钙化合物及其新方法
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KR100829534B1 (ko) 2008-05-16
KR20070024521A (ko) 2007-03-02
JP4741581B2 (ja) 2011-08-03
CN1925857A (zh) 2007-03-07
JP2007535508A (ja) 2007-12-06
EP1741431A1 (en) 2007-01-10
US20080207643A1 (en) 2008-08-28
EP1741431B1 (en) 2012-08-15
CN1692906A (zh) 2005-11-09

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