CN101411703A - A pharmaceutical composition for treating cardiovascular diseases - Google Patents

Abstract

The invention relates to a pharmaceutical composition for treating cardiovascular diseases, which comprises atorvastatin calcium and probucol in therapeutic dose and a pharmaceutically acceptable carrier or excipient.

Description

A kind of pharmaceutical composition for treating cardiovascular disease

technical field

The invention relates to the field of drug therapy, and more specifically relates to a drug composition for treating cardiovascular diseases.

Background technique

In my country, cardiovascular and cerebrovascular diseases are the number one cause of death. With the improvement of living standards, people's diet structure changes, activity decreases, cholesterol intake and body mass index increase, all of which are risk factors for cardiovascular and cerebrovascular diseases. The incidence of cardiovascular and cerebrovascular diseases in my country has been increasing year by year in recent years.

Among cardiovascular diseases hypertension, myocardial infarction and angina pectoris are among the most common causes of death in both men and women. In addition to coronary artery disease, cerebrovascular disease and stroke are the most common causes of death. In addition, cardiovascular disease causes significant disability from stroke, congestive heart failure, peripheral vascular disease, venous insufficiency, and multi-infarct dementia. Most cardiovascular disease is a direct result of atherosclerosis.

A variety of drugs are available for the treatment of cardiovascular disease. In the case that a single drug cannot achieve ideal treatment, compound prescriptions and drug combinations are often used in the clinical treatment of cardiovascular diseases. The invention relates to a pharmaceutical composition of atorvastatin calcium and probucol for treating cardiovascular diseases.

Atorvastatin calcium, the English name is Atorvastatin calcium, its chemical name is 7-[2-(4-fluorophenyl)-3-phenyl-4-(anilinoformyl)-5-(2-propyl) ) Calcium pyrrol-1-yl]-3,5-dihydroxyheptanoate. The chemical structural formula is as follows:

Atorvastatin calcium is a novel 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Atorvastatin calcium itself is inactive, and the hydrolyzate after oral absorption competitively inhibits the rate-limiting enzyme hydroxymethylglutaryl-CoA reductase in the process of cholesterol synthesis in the body, reducing the synthesis of cholesterol and reducing low-density lipids. The synthesis of protein receptors increases, and the main site of action is in the liver. As a result, blood cholesterol and low-density lipoprotein cholesterol levels are reduced, serum triglyceride levels are moderately reduced, and blood high-density lipoprotein levels are increased. Thus, it has an effect on the prevention and treatment of atherosclerosis and coronary heart disease. Atorvastatin calcium is clinically used in the treatment of hypercholesterolemia and mixed hyperlipidemia; prevention and treatment of coronary heart disease and cerebral apoplexy.

Oral absorption of atorvastatin calcium is good, because of extensive first-pass metabolism in the liver, the absolute bioavailability is low, about 12%. This product is metabolized into various active metabolites in the liver by cytochrome P450 3A4. The average plasma half-life of atorvastatin is about 14 hours, but due to the influence of its active metabolite, the actual half-life of HMG-CoA reductase inhibition is 20-30 hours. The protein binding rate of atorvastatin is 98%, most of which are excreted in bile in the form of metabolites.

According to relevant patents and literatures, it is known that atorvastatin calcium is an unstable substance sensitive to heat, moisture, light and low pH value. Under the above conditions, atorvastatin calcium transforms from carboxylic acid form to lactone form . Therefore, keeping atorvastatin calcium stable in pharmaceutical preparations is an important problem to be solved in the development of atorvastatin calcium-containing drugs. Researchers have used different methods to enhance the stability of atorvastatin calcium in pharmaceutical formulations, such as: adding pharmaceutical excipients for stabilizing atorvastatin calcium to pharmaceutical formulations; adding alkaline agents to pharmaceutical compositions or buffer.

Probucol, English name: Probucol; chemical name: 4,4'-[(1-methylethylene)bis(sulfur)]-bis[2,6-bis(1,1-dimethylethane) base) phenol]. Its chemical structural formula is as follows:

Probucol is a lipid-regulating drug and has anti-atherosclerotic effects. Its lipid-lowering effect is to reduce blood cholesterol and low-density lipoprotein by reducing cholesterol synthesis and promoting cholesterol decomposition, and also changes the properties and functions of high-density lipoprotein subtypes to reduce blood high-density lipoprotein cholesterol. Probucol had little effect on blood triglycerides. Probucol has significant antioxidant effect, can inhibit the formation of foam cells, delay the formation of atherosclerotic plaque, and subside the formed atherosclerotic plaque. Probucol is clinically used to treat hypercholesterolemia.

The absorption of probucol through the gastrointestinal tract is limited and irregular, and its absorption can be maximized if it is taken with food. The peak plasma concentration is reached 18 hours after oral administration of this product, and the T1/2 is 52-60 hours. Take this product every day, the blood concentration will gradually increase, and reach the steady state level in 3-4 months. This product produces metabolites in the body. 84% of the oral dose is excreted from the feces, 1%-2% is excreted from the urine, the feces is mainly the original form, and the urine is mainly metabolites.

Probucol is almost insoluble in water, so probucol cannot be made into injections, and solid preparations such as tablets are usually used in clinical practice. Probucol is difficult to absorb into the blood and is almost always excreted unchanged. On the other hand, the rate and amount of absorption of probucol varies significantly between individual patients. Researchers have been investigating ways to improve probucol absorption and reduce differences in absorption between individuals.

Contents of the invention

The invention relates to a pharmaceutical composition for treating cardiovascular diseases. The composition of the invention contains atorvastatin calcium, probucol and pharmaceutically acceptable auxiliary materials. The composition of the present invention can not only improve the single treatment effect of atorvastatin calcium and probucol in treating cardiovascular diseases, but also have synergistic effect, and the pharmaceutical composition of the present invention can improve the compliance of patients after being prepared into pharmaceutical preparations. At the same time, the researchers of the present invention surprisingly found that atorvastatin calcium has good stability when the pharmaceutical composition of atorvastatin calcium and probucol is prepared into pharmaceutical preparations. The combination of atorvastatin calcium and probucol enhances the stability of atorvastatin calcium in pharmaceutical preparations.

The pharmaceutical composition of the present invention contains atorvastatin calcium as an active ingredient. The pharmaceutical composition of the present invention per unit preparation contains 5mg-100mg of atorvastatin calcium. Preferably 10mg-40mg, more preferably 10mg-20mg, most preferably 10mg.

The pharmaceutical composition of the present invention contains probucol as an active ingredient. The pharmaceutical composition of the present invention per unit preparation contains 0.1g-1g of probucol. Preferably 0.2g-0.5g, more preferably 0.5g.

The pharmaceutically acceptable auxiliary materials in the pharmaceutical composition of the present invention can be any auxiliary materials that can be prepared into pharmaceutical preparations together with atorvastatin calcium and probucol and used for clinical treatment. The auxiliary materials of the present invention include but are not limited to: fillers, wetting agents and binders, disintegrants, lubricants and the like. Fillers include lactose, microcrystalline cellulose, starch, powdered sugar, dextrin, mannitol, calcium sulfate, and the like. The fillers are preferably lactose and microcrystalline cellulose. Wetting agents and binders include sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, sucrose, polyvinylpyrrolidone, and the like. The wetting agent and binder are preferably hydroxypropyl cellulose and hydroxypropyl methylcellulose. Disintegrants include sodium carboxymethyl starch (CMS-Na), cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, and the like. The disintegrating agent is preferably sodium carboxymethyl starch (CMS-Na). Lubricants include magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, and the like. Lubricants are preferably magnesium stearate and talcum powder.

In addition to containing atorvastatin calcium and probucol, the pharmaceutical composition of the present invention preferably contains lactose, microcrystalline cellulose, corn starch, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, One or more pharmaceutically acceptable excipients of peptide dioxide, magnesium stearate, talcum powder, iron oxide, and sodium starch glycolate.

The pharmaceutical composition of the invention is prepared by mixing atorvastatin calcium, probucol and pharmaceutically acceptable auxiliary materials. The pharmaceutical composition of the present invention is preferably administered orally for the treatment of cardiovascular diseases. The pharmaceutical composition of the present invention administered orally can be prepared in the form of ordinary tablets, granules, capsules, powders, sustained-release tablets and the like. Ordinary tablets or capsules are preferred. The pharmaceutical composition of the present invention can be prepared into tablets and capsules by adopting common techniques in pharmaceutical preparations.

The "unit preparation" in the description of the present invention refers to the smallest independent unit of each dosage form, such as the "tablet" of a tablet and the "granule" of a capsule.

Detailed ways

Example 1

Prescription (per 1000 tablets):

Atorvastatin Calcium 10g

Probucol 500g

Sodium carboxymethyl starch 50g

cornstarch 3000g

Magnesium Stearate 300g

Pass atorvastatin calcium and probuco through a 40-mesh sieve. Thoroughly mix atorvastatin calcium and probucol with cornstarch and carboxymethyl starch sodium according to the prescription amount, mix with magnesium stearate and compress into tablets to obtain the product.

Example 2

Prescription (per 1000 tablets):

Atorvastatin Calcium 10g

Probucol 500g

Sodium carboxymethyl starch 50g

Lactose 1000g

Magnesium stearate 200g

Pass atorvastatin calcium and probuco through a 40-mesh sieve. Thoroughly mix atorvastatin calcium, probucol, lactose and carboxymethyl starch sodium according to the prescription amount, mix with magnesium stearate and compress into tablets to obtain the product.

Example 3

Prescription (per 1000 capsules):

Atorvastatin Calcium 10g

Probucol 500g

Sodium hydroxymethyl starch 40g

Hydroxypropyl methylcellulose solution (1%) 50g

Microcrystalline Cellulose 800g

Magnesium stearate 200g

Pass atorvastatin calcium and probu through an 80-mesh sieve. After fully mixing atorvastatin calcium, probucol, microcrystalline cellulose and carboxymethyl starch sodium according to the prescription quantity, the soft material was prepared with the prescription quantity of hydroxypropyl methylcellulose solution, granulated, dried, Sieve through a 18-mesh sieve, mix thoroughly with the prescribed amount of magnesium stearate, and pack into capsules.

The investigation of the stability of atorvastatin calcium in the composition of the present invention

Adopting high performance liquid chromatography to detect that the content in the pharmaceutical composition of Examples 1-3 of the present invention stored for more than 6 months at a humidity of 75% and a temperature of 40° C. is higher than 98%, indicating that Atorval Statin calcium has good stability in the composition of the present invention. The detection method is as follows.

Determination according to high performance liquid chromatography (Chinese Pharmacopoeia 2000 edition two appendix VD). Chromatographic conditions and system suitability test: use octadecylsilane bonded silica gel as filler; acetonitrile-tetrahydrofuran-0.05mol/L ammonium citrate solution (0.05mol/L citric acid is adjusted to pH 4.0 with ammonia water) (30:20:50) is the mobile phase; the detection wavelength is 244nm. The number of theoretical plates calculated according to the peak of atorvastatin is not less than 3500. The separation degree of atorvastatin peak and each impurity peak should meet the requirement. Determination method: Take an appropriate amount of fine powder of the sample to be tested, accurately weigh it, add acetonitrile-0.05mol/L ammonium citrate solution (0.05mol/L citric acid solution adjust the pH value to 7.4 with ammonia water) (50:50) to dissolve And quantitatively dilute it to make a solution containing about 0.05mg per 1ml, accurately measure 20μl, inject it into a liquid chromatograph, and record the chromatogram; take another atorvastatin calcium reference substance, and measure it in the same way. According to the external standard method to calculate the peak area, that is.

Claims (7)

1. A pharmaceutical composition for treating cardiovascular disease, containing atorvastatin calcium, probucol and pharmaceutically acceptable auxiliary materials. 2. The composition according to claim 1, wherein the pharmaceutical composition per unit preparation contains 5 mg-100 mg of atorvastatin calcium and 0.1 g-1 g of probucol. 3. The composition according to claim 1, wherein the pharmaceutical composition per unit preparation contains 10 mg-40 mg of atorvastatin calcium and 0.2 g-0.5 g of probucol. 4. The composition according to claim 1, wherein the pharmaceutical composition comprises 10 mg of atorvastatin calcium and 0.5 g of probucol per unit preparation. 5. The composition according to any one of claims 1-4, wherein the pharmaceutically acceptable auxiliary materials include one or more of fillers, wetting agents and binders, disintegrants, and lubricants. 6. The composition of claim 5, wherein the filler is lactose or microcrystalline cellulose, the wetting agent and the binding agent are hydroxypropyl cellulose or hydroxypropyl methyl cellulose, and the disintegrant is carboxymethyl Sodium starch, the lubricant is magnesium stearate or talc. 7. any described composition of claim 1-4, wherein the pharmaceutically acceptable auxiliary material comprises lactose, microcrystalline cellulose, corn starch, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose , one or more of peptide dioxide, magnesium stearate, talc, iron oxide, sodium starch glycolate.