CN103877042A - Rosuvastatin calcium oral composition for increasing dissolution rate and preparation method of composition - Google Patents

Abstract

The invention relates to a rosuvastatin calcium oral composition for increasing dissolution rate and a preparation method of the composition. The composition is characterized by mainly comprising the following components in parts by weight: 0.5 part of rosuvastatin calcium, 0.02-0.05 part of solubilizer, 0.20-0.40 part of binder, 3.00-5.0 parts of filler, 0.01-0.1 part of lubricant and 0.30-1.5 parts of disintegrating agent. The preparation provided by the invention improves the dissolution rate of the medicines, so that the clinical curative effect is improved.

Description

A kind of rosuvastain calcium Orally administered composition that increases dissolution and preparation method thereof

Invention field

The present invention relates to chemical pharmacy field, be specifically related to a kind of rosuvastain calcium oral formulations that increases dissolution and preparation method thereof.

Background of invention

Cardiovascular disease is one of disease that harm humans health (particularly person in middle and old age) is the most common, the most serious, dyslipidemia is the important risk factor of atherosclerosis, coronary heart disease and other cardiovascular and cerebrovascular disease, fat regulation medicine can reduce incidence rate and the mortality rate of these diseases, and the control of cardiovascular disease is produced to positive effect and far-reaching influence.Along with the arrival of social population's aging, the disease ratios such as the hypertension being caused by hyperlipidemia in old people's cardiovascular disease are just being increases trend year by year, and people's life security in serious threat.Therefore, seek that curative effect is showing, safe and reliable blood lipid-lowering medicine, be always one of the world of medicine for a long time and rather popular research topic.

Hyperlipoproteinemia, refers to the class disease that cholesterol in the blood plasma that a variety of causes causes and/or triglyceride level raise.All lipoproteins all contain lipid, therefore as long as lipoprotein excessive (hyperlipoproteinemia) will cause blood lipid level rising (hyperlipemia).Hyperlipemia and hyperlipoproteinemia look it is two different concepts, but because blood fat is to turn round with the form of lipoprotein in blood, therefore in fact namely hyperlipoproteinemia of hyperlipemia.

From clinically, hyperlipemia can be divided into following four classes: 1) hypercholesterolemia: serum TC level increases; 2) combined hyperlipidemia familial: serum TC and TG level all increase; 3) hypertriglyceridemia: serum TG level increases; 4) low hdl mass formed by blood stasis: Serum HDL-C level lowers.

Statins is 3-hydroxy-3-methyl glutaryl base-coenzyme A (HMG-CoA) reductase inhibitor, and HMG-CoA is the early stage and rate-limiting step of the solid liquor-saturated biosynthesis pathway of gallbladder to the conversion of mevalonic acid.This step is by reductase catalysis, and inhibin can suppress this conversion reaction of HMG-CoA reduction contribute to a feast catalysis.Therefore, HMG-CoA reductase inhibitor is effective lipid lowerers.

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 in vivo the rate-limiting enzyme HMG-CoA reductase in cholesterol biosynthesis process, make the synthetic minimizing of cholesterol, also make the synthetic increase of low density lipoprotein receptor, Main Function position is at liver, result reduces cholesterolemia and low-density lipoprotein cholesterol level, the control generation effect to atherosclerosis and coronary heart disease thus.This product also reduces serum triglyceride level and increases blood hdl level.Rosuvastatin has 5,10,20 and the tablet of 40mg.In clinical trial, most clothes for patients with 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 patient's that cholesterol levels is very high predose, and the dosage of 40mg only should use in the time that 20mg dosage treatment curative effect is not enough.Professor Shepherd has completed the clinical trial of statins effect for reducing fat comparison recently, the medication result of 8 weeks shows: Rosuvastatin 10mg (n=539) LDL-C compliance rate is 80%, and atorvastatin 10mg (n=529) compliance rate is 63% (P<0.001), 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 respectively 37% (P<0.001), 43% and 48%; Simvastatin is incremented to 20mg, 40mg from 10mg, and LDL-C reduces respectively 28%, 35% and 39% (the equal <0.001 of P value); Pravastatin is incremented to 20mg, 40mg from 10mg, reduces LDL-C and is respectively 20%, 24% and 30% (the equal <0.001 of P value).The Lipid-lowering activities of Rosuvastatin and safety and pravastatin and simvastatin have been carried out the clinical randomized controlled research of 52 weeks by Brown WV etc., result shows, in medication after 12 weeks, the low-density lipoprotein cholesterol (LDL-C) of Rosuvastatin 5mg and 10mg dosage group has declined respectively 39.1% and 47.4%, and there were significant differences (P<0.05) with pravastatin 20mg group (decline 26.5%) and simvastatin 20mg group (decline 34.6%).After medication 52 weeks, 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 pravastatin group is only 60%, simvastatin group is 72.5%, (at latter 40 weeks, the patient dose that does not reach target doubled) 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 clinical trial before listing, heavy dose of (80mg) group has 7 routine patients that life-threatening rhabdomyolysis has occurred, and therefore query has just been in its safety at that time.In listing pre-Clinical, also find, Rosuvastatin also can damage some patients' renal function (do not observe other Statins and have similar untoward reaction).Finally, FDA ratifies its listing because considering the advantage (drug effect is slightly better than other Statins) of Rosuvastatin, but advises that taking dose is from 5mg～10mg, and maximal dose is no more than 40mg.

Domestic existing Rosuvastatin calcium preparation is mainly tablet at present.The invention provides a kind of Orally administered composition that increases Rosuvastatin dissolubility of calcium, can significantly improve dissolution rate and bioavailability, dosage is accurate, and steady quality facilitates patient to carry and is convenient to take.

Summary of the invention

The object of the present invention is to provide a kind of Orally administered composition that increases Rosuvastatin dissolubility of calcium and preparation method thereof, and through repetition test, each component screening is arrived to weight ratio of the present invention, be surprised to find that the tablet quality obtaining is stable, stripping is fast, in body, distribute rapidly, bioavailability is high.

On the one hand, the invention provides a kind of rosuvastain calcium Orally administered composition, it is for containing following component level weight ratio:

Rosuvastain calcium: 0.5

Solubilizing agent: 0.02～0.05

Binding agent: 0.20～0.40

Filler: 3.00～5.0

Lubricant: 0.01～0.1

Disintegrating agent: 0.30～1.5.

Some embodiments therein, compositions of the present invention, it is for containing following component level weight ratio:

Rosuvastain calcium: 0.5

Solubilizing agent: 0.03～0.04

Binding agent: 0.25～0.40

Filler: 4.00～5.0

Lubricant: 0.05～0.08

Disintegrating agent: 0.6～1.00.

In other embodiments, compositions of the present invention, it is for containing following component level weight ratio:

Rosuvastain calcium: 0.5

Solubilizing agent: 0.04

Binding agent: 0.40

Filler: 4.50

Lubricant: 0.08

Disintegrating agent: 1.00.

Some embodiments therein, compositions of the present invention, wherein, solubilizing agent is selected from Labraso, sodium lauryl sulphate, tween 80 or sorbester p17; Binding agent is selected from starch, polyvinylpyrrolidone, Polyethylene Glycol, sodium carboxymethyl cellulose, ethyl cellulose or hypromellose; Filler is selected from sucrose, lactose, mannitol, microcrystalline Cellulose, starch or dextrin, disintegrating agent is selected from hyprolose, dried starch, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, and lubricity agent is selected from magnesium stearate, Pulvis Talci, silicon dioxide or polyethylene glycols.

In other embodiments, compositions of the present invention, wherein solubilizing agent is Labraso; Binding agent is starch; Filler is one or more in sucrose or lactose; Disintegrating agent is hyprolose; Lubricity agent is magnesium stearate.

Some embodiments therein, compositions of the present invention, its dosage form is tablet.

In other embodiments, compositions of the present invention, wherein, formula consists of:

Rosuvastain calcium 5.0g

Starch 5.0g

Lactose 60.0g

Sucrose 10.0g

Hyprolose 15.0g

Magnesium stearate 1.0g

Labraso 0.8g.

On the other hand, the present invention relates to a kind of preparation method of rosuvastain calcium Orally administered composition, it comprises following steps:

1) principal agent and adjuvant were pulverized respectively 80 mesh sieves, and magnesium stearate is crossed 60 mesh sieves, for subsequent use;

2) take supplementary material by recipe quantity, mix by equivalent incremental method, and in blender, be mixed to evenly;

3) add 0.6% Labraso to granulate fast, then add 8% starch slurry, soft material processed, granulates fast, obtains wet granular;

4) 60 ℃ of wet granulars are dried to moisture at 2.0-4.0%, cross 18 mesh sieve granulate;

5) add magnesium stearate mix homogeneously, after the assay was approved, tabletting, to obtain final product.

Feature of the present invention is by increasing dissolution rate, improves the bioavailability of medicine.

The specific embodiment

Further explain the present invention below in conjunction with embodiment, but embodiment does not limit in any form to the present invention.

Embodiment 1

Rosuvastain calcium 5.0g

Starch 5.0g

Lactose 60.0g

Sucrose 10.0g

Hyprolose 15.0g

Magnesium stearate 1.0g

Labraso 0.8g

Make 1000

Preparation technology:

1) principal agent and adjuvant were pulverized respectively 80 mesh sieves, and magnesium stearate is crossed 60 mesh sieves, for subsequent use;

2) take supplementary material by recipe quantity, mix by equivalent incremental method, and in blender, be mixed to evenly;

3) add 0.6% Labraso to granulate fast, then add 8% starch slurry, soft material processed, granulates fast, obtains wet granular;

4) 60 ℃ of wet granulars are dried to moisture at 2.0-4.0%, cross 18 mesh sieve granulate;

5) add magnesium stearate mix homogeneously, after the assay was approved, tabletting, to obtain final product;

The present invention uses conventional equipment, and preparation technology is simple, and dosage is accurate, steady quality.This medicine is rapid-action, have good toleration feature, and therefore therapeutic scheme is will ` easy.For patient, provide a kind of better treatment to select, so the agent of development rosuvastatin calcium tablets is of great significance clinical.

Formula of the present invention obtains through screening, and concrete condition is as follows:

1, the foundation of dosage form selection

Tablet is applicable to all kinds of patients of oral solid formulation.Tablet has that dosage is accurate, content is even, and chemical stability is good, carries, transportation and easy to use, and institutional, the automaticity that cost is lower, output is high, produce is compared with advantages of higher, and therefore this dosage form is occupied absolute advantage on market;

2, the selection of solubilizing agent

The prerequisite absorbing in gastrointestinal tract due to medicine is to be dissolved in gastro-intestinal Fluid.In the time that drug solubility is less than 0.3%, dissolution rate becomes the restrictive factor of whole absorption process.Therefore dissolution rate is also the principal element that determines its absorption.Rosuvastain calcium belongs to insoluble drug, is the rate-limiting factor that affects principal agent absorption and even bioavailability at gastrointestinal process in leaching, and in prescription, adding solubilizing agent (Labraso) is a kind of effectively short hands section of inhaling;

According to bibliographical information, the solubilizing effect in phosphate buffered solution (pH7.4) is different to rosuvastatin calcium tablets to use solubilizing agent.In former preparation prescription, increase solubilizing agent (Labraso), other supplementary product kind and consumption are constant.By making sample under tablet producing technology item, the dissolution of measuring in phosphate buffered solution (pH7.4) take this product in 40 minutes is investigation index, the results are shown in Table 1:

Table 1 do not use solubilizing agent and use solubilizing agent rosuvastatin calcium tablets mass ratio

By known with commercially available product contrast, using after solubilizing agent, the character of medicine, related substance, content do not have much variations, and the dissolution of medicine obviously raises.Result of the test shows, the quality of product of the present invention is stablized controlled.

Although the present invention describes with reference to specific embodiment, this description not meaning that is construed as limiting the present invention.With reference to description of the invention, other distortion of the disclosed embodiments, all can expect for those skilled in the art.Therefore, such distortion can not depart from scope and the spirit that affiliated claim limits.

Claims (8)

1. a rosuvastain calcium Orally administered composition, it is for containing following component level weight ratio:

Rosuvastain calcium: 0.5

Solubilizing agent: 0.02～0.05

Binding agent: 0.20～0.40

Filler: 3.00～5.0

Lubricant: 0.01～0.1

Disintegrating agent: 0.30～1.5.

2. compositions according to claim 1, it is for containing following component level weight ratio:

Rosuvastain calcium: 0.5

Solubilizing agent: 0.03～0.04

Binding agent: 0.25～0.40

Filler: 4.00～5.00

Lubricant: 0.05～0.08

Disintegrating agent: 0.6～1.00.

3. compositions according to claim 1, it is for containing following component level weight ratio:

Rosuvastain calcium: 0.5

Solubilizing agent: 0.04

Binding agent: 0.40

Filler: 4.50

Lubricant: 0.08

Disintegrating agent: 1.00.

4. according to the compositions described in claim 1-3 any one, wherein, solubilizing agent is selected from Labraso, sodium lauryl sulphate, tween 80 or sorbester p17; Binding agent is selected from starch, polyvinylpyrrolidone, Polyethylene Glycol, sodium carboxymethyl cellulose, ethyl cellulose or hypromellose; Filler is selected from sucrose, lactose, mannitol, microcrystalline Cellulose, starch or dextrin, disintegrating agent is selected from hyprolose, dried starch, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, and lubricity agent is selected from magnesium stearate, Pulvis Talci, silicon dioxide or polyethylene glycols.

Compositions according to claim 4, wherein solubilizing agent is Labraso; Binding agent is starch; Filler is one or more in sucrose or lactose; Disintegrating agent is hyprolose; Lubricity agent is magnesium stearate.

6. compositions according to claim 1, its dosage form is tablet.

7. compositions according to claim 1, wherein, formula consists of:

Rosuvastain calcium 5.0g

Starch 5.0g

Lactose 60.0g

Sucrose 10.0g

Hyprolose 15.0g

Magnesium stearate 1.0g

Labraso 0.8g.

8. a preparation method for rosuvastain calcium Orally administered composition described in claim 1-7 any one, it comprises following steps:

1) principal agent and adjuvant were pulverized respectively 80 mesh sieves, and magnesium stearate is crossed 60 mesh sieves, for subsequent use;

2) take supplementary material by recipe quantity, mix by equivalent incremental method, and in blender, be mixed to evenly;

3) add 0.6% Labraso to granulate fast, then add 8% starch slurry, soft material processed, granulates fast, obtains wet granular;

4) 60 ℃ of wet granulars are dried to moisture at 2.0-4.0%, cross 18 mesh sieve granulate;

5) add magnesium stearate mix homogeneously, after the assay was approved, tabletting, to obtain final product.