CN105147636B - Rosuvastatin calcium capsule and preparation method thereof - Google Patents
Rosuvastatin calcium capsule and preparation method thereof Download PDFInfo
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- CN105147636B CN105147636B CN201510508144.2A CN201510508144A CN105147636B CN 105147636 B CN105147636 B CN 105147636B CN 201510508144 A CN201510508144 A CN 201510508144A CN 105147636 B CN105147636 B CN 105147636B
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Abstract
The invention discloses a kind of Rosuvastatin calcium capsule, the component including following parts by weight: 40-60 parts of rosuvastain calcium solid dispersions, 40-60 parts of microcrystalline cellulose, 1-5 parts of magnesium stearate.The invention also discloses the preparation methods of the Rosuvastatin calcium capsule.Rosuvastain calcium capsule dissolubility of the present invention is good, and stability is high, and preparation method is simple, is suitable for being mass produced.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, it is related to a kind of Rosuvastatin calcium preparation and preparation method thereof, and in particular to
Rosuvastatin calcium capsule and preparation method thereof.
Background technique
Rosuvastain calcium is a kind of selective HMG-CoA reductase inhibitor, is developed by Astrazeneca AB,
It is listed in multiple countries and regions such as the U.S., Japan, Europe, China, trade name " CRESTOR " (Chinese trade name: can determine,
" CRESTOR " is the registered trademark of AstraZeneca group company).
Rosuvastain calcium, English name: Rosuvastatin Calcium, CAS registration number: 147098-20-2, chemical name
Are as follows: double-[E-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyl -2- [methyl (mesyl) amino]-pyrimidine -5- base] (3R, 5S) -
3,5- dihydroxy heptyl -6- olefin(e) acid] calcium salt (2:1).Molecular formula: (C22H27FN3O6S)2Ca, structural formula are as follows:
Rosuvastain calcium is the third generation statins of fully synthetic single enantiomter, belongs to β-hydroxyl-Beta-methyl
Glutaryl coenzyme A (HMG-CoA) reductase inhibitor has Regulating Blood Lipid Effect.Rosuvastatin calcium tablets are a kind of reducing blood lipid
Class solid orally ingestible, must first be in gastro-intestinal Fluid to dissolve out in the gastrointestinal tract can just be absorbed and reach body circulation, and drug exists
Intracorporal release and absorption directly affect its drug effect.Improving the medicine dissolution rate is an important finger for controlling medicine preparation quality
Mark.Therefore, the In Vitro Dissolution behavior for studying rosuvastatin calcium tablets is significant.
Due to the β in rosuvastain calcium molecule on heptenoic acid chain, δ-hydroxyl is highly unstable, especially carbon-to-carbon double bond
Adjacent hydroxyl is easily oxidized into ketone, and molecule inner ring condensation can also occur and generate lactone, therefore in higher temperature
Or in higher levels of humidity environment, rosuvastain calcium is easy to degrade, the primary product of formation be (3R, 5S) lactone degradant and
Oxidation product, to cause difficulty to preparation production and storage.It can be seen that being prepared by prescription screening and Study on Preparation
A kind of rosuvastain calcium oral solid formulation that stability is strong is particularly important.
WO01/054669 discloses a kind of tablet containing HMG-CoA reductase inhibitor, by adding into preparation prescription
Enter the stability that the multivalent salts such as Mg salt, Zn salt, Al salt improve main ingredient in tablet.This method is increasing the same of preparation stability
When, impurity content but, which is brought, to preparation increases very fast problem.
WO2008/035128 discloses a kind of new pharmaceutical composition comprising amorphous rosuvastatin calcium, by adding
Enter the alkaline matters such as magnesium hydroxide and/or calcium acetate or calcium gluconate or calcium glycerophosphate or aluminium hydroxide, to improve preparation
Stability.However, the addition of a large amount of alkaline agent is unfavorable for pharmaceutical preparation molding, and it is also possible into alkaline agent after human body
Lead to a variety of unexpected side effects, in some instances it may even be possible to lead to the decline of drug bioavailability.
CN102028658A discloses a kind of rosuvastain calcium lipidosome solid preparation, by rosuvastain calcium, soybean
Lecithin, cholesterol, Tween 80, deoxysodium cholate are made.By the way that rosuvastain calcium solid pharmaceutical preparation made from liposome is made
Although increasing stability, due to Liposomal formulation complex process, quality is difficult to control, and the phosphatide price as auxiliary material
It is very high, cause preparation at high cost, is unfavorable for production and sales.
In addition, in water or in 0.1mol/L hydrochloric acid or 0.1mol/L sodium hydroxide solution almost due to rosuvastain calcium
Rosuvastain calcium oral solid formulation that is insoluble, therefore conventionally preparing, it is not high in the presence of accumulation dissolution rate, in vivo
The lower problem of bioavilability.Meanwhile although the effect for reducing fat of rosuvastain calcium is significant, larger dose (10-
" peak valley " fluctuation of blood concentration is also easy to produce when 40mg) taking, so that such as rhabdomyolysis, albuminuria, nephrosis, renal failure occur
It exhausts, hepatotoxicity wind agitation, pharyngitis, the adverse reactions such as headache and influenza-like symptom.
Summary of the invention
In order to solve deficiency in the prior art, the first technical problem to be solved by the present invention is to provide auspicious relax of one kind and cuts down
Statin calcium capsule.
A kind of Rosuvastatin calcium capsule comprising the component of following parts by weight: rosuvastain calcium solid dispersions 40-
60 parts, 40-60 parts of microcrystalline cellulose, 1-5 parts of magnesium stearate.
The rosuvastain calcium solid dispersions, are prepared by following steps:
(1) 10-20g rosuvastain calcium is dissolved in 10-30ml organic solvent, obtains solution a；
(2) 40-60g solid carrier is dissolved in 150-300ml organic solvent, obtains solution b；
(3) solution a is added in solution b while stirring, rotary evaporation at 30-55 DEG C, after removing organic solvent, freeze-drying
Obtain powdered rosuvastain calcium solid dispersions.
The organic solvent of the step (1) and step (2) is selected from methylene chloride and/or chloroform, preferably methylene chloride.
The solid carrier is selected from polyethylene pyrrole network alkanone and/or poloxamer, preferably polyethylene pyrrole network alkanone and pool
The mixture of Luo Shamu mass ratio 2:1-4:1.
The present invention also provides the preparation methods of the Rosuvastatin calcium capsule comprising following steps:
(1) rosuvastain calcium solid dispersions are prepared；
(2) rosuvastain calcium solid dispersions, microcrystalline cellulose and magnesium stearate are weighed according to the ratio, are uniformly mixed, dress
Enter capsule.
It can control each capsule about 20mg containing rosuvastain calcium.
In the present invention,
Polyvinylpyrrolidone, No. CAS: 84057-81-8, poloxamer, No. CAS: 9003-11-6.Methylene chloride, CAS
Number: 75-09-2.Chloroform, No. CAS: 67-66-3.Microcrystalline cellulose, No. CAS: 9004-34-6.Magnesium stearate, No. CAS: 557-
04-0。
Rosuvastain calcium capsule dissolubility of the present invention is good, and stability is high, and preparation method is simple, is suitable for big
Large-scale production.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that following embodiment is only used
In invention is further explained, it should not be understood as limiting the scope of the invention.The people that is skilled in technique in the field
Member can make some nonessential modifications and adaptations to the present invention according to the content of aforementioned present invention.
Rosuvastain calcium solid dispersions described in embodiment 1-3, prepare by the following method:
(1) 20g rosuvastain calcium is dissolved in 15ml methylene chloride, obtains solution a；
(2) 45g solid carrier is dissolved in 200ml methylene chloride, obtains solution b；
(3) solution a is added in solution b while stirring, rotary evaporation at 40 DEG C, after removing methylene chloride, is lyophilized
To powdered rosuvastain calcium solid dispersions.
The preparation method of Rosuvastatin calcium capsule described in embodiment 1-3 comprising following steps:
(1) rosuvastain calcium solid dispersions are prepared；
(2) rosuvastain calcium solid dispersions, microcrystalline cellulose and magnesium stearate are weighed according to the ratio, are uniformly mixed, dress
Enter capsule, controls each capsule about 20mg containing rosuvastain calcium.
Embodiment 1
Rosuvastatin calcium capsule, including following component: 48 grams of rosuvastain calcium solid dispersions, microcrystalline cellulose 50
Gram, 2 grams of magnesium stearate.
Wherein, preparing solid carrier used in the rosuvastain calcium solid dispersions of embodiment 1 is polyethylene
The mixture of pyrrole network alkanone and poloxamer mass ratio 3:1.
Embodiment 2
It is prepared as described in Example 1.
The difference from embodiment 1 is that: used in the rosuvastain calcium solid dispersions process of preparation embodiment 2
Solid carrier replace with polyethylene pyrrole network alkanone.
Embodiment 3
It is prepared as described in Example 1.
The difference from embodiment 1 is that: used in the rosuvastain calcium solid dispersions process of preparation embodiment 3
Solid carrier replace with poloxamer.
Test case dissolution rate and stability test
According to Chinese Pharmacopoeia version annex the second method of XC in 2010, Rosuvastatin calcium capsule made from embodiment 1-3 is measured
Dissolution rate.Method particularly includes: using phosphate buffer (pH6.8) 900ml as dissolution medium, revolving speed is 50 turns per minute, according to
Method operation, when through 5min, takes solution appropriate respectively, filters, discards 10ml primary filtrate, take subsequent filtrate as test solution；Separately
Take reference substance appropriate, it is accurately weighed, add methanol to dissolve and quantifies the solution for diluting and being made in every 1ml containing about 0.28mg, precision amount
1ml is taken, is set in 50ml measuring bottle, scale is diluted to dissolution medium, shakes up, as reference substance solution.It is molten that precision measures test sample
Liquid and each 100 μ l of reference substance solution are injected separately into liquid chromatograph, record chromatogram.By external standard method with every bag of calculated by peak area
The amount of dissolution.Limit is the 70% of labelled amount, should meet regulation.
Rosuvastatin calcium capsule made from 1-3 is accelerated to save 6 months under conditions of 40 DEG C, 75% relative humidity,
Then it further takes out drug and tests its dissolution rate, probation stability.
Test result is shown in Table 1.
Table 1: dissolution rate test result
| The dissolution rate (%) of 5min at 0 day | The dissolution rate (%) of 5min after accelerating 6 months | |
| Embodiment 1 | 96.8 | 95.9 |
| Embodiment 2 | 93.9 | 93.4 |
| Embodiment 3 | 94.2 | 93.6 |
Rosuvastatin calcium capsule 5min dissolution rate of the invention is high it can be seen from test case result, and at 40 DEG C,
Dissolution rate is still good after accelerating 6 months under conditions of 75% relative humidity, and stability is high.Especially embodiment 1 prepares auspicious relax and cuts down
Solid carrier used in during statin calcium solid dispersions is the mixed of polyethylene pyrrole network alkanone and poloxamer mass ratio 3:1
Object is closed, compared with polyethylene pyrrole network alkanone or poloxamer is used alone in embodiment 2-3, dissolution rate is higher, and effect is more preferable.
Claims (2)
1. Rosuvastatin calcium capsule, which is characterized in that the component including following parts by weight: rosuvastain calcium solid dispersions
40-60 parts, 40-60 parts of microcrystalline cellulose, 1-5 parts of magnesium stearate；
The rosuvastain calcium solid dispersions, are prepared by following steps:
(1) 10-20g rosuvastain calcium is dissolved in 10-30ml organic solvent, obtains solution a；
(2) 40-60g solid carrier is dissolved in 150-300ml organic solvent, obtains solution b；
(3) solution a is added in solution b while stirring, rotary evaporation at 30-55 DEG C, after removing organic solvent, freeze-drying；
The solid carrier is the mixture of polyethylene pyrrole network alkanone and poloxamer mass ratio 2:1-4:1；
The organic solvent of the step (1) and step (2) is selected from methylene chloride and/or chloroform.
2. the preparation method of Rosuvastatin calcium capsule described in claim 1 comprising following steps:
(1) rosuvastain calcium solid dispersions are prepared；
(2) rosuvastain calcium solid dispersions, microcrystalline cellulose and magnesium stearate are weighed according to the ratio, is uniformly mixed, and glue is packed into
Capsule.
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| CN110151725B (en) * | 2019-06-26 | 2021-06-18 | 海南通用三洋药业有限公司 | Stable rosuvastatin calcium capsule and preparation method thereof |
| CN113143882A (en) * | 2021-04-30 | 2021-07-23 | 海南通用三洋药业有限公司 | Preparation method of rosuvastatin calcium capsule and rosuvastatin calcium capsule |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101066264A (en) * | 2007-06-12 | 2007-11-07 | 杨喜鸿 | Solid olmesartan medoxmil dispersion and its prepn and medicinal application |
| CN102258459A (en) * | 2011-08-17 | 2011-11-30 | 南京正宽医药科技有限公司 | Rosuvastatin calcium oral solid preparation and applications thereof |
| CN104434826A (en) * | 2014-11-08 | 2015-03-25 | 鲁南贝特制药有限公司 | Rosuvastatin calcium dispersible tablet |
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2015
- 2015-08-18 CN CN201510508144.2A patent/CN105147636B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101066264A (en) * | 2007-06-12 | 2007-11-07 | 杨喜鸿 | Solid olmesartan medoxmil dispersion and its prepn and medicinal application |
| CN102258459A (en) * | 2011-08-17 | 2011-11-30 | 南京正宽医药科技有限公司 | Rosuvastatin calcium oral solid preparation and applications thereof |
| CN104434826A (en) * | 2014-11-08 | 2015-03-25 | 鲁南贝特制药有限公司 | Rosuvastatin calcium dispersible tablet |
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Effective date of registration: 20181026 Address after: 311400 Room 102, 10 new road, Fuchun street, Fuyang District, Hangzhou, Zhejiang. Applicant after: Fuyang Hangzhou Ding Chuang Technology Co., Ltd. Address before: 200137 1F79 14, 528 Yang Gao Bei Road, Pudong New Area, Shanghai. Applicant before: Shanghai Taohong Chemical Technology Co., Ltd. |
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Effective date of registration: 20201112 Address after: 274100 north section of East Luhua Road, industrial park, Dingtao district (Yantai), Heze City, Shandong Province (in the hospital of Shandong Shuzhong Pharmaceutical Co., Ltd.) Patentee after: Heze Hongze Trade Co., Ltd Address before: Fuyang New District Fuchun street 311400 Hangzhou Road, Zhejiang province No. 10 Room 102 Patentee before: HANGZHOU FUYANG DINGCHUANG TECHNOLOGY Co.,Ltd. |
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