CN1803144A - Pharmaceutical composition containing clofibrate compound and B family vitamin - Google Patents

Abstract

The invention relates to an anti-atherosclerosis pharmaceutical composition containing clofibrate ester compounds and B vitamins, comprising a therapeutically effective dose of clofibrate ester compounds and one of their active metabolites, salts or esters , one or more of the B vitamins in a therapeutically effective amount, and a pharmaceutically acceptable carrier; wherein the content of clofibrate ester compounds and their active metabolites, salts or esters is 100-1500 mg, The content of B vitamins is 0.1-50 mg. The invention has the advantages that it can improve the curative effect of clofibrate ester lipid-lowering drugs, is superior to clofibrate ester lipid-lowering drugs in terms of vascular endothelial protection and anti-atherosclerosis, and reduces the clofibrate ester lipid-lowering drugs. The side effect of medicine, and the pharmaceutical composition that toxicity does not increase. In addition, it can make it convenient for patients to take medicine and reduce medical expenses.

Description

Pharmaceutical composition containing clofibrate ester compound and B vitamins

technical field

The invention relates to a pharmaceutical composition containing clofibrate ester compounds and B vitamins, in particular to a chemical medicine composition for treating and preventing atherosclerosis and related diseases, and belongs to the field of pharmacy.

Background technique

Cardiovascular disease is the first or second cause of death in my country, and the incidence and mortality of coronary heart disease are on the rise. Several risk factors such as hyperlipidemia, hypertension, smoking and diabetes play an important role in the pathogenesis of coronary heart disease, and the understanding of the significance of hypertriglyceridemia (TG) in atherosclerosis is deepening in recent years. More and more research data suggest that there is a correlation between hypertriglyceridemia and coronary heart disease, especially the abnormal quantity and quality of circulating triglyceride-rich lipoproteins may be the key to the development of coronary heart disease Factor (Chen Hong, et al. Journal of Hypertension. 2003, 11(suppl): 41-3). The prevalence rate of high TG in our country is 22.9% for males and 16.5% for females, and it is as high as 34.4% and 27.0% in some regions respectively. High TG is the most common type of clinical hyperlipidemia in my country. The risk factors of cardiovascular disease are in Aggregation occurs in patients with hypertriglyceridemia. (Wang Wei, et al. Chinese Journal of Epidemiology. 2001.22(1): 26-29) (Zhang Rihua, et al. Chinese General Medicine. 2003.6(1): 19-21). Therefore, the prevention and treatment of hyperlipidemia has become an important link in the prevention and treatment of atherosclerosis.

Reasonable diet and life adjustment are extremely important to prevent and treat hyperlipidemia. Recently, newly developed lipid-lowering drugs have been able to partially control diet therapy. The drugs commonly used in clinic to regulate blood lipids are HMG-CoA reductase inhibitors (statins), clofibrates, bile acid complexing agents, nicotinic acid, etc., wherein clofibrates are hypertriglyceridemia The drug of choice for dyslipidemia (thematic group for the prevention and treatment of dyslipidemia. Suggestions for the prevention and treatment of dyslipidemia. Chinese Journal of Cardiovascular Diseases, 1997, 25: 169-75). Common clofibrate esters are Fenofibrate, Gemfibrozil, Clofibrate, Etofylline Clofibrate, Bezafibrate, Cyproterone Ciprofibrate, Lifibrate, Alufibrate, Simfibrate, Beclobrate, Etofibrate, etc.

However, studies in recent years have shown that clofibrate can increase plasma homocysteine levels in patients with CAD, and the mechanism may be through the activation of alpha receptors (peroxisome proliferator-activated receptor alpha) by catalase growth factor. way. (Eur J Cardiovasc Prev Rehabil.2004;11(3):244-9)(J Cardiovasc Pharmacol.2004;43(3):452-3)(Lancet.2001;358(9275):39-40). In addition, elevated plasma homocysteine levels are associated with an increased risk of CHD. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) report pointed out that homocysteine should attract more attention as a new risk factor for CHD ( Circulation. 200217;106(25):3143-421). The main harm of hyperlipidemia is to cause stroke, coronary heart disease, myocardial infarction, and sudden cardiac death, and its treatment goal is to prevent atherosclerosis and coronary heart disease. Therefore, it is necessary to control the level of plasma homocysteine while lowering blood lipids, especially for the increase of plasma homocysteine caused by clofibrate drugs.

Contents of the invention

One of the purposes of the present invention is to overcome the above-mentioned deficiencies in the existence of clofibrate lipid-lowering drugs, and provide a kind of lipid-lowering drugs that are better than clofibrate esters in terms of vascular endothelial protection and anti-atherosclerosis. The side effect of bebutin ester class lipid-lowering drug, but the drug composition that toxicity does not increase.

The second object of the present invention is to use the above pharmaceutical composition for preventing, delaying the occurrence of atherosclerosis and related diseases, delaying its progress or preventing recurrence.

To achieve the above object, the present invention adopts the following technical solutions:

An anti-atherosclerosis pharmaceutical composition containing clofibrate ester compounds and B vitamins, comprising a therapeutically effective amount of clofibrate ester compounds and one of their active metabolites, salts or esters, One or more of the B vitamins in a therapeutically effective amount, and a pharmaceutically acceptable carrier; wherein the content of clofibrate ester compounds and their pharmaceutical precursors, active metabolites, salts or esters is 100-1500mg, and the content of B vitamins is 0.1-50mg.

The anti-atherosclerosis pharmaceutical composition is used for the prevention and treatment of cardiovascular disease, cerebrovascular disease, and peripheral vascular disease. Cardiovascular disease refers especially to coronary heart disease, including death from coronary heart disease, myocardial infarction, and coronary artery revascularization. Among cerebrovascular diseases, especially stroke and transient ischemic attack. Among them, it is preferentially used to prevent, delay the occurrence of atherosclerosis and related diseases, treat atherosclerosis and related diseases, delay its progress or prevent recurrence.

The clofibrate ester compound is selected from fenofibrate, gemfibrozil, clofibrate, ydodol, bezafibrate, ciprofibrate, libet, aluminum clofibrate, bis One of fibrate and its active metabolites, salts or esters.

Through experimental research and clinical data, the contents of clofibrate ester compounds are: fenofibrate (100-300mg), gemfibrozil (300-1200mg), clofibrate (250-1500mg), yadolate (250~750mg), bezafibrate (200~600mg), ciprofibrate (100~300mg), libet (25~150mg), clofibrate aluminum (250~1500mg), bisfibrate ( 250-1500mg), berofibrate (100-300mg), etofibrate (300-900mg), the content of active metabolites, salts or esters of the above-mentioned substances is equivalent to the content of the corresponding above-mentioned substances.

The B vitamins are selected from one or more of vitamin B6, vitamin B12, folic acid and calcium leucovorin.

The vitamin B6 substances include pyridoxine, pyridoxal, pyridoxamine, pyridoxal phosphate, pyridoxamine phosphate and derivatives of the above substances and substances that can release/generate such compounds in vivo.

The vitamin B12 substances include cobalamin, methylcobalamin, 5'deoxyadenosylcobalamin, hydroxocobalamin, cyanocobalamin and other cobalamin derivatives and cobalamin that can be released/generated in the body amine substances.

The folic acid substances include folic acid, calcium leucovorin, L-methylfolate, folate, folic acid or an active metabolite of folate and substances that can release/generate folic acid in the body.

The therapeutically effective doses of B vitamins in the present invention are respectively: 0.2-10 mg of folic acid, 0.1-2 mg of vitamin B12 and 0.5-50 mg of vitamin B6. The more preferable therapeutically effective doses are: 0.2-5 mg of folic acid substances, 0.25-2 mg of vitamin B12 substances, and 5-50 mg of vitamin B6 substances.

The present invention is preferably a pharmaceutical composition with the following components as active ingredients: wherein the clofibrate ester compound is selected from fenofibrate (100-300 mg), gemfibrozil (300-1200 mg), bezafibrate (200~600mg), ciprofibrate (100~200mg); B vitamins are selected from folic acid (0.2~5mg), calcium leucovorin (0.2~5mg), vitamin B12 (0.25~2mg) and vitamin B6 (5 ~ 50mg) in one or more.

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from fenofibrate (100-300 mg), and the B vitamins are preferably selected from folic acid (0.2-5 mg) or leucovorin Calcium (0.2 ~ 5mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from fenofibrate (100-300 mg), and the B vitamin is B6 (5-50 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from fenofibrate (100-300 mg), and the B vitamin is B12 (0.25-2 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from fenofibrate (100-300 mg), and the B vitamins are folic acid (0.2-5 mg) and B6 (5-50 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from fenofibrate (100-300 mg), and the B vitamins are folic acid (0.2-5 mg) and B12 (0.25-2 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from gemfibrozil (300-1200 mg), and the B vitamins are preferably selected from folic acid (0.2-5 mg) or leucovorin Calcium (0.2 ~ 5mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from gemfibrozil (300-1200 mg), and the B vitamin is B6 (5-50 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from gemfibrozil (300-1200 mg), and the B vitamin is B12 (0.25-2 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from gemfibrozil (300-1200 mg), and the B vitamins are folic acid (0.2-5 mg) and B6 (5-50 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from gemfibrozil (300-1200 mg), and the B vitamins are folic acid (0.2-5 mg) and B12 (0.25-2 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from bezafibrate (200-600 mg), and the B vitamins are preferably selected from folic acid (0.2-5 mg) or leucovorin Calcium (0.2 ~ 5mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from bezafibrate (200-600 mg), and the B vitamin is B6 (5-50 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from bezafibrate (200-600 mg), and the B vitamin is B12 (0.25-2 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from bezafibrate (200-600 mg), and the B vitamins are folic acid (0.2-5 mg) and B6 (5-50 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from bezafibrate (200-600 mg), and the B vitamins are folic acid (0.2-5 mg) and B12 (0.25-2 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from ciprofibrate (100-200 mg), and the B vitamins are preferably selected from folic acid (0.2-5 mg) or leucovorin Calcium (0.2 ~ 5mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from ciprofibrate (100-200 mg), and the B vitamin is B6 (5-50 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from ciprofibrate (100-200 mg), and the B vitamin is B12 (0.25-2 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from ciprofibrate (100-200 mg), and the B vitamins are folic acid (0.2-5 mg) and B6 (5-50 mg).

The more preferred combination of the present invention is: the clofibrate ester compound is preferably selected from ciprofibrate (100-200 mg), and the B vitamins are folic acid (0.2-5 mg) and B12 (0.25-2 mg).

The anti-atherosclerosis pharmaceutical composition containing clofibrate esters and B vitamins may further comprise an effective therapeutic amount of an active ingredient selected from the group consisting of HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, squalene epoxidase, squalene synthase, acyl-CoA-cholesterol acyltransferase, probucol, niacin, cholesterol absorption inhibitors, bile acid sequestrants, LDL Receptor inducers, aspirin, beta-blockers, vitamin C, vitamin E, beta-carotene.

The pharmaceutical composition can be made into ordinary tablets, ordinary capsules, granules, sustained-release tablets, sublingual tablets, orally rapidly disintegrating tablets, dispersible tablets, enteric-coated tablets, enteric-coated capsules, delayed-release tablets, timed/bit Release tablets, sustained-release capsules, controlled-release capsules, capsules containing pellets or small tablets, pH-dependent capsules containing pellets or small tablets, granules, oral liquids, films, patches and other dosage forms.

The pharmaceutical composition also contains a pharmaceutically acceptable carrier, which can be made into common oral preparations, including common tablets, common capsules, granules, etc. Excipients and adjuvants for formulating active compounds into pharmaceutical preparations, such as starch, microcrystalline cellulose, inorganic salts, sucrose, dextrin, lactose, powdered sugar, glucose, sodium chloride, cysteine, citric acid The composition of one or more substances such as sodium sulfite and the like belongs to common knowledge in the art.

The pharmaceutical composition also contains pharmaceutically acceptable carriers, which can be made into slow-release tablets, including excipients and auxiliary materials. The excipients and adjuvants include hypromellose and/or ethyl cellulose and/or polyacrylic acid resins and/or polycarboxyvinyls and/or alginic acid soluble / Insoluble salts and/or other excipients that play a sustained release role, hypromellose adopts various commodities containing hydroxypropyl methylcellulose (HPMC), such as various specifications of Methocel, ethyl cellulose The element adopts various commodities containing ethyl cellulose (EC), and the polyacrylic resin adopts polyacrylic resin II, III or the like such as acrylic resin (Eudragit) of various specifications. The above-mentioned auxiliary materials are porogens, adhesives, lubricants, emulsifiers, membrane materials, solvents or other auxiliary materials. The porogens can be sucrose, mannitol, starch, talcum powder, silicon dioxide, etc.; Use polyvinylpyrrolidone, hypromellose, etc.; wetting agent can use water, absolute ethanol, ethanol-water solution of various concentrations; lubricant can use stearic acid, magnesium stearate, talcum powder, starch, paraffin etc.; tartaric acid, citric acid, etc. can be used as solubilizer; span80\span85 can be used as emulsifier; polyvinyl alcohol, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, etc. can be used as membrane material The foaming agent can be basic magnesium carbonate, sodium bicarbonate, etc.; the bleaching aid can be cetyl alcohol, stearyl alcohol, beeswax, etc.; the solvent can be absolute ethanol, ethanol, water, etc.;

The pharmaceutical composition also contains pharmaceutically acceptable carriers, which can be made into controlled-release tablets, including active drugs and auxiliary materials for controlled release. The above-mentioned excipients for controlling release are polyoxyethylene and/or hypromellose and/or ethyl cellulose and/or sodium chloride and/or lactose and/or mannitol and/or fructose and/or glucose and/or Or sucrose/or low-substituted hydroxypropyl cellulose and/or croscarmellose sodium and/or crospovidone and/or cellulose acetate. The above-mentioned auxiliary materials are drug carriers, swelling materials, penetration aids, solubilizers, adhesives, wetting agents, lubricants, colorants, porogens, film materials, anti-sticking agents, plasticizers, light-shielding agents, solvent. Drug carriers and swelling materials can be polyoxyethylene, hypromellose, ethyl cellulose, glyceryl behenate, etc.; penetration enhancers can be sodium chloride, lactose, mannitol, fructose, glucose, sucrose, etc. The solubilizing agent can use sodium lauryl sulfate or poloxamer, etc.; the adhesive can use polyvinylpyrrolidone, hypromellose, etc.; the wetting agent can use water, absolute ethanol, ethanol of various concentrations -Aqueous solution; lubricants can be stearic acid, magnesium stearate, talcum powder, starch, paraffin, etc.; colorants can be iron oxide red, iron oxide yellow, etc.; porogens can be sucrose, mannitol, polyethylene glycol Alcohol, titanium dioxide, talcum powder, silicon dioxide, etc.; membrane materials can be cellulose acetate, ethyl cellulose, etc.; solvents can be acetone, absolute ethanol, ethanol, water, etc.

The pharmaceutical composition also contains pharmaceutically acceptable carriers, which can be made into sublingual tablets, orally rapidly disintegrating tablets or dispersible tablets, etc., including excipients and auxiliary materials. The excipients and auxiliary materials include low-substituted hydroxypropyl methylcellulose, microcrystalline cellulose, sodium carboxymethyl starch, cross-linked carmellose sodium, cross-linked polyvinylpyrrolidone, processed agar and mannitol, lactose etc.

The pharmaceutical composition also contains a pharmaceutically acceptable carrier, which can be made into enteric-coated tablets or capsules, etc., including excipients and auxiliary materials. The excipients and auxiliary materials include starch microcrystalline cellulose, inorganic Salts, hydroxypropylmethylcellulose, ethylcellulose, polyacrylic resins, carbopols, soluble/insoluble salts of alginic acid, stearyl alcohol, octadecanoic acid, sucrose, dextrin, lactose, Composition of one or several substances such as sugar powder, glucose, sodium chloride, cysteine, citric acid and sodium sulfite, etc. Enteric coating materials include: shellac, cellulose acetate phthalate, acrylic resins (such as Eudragit L and S types, etc.), polyvinyl acetate phthalate, hypromellose phthalate, hypromellose acetate succinate, and plasticizers (such as phthalic acid Diethyl Ester, Polyethylene Glycol, Propylene Glycol, Triacetin, Dimethyl Phthalate, Dibutyl Sebacate, Triethyl Citrate, Tributyl Citrate, Acetyl Triethyl Citrate Esters, castor oil and various percentages of acetylated monoglycerides, etc.) and porogens (such as PEG6000, etc.) and other pharmaceutical excipients.

The pharmaceutical composition also contains a pharmaceutically acceptable carrier, which can be made into a delayed release tablet or a timed (position) release tablet, including excipients and auxiliary materials, and the described excipients and auxiliary materials include starch, microcrystalline cellulose , inorganic salts, hydroxypropyl methylcellulose, ethyl cellulose, polyacrylic resins, carbopol, soluble/insoluble salts of alginic acid, stearyl alcohol, stearic acid, sucrose, dextrin, The composition of one or more substances such as lactose, powdered sugar, glucose, sodium chloride, cysteine, citric acid and sodium sulfite, the coating material that described delay release or timing (position) release comprises: Shellac, cellulose acetate phthalate, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic resins (such as Eudragit L and S types, etc.), polyvinyl acetate phthalate , hypromellose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, and plasticizers (such as diethyl phthalate, polyethylene Glycol, propylene glycol, triacetin, dimethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil and various Various percentages of acetylated monoglycerides, etc.) and porogens (such as PEG6000, etc.) and other pharmaceutical excipients.

The pharmaceutical composition also contains pharmaceutically acceptable carriers, which can be made into sustained-release capsules, controlled-release capsules, capsules containing pellets or small tablets, pH-dependent capsules containing pellets or small tablets, etc., including excipients and Auxiliary material, described excipient and auxiliary material have the soluble/ Insoluble salts, stearyl alcohol, octadecanoic acid, sucrose, dextrin, lactose, powdered sugar, glucose, sodium chloride, cysteine, citric acid and sodium sulfite, etc., including one or more substances Clothing materials include shellac, cellulose acetate, cellulose acetate phthalate, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic resins (such as Eudragit series), polyvinyl acetate benzene two Formate, hypromellose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, glyceryl monostearate, and plasticizers (such as Diethyl Phthalate, Polyethylene Glycol, Propylene Glycol, Triacetin, Dimethyl Phthalate, Dibutyl Sebacate, Triethyl Citrate, Tributyl Citrate, Acetyl Triethyl citrate, castor oil and various percentages of acetylated monoglycerides, etc.) and porogens (such as PEG6000, etc.) and other pharmaceutical excipients.

The pharmaceutical composition also contains pharmaceutically acceptable carriers, which can be made into dosage forms such as granules, oral liquids, films, patches and the like. When made into patches and films, the pharmaceutically acceptable carrier includes excipients and adjuvants that help active compounds to be formulated into pharmaceutical preparations, such as polyvinyl alcohol, cellulose triacetate, ethylene-vinyl acetate copolymer Polyvinylpyrrolidone, polyacrylamide, polyisobutylene pressure-sensitive adhesive, acrylic resin pressure-sensitive adhesive, silicone pressure-sensitive adhesive, etc., and backings such as polyvinyl chloride, polyethylene, aluminum foil, polypropylene, polyester, etc. Material, polyethylene, polystyrene, polypropylene and other protective films, etc., or a combination of several substances.

The formulations of the present invention can be used simultaneously or sequentially in any order, preferably simultaneously. The above-mentioned simultaneous use includes fixed combination and non-fixed combination, and the best use is fixed combination.

The preparation of the present invention can be taken 1 to 3 times a day, or once a day or every other day or several days apart in a slow-release or controlled-release manner, wherein it is preferably taken once a day.

Said pharmaceutical composition can be used alternatively in the form of "combination kit". The above-mentioned "combination medicine box" is a box-shaped container containing a combination of medicines in various dosage forms and instructions for taking them. "Combined medicine box" is more suitable for individualized medicine.

The invention is used for people who have no clinical symptoms of atherosclerosis but carry risk factors for atherosclerosis and related diseases, and can prevent and delay the occurrence of atherosclerosis and related diseases. The invention is used for people with clinical symptoms of atherosclerosis and related diseases to treat atherosclerosis and related diseases, delay the process or prevent recurrence.

The beneficial effect of the present invention is: the present invention provides a kind of pharmaceutical composition, and this pharmaceutical composition can improve the curative effect of lipid-lowering medicine of clofibrate ester class, is superior to clofibrate in terms of vascular endothelial protection and anti-atherosclerosis The butyl ester lipid-lowering drug is a pharmaceutical composition that reduces the side effects of the clofibrate lipid-lowering drug without increasing the toxicity. In addition, it can make it convenient for patients to take medicine and reduce medical expenses.

The present invention will be further described below in conjunction with the specific embodiments, and the present invention is not limited. Any equivalent replacement in the field according to the content of the present invention belongs to the protection scope of the present invention.

Detailed ways

The preparation of embodiment 1 fenofibrate folic acid tablet

Recipe: Fenofibrate 100g

Folic acid 0.4g

Lactose 50g

Starch 50g

Sodium carboxymethyl starch 20g

10% starch slurry Appropriate amount

Magnesium Stearate Appropriate amount

Preparation method: crush the original and auxiliary materials through a 120-mesh sieve, weigh the prescription amount of fenofibrate, folic acid, lactose starch and sodium carboxymethyl starch, crush and sieve, mix evenly, and make a soft material with an appropriate amount of 10% starch slurry , granulate, dry at 40°C to 60°C until the water content is about 3%, take it out, granulate, mix the granule with an appropriate amount of magnesium stearate, and press it into 1000 tablets according to the conventional method.

The preparation of embodiment 2 fenofibrate folic acid tablets

Recipe: Fenofibrate 100g

Folic acid 0.8g

Direct-pressed microcrystalline cellulose 60g

pregelatinized starch 40g

Micropowder silica gel Appropriate amount

Magnesium Stearate Appropriate amount

Preparation method: crush the original and auxiliary materials through a 120-mesh sieve, weigh the prescription amount of fenofibrate, folic acid, direct-pressed microcrystalline cellulose, pregelatinized starch, micropowder silica gel and magnesium stearate, mix evenly, and powder directly Pressed into 1000 pieces.

The preparation of embodiment 3 fenofibrate folic acid capsules

Formula: Fenofibrate 100g

Folic acid 5g

Microcrystalline Cellulose 50g

Starch 50g

PVP 20g

10% starch slurry Appropriate amount

Micropowder silica gel Appropriate amount

Preparation method: crush the original and auxiliary materials through a 120-mesh sieve, weigh the prescription amount of fenofibrate, folic acid, lactose starch and PVP, crush and sieve, mix evenly, and make a soft material with an appropriate amount of 10% starch slurry, granulate, Dry at 40°C to 60°C until the water content is about 3%, take it out, granulate, mix the granule with an appropriate amount of talcum powder, and fill 1000 capsules according to the conventional method.

The preparation of embodiment 4 gemfibrozil folic acid tablets

Recipe: Gemfibrozil 600g

Folic acid 0.4g

Calcium hydrogen phosphate 160g

Sodium carboxymethyl starch 40g

10% starch slurry Appropriate amount

Magnesium Stearate Appropriate amount

Preparation method: crush the raw and auxiliary materials through a 120-mesh sieve, weigh the prescription amount of gemfibrozil, folic acid, lactose, starch and sodium carboxymethyl starch, crush and sieve, mix evenly, and make a soft gelatin powder with an appropriate amount of 10% starch slurry. material, granulated, dried at 40°C to 60°C until the water content is about 3%, taken out, sized, mixed evenly with an appropriate amount of magnesium stearate, and pressed into 1000 tablets according to conventional methods.

Example 5 Preparation of Gemfibrozil B6 Tablets

Recipe: Gemfibrozil 600g

Vitamin B6 5g

Direct-pressed microcrystalline cellulose 200g

Sodium carboxymethyl starch 40g

Micropowder silica gel Appropriate amount

Magnesium Stearate Appropriate amount

Preparation method: crush the original and auxiliary materials through a 120-mesh sieve, weigh the prescription amount of gemfibrozil, vitamin B6, direct-pressed microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, micropowder silica gel and stearic acid Magnesium, mixed evenly, the powder is directly pressed into 1000 tablets.

The preparation of embodiment 6 gemfibrozil B12 capsules

Recipe: Gemfibrozil 300g

Vitamin B12 1.0g

Microcrystalline Cellulose 100g

Starch 50g

Sodium carboxymethyl starch 20g

10% starch slurry Appropriate amount

Micropowder silica gel Appropriate amount

Preparation method: crush the original and auxiliary materials through a 120-mesh sieve, weigh the prescription amount of gemfibrozil, vitamin B12, lactose, starch and sodium carboxymethyl starch, crush and sieve, mix evenly, and make it with an appropriate amount of 10% starch slurry Soft material, granulated, dried at 40°C to 60°C until the water content is about 3%, taken out, sized, mixed evenly with an appropriate amount of talcum powder, and filled with 1000 capsules according to the conventional method.

The preparation of embodiment 7 bezafibrate folic acid tablet

Recipe: Bezafibrate 200g

Folic acid 0.4g

Lactose 75g

Starch 75g

PVP 30g

10% starch slurry Appropriate amount

Magnesium Stearate Appropriate amount

Preparation method: crush the raw materials and auxiliary materials through a 120-mesh sieve, weigh the prescription amount of bezafibrate, folic acid, lactose, starch and PVP, crush and sieve, mix evenly, make a soft material with an appropriate amount of 10% starch slurry, and granulate , Dry at 40°C to 60°C until the water content is about 3%, take it out, granulate, mix the granule with an appropriate amount of magnesium stearate, and press it into 1000 tablets according to the conventional method.

The preparation of embodiment 8 bezafibrate folic acid tablet

Recipe: Bezafibrate 200g

Folic acid 5g

Direct-pressed microcrystalline cellulose 100g

Pregelatinized starch 50g

Sodium carboxymethyl starch 30g

Micropowder silica gel Appropriate amount

Magnesium Stearate Appropriate amount

Preparation method: crush the raw materials and auxiliary materials through a 120-mesh sieve, weigh the prescription amount of bezafibrate, folic acid, direct-pressed microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, micronized silica gel and magnesium stearate , mix evenly, and press the powder directly into 1000 pieces.

The preparation of embodiment 9 ciprofibrate folic acid capsules

Recipe: Ciprofibrate 100g

Folic acid 0.8g

Microcrystalline Cellulose 50g

Sodium carboxymethyl starch 30g

Starch 50g

10% starch slurry Appropriate amount

Appropriate amount of talcum powder

Preparation method: crush the raw materials and auxiliary materials through a 120-mesh sieve, weigh the prescription amount of fenofibrate, folic acid, lactose, starch and sodium carboxymethyl starch, crush and sieve, mix evenly, and use an appropriate amount of 10% starch slurry to make soft material, granulated, dried at 40°C to 60°C until the water content is about 3%, taken out, sized, mixed evenly with an appropriate amount of talcum powder, and filled with 1000 capsules according to the conventional method.

Example 10. Preparation of Fenofibrate Sustained Release Capsules

1) Drug content:

Fenofibrate 200g

Folic acid 0.8g

2) Preparation of blank pellet cores: Weigh 500 g of microcrystalline cellulose (CP2000) and place it in a centrifugal coating granulator, use distilled water as a binder, and start the centrifugal coating granulator according to the following parameters: the speed of the main engine is 200r min ^{- 1.} The blast flow rate is 400L·min ^-1 , the jet pressure is 0.1～0.3MPa, the jet flow rate is 15～20L·min ^-1 , the spray flow rate changes with the granulation time, and the speed of the spray pump is adjusted to 50r·min ^-1 , Continue for 5 minutes, then reduce the spray flow rate to 20r·min ^-1 , until the material is in a flocculent flow state; then it is the powder supply stage, control the powder slurry ratio, and maintain the material in a flocculent flow state, and this process continues until the mould. To achieve the target pellet core, stop the powder supply, reduce the speed of the shotcrete pump to 2r·min ^-1 , and polish for 4min. Open the discharge port, take out the finished product, let it dry at room temperature until nearly dry, then dry it at 60°C for 2 hours, and screen to select the target blank pellet core.

3) Preparation of drug-containing pellet cores: The drug-containing pellets were prepared by centrifugal granulation, with 500 g of MCC blank pellets as the mother core and distilled water as the binder, and the experiment was carried out by powder layering method. In the prescription, MCC (CP2000) is used as the diluent, SDS is used as the surfactant, and the medicine accounts for 80% of the total amount of the mixed powder. Fixed host speed 200r·min ^-1 , jet flow~20L·min ^-1 , jet pressure 0.1~0.3MPa, blast flow 400L·min-1, spray pump speed 16r·min-1, powder supply speed 8r·min ^-1 . After powder supply, polish the pellets in a pot for 4 minutes, take out the finished product, dry it in the shade, then dry it at 40°C for 2 hours, and sieve it.

4) Coating with pill core:

Coating formula 1 is: containing pill core 200g

NE30D 15g

Talc powder 2g

SDS 0.06g

Water 12ml

Preparation of coating solution: Add talcum powder and SDS to water, stir for 10 minutes to make it uniform, slowly pour Eudragit® NE30D into the above suspension, and stir evenly. Sieve through 80 mesh. Stir continuously during the coating process. Coating is carried out according to the coating solution prescription, and the coating process conditions are as follows: the blast flow rate through the blower is selected as 40Hz, the spray pressure is 0.1Mpa, the speed of the constant flow pump is adjusted to 0.8~1.2ml·min ^-1 , and the coating temperature About 25°C.

Coating formula 2 is: containing pill core 200g

RS30D 6g

Talc powder 0.8g

PEG6000 0.1g

TEC 0.3g

SDS 0.01g

Water 10ml

Preparation of coating solution: Add PEG6000 into water (heat properly to dissolve), then add talcum powder and other additives, stir for 10 minutes, slowly pour Eudragit® RS30D into the above suspension, and stir well. Sieve through 80 mesh. Stir continuously during the coating process.

5) Fill the capsules with fenofibrate powder and folic acid pellets according to the prescribed amount of medicine, to obtain the product.

Example 11. Combined application of fenofibrate and folic acid synergistically resists atherosclerosis (As)

Forty-eight healthy male New Zealand big-eared white rabbits (body weight 1.8-2.2kg) were randomly divided into 6 groups according to body weight, with 8 rabbits in each group, which were normal control group, model group, fenofibrate group (5mg/kg), Folic acid group (0.25mg/kg), fenofibrate + folic acid group (5+0.02mg/kg), fenofibrate + folic acid group (5+0.25mg/kg). The normal control group was fed with basal feed, and the model group and each treatment group were fed with high-fat feed (containing 96% basal feed, 0.5% cholesterol, 3.5% lard). After feeding for 12 weeks for 8 weeks, the animals were anesthetized with ether, and the animals were sacrificed by carotid artery bloodletting, and the levels of plasma endothelin and nitric oxide were measured. Aortic samples were collected, and the area of aortic lipid plaque was detected by image analysis.

Results: Visible to the naked eye, the rabbits in the model group and each treatment group had different degrees of light yellow lipid plaque attached to the aortic wall, and in the rabbits with mild lesions, lipid plaque was only seen in the ascending aorta or aortic arch, and the It is distributed in a focal shape; in rabbits with serious lesions, the lipid accumulation extends diffusely downward from the ascending aorta and aortic arch, and can reach the thoracic aorta, abdominal aorta and their bifurcations in a cord-like or irregular manner Distributed in small flakes, protruding from the intimal surface; the plaque formation on the aortic wall of rabbits in the model group was the most serious; followed by the folic acid group and the fenofibrate group; the lesions were milder in the fenofibrate + folic acid group; The aortic wall of the rabbits in the group was smooth and grayish white without plaque.

Typical aortic lipid plaque structure under the microscope shows endothelial cell damage, inflammatory cell infiltration, foam cell aggregation, cell necrosis, fibroblast hyperplasia and smooth muscle cell proliferation. The degree of lesion in each group was basically consistent with the naked eye observation.

The mean value % of aortic plaque area of experimental rabbits in the fenofibrate + folic acid group was lower than that of the folic acid group and the fenofibrate group, and the aortic plaque area of the fenofibrate group was lower than that of the folic acid group; The area of arterial plaque tended to decrease compared with the area of aortic wall plaque in the model group, but there was no significant difference. See Table 1.

Compared with the normal group, the endothelin level in the model group was significantly increased, and the NO was significantly decreased; compared with the model group, the endothelin level was significantly decreased, and the NO was significantly increased in the fenofibrate group; the curative effect of the fenofibrate + folic acid group was superior In the fenofibrate single-use group; the endothelin level of the folic acid group tended to decrease compared with the model group, and the NO level tended to increase, but there was no significant difference. See Table 1.

Conclusion: The combination of folic acid and fenofibrate can synergistically protect the vascular endothelium and reduce the formation of atherosclerotic plaque, thereby achieving a synergistic anti-AS effect.

Table 1 The effect of fenofibrate + folic acid on rabbit atherosclerosis (x ± s, n = 8) group Dose (mg/kg) mean aortic wall plaque area % ET (pg/ml) NO (μmol/L) Normal control model group folic acid group fenofibrate fenofibrate + folic acid fenofibrate + folic acid --0.2555+0.025+0.25 017.0±4.714.6±5.111.2±3.9**6.9±2.8** ^▲▲ 5.6±2.3** ^▲▲ 115.3±23.7210.2±25.7196.6±20.0176.4±18.5*155.6±11.5** ^▲ 148.1±20.5** ^▲▲ 170.3±37.860.1±13.176.6±19.796.5±21.2**119.9±15.4** ^▲▲ 138.1±24.2** ^▲▲

Note: Compared with the model group *P<0.05, **P<0.01; compared with the fenofibrate group ^▲ P<0.05, ^▲▲ P<0.01

Example 12. Combined application of gemfibrozil + folic acid synergistically resists atherosclerosis

Forty-eight healthy male New Zealand big-eared white rabbits (body weight 1.8-2.2kg) were randomly divided into 6 groups according to body weight, with 8 rabbits in each group, which were normal control group, model group, gemfibrozil group (30mg/kg), Folic acid group (0.25mg/kg), gemfibrozil + folic acid group (30+0.02mg/kg), gemfibrozil + folic acid group (30+0.25mg/kg). The normal control group was fed with basal feed; the model group and each treatment group were fed with high-fat feed (containing 96% basal feed, 0.5% cholesterol, 3.5% lard). 8 weeks, a total of 12 weeks of feeding. Plasma endothelin and nitric oxide levels were measured. Aortic samples were collected, and the area of aortic lipid plaque was detected by image analysis.

Results: Gemfibrozil + folic acid group rabbit aortic wall plaque area % mean was lower than folic acid and gemfibrozil group, the aortic plaque area of gemfibrozil group was lower than folic acid group; the aortic plaque area of folic acid group The plaque area tended to decrease compared with the model group aortic wall plaque area, but there was no significant difference. See Table 2.

Compared with the normal group, the endothelin level in the model group was significantly increased, and the NO was significantly decreased; compared with the model group, the endothelin level was significantly decreased, and the NO was significantly increased in the gemfibrozil group; the curative effect of the gemfibrozil + folic acid group was superior In the gemfibrozil single-use group; the endothelin level of the folic acid group tended to decrease compared with the model group, and the NO level tended to increase, but there was no significant difference. See Table 2.

Conclusion: The combination of folic acid and gemfibrozil can synergistically protect the vascular endothelium and reduce the formation of atherosclerotic plaque, thereby achieving a synergistic anti-AS effect.

Table 2 The effect of gemfibrozil+folic acid on rabbit atherosclerosis (x±s, n=8) group Dose (mg/kg) mean aortic wall plaque area % ET (pg/ml) NO (μmol/L) Normal control model group Gemfibrozil folic acid Gemfibrozil + folic acid gemfibrozil + folic acid --0.253030+0.0230+0.25 024.4±7.020.0±8.416.4±3.3*12.8±2.6** ^▲ 9.5±2.7** ^▲▲ 134.6±17.7247.2±45.4215.7±31.4200.7±31.3*161.4±21.3** ^▲▲ 152.1±30.4** ^▲▲ 148.2±27.548.4±9.162.1±14.272.1±21.1*103.3±25.4** ^▲ 101.1±34.2** ^▲

Note: Compared with the model group *P<0.05, **P<0.01; compared with the fenofibrate group ^▲ P<0.05, ^▲▲ P<0.01

Example 13. Combined application of ciprofibrate and vitamin B6 synergistically resists atherosclerosis

40 healthy male New Zealand big-eared white rabbits (body weight 1.8-2.2kg) were randomly divided into 5 groups according to body weight, 8 rabbits in each group, which were normal control group, model group, ciprofibrate group (5mg/kg), Vitamin B6 group (0.3mg/kg), ciprofibrate+vitamin B6 group (5+0.3mg/kg). The normal control group was fed with basal feed, and the model group and each treatment group were fed with high-fat feed (containing 96% basal feed, 0.5% cholesterol, 3.5% lard). After feeding for 12 weeks for 8 weeks, the animals were anesthetized with ether, and the animals were sacrificed by carotid artery bloodletting, and the levels of plasma endothelin and nitric oxide were measured. Aortic samples were collected, and the area of aortic lipid plaque was detected by image analysis.

Results: Visible to the naked eye, the rabbits in the model group and each treatment group had different degrees of light yellow lipid plaque attached to the aortic wall, and in the rabbits with mild lesions, lipid plaque was only seen in the ascending aorta or aortic arch, and the It is distributed in a focal shape; in rabbits with serious lesions, the lipid accumulation extends diffusely downward from the ascending aorta and aortic arch, and can reach the thoracic aorta, abdominal aorta and their bifurcations in a cord-like or irregular manner Distributed in small flakes, protruding on the surface of the intima; the plaque formation on the aortic wall of rabbits in the model group was the most serious; the vitamin B6 group and the ciprofibrate group followed in turn; the ciprofibrate+vitamin B6 group had mild lesions; and The aortic wall of the rabbits in the normal control group was smooth and grayish white without plaque.

Typical aortic lipid plaque structure under the microscope shows endothelial cell damage, inflammatory cell infiltration, foam cell aggregation, cell necrosis, fibroblast hyperplasia and smooth muscle cell proliferation. The degree of lesion in each group was basically consistent with the naked eye observation.

The experimental rabbit aortic wall plaque area % mean value of ciprofibrate+vitamin B6 group is lower than vitamin B6 group and ciprofibrate group, and the aortic plaque area of ciprofibrate group is lower than vitamin B6 group; The aortic plaque area of the B6 group tended to decrease compared with the model group, but there was no significant difference. See Table 3.

Compared with the normal group, the endothelin level of the model group was significantly increased, and the NO was significantly decreased; compared with the model group, the endothelin level was significantly decreased, and the NO was significantly increased in the ciprofibrate group; the curative effect of the ciprofibrate+vitamin B6 group was Compared with the model group, the level of endothelin in the vitamin B6 group tended to decrease, while NO increased, but there was no significant difference. See Table 3.

Conclusion: The combination of vitamin B6 and ciprofibrate can synergistically protect the vascular endothelium and reduce the formation of atherosclerotic plaque, thereby achieving a synergistic anti-AS effect.

Table 3 The effect of ciprofibrate+vitamin B6 on rabbit atherosclerosis (x±s, n=8) group Dose (mg/kg) mean aortic wall plaque area % ET (pg/ml) NO (μmol/L) Normal control model group vitamin B6 ciprofibrate ciprofibrate+VitB6 --0.355+0.3 020.3±5.216.6±2.913.8±6.1**7.0±4.0** ^▲ 144.0±33.9265.1±45.9207.9±50.4*186.5±38.7**145.0±31.5** ^▲▲ 209.6±49.190.5±.3.3116.6±39.3135.5±31.9**102.4±30.9** ^▲

Note: Compared with the model group *P<0.05, **P<0.01; compared with the ciprofibrate group ^▲ P<0.05, ^▲▲ P<0.01

Example 14. Combined application of ciprofibrate + vitamin B12 synergistically resists atherosclerosis

The experimental method was the same as that in Example 7. 40 rabbits were randomly divided into 5 groups, namely normal control group, model group, ciprofibrate group (5mg/kg), vitamin B12 group (0.1mg/kg), ciprofibrate group (0.1mg/kg), Fibrate+vitamin B12 group (5+0.1mg/kg). The results showed that the curative effect of ciprofibrate+vitamin B12 group was significantly better than that of ciprofibrate alone group and vitamin B12 group in terms of aortic wall plaque area and endothelial function indexes endothelin and NO levels; Vitamin B12 has a synergistic anti-AS effect.

Example 15. Combined application of fenofibrate + folic acid + vitamin B6 synergistically resists atherosclerosis

The experimental method is the same as in Example 7. 40 rabbits were randomly divided into 5 groups, namely normal control group, model group, fenofibrate group (5mg/kg), folic acid+B6 group (0.02+0.3mg/kg) , Fenofibrate + folic acid + vitamin B6 group (5+0.02+0.3mg/kg). The results showed that the curative effect of fenofibrate + folic acid + vitamin B6 group was significantly better than that of fenofibrate single use group and folic acid + vitamin B6 group in terms of aortic wall plaque area and endothelial function indicators endothelin and NO levels; Norbate has synergistic anti-AS effect with folic acid and vitamin B6.

Example 16. Combined application of gemfibrozil + folic acid + vitamin B12 synergistically resists atherosclerosis

Experimental method is the same as embodiment 7, and 40 domestic rabbits are divided into 5 groups at random, are respectively normal control group, model group, gemfibrozil group (30mg/kg), folic acid+vitamin B12 group (0.02+0.1mg/kg ), gemfibrozil + folic acid + vitamin B12 group (30+0.02+0.1mg/kg). The results showed that in terms of aortic wall plaque area and endothelial function indicators endothelin and NO levels, the curative effect of gemfibrozil + folic acid + vitamin B12 group was significantly better than that of gemfibrozil alone group and folic acid + B12 group; Qi, folic acid and vitamin B12 have a synergistic anti-AS effect.

Claims (19)

1. An anti-atherosclerosis pharmaceutical composition containing clofibidine ester compounds and B vitamins, consisting of a therapeutically effective amount of clofibidine ester compounds and their active metabolites, salts or esters one or more of B vitamins in a therapeutically effective amount, and a pharmaceutically acceptable carrier; wherein the content of clofibrate ester compounds and their active metabolites, salts or esters is 100-1500 mg , The content of B vitamins is 0.1-50 mg. 2. anti-atherosclerosis pharmaceutical composition according to claim 1, is characterized in that: described clofibrate ester compound is selected from fenofibrate, gemfibrozil, clofibrate, yadolate , bezafibrate, ciprofibrate, libet, aluminum clofibrate, double fibrate, berofibrate, etofibrate and its active metabolites, salts or esters. 3. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: the B vitamins are selected from one or more of vitamin B6, vitamin B12, folic acid and calcium leucovorin. kind. 4. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said clofibrate ester compound is preferably selected from fenofibrate (100-300 mg), said B vitamins It is preferably selected from folic acid (0.2-5 mg) or calcium leucovorin (0.2-5 mg). 5. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said clofibrate ester compound is preferably selected from fenofibrate (100-300 mg), said B vitamins It is B6 (5~50mg). 6. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said clofibrate ester compound is preferably selected from fenofibrate (100-300 mg), said B vitamins It is B12 (0.25~2mg). 7. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said clofibrate ester compound is preferably selected from gemfibrozil (300-1200 mg), said B vitamins It is preferably selected from folic acid (0.2-5 mg) or calcium leucovorin (0.2-5 mg). 8. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said clofibrate ester compound is preferably selected from gemfibrozil (300-1200 mg), said B vitamins It is B6 (5~50mg). 9. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said clofibrate ester compound is preferably selected from gemfibrozil (300-1200 mg), said B vitamins It is B12 (0.25~2mg). 10. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said clofibrate ester compound is preferably selected from bezafibrate (200-600 mg), said B vitamins It is preferably selected from folic acid (0.2-5 mg) or calcium leucovorin (0.2-5 mg). 11. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said clofibrate ester compound is preferably selected from bezafibrate (200-600 mg), said B vitamins It is B6 (5~50mg). 12. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: the clofibrate ester compound is preferably selected from bezafibrate (200-600 mg), and the B vitamins are B12 (0.25 ~ 2mg). 13. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said clofibrate ester compound is preferably selected from ciprofibrate (100-200 mg), said B vitamins It is preferably selected from folic acid (0.2-5 mg) or calcium leucovorin (0.2-5 mg). 14. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said clofibrate ester compound is preferably selected from ciprofibrate (100-200 mg), said B vitamins It is B6 (5~50mg). 15. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said clofibrate ester compound is preferably selected from ciprofibrate (100-200 mg), said B vitamins It is B12 (0.25~2mg). 16. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: said pharmaceutical composition further comprises a therapeutically effective active ingredient selected from the group consisting of HMG-CoA reductase inhibitors agent, HMG-CoA synthase inhibitor, squalene epoxidase, squalene synthase, acyl-CoA-cholesterol acyltransferase, probucol, niacin, cholesterol absorption inhibitor, bile acid sequestrant, low density Lipoprotein receptor inducers, aspirin, beta-blockers, vitamin C, vitamin E, beta-carotene. 17. The pharmaceutical composition according to any one of claims 1 to 16, characterized in that: the pharmaceutical composition can be made into ordinary tablets, ordinary capsules, granules, sustained-release tablets, sublingual tablets, Orally disintegrating tablets, dispersible tablets, enteric-coated tablets, enteric-coated capsules, delayed-release tablets, timed/bit-release tablets, sustained-release capsules, controlled-release capsules, capsules containing pellets or minitablets, pH-dependent capsules containing pellets or minitablets Capsules, granules, oral liquids, films, patches and other dosage forms. 18. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: it is used for cardiovascular disease, especially coronary heart disease, including coronary heart disease death, myocardial infarction, coronary artery reconstruction; cerebrovascular disease, Especially stroke and transient ischemic attack; and treatment of peripheral vascular disease. 19. The anti-atherosclerosis pharmaceutical composition according to claim 1, characterized in that: it is used to prevent, delay the occurrence of atherosclerosis and related diseases, treat atherosclerosis and related diseases, delay its progress or prevent relapse.