CN101357132B - Composition for treating hyperlipemia - Google Patents
Composition for treating hyperlipemia Download PDFInfo
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- CN101357132B CN101357132B CN2008101104303A CN200810110430A CN101357132B CN 101357132 B CN101357132 B CN 101357132B CN 2008101104303 A CN2008101104303 A CN 2008101104303A CN 200810110430 A CN200810110430 A CN 200810110430A CN 101357132 B CN101357132 B CN 101357132B
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Abstract
The invention provides a new composite for curing hyperlipemia; the composite comprises a first active ingredient acipimox and a second active ingredient selected from rosuvastatin or medical salt, ester or solvate; the weight ratio (calculated by free acid) of the first active ingredient and the second active ingredient is 15-100:1, the optimal weight ratio thereof is 40-100:1 and the further optimal weight ratio thereof is 60:1; when the acipimox and rosuvastatin are used together, the effect of reducing fat is obviously superior to the single drug prescription with the same dosage, which proves that the combining use of the two drugs has cooperativity effect and does not have obvious toxic effect simultaneously; moreover, the effect of reducing fat is more obvious compared with the combining use of the acipimox and pravastatin and the combining use of the acipimox and lovastatin.
Description
Technical field
The present invention is that the application number submitted on June 16th, 2005 is 200580006900.6, denomination of invention is divided an application for the patent application of " compositions of treatment hyperlipidemia ".
The present invention relates to a kind of compositions of new treatment hyperlipidemia, it contains the pharmaceutically useful salt of acipimox and rosuvastatin or rosuvastatin, ester or solvate.
Background technology:
Rosuvastatin (Rosuvastatin) is to have carried out broad research both at home and abroad also at the HMG-CoA of multinational listing reductase inhibitor, it is by optionally suppressing the rate-limiting enzyme HMG-CoA reductase in the cholesterol building-up process in vivo, 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, thus to the control generation effect of atherosclerosis and coronary heart disease.This product also reduces serum triglyceride level and increases the blood hdl level.Rosuvastatin has 5,10,20 and the tablet of 40mg.In clinical trial, most patients take 5 or the starting dose of 10mg just reached the target LDL-C level that NCEP (NationalCholesterol Education Program) is recommended.20mg dosage can be used as the very high patient's of cholesterol levels predose, and the dosage of 40mg only should use when 20mg dosage treatment curative effect is not enough.Professor Shepherd has finished a statins effect for reducing fat clinical trial relatively recently, the result in 8 weeks of medication shows: rosuvastatin 10mg (n=539) LDL-C compliance rate is 80%, and atorvastatin 10mg (n=529) compliance rate is 63% (P＜0.001), and atorvastatin 20mg (n=925) LDL-C compliance rate is 74% (P＜0.01).Jones PH studies show that: rosuvastatin 10mg reduces LDL-C46%, and atorvastatin is incremented to 20mg, 40mg from 10mg, and LDL-C reduces by 37% (P＜0.001), 43% and 48% respectively; Simvastatin is incremented to 20mg, 40mg from 10mg, and LDL-C reduces by 28%, 35% and 39% (the P value all＜0.001) respectively; Pravastatin is incremented to 20mg, 40mg from 10mg, reduces LDL-C and is respectively 20%, 24% and 30% (the P value all＜0.001).Active and safety and pravastatin and simvastatin have carried out the clinical randomized controlled research in 52 weeks to Brown WV etc. with the blood fat reducing of rosuvastatin, the result shows, after 12 weeks of medication, the low-density lipoprotein cholesterol (LDL-C) of rosuvastatin 5mg and 10mg dosage group has descended 39.1% and 47.4% respectively, and there were significant differences (P＜0.05) to organize (descending 34.6%) with pravastatin 20mg group (descending 26.5%) and simvastatin 20mg.After 52 weeks of medication, rosuvastatin 5mg and 10mg group reach u.s. national cholesterol education program and recommend the ratio of LDL-C target to be respectively 88% and 87.5%, and the pravastatin group only is 60%, the simvastatin group is 72.5%, (in 40 weeks of back, the patient dose that does not reach target doubles) equal well-tolerated of all experimental group patients
[1]Although rosuvastatin has so potent advantage, but its untoward reaction and other statins are compared and are wanted serious, in the clinical trial before listing, heavy dose of (80mg) group has 7 routine patients that life-threatening rhabdomyolysis has taken place, and therefore query just has been in its safety at that time.Find that also rosuvastatin also can damage some patients " renal function (do not observe other Statins similar untoward reaction is arranged) in the listing pre-Clinical.Finally, FDA ratifies its listing because of the advantage (drug effect is better than other Statins slightly) of considering rosuvastatin, but advises taking dose from 5mg～10mg, and maximal dose is no more than 40mg.
Acipimox (Acipimox) is a kind of nicotinic acid derivates of synthetic, and the oral post-absorption of this medicine is rapid, obeys that plasma concentration promptly reaches the peak in back 2 hours, and the half-life is 2 hours.Acipimox combines with plasma protein, almost discharges from urine unchangeably, mainly acts on fatty tissue, suppresses fatty tissue and discharges non-esterified fatty acid, reduces the generation of TG, VLDL and LDL.And, quicken the degraded of VLDL by activating lipoprotein lipase, increase blood plasma HDL level by suppressing hepatic lipase.Acipimox is a kind of safe, effectively and easy blood lipid regulation medicine of tolerance, is particularly useful for that the serum TG level obviously raises, the HDL-C level is obviously low, and the TC level is slight to rise or normal diabetics.
At present, the research tendency in this field is that the blood lipid regulation medicine of two kinds of different mechanism of action is made compound preparation, can bring into play synergism, reduces toxic and side effects simultaneously.
European patent application EP 0373507 discloses the preparation of compositions that HMG-CoA reductase inhibitor pravastatin, lovastatin, velostatin are respectively 5mg, 10mg, 20mg, 40mg and nicotinic acid 500mg, but do not have to disclose the experimental data of its beneficial effect and best proportioning, more do not relate to acipimox and rosuvastatin compositions and best proportioning.
" comparison of treatment hyperlipidemia is used and share to lovastatin and inositol nicotinate list " is published in " angiocardiology progress " 1996 the 17th the 6th phases of volume, and open lovastatin and inositol nicotinate share the cured disease of the high blood of treatment; " observation of curative effect of treatment hyperlipidemia is used and share to pravastatin and inositol nicotinate list " was published in " Chinese arteriosclerosis magazine " 1997, and the 5th the 3rd phase of volume, open pravastatin and inositol nicotinate share the treatment hyperlipidemia.The two does not all relate to the compositions and the best proportioning of acipimox and rosuvastatin.
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 do not have to disclose the experimental data of its beneficial effect and best proportioning, more do not relate to acipimox and rosuvastatin compositions and best proportioning.
Summary of the invention
The objective of the invention is the screening experiment by a series of science, a kind of pharmaceutical composition of new treatment hyperlipemia is provided, its advantage is that effect is strong, toxic and side effects is low and is easy to use.This pharmaceutical composition contains a certain proportion of acipimox and rosuvastatin or acipimox and the pharmaceutically useful salt of rosuvastatin, ester or solvate, because two kinds of mechanism of drug action differences, effect for reducing fat will be more comprehensive after the composition compositions, and two class drug combinations have synergism, and its effect for reducing fat obviously is better than the folk prescription of same dose; Though rosuvastatin has more powerful lipid-lowering effect; but but there is the risk of the rhabdomyolysis that crisis life takes place in heavy dose of rosuvastatin; by acipimox 5 usefulness; significantly reduced the consumption of rosuvastatin in the compositions; make compositions in effective blood fat reducing level, greatly reduce the drug risk of rosuvastatin, this compositions only needed medication once on 1st simultaneously; medication is convenient, and this will improve patient's compliance greatly.
In addition, compare research by compositions to US5260305A in compositions of the present invention and the background technology and CN1425374A, in experiment, be surprised to find that, the use of uniting of acipimox and rosuvastatin is reducing serum total cholesterol, serum triglycerides and low-density lipoprotein cholesterol aspect not only exist the obvious synergistic effect, and with the use of uniting of acipimox and pravastatin, the use of uniting of acipimox and lovastatin is compared, lipid-lowering effect is more obvious, aspect the high density lipoprotein increasing cholesterol, apparent in view advantage is arranged also.
The compositions of treatment hyperlipidemia provided by the invention comprises two kinds of active component, and first active component is an acipimox, and second active component is selected from rosuvastatin or its pharmaceutically useful salt, ester or solvate.The pharmaceutically useful salt of rosuvastatin is suitable rosuvastatin physiological acceptable salt, comprises that it can be sodium salt, calcium salt, potassium salt, magnesium salt, zinc salt, iron salt derived from inorganic and the organic formed salt of alkali.The pharmaceutically useful ester of described rosuvastatin is the suitable acceptable ester of rosuvastatin physiology, comprises derived from aliphatic alcohol, aromatic alcohol, the formed ester of heterocyclic alcohol, can be methyl ester, ethyl ester, allyl ester, phenyl ester.
The present invention is that example is screened the weight ratio of two kinds of active component with the rosuvastatin calcium, take all factors into consideration their degree active to the blood fat reducing of high blood lipid model rat and untoward reaction, can think that acipimox and rosuvastatin are (in free acid, down with) weight ratio at 15-100: have lipid-lowering effect and slighter untoward reaction preferably in 1 scope, preferred ratio is 40-100: 1, and further preferred ratio is 60: 1; Wherein acipimox is preferably made slow-released part.The dosage form of the pharmaceutical preparation of said composition comprises solid preparations such as tablet, capsule, granule, pill, drop pill.
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 rosuvastatin 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 (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 the time with compositions of the present invention, when especially adopting preferred proportioning, compare during with the acipimox of independent application effective dose or rosuvastatin, compositions of the present invention provides astonishing better effect, toxicity does not increase simultaneously, reaching under the situation of identical lipid-lowering effect, two class medicines, 5 usefulness greatly reduce the using dosage of every kind of medicine, and this has just significantly reduced the untoward reaction of acipimox and the drug risk of rosuvastatin.Compositions of the present invention can 1-2 administration every day, is preferably once a day.
In addition, we find that in screening experiment the pharmacologically active of rosuvastatin is very little with its salt that is become, ester or solvate relation in the present composition, and the active size of its blood fat reducing is main relevant with the amount of rosuvastatin free acid.So atorvastatin can be any salt that can be medicinal among the present invention, also can for any atorvastatin can be medicinal ester, perhaps solvate.
The specific embodiment:
Now further specify content of the present invention, but range of application of the present invention is not limited to the following example by following embodiment.
Embodiment 1
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, rosuvastatin calcium (its weight is in free acid, down together) 5g
Hydroxypropyl cellulose 15g
Pregelatinized Starch 10g
The ethanol solution 30g of 6%PVP
Rikemal B 200 1g
Preparation technology: rosuvastatin calcium is crossed 100 mesh sieves, 80 mesh sieves are crossed in hydroxypropyl cellulose, pregelatinized Starch, take by weighing the rosuvastatin 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.
Embodiment 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, rosuvastatin calcium 10g
Hydroxypropyl cellulose 30g
Pregelatinized Starch 20g
The ethanol solution 50g of 6%PVP
Rikemal B 200 2g
Preparation technology: rosuvastatin calcium is crossed 100 mesh sieves, 80 mesh sieves are crossed in hydroxypropyl cellulose, pregelatinized Starch, take by weighing the rosuvastatin 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.
Embodiment 3
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, rosuvastatin calcium 5g
Sodium carboxymethyl cellulose 30g
Lactose 20g
The 95% alcoholic solution 50g of 6%PVP
Magnesium stearate 2g
Preparation technology: rosuvastatin calcium is crossed 100 mesh sieves, sodium carboxymethyl cellulose, lactose are crossed 80 mesh sieves, take by weighing the rosuvastatin 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.
Embodiment 4
A, acipimox 500g
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, rosuvastatin calcium 5g
Pregelatinized Starch 50g
Mannitol 50g
The 95% alcoholic solution 100g of 6%PVP
Micropowder silica gel 5g
Preparation technology: rosuvastatin calcium is crossed 100 mesh sieves, pregelatinized Starch, mannitol are crossed 80 mesh sieves, take by weighing the rosuvastatin calcium of recipe quantity and pregelatinized Starch, mannitol mix homogeneously, progressively increase behind method and the rosuvastatin mixing by equivalent, 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.
Embodiment 5
A, acipimox 500g
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, rosuvastatin calcium 10g
Hydroxypropyl cellulose 15g
Dextrin 20g
The 95% alcoholic solution 50g of 6%PVP
Pulvis Talci 2g
Preparation technology: rosuvastatin calcium is crossed 100 mesh sieves, hydroxypropyl cellulose, dextrin are crossed 80 mesh sieves, take by weighing the rosuvastatin 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.
Embodiment 6
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 granulating and coating machine (Taiwan unit becomes machinery plant), go into wind pressure 0.5bar, 30 ℃ of inlet air temperature, spray gun pressure (CYL) 3bar, atomizing pressure (CAP1) 0.8bar, pour 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, rosuvastatin calcium 5g
Celphere 90g
7%PVP solution (solvent is 90% ethanol) 50g
Preparation technology: rosuvastatin 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, CYL3bar, CAP10.8bar 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 acipimox and rosuvastatin calcium in per two capsules and 30mg fills, and gets final product.
Embodiment 7
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, CYL3bar, CAP10.8bar 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, CYL3bar, 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 rosuvastatin calcium piller according to the requirement of b among the embodiment 5, adopt hard capsule medicine filling machine to be respectively 300mg with the acipimox piller that makes among this routine b and 30mg fills, get final product according to the weight that contains acipimox and rosuvastatin calcium in per two capsules.
Embodiment 8
A, acipimox 200g
Celphere 200g
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, CYL3bar, CAP10.8bar pours celphere into, pelletize, blanking velocity 4rpm, the pump 12% of wriggling, rotary speed 165rpm sprays into 7%PVP solution (solvent is 90% ethanol).Pelletize finishes, 50 ℃ of oven dry, discharging.
B, rosuvastatin calcium 20g
Celphere 150g
7%PVP solution (solvent is 90% ethanol) 150g
Preparation technology: rosuvastatin 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, CYL3bar, CAP10.8bar pours celphere into, 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.
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 rosuvastatin calcium in per two capsules and 40mg fills, and gets final product.
Embodiment 9
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, CYL3bar, CAP10.8bar 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, CAP11.0bar, 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, rosuvastatin calcium 20g
Celphere 150g
7%PVP solution (solvent is 90% ethanol) 150g
Preparation technology: rosuvastatin 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 CYL3bar, CAP10.8bar 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 rosuvastatin calcium in per two capsules and 40mg fills, and gets final product.
Embodiment 10 acipimoxs and rosuvastatin calcium compound recipe are to the proportioning screening of serum lipids in rats lipid-lowering effect
This test objective is to determine that by screening toxicity is low, act on acipimox strong and easy to use and rosuvastatin calcium compound preparation compatibility is formed.Adopt normal Wistar rats or high lipid food to cause hyperlipemia model of rats.Being subjected to the test product acipimox is that Lunan Pharmacy Co. Ltd produces, and rosuvastatin calcium is produced by AstraZeneca company.Found that, raise with high lipid food after 14 days that T-CHOL, triglyceride and low-density lipoprotein cholesterol all obviously raise in the rat blood serum, form hyperlipemia model.(after 5～40mg/kg) 14 days, T-CHOL, triglyceride, low-density lipoprotein cholesterol all obviously descend in the serum, and HDL-C raises to gavage acipimox (100～500mg/kg) and (or) rosuvastatin calcium to rat model.Single wherein a kind of medicine or two medicines, 5 usefulness used, its effect is strengthened with dosage escalation.
The result shows that acipimox and rosuvastatin calcium 5 usefulness have obvious therapeutic action to the serum lipids in rats due to the high lipid food, and effect is relevant with the dosage of two kinds of medicines.From drug effect and toxicity two aspect analyses, rosuvastatin calcium 5mg/kg and acipimox 300mg/kg 5 usefulness effects are better.
1 test objective
Determine that by screening acipimox and rosuvastatin calcium compound preparation form, the compound preparation toxic and side effects is low to reach, effect comprehensively and the purpose of enhancing, (as 1 medication every day) easy to use.On above-mentioned experiment basis,, carry out the dose-effect relationship and the interactional test of many components of compound preparation, provide experimental basis for declaring the exploitation compound preparation by relevant requirements.
2 are subjected to the reagent thing
2.1 acipimox (Acipimox)
Lot number: 0307002
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 the preceding 1%CMC of using mixing, be made into the test desired concn.
2.2 rosuvastatin (Rosuvastatin)
Lot number: 030205
Purity: greater than 99.0%
Production unit: Astrazeneca AB
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 laboratory 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
Age was 9 week～10 weeks.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 [2]
Hyperlipemia model of rats adopts high lipid food to cause the hyperlipemia method.The high lipid food prescription is as follows: normal feedstuff 87.3%, cholesterol 2%, Adeps Sus domestica 10%, methylthiouracil 0.2%, Fel Sus domestica salt 0.5%, each composition guarantees mix homogeneously.Continuous 2 weeks.Give high lipid food during the administration every other day, all the other times give normal feedstuff.
5 acipimoxs and rosuvastatin calcium are to the influence of normal rat fat
[2]
5.1 dosage is selected
Acipimox dosage 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 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 50mg/kg/day.In conjunction with bibliographical information
[3], 1 time/day medication is adopted in this test in addition, thus in this test acipimox dosage be made as 100,200,300,500mg/kg.
The dosage of rosuvastatin is 5～20mg/ time (calculate by body weight for humans 60kg, above-mentioned dosage is 0.1-0.3mg/kg) clinically, and 1 time/day, measure maximum and be no more than 40mg every day
[3]By body surface area is the dosage equivalence principle reckoning of unit, above-mentioned people's common dose is converted into rat dosage and is about 0.5-1.5mg/kg, in conjunction with bibliographical information, with rosuvastatin calcium dosage in this test (in free acid, down with) be made as 5,10,20,40mg/kg.
5.2 group setting
According to above-mentioned dosage setting,, the intact animal is divided into according to randomly assigne: (1) normal control group by the serum total cholesterol level homeostatic principle; (6) acipimox 100mg/kg group; (7) acipimox 200mg/kg group; (8) acipimox 300mg/kg group; (9) acipimox 500mg/kg group; (10) rosuvastatin calcium 5mg/kg group; (11) rosuvastatin calcium 10mg/kg group; (12) rosuvastatin calcium 20mg/kg group; (13) rosuvastatin calcium 40mg/kg group; (14) acipimox 200mg/kg and rosuvastatin calcium 5mg/kg group; (15) acipimox 200mg/kg and rosuvastatin calcium 10mg/kg group; (16) acipimox 200mg/kg and rosuvastatin calcium 20mg/kg group; (17) acipimox 200mg/kg and rosuvastatin calcium 40mg/kg group; (18) acipimox 300mg/kg and rosuvastatin calcium 5mg/kg group; (19) acipimox 300mg/kg and rosuvastatin calcium 10mg/kg group; (20) acipimox 300mg/kg and rosuvastatin calcium 20mg/kg group (21) acipimox 500mg/kg and rosuvastatin calcium 10mg/kg group.Every group 6, male.
5.4 administration
The clinical administration approach 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.14:00～16:00 administration.
5.5 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 rosuvastatin calcium are to the influence of rat model blood fat
6.1 dosage foundation
Test with normal rat.
6.2 group setting
According to above-mentioned dosage setting,, the intact animal is divided into according to randomly assigne: (1) normal control group by the serum total cholesterol level homeostatic principle; (2) model control group; (3) acipimox 150mg/kg group; (4) acipimox 200mg/kg group; (5) acipimox 300mg/kg group; (6) acipimox 400mg/kg group; (7) acipimox 500mg/kg group; (8) rosuvastatin calcium 5mg/kg group; (9) rosuvastatin calcium 10mg/kg group; (10) rosuvastatin calcium 20mg/kg group; (11) rosuvastatin calcium 40mg/kg group; (12) acipimox 150mg/kg and rosuvastatin calcium 10mg/kg group; (13) acipimox 200mg/kg and rosuvastatin calcium 10mg/kg group; (14) acipimox 300mg/kg and rosuvastatin calcium 5mg/kg group; (15) acipimox 300mg/kg and rosuvastatin calcium 10mg/kg group; (16) acipimox 300mg/kg and rosuvastatin calcium 20mg/kg group; (17) acipimox 400mg/kg and rosuvastatin calcium 5mg/kg group (18) acipimox 500mg/kg and rosuvastatin calcium 5mg/kg group.Every group 10, male.
6.3 administration
The clinical administration approach 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
Test with normal rat.
7 result of the tests
7.1 acipimox and rosuvastatin calcium are to the influence of normal rat fat
After the normal rat administration 4 days, the T-CHOL and the low-density lipoprotein cholesterol of acipimox, rosuvastatin calcium and drug combination group all decrease, HDL-C rising (table 1).Serum triglycerides slightly descends after the administration, but no difference of science of statistics.The effect of drug combination group is better than single medicine.
Table 1 acipimox and rosuvastatin calcium and compatibility are to the influence of normal rat fat
Annotate: * and normal control group compare, * P＜0.05, * * P＜0.01
7.2 acipimox and rosuvastatin calcium are to the influence of rat model blood fat
Rat is raised with the high lipid food administration of dividing into groups after 14 days.The dosage of acipimox is from 100～500mg/kg, and the dosage of rosuvastatin calcium is formed the drug combination group from 5～40mg/kg.After the administration 14 days, compare with model control group, each dosage group serum total cholesterol of acipimox and rosuvastatin calcium, triglyceride, low-density lipoprotein cholesterol be significantly decline (table 2) all.
Part acipimox dosage group reaches with rosuvastatin calcium drug combination group rat blood serum alanine aminotransferase and raises, high dose group rising amplitude big (table 3).It is similar to serum alanine aminotransferase that each organizes in the rat blood serum creatine kinase activity variation tendency.Therefore in compound recipe, should reduce the dosage of rosuvastatin calcium as far as possible, better with acipimox 300mg/kg and rosuvastatin calcium 5mg/kg dose compatibility, less to creatine kinase in the serum and the active influence of serum alanine aminotransferase.
Table 2 acipimox and rosuvastatin and compound recipe are to the influence of rat model blood fat
Annotate: compare ###P＜0.001 with the normal control group; Compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with model control group
Table 3 acipimox and rosuvastatin calcium and compound recipe are to the influence of rat model serum alanine aminotransferase and creatine kinase
Annotate: compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with model control group
8 conclusions
Acipimox and rosuvastatin calcium 5 usefulness have obvious therapeutic action 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, we are in test kind of discovery, when the dosage ratio of acipimox and rosuvastatin 15: 1-100: in the time of in 1 the scope, each dosage group has all obtained good concertedness effect, and the acipimox that the present invention found and the ratio range of rosuvastatin and the disclosed acipimox of CN03122340.0 and 10: 1 ratio of rosuvastatin are having more advantage aspect reduction serum total cholesterol and the rising serum high-density cholesterol.Simultaneously we are in conjunction with the rising (untoward reaction) to rat model serum alanine aminotransferase and creatine kinase of acipimox and rosuvastatin calcium compound recipe, find, when the ratio of acipimox and rosuvastatin during less than 15: 1, though also can obtain certain concertedness blood fat reducing effect,, when each dosage group administration, because the administration total amount is too low, can not obtain ideal lipid-lowering effect, or because the dosage of rosuvastatin is too high, untoward reaction strengthens.When the dosage of rosuvastatin is 5mg/kg, the activity of serum alanine aminotransferase and creatine kinase is compared as broad as long with model control group, when consumption during greater than 10mg/kg, serum alanine aminotransferase and creatine kinase are along with the increase of dosage raises rapidly.When the consumption proportion of acipimox and rosuvastatin during,, can not obtain significant concertedness effect because the consumption of rosuvastatin is too small greater than 100: 1.Acipimox 300mg/kg and rosuvastatin calcium 5mg/kg dosage 5 usefulness effects are remarkable, do not have tangible toxic action simultaneously again.Take all factors into consideration the degree of lipid-lowering effect and untoward reaction, the weight ratio of acipimox and rosuvastatin is at 40-100: in 1 the scope, better effect and lower untoward reaction are arranged.In addition, this result of the test finds that acipimox administration every day of higher dosage also has significant effect for reducing blood fat 1 time, and toxicity is little, and this is that acipimox and rosuvastatin calcium are formed compound recipe, realizes that administration every day provides experimental basis 1 time.
Embodiment 11 acipimoxs and rosuvastatin are united lipid-lowering effect that use and acipimox and pravastatin, acipimox and lovastatin unite use relatively
The proportioning of the acipimox rosuvastatin that we are screened according to embodiment 10 and US5260305A and the disclosed compositions of CN1425374A compare research, the unexpected discovery in experiment, and verified that by a large amount of zooperies the acipimox rosuvastatin unites use and reducing serum total cholesterol, serum triglycerides and low-density lipoprotein cholesterol aspect not only exist the obvious synergistic effect, and unite use with the acipimox pravastatin, the acipimox lovastatin is united use and is compared, significant difference is arranged, lipid-lowering effect is more obvious, aspect the high density lipoprotein increasing cholesterol, apparent in view advantage is arranged also.
11.1 prepared with embodiment 10 by reagent thing, animal, hyperlipemia model of rats.
11.2 group setting
By the serum total cholesterol level homeostatic principle, rat model is divided at random:
The normal control group;
Model control group;
Acipimox 300mg/kg pravastatin 20mg/kg group;
Acipimox 300mg/kg lovastatin 10mg/kg group;
Acipimox 200mg/kg rosuvastatin 10mg/kg group;
Acipimox 300mg/kg rosuvastatin 5mg/kg group;
Acipimox 300mg/kg rosuvastatin 10mg/kg group;
Acipimox 300mg/kg rosuvastatin 20mg/kg group;
Acipimox 400mg/kg rosuvastatin 5mg/kg group;
Acipimox 500mg/kg rosuvastatin 5mg/kg group.
11.3 administration
With 6.3 among the embodiment 10.
11.4 detection index
Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), HDL-C (HDL-L).
11.5 experimental result
Rat is raised with the high lipid food administration of dividing into groups after 14 days.After the administration 14 days, each dosage group of acipimox rosuvastatin has significant difference comparing with acipimox 300mg/kg pravastatin 20mg/kg group, acipimox 300mg/kg lovastatin 10mg/kg group aspect reduction serum total cholesterol, serum triglycerides and the low-density lipoprotein cholesterol; Aspect the high density lipoprotein increasing cholesterol, apparent in view advantage is arranged also.Our result of the test proves that fully acipimox and rosuvastatin unite use and have beyond thought effect aspect blood fat reducing, acipimox and rosuvastatin have not only been obtained significant concertedness effect, and and disclosed acipimox of prior art and lovastatin, the use of uniting of acipimox and pravastatin has more advantage.Concrete outcome sees Table 5.
Table 5 acipimox rosuvastatin is united use and is united the use lipid-lowering effect relatively with acipimox pravastatin, acipimox lovastatin
Annotate: compare ###P＜0.001 with the normal control group; Compare * * P＜0.01, * * * P＜0.001 with model control group;
Cut down the 10mg/kg group with the general 20mg/kg of cutting down group of Ah former times 300+ and Ah former times 300+ Lip river and compare,
★P＜0.05,
★ ★P＜0.01,
★ ★ ★P＜0.001.
List of references
[1]Brown?WV，Bays?HE?et?al，Efficacy?and?safety?of?rosuvastatin?compared?with?pravastatin?andsimvaststin?in?patients?with?hypercholesterolemia：a?randomized，double-blined，52-weektrial.
[2] Xu Shuyun, Bian Rulian, Chen Xiu chief editor. pharmacological experiment methodology (third edition), the People's Health Publisher publishes, in January, 2002,1201-1202
[3] OLBETAM (acipimox) description (Pharmacia, New Zealand)
[4]Al-Shurbaji?A，et?al.The?effect?of?Acipimox?on?triacylglycerol?metabolism?inrat.Scand?J?Clin?Lab?Invest，1990，50(2)：203-208
[5] Crestor (Rosuvastatin) description.
Claims (3)
1. a compositions for the treatment of hyperlipidemia is characterized in that, described compositions comprises:
A) first active component: acipimox;
B) second active component: rosuvastatin calcium;
The ratio of first active component and second active component (in free acid) is 40-100: 1.
2. according to the described compositions of claim 1, it is characterized in that the weight ratio of acipimox and rosuvastatin calcium (in free acid) is 60: 1.
3. according to claim 1 or 2 described compositionss, it is characterized in that described compositions is tablet, capsule, granule, pill or drop pill.
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