CN102309467A - Preparation method of atorvastatin calcium capsule - Google Patents
Preparation method of atorvastatin calcium capsule Download PDFInfo
- Publication number
- CN102309467A CN102309467A CN2010102124212A CN201010212421A CN102309467A CN 102309467 A CN102309467 A CN 102309467A CN 2010102124212 A CN2010102124212 A CN 2010102124212A CN 201010212421 A CN201010212421 A CN 201010212421A CN 102309467 A CN102309467 A CN 102309467A
- Authority
- CN
- China
- Prior art keywords
- atorvastatin calcium
- preparing
- capsule
- solid dispersion
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a preparation method of an atorvastatin calcium capsule preparation, and the method comprises the following steps: uniformly mixing amorphous atorvastatin calcium with a water-soluble solid dispersion carrier; heating to melt the solid dispersion carrier, and cooling and curing after the amorphous atorvastatin calcium is uniformly dispersed in the molten dispersion carrier; drying the obtained mixture at a low temperature to obtain mixture particles; and then mixing the obtained particles with other medicinal auxiliary materials, and filling into capsules. By utilizing the preparation method provided by the invention, the dispersion degree of the atorvastatin calcium raw material is improved, the granularity of the medicament is reduced, and the specific surface area is increased, so that the dissolution rate is improved.
Description
Technical field
The present invention relates to a kind of preparation that is used to treat primary hypercholesterolemia and preparation method thereof, in particular to a kind of atorvastatin calcium capsule preparation that is used to treat primary hypercholesterolemia and preparation method thereof.
Background technology
The chemical name of Atorvastatin calcium is: [R-(R; R)]-2-(4-fluorophenyl)-β; Beta-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(aniline) carbonyl]-1 hydrogen-pyrroles-1-enanthic acid calcium trihydrate is synthetic in recent years selectivity, competitive 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-C
0A) reductase inhibitor falls the ester effect and is higher than other HMG-C
0The A reductase inhibitor.Primary hypercholesterolemia patient; Comprise familial hypercholesterolemia (heterozygosis subtype) or combined hyperlipidemia (IIa and the IIb type that are equivalent to the Fredrickson classification method) patient; If Diet Therapy and other non-drug therapy curative effect are dissatisfied, use these article and can treat its T-CHOL rising, low-density lipoprotein cholesterol rising, apolipoprotein B rising and triglyceride rising.Homozygote familial hypercholesterolemia patient, Atorvastatin calcium can share with other blood fat reducing therapy or use (when not having other treatment means) separately, with hypercholesterolemia reducing and low-density lipoprotein cholesterol.
CN1630510A discloses the pharmaceutical formulation of a kind of Atorvastatin calcium as active component.A kind of atorvastatin calcium capsule preparation and preparation method thereof is also disclosed among the CN101185641A.But no matter be marketed tablet or capsule preparations at present, all ubiquity the dissatisfactory problem of stripping and bioavailability aspect.
Summary of the invention
In order to address the above problem; One object of the present invention is to provide a kind of method for preparing of atorvastatin calcium capsule preparation; The atorvastatin calcium capsule preparation that uses this preparation technology to prepare can solve the problem of stripping and bioavailability aspect, has crucial clinical practice and extensive market prospects.
Another object of the present invention provides a kind of atorvastatin calcium capsule preparation with improved dissolving out capability and bioavailability.
For realizing first purpose of the present invention, the invention provides a kind of method for preparing of atorvastatin calcium capsule preparation, comprising:
(1) with amorphous atorvastatin calcium and water-soluble solid dispersible carrier mix homogeneously, the heating make the fusion of solid dispersion carrier, make amorphous atorvastatin calcium be dispersed in fused dispersible carrier after, cooling curing;
(2) after the mixture cold drying with step (1) acquisition, obtain the granule of mixture;
(3) granule that step (2) is obtained is inserted capsule with after other pharmaceutic adjuvant mixes.
Preferably, in the step (1), the weight ratio of amorphous atorvastatin calcium and solid dispersion carrier is 1: 5 to 1: 10, is more preferably 1: 9-1: 10.
According to an embodiment of the invention; Said solid dispersion carrier can be selected from one or more in the water-soluble macromolecule chemical compounds such as PEG4000, PEG6000; Be preferably PEG4000 and/or PEG6000; Further preferred, it is 60-65 ℃ that heating described in step this moment (1) makes the fused temperature of solid dispersion carrier.
According to another implementation of the invention, the cooling curing in the step (1) is to carry out under-5 ℃-0 ℃.Preferred, described cooling curing is in ice-water bath, to carry out.
According to an embodiment of the invention, the cold drying in the step (2) is for being lower than under 60 ℃ the temperature cold drying 20-24 hour; Preferably be lower than under 40 ℃ the temperature cold drying 20-24 hour.
Preferably, in step (2), after cold drying, also comprise the step of the granule of mixture being crossed screen cloth.Further, behind the screen cloth, the grain diameter of acquisition is at least 60 orders excessively.Further again, behind the screen cloth, the grain diameter of acquisition is at least 80 orders excessively.
Those skilled in the art can add the suitable pharmaceutic adjuvant of appropriate amount according to the known technology and the needs of its grasp.Can select adjuvant commonly used to help large scale investment production.Pharmaceutic adjuvant described in the present invention can comprise filler and/or lubricant.Described filler can be selected from one or more in corn starch, sucrose, lactose, pregelatinized Starch, dextrin, microcrystalline Cellulose, hyprolose, hypromellose, sodium carboxymethyl cellulose, the mannitol etc.Said lubricant can be selected from one or more in stearate, silicon dioxide, Pulvis Talci, calcium phosphate, silicic acid or the silicate.
Preferably, in the method for preparing of the present invention in the prepared atorvastatin calcium capsule each grain contain the 10mg Atorvastatin calcium.
In the method for preparing of the present invention, the mass ratio of all pharmaceutic adjuvants and Atorvastatin calcium is 8: 1-32: 1.All pharmaceutic adjuvants comprise solid dispersion carrier and other pharmaceutic adjuvant.
For realizing another object of the present invention, the present invention also provides a kind of atorvastatin calcium capsule preparation that utilizes method for preparing.
In view of the existing atorvastatin calcium tablet in market and capsule general lower phenomenon aspect stripping and bioavailability; Having introduced solid dispersion technology among the present invention increases dissolubility and the rate of release of medicine; Thereby improve its bioavailability, according to Noyes-Whitney dissolution rate equation, dissolution rate be dispersed into direct ratio; The present invention passes through appropriate method just; Improve the dispersion of Atorvastatin calcium raw material, reduce drug particle size, improve its dissolution rate thereby increase its specific surface area.
The specific embodiment
Embodiment 1:
The method for making of 1000 atorvastatin calcium capsules:
10g Atorvastatin calcium raw material and 90g PEG6000 are heated to 60 ℃ jointly are molten condition, rapidly mixture is put cooling rapidly on the metallic plate in the ice-water bath, in the low temperature below 60 ℃ dry 24 hours; Take out the solid drying thing; Cross 80 eye mesh screens, keep certain particle as far as possible, add 50g lactose, 49g microcrystalline Cellulose, 1g magnesium stearate then; Mixed 15 minutes, and the mixture of made granule and powder is inserted in No. 2 capsules promptly got.
Be the improvement of checking the present invention to drug dissolution and bioavailability, other two kinds of preparation methods and the existing tablet in market that we have also quoted capsule compare.
Comparing embodiment 2:
Capsule one:
Behind 50g lactose, 90g PEG6000,10g Atorvastatin calcium, 49g microcrystalline Cellulose, 10g magnesium stearate mix homogeneously, directly be filled in the capsule, get atorvastatin calcium capsule.
Comparing embodiment 3:
Capsule two:
Behind 50g lactose, 90g PEG6000,10g Atorvastatin calcium mix homogeneously; (hypromellose is dissolved in the ethanol of 10%～95% (V/V) with the hypromellose alcoholic solution; Process 0.1%～15% concentration (g/ml)) make wet grain, be lower than under 60 ℃ the temperature then, or in being lower than 60 ℃ drying under reduced pressure case, drying; Add the 49g microcrystalline Cellulose behind the granulate and be mixed together participation granulation, 10g magnesium stearate with raw material; Mix homogeneously is filled in the Capsules, gets atorvastatin calcium capsule.
Embodiment 4: the effect comparison test
The atorvastatin calcium capsule and the marketed tablet of atorvastatin calcium capsule that the embodiment of the invention 1 is prepared and comparing embodiment 2 and 3 preparations have been carried out bioavailability contrast test in dissolution in vitro and the body, and the result is following:
1, dissolution contrast test:
6 of these article of getting; According to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C, second method); The RCZ-8B medicament dissolution instrument that the instrument that uses is produced as Radio Factory of Tianjin Univ.; Second subtraction unit is made up of stirring paddle and stripping rotor, and the vertical axis of loom when rotation and stripping rotor all must not be greater than 2mm in the deviation of any point; Instrument generally is furnished with 6 cover determinators, can once measure 6 atorvastatin calcium capsules.With water 900ml is dissolution medium, and rotating speed is that per minute 50 changes, operation in accordance with the law, and in the time of 45 minutes, it is an amount of to get solution, filters, and gets subsequent filtrate as need testing solution; Other gets the Atorvastatin calcium reference substance and (is equivalent to C approximately in right amount
33H
35FN
2O
510mg), the accurate title, decide, and puts in the 10ml measuring bottle, adds dissolve with methanol and be diluted to scale, shakes up, and precision is measured 1ml, puts in the 100ml measuring bottle, and it is rare to scale to add water, shakes up, as reference substance solution.Use octadecylsilane chemically bonded silica to be filler; With acetonitrile-oxolane-0.05mol/L citric acid soln (transferring PH4.0 with ammonia) (30: 20: 50) is mobile phase; The detection wavelength is 244nm, and number of theoretical plate calculates by the atorvastatin peak and is not less than 3500, and the separating degree of atorvastatin peak and other impurity peaks should meet the requirements.According to above-mentioned chromatographic condition test, precision measures need testing solution and each 20ul of reference substance solution injects chromatograph of liquid, goes out every stripping quantity with calculated by peak area by external standard method.Limit is 80% of a labelled amount, should be up to specification.
Result of the test:
| Product | Dissolution |
| The invention sample | 99％ |
| Capsule one | 88％ |
| Capsule two | 89％ |
| The market tablet | 84％ |
Have above data to find out, its dissolution of medicine that atorvastatin calcium capsule method for preparing provided by the present invention obtains will be apparently higher than market prior dosage form.
2, bioavailability contrast test in the body
22 experimenters are intersected oral atorvastatin calcium capsule 20mg of the present invention (10mg/ grain * 2) and 3 kinds of contrast atorvastatin calcium preparation 20mg (10mg/ sheet * 2 slice) at random, with the 200ml warm water delivery service.Respectively at taking medicine preceding and taking medicine 0.33,0.67,1,1.5,2,3,5,8,12,24, the 48 hour blood sample collection in back; Measure the concentration of atorvastatin in the blood plasma with the LC/MS/MS method; And test data handled through the 3P97 program, below be the data contrasts:
| C max (μg·L -1) | T max (h) | AUC (0-∞) (μg·L -1) | |
| The invention sample | 11.47±3.36 | 7.56±2.25 | 69.6±16.56 |
| Capsule one | 7.71±3.16 | 10.64±3.21 | 52.3±14.66 |
| Capsule two | 7.88±3.18 | 10.07±2.32 | 53.1±14.22 |
| The market tablet | 7.56±3.04 | 10.88±3.35 | 50.1±14.66 |
Have above data to find out, its bioavailability of medicine that atorvastatin calcium capsule method for preparing provided by the present invention obtains will be apparently higher than market prior dosage form.To the relative bioavailability of tablet even reach 140%.
3, the stability contrast is investigated
The existing tablet of capsule and market of method for preparing preparation provided by the present invention has been carried out long-term reserved sample observing; Under temperature (25 ± 2) ℃, relative humidity 60%-10% condition, to place 550 days, sample thief carries out dissolution determination; Compare with freshly prepd capsule; Through the basic no change of its dissolution of capsule of long term test, but the existing tablet in market obviously drops to about 80% the experimental result explanation; The prepared medicine of atorvastatin calcium capsule method for preparing provided by the invention does not have catabiosis, and sample stability is good.
Through the investigation of above three aspects, can well prove that the method for preparing of atorvastatin calcium capsule provided by the present invention has solved the problem of atorvastatin calcium tablet aspect dissolution and bioavailability effectively.
Claims (10)
1. the method for preparing of an atorvastatin calcium capsule preparation is characterized in that this method for preparing comprises:
(1) with amorphous atorvastatin calcium and water-soluble solid dispersible carrier mix homogeneously, the heating make the fusion of solid dispersion carrier, make amorphous atorvastatin calcium be dispersed in fused dispersible carrier after, cooling curing;
(2) after the mixture cold drying with step (1) acquisition, obtain the granule of mixture;
(3) granule that step (2) is obtained is inserted capsule with after other pharmaceutic adjuvant mixes.
2. method for preparing according to claim 1 is characterized in that: in the step (1), the weight ratio of amorphous atorvastatin calcium and solid dispersion carrier is 1: 5 to 1: 10, is more preferably 1: 9-1: 10.
3. method for preparing according to claim 1 is characterized in that: said solid dispersion carrier is selected from one or more among PEG4000, the PEG6000.
4. method for preparing according to claim 3 is characterized in that: it is 60-65 ℃ that heating described in the step (1) makes the fused temperature of solid dispersion carrier.
5. according to arbitrary described method for preparing among the claim 1-4, it is characterized in that: the cooling curing in the step (1) is to carry out under-5 ℃～0 ℃; Preferred, the cooling curing in the said step (1) is in ice-water bath, to carry out.
6. according to arbitrary described method for preparing among the claim 1-4, it is characterized in that: the cold drying in the step (2) is for being lower than under 60 ℃ the temperature cold drying 20-24 hour; Cold drying in the preferred step (2) is for being lower than under 40 ℃ the temperature cold drying 20-24 hour.
7. according to arbitrary described method for preparing among the claim 1-4, it is characterized in that: in the step (2), after cold drying, also comprise the step of the granule of mixture being crossed screen cloth; Preferably, behind the screen cloth, the grain diameter of acquisition is at least 60 orders excessively; Preferred, behind the screen cloth, the grain diameter of acquisition is at least 80 orders excessively.
8. according to arbitrary described method for preparing among the claim 1-4, it is characterized in that: in the said method for preparing in the prepared atorvastatin calcium capsule each grain contain the 10mg Atorvastatin calcium.
9. according to arbitrary described method for preparing among the claim 1-4; It is characterized in that: in the said method for preparing; The mass ratio of all pharmaceutic adjuvants and Atorvastatin calcium is 8: 1-32: 1, and wherein all pharmaceutic adjuvants comprise solid dispersion carrier and other pharmaceutic adjuvant.
10. according to the prepared atorvastatin calcium capsule preparation of arbitrary described method among the claim 1-9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102124212A CN102309467A (en) | 2010-06-29 | 2010-06-29 | Preparation method of atorvastatin calcium capsule |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102124212A CN102309467A (en) | 2010-06-29 | 2010-06-29 | Preparation method of atorvastatin calcium capsule |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102309467A true CN102309467A (en) | 2012-01-11 |
Family
ID=45423290
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102124212A Pending CN102309467A (en) | 2010-06-29 | 2010-06-29 | Preparation method of atorvastatin calcium capsule |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102309467A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102935076A (en) * | 2012-11-29 | 2013-02-20 | 康普药业股份有限公司 | Capsule containing atorvastatin sodium and preparation method thereof |
| CN108421045A (en) * | 2018-04-02 | 2018-08-21 | 北京海晶生物医药科技有限公司 | A kind of Atorvastatin calcium composition, preparation and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1234233A (en) * | 1999-04-07 | 1999-11-10 | 沈阳东宇企业集团有限公司研究院 | Solid dispersion of Lamola azole |
| US20030162827A1 (en) * | 2002-01-30 | 2003-08-28 | Suresh Venkataram | HMG CoA reductase inhibiting composition, method of preparation thereof and method for competitively inhibiting HMG CoA reductase using such composition |
| CN1682883A (en) * | 2005-03-03 | 2005-10-19 | 深圳海王药业有限公司 | Sarcandra solid dispersion and its preparing method |
| CN101543476A (en) * | 2009-05-05 | 2009-09-30 | 中山大学 | A naringin solid dispersion and the preparation method, and the application thereof |
-
2010
- 2010-06-29 CN CN2010102124212A patent/CN102309467A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1234233A (en) * | 1999-04-07 | 1999-11-10 | 沈阳东宇企业集团有限公司研究院 | Solid dispersion of Lamola azole |
| US20030162827A1 (en) * | 2002-01-30 | 2003-08-28 | Suresh Venkataram | HMG CoA reductase inhibiting composition, method of preparation thereof and method for competitively inhibiting HMG CoA reductase using such composition |
| CN1682883A (en) * | 2005-03-03 | 2005-10-19 | 深圳海王药业有限公司 | Sarcandra solid dispersion and its preparing method |
| CN101543476A (en) * | 2009-05-05 | 2009-09-30 | 中山大学 | A naringin solid dispersion and the preparation method, and the application thereof |
Non-Patent Citations (3)
| Title |
|---|
| 刘畅等: "乌拉地尔固体分散体的制备", 《齐齐哈尔医学院学报》, vol. 31, no. 12, 28 June 2010 (2010-06-28), pages 1929 - 1930 * |
| 李永吉: "《中药药剂学》", 31 July 2009, article "固体分散技术", pages: 270-271 * |
| 陈晓燕等: "固体分散技术提高黄芩提取物溶出度的研究", 《中国医院药学杂志》, vol. 28, no. 22, 31 December 2008 (2008-12-31), pages 1927 - 1930 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102935076A (en) * | 2012-11-29 | 2013-02-20 | 康普药业股份有限公司 | Capsule containing atorvastatin sodium and preparation method thereof |
| CN108421045A (en) * | 2018-04-02 | 2018-08-21 | 北京海晶生物医药科技有限公司 | A kind of Atorvastatin calcium composition, preparation and preparation method thereof |
| CN108421045B (en) * | 2018-04-02 | 2021-09-24 | 北京海晶生物医药科技有限公司 | Atorvastatin calcium composition, preparation and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101641517B1 (en) | Solid pharmaceutical formulations comprising BIBW 2992 | |
| CN101816639B (en) | Tablets of mosapride citrate and preparation method thereof | |
| CN102861106A (en) | Preparation method of compound paracetamol and amantadine pellets | |
| CN104306344B (en) | A kind of Azilsartan tablet and preparation technology thereof | |
| CN101322695B (en) | Piclofenac potassium sustained release capsule and preparing technique thereof | |
| CN103830192A (en) | Tenofovir disoproxil fumarate tablets allowing direct powder compression and preparation method thereof | |
| CN105125545A (en) | Medicine composition containing pitavastatin calcium and preparing method thereof | |
| CN101322694A (en) | Piclofenac potassium sustained release tablets and preparing technique thereof | |
| CN100411612C (en) | Quick-disintegration tablets of calcium atovastatine, and its prepn. method | |
| CN102309467A (en) | Preparation method of atorvastatin calcium capsule | |
| CN103356495B (en) | A kind of Letrozole tablet and preparation method thereof | |
| CN102268042B (en) | Minodronate crystalform II and preparation method thereof | |
| CN106265557A (en) | Pharmaceutical composition containing ticagrelor | |
| CN102451168B (en) | Preparation method of naringenin tablet | |
| CN101185641A (en) | Atorvastatin calcium capsule and preparation method | |
| CN103385863B (en) | Sodium azulene sulfonate sustained-release preparation | |
| CN101991859A (en) | Beta-cyclodextrin inclusion compound of huperzine A, and preparation method and preparation thereof | |
| CN103948562A (en) | Desloratadine capsule and preparation method thereof | |
| CN102772390A (en) | Venlafaxine hydrochloride sustained release capsule and preparation method thereof | |
| CN104586807B (en) | Sustained release preparation for treating Alzheimer's disease and preparation method thereof | |
| CN103709329B (en) | A kind of dispersive tablets of Fuyankang for gynecological inflammation pharmaceutical excipient compound and preparation method thereof and application | |
| CN105017119A (en) | Lipid-lowering drug ezetimibe compound | |
| CN104116719B (en) | A kind of huperzine A is adjusted and is released tablet composition and preparation method thereof | |
| CN105106135A (en) | Ezetimibe pharmaceutical composition dry suspension for treatment of cardio-cerebral vascular system diseases | |
| CN105232472A (en) | Pharmaceutical Ezetimibe composition granules treating hyperlipidemia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20120111 |