CN110974793A

CN110974793A - Rosuvastatin calcium tablet and preparation method thereof

Info

Publication number: CN110974793A
Application number: CN201911365865.7A
Authority: CN
Inventors: 张贵民; 刘仁涛; 朱子
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2019-12-26
Filing date: 2019-12-26
Publication date: 2020-04-10

Abstract

The invention discloses a pharmaceutical composition and a tablet of rosuvastatin calcium and a preparation method thereof, belonging to the technical field of medicines. The rosuvastatin calcium composition mainly contains a rosuvastatin calcium raw material and a stabilizer, the rosuvastatin calcium raw material and the stabilizer are prepared according to a certain proportion, the rosuvastatin tablet can be prepared after the composition and pharmaceutical excipients are granulated and tabletted by a dry method, the stability of the preparation is remarkably improved by reasonably adding the pharmaceutical excipients, the stability effect of the tablet is remarkable compared with that of the existing tablet, the preparation process is simple, the raw materials are low in price, and the rosuvastatin calcium composition is suitable for industrial large-scale production.

Description

Rosuvastatin calcium tablet and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a rosuvastatin calcium pharmaceutical composition, a rosuvastatin calcium tablet and a preparation method thereof.

Background

The vascular diseases are common diseases of human beings, the number of patients suffering from the diseases is large, the morbidity and mortality rate of the diseases is increased year by year, about 1500 million people die of the cardiovascular and cerebrovascular diseases every year in the world according to the statistics of the world health organization, the China is a country with high incidence of the vascular diseases, the incidence rate of the cardiovascular and cerebrovascular diseases is as high as 8 percent, and the mortality rate is close to 50 percent of the total mortality rate; on average, one person dies from cardiovascular and cerebrovascular diseases every 20 seconds, and the cardiovascular and cerebrovascular diseases mainly originate from atherosclerosis, wherein the atherosclerosis is mainly taken as the main factor, and the hyperlipidemia is mainly manifested.

Hyperlipidemia is a systemic lipid metabolism disorder characterized by elevated serum cholesterol (TC), Triglycerides (TG) and/or low-density lipoproteins (LDL) and/or low serum high-density lipoproteins (HDL). Over 20 years, reduction of serum low density lipoprotein cholesterol (LDL-C) has been shown to significantly reduce cardiovascular morbidity, mortality, and total mortality through a number of clinical trials of secondary and primary prevention of coronary heart disease. In recent years, the development of new statin LIPID-modulating drugs on the market, which can effectively reduce serum low density lipoprotein (LDL-C) blood cholesterol, has been continued since 1994, 5 large-scale clinical studies (4S, WOSCAPS, CARE, LIPID, AFCAPS/TexsCAPS) with milestone significance have been published, and the results thereof have consistently confirmed: the application of statin lipid-lowering drugs can obviously reduce the level of plasma cholesterol (mainly LDL-C), and simultaneously can obviously reduce the incidence rate of coronary heart disease population and non-coronary event and the death rate of coronary heart disease, without increasing the death rate of non-cardiovascular diseases. Therefore, lowering LDL-C has become one of the important measures for preventing and treating coronary heart disease.

Rosuvastatin calcium (rosuvastatin calcium) was developed by yamazai (shinonogi, osaka), was assigned to Zeneca, england, 4 months 1998, and was named rosuvastatin. Phase I, phase IIa and phase IIb clinical validation of the drug was completed in the united states at month 2 1999, and phase III clinical validation was accelerated. In 12 months of 2000, AstraZeneca designated rosuvastatin under the trade name Crestortm. Rosuvastatin is a selective HMG-CoA reductase inhibitor. HMG-CoA reductase inhibitors are rate-limiting enzymes that convert 3-hydroxy-3-methylglutaryl-coenzyme a to mevalonate, a precursor to cholesterol. The main site of action of rosuvastatin is the liver, the cholesterol-lowering target organ. Rosuvastatin increases the number of hepatic LDL cell surface receptors, promotes LDL absorption and catabolism, inhibits hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

Rosuvastatin has better effect on treating heterozygous family hereditary hyperlipidemia patients than atorvastatin, has better effect on reducing LDL-C (very low density lipoprotein cholesterol) than simvastatin and pravastatin, can reduce the content of Low Density Lipoprotein (LDL) and increase the content of High Density Lipoprotein (HDL) beneficial to human bodies by 14 percent, has the best lipid-lowering effect in a plurality of antilipemic drugs through comprehensive analysis, is called as 'super statin' in the industry, and has profound significance on researching and improving the lipid-lowering effect.

Chemical name of rosuvastatin calcium: bis- (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -pyrimidin-5-yl ] (3R, 5S) -3, 5-hydroxyhept-6-enoic acid ] calcium salt (2: 1) of the formula:

because β, delta-hydroxyl on the heptenoic acid in the rosuvastatin calcium molecule is very unstable, especially the hydroxyl adjacent to a carbon-carbon double bond is very easy to be oxidized into a ketone functional group, and intramolecular cyclization can also occur to generate lactone, the rosuvastatin calcium is very easy to degrade in a higher temperature or higher humidity environment, and the formed main products are (3R, 5S) lactone degradation products and oxidation products, thereby causing difficulty to the production and storage of the preparation.

In the prior art, CN102860994A describes a rosuvastatin calcium tablet, which consists of a tablet core and a coating layer, and is characterized in that: the tablet core is composed of rosuvastatin calcium, lactose, microcrystalline cellulose, a disintegrating agent and a lubricant, wherein the lactose is spray-dried lactose or granular lactose, and the microcrystalline cellulose is flow-through steam-dried microcrystalline cellulose or spray-dried microcrystalline cellulose. The technical scheme mainly improves the stability by preparing the coating layer.

Patent WO2008035128 describes a novel pharmaceutical composition comprising amorphous rosuvastatin calcium, wherein magnesium hydroxide and/or calcium acetate or calcium gluconate or calcium glycerophosphate or aluminium hydroxide is used as stabilizer. The main component easy to absorb water is used as an auxiliary material, and a dry environment is provided for the raw material medicine through the characteristic of easy absorption of moisture, so that the rosuvastatin calcium is prevented from being degraded.

WO02089788 describes pharmaceutical compositions comprising statins, the stability of which is provided by the addition of an amino sugar (e.g. N-methyl-glucosamine). According to the description, amino sugars have the advantage over inorganic alkaline earth metal salts that they do not irritate the intestinal mucosa.

The tablets are prepared by adopting wet granulation in Chinese patents CN200710024860.9 and CN00122484.0, and the exposure time of rosuvastatin in a wet and hot environment is increased by the wet granulation, so that the generation amount of impurities is obviously increased, and the wet granulation is dried at high temperature, thereby having adverse effect on the quality of the product.

CN1091634A discloses a stable pharmaceutical composition containing a statin compound, which is stabilized by the addition of an alkaline medium (such as a carbonate or bicarbonate) which is capable of maintaining the pH of an aqueous solution or dispersion of the composition at least 8.

Commercially available pharmaceutical compositions (under the trade name Crestor) are described in patent specifications such as WO0154668, WO0154669 or US6316460, according to which the preparation of stable pharmaceutical compositions comprising rosuvastatin calcium cannot be accomplished only by using pH adjuvanting agents, but rather the presence of polyvalent metal salts is also required to prevent the formation of lactones and oxidative decomposition products.

In the pharmaceutical composition, inorganic salts of polyvalent metals (Ca, mg, Zn, Al, Fe and combinations thereof) are used as stabilizing additives, such as aluminum silicate, magnesium silicate, calcium orthophosphate, magnesium orthophosphate and aluminum orthophosphate. The commercially available (trade name: Crestor) pharmaceutical composition comprises calcium phosphate as a stabilizer. The method can increase the stability of the preparation, but also bring about the problem that the content of impurities in the preparation is increased more quickly.

In summary, the existing method for improving the stability of rosuvastatin calcium preparation mainly comprises the steps of adjusting pH, preparing a specific preparation formulation and forming a coating, wherein alkaline substances such as sodium hydroxide and the like are usually added for adjusting pH, and part of the alkaline substances are required to be matched with heavy metal ions, so that the heavy metal ions have numerous adverse effects on human bodies, most notably various metal ions have adverse reactions causing constipation, and in addition, middle-aged and elderly people with hyperlipidemia have a large proportion, and the alkaline substances such as sodium hydroxide and the like are adopted, so that the gastric acid secretion capacity of the elderly is known to be reduced, the pH value of gastric acid can be further increased by taking alkaline medicines for a long time, symptoms such as dyspepsia, tail discomfort and the like are caused, in addition, the alkaline substances can be rapidly disintegrated to cause corrosion and damage to gastrointestinal tracts, and are extremely unfavorable to patients with gastric ulcer, and the difficulty, is not suitable for large-scale industrial production.

In conclusion, a drug composition which has small adverse reaction on a human body and simple preparation process and remarkably improves the stability of the rosuvastatin calcium preparation is urgently needed to be researched and researched for a long time, the stability of the rosuvastatin calcium preparation prepared by adopting the specific drug composition is remarkably improved, the increase range of degradation products is small under the conditions of storage, high temperature and strong light, the shelf life is longer, the preparation process is simple and is suitable for large-scale industrial production, and the problem of the stability of the rosuvastatin calcium preparation is solved by the occurrence of the rosuvastatin composition. Has obvious promoting effect on the application of the medicine in clinical China.

Disclosure of Invention

In view of the defects in the prior art, the inventor further optimizes preparation auxiliary materials and a preparation process, and provides the rosuvastatin composition and the tablet thereof, which have the advantages of good stability, small side effect and simple preparation method.

In order to solve the problems in the prior art and achieve the expected effect of the invention, the invention adopts the following technical scheme:

the invention provides a rosuvastatin calcium pharmaceutical composition, which contains rosuvastatin calcium and a stabilizer, wherein the mass ratio of rosuvastatin calcium to the stabilizer is 1:0.01-0.08, the mass ratio of rosuvastatin calcium to the stabilizer is preferably 1:0.01-0.05, more preferably 1:0.02-0.05, and the adopted stabilizer comprises any one or more of dibutyl hydroxy toluene, butyl hydroxy anisole, calcium citrate and β cyclodextrin, and is preferably dibutyl hydroxy toluene.

The pharmaceutical composition provided by the invention also contains a filling agent, wherein the mass ratio of rosuvastatin calcium to the filling agent is 1:10-15, preferably 1:12, meanwhile, the adopted pharmaceutical composition also contains a disintegrating agent and a lubricating agent, and the mass ratio of the components in the composition is as follows:

more preferably, the mass ratio of each component of the pharmaceutical composition can also be:

the filler in the components is one or more of pregelatinized starch, mannitol and microcrystalline cellulose; the disintegrating agent is any one or more of carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose and croscarmellose sodium; the lubricant is one or more of magnesium stearate or sodium stearyl fumarate, and is preferably sodium stearyl fumarate.

The preferred proportion of each component is as follows:

a rosuvastatin tablet, which contains the above pharmaceutical composition. The rosuvastatin calcium tablet is prepared by adopting a dry granulation tabletting method, and the preparation method of the dry granulation tabletting comprises the following steps:

(1) weighing the medicinal auxiliary materials and rosuvastatin calcium according to the prescription amount, uniformly mixing rosuvastatin calcium, a stabilizer, a filling agent and a disintegrating agent, and performing dry granulation;

(2) mixing the prepared granules with a lubricant, and tabletting.

The preparation prepared by the composition is not limited to tablets, and can also be oral preparations such as capsules, dispersible tablets and the like.

The invention obviously improves the stability of the rosuvastatin calcium tablet by adopting the technical scheme, and the preparation stability is superior to that of the original medicine.

The tablet obtained by the invention has stable color, long shelf life, uniform component content and simple preparation process, and is very suitable for large-scale industrial production;

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The present invention is further described in the following detailed description with reference to specific examples, but the embodiments of the invention are not limited to the examples described below, and any other changes, modifications, substitutions, combinations, and simplifications that may be made based on the spirit of the present invention should be considered as equivalents and included in the scope of the present invention.

In the following examples rosuvastatin calcium and other pharmaceutical excipients were purchased from Shandong New Times pharmaceutical Co,

example 1: rosuvastatin calcium tablet

Prescription composition 1000 tablets

Composition (I)	Weight (g)
		Rosuvastatin calcium	10
Dibutylhydroxytoluene	0.5
		Mannitol	60
Microcrystalline cellulose	60
		Sodium starch glycolate	7
Stearic acid sodium fumarate	1

The preparation process comprises the following steps:

taking the rosuvastatin calcium raw material, the dibutyl hydroxy toluene, the mannitol, the microcrystalline cellulose and the carboxymethyl starch sodium according to the prescription amount, uniformly mixing in a mixer, performing dry granulation, adding the sodium stearyl fumarate according to the prescription amount, uniformly mixing, and tabletting to obtain the tablet.

Example 2: rosuvastatin calcium tablet

Prescription for preparing 1000 tablets

The preparation process comprises the following steps: the preparation method of example 1 was used.

Example 3: rosuvastatin calcium tablet

Prescription for preparing 1000 tablets

Composition (I)	Weight (g)
		Rosuvastatin calcium	10
Dibutylhydroxytoluene	0.5
		Pregelatinized starch	80
Microcrystalline cellulose	60
		Sodium starch glycolate	7
Stearic acid sodium fumarate	0.5

Example 4: prescription for preparing 1000 tablets from rosuvastatin calcium tablets

Composition (I)	Weight (g)
		Rosuvastatin calcium	10
Dibutylhydroxytoluene	0.2
		Mannitol	70
Pregelatinized starch	30
		Microcrystalline cellulose	50
Sodium starch glycolate	5
		Stearic acid sodium fumarate	1

Comparative example 1: prescription for preparing 1000 tablets from rosuvastatin calcium tablets

Composition (I)	Weight (g)
		Rosuvastatin calcium	10
Butylated hydroxyanisole	1.0
		Mannitol	30
Microcrystalline cellulose	90
		Sodium starch glycolate	7
Magnesium stearate	1

Comparative example 2: prescription for preparing 1000 tablets from rosuvastatin calcium tablets

Composition (I)	Weight (g)
		Rosuvastatin calcium	10
Glutathione	0.5
		Mannitol	60
Pregelatinized starch	70
		Low-substituted hydroxypropyl cellulose	6
Magnesium stearate	0.5

Comparative example 3: prescription for preparing 1000 tablets from rosuvastatin calcium tablets

Comparative example 4: rosuvastatin calcium tablet

Prescription for preparing 1000 tablets

Composition (I)	Weight (g)
		Rosuvastatin calcium	10
Dibutylhydroxytoluene	0.4
		Mannitol	70
Pregelatinized starch	30
		Microcrystalline cellulose	50
Sodium starch glycolate	5
		Silicon dioxide	0.2
Magnesium stearate	0.5

The preparation process comprises the following steps:

taking the rosuvastatin calcium raw material, the dibutyl hydroxy toluene, the mannitol, the pregelatinized starch, the microcrystalline cellulose and the carboxymethyl starch sodium according to the prescription amount, uniformly mixing in a mixer, performing wet granulation by 30% ethanol, drying at 50 ℃, adding the sodium stearyl fumarate according to the prescription amount, uniformly mixing, and tabletting to obtain the rosuvastatin calcium tablet.

Comparative example 5: rosuvastatin calcium tablet

Prescription for preparing 1000 tablets

Composition (I)	Weight (g)
		Rosuvastatin calcium	10
Dibutylhydroxytoluene	0.4
		Microcrystalline cellulose	50
Sodium starch glycolate	5
		Silicon dioxide	0.2
Magnesium stearate	0.5

The preparation process comprises the following steps:

taking the microcrystalline cellulose, the carboxymethyl starch sodium and the dibutyl hydroxy toluene according to the prescription amount, uniformly mixing in a mixer, granulating by using ethanol, and drying at 50 ℃. Adding magnesium stearate and silicon dioxide according to the prescription amount, mixing evenly and tabletting to obtain the tablet.

Commercially available Aslicon pharmaceutical Co., Ltd, manufactured by Kedite, size 10 mg.

1. Comparison of test results

TABLE 1 analysis of the basic parameters of the tablets of the examples and comparative examples obtained

	Compressibility	Average hardness (N)	Disintegration time (min)	Degree of friability
					Example 1	Is preferably used	73.2	1	Meets the requirements
Example 2	Is preferably used	75.1	1	Meets the requirements
					Example 3	Is preferably used	74.5	2	Meets the requirements
Example 4	Is preferably used	73.6	2	Meets the requirements
					Comparative example 1	Is preferably used	72.1	7	Meets the requirements
Comparative example 2	Is preferably used	68.9	6	Meets the requirements
					Comparative example 3	Is preferably used	70.5	6	Meets the requirements
Comparative example 4	Is preferably used	73.9	8	Meets the requirements
					Comparative example 5	Is preferably used	71.3	10	Conform toRequire that
Reference formulation	---	80.25	4	Meets the requirements

From table 1, it is known that: the longer disintegration time of the comparative example compared to the reference formulation, the examples, affects the equivalence of the in vivo test.

2. Stability comparison of tablets obtained in examples and comparative examples

The tablets prepared in the examples and the comparative examples were put in a high temperature (60 ℃), high light (4500lx), and 75 ± 5% constant temperature and humidity chamber for accelerated test for 3 months, and the related substances were detected at 0 day and 3 months, respectively.

TABLE 2 comparison of the stability accelerated for 6 months between examples and comparative examples

As can be seen from the data in Table 2, the analysis result of the accelerated test shows that the impurity content of the tablet prepared by the invention after the accelerated test is far lower than that of the comparative example and the original medicine, and the obtained product has stable quality. Meanwhile, after an accelerated test, the total impurities of the product still meet the medicinal requirements of the preparation, the storage period of the product is obviously prolonged, and the quality guarantee period of the product is effectively prolonged.

Claims

1. A pharmaceutical composition of rosuvastatin calcium comprises rosuvastatin calcium and a stabilizer, and is characterized in that the mass ratio of rosuvastatin calcium to stabilizer is 1: 0.01-0.08.

2. The pharmaceutical composition according to claim 1, wherein the mass ratio of rosuvastatin calcium to stabilizer is 1:0.01 to 0.05, preferably 1:0.02 to 0.05.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition further comprises a bulking agent, and the mass ratio of rosuvastatin calcium to the bulking agent is 1:10 to 15, preferably 1: 12.

4. The pharmaceutical composition of claim 1, wherein the stabilizer comprises one or more of butylated hydroxytoluene, butylated hydroxyanisole, calcium citrate, and β cyclodextrin.

5. The pharmaceutical composition according to claim 3, wherein the composition further comprises a disintegrant and a lubricant, and the composition comprises the following components in percentage by mass:

6. the pharmaceutical composition of claim 3, wherein the composition further comprises a disintegrant and a lubricant, and the composition comprises the following components in percentage by mass:

7. the pharmaceutical composition according to claim 6, wherein the filler is one or more of pregelatinized starch, mannitol, and microcrystalline cellulose; the disintegrating agent is any one or more of carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose and croscarmellose sodium; the lubricant is one or more of magnesium stearate or sodium stearyl fumarate, and is preferably sodium stearyl fumarate.

8. The pharmaceutical composition according to claim 7, wherein the mass ratio of the components is as follows:

9. rosuvastatin calcium tablet characterized by a composition comprising the pharmaceutical according to any of claims 1 to 8.

10. The process for the preparation of rosuvastatin calcium tablet according to claim 9, wherein the dry granulation tableting is characterized in that the dry granulation tableting comprises the following steps:

(1) weighing the medicinal auxiliary materials and rosuvastatin calcium according to the prescription amount, uniformly mixing the rosuvastatin calcium, the stabilizing agent, the filling agent and the disintegrating agent, and performing dry granulation

(2) Mixing the prepared granules with a lubricant, and tabletting.