CN1307996C - Composition for treating hyperlipemia - Google Patents
Composition for treating hyperlipemia Download PDFInfo
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- CN1307996C CN1307996C CNB2004100478607A CN200410047860A CN1307996C CN 1307996 C CN1307996 C CN 1307996C CN B2004100478607 A CNB2004100478607 A CN B2004100478607A CN 200410047860 A CN200410047860 A CN 200410047860A CN 1307996 C CN1307996 C CN 1307996C
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Abstract
The present invention provides a new drug treatment composition for treating hyperlipidemia, which is charactered in that it contains an effective volume of Acipimox and Simvastatin, and it has a weight ratio of (10 ~ 80): 1, a preferable weight ratio of (10 ~ 40): 1, and further preferable weight ratio of 15:1. Its lipid-lowering effect is superior to the same dose of signal prescription, which indicates the two drugs have synergistic effects, and at the same time have no obvious toxicity.
Description
Affiliated technical field
The present invention relates to treat the new compositions of hyperlipidemia, particularly contain the compositions of acipimox and simvastatin and pharmaceutic adjuvant.
Background technology
Along with the continuous development of medical science, people recognize cholesterol, fatty equal size is too high is the basic cause of disease that cardiovascular disease takes place, and hyperlipidemia is that coronary heart disease and hypertensive main hazard factor take place.Therefore, people begin the exploitation of blood lipid regulation medicine as the emphasis of preventing and treating cardiovascular disease.From late 1980s, blood lipid-lowering medicine is released in a large number, and wherein statins is subjected to people's favorable comment, and its clinical efficacy good is that other all kinds of blood lipid regulation medicines institute is incomparable.During the last ten years, finishing of the extensive coronary heart disease control test in several worlds, confirm that statins can reduce evidence of coronary heart diseases and mortality rate, and the atheromatous plaque development that has formed is slowed down, even go down, thereby broken the irreversible traditional view of coronary heart disease, risen in the whole world by the blood fat revolution that cause in " his spit of fland ".At present, the world of medicine is filled with unbounded confidence in the effect that prevents and treats aspect the cardiovascular disease to fat regulation medicine, transfers the fat therapy will become the main method of 21 century angiocardiopathy preventing.
Simvastatin (Simvastatin) is to have carried out broad research both at home and abroad and at hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor of multinational listing, the non-activity of this product own, hydrolyzate after the oral absorption suppresses rate-limiting enzyme hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase in the cholesterol building-up process in vivo competitively, make the synthetic minimizing of cholesterol, also make the synthetic increase of low density lipoprotein receptor, main site of action is at liver, the result reduces cholesterolemia and low-density lipoprotein cholesterol level, moderate reduces serum triglyceride level and increases high density lipoprotein level of serum, thus effective atherosis the and coronary heart disease of prevention of arterial.The general toleration of simvastatin is good, and most of untoward reaction is slight and be one to cross property.In controlled clinical trial, have only＜2% patient is because of the untoward reaction drug withdrawal.In the clinical trial of existing matched group, the untoward reaction of the incidence rate relevant with medicine 〉=1% has: stomachache, constipation, flatulence, incidence rate has tired, unable, headache in 0.5%～0.9% untoward reaction, finds that the report of myopathy is very rare.
Acipimox (Acipimox) is a kind of nicotinic acid derivates of synthetic, can suppress the decomposition of fatty tissue, reducing free fatty discharges from fatty tissue, thereby triglyceride reducing (TG) synthesizing in liver, and, make the lowering of concentration of triglyceride in the serum (TG) and T-CHOL (TC) by suppressing the synthetic of very low density lipoprotein (VLDL) (VLDL) and low density lipoprotein, LDL (LDL).This product also can suppress the activity of liver fat enzyme, reduces the decomposition of high density lipoprotein (HDL).This medicine oral absorption is rapid, behind the medicine in 2 hours blood drug level be peaking, the half-life is 2 hours.This medicine does not combine with plasma protein, not by metabolism, mainly discharges through urine with original shape.Clinically, acipimox can effectively treat high triglyceride disease (IV type), hypercholesterolemia (IIa type) and high triglyceride merges hypercholesterolemia (IIb type), is a kind of lipid regulating agent of safe, effective, better tolerance.。
At present, the research tendency in this field is that the lipid regulating agent of two kinds of different mechanism of action is made compound preparation, thereby makes effect for reducing fat more comprehensive, also can bring into play synergism simultaneously, heightens the effect of a treatment, and reduces toxic and side effects.
U.S. Pat 5260305A discloses the compositions of HMG-CoA reductase inhibitor pravastatin and nicotinic acid and derivant thereof, specifically disclosing specification is the preparation of compositions of pravastatin 5mg, 10mg, 20mg, 40mg and acipimox 750mg, but does not have to disclose the pharmacological experimental data of its beneficial effect and best proportioning.
Chinese patent application CN1425374A discloses acipimox and lovastatin compositions, disclosed ratio is that the weight ratio of acipimox and lovastatin is 25～50: 1, preferred ratio is 25: 1 or 37.5: 1, but does not disclose the best proportioning and the corresponding pharmacological experimental data of acipimox and simvastatin compound recipe.
Goal of the invention
The objective of the invention is screening experiment, a kind of pharmaceutical composition of new treatment hyperlipemia be provided by a series of science, its advantage be effect comprehensively and enhancing, toxic and side effects is low and easy to use.This medicine contains the acipimox and the simvastatin of special ratios, because two medicine mechanism of action differences, it will be more comprehensive forming after the compositions effect for reducing fat, and two medicines have share synergism, and its effect for reducing fat obviously is better than the folk prescription of same dose; In addition, by the consumption of simvastatin in the choose reasonable compositions, make compositions effectively not have obvious toxic and side effects again in the blood fat reducing level, this compositions only needed medication once on 1st simultaneously, and medication is convenient, and this will improve patient's compliance greatly.
Summary of the invention
Compositions of the present invention is made up of acipimox and simvastatin and pharmaceutic adjuvant, and wherein the weight ratio of acipimox and simvastatin is 10～80: 1, preferred ratio be 10～40: 1, further preferred ratio be 15: 1.The dosage form of the pharmaceutical preparation of said composition, comprise solid preparations such as tablet, capsule, granule, pill, drop pill, can be according to general formulation method preparation well known in the art, acipimox content is equivalent to the daily dose of about 200～750mg with the compositions administration time, simvastatin content is equivalent to the daily dose of 5～80mg, and wherein preferred simvastatin content is equivalent to the daily dose of 10～30mg.
Compositions of the present invention is being made solid preparation, during as tablet or capsule,, preferably the acipimox of effective dose is made slow-released part for reaching persistent therapeutic effect, make slow releasing preparation jointly with the simvastatin of effective dose again, as slow releasing tablet, slow releasing capsule etc.Correspondingly, pharmaceutically useful adjuvant comprises diluent, as starch, lactose, mannitol, pregelatinized Starch, dextrin, microcrystalline Cellulose; Disintegrating agent is as carboxymethyl starch sodium, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose; Slow releasing agent is as ethyl cellulose, hydroxypropyl emthylcellulose-4M, hydroxypropyl emthylcellulose-15M; Youteqi RS-100, RL100, RS30D, RL30D, NE30D, and Sulisi (Surelease, the aqueous dispersion of ethyl cellulose) binding agent, as polyvinylpyrrolidone, crospolyvinylpyrrolidone, lubricant is as magnesium stearate, Pulvis Talci, micropowder silica gel etc.
Compare with the compound preparation that lovastatin is formed with the slow release nicotinic acid that Kos Pharmaceuticals company develops, pharmaceutical composition of the present invention replaces nicotinic acid with acipimox, the acipimox scope of application is similar to nicotinic acid, but compare with nicotinic acid and to have following advantage: 1. do not have first validity response, the half-life is longer; 2. the persistent period of lipotropism fat decomposition longer, usefulness is stronger, the rebound phenomenon of no non-esterified fatty acid; 3. can obviously improve glucose tolerance, can reduce fasting glucose about 15%, not with oral antidiabetic drug generation reciprocal action, so can be used for diabetics; 4. do not cause Study on Changes of Blood Uric, can be used for the hyperuricemia patient; 5. it is few the high person of liver transaminase to occur; Flush and skin itching symptom person only about 6% arranged after 6. taking medicine, obviously be less than clothes nicotinic acid therapist, and mostly after taking medicine several days, alleviate voluntarily gradually or disappears, generally do not influence the patient and continue to treat.In addition, replace lovastatin, can greatly reduce untoward reaction such as liver toxicity and muscle poison that the latter brings with simvastatin.
Compositions of the present invention is by the research work of pharmacology aspect, show when adopting compositions of the present invention, when especially adopting preferred proportioning, compare with the acipimox or the simvastatin of independent application effective dose, compositions of the present invention provides astonishing better effect, toxicity does not increase simultaneously, thereby the safe dose scope is big
Curative effect lasting time is long, and resultant effect is good, and is easy to use.Compositions of the present invention can 1～2 administration every day, is preferably every day 1 time.
The specific embodiment
Now further specify content of the present invention, but range of application of the present invention is not limited to following example by following example.
Example 1
A, acipimox 200g
Celphere 250g
7%PVP solution (solvent is 90% ethanol) 200g
Preparation technology: acipimox is crossed 120 mesh sieves, and recipe quantity takes by weighing, and pours in the hopper.Drive the granulating and coating machine, go into wind pressure 0.5bar, 30 ℃ of inlet air temperature, spray gun pressure (CYL) 3bar, atomizing pressure (CAP1) 0.8bar pours celphere into, pelletize, blanking velocity 4rpm, the pump 12% of wriggling, rotary speed 145rpm, spray 7%PVP solution (solvent is 90% ethanol).Pelletize finishes, 50 ℃ of oven dry, discharging.
B, simvastatin 5g
Celphere 30g
7%PVP solution (solvent is 90% ethanol) 30g
Preparation technology: simvastatin is crossed 120 mesh sieves, and recipe quantity takes by weighing, and pours in the hopper.Drive the granulating and coating machine, go into wind pressure 0.5bar, 30 ℃ of inlet air temperature, CYL:3bar, CAP1:0.8bar falls celphere, pelletize, blanking velocity 4rpm, the pump 6% of wriggling, rotary speed 160rpm, spray 7%PVP solution (solvent is 90% ethanol).Pelletize finishes, 45 ℃ of oven dry, discharging.
C, the piller that a and b are made adopts hard capsule medicine filling machine to be respectively 200mg according to the weight that contains acipimox and simvastatin in per two capsules and 5mg fills, and gets final product.
Example 2
A, acipimox 200g
Lactose 30g
Carboxymethyl starch sodium 30g
Microcrystalline Cellulose 18g
The ethanol solution 100g of 6%PVP
Magnesium stearate 2g
Preparation technology: acipimox is crossed 100 mesh sieves, lactose, carboxymethyl starch sodium, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the acipimox of recipe quantity and lactose, carboxymethyl starch sodium, microcrystalline Cellulose mix homogeneously, adding the 6%PVP ethanol solution granulates in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
B, simvastatin 10g
Hydroxypropyl cellulose 15g
Pregelatinized Starch 10g
The ethanol solution 30g of 6%PVP
Rikemal B 200 1g
Preparation technology: simvastatin is crossed 100 mesh sieves, 80 mesh sieves are crossed in hydroxypropyl cellulose, pregelatinized Starch, take by weighing the simvastatin of recipe quantity and hydroxypropyl cellulose, pregelatinized Starch mix homogeneously, the ethanol solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the Rikemal B 200 of recipe quantity in the dried granule.
C, with above-mentioned a, two kinds of components of b adopt the bi-layer tablet press stamping promptly to get double-layer tablet.
Example 3
A, acipimox 200g
Lactose 30g
Carboxymethyl starch sodium 30g
Microcrystalline Cellulose 18g
The ethanol solution 100g of 6%PVP
Magnesium stearate 2g
Preparation technology: acipimox is crossed 100 mesh sieves, lactose, carboxymethyl starch sodium, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the acipimox of recipe quantity and lactose, carboxymethyl starch sodium, microcrystalline Cellulose mix homogeneously, adding the 6%PVP ethanol solution granulates in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
B, simvastatin 20g
Hydroxypropyl cellulose 30g
Pregelatinized Starch 20g
The ethanol solution 50g of 6%PVP
Rikemal B 200 2g
Preparation technology: simvastatin is crossed 100 mesh sieves, 80 mesh sieves are crossed in hydroxypropyl cellulose, pregelatinized Starch, take by weighing the simvastatin of recipe quantity and hydroxypropyl cellulose, pregelatinized Starch mix homogeneously, the ethanol solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the Rikemal B 200 of recipe quantity in the dried granule.
C, with above-mentioned a, two kinds of components of b adopt the bi-layer tablet press stamping promptly to get double-layer tablet.
Example 4
A, acipimox 300g
Hydroxypropyl emthylcellulose-4M 40g
Microcrystalline Cellulose 30g
The ethanol solution 150g of 8%PVP
Magnesium stearate 2g
Preparation technology: acipimox is crossed 100 mesh sieves, hydroxypropyl cellulose-4M, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the acipimox of recipe quantity and hydroxypropyl cellulose-4M, microcrystalline Cellulose mix homogeneously, adding the 8%PVP ethanol solution granulates in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
B, simvastatin 20g
Sodium carboxymethyl cellulose 30g
Lactose 20g
The 95% alcoholic solution 50g of 6%PVP
Magnesium stearate 2g
Preparation technology: simvastatin is crossed 100 mesh sieves, sodium carboxymethyl cellulose, lactose are crossed 80 mesh sieves, take by weighing the simvastatin of recipe quantity and sodium carboxymethyl cellulose, lactose mix homogeneously, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
C, with above-mentioned a, two kinds of components of b adopt the bi-layer tablet press punching press promptly to get double-layer tablet.
Example 5
A, acipimox 300g
Celphere 250g
7%PVP solution (solvent is 90% ethanol) 200g
Preparation technology: acipimox is crossed 120 mesh sieves, and recipe quantity takes by weighing, and pours in the hopper.Drive the granulating and coating machine, go into wind pressure 0.5bar, 30 ℃ of inlet air temperature, CYL:3bar, CAP1:0.8bar pours celphere into, pelletize, blanking velocity 4rpm, the pump 12% of wriggling, rotary speed 145rpm, spray 7%PVP solution (solvent is 90% ethanol).Pelletize finishes, 50 ℃ of oven dry, discharging.
What make among b, a contains the acipimox piller
Surelease 90g
Pulvis Talci 1g
Pure water 50g
Preparation technology: pour the acipimox piller that contains that makes among a into rotating disk, drive the granulating and coating machine, go into wind pressure 1.0bar, 30 ℃ of inlet air temperature, CYL:3bar, CAP1:1.5bar, the pump 5% of wriggling, rotary speed 180rpm sprays into the pure water solution of Surelease.Coating finishes, 50 ℃ of oven dry, discharging.
C, make the simvastatin piller, adopt hard capsule medicine filling machine to be respectively 300mg with the acipimox piller that makes among this routine b and 10mg fills, get final product according to the weight that contains acipimox and simvastatin in per two capsules according to the requirement of b in the example 5.
Example 6
A, acipimox 300g
Celphere 300g
7%PVP solution (solvent is 90% ethanol) 200g
Preparation technology: acipimox is crossed 120 mesh sieves, and recipe quantity takes by weighing, and pours in the hopper.Drive the granulating and coating machine, go into wind pressure 0.5bar, 30 ℃ of inlet air temperature, CYL:3bar, CAP1:0.8bar pours celphere into, pelletize, blanking velocity 4rpm, the pump 12% of wriggling, rotary speed 145rpm sprays into 7%PVP solution (solvent is 90% ethanol).Pelletize finishes, 50 ℃ of oven dry, discharging.
What make among b, a contains the acipimox piller
Ethyl cellulose 40g
Stearic acid 70g
Polyethylene Glycol-6000 6g
Pulvis Talci 12g
95% ethanol 1000g
Preparation technology: the acipimox piller that contains that makes among a is poured in the hopper.Drive the granulating and coating machine, 30 ℃ of inlet air temperature are gone into wind pressure 0.5bar, 30 ℃ of inlet air temperature, and CYL3bar, CAP1 1.0bar, the pump 6% of wriggling, rotary speed 175rpm sprays into 95% alcoholic solution of ethyl cellulose, stearic acid and Polyethylene Glycol-6000.Coating finishes, 50 ℃ of oven dry, discharging.
C, simvastatin 5g
Celphere 30g
7%PVP solution (solvent is 90% ethanol) 30g
Preparation technology: simvastatin is crossed 120 mesh sieves, and recipe quantity takes by weighing, and pours in the hopper, drives the granulating and coating machine, goes into wind pressure 0.5bar, 30 ℃ of inlet air temperature, and CYL:3bar, CAP1:0.8bar pours celphere into, pelletize.Blanking velocity 4rpm, the pump 12% of wriggling, rotary speed 120rpm sprays into 7%PVP solution (solvent is 90% ethanol).Pelletize finishes, 45 ℃ of oven dry, discharging.
D, the piller that b and c are made adopts hard capsule medicine filling machine to be respectively 300mg according to the weight that contains acipimox and simvastatin in per two capsules and 5mg fills, and gets final product.
Example 7
A, acipimox 400g
Mannitol 10g
Lactose 40g
Microcrystalline Cellulose 20g
The 95% alcoholic solution 120g of 6%PVP
Magnesium stearate 2g
Preparation technology: acipimox is crossed 100 mesh sieves, mannitol, lactose, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the acipimox of recipe quantity and mannitol, lactose, microcrystalline Cellulose mix homogeneously, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
B, simvastatin 5g
Pregelatinized Starch 50g
Mannitol 50g
Lactose 40g
The 95% alcoholic solution 100g of 6%PVP
Micropowder silica gel 5g
Preparation technology: simvastatin is crossed 100 mesh sieves, pregelatinized Starch, mannitol, lactose are crossed 80 mesh sieves, take by weighing the simvastatin of recipe quantity and pregelatinized Starch, mannitol, lactose mix homogeneously, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
C, with above-mentioned a, two kinds of components of b adopt the bi-layer tablet press punching press promptly to get double-layer tablet.
Example 8
A, acipimox 400g
Lactose 30g
Hydroxypropyl emthylcellulose-15M 20g
The 95% alcoholic solution 150g of 8%PVP
Rikemal B 200 2g
Preparation technology: acipimox is crossed 100 mesh sieves, lactose, hydroxypropyl emthylcellulose-15M cross 80 mesh sieves, take by weighing the acipimox of recipe quantity and lactose, hydroxypropyl emthylcellulose-15M mix homogeneously, 95% alcoholic solution that adds 8%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the Rikemal B 200 of recipe quantity in the dried granule.
B, simvastatin 10g
Hydroxypropyl cellulose 25g
Dextrin 20g
The 95% alcoholic solution 50g of 6%PVP
Pulvis Talci 2g
Preparation technology: simvastatin is crossed 100 mesh sieves, hydroxypropyl cellulose, dextrin are crossed 80 mesh sieves, take by weighing the simvastatin of recipe quantity and hydroxypropyl cellulose, dextrin mix homogeneously, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the Pulvis Talci of recipe quantity in the dried granule.
C, with above-mentioned a, two kinds of components of b adopt the bi-layer tablet press punching press promptly to get double-layer tablet.
The compound recipe screening of example 9 acipimoxs and simvastatin compound treatment rat hyperlipidemia
Summary:
The purpose of this test is to determine that toxicity is low, act on the acipimox strong, easy to use and the composition of simvastatin compound preparation by screening.Adopt high lipid food to bring out hyperlipemia model of rats, gavage acipimox (100～400mg/kg) and (or) simvastatin (2.5～30mg/kg) 14 days continuously for rat model.Found that, acipimox and simvastatin 5 usefulness have the obvious treatment effect to the serum lipids in rats due to the high lipid food, lipid-lowering effect is relevant with the dosage of two kinds of medicines, acipimox 200mg/kg and simvastatin 10mg/kg acipimox 200mg/kg and simvastatin 20mg/kg and acipimox 300mg/kg and simvastatin 20mg/kg drug combination group effect are remarkable, can significantly reduce the rat blood serum T-CHOL, triglyceride, low-density lipoprotein cholesterol level, remarkable high density lipoprotein increasing cholesterol levels, and These parameters all shown synergism.Wherein acipimox 300mg/kg and simvastatin 20mg/kg drug combination group most pronounced effects, the compound recipe that preferred acipimox 300mg/kg and simvastatin 20mg/kg form.In this test dose scope, the obviously influence of the active nothing of the drug combination group pair sero-enzyme relevant with liver toxicity and muscle poison.
1 test objective
By screening the composition of determining acipimox and simvastatin compound preparation, the compound preparation toxic and side effects is low to reach, effect comprehensively, effect strengthens, purpose easy to use.
2 are subjected to the reagent thing
2.1 nicotinic acid derivates
Nomenclature of drug: acipimox (Acipimox)
Lot number: 0207002
Purity: greater than 99.7%
Production unit: Lunan Pharmacy Co. Ltd
Preservation condition: shady and cool dry place preserves 1 year half effect duration.
Compound method: face with preceding usefulness 1% sodium carboxymethyl cellulose (CMC) mixing, be made into the test desired concn.
2.2 statins
Nomenclature of drug: simvastatin (Simvastatin)
Lot number: 021002
Purity: greater than 99.0%
Production unit: the big pharmaceutical factory of the auspicious nation in Zhejiang
Preservation condition: shady and cool dry place preserves 2 years effect duration.
Compound method: face with the preceding 1%CMC of using mixing, be made into the test desired concn.
3 animals
3.1 strain and source
The Wistar rat, the breeding of Military Medical Science Institute medical experiment animal center, the laboratory animal quality licence number is the moving word D01-3039 of doctor.
3.2 body weight and sex
9 week～10 weeks of age, body weight 180-220g, male.
3.3 raising condition
The regularly air draft of Animal Lab. air, illumination are good, room temperature.Every cage is raised 5 animals, and raising with the court's Experimental Animal Center is the expanded pellet diet of rat preparation specially, freely drinks water.The zoopery condition quality certification number is the moving word D01-2051 of doctor.Before on-test, observe 1 weeks such as animal feed, activity and feces, select healthy animal to enter test.
4 hyperlipemia model of rats preparations [1]
Hyperlipemia model of rats adopts high lipid food to cause the hyperlipemia method.The high lipid food prescription is as follows: normal feedstuff 86.3%, cholesterol 3%, Adeps Sus domestica 10%, methylthiouracil 0.2%, Fel Sus domestica salt 0.5% guarantee each composition mix homogeneously.Continuous 2 weeks.Give high lipid food during the administration every other day.
5 acipimoxs and simvastatin are to the influence of normal rat fat level
5.1 dosage is provided with foundation
The dosage of acipimox is 250mg/ time (calculate by body weight for humans 60kg, above-mentioned dosage is 4.2mg/kg) clinically, and 2～3 times/day, measure maximum and be no more than 1200mg[2 every day].By body surface area is the dosage equivalence principle reckoning of unit, and above-mentioned people's common dose is converted into rat dosage and is about 50mg/kg/day.Again in conjunction with bibliographical information [3], with the dosage setting of acipimox in this test be 100,200,300,400mg/kg.
The dosage of simvastatin is 10mg/ time (calculate by body weight for humans 60kg, above-mentioned dosage is 0.17mg/kg) clinically, 1 time/day, measures maximum every day and is no more than 80mg [4].By body surface area is the dosage equivalence principle reckoning of unit, and above-mentioned people's common dose is converted into rat dosage and is about 0.85mg/kg.Bibliographical information, simvastatin 5mg/kg can make that low-density lipoprotein cholesterol and triglyceride levels significantly reduce [5,6,7] in the serum on the animal hyperlipemia model that high lipid food causes, with the dosage setting of simvastatin in this test be 2.5,5,10,20,30mg/kg.
5.2 group setting
According to above-mentioned dosage setting,, the intact animal is divided at random: (1) normal control group by the serum total cholesterol level homeostatic principle; (2) acipimox 100mg/kg group; (3) acipimox 200mg/kg group; (4) acipimox 300mg/kg group; (5) acipimox 400mg/kg group; (6) simvastatin 2.5mg/kg group; (7) simvastatin 5mg/kg group; (8) simvastatin 10mg/kg group; (9) simvastatin 20mg/kg group; (10) simvastatin 30mg/kg group; (11) acipimox 200mg/kg and simvastatin 5mg/kg group; (12) acipimox 200mgg/kg and simvastatin 10mg/kg group; (13) acipimox 200mg/kg and simvastatin 20mg/kg group; (14) acipimox 300mg/kg and simvastatin 5mg/kg group; (15) acipimox 300mg/kg and simvastatin 10mg/kg group; (16) acipimox 300mg/kg and simvastatin 20mg/kg group; (17) acipimox 400mg/kg and simvastatin 5mg/kg group; (18) acipimox 400mg/kg and simvastatin 10mg/kg group.Every group 10.
5.3 administration
The route of administration of clinical plan usefulness is oral, so administration by gavage administration, continuous irrigation stomach 4 days are adopted in this test.Irritating stomach all carries out after the animal feed.Every day 1 time.The administration volume is the 0.3ml/100g body weight.
5.4 detection index
The serum chemistry index comprises T-CHOL (TC), alanine aminotransferase (ALT), creatine kinase (CK), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), HDL-C (HDL-L).Wherein alanine aminotransferase (ALT), creatine kinase (CK) detectable adopt Beijing Zhongsheng Biological Engineering High Technology Company's product, measure with the SABA/18 automatic clinical chemistry analyzer; All the other reagent adopt Japanese Luo Shi reagent company product, measure with Hitachi's 7020 automatic biochemistry analyzers.Fasting is 16 hours before the assay method reference reagent description blood sampling.
6 acipimoxs and simvastatin are to the influence of hyperlipidemia rats blood lipid level
6.1 dosage is provided with foundation
With the experiment of 5.1 normal rats.
6.2 group setting
According to above-mentioned dosage setting,, rat model is divided at random by the serum total cholesterol level homeostatic principle:
(1) normal control group; (2) model control group; (3) acipimox 100mg/kg group; (4) acipimox 200mg/kg group; (5) acipimox 300mg/kg group; (6) acipimox 400mg/kg group; (7) simvastatin 2.5mg/kg group; (8) simvastatin 5mg/kg group; (9) simvastatin 10mg/kg group; (10) simvastatin 20mg/kg group; (11) simvastatin 30mg/kg group; (12) acipimox 200mg/kg and simvastatin 5mg/kg group; (13) acipimox 200mg/kg and simvastatin 10mg/kg group; (14) acipimox 200mg/kg and simvastatin 20mg/kg group; (15) acipimox 300mg/kg and simvastatin 5mg/kg group; (16) acipimox 300mg/kg and simvastatin 10mg/kg group; (17) acipimox 300mg/kg and simvastatin 20mg/kg group; (18) acipimox 400mg/kg and simvastatin 5mg/kg group; (19) acipimox 400mg/kg and simvastatin 10mg/kg group.Every group 10.
6.3 administration
The route of administration of clinical plan usefulness is oral, so administration by gavage administration, continuous irrigation stomach 14 days are adopted in this test.Irritating stomach all carries out after the animal feed.Every day 1 time.The administration volume is the 0.3ml/100g body weight.
6.4 detection index
With the experiment of 5.4 normal rats.
The test that influences each other of 7 acipimoxs and simvastatin compound recipe different component
7.1 group setting
From significant acipimox of curative effect and simvastatin dosage group, determine the dosage of acipimox and simvastatin compound recipe: (1) normal control group; (2) model control group; (3) acipimox 200mg/kg; (4) acipimox 300mg/kg; (5) simvastatin 10mg/kg; (6) simvastatin 20mg/kg; (7) acipimox 200mg/kg and simvastatin 10mg/kg group compound recipe group; (8) acipimox 200mg/kg and simvastatin 20mg/kg group compound recipe group; (9) acipimox 300mg/kg and simvastatin 20mgg/kg group compound recipe group.Every group 10.Measure serum total cholesterol level before the grouping, press the homeostatic principle random packet.Every group 10.
7.2 administration and detection index
With aforementioned 5.3 and 5.4.
8 result of the tests
8.1 acipimox and simvastatin are to the influence of normal rat fat level
After the normal rat administration 4 days, the T-CHOL and the low-density lipoprotein cholesterol of acipimox, simvastatin and drug combination group all decrease, and the HDL-C level raises, and serum triglycerides slightly descends after the administration, but no difference of science of statistics sees Table 1.
Table 1 acipimox and simvastatin and compound recipe are to the influence of normal rat fat
| Group | Serum total cholesterol (mmol/L) | Serum triglycerides (mmol/L) | Low-density lipoprotein cholesterol (mmol/L) | HDL-C (mmol/L) |
| The hot 10mg/kg of the hot 5mg/kg Ah of Normal group Acipimox 100mg/kg Acipimox 200mg/kg Acipimox 300mg/kg Acipimox 400mg/kg Simvastatin 2.5mg/kg Simvastatin 5mg/kg Simvastatin 10mg/kg Simvastatin 20mg/kg Simvastatin 30mg/kg Ah 200+ 200+ hot 10mg/kg Ah 200+ hot 20mg/kg Ah 300+ hot 5mg/kg Ah 300+ hot 10mg/kg Ah 300+ hot 20mg/kg Ah 400+ hot 5mg/kg Ah 400+ | 1.68±0.20 1.52±0.31 1.56±0.26 1.41±0.23 * 1.44±0.27 * 1.53±0.27 1.47±0.25 1.44±0.26 * 1.46±0.24 * 1.41±0.29 * 1.45±0.32 1.38±0.24 ** 1.35±0.26 ** 1.42±0.28 * 1.41±0.30 * 1.31±0.22 ** 1.49±0.27 1.44±0.30 | 0.69±0.26 0.64±0.27 0.62±0.26 0.6±0.31 0.59±0.25 0.68±0.25 0.61±0.23 0.62±0.32 0.65±0.24 0.57±0.26 0.67±0.28 0.54±0.25 0.51±0.27 0.57±0.16 0.52±0.31 0.58±0.27 0.62±0.30 0.57±0.30 | 0.3±0.15 0.27±0.14 0.25±0.15 0.2±0.11 0.25±0.14 0.28±0.15 0.25±0.19 0.21±0.13 0.21±0.09 0.22±0.11 0.24±0.12 0.23±0.09 0.17±0.06 * 0.21±0.09 0.20±0.09 0.16±0.10 * 0.25±0.14 0.22±0.12 | 0.92±0.13 0.98±0.17 0.95±0.17 1.04±0.20 1.12±0.19 * 0.91±0.10 0.95±0.12 0.96±0.11 1.05±0.13 1.01±0.16 1.03±0.17 1.12±0.20 * 1.16±0.29 * 1.05±0.21 1.07±0.26 1.15±0.27 * 1.11±0.18 * 1.16±0.24 * |
Annotate: compare with the normal control group,
*P＜0.05,
*P＜0.01
8.2 acipimox and simvastatin are to the influence of rat model blood lipid level
Rat is raised with the high lipid food administration of dividing into groups after 14 days.The dosage range of acipimox is 100～400mg/kg, and the dosage range of simvastatin is 2.5～30mg/kg, forms the drug combination group.After the administration 14 days, compare with model control group, each dosage group serum total cholesterol of acipimox and simvastatin, triglyceride, low-density lipoprotein cholesterol all have decline in various degree, and the HDL-C level all raises to some extent, sees Table 2.
Compare with model control group, the serum total cholesterol of acipimox 200mg/kg and simvastatin 10mg/kg, acipimox 200mg/kg and simvastatin 20mg/kg and acipimox 300mg/kg and three drug combination groups of simvastatin 20mg/kg rat, triglyceride, low-density lipoprotein cholesterol level all significantly reduce, and the HDL-C level all significantly raises.Compare with the acipimox or the simvastatin folk prescription group of same dose, above-mentioned three drug combination group serum total cholesterols, triglyceride, low-density lipoprotein cholesterol level all significantly reduce, the HDL-C level all significantly raises, and These parameters is all shown synergism.Wherein remarkable with acipimox 300mg/kg and simvastatin 20mg/kg drug combination group effect.
Table 2 acipimox and simvastatin and compound recipe are to the influence of rat model blood fat
| Group | Serum total cholesterol (mmol/L) | Serum triglycerides (mmol/L) | Low-density lipoprotein cholesterol (mmol/L) | HDL-C (mmol/L) |
| The hot 10mg/kg of the hot 5mg/kg Ah of Normal group model control group Acipimox 100mg/kg Acipimox 200mg/kg Acipimox 300mg/kg Acipimox 400mg/kg Simvastatin 2.5mg/kg Simvastatin 5mg/kg Simvastatin 10mg/kg Simvastatin 20mg/kg Simvastatin 30mg/kg Ah 200+ 200+ hot 10mg/kg Ah 200+ hot 20mg/kg Ah 300+ hot 5mg/kg Ah 300+ hot 10mg/kg Ah 300+ hot 20mg/kg Ah 400+ hot 5mg/kg Ah 400+ | 1.58±0.25 11.75±2.01 ### 11.30±1.60 10.32±0.76 * 9.44±1.51 ** 8.58±0.81 *** 11.65±1.91 10.14±1.04 * 8.70±1.61 ** 7.85±0.90 *** 7.93±0.95 *** 9.02±0.79 * 6.33±0.59 *** 5.30±1.30 *** 8.36±0.99 *** 6.19±0.41 *** 4.16±1.41 *** 7.25±0.67 *** 6.65±0.77 *** | 0.43±0.08 2.19±0.52 ### 2.25±0.67 2.00±1.44 1.67±0.51 * 1.54±0.35 ** 2.23±0.37 2.12±0.45 1.75±0.40 * 1.64±0.21 ** 1.27±0.60 ** 2.05±0.49 1.41±0.23 *** 1.15±0.25 *** 1.72±0.33 * 1.58±0.29 ** 0.88±0.26 *** 1.62±0.29 ** 1.58±0.65 * | 0.13±0.08 8.06±1.17 ### 7.88±1.27 7.15±0.59 * 7.12±0.70 * 6.75±1.36 * 7.96±1.21 7.63±0.44 6.89±0.50 ** 6.79±0.66 ** 6.71±0.48 ** 7.07±0.70 * 5.51±0.70 *** 5.31±0.64 *** 6.93±0.46 * 5.61±0.46 *** 5.22±1.31 *** 6.95±1.20 * 5.65±0.47 *** | 1.05±0.12 3.34±0.55 ### 3.42±0.57 3.47±0.58 3.89±0.63 3.95±0.65 * 3.38±0.36 3.41±0.58 3.46±0.65 3.69±0.59 3.94±0.64 * 3.54±0.45 3.94±0.64 * 3.93±0.59 * 3.68±0.70 3.82±0.56 4.36±0.80 ** 3.67±0.67 3.93±0.43 * |
Annotate: compare ###P＜0.001 with the normal control group; Compare with model control group,
*P＜0.05,
*P＜0.01,
* *P＜0.001
8.3 acipimox and simvastatin are to the active influence of rat model sero-enzyme
This experiment is estimated the influence to rat model liver function and skeletal muscle tissue of acipimox and simvastatin and compound recipe by measuring medication level of alanine aminotransferase and creatine kinase in the high blood lipid model rat blood serum after 14 days.The result shows, compares with model control group, and (100～400mg/kg) group model rat blood serum alanine aminotransferases and creatine kinase level all do not have significant difference (P＞0.05) to each dosage of acipimox; (These parameters is not also seen significant difference (P＞0.05) to each dosage of simvastatin in 2.5～30mg/kg) the group model rat blood serums, each drug combination group rat blood serum alanine aminotransferase of simvastatin and acipimox and serum creatine kinase have no significant change (P＞0.05), see Table 3.
Table 3 acipimox and simvastatin and compound recipe swash rat model serum alanine aminotransferase and creatine
The influence of enzyme
| Group | Alanine aminotransferase (nmol.s-1/L) | Creatine kinase (U/L) |
| The hot 10mg/kg of the hot 5mg/kg Ah of Normal group model control group Acipimox 100mg/kg Acipimox 200mg/kg Acipimox 300mg/kg Acipimox 400mg/kg Simvastatin 2.5mg/kg Simvastatin 5mg/kg Simvastatin 10mg/kg Simvastatin 20mg/kg Simvastatin 30mg/kg Ah 200+ 200+ hot 10mg/kg Ah 200+ hot 20mg/kg Ah 300+ hot 5mg/kg Ah 300+ hot 10mg/kg Ah 300+ hot 20mg/kg Ah 400+ hot 5mg/kg Ah 400+ | 604.6±107.2 678.1±140.4 619.6±110.4 649.3±78.3 660.2±130.1 647.6±116.8 642.3±121.6 586.8±121.9 617.6±104.0 651.4±104.5 672.0±151.6 659.7±118.1 636.9±107.3 640.3±134.8 655.7±119.2 644.0±124.7 608.1±111.5 625.5±145.2 653.3±129.7 | 365.3±248.6 327.7±105.5 361.4±100.9 324.8±102.7 336.1±118.3 357.7±122.8 364.6±105.9 370.7±131.2 372.2±100.1 382.2±103.8 376.8±122.8 376.1±108.1 365.3±119.4 360.3±112.1 371.4±113.5 378.1±107.7 360.6±112.6 368.6±108.4 369.9±116.2 |
8.4 the different component test that influences each other in acipimox and the simvastatin compound recipe
High blood lipid model rat successive administration is after 14 days, compare with the folk prescription of same dose, acipimox and simvastatin drug combination group all can obviously reduce T-CHOL in the rat model serum, triglyceride, low-density lipoprotein cholesterol level and obvious high density lipoprotein increasing cholesterol levels, see Table 4.
Analysis-by-synthesis, compare with model control group, acipimox 200mg/kg and simvastatin 10mg/kg, acipimox 200mg/kg and simvastatin 20mg/kg and acipimox 300mgg/kg and simvastatin 20mgg/kg drug combination group effect are remarkable, can significantly reduce rat blood serum T-CHOL, triglyceride, low-density lipoprotein cholesterol level, significantly the high density lipoprotein increasing cholesterol levels.Compare with the acipimox or the simvastatin folk prescription group of same dose, above-mentioned three drug combination group serum total cholesterols, triglyceride, low-density lipoprotein cholesterol level all significantly reduce, the HDL-C level all significantly raises, and three drug combination groups all show synergism to These parameters.Wherein acipimox 300mg/kg and simvastatin 20mg/kg drug combination group most pronounced effects, the compound recipe that therefore preferred acipimox 300mg/kg and simvastatin 20mg/kg form.
The effect of different component treatment serum lipids in rats in table 4 acipimox and the simvastatin compound recipe
| Group | Serum total cholesterol (mmol/L) | Serum triglycerides (mmol/L) | Low-density lipoprotein cholesterol (mmol/L) | HDL-C (mmol/L) |
| The hot 20mg/kg of the hot 20mg/kg Ah of the hot 10mg/kg Ah of Normal group model control group Acipimox 200mg/kg Acipimox 300mg/kg Simvastatin 10mg/kg Simvastatin 20mg/kg Ah 200+ 200+ 300+ | 1.84±0.40 11.56±2.53 ### 9.51±1.48 * 8.74±1.48 ** 8.88±1.16 ** 7.72±1.47 *** 5.85±1.53 ***，!!!，@@@ 4.45±1.40 ***，!!!，&&& 3.14±1.41 ***，^^^，&&& | 0.66±0.24 2.28±0.62 ### 1.95±0.63 1.69±0.57 * 1.71±0.52 * 1.43±0.64 ** 1.15±0.39 ***，!!，@ 0.82±0.26 ***.!!!，& 0.52±0.16 ***，^^^，&&& | 0.24±0.08 8.18±1.43 ### 7.05±0.72 * 6.87±1.54 * 6.85±0.46 * 6.61±0.74 ** 5.17±1.56 ***，!!，@@ 4.92±0.78 ***，!!!，&&& 4.71±1.33 ***，^^，&& | 1.00±0.28 2.83±0.55 ###3.24±0.47 3.34±0.67 *3.48±0.73 *3.60±0.58 **4.22±0.42 ***，!!!，@4.35±0.55 ***，!!!，&4.49±0.42 ***，^^^，&& |
Annotate: compare ###P＜0.001, ##P＜0.01, #P＜0.05 with the normal control group
Compare with model control group,
*P＜0.05,
*P＜0.01,
* *P＜0.001
Compare with acipimox 200mg/kg group,! ! ! P＜0.001,! ! P＜0.01
Compare ， @P＜0.05 ， @@P＜0.01 ， @@@P＜0.001 with simvastatin 10mg/kg group
Compare ^^^P＜0.001 with acipimox 300mg/kg group
Compare ， ﹠amp with simvastatin 20mg/kg group; ﹠amp; ﹠amp; P＜0.001 ， ﹠amp; P＜0.05
9 conclusions
Acipimox and simvastatin 5 usefulness have the obvious treatment effect to the serum lipids in rats due to the high lipid food, lipid-lowering effect is relevant with the dosage of two kinds of medicines, acipimox 200mg/kg and simvastatin 10mg/kg, acipimox 200mg/kg and simvastatin 20mg/kg and acipimox 300mg/kg and simvastatin 20mg/kg drug combination group effect are remarkable, can significantly reduce rat blood serum T-CHOL, triglyceride, low-density lipoprotein cholesterol level, remarkable high density lipoprotein increasing cholesterol levels, and These parameters all shown synergism.Wherein acipimox 300mg/kg and simvastatin 20mg/kg drug combination group most pronounced effects, the compound recipe that preferred acipimox 300mg/kg and simvastatin 20mg/kg form.In this test dose scope, the drug combination group is to the obviously influence of the active nothing of sero-enzyme, and tentatively showing does not have tangible toxic action to liver and striped muscle.In addition, the clinical usage of acipimox folk prescription is 3 times/day at present, originally experimental results show that, acipimox still has significant effect for reducing blood fat 1 time/day, and toxicity is little, only medication provides reliable experimental evidence 1 time for acipimox and simvastatin are formed behind the compound recipe one for this, and this will make things convenient for the patient to take greatly, improves patient's compliance.
List of references
[1] Xu Shuyun, Bian Rulian, Chen Xiu chief editor. pharmacological experiment methodology (third edition), the People's Health Publisher publishes, in January, 2002,1201-1202
[2] OLBETAM (acipimox) description (Pharmacia, New Zealand)
[3]Al-Shurbajii A，et al.The effect of Acipimox on triacylglycerol metabolism inrat.Scand J Clin Lab Invest，1990，50(2)：203-208
[4] simvastatin, two ones of Pharmacopoeia of People's Republic of China versions in 2000, clinical application notice, 291-292
[5] Wei Yun etc., the research of simvastatin effect for reducing blood fat. the northwest pharmaceutical journal is learned, and 1998; 13 (6): 253-254
[6] Zheng Gaoli etc., the experimentation of simvastatin effect for reducing blood fat, the Academy of Medical Sciences, Zhejiang journal, 1999; (39): 21-22
[7] Yan Xiaoyan etc., simvastatin are to the influence of high fat raising rabbit blood fat, and contemporary Chinese is used pharmaceutical journal, 2000; 17 (4): 263-266
Claims (3)
1. pharmaceutical composition that contains acipimox and simvastatin or its solvate, the weight ratio that it is characterized in that acipimox and simvastatin is 10～15: 1.
2. pharmaceutical composition that contains acipimox and simvastatin or its solvate, the weight ratio that it is characterized in that acipimox and simvastatin is 40～80: 1.
3. the pharmaceutical composition that contains acipimox and simvastatin as claimed in claim 1 or 2 is characterized in that it is tablet, capsule, granule, pill or drop pill.
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Non-Patent Citations (3)
| Title |
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| The additional effects of acipimox to simvastatin in thetreatment of combined hyperlipidemia. Hoogerbrugge,N,et al,j.intern.med.,Vol.241 No.2 1997 * |
| TITLE Tolerability and effects of high doses acipimox asadditional lipid-lowering therapy in familialhypercholesterolemia. Stuyt,P. M. J,et al,neth.j.med.,Vol.53 No.5 1998 * |
| TITLE Tolerability and effects of high doses acipimox asadditional lipid-lowering therapy in familialhypercholesterolemia. Stuyt,P. M. J,et al,neth.j.med.,Vol.53 No.5 1998;The additional effects of acipimox to simvastatin in thetreatment of combined hyperlipidemia. Hoogerbrugge,N,et al,j.intern.med.,Vol.241 No.2 1997 * |
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