CN1323665C - Composition for treating hyperlipemia - Google Patents
Composition for treating hyperlipemia Download PDFInfo
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- CN1323665C CN1323665C CNB2004100478594A CN200410047859A CN1323665C CN 1323665 C CN1323665 C CN 1323665C CN B2004100478594 A CNB2004100478594 A CN B2004100478594A CN 200410047859 A CN200410047859 A CN 200410047859A CN 1323665 C CN1323665 C CN 1323665C
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Abstract
The present invention provides a new medical composition for treating hyperlipemia. The new medical composition is characterized in that the new medical composition contains an effective quantity of nicotinic acid and rosuvastatin calcium; the weight ratio (taking free acid as reference) of the nicotinic acid to the rosuvastatin calcium is (15-160): 1, the optimized weight ratio is (30-160): 1, and the further optimized weight ratio is 100: 1. Blood fat reducing effect obtained by combining the nicotinic acid and the rosuvastatin calcium is obviously superior to the blood fat reducing effect obtained by using singly the nicotinic acid or the rosuvastatin calcium of the same dosage as the combination of the nicotinic acid and the rosuvastatin calcium, which indicates that the nicotinic acid and the rosuvastatin calcium have synergistic effect and have no obvious toxicity. The medical composition has accidental evident effect in preventing and treating unstable angina pectoris along with the hyperlipemia and is obviously superior to the nicotinic acid or the rosuvastatin calcium of the same dosage, and the new medical composition has obvious synergistic effect. Therefore, the new medical composition is an ideal selection for patients suffering from coronary heart diseases.
Description
Affiliated technical field
The present invention relates to treat the new compositions of hyperlipidemia, particularly contain the compositions of nicotinic acid and rosuvastatin calcium and pharmaceutic adjuvant.
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 (National Cholesterol 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.
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 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, but do not relate to derivant and the rosuvastatin compositions and the best proportioning of nicotinic acid or nicotinic acid.
" 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 treatment hyperlipidemia; " 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 derivant and the rosuvastatin compositions and the best proportioning of nicotinic acid or nicotinic acid.
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 derivant and the rosuvastatin compositions and the best proportioning of nicotinic acid or nicotinic acid.
Goal 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 medicine contains the nicotinic acid and the rosuvastatin calcium of special ratios, because two kinds of mechanism of drug action differences, it will be more comprehensive forming after the compositions effect for reducing fat, 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 calcium 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 with derivant 5 usefulness of nicotinic acid or nicotinic acid; significantly reduced the consumption of rosuvastatin in the compositions; make compositions in effective blood fat reducing level, greatly reduce the drug risk of rosuvastatin calcium, this compositions only needed medication once on 1st simultaneously; medication is convenient, and this will improve patient's compliance greatly.
Technical scheme:
Compositions of the present invention is made up of nicotinic acid or the pharmaceutically useful ester of nicotinic acid and rosuvastatin calcium and pharmaceutic adjuvant, wherein the weight ratio of nicotinic acid and rosuvastatin calcium is that 15～160: 1 (weight of rosuvastatin calcium is in free acid, down together), preferred ratio is 30～160: 1, further preferred ratio is 100: 1, and wherein nicotinic acid is preferably made slow-released part.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 150～1000mg, the rosuvastatin calcium content is equivalent to the daily dose of 2～40mg, and wherein preferred rosuvastatin calcium content is equivalent to the daily dose of 5～20mg.
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 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 nicotinic acid of independent application effective dose with rosuvastatin calcium, 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 nicotinic acid class medicine and the drug risk of rosuvastatin calcium.Compositions of the present invention can 1～2 administration every day, is preferably once a day.
Rosuvastatin can be any salt that can be medicinal among the present invention, and promptly suitable rosuvastatin physiologically acceptable salt comprises derived from inorganic and the organic formed salt of alkali, is sodium salt, calcium salt, potassium salt, magnesium salt, zinc salt, iron salt.Rosuvastatin can be medicinal ester be the suitable acceptable ester of rosuvastatin physiology, comprise derived from aliphatic alcohol, aromatic alcohol, the formed ester of heterocyclic alcohol, be methyl ester, ethyl ester, allyl ester, phenyl ester.
The derivant of nicotinic acid comprises acipimox (Acipimox), inositol niacinate, vitamin E Nicotinate among the present invention.
The specific embodiment:
Now further specify content of the present invention, but range of application of the present invention is not limited only to following example by following example.
Example 1
A, nicotinic acid 500g
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, 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.
Example 2
A, nicotinic acid 500g
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, 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.
Example 3
A, nicotinic acid 300g
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, rosuvastatin calcium 20g
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.
Example 4
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, rosuvastatin calcium 30g
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, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
C, with above-mentioned a, two kinds of components of b adopt the bi-layer tablet press punching press promptly to get double-layer tablet.
Example 5
A, 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, 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.
Example 6
A, nicotinic acid 500g
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 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 15g
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, 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 rosuvastatin calcium in per two capsules and 30mg fills, and gets final product.
Example 7
A, nicotinic acid 750g
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, CYL3bar, 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, go into 30 ℃ of demeanour, 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 in the example 5, adopt hard capsule medicine filling machine to be respectively 300mg with the nicotinic acid piller that makes among this routine b according to the weight that contains nicotinic acid and rosuvastatin calcium in per two capsules, fill with 30mg, get final product.
Example 8
A, nicotinic acid 500g
Celphere 200g
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, CYL3bar, CAP1 0.8bar 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, CAP1 0.8bar 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 nicotinic acid and rosuvastatin calcium in per two capsules and 40mg fills, and gets final product.
Example 9
A, nicotinic acid 750g
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, CYL3bar, CAP1 0.8bar pours celphere into, pelletize, blanking velocity 4rpm, the pump 12% of wriggling, rotary speed 145 rpm spray 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 CYL3bar, CAP1 1.0bar, the pump 6% of wriggling, rotary speed 175rpm sprays into 95% alcoholic solution of ethyl cellulose, stearic acid and Polyethylene Glycol-6000.Coating finishes, 50 ℃ of oven dry, discharging.
C, Luo Sutating 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, 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 800mg according to the weight that contains nicotinic acid and rosuvastatin calcium in per two capsules and 5mg fills, and gets final product.
The proportioning screening of example 10 nicotinic acid and rosuvastatin calcium compound treatment rat hyperlipidemia
[summary] this test objective is to determine that by screening toxicity is low, act on nicotinic acid 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 test product nicotinic acid 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.Gavage nicotinic acid (150～800mg/kg) and (or) rosuvastatin calcium (5～40mg/kg to rat model, in free acid, down together) after 14 days, T-CHOL, triglyceride, low-density lipoprotein cholesterol all obviously descend in the serum, and HDL-C raises.Single wherein a kind of medicine or two medicines, 5 usefulness used, its effect is strengthened with dosage escalation.
The result shows that nicotinic acid 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 nicotinic acid 500mg/kg 5 usefulness effects are better.
1 test objective
Determine that by screening nicotinic acid or nicotinic acid and rosuvastatin calcium compound preparation forms, 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 nicotinic acid
Lot number: 0306004
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 calcium (Rosuvastatin Calcium)
Lot number: 030206
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.
The preparation of 4 hyperlipemia model of rats
[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 nicotinic acid and rosuvastatin calcium are to the influence of normal rat fat
[2]
5.1 dosage is selected
To be used for the dosage of blood fat reducing be (to calculate by body weight for humans 60kg for 1000～2000mg/ time to nicotinic acid clinically, above-mentioned dosage is 16.8～33.6mg/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 300mg/kg/day.1 time/day medication is adopted in this test, thus in this test nicotinic acid dosage be made as 150,300,500,800mg/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
[4]By body surface area is the dosage equivalence principle reckoning of unit, and above-mentioned people's common dose is converted into rat dosage and is about 0.5-1.5mg/kg.In conjunction with bibliographical information, with rosuvastatin calcium dosage in this test 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; (2) nicotinic acid 150mg/kg group; (3) nicotinic acid 300mg/kg group; (4) nicotinic acid 500mg/kg group; (5) nicotinic acid 800mg/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) nicotinic acid 300mg/kg and rosuvastatin calcium 10mg/kg group; (15) nicotinic acid 300mg/kg and rosuvastatin calcium 20mg/kg group; (16) nicotinic acid 500mg/kg and rosuvastatin calcium 5mg/kg group; (17) nicotinic acid 500mg/kg and rosuvastatin calcium 10mg/kg group; (18) nicotinic acid 500mg/kg and rosuvastatin calcium 20mg/kg group; (19) nicotinic acid 500mg/kg and rosuvastatin calcium 40mg/kg group; (20) nicotinic acid 800mg/kg and rosuvastatin calcium 5mg/kg group; (21) nicotinic acid 800mg/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 nicotinic acid 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) nicotinic acid 150mg/kg group; (4) nicotinic acid 300mg/kg group; (5) nicotinic acid 500mg/kg group; (6) nicotinic acid 800mg/kg group; (11) rosuvastatin calcium 5mg/kg group; (12) rosuvastatin calcium 10mg/kg group; (13) rosuvastatin calcium 20mg/kg group; (14) rosuvastatin calcium 40mg/kg group; (15) nicotinic acid 300mg/kg and rosuvastatin calcium 10mg/kg group; (16) nicotinic acid 300mg/kg and rosuvastatin calcium 20mg/kg group; (17) nicotinic acid 500mg/kg and rosuvastatin calcium 5mg/kg group; (18) nicotinic acid 500mg/kg and rosuvastatin calcium 10mg/kg group; (19) nicotinic acid 500mg/kg and rosuvastatin calcium 20mg/kg group; (20) nicotinic acid 500mg/kg and rosuvastatin calcium 40mg/kg group; (21) nicotinic acid 800mg/kg and rosuvastatin calcium 5mg/kg group; (22) nicotinic acid 800mg/kg and rosuvastatin calcium 10mg/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 nicotinic acid 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 nicotinic acid, 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.
1 nicotinic acid and rosuvastatin calcium and compatibility are to the influence of normal rat fat
| Group | T-CHOL (mmol/L) | Triglyceride (mmol/L) | Low-density lipoprotein cholesterol (mmol/L) | HDL-C (mmol/L) |
| Normal group nicotinic acid 150mg/kg nicotinic acid 300mg/kg nicotinic acid 500mg/kg nicotinic acid 800mg/kg rosuvastatin calcium 5mg/kg rosuvastatin calcium 10mg/kg rosuvastatin calcium 20mg/kg rosuvastatin calcium 40mg/kg cigarette 300 Luo Su 10mg/kg cigarettes 300 Luo Su 20mg/kg cigarettes 500 Luo Su 5mg/kg cigarettes 500 Luo Su 10mg/kg cigarettes 500 Luo Su 20mg/kg cigarettes 500 Luo Su 40mg/kg cigarettes 800 Luo Su 5mg/kg cigarettes 800 Luo Su 10mg/kg | 2.07±0.28 1.90±0.25 1.87±0.28 1.75±0.31 1.67±0.29 2.00±0.11 1.92±0.37 1.83±0.26 1.73±0.33 1.63±0.35 1.54±0.29 1.50±0.34 1.51±0.18 1.46±0.40 * 1.70±0.25 1.41±0.33 * 1.58±0.27 | 0.88±0.56 0.81±0.43 0.79±0.39 0.72±0.44 0.69±0.36 0.73±0.32 0.68±0.08 0.67±0.20 0.60±0.21 0.61±0.13 0.67±0.19 0.63±0.22 0.66±0.34 0.62±0.26 0.59±0.33 0.61±0.29 0.58±0.16 | 0.44±0.10 0.40±0.12 0.39±0.15 0.34±0.13 0.33±0.25 0.39±0.09 0.36±0.10 0.32±0.10 0.35±0.22 0.33±0.11 0.35±0.14 0.36±0.23 0.32±0.19 0.35±0.30 0.32±0.09 0.37±0.17 0.31±0.20 | 0.83±0.09 0.85±0.11 0.87±0.13 0.90±0.12 0.92±0.22 1.11±0.30 1.10±0.14 * 1.06±0.19 1.05±0.47 1.01±0.46 1.10±0.15 1.12±0.19 1.09±0.25 1.05±0.22 1.11±0.31 1.13±0.19 1.08±0.41 |
Annotate: * and normal control group compare, * P＜0.05, * * P＜0.01
7.2 nicotinic acid 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 nicotinic acid is from 300～800mg/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 nicotinic acid and rosuvastatin calcium, triglyceride, low-density lipoprotein cholesterol all descend.(table 2).Analysis-by-synthesis, nicotinic acid 500mg/kg and rosuvastatin calcium 5mg/kg, nicotinic acid 800mg/kg and rosuvastatin calcium 10mg/kg drug combination effect are remarkable, and serum total cholesterol, triglyceride, low-density lipoprotein cholesterol are all shown synergism.
Part nicotinic acid 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 should reduce the dosage of rosuvastatin calcium in compound recipe as far as possible, with nicotinic acid 500mg/kg and rosuvastatin calcium 5mg/kg dosage, compatibility is better, and is less to creatine kinase in the serum and the active influence of serum alanine aminotransferase.
Table 2 nicotinic acid and rosuvastatin calcium and compound recipe are to the influence of rat model blood fat
| Group | Serum total cholesterol (mmol/L) | The sliding triglyceride (mmol/L) of blood | Low-density lipoprotein cholesterol (mmol/L) | HDL-C (mmol/L) |
| The normal control group | 1.93±0.30 | 0.63±0.13 | 0.41±0.10 | 1.07±0.20 |
| Model control group nicotinic acid 150mg/kg nicotinic acid 300mg/kg nicotinic acid 500mg/kg nicotinic acid 800mg/kg rosuvastatin calcium 5mg/kg rosuvastatin calcium 10mg/kg rosuvastatin calcium 20mg/kg rosuvastatin calcium 40mg/kg cigarette 300 Luo Su 10mg/kg cigarettes 300 Luo Su 20mg/kg cigarettes 500 Luo Su 5mg/kg cigarettes 500 Luo Su 10mg/kg cigarettes 500 Luo Su 20mg/kg cigarettes 500 Luo Su 40mg/kg cigarettes 800 Luo Su 5mg/kg cigarettes 800 Luo Su 10mg/kg | 5.75±0.33 **** 5.56±0.35 5.17±0.40 ** 4.77±0.36 *** 4.49±0.50 *** 4.77±0.47 *** 4.36±0.44 *** 4.22±0.38 *** 3.77±0.37 *** 4.06±0.34 *** 3.88±0.27 *** 3.46±0.56 *** 3.57±0.29 *** 3.46±0.35 *** 3.61±0.37 *** 3.59±0.26 *** 3.25±0.41 *** | 2.27±0.26 **** 2.24±0.15 2.20±0.23 2.03±0.34 1.59±0.17 *** 2.20±0.15 2.10±0.20 1.41±0.41 *** 1.21±0.10 *** 1.78±0.13 ** 1.65±0.25 *** 1.19±0.16 *** 1.32±0.47 *** 1.28±0.35 ** 1.33±0.22 *** 1.27±0.34 *** 1.08±0.18 *** | 3.26±0.09 **** 3.20±0.25 3.01±0.29 * 2.65±0.38 *** 2.11±0.23 *** 2.96±0.61 2.77±0.59 * 2.20±0.26 *** 1.99±0.45 *** 2.45±0.32 *** 2.37±0.37 *** 1.56±0.25 *** 1.69±0.29 *** 1.72±0.39 *** 1.58±0.41 *** 1.56±0.34 *** 1.40±0.17 *** | 0.99±0.11 1.08±0.14 0.99±0.18 1.15±0.26 1.21±0.33 * 0.94±0.14 0.98±0.15 1.17±0.31 1.27±0.25 ** 1.13±0.15 1.27±0.18 *** 1.51±0.20 *** 1.43±0.31 ** 1.46±0.22 ** 1.44±0.35 ** 1.50±0.27 *** 1.55±0.34 *** |
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 nicotinic acid and rosuvastatin calcium and compound recipe are to the influence of rat model serum alanine aminotransferase and creatine kinase
| Group | Alanine aminotransferase (nmol.s -1/L) | Creatine kinase (U/L) |
| Normal group model control group nicotinic acid 150mg/kg nicotinic acid 300mg/kg nicotinic acid 50mg/kg nicotinic acid 800mg/kg Luo Su 5mg/kg Luo Su 10mg/kg Luo Su 20mg/kg Luo Su 40mg/kg cigarette 300 Luo Su 10mg/kg cigarettes 300 Luo Su 20mg/kg cigarettes 500 Luo Su 5mg/kg cigarettes 500 Luo Su 10mg/kg cigarettes 500 Luo Su 20mg/kg cigarettes 500 Luo Su 40mg/kg cigarettes 800 Luo Su 5mg/kg cigarettes 800 Luo Su 10mg/kg | 527.9±144.8 683.5±245.6 650.4±234.5 679.5±325.4 643.7±267.7 688.2±198.1 826.1±328.8 859.4±309.9 * 868.7±620.6 1504.0±864.9 ** 589.3±156.4 867.2±187.5 736.9±209.6 802.7±179.3 833.5±236.7 1407.8±809.1 ** 765.1±207.5 695.8±193.9 | 507.2±194.6 ** 287.2±68.5 256.3±55.7 280.6±46.9 265.8±33.4 271±125 345.6±219.5 363.4±126.0 589.2±335.8 * 1450.2±1385.2 * 325.6±103.5 469.3±121.8 300.4±201.6 335.6±179.5 509.2±302.4 1523.7±1092.7 * 320.9±220.4 473.1±187.9 |
Annotate: compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with model control group
8 conclusions
Nicotinic acid 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, wherein with nicotinic acid 500mg/kg and rosuvastatin calcium 5mg/kg dosage, 5 usefulness effects are remarkable, do not have tangible toxic action simultaneously again.In addition, this result of the test finds that nicotinic acid administration every day of higher dosage also has significant effect for reducing blood fat 1 time, and toxicity is little, and this is that nicotinic acid and rosuvastatin calcium are formed compound recipe, realizes that administration every day provides experimental basis 1 time.
The nicotinic acid of example 11. different release times and rosuvastatin calcium compound recipe are to the prophylactic treatment effect of clinical hyperlipemic patients unstable angina pectoris
1 test objective
Animal experiment is screened determined nicotinic acid and rosuvastatin calcium compound preparation (weight ratio is 100: 1), be used for hyperlipidemia companion functions in patients with unstable angina, to observe its prophylactic treatment effect.
2 are subjected to the reagent thing
2.1 nomenclature of drug: nicotinic acid
Lot number: 0304001
Purity: greater than 99.6%
Production unit: Lunan Pharmacy Co. Ltd
Preservation condition: shady and cool dry place preserves 1 year half effect duration.
2.2 nomenclature of drug: rosuvastatin (Rosuvastatin)
Lot number: 030205
Purity: greater than 99.0%
Production unit: Astrazeneca AB
2.3 nomenclature of drug: nicotinic acid rosuvastatin (Rosuvastatin) ordinary tablet, every contains nicotinic acid 500mg, rosuvastatin calcium 5mg.
Lot number: 0305003
Production unit: Lunan Pharmacy Co. Ltd
Preservation condition: shady and cool dry place preserves 1 year half effect duration.
2.4 nomenclature of drug: nicotinic acid rosuvastatin (Rosuvastatin) slow releasing tablet, every contains nicotinic acid 500mg, rosuvastatin calcium 5mg.
Lot number: 0304002
Production unit: Lunan Pharmacy Co. Ltd
Preservation condition: shady and cool dry place preserves 1 year half effect duration.
3 are tried the patient selects
The patient of the various hyperlipidemia companion unstable angina pectoris of clinical definite.
4. dosage regimen
All are tried the patient according to myocardial ischemia incident occurrence frequency and the isostatic principle of myocardial infarction area, be divided into placebo group, nicotinic acid group, rosuvastatin calcium group, nicotinic acid Luo Sutating ordinary tablet group and nicotinic acid Luo Sutating slow releasing tablet group at random.Dosage is provided with foundation,, dosage is set at rosuvastatin calcium 5mg, nicotinic acid 500mg, decoction being taken at a draught every night according to the optimal proportion of resulting rosuvastatin calcium of zoopery and nicotinic acid compositions and the common dose of two kinds of clinical drugs.
5. detection index
The angina pectoris attacks frequency, serum lactate dehydrogenase (SLD) (LDH) activity.
6. result of the test
The patient of hyperlipidemia companion unstable angina pectoris measures the activity of anginal seizure frequency and serum lactate dehydrogenase (SLD) in the week before medication, after the random packet, give corresponding Drug therapy, the 16th week after administration is measured anginal seizure frequency and serum lactate dehydrogenase (SLD) activity once more.The result is as follows:
| Group | Angina pectoris attacks frequency time/week | Serum LDH UL -1 |
| Placebo group nicotinic acid group rosuvastatin calcium group cigarette+sieve ordinary tablet group cigarette+sieve slow releasing tablet group | 5.9±2.9 4.5±2.4 3.0±1.8 * 2.1±1.0 **# 0.8±1.2 ***###&& | 251.4±45.2 205.6±50.6 * 205.2±43.4 148.9±53.1 **& 105.7±43.9 ***###&& |
Annotate:
*Compare with placebo group, P＜0.05,
* *Compare P＜0.001 with placebo group
# compares with the nicotinic acid group, P＜0.05, and ### compares with the nicotinic acid group, P＜0.001
﹠amp; Compare P＜0.05 ， ﹠amp with the rosuvastatin calcium group; ﹠amp; Compare P＜0.01 with the rosuvastatin calcium group
7. conclusion
Nicotinic acid 500mg and rosuvastatin calcium 5mg 5 usefulness have synergitic prophylactic treatment effect to clinical hyperlipidemia companion functions in patients with unstable angina.And wherein the effect of slow releasing tablet is ideal.
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-week trial.
[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]Al-Shurbaji A，et al.The effect of Acipimox on triacylglycerolmetabolism in rat.Scand J Clin Lab Invest，1990，50(2)：203-208
[4] Crestor (Rosuvastatin) description
Claims (1)
1. the purposes of pharmaceutical composition in preparation treatment medicaments for coronary disease that comprises nicotinic acid and rosuvastatin or rosuvastatin salt, rosuvastatin ester.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260440A (en) * | 1991-07-01 | 1993-11-09 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives |
| US6316460B1 (en) * | 2000-01-26 | 2001-11-13 | Astrazeneca Ab | Pharmaceutical compositions |
| CN1457786A (en) * | 2003-04-30 | 2003-11-26 | 鲁南制药股份有限公司 | Composition for curing hyperlipemia |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260440A (en) * | 1991-07-01 | 1993-11-09 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives |
| US6316460B1 (en) * | 2000-01-26 | 2001-11-13 | Astrazeneca Ab | Pharmaceutical compositions |
| CN1457786A (en) * | 2003-04-30 | 2003-11-26 | 鲁南制药股份有限公司 | Composition for curing hyperlipemia |
Non-Patent Citations (4)
| Title |
|---|
| 乳酸脱氢酶同工酶分析在心脏病诊疗中的探讨 江木林，陈晓舟，杨国锋，宁夏医学杂志，第23卷第8期 2001 * |
| 乳酸脱氢酶同工酶分析在心脏病诊疗中的探讨 江木林，陈晓舟，杨国锋，宁夏医学杂志，第23卷第8期 2001;心绞痛的药物治疗平价 钟尹元，中国药物与临床，第4卷第3期 2004;血清乳酸脱氢酶及其同工酶测定在冠心病中的应用 董志远，寇丽筠，国外医学临床生物化学与检验学分册，第15卷第2期 1994 * |
| 心绞痛的药物治疗平价 钟尹元，中国药物与临床，第4卷第3期 2004 * |
| 血清乳酸脱氢酶及其同工酶测定在冠心病中的应用 董志远，寇丽筠，国外医学临床生物化学与检验学分册，第15卷第2期 1994 * |
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