CN1911213A - Soft capsule of atovastatine salts and prepn. method therefor - Google Patents
Soft capsule of atovastatine salts and prepn. method therefor Download PDFInfo
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- CN1911213A CN1911213A CNA2006100481897A CN200610048189A CN1911213A CN 1911213 A CN1911213 A CN 1911213A CN A2006100481897 A CNA2006100481897 A CN A2006100481897A CN 200610048189 A CN200610048189 A CN 200610048189A CN 1911213 A CN1911213 A CN 1911213A
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- soft capsule
- atorvastatin
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Abstract
A soft capsule of lipitor salt with high stability and disintegrating speed is prepared from lipitor salt, auxiliary, and soft shell prepared from gelatin, glycerin, distilled water, ethylparaben, Fe2O3, microcrystalline cellulose and antioxidant. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation and preparation method, especially atorvastatin salt soft capsule and preparation method thereof belongs to medical technical field.
Background technology
Atorvastatin (Atorvastatin Calcium) is a kind of selectivity, the competitive inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, the HMG-CoA reductase is a rate-limiting enzyme, and this enzyme is converted into mevalonic acid (comprising the precursor of cholesterol at interior sterin) with 3-hydroxy-3-methyl-glutaryl coenzyme A.Triglyceride and cholesterol are merged into C-VLDL (VLDL) and are discharged in the blood plasma with further conveying surrounding tissue in liver.Low-density lipoprotein cholesterol (LDL) is formed by C-VLDL (VLDL) and main low-density lipoprotein cholesterol (LDL) receptor catabolism by high-affinity.
Thereby HMG-CoA reductase and the synthetic of cholesterol that atorvastatin passes through to suppress in the liver reduce cholesterol and lipoprotein levels in the blood plasma, and pass through to increase liver low-density lipoprotein cholesterol (LDL) receptor of cell surface to strengthen picked-up and the metabolism of LDL.
The clinical use determined curative effect of Atorvastatin calcium, effect are remarkable, but atorvastatin and officinal salt bitter in the mouth thereof, soluble,very slightly in water, and poor stability, it is all extremely sensitive for environment and the light of heat, moist, low PH.Under acid environment, atorvastatin can be degraded into corresponding lactone especially.Therefore, when being made into dosage form such as tablet or powder, can make it become unstable or stability reduces.
Summary of the invention
Technical problem to be solved by this invention is that the defective that overcomes prior art provides a kind of principal agent bitterness of covering, and has protection against the tide, anti-oxidation, lucifuge, improves atorvastatin salt soft capsule of medicine stability and preparation method thereof.
The alleged problem of the present invention is to solve like this:
A kind of atorvastatin salt soft capsule, form by content and soft softgel shell, its special feature is: described content is principal agent atorvastatin salt and adjuvant, and described soft softgel shell unit meter proportioning by weight is as follows: gelatin 80-120, glycerol 40-50, distilled water 100-120, ethyl hydroxybenzoate 0.1-0.3, iron sesquioxide 2-4, microcrystalline Cellulose 0.1-1, antioxidant 1-5.
Above-mentioned atorvastatin salt soft capsule, described antioxidant are selected from a kind of or its combination in glycine, sodium pyrosulfite, vitamin E, the carotene.
Above-mentioned atorvastatin salt soft capsule, described content unit meter proportioning by weight is as follows: atorvastatin salt 10-80, disintegrating agent 2-10, suspending agent 2-8, emulsifying agent 2-5, disperse medium 200-400, described atorvastatin salt is selected from one or more in Atorvastatin calcium, atorvastatin magnesium, atorvastatin aluminum, atorvastatin zinc, the atorvastatin ferrum.
Above-mentioned atorvastatin salt soft capsule, described disintegrating agent is selected from one or more in carboxymethyl starch, microcrystalline cellulose, the starch; Suspending agent is selected from one or more in Cera Flava, aluminum monostearate, ethyl cellulose, the micropowder silica gel; Emulsifying agent is selected from one or more in emulsifying agent Tween, span type emulsifying agent, the poloxamer; Disperse medium is selected from Polyethylene Glycol, polyglycol ether, aliphatic alcohol, polyoxyethylene glyceride or Semen Maydis oil.
A kind of atorvastatin salt preparation of soft capsule method, it carries out as follows:
A. get soft each raw material of softgel shell softgel shell by proportioning, in changing the glue cylinder, heat, mixing, vacuum is removed bubble, crosses 60 mesh sieves, elimination impurity, sampling and measuring moisture and viscosity, insulation is standby down at 60-70 ℃ after the assay was approved;
B. after getting emulsifying agent adding disperse medium by said ratio, place Sandwich pot,, make emulsifying agent and disperse medium fusion mixing, fully mix by proportioning adding disintegrating agent, suspending agent again in 60 ℃ of heating of water-bath, standby;
C. by proportioning with principal agent atorvastatin salt and above-mentioned adjuvant mix homogeneously after, mistake colloid mill 2 times, porphyrize is standby;
D. determine the content loading amount according to drug content;
E. with compacting legal system soft capsule;
F. the soft capsule that makes is put typing drying in the tumble-dryers, with 95% ethanol flush away soft capsule surface oil, soft capsule is put the drying room inner drying again;
G. with dried soft capsule check, packing.
The present invention improves soft capsule according to the characteristic of atorvastatin and officinal salt thereof, has solved the problem that the soft capsule shell water content influences disintegration by add antioxidant in soft capsule shell; By in the capsule material, adding microcrystalline Cellulose, solved medicine in the process of circulation because of the resting period the long or too high problem that absorption takes place of temperature.The present invention has the following advantages: 1, the soft capsule dosage form content all independently is stored in the softgel shell, avoid and prevented in use bad or preserve improper decomposition, oxidation and the loss that causes effective ingredient because of air-proof condition, ensured the quality of product effectively, made the usefulness of product obtain desirable performance; 2, the soft capsule disintegration time is short, stripping is rapid, bioavailability is high, dosage is accurate, easily absorption; 3. deposit and store easy; 4. soft capsule can be covered the bitterness of principal agent, is easy to take.
The specific embodiment
The present invention is made up of content and soft softgel shell, and atorvastatin and officinal salt thereof are made soft capsule dosage form, can solve medicine use or the process of circulation in bad or preserve improper decomposition, oxidation and the losing issue that causes effective ingredient because of air-proof condition.Atorvastatin salt in the content is selected from Atorvastatin calcium, atorvastatin magnesium, atorvastatin aluminum, atorvastatin zinc, the atorvastatin ferrum one or more, preferred Atorvastatin calcium; Disintegrating agent is selected from one or more in carboxymethyl starch, microcrystalline cellulose, the starch, preferred starch; Suspending agent is selected from one or more in Cera Flava, aluminum monostearate, ethyl cellulose, the micropowder silica gel, preferred micropowder silica gel; Emulsifying agent is selected from emulsifying agent Tween such as tween 20, Tween-65, tween 80, Tween-81, tween 85 etc., span type emulsifying agent such as Arlacel-40, Arlacel-80 etc., a kind of in the poloxamer or several mixture arbitrarily, a kind of in preferred Arlacel-80, the poloxamer or both mixture; Disperse medium is selected from vegetable oil such as Semen Maydis oil, Oleum Ricini, soybean oil, olive oil.Preferably corn oil.Using Semen Maydis oil as disperse medium, is because the Semen Maydis oil stable in properties automatic oxidation reaction can not take place, thereby avoid content and gelatin to react, and generates cross-linking agent and causes dissolution rate to reduce.
Soft capsule casing material is selected from gelatin, glycerol, distilled water, ethyl hydroxybenzoate, iron sesquioxide, microcrystalline Cellulose, antioxidant.Antioxidant is selected from the one or more combination in glycine, sodium pyrosulfite, vitamin E, the carotene.Owing to contain than poly-glycerine in the soft softgel shell, adsorption phenomena can take place under resting period length or temperature condition with higher, the present invention adds microcrystalline Cellulose in the capsule material, can solve absorption problem preferably.The present invention finds that the water content of soft capsule shell can influence disintegration in research process.Its reason is that the oxygen penetration capacity of flexible glue cyst membrane is direct and the cyst membrane water content is proportional, so moisture can quicken the oxidation of gelatin, makes the aging quickening of cyst wall, causes disintegration time to prolong.Be head it off, the present invention has carried out a large amount of tests, determines to add quantitative antioxidant with the aged problem of effective solution softgel shell in softgel shell.The present invention when finding to be controlled at the consumption of microcrystalline Cellulose in softgel shell between the 0.1-1 weight portion, can be good at solving the soft capsule absorption problem by a large amount of investigative tests, makes the preservation condition of soft capsule be unlikely to harsh; When being controlled at the consumption of antioxidant in softgel shell between the 1-5 weight portion, can effectively solve the softgel shell problem of aging, the soft capsule holding time is increased.The present invention adds Celluloasun Microcrystallisatum and antioxidant and separately weight proportion has been carried out research and quantizes in softgel shell, used Semen Maydis oil as disperse medium in content.The present invention can not only control the absorption of soft capsule to moisture, reduce the increase of moisture in the soft capsule, delay the oxidation of gelatin in the soft capsule, and can also prevent that soft capsule content and gelatin from reacting, thereby make atorvastatin salt soft capsule of the present invention have the stable in properties that common soft capsule does not possess, storage time is long, and disintegration time is short, and stripping waits the significance characteristics rapidly.
The present invention is carried out comparative test disintegration, and the result is as follows:
Get the middle test agent of three batches of preferred embodiments, 60 every batch, random packet also is numbered sample sets, get 60 of the common soft capsules of atorvastatin salt, random packet also is numbered matched group, and sample sets is corresponding one by one with matched group, 30 ± 2 ℃ of temperature, place under relative humidity 65% ± 5% condition after one month, check in accordance with the law, the results are shown in following table according to inspection technique disintegration (2005 editions two appendix XA of Chinese Pharmacopoeia).
| The present invention | Matched group | |
| Disintegration time | (1)8′12″ | (1)26′54″ |
| (2)8′08″ | (2)25′58″ | |
| (3)8′21″ | (3)27′32″ | |
| (4)8′14″ | (4)26′47″ | |
| (5)7′52″ | (5)26′36″ | |
| (6)8′12″ | (6)25′32″ | |
| (7)8′43″ | (7)28′24″ | |
| (8)8′23″ | (8)27′54″ | |
| (9)7′58″ | (9)25′19″ | |
| (10)9′02″ | (10)24′56″ |
By The above results as seen, soft capsule of the present invention not only can satisfy the requirement of Chinese Pharmacopoeia, and shortens greatly than common soft capsule disintegration time.
Below provide several specific embodiments:
Embodiment one, preparation specification are the soft capsule of 10mg, in 1000 contained components of soft capsule:
1, softgel shell
Gelatin 80g
Glycerol 40g
Distilled water 100g
Ethyl hydroxybenzoate 0.10g
Iron sesquioxide 2.0g
Microcrystalline Cellulose 0.10g
Sodium pyrosulfite 1.0g
2, content
Supplementary material title consumption
Atorvastatin salt
(in atorvastatin) 10.0g
Starch 10.0g
Micropowder silica gel 8.0g
Poloxamer 3.5g
Arlacel-80 1.5g
Semen Maydis oil 400.0g
Embodiment two, preparation specification are the soft capsule of 80mg, in 1000 contained components of soft capsule:
1, softgel shell
Gelatin 120g
Glycerol 50g
Distilled water 120g
Ethyl hydroxybenzoate 0.30g
Iron sesquioxide 4.0g
Microcrystalline Cellulose 1.0g
Vitamin E 5.0g
2, content
Supplementary material title consumption
Atorvastatin salt
(in atorvastatin) 80.0g
Starch 2.0g
Ethyl cellulose 2.0g
Poloxamer 1.0g
Tween 80 1.0g
Oleum Ricini 200.0g
Embodiment three, preparation specification are the soft capsule of 20mg, in 1000 contained components of soft capsule:
1, softgel shell
Gelatin 90g
Glycerol 42g
Distilled water 105g
Ethyl hydroxybenzoate 0.15g
Iron sesquioxide 2.5g
Microcrystalline Cellulose 0.2g
Glycine 1.5g
2, content
Supplementary material title consumption
Atorvastatin salt (in atorvastatin) 20.0g
Starch 4.0g
Cera Flava 3.0g
Poloxamer 1.5g
Arlacel-80 2.5g
Soybean oil 350.0g
Embodiment four, preparation specification are the soft capsule of 40mg/ grain, in 1000 contained components of soft capsule:
1, softgel shell
Gelatin 100g
Glycerol 45g
Distilled water 110g
Ethyl hydroxybenzoate 0.20g
Iron sesquioxide 3.0g
Microcrystalline Cellulose 0.5g
Glycine 2.5g
2, content
Supplementary material title consumption
Atorvastatin salt (in atorvastatin) 40.0g
Starch 6.0g
Aluminum monostearate 6.0g
Poloxamer 2.5g
Arlacel-80 2.5g
Olive oil 300.0g
Embodiment five, preparation specification are the soft capsule of 60mg/ grain, in 1000 contained components of soft capsule:
1, softgel shell
Gelatin 110g
Glycerol 47g
Distilled water 115g
Ethyl hydroxybenzoate 0.25g
Iron sesquioxide 3.5g
Microcrystalline Cellulose 0.7g
Carotene 4.0g
2, content
Supplementary material title consumption
Atorvastatin salt (in atorvastatin) 60.0g
Starch 8.0g
Micropowder silica gel 7.0g
Poloxamer 2.5g
Arlacel-80 1.5g
Semen Maydis oil 250.0g
Preparation method:
A. get soft each raw material of softgel shell softgel shell by said ratio, in changing the glue cylinder, heat, mixing, vacuum is removed bubble, crosses 60 mesh sieves, elimination impurity.Sampling and measuring moisture and viscosity, insulation is standby down at 60-70 ℃ after the assay was approved;
B. after getting emulsifying agent adding disperse medium by said ratio, place Sandwich pot,, make emulsifying agent and disperse medium fusion mixing, fully mix by proportioning adding disintegrating agent, suspending agent again in 60 ℃ of heating of water-bath, standby;
C. by said ratio with principal agent atorvastatin salt and above-mentioned adjuvant mix homogeneously after, mistake colloid mill 2 times, porphyrize is standby;
D. determine the content loading amount according to drug content;
E. with compacting legal system soft capsule;
F. the soft capsule that makes is put typing drying in the tumble-dryers, with 95% ethanol flush away soft capsule surface oil, soft capsule is put the drying room inner drying again;
G. dried soft capsule is checked under the light platform, and underproof soft capsule is picked out the back packing.
Claims (6)
1. atorvastatin salt soft capsule, form by content and soft softgel shell, it is characterized in that: described content is principal agent atorvastatin salt and adjuvant, and described soft softgel shell composition unit is by weight counted: gelatin 80-120, glycerol 40-50, distilled water 100-120, ethyl hydroxybenzoate 0.1-0.3, iron sesquioxide 2-4, microcrystalline Cellulose 0.1-1, antioxidant 1-5.
2. atorvastatin salt soft capsule according to claim 1 is characterized in that: described antioxidant is selected from a kind of or its combination in glycine, sodium pyrosulfite, vitamin E, the carotene.
3. atorvastatin salt soft capsule according to claim 2, it is characterized in that: described content unit meter proportioning by weight is as follows: atorvastatin salt 10-80, disintegrating agent 2-10, suspending agent 2-8, emulsifying agent 2-5, disperse medium 200-400, described atorvastatin salt is selected from one or more in Atorvastatin calcium, atorvastatin magnesium, atorvastatin aluminum, atorvastatin zinc, the atorvastatin ferrum.
4. atorvastatin salt soft capsule according to claim 3, it is characterized in that: described disintegrating agent is selected from one or more in carboxymethyl starch, microcrystalline cellulose, the starch; Suspending agent is selected from one or more in Cera Flava, aluminum monostearate, ethyl cellulose, the micropowder silica gel; Emulsifying agent is selected from one or more in emulsifying agent Tween, span type emulsifying agent, the poloxamer; Disperse medium is selected from Polyethylene Glycol, polyglycol ether, aliphatic alcohol, polyoxyethylene glyceride or vegetable oil.
5. atorvastatin salt soft capsule according to claim 4 is characterized in that: described disintegrating agent is a starch; Suspending agent is micropowder silica gel; Emulsifying agent is a kind of or both mixture in Arlacel-80, the poloxamer; Disperse medium is a Semen Maydis oil.
6. according to claim 1,2,3,4 or 5 described atorvastatin salt preparation of soft capsule methods, it is characterized in that it carries out as follows:
A. get soft each raw material of softgel shell softgel shell by proportioning, in changing the glue cylinder, heat, mixing, vacuum is removed bubble, crosses 60 mesh sieves, elimination impurity, sampling and measuring moisture and viscosity, insulation is standby down at 60-70 ℃ after the assay was approved;
B. after getting emulsifying agent adding disperse medium by proportioning, place Sandwich pot,, make emulsifying agent and disperse medium fusion mixing, fully mix by proportioning adding disintegrating agent, suspending agent again in 60 ℃ of heating of water-bath, standby;
C. by proportioning with principal agent atorvastatin salt and above-mentioned adjuvant mix homogeneously after, mistake colloid mill 2 times, porphyrize is standby;
D. determine the content loading amount according to drug content;
E. prepare soft capsule with pressing;
F. the soft capsule that makes is put typing drying in the tumble-dryers, with 95% ethanol flush away soft capsule surface oil, soft capsule is put the drying room inner drying again;
G. with dried soft capsule check, packing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100481897A CN100450471C (en) | 2006-08-25 | 2006-08-25 | Soft capsule of atovastatine salts and prepn. method therefor |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100481897A CN100450471C (en) | 2006-08-25 | 2006-08-25 | Soft capsule of atovastatine salts and prepn. method therefor |
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| CN1911213A true CN1911213A (en) | 2007-02-14 |
| CN100450471C CN100450471C (en) | 2009-01-14 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102018695A (en) * | 2010-12-03 | 2011-04-20 | 中国药科大学 | Atenolol soft capsule and preparation method thereof |
| CN101444300B (en) * | 2008-12-29 | 2012-08-08 | 陈金显 | Chewable soft capsule |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2711703B2 (en) * | 1989-01-06 | 1998-02-10 | 東海カプセル株式会社 | Soft capsule |
| CN1593401A (en) * | 2004-06-24 | 2005-03-16 | 王智瑛 | Easily absorbed simvastatin soft capsule composition |
| CN1799622B (en) * | 2005-01-05 | 2010-05-26 | 张红 | Mind-tranquilizing brain-replenishing soft capsule, its preparation process and quality control method |
-
2006
- 2006-08-25 CN CNB2006100481897A patent/CN100450471C/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101444300B (en) * | 2008-12-29 | 2012-08-08 | 陈金显 | Chewable soft capsule |
| CN102018695A (en) * | 2010-12-03 | 2011-04-20 | 中国药科大学 | Atenolol soft capsule and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN100450471C (en) | 2009-01-14 |
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