CN105147636A - Rosuvastatin calcium capsule and preparation method thereof - Google Patents
Rosuvastatin calcium capsule and preparation method thereof Download PDFInfo
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- CN105147636A CN105147636A CN201510508144.2A CN201510508144A CN105147636A CN 105147636 A CN105147636 A CN 105147636A CN 201510508144 A CN201510508144 A CN 201510508144A CN 105147636 A CN105147636 A CN 105147636A
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Abstract
The invention discloses a rosuvastatin calcium capsule. The rosuvastatin calcium capsule comprises components in parts by weight as follows: 40-60 parts of a rosuvastatin calcium solid dispersion, 40-60 parts of microcrystalline cellulose and 1-5 parts of magnesium stearate. The invention further discloses a preparation method of the rosuvastatin calcium capsule. The rosuvastatin calcium capsule has high dissolution rate and high stability, and the preparation method is simple and suitable for mass production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of Rosuvastatin calcium preparation and preparation method thereof, be specifically related to Rosuvastatin calcium capsule and preparation method thereof.
Background technology
Rosuvastain calcium is a kind of selectivity HMG-CoA reductase inhibitor, developed by Astrazeneca AB, in multiple countries and regions listing such as the U.S., Japan, Europe, China, trade name " CRESTOR " (Chinese trade name: can determine, " CRESTOR " is the registered trade mark of AstraZeneca group company).
Rosuvastain calcium; English name: RosuvastatinCalcium; CAS registration number: 147098-20-2; chemistry is by name: two-[E-7-[4-(the fluorine-based phenyl of 4-)-6-isopropyl-2-[methyl (mesyl) is amino]-pyrimidine-5-base] (3R; 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid] calcium salt (2:1).Molecular formula: (C
22h
27fN
3o
6s)
2ca, structural formula is:
Rosuvastain calcium is the third generation statins of complete synthesis single enantiomer, belongs to HMG-CoA (HMG-CoA) reductase inhibitor, has Regulating Blood Lipid Effect.Rosuvastatin calcium tablets is a kind of blood fat reducing class solid orally ingestible, in the gastrointestinal tract must first in gastro-intestinal Fluid stripping could be absorbed and arrive body circulation, medicine emission and absorption in vivo directly affects its drug effect.Improving this medicine dissolution is the important indicator controlling medicine preparation quality.Therefore, the In Vitro Dissolution behavior studying rosuvastatin calcium tablets is significant.
Due to the β on heptenoic acid chain in rosuvastain calcium molecule, δ-hydroxyl is very unstable, especially the hydroxyl that carbon-to-carbon double bond is adjacent is easy to be oxidized to ketone, also can there is molecule inner ring condensation and generate lactone, therefore, in higher temperature or higher levels of humidity environment, rosuvastain calcium is easy to degraded, and the primary product of formation is (3R, 5S) lactone degradant and oxidation product, thus cause difficulty to preparation production and storage.As can be seen here, prepare the strong rosuvastain calcium oral solid formulation of a kind of stability by prescription screening and Study on Preparation and seem particularly important.
WO01/054669 discloses a kind of tablet containing HMG-CoA reductase inhibitor, improves the stability of principal agent in tablet by adding the multivalent salts such as Mg salt, Zn salt, Al salt in preparation prescription.This method, while increase preparation stability, but brings impurity content increase problem faster to preparation.
WO2008/035128 discloses a kind of new pharmaceutical composition comprising amorphous rosuvastatin calcium, by adding magnesium hydroxide and/or calcium acetate or calcium gluconate or the alkaline matter such as calcium glycerophosphate or aluminium hydroxide, improves the stability of preparation.But, the adding and be unfavorable for pharmaceutical preparation molding of a large amount of alkaline agents, and after entering human body, alkaline agent also may cause multiple unforeseeable side effect, even may cause the decline of drug bioavailability.
CN102028658A discloses a kind of rosuvastain calcium lipidosome solid preparation, and by rosuvastain calcium, soybean lecithin, cholesterol, Tween 80, sodium deoxycholate is made.Although add stability by the rosuvastain calcium solid preparation making liposome obtained, but due to Liposomal formulation complex process, difficult quality controls, and very high as the phospholipid price of adjuvant, causes preparation cost high, is unfavorable for production and sales.
In addition, because rosuvastain calcium is in water or almost insoluble in 0.1mol/L hydrochloric acid or 0.1mol/L sodium hydroxide solution,, all there is accumulation dissolution not high in the rosuvastain calcium oral solid formulation therefore conventionally prepared, the problem that in body, bioavailability is lower.Simultaneously, although the effect for reducing fat of rosuvastain calcium is remarkable, but larger dose (10-40mg) easily produces " peak valley " fluctuation of blood drug level when taking, thus occurs as untoward reaction such as rhabdomyolysis, albuminuria, nephropathy, renal failure, liver toxicity, pharyngitis, headache and influenza-like symptoms.
Summary of the invention
In order to solve deficiency of the prior art, one of technical problem to be solved by this invention is to provide a kind of Rosuvastatin calcium capsule.
A kind of Rosuvastatin calcium capsule, it comprises the component of following weight portion: rosuvastain calcium solid dispersion 40-60 part, microcrystalline Cellulose 40-60 part, magnesium stearate 1-5 part.
Described rosuvastain calcium solid dispersion, is prepared from 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) join in solution b by solution a while stirring, rotary evaporation at 30-55 DEG C, after removing organic solvent, lyophilizing obtains Powdered rosuvastain calcium solid dispersion.
The organic solvent of described step (1) and step (2) is all selected from dichloromethane and/or chloroform, is preferably dichloromethane.
Described solid carrier is selected from polyethylene pyrrole network alkane ketone and/or poloxamer, is preferably the mixture of polyethylene pyrrole network alkane ketone and poloxamer mass ratio 2:1-4:1.
Present invention also offers the preparation method of described Rosuvastatin calcium capsule, it comprises the steps:
(1) rosuvastain calcium solid dispersion is prepared;
(2) take rosuvastain calcium solid dispersion, microcrystalline Cellulose and magnesium stearate by proportioning, mix homogeneously, incapsulate.
Each capsule can be controlled and be about 20mg containing rosuvastain calcium.
In the present invention,
Polyvinylpyrrolidone, No. CAS: 84057-81-8, poloxamer, No. CAS: 9003-11-6.Dichloromethane, No. CAS: 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 large-scale production.
Detailed description of the invention
Be specifically described the present invention below by embodiment, what be necessary to herein means out is that following examples are only used to further illustrate the present invention, and can not be interpreted as limiting the scope of the invention.The person skilled in the art in this field according to the content of the invention described above, can make some nonessential improvement and adjustment to the present invention.
The solid dispersion of rosuvastain calcium described in embodiment 1-3, prepare by the following method:
(1) 20g rosuvastain calcium is dissolved in 15ml dichloromethane, obtains solution a;
(2) 45g solid carrier is dissolved in 200ml dichloromethane, obtains solution b;
(3) join in solution b by solution a while stirring, rotary evaporation at 40 DEG C, after removing dichloromethane, lyophilizing obtains Powdered rosuvastain calcium solid dispersion.
The preparation method of the calcium capsule of Rosuvastatin described in embodiment 1-3, it comprises the steps:
(1) rosuvastain calcium solid dispersion is prepared;
(2) take rosuvastain calcium solid dispersion, microcrystalline Cellulose and magnesium stearate by proportioning, mix homogeneously, incapsulate, control each capsule and be about 20mg containing rosuvastain calcium.
Embodiment 1
Rosuvastatin calcium capsule, comprises following component: rosuvastain calcium solid dispersion 48 grams, microcrystalline Cellulose 50 grams, magnesium stearate 2 grams.
Wherein, the mixture that the solid carrier used in the rosuvastain calcium solid dispersion of embodiment 1 is polyethylene pyrrole network alkane ketone and poloxamer mass ratio 3:1 is prepared.
Embodiment 2
Be prepared by the method for embodiment 1.
Be with the difference of embodiment 1: prepare the solid carrier used in the rosuvastain calcium solid dispersion process of embodiment 2 and replace with polyethylene pyrrole network alkane ketone.
Embodiment 3
Be prepared by the method for embodiment 1.
Be with the difference of embodiment 1: prepare the solid carrier used in the rosuvastain calcium solid dispersion process of embodiment 3 and replace with poloxamer.
Test case dissolution and stability test
According to Chinese Pharmacopoeia version annex XC second method in 2010, measure the dissolution of the Rosuvastatin calcium capsule that embodiment 1-3 obtains.Concrete grammar is: with phosphate buffer (pH6.8) 900ml for dissolution medium, and rotating speed is 50 turns per minute, operates in accordance with the law, when 5min, gets solution respectively appropriate, filters, and discards 10ml just filtrate, gets subsequent filtrate as need testing solution; Separately get reference substance appropriate, accurately weighed, add dissolve with methanol and quantitatively dilute the solution made about containing 0.28mg in every 1ml, precision measures 1ml, puts in 50ml measuring bottle, is diluted to scale with dissolution medium, shake up, in contrast product solution.Precision measures need testing solution and each 100 μ l of reference substance solution, respectively injection liquid chromatography, record chromatogram.By external standard method with the stripping quantity of calculated by peak area every bag.Limit is 70% of labelled amount, should conform with the regulations.
By Rosuvastatin calcium capsule obtained for 1-3 at 40 DEG C, accelerate preservation 6 months under the condition of 75% relative humidity, and then removing pharmaceutical producs tests its dissolution, probation stability.
Test result is in table 1.
Table 1: dissolution test result
| The dissolution (%) of 5min when 0 day | Accelerate the dissolution (%) of 5min after 6 months | |
| Embodiment 1 | 96.8 | 95.9 |
| Embodiment 2 | 93.9 | 93.4 |
| Embodiment 3 | 94.2 | 93.6 |
As can be seen from test case result, Rosuvastatin calcium capsule 5min dissolution of the present invention is high, and at 40 DEG C, still well, stability is high to accelerate dissolution after 6 months under the condition of 75% relative humidity.Especially embodiment 1, prepare the mixture that the solid carrier that uses in rosuvastain calcium solid dispersion process is polyethylene pyrrole network alkane ketone and poloxamer mass ratio 3:1, compared with being used alone polyethylene pyrrole network alkane ketone or poloxamer with embodiment 2-3, dissolution is higher, better effects if.
Claims (5)
1. Rosuvastatin calcium capsule, is characterized in that, comprises the component of following weight portion: rosuvastain calcium solid dispersion 40-60 part, microcrystalline Cellulose 40-60 part, magnesium stearate 1-5 part.
2. Rosuvastatin calcium capsule as claimed in claim 1, it is characterized in that, described rosuvastain calcium solid dispersion, is prepared from 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) while stirring solution a is joined in solution b, rotary evaporation at 30-55 DEG C, after removing organic solvent, lyophilizing.
3. Rosuvastatin calcium capsule as claimed in claim 2, is characterized in that: the organic solvent of described step (1) and step (2) is all selected from dichloromethane and/or chloroform.
4. Rosuvastatin calcium capsule as claimed in claim 2, is characterized in that: described solid carrier is the mixture of polyethylene pyrrole network alkane ketone and poloxamer mass ratio 2:1-4:1.
5. the preparation method of Rosuvastatin calcium capsule according to any one of claim 2-4, it comprises the steps:
(1) rosuvastain calcium solid dispersion is prepared;
(2) take rosuvastain calcium solid dispersion, microcrystalline Cellulose and magnesium stearate by proportioning, mix homogeneously, incapsulate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110151725A (en) * | 2019-06-26 | 2019-08-23 | 海南通用三洋药业有限公司 | A kind of stable rosuvastain 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 |
-
2015
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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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110151725A (en) * | 2019-06-26 | 2019-08-23 | 海南通用三洋药业有限公司 | A kind of stable rosuvastain 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 |
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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. |