CN1568993A - Composition for treating hyperlipemia - Google Patents
Composition for treating hyperlipemia Download PDFInfo
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- CN1568993A CN1568993A CN 200410024067 CN200410024067A CN1568993A CN 1568993 A CN1568993 A CN 1568993A CN 200410024067 CN200410024067 CN 200410024067 CN 200410024067 A CN200410024067 A CN 200410024067A CN 1568993 A CN1568993 A CN 1568993A
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Abstract
The invention discloses a novel composition for treating hyperlipemia, which comprises effective dose of Nicotinic Acid and Atorvastatin calcium by the weight ratio is (30-240) : 1.
Description
Affiliated technical field
The present invention relates to treat the new compositions of hyperlipidemia, particularly contain the compositions of nicotinic acid and Atorvastatin calcium 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.
Atorvastatin (Atorvastatin) is a third generation Statins fat regulation medicine, is a kind of complete synthesis hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor, and nineteen ninety-five goes on the market with calcium salt forms in the U.S. first.Its chemical name is: [R-(R ', R ')]-2-(4-fluorophenyl)-β δ-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(aniline) carbonyl]-1-hydrogen-pyrroles-1-enanthic acid calcium trihydrate.
Structural formula:
Molecular formula: (C
33H
34FN
2O
5)
2Ca3H
2O
Usually said atorvastatin just is meant above-mentioned calcium salt trihydrate, or is called Atorvastatin calcium.China's guiding doctor's net (www.daoyi.com/drug/html/200009/6000000189670.html) is summarized as follows its drug effect:
1, suppresses the HMG-CoA reductase.The HMG-CoA reductase is the rate-limiting enzyme in the cholesterol synthase system, and by the inhibitory action to it, cholesterol is synthetic to be reduced thereby make.Atorvastatin is identical with pravastatin (pravastatin), biological activity is promptly arranged after the oral absorption, and lovastatin (lovastatin) and simvastatin (simvastatin) is prodrug, in vivo ability biologically active after the metabolism.Therefore atorvastatin plays a role faster than lovastatin and simvastatin.This medicine is strong than other similar medicines to the inhibitory action of HMG-CoA reductase.Atorvastatin is 73nmol.L to inhibiting 50% inhibition concentration of HMG-CoA reductase (IC50)
-1, and pravastatin is 2650nmol.L
-1Atorvastatin 80mg/d, pravastatin 40mg/d, simvastatin 40mg/d make blood plasma methyldihydroxypentanoic acid (MVA) concentration reduce 59%, 32% and 49% respectively.In addition, the single dose atorvastatin is long than other similar medicines to the inhibiting persistent period of HMG-CoA reductase.
2, increase low density lipoprotein, LDL (LDL) receptor.Atorvastatin makes in the blood plasma by the inhibitory action to the HMG-CoA reductase and histiocyte inner cholesterol concentration all reduces, and can stimulate ldl receptor density increase in the liver, strengthens thereby blood plasma low-density lipoprotein cholesterol (LDL-C) is removed.Liver L DL receptor can combine with very low density lipoprotein (VLDL) (VLDL), the VLDL degraded is increased, thereby make triglyceride (TG) lowering of concentration.
3, suppressing C-VLDL (VLDL-C) synthesizes.Cholesterol is that synthetic VLDL is essential, and this medicine reduces by making plasma cholesterol concentration, makes the synthetic and secretion minimizing of VLDL.VLDL carries and to transport TG essential, and VLDL-C is again the precursor of LDL-C, so this medicine can make TG, VLDL-C, LDL-C all reduce.
4 study of anti-atherogenic effect.Atorvastatin soaks into by blood fat reducing, minimizing lipid and foam cell forms, and is favourable to postponing atherosclerotic lesion.This medicine can prevent that still atheromatous plaque from breaking.In addition, experiment in vitro shows that atorvastatin can suppress vascular smooth muscle propagation and migration.Zoopery shows that this medicine 2.5mg/kg can make rabbit arterial atherosclerotic plaque area reduce by 67% (P＜0.05), and lovastatin, pravastatin, the simvastatin of same dosage do not have this effect; This medicine still has the platelet activation of inhibition, reduces effects such as blood viscosity, anticoagulant.Clinical research shows after 22 routine hyperlipemia patients use this medicine 80mg/d makes plasma viscosity reduce by 10%, and the activity of proconvertin reduces by 8%, and the platelet aggregation rate that TXA2. (TXA2) is brought out reduces by 11%.These effects are all favourable to preventing atherosclerosis.
The general toleration of atorvastatin is good, and most of untoward reaction is slight, compares with lovastatin, and patient's toleration is better.
Nicotinic acid and derivant thereof can be passed through to reduce cyclic adenosine monophosphate (cAMP) level and the inhibitory hormone sensitive lipase in fatty tissue, the catabolism that directly suppresses fat, make TG be difficult for being decomposed into free fatty (FFA), cause FFA concentration reduction in the blood, the lack of material of the synthetic TG of liver, reduce so that VLDL is synthetic, cause that Secondary cases LDL produces minimizing.In addition, this medicine directly suppresses liver and synthesizes the reason that VLDL also may be reduction LDL.Nicotinic acid and derivant thereof can reduce LDL, TG level by reducing the VLDL generation, and then reduce the TC level, promptly reduce to have the blood plasma lipoprotein level that causes arteriosclerosis (AS) effect, and raising has the HDL level of anti-AS effect.
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 nicotinic acid 750mg, but does not have to disclose the pharmacological experimental data of its beneficial effect and best proportioning.
Chinese patent application CN1425374A discloses nicotinic acid and lovastatin compositions, disclosed ratio is that the weight ratio of nicotinic acid and lovastatin is 25～50: 1, preferred ratio is 25: 1 or 37.5: 1, but does not relate to the best proportioning and the corresponding pharmacological experimental data of nicotinic acid and atorvastatin 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 the effect enhancing, toxic and side effects is low and easy to use.This medicine contains the nicotinic acid and the atorvastatin calcium salt trihydrate (hereinafter to be referred as Atorvastatin calcium) of special ratios, because two medicine mechanism of action differences, effect for reducing fat will be more comprehensive after the composition compositions, 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 Atorvastatin calcium 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 nicotinic acid and Atorvastatin calcium and pharmaceutic adjuvant, and wherein the weight ratio of nicotinic acid and Atorvastatin calcium is 30～240: 1, preferred ratio be 30～90: 1, further preferred ratio be 90: 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, nicotinic acid content is equivalent to the daily dose of about 600～2250mg with the compositions administration time, the atorvastatin calcium content is equivalent to the daily dose of 5～80mg, and wherein preferred atorvastatin calcium 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 nicotinic acid of effective dose is made slow-released part for reaching persistent therapeutic effect, make slow releasing preparation jointly with the Atorvastatin calcium 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.
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 nicotinic acid or the Atorvastatin calcium of independent application effective dose, compositions of the present invention provides astonishing better effect, and 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, nicotinic acid 600g
Celphere 250g
7%PVP solution (solvent is 90% ethanol) 200g
Preparation technology: nicotinic acid 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, Atorvastatin calcium 5g
Celphere 30g
7%PVP solution (solvent is 90% ethanol) 30g
Preparation technology: Atorvastatin calcium 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 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 nicotinic acid and Atorvastatin calcium in per two capsules and 5mg fills, and gets final product.
Example 2
A, nicotinic acid 600g
Lactose 30g
Carboxymethyl starch sodium 30g
Microcrystalline Cellulose 18g
The ethanol solution 100g of 6%PVP
Magnesium stearate 2g
Preparation technology: nicotinic acid is crossed 100 mesh sieves, lactose, carboxymethyl starch sodium, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the nicotinic acid 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, Atorvastatin calcium 10g
Hydroxypropyl cellulose 15g
Pregelatinized Starch 10g
The ethanol solution 30g of 6%PVP
Rikemal B 200 1g
Preparation technology: Atorvastatin calcium is crossed 100 mesh sieves, 80 mesh sieves are crossed in hydroxypropyl cellulose, pregelatinized Starch, take by weighing the Atorvastatin calcium 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, every weight that contains nicotinic acid and Atorvastatin calcium is respectively 200mg and 10mg.
Example 3
A, nicotinic acid 600g
Lactose 30g
Carboxymethyl starch sodium 30g
Microcrystalline Cellulose 18g
The ethanol solution 100g of 6%PVP
Magnesium stearate 2g
Preparation technology: nicotinic acid is crossed 100 mesh sieves, lactose, carboxymethyl starch sodium, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the nicotinic acid 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, Atorvastatin calcium 20g
Hydroxypropyl cellulose 30g
Pregelatinized Starch 20g
The ethanol solution 50g of 6%PVP
Rikemal B 200 2g
Preparation technology: Atorvastatin calcium is crossed 100 mesh sieves, 80 mesh sieves are crossed in hydroxypropyl cellulose, pregelatinized Starch, take by weighing the Atorvastatin calcium 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, every weight that contains nicotinic acid and Atorvastatin calcium is respectively 200mg and 20mg.
Example 4
A, nicotinic acid 900g
Hydroxypropyl emthylcellulose-4M 40g
Microcrystalline Cellulose 30g
The ethanol solution 150g of 8%PVP
Magnesium stearate 2g
Preparation technology: nicotinic acid is crossed 100 mesh sieves, hydroxypropyl cellulose-4M, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the nicotinic acid 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, Atorvastatin calcium 20g
Sodium carboxymethyl cellulose 30g
Lactose 20g
The 95% alcoholic solution 50g of 6%PVP
Magnesium stearate 2g
Preparation technology: Atorvastatin calcium is crossed 100 mesh sieves, sodium carboxymethyl cellulose, lactose are crossed 80 mesh sieves, take by weighing the Atorvastatin calcium 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, every weight that contains nicotinic acid and Atorvastatin calcium is respectively 300mg and 20mg.
Example 5
A, nicotinic acid 900g
Celphere 250g
7%PVP solution (solvent is 90% ethanol) 200g
Preparation technology: nicotinic acid 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 nicotinic acid piller
Surelease?????????????????????????????90g
Pulvis Talci 1g
Pure water 50g
Preparation technology: pour the nicotinic acid 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 Atorvastatin calcium piller, adopt hard capsule medicine filling machine to be respectively 300mg with the nicotinic acid piller that makes among this routine b and 10mg fills, get final product according to the weight that contains nicotinic acid and Atorvastatin calcium in per two capsules according to the requirement of b in the example 5.
Example 6
A, nicotinic acid 900g
Celphere 300g
7%PVP solution (solvent is 90% ethanol) 200g
Preparation technology: nicotinic acid 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 nicotinic acid piller
Ethyl cellulose 40g
Stearic acid 70g
Polyethylene Glycol-6000 6g
Pulvis Talci 12g
95% ethanol 1000g
Preparation technology: the nicotinic acid 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 CYL:3bar, 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, Atorvastatin calcium 5g
Celphere 30g
7%PVP solution (solvent is 90% ethanol) 30g
Preparation technology: Atorvastatin calcium 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 nicotinic acid and Atorvastatin calcium in per two capsules and 5mg fills, and gets final product.
Example 7
A, nicotinic acid 1200g
Mannitol 10g
Lactose 40g
Microcrystalline Cellulose 20g
The 95% alcoholic solution 120g of 6%PVP
Magnesium stearate 2g
Preparation technology: nicotinic acid is crossed 100 mesh sieves, mannitol, lactose, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the nicotinic acid 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, Atorvastatin calcium 5g
Pregelatinized Starch 50g
Mannitol 50g
Lactose 40g
The 95% alcoholic solution 100g of 6%PVP
Micropowder silica gel 5g
Preparation technology: Atorvastatin calcium is crossed 100 mesh sieves, pregelatinized Starch, mannitol, lactose are crossed 80 mesh sieves, take by weighing the Atorvastatin calcium 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, every weight that contains nicotinic acid and Atorvastatin calcium is respectively 400mg and 5mg.
Example 8
A, nicotinic acid 1200g
Lactose 30g
Hydroxypropyl emthylcellulose-15M 20g
The 95% alcoholic solution 150g of 8%PVP
Rikemal B 200 2g
Preparation technology: nicotinic acid is crossed 100 mesh sieves, lactose, hydroxypropyl emthylcellulose-15M cross 80 mesh sieves, take by weighing the nicotinic acid 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, Atorvastatin calcium 10g
Hydroxypropyl cellulose 25g
Dextrin 20g
The 95% alcoholic solution 50g of 6%PVP
Pulvis Talci 2g
Preparation technology: Atorvastatin calcium is crossed 100 mesh sieves, hydroxypropyl cellulose, dextrin are crossed 80 mesh sieves, take by weighing the Atorvastatin calcium 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, every weight that contains nicotinic acid and Atorvastatin calcium is respectively 400mg and 10mg.
The compound recipe screening of example 9 nicotinic acid and Atorvastatin calcium compound treatment rat hyperlipidemia
Summary:
The purpose of this test is to determine that by screening toxicity is low, act on the nicotinic acid strong, easy to use and the composition of Atorvastatin calcium compound preparation.Adopt high lipid food to bring out hyperlipemia model of rats, gavage nicotinic acid (300～1200mg/kg) and (or) Atorvastatin calcium (2.5～30mg/kg) 14 days continuously for rat model.Found that, nicotinic acid and Atorvastatin calcium 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, nicotinic acid 600mg/kg and Atorvastatin calcium 10mg/kg, nicotinic acid 600mg/kg and Atorvastatin calcium 20mg/kg and nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/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 nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/kg drug combination group most pronounced effects, the compound recipe that preferred nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/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 and musclar toxicity.
1 test objective
By screening the composition of determining nicotinic acid and Atorvastatin calcium compound preparation, the compound preparation toxic and side effects is low to reach, effect comprehensively and enhancing, purpose easy to use.
2 are subjected to the reagent thing
Nomenclature of drug: nicotinic acid
Lot number: 0208003
Purity: greater than 99.7%
Production unit: Lunan Pharmacy Co. Ltd
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: Atorvastatin calcium (Atorvastatin)
Lot number: 031102
Purity: greater than 99.0%
Production unit: Shandong Xinshidai Pharmaceutical Industry Co., Ltd.'s self-control
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.
The preparation of 4 hyperlipemia model of rats
[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 nicotinic acid and Atorvastatin calcium are to the influence of normal rat fat level
5.1 dosage is provided with foundation
The dosage of nicotinic acid (calculates by body weight for humans 60kg for 750～2000mg/ time clinically, above-mentioned dosage is 12.6～35mg/kg), 3 times/day is the dosage equivalence principle reckoning of unit by body surface area, and above-mentioned people's common dose is converted into rat dosage and is about 150～400mg/kg/day.In conjunction with bibliographical information
[3], with the dosage setting of nicotinic acid in this test be 300,600,900,1200mg/kg.
The dosage of Atorvastatin calcium is 10mg/ time (calculate by body weight for humans 60kg, above-mentioned dosage is 0.17mg/kg) clinically, and 1 time/day, measure maximum and be no more than 80mg every day
[3]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.In conjunction with bibliographical information
[5-8], with the dosage setting of Atorvastatin calcium 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) nicotinic acid 300mg/kg group; (3) nicotinic acid 600mg/kg group; (4) nicotinic acid 900mg/kg group; (5) nicotinic acid 1200mg/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) nicotinic acid 600mg/kg and Atorvastatin calcium 5mg/kg group; (12) nicotinic acid 600mg/kg and Atorvastatin calcium 10mg/kg group; (13) nicotinic acid 600mg/kg and Atorvastatin calcium 20mg/kg group; (14) nicotinic acid 900mg/kg and Atorvastatin calcium 5mg/kg group; (15) nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/kg group; (16) nicotinic acid 900mg/kg and Atorvastatin calcium 20mg/kg group; (17) nicotinic acid 1200mg/kg and Atorvastatin calcium 5mg/kg group; (18) nicotinic acid 1200mg/kg and Atorvastatin calcium 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 nicotinic acid and Atorvastatin calcium 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: (1) normal control group by the serum total cholesterol level homeostatic principle; (2) model control group; (3) nicotinic acid 300mg/kg group; (4) nicotinic acid 600mg/kg group; (5) nicotinic acid 900mg/kg group; (6) nicotinic acid 1200mg/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) nicotinic acid 600mg/kg and Atorvastatin calcium 5mg/kg group; (13) nicotinic acid 600mg/kg and Atorvastatin calcium 10mg/kg group; (14) nicotinic acid 600mg/kg and Atorvastatin calcium 20mg/kg group; (15) nicotinic acid 900mg/kg and Atorvastatin calcium 5mg/kg group; (16) nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/kg group; (17) nicotinic acid 900mg/kg and Atorvastatin calcium 20mg/kg group; (18) nicotinic acid 1200mg/kg and Atorvastatin calcium 5mg/kg group; (19) nicotinic acid 1200mg/kg and Atorvastatin calcium 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 nicotinic acid and Atorvastatin calcium compound recipe different component
7.1 group setting
From significant nicotinic acid of curative effect and Atorvastatin calcium dosage group, determine the dosage of nicotinic acid and Atorvastatin calcium compound recipe: (1) normal control group; (2) model control group; (3) nicotinic acid 600mg/kg; (4) nicotinic acid 900mg/kg; (5) Atorvastatin calcium 10mg/kg; (6) Atorvastatin calcium 20mg/kg; (7) nicotinic acid 600mg/kg and Atorvastatin calcium 10mg/kg group compound recipe group; (8) nicotinic acid 600mg/kg and Atorvastatin calcium 20mg/kg group compound recipe group; (9) nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/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 6.3 and 5.4.
8 result of the tests
8.1 nicotinic acid and Atorvastatin calcium are to the influence of normal rat fat level
After the normal rat administration 4 days, T-CHOL, serum triglycerides, the low-density lipoprotein cholesterol of nicotinic acid, Atorvastatin calcium and drug combination group all decrease, and the HDL-C level raises, and sees Table 1.
Table 1 nicotinic acid and Atorvastatin calcium and compound recipe are to the influence of normal rat fat
The solid high density lipoprotein gallbladder of serum total cholesterol serum triglycerides low density lipoprotein, LDL gallbladder
Group
(mmol/L) (mmol/L) alcohol (mmol/L) sterin (mmol/L)
Normal control group 1.73 ± 0.18 0.73 ± 0.24 0.33 ± 0.11 0.96 ± 0.18
Nicotinic acid 300mg/kg 1.61 ± 0.34 0.71 ± 0.26 0.31 ± 0.12 0.98 ± 0.17
Nicotinic acid 600mg/kg 1.53 ± 0.27 0.69 ± 0.32 0.27 ± 0.12 0.99 ± 0.22
Nicotinic acid 900mg/kg 1.51 ± 0.27
*0.63 ± 0.29 0.28 ± 0.13 1.16 ± 0.25
Nicotinic acid 1200mg/kg 1.48 ± 0.26
*0.57 ± 0.35 0.25 ± 0.15 1.19 ± 0.12
*
Atorvastatin calcium 2.5mg/kg 1.67 ± 0.32 0.69 ± 0.34 0.31 ± 0.14 0.98 ± 0.12
Atorvastatin calcium 5mg/kg 1.63 ± 0.31 0.67 ± 0.29 0.26 ± 0.15 0.97 ± 0.10
Atorvastatin calcium 10mg/kg 1.51 ± 0.30 0.65 ± 0.35 0.24 ± 0.10
*1.05 ± 0.23
Atorvastatin calcium 20mg/kg 1.45 ± 0.23
*0.55 ± 0.17 0.22 ± 0.09
*1.06 ± 0.14
Atorvastatin calcium 30mg/kg 1.40 ± 0.28
*0.51 ± 0.19
*0.19 ± 0.11
*1.06 ± 0.17
Nicotinic acid 600+ atropic 5mg/kg 1.55 ± 0.25 0.61 ± 0.36 0.23 ± 0.10
*1.07 ± 0.22
Nicotinic acid 600+ atropic 10mg/kg 1.46 ± 0.26
*0.49 ± 0.10
*0.19 ± 0.11
*1.16 ± 0.15
*
Nicotinic acid 600+ atropic 20mg/kg 1.39 ± 0.30
*0.46 ± 0.12
*0.17 ± 0.07
* *1.18 ± 0.15
*
Nicotinic acid 900+ atropic 5mg/kg 1.44 ± 0.24
*0.63 ± 0.23 0.26 ± 0.08 0.98 ± 0.23
Nicotinic acid 900+ atropic 10mg/kg 1.40 ± 0.25
*0.50 ± 0.09
*0.18 ± 0.13
*1.21 ± 0.16
*
Nicotinic acid 900+ atropic 20mg/kg 1.44 ± 0.26
*0.50 ± 0.16
*0.19 ± 0.08
*1.08 ± 0.23
Nicotinic acid 1200+ atropic 5mg/kg 1.43 ± 0.30
*0.52 ± 0.14
*0.25 ± 0.10 1.04 ± 0.16
Nicotinic acid 1200+ atropic 10mg/kg 1.41 ± 0.35
*0.51 ± 0.16
*0.24 ± 0.09
*1.12 ± 0.20
Annotate: compare with the normal control group,
*P＜0.05,
*P＜0.01
8.2 nicotinic acid and Atorvastatin calcium 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 nicotinic acid is 300～1200mg/kg, and the dosage range of Atorvastatin calcium 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 nicotinic acid and Atorvastatin calcium, 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 nicotinic acid 600mg/kg and Atorvastatin calcium 10mg/kg, nicotinic acid 600mg/kg and Atorvastatin calcium 20mg/kg and nicotinic acid 900mg/kg and three drug combination groups of Atorvastatin calcium 10mg/kg rat, triglyceride, low-density lipoprotein cholesterol level all significantly reduce, and the HDL-C level all significantly raises.Compare with the nicotinic acid or the Atorvastatin calcium 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 nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/kg drug combination group effect.
Table 2 nicotinic acid and Atorvastatin calcium 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 normal control group | ?1.73±0.18 | ?0.70±0.16 | 0.24±0.13 | 0.96±0.18 |
| Model control group | ?13.70±2.81 ### | ?2.22±0.53 ### | 9.25±1.20 ### | 3.85±0.8 ### |
| Nicotinic acid 300mg/kg | ?13.19±2.30 | ?1.99±0.44 | 8.43±1.09 | 3.94±0.60 |
| Nicotinic acid 600mg/kg | ?10.84±3.08 * | ?1.76±0.56 | 8.22±0.41 * | 4.36±0.59 |
| Nicotinic acid 900mg/kg | ?10.70±2.39 * | ?1.67±0.57 * | 7.78±0.87 ** | 4.57±0.55 |
| Nicotinic acid 1200mg/kg | ?11.19±2.46 | ?1.70±0.58 | 7.66±0.44 ** | 4.72±0.56 * |
| Atorvastatin calcium 2.5mg/kg | ?13.68±1.88 | ?2.23±0.59 | 8.83±0.75 | 4.15±0.93 |
| Atorvastatin calcium 5mg/kg | ?12.40±2.64 | ?1.96±0.50 | 8.16±0.81 * | 4.20±0.58 |
| Atorvastatin calcium 10mg/kg | ?11.22±2.10 * | ?1.87±0.26 * | 8.09±0.56 * | 4.46±0.40 |
| Atorvastatin calcium 20mg/kg | ?10.26±2.66 * | ?1.70±0.46 * | 7.75±0.28 ** | 4.51±0.35 * |
| Atorvastatin calcium 30mg/kg | ?9.90±2.68 ** | ?1.75±0.55 | 7.96±0.63 * | 4.58±0.26 * |
| Nicotinic acid 600+ atropic 5mg/kg | ?10.78±2.52 * | ?1.54±0.18 ** | 7.78±0.54 ** | 4.43±0.54 |
| Nicotinic acid 600+ atropic 0mg/kg | ?7.20±1.60 ** | ?1.18±0.16 *** | 6.53±0.43 *** | 5.26±0.33 *** |
| Nicotinic acid 600+ atropic 20mg/kg | ?6.06±2.05 *** | ?1.06±0.21 *** | 6.52±0.58 *** | 5.41±0.38 *** |
| Nicotinic acid 900+ atropic 5mg/kg | ?10.17±2.24 ** | ?1.41±0.25 *** | 7.11±0.75 *** | 4.76±0.56 * |
| Nicotinic acid 900+ atropic 10mg/kg | ?7.09±2.08 *** | ?1.06±0.23 *** | 5.93±0.77 *** | 5.43±0.51 *** |
| Nicotinic acid 900+ atropic 20mg/kg | ?7.16±2.57 *** | ?1.11±0.28 *** | 6.18±0.46 *** | 5.45±0.50 *** |
| Nicotinic acid 1200+ atropic 5mg/kg | ?9.08±1.85 *** | ?1.34±0.29 *** | 6.37±0.81 *** | 5.11±0.46 ** |
| Nicotinic acid 1200+ atropic 10mg/kg | ?8.25±2.53 *** | ?1.28±0.32 *** | 6.15±0.73 *** | 5.46±0.44 *** |
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 nicotinic acid and Atorvastatin calcium 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 nicotinic acid and Atorvastatin calcium 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 (300～1200mg/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 nicotinic acid; (These parameters is not also seen significant difference (P＞0.05) to each dosage of Atorvastatin calcium in 2.5～30mg/kg) the group model rat blood serums, each drug combination group rat blood serum alanine aminotransferase of Atorvastatin calcium and nicotinic acid and serum creatine kinase have no significant change (P＞0.05), see Table 3.
Table 3 nicotinic acid and Atorvastatin calcium and compound recipe are to the influence of rat model serum alanine aminotransferase and creatine kinase
Alanine aminotransferase
Group
Creatine swashs (U/L)
(nmol.s
-1/L)
Normal control group 639.0 ± 111.0 351.3 ± 144.7
Model control group 667.1 ± 109.0 373.5 ± 112.9
Nicotinic acid 300mg/kg 640.9 ± 117.1 361.2 ± 106.9
Nicotinic acid 600mg/kg 645.9 ± 124.4 354.6 ± 1104
Nicotinic acid 900mg/kg 655.0 ± 110.0 380.3 ± 120.6
Nicotinic acid 1200mg/kg 642.2 ± 114.7 377.5 ± 103.9
Atorvastatin calcium 2.5mg/kg 635.6 ± 115.8 364.6 ± 105.4
Atorvastatin calcium 5mg/kg 674.3 ± 132.4 367.5 ± 132.1
Atorvastatin calcium 10mg/kg 650.9 ± 101.3 389.2 ± 119.6
Atorvastatin calcium 20mg/kg 640.7 ± 95.1 378.6 ± 109.8
Atorvastatin calcium 30mg/kg 66.9 ± 117.2 384.0 ± 120.5
Nicotinic acid 600+ atropic 5mg/kg 653.6 ± 110.0 374.3 ± 101.0
Nicotinic acid 600+ atropic 10mg/kg 669.5 ± 123.5 353.5 ± 124.1
Nicotinic acid 600+ atropic 20mg/kg 641.7 ± 125.6 367.6 ± 111.9
Nicotinic acid 900+ atropic 5mg/kg 604.3 ± 132.1 361.7 ± 115.7
Nicotinic acid 900+ atropic 10mg/kg 647.5 ± 128.7 370.5 ± 130.5
Nicotinic acid 900+ atropic 20mg/kg 646.3 ± 124.5 372.0 ± 117.8
Nicotinic acid 1200+ atropic 5mg/kg 651.4 ± 136.7 369.6 ± 103.7
Nicotinic acid 1200+ atropic 10mg/kg 647.8 ± 140.1 375.9 ± 119.4
8.4 the different component test that influences each other in nicotinic acid and the Atorvastatin calcium compound recipe
High blood lipid model rat successive administration is after 14 days, compare with the folk prescription of same dose, nicotinic acid and Atorvastatin calcium 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, nicotinic acid 600mg/kg and Atorvastatin calcium 10mg/kg, nicotinic acid 600mg/kg and Atorvastatin calcium 20mg/kg and nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/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 nicotinic acid or the Atorvastatin calcium 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 nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/kg drug combination group most pronounced effects, the compound recipe that therefore preferred nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/kg form.
The effect of different component treatment serum lipids in rats in table 4 nicotinic acid and the Atorvastatin calcium compound recipe
Serum total cholesterol serum triglycerides low-density lipoprotein cholesterol high density lipoprotein gallbladder is solid
Group
(mmol/L) (mmol/L) (mmol/L) alcohol (mmol/L)
Normal control group 2.08 ± 0.91 0.77 ± 0.13 0.31 ± 0.19 1.25 ± 0.55
Model control group 12.10 ± 2.29
###2.16 ± 0.55
###8.90 ± 1.31
###3.16 ± 1.22***
Nicotinic acid 600mg/kg 10.35 ± 1.62 1.78 ± 0.68 7.25 ± 1.88
*4.22 ± 1.15
Nicotinic acid 900mg/kg 8.67 ± 1.83
*1.69 ± 0.51 6.93 ± 1.28
*4.56 ± 0.57
*
Atorvastatin calcium 10mg/kg 10.23 ± 1.67
*1.53 ± 0.67
*731 ± 1.85
*4.45 ± 1.36
*
Atorvastatin calcium 20mg/kg 9.66 ± 2.27
*1.46 ± 0.51
*6.89 ± 1.61
*4.50 ± 1.04
*
Nicotinic acid 600+ atropic 10mg/kg 7.40 ± 1.65
* *,! ， @@0.98 ± 0.27
* *,! , @4.95 ± 1.21
* *,! ， @@5.98 ± 1.02
* *,! , @
Nicotinic acid 600+ atropic 20mg/kg 6.39 ± 1.86
* *,! ， ﹠amp; ﹠amp; ﹠amp;0.83 ± 0.21
* *,! ， ﹠amp; ﹠amp;4.29 ± 1.68
* *,! ， ﹠amp; ﹠amp;6.01 ± 1.37
* *,! ， ﹠amp;
Nicotinic acid 900+ atropic 10mg/kg 4.86 ± 1.08
* *, ^^^ ， @@@0.75 ± 0.28
* *, ^^^ ， @@3.92 ± 1.25
* *, ^^^ ， @@@6.43 ± 1.02
* *, ^^^ ， @@
Annotate: compare ###P＜0.01, #P＜0.05 with the normal control group
Compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with model control group
Compare with nicotinic acid 600mg/kg group,! P＜0.001,! P＜0.01
Compare ， @P＜0.05 ， @@P＜0.01 with Atorvastatin calcium 10mg/kg group.@@@P＜0.001
Compare ^^^P＜0.001 with nicotinic acid 900mg/kg group
Compare ， ﹠amp with Atorvastatin calcium 20mg/kg group; ﹠amp; ﹠amp; P＜0.001 ， ﹠amp; P＜0.05
9 conclusions
Nicotinic acid and Atorvastatin calcium 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, nicotinic acid 600mg/kg and Atorvastatin calcium 10mg/kg, nicotinic acid 600mg/kg and Atorvastatin calcium 20mg/kg and nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/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 nicotinic acid 900mg/kg and Atorvastatin calcium calcium 10mg/kg drug combination group most pronounced effects, the compound recipe that preferred nicotinic acid 900mg/kg and Atorvastatin calcium 10mg/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 nicotinic acid folk prescription is 3 times/day at present, originally experimental results show that, nicotinic acid still has significant effect for reducing blood fat 1 time/day, and toxicity is little, only medication provides reliable experimental evidence 1 time for nicotinic acid and Atorvastatin calcium 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, the Chen Xiu chief editor, pharmacological experiment methodology (third edition), the People's Health Publisher publishes, in January, 2002,1201-1202
[2]Scand?J?Clin?Lab?Invest，1990，50(2)：203-208
[3] atorvastatin calcium tablet operation instructions, http://www.sda.gov.cn, state food drug control board web
[4]Clin.Chim.Acta.2004，339(1-2)：189-194
[5]Int.J.Cardiol.2003，91(1)：59-69
[6]Metabolism?2003，52(5)：609-615
[7]Biochim.Biophys.Acta.2002，1580(2-3)：161-170
Claims (10)
1, a kind of treatment hyperlipidemia compositions is characterized in that described compositions comprises:
(1) first active component, it is nicotinic acid (NicotinicAcid);
(2) second active component, it is selected from salt, ester or the solvate that atorvastatin (Atorvastain) or its can be medicinal:
(3) one or more other pharmaceutically useful active component or non-active ingredient.
2, according to the described compositions of claim 1, it is characterized in that the salt that described atorvastatin can be medicinal is suitable atorvastatin physiologically acceptable salt, comprise derived from inorganic and organic salt that alkali forms, as sodium salt, calcium salt, potassium salt, zinc salt, iron salt etc.
3, according to the described compositions of claim 1, it is characterized in that the ester that described atorvastatin can be medicinal is the suitable acceptable ester of atorvastatin physiology, comprise derived from aliphatic alcohol, aromatic alcohol, the formed ester of heterocyclic alcohol, as methanol, hexanol, 1-propenol-3, benzene alcohol etc.
4,, it is characterized in that second active component is Atorvastatin calcium according to the described compositions of claim 1～2.
5,, it is characterized in that the weight ratio of nicotinic acid and Atorvastatin calcium is (30～240): 1 according to the described compositions of claim 4.
6,, it is characterized in that the weight ratio of preferred nicotinic acid and Atorvastatin calcium is (30～90): 1 according to the described compositions of claim 4.
7,, it is characterized in that the weight ratio of further preferred nicotinic acid and Atorvastatin calcium is 90: 1 according to the described compositions of claim 4.
8, according to the described compositions of claim 7, it is characterized in that the amount of further preferred nicotinic acid is 900mg, correspondingly, the weight ratio of Atorvastatin calcium is 10mg.
9, the medical preparation made of 1～8 described compositions.
10, according to the described compositions of claim 1～9, its dosage form comprises tablet, capsule, granule, pill, drop pill.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101559058B (en) * | 2008-04-16 | 2011-07-20 | 北京本草天源药物研究院 | Pharmaceutical composition for treating dyslipidemia |
| CN102349906A (en) * | 2011-10-12 | 2012-02-15 | 广西方略药业集团有限公司 | Atorvastatin calcium and nicotinic acid composition and preparation method thereof |
| CN103945857A (en) * | 2011-09-15 | 2014-07-23 | 可劳迈戴斯有限公司 | Pterostilbene and statin combination for treatment of metabolic disease, cardiovascular disease, and inflammation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101559058B (en) * | 2008-04-16 | 2011-07-20 | 北京本草天源药物研究院 | Pharmaceutical composition for treating dyslipidemia |
| CN103945857A (en) * | 2011-09-15 | 2014-07-23 | 可劳迈戴斯有限公司 | Pterostilbene and statin combination for treatment of metabolic disease, cardiovascular disease, and inflammation |
| CN102349906A (en) * | 2011-10-12 | 2012-02-15 | 广西方略药业集团有限公司 | Atorvastatin calcium and nicotinic acid composition and preparation method thereof |
| CN102349906B (en) * | 2011-10-12 | 2015-05-13 | 广西方略药业集团有限公司 | Atorvastatin calcium and nicotinic acid composition and preparation method thereof |
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