CN101185641A - Atorvastatin calcium capsule and preparation method - Google Patents
Atorvastatin calcium capsule and preparation method Download PDFInfo
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- CN101185641A CN101185641A CNA200710194917XA CN200710194917A CN101185641A CN 101185641 A CN101185641 A CN 101185641A CN A200710194917X A CNA200710194917X A CN A200710194917XA CN 200710194917 A CN200710194917 A CN 200710194917A CN 101185641 A CN101185641 A CN 101185641A
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- atorvastatin calcium
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- atorvastatin
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Abstract
The invention relates to an atorvastatin calcium capsule preparation used for treating patients with essential hypercholesterolemia and the preparation method thereof. The main component of the preparation is an amorphous atorvastatin calcium bulk drug. The amorphous atorvastatin calcium crude drug is prepared into particle, powder, or particle and powder by using one or a plurality of excipients, then filled in gastro dissolved capsules.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of pharmaceutical preparation and preparation method, particularly, provide a kind of atorvastatin calcium capsule agent that is used for the treatment of 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, be 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, application this product can be treated its T-CHOL rising, low-density lipoprotein cholesterol rising, apolipoprotein B raises and triglyceride raises.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.
About Atorvastatin calcium, can also be made into tablet in the prior art, capsule has than tablet that disintegrate is fast, the medicine stripping waits advantage fully.
The purpose of this invention is to provide atorvastatin calcium capsule agent and preparation method, have crucial clinical practice and extensive market prospects.
Summary of the invention
The objective of the invention is to atorvastatin calcium capsule agent and preparation method.Preparation technique of the present invention may further comprise the steps:
First kind: after using adjuvant and amorphous atorvastatin calcium mix homogeneously, directly be filled in the stomach dissolution type Capsules.
Second kind: use adjuvant that amorphous atorvastatin calcium is made granule, or make powder, or make granule and powder, then it is filled in the stomach dissolution type Capsules.
In the above-described embodiment, described adjuvant is the conventional adjuvant of using of pharmaceutical field, and preferred adjuvant is selected from one or more in lactose, sucrose, Pulvis Talci, hypromellose, polyvinylpyrrolidone, ethanol, polyoxyethylene sorbitan monoleate, silicon dioxide, magnesium stearate, starch and the pregelatinized Starch.
In the above-described embodiment, preferred adjuvant: the ratio of amorphous atorvastatin calcium is 8: 1～32: 1 (W/W).
In the above-described embodiment, preferably make capsule in the following manner: hypromellose or polyvinylpyrrolidone are dissolved in the ethanol of 10%～95% (V/V), make 0.1%～15% concentration (g/ml); Or starch or dextrin is suspended in the boiling water, make 1%～10% concentration (W/W)
In further embodiment, preparation technique of the present invention may further comprise the steps:
One, behind adjuvant and the amorphous atorvastatin calcium mix homogeneously, directly is filled in the stomach dissolution type Capsules.
Two, behind adjuvant and the amorphous atorvastatin calcium mix homogeneously,, be lower than under 60 ℃ the temperature then, or in being lower than 60 ℃ drying under reduced pressure case, drying, be filled in behind the granulate in the stomach dissolution type Capsules with the wet grain of binding agent system.
Another aspect of the present invention relates to the pharmaceutical preparation of being made by described preparation technique, preferably in described pharmaceutical preparation, contains the atorvastatin of 10mg in each capsules.
Description of drawings:
Fig. 1 is that the external stripping curve of atorvastatin calcium capsule of the present invention and import reference atorvastatin calcium tablet (lipitor, Pfizer Inc. produces) compares;
The specific embodiment:
Further specify the present invention below by embodiment.It should be understood that; what the present invention was claimed is the atorvastatin calcium capsule agent; the preparation method of the embodiment of the invention is only used for illustrating the present invention; rather than limitation of the present invention; under design prerequisite of the present invention, all preparation methoies that relates to the atorvastatin calcium capsule agent all belong to the scope of protection of present invention.Except as otherwise noted, percent among the present invention is percetage by weight, in addition, (W/W) in the description of the present invention is meant weight ratio or weight ratio concentration, (V/V) be meant volume ratio or volume by volume concentration, W/V is meant the ratio (for example, grams per milliliter, g/ml or kg/liter) of weight and volume.
Embodiment 1: preparation atorvastatin calcium capsule (specification: 10mg)
Behind 1600g lactose, 100g Atorvastatin calcium, 35g silicon dioxide, 8g magnesium stearate mix homogeneously, directly be filled in the stomach dissolution type Capsules, get atorvastatin calcium capsule.
Embodiment 2: preparation atorvastatin calcium capsule (specification: 10mg)
Behind 1600g lactose, 100g Atorvastatin calcium mix homogeneously, " hypromellose is dissolved in the ethanol of 10%～95% (V/V); make 0.1%～15% concentration (g/ml) " with the hypromellose alcoholic solution and makes wet grain, be lower than under 60 ℃ the temperature then, or in being lower than 60 ℃ drying under reduced pressure case, dry, add 35g silicon dioxide, 8g magnesium stearate, 52g carboxymethylstach sodium behind the granulate, mix homogeneously is filled in the stomach dissolution type Capsules.Get atorvastatin calcium capsule.
Embodiment 3: preparation atorvastatin calcium capsule (specification: 10mg)
Behind 1600g lactose, 100g Atorvastatin calcium mix homogeneously, " polyvinylpyrrolidone is dissolved in the ethanol of 10%～95% (V/V); make 0.1%～15% concentration (g/ml) " with the polyvinylpyrrolidone alcoholic solution and makes wet grain, be lower than under 60 ℃ the temperature then, or in being lower than 60 ℃ drying under reduced pressure case, dry, add 35g silicon dioxide, 8g magnesium stearate, 52g carboxymethylstach sodium behind the granulate, mix homogeneously is filled in the stomach dissolution type Capsules.Get atorvastatin calcium capsule.
Embodiment 4: preparation atorvastatin calcium capsule (specification: 10mg)
Behind 1600g lactose, 100g Atorvastatin calcium mix homogeneously, " starch is suspended in the boiling water; make 1%～10% concentration (W/W) " with starch slurry and makes wet grain, be lower than under 60 ℃ the temperature then, or in being lower than 60 ℃ drying under reduced pressure case, dry, add 35g silicon dioxide, 8g magnesium stearate, 52g carboxymethylstach sodium behind the granulate, mix homogeneously is filled in the stomach dissolution type Capsules.Get atorvastatin calcium capsule.
Embodiment 5: preparation atorvastatin calcium capsule (specification: 10mg)
Behind 1600g lactose, 100g Atorvastatin calcium mix homogeneously, make wet grain with dextrin slurry " dextrin being suspended in the boiling water; make 1%～10% concentration (W/W) ", be lower than under 60 ℃ the temperature then, or in being lower than 60 ℃ drying under reduced pressure case, dry, add 35g silicon dioxide, 8g magnesium stearate, 52g carboxymethylstach sodium behind the granulate, mix homogeneously is filled in the stomach dissolution type Capsules.Get atorvastatin calcium capsule.
Embodiment 6: preparation atorvastatin calcium capsule (specification: 10mg)
1600g lactose, the 100g Atorvastatin calcium airpillow-dry of packing into is granulated in the pot, boiling mixed after 5 minutes, " hypromellose is dissolved in the ethanol of 10%～95% (V/V); make 0.1%～15% concentration (g/ml) " granulation of whitewashing with the hypromellose alcoholic solution, temperature of charge be controlled at 60 ℃ below, add 35g silicon dioxide, 8g magnesium stearate, 52g carboxymethylstach sodium behind the granulate, mix homogeneously is filled in the stomach dissolution type Capsules.Get atorvastatin calcium capsule.
Embodiment 7: preparation atorvastatin calcium capsule (specification: 10mg)
1600g lactose, the 100g Atorvastatin calcium airpillow-dry of packing into is granulated in the pot, boiling mixed after 5 minutes, " polyvinylpyrrolidone is dissolved in the ethanol of 10%～95% (V/V); make 0.1%～15% concentration (g/ml) " granulation of whitewashing with the polyvinylpyrrolidone alcoholic solution, temperature of charge be controlled at 60 ℃ below, add 35g silicon dioxide, 8g magnesium stearate, 52g carboxymethylstach sodium behind the granulate, mix homogeneously is filled in the stomach dissolution type Capsules.Get atorvastatin calcium capsule.
Atorvastatin calcium capsule of the present invention has carried out bioavailability test in dissolution in vitro and the body, and the result is as follows:
Effect embodiment 1: the dissolution in vitro test
Get 6 of this product, 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, in contrast product solution.With octadecylsilane chemically bonded silica is 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 labelled amount, and is up to specification.
Result of the test:
| Product | Dissolution |
| Embodiment 1 | 99％ |
| Embodiment 2 | 91％ |
| Embodiment 3 | 93％ |
| Embodiment 4 | 90％ |
| Embodiment 5 | 94％ |
| Embodiment 6 | 89％ |
| Embodiment 7 | 99％ |
The atorvastatin calcium capsule that result of the test confirms to prepare in the embodiment of the invention is in 900ml water, and the stripping quantity in the time of 45 minutes all greater than 80% of labelled amount, meets national standard.
Effect embodiment 2: bioavailability test in the body
22 experimenters are intersected oral atorvastatin calcium capsule 20mg of the present invention (10mg/ grain * 2) and import reference atorvastatin calcium tablet (lipitor, Pfizer Inc. produces) 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, utilize variance analysis and two one-side t check respectively the bioequivalence of atorvastatin calcium capsule of the present invention and reference lipitor tablet to be estimated.The result: oral Atorvastatin calcium tried and reference preparation after, the C of Atorvastatin calcium
MaxBe respectively 7.98 ± 3.25 μ gL
-1With 8.47 ± 3.36 μ gL
-1T
MaxBe respectively 1.37 ± 0.64h and 1.20 ± 1.01h; T1/2 is respectively 10.64 ± 3.21h and 10.01 ± 1.81h; AUC
(0-t)Be respectively 52.70 ± 13.79 μ gL
-1H and 51.83 ± 17.52 μ gL
-1H; AUC
(0-∞)Be respectively 55.45 ± 14.66 μ gL
-1H and 54.09 ± 17.79 μ gL
-1H.Area under the drug-time curve AUC by the atorvastatin of every oral two kinds of preparations of experimenter
(0-t), calculating the relative bioavailability that is subjected to test preparation, the average relative bioavailability that must be subjected to the test preparation atorvastatin is 106.0 ± 23.8%.
Studies show that, the atorvastatin of atorvastatin calcium capsule of the present invention and the atorvastatin of reference preparation are at the intravital absorption of people, distribution, the equal basically identical of elimination process, results of statistical analysis shows that atorvastatin does not have significant difference (P＞0.05) at the intravital pharmacokinetic parameter of people behind oral two kinds of atorvastatin calcium preparation.Through two difference analysis with than the one-side t check, show that atorvastatin calcium capsule agent of the present invention and import reference atorvastatin calcium tablet (lipitor) have bioequivalence.
Effect embodiment 3:
External stripping curve relatively for atorvastatin calcium capsule of the present invention and import reference atorvastatin calcium tablet (lipitor, Pfizer Inc. produces)
The result is referring to Fig. 1, and according to this accompanying drawing as can be seen, atorvastatin calcium capsule of the present invention is faster than the medicine stripping of atorvastatin calcium tablet.
In the body in the bioavailability test, the blood drug level average of 22 experimenter's oral test preparation atorvastatin calcium capsules and reference preparation atorvastatin calcium tablet (lipitor, Pfizer Inc. produces) back atorvastatin relatively:
| Time (h) | 0.33 | 0.67 | 1.0 | 1.5 | 2.0 | 3.0 | 5.0 | 8.0 | 12.0 | 24.0 | 48.0 |
| Tablet | 2.83 | 5.00 | 4.77 | 5.26 | 3.95 | 3.22 | 2.76 | 1.99 | 1.39 | 0.57 | 0.15 |
| Capsule | 4.85 | 6.12 | 5.58 | 5.16 | 3.95 | 3.12 | 2.74 | 1.98 | 1.52 | 0.56 | 0.14 |
In external stripping curve and the body blood drug level average of atorvastatin as can be seen, atorvastatin calcium capsule of the present invention is compared with import reference atorvastatin calcium tablet, it is fast to have an external stripping, rapid-action advantage in the body.
Claims (7)
1. atorvastatin calcium capsule agent is made up of amorphous atorvastatin calcium and pharmaceutic adjuvant, wherein adjuvant: Atorvastatin calcium=8: 1～32: 1 (W/W).
2. capsule as claimed in claim 1, it is characterized in that described adjuvant is selected from one or more in lactose, sucrose, Pulvis Talci, hypromellose, polyvinylpyrrolidone, ethanol, polyoxyethylene sorbitan monoleate, silicon dioxide, magnesium stearate, starch and the pregelatinized Starch.
3. capsule as claimed in claim 1 is characterized in that, contains the atorvastatin of 10mg in each capsules.
4. the preparation method of the described capsule of claim 1 is characterized in that using adjuvant that amorphous atorvastatin calcium is made granule, or makes powder, or makes granule and powder, then it is filled in the stomach dissolution type Capsules.
5. the described preparation method of claim 4 is characterized in that, behind adjuvant and Atorvastatin calcium mix homogeneously, directly is filled in the stomach dissolution type Capsules.
6. the described preparation method of claim 4 is characterized in that, behind adjuvant and Atorvastatin calcium mix homogeneously, with the wet grain of binding agent system, be lower than under 60 ℃ the temperature then, or in being lower than 60 ℃ drying under reduced pressure case, drying, be filled in behind the granulate in the stomach dissolution type Capsules.
7. the preparation method of claim 6 is characterized in that, hypromellose or polyvinylpyrrolidone are dissolved in the ethanol of 10%～95% (V/V), makes 0.1%～15% concentration (g/ml); Or starch or dextrin is suspended in the boiling water, make 1%～10% concentration (W/W)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710194917XA CN101185641A (en) | 2007-12-06 | 2007-12-06 | Atorvastatin calcium capsule and preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710194917XA CN101185641A (en) | 2007-12-06 | 2007-12-06 | Atorvastatin calcium capsule and preparation method |
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| CN101185641A true CN101185641A (en) | 2008-05-28 |
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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 |
| CN106955355A (en) * | 2016-01-08 | 2017-07-18 | 北京百奥药业有限责任公司 | Pharmaceutical composition, preparation and its application of statins and Lumbrokinase |
| CN109044989A (en) * | 2018-10-09 | 2018-12-21 | 河南师范大学 | A kind of atorvastatin calcium capsule preparation and preparation method thereof |
-
2007
- 2007-12-06 CN CNA200710194917XA patent/CN101185641A/en active Pending
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 |
| CN106955355A (en) * | 2016-01-08 | 2017-07-18 | 北京百奥药业有限责任公司 | Pharmaceutical composition, preparation and its application of statins and Lumbrokinase |
| CN109044989A (en) * | 2018-10-09 | 2018-12-21 | 河南师范大学 | A kind of atorvastatin calcium capsule preparation and preparation method thereof |
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Open date: 20080528 |