CN101766598A - Drug combination containing perindopril - Google Patents
Drug combination containing perindopril Download PDFInfo
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- CN101766598A CN101766598A CN200810242989A CN200810242989A CN101766598A CN 101766598 A CN101766598 A CN 101766598A CN 200810242989 A CN200810242989 A CN 200810242989A CN 200810242989 A CN200810242989 A CN 200810242989A CN 101766598 A CN101766598 A CN 101766598A
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- perindopril
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Abstract
The invention discloses a drug combination containing perindopril. The drug combination comprises perindopril or salts thereof as the active components and contains one or more medicinal excipients. The drug combination of the invention can effectively improve the stability of perindopril, particularly, the content of the active components remains 98.86% after the accelerated test of capsules for 6 months.
Description
Technical field
The invention belongs to the chemicals field, be specifically related to a kind of pharmaceutical composition that contains perindopril.
Background technology
Perindopril chemically is being called (2S, 3 α S, 7 α S)-((2-(1-(carbethoxyl group)-(S)-Ding amino)-(S)-propiono)) octahydro-indole-2-carboxylic acid.Be a kind of angiotensin-convertion enzyme inhibitor, be used for the treatment of cardiovascular disease, especially treat hypertension and heart failure.Perindopril and contain its pharmaceutical composition.
Known angiotensin-convertion enzyme inhibitor is degraded in the following manner: 1 side chain ester bond hydrolysis; 2 intramolecular cyclizations; 3 chiral centre isomerization; 4 oxidations.Perindopril mainly is to degrade by hydrolysis and intramolecular cyclization.Impurity B and F in European Pharmacopoeia 5.0, degradation impurity have been called.The stable distinct methods of angiotensin-convertion enzyme inhibitor pharmaceutical composition that makes known in the state of the art has: WO01/15724, EP280999, EP408273, GB2394660, EP0049658 etc.But this stability problem does not solve as yet fully.Therefore, still exist improving the demand of perindopril pharmaceutical composition stability.
Discover,, can effectively improve the perindopril stability of drug by the special process processing.
Summary of the invention
The objective of the invention is provides a kind of pharmaceutical composition that contains perindopril in order to overcome the not good problem of perindopril medicine stability.
Purpose of the present invention can reach by following measure:
A kind of pharmaceutical composition that contains perindopril, this pharmaceutical composition is an active component with perindopril or its salt, and comprises one or more pharmaceutically useful excipient, wherein perindopril salt is the tert-butylamine salt or the arginine salt of perindopril.
Perindopril or its salt account for 1%～25% of drug regimen amount.Pharmaceutically useful excipient is selected from one or more in filler, disintegrating agent, fluidizer, lubricant or the binding agent.
Preparation method is to adopt suitable technology, and with drug powder or add proper auxiliary materials and make medicament mixed powder or granule piller, small pieces, filling requires medicine that suitable flowability properties should be arranged in Capsules.Content uniformity is met the requirements, and guarantee that dosage is accurate.For the principal agent perindopril is dispersed in the adjuvant mixture, intend it was pulverized 80～100 Mu Sieve, carry out pretreatment.Relatively poor through pulverizing thin perindopril and homemade oral solid formulation pharmaceutic adjuvant self flowability, do not meet the requirement of filled hard wafer.In order to improve flowability, intend adopting wet granulation technology, make the granule of good fluidity.Like this, can improve its flowability greatly, make content uniformity up to specification.According to the experience of research and production hard capsule, intending with the Diluted Alcohol is wetting agent, and through test, concentration of alcohol is advisable with 20%; Plan is lubricant with the magnesium stearate.Make granular size, hardness, disintegrative and the flowability of making all desirable.
80-100 mesh sieve used herein is a defined unanimity in the Chinese Pharmacopoeia.Selecting the 80-100 order to sieve, is in order to guarantee the perindopril uniform particles, to be easy to be scattered in the adjuvant mixture.Pharmaceutical composition of the present invention can contain one or more other pharmaceutical excipients, for example, and filler, disintegrating agent, fluidizer, lubricant, binding agent etc.
Filler is selected from microcrystalline Cellulose, starch, pregelatinized Starch, sucrose, glucose, mannitol, sorbitol, calcium phosphate, sodium chloride, hydrogenated vegetable oil, magnesium carbonate, magnesium oxide, Pulvis Talci, polyacrylate etc.Preferred filler is a microcrystalline Cellulose.
Disintegrating agent is selected from starch, pregelatinized Starch, Carboxymethyl cellulose sodium, crosslinked Carboxymethyl cellulose sodium, carboxymethylcellulose calcium, methylcellulose, Powderd cellulose, silicified microcrystalline cellulose, crospolyvinylpyrrolidone, alginic acid, sodium alginate, aluminium-magnesium silicate, polacrilin potassium etc.Preferred disintegrating agent is silicified microcrystalline cellulose, polacrilin potassium.
Binding agent is selected from starch, pregelatinized Starch, gelatin, Carboxymethyl cellulose sodium, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, ethyl cellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, arabic gum, carbomer, dextrin, hydrogenated vegetable oil, glucose syrup, aluminium-magnesium silicate, maltose, polyacrylate, zein.
Fluidizer is selected from magnesium stearate, calcium stearate, aluminium stearate, stearic acid, Palmic acid, Polyethylene Glycol, magnesium trisilicate, calcium phosphate, silicon dioxide, Pulvis Talci, Powderd cellulose, starch etc.Be preferably silicon dioxide.
Lubricant is selected from stearic acid, calcium stearate, aluminium stearate, aluminium stearate, Pulvis Talci, tristerin, hydrogenated vegetable oil, mineral oil, Polyethylene Glycol, sodium benzoate, Pulvis Talci etc.Be preferably magnesium stearate.
Comprise in the pharmaceutical composition of the present invention that perindopril exists with the form of salt.Its salt mainly contains tert-butylamine salt, arginine salt etc.
Per unit contains 0.1 to 20mg perindopril in the pharmaceutical composition of the present invention, the perindopril of preferred 2-8mg, more preferably 2,4, the perindopril (comprising form) of 8mg with salt.
Pharmaceutical composition of the present invention can effectively improve the perindopril stability of drug, and after 6 months capsule accelerated test finished, content of active substance still was 98.86%.
The specific embodiment
The following example is explained the present invention, but limits the present invention never in any form
Embodiment 1:
Perindopril arginine salt 2g
Microcrystalline Cellulose 50g
Lactose 25g
Starch 20g
20% ethanol is an amount of
Magnesium stearate is an amount of
??????????????????????
Make 1000
Get perindopril, pulverized 80～100 Mu Sieve, with the equivalent incremental method successively with starch, lactose and microcrystalline Cellulose mix homogeneously.It is an amount of to add 20% alcoholic solution, makes suitable soft material, and 20 Mu Sieve granulate.Wet grain is in dry below 60 ℃, and dry granular is with 20 Mu Sieve granulate.Add the magnesium stearate mix homogeneously, filling is in No. 3 Capsuleses, promptly.
Embodiment 2
Get perindopril 4g, microcrystalline Cellulose 70g, lactose 55g, polacrilin potassium 20g, magnesium stearate and silicon dioxide are an amount of, and the technology tabletting is made 1000 tablets of tablets routinely.
It is 75% that embodiment 1 gained capsule is placed relative humidity, and temperature is in 60 ℃ the calorstat 6 months, respectively at 1,2,3,6 month sample analysis, and with 0 day sample relatively.
Perindopril capsule accelerated test result
| Time (moon) | Content (%) | Isomer is checked | Related substance (%) | Dissolution (%) ± SD |
| ??0 | ??99.64 | ??0.01 | ??0.97 | ??90.30±2.9 |
| ??1 | ??99.49 | ??0.02 | ??1.10 | ??90.16±2.6 |
| ??2 | ??99.35 | ??0.01 | ??1.17 | ??89.78±3.0 |
| ??3 | ??99.18 | ??0.01 | ??1.23 | ??90.82±2.8 |
| ??6 | ??98.86 | ??0.02 | ??1.27 | ??89.57±3.0 |
Chromatographic condition and system suitability test: with the octadecylsilane chemically bonded silica is filler, methanol-phosphate buffer (is got potassium dihydrogen phosphate 2g and is added phosphoric acid 3ml, add triethylamine 3ml, be dissolved in water and be diluted to 1000ml) (55: 45) for mobile phase, flow velocity 1.0ml/min, detect wavelength 215nm, column temperature: 40 ℃, number of theoretical plate calculates with the perindopril peak should be not less than 1000.
It is an amount of to get this product, and accurate the title decides, and adds mobile phase dissolving and dilution and makes the solution that every 1ml contains this product 0.5mg approximately, shakes up, as need testing solution; Precision is measured need testing solution 1.0ml, place the 100ml measuring bottle, add mobile phase and be diluted to scale, solution in contrast, get contrast solution 20 μ l and inject chromatograph of liquid, regulate detection sensitivity, make the main constituent peak be about 10%～20% of full scale, get each 20 μ l of contrast solution and need testing solution again, inject chromatograph of liquid, the record chromatogram is to 2.0 times of main constituent peak retention time, in the need testing solution chromatogram, if any impurity peaks, single impurity and each impurity peak area summation (desolventizing outside the peak) compare to determine with contrast solution main peak area.
Claims (9)
1. a pharmaceutical composition that contains perindopril is characterized in that this pharmaceutical composition is an active component with perindopril or its salt, and comprises one or more pharmaceutically useful excipient.
2. the pharmaceutical composition that contains perindopril according to claim 1 is characterized in that tert-butylamine salt or arginine salt that described perindopril salt is perindopril.
3. the pharmaceutical composition that contains perindopril according to claim 1 is characterized in that perindopril or its salt account for 1%～25% of drug regimen amount.
4. the pharmaceutical composition that contains perindopril according to claim 1 is characterized in that described pharmaceutically useful excipient is selected from one or more in filler, disintegrating agent, fluidizer, lubricant or the binding agent.
5. the pharmaceutical composition that contains perindopril according to claim 4 is characterized in that described filler is selected from one or more in microcrystalline Cellulose, starch, pregelatinized Starch, sucrose, glucose, mannitol, sorbitol, calcium phosphate, sodium chloride, hydrogenated vegetable oil, magnesium carbonate, magnesium oxide, Pulvis Talci or the polyacrylate.
6. the pharmaceutical composition that contains perindopril according to claim 4 is characterized in that described disintegrating agent is selected from one or more in starch, pregelatinized Starch, Carboxymethyl cellulose sodium, crosslinked Carboxymethyl cellulose sodium, carboxymethylcellulose calcium, methylcellulose, Powderd cellulose, silicified microcrystalline cellulose, crospolyvinylpyrrolidone, alginic acid, sodium alginate, aluminium-magnesium silicate or the polacrilin potassium.
7. the pharmaceutical composition that contains perindopril according to claim 4 is characterized in that described fluidizer is selected from one or more in magnesium stearate, calcium stearate, aluminium stearate, stearic acid, Palmic acid, Polyethylene Glycol, magnesium trisilicate, calcium phosphate, silicon dioxide, Pulvis Talci, Powderd cellulose or the starch.
8. the pharmaceutical composition that contains perindopril according to claim 4 is characterized in that described lubricant is selected from one or more in stearic acid, calcium stearate, aluminium stearate, aluminium stearate, Pulvis Talci, tristerin, hydrogenated vegetable oil, mineral oil, Polyethylene Glycol, sodium benzoate or the Pulvis Talci.
9. the pharmaceutical composition that contains perindopril according to claim 4 is characterized in that described binding agent is selected from one or more in starch, pregelatinized Starch, gelatin, Carboxymethyl cellulose sodium, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, ethyl cellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, arabic gum, carbomer, dextrin, Hydrogenization vegetable oil, glucose syrup, aluminium-magnesium silicate, maltose, polyacrylate or the zein.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810242989A CN101766598A (en) | 2008-12-31 | 2008-12-31 | Drug combination containing perindopril |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810242989A CN101766598A (en) | 2008-12-31 | 2008-12-31 | Drug combination containing perindopril |
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| CN101766598A true CN101766598A (en) | 2010-07-07 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN200810242989A Pending CN101766598A (en) | 2008-12-31 | 2008-12-31 | Drug combination containing perindopril |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103822996A (en) * | 2014-03-20 | 2014-05-28 | 东英（江苏）药业有限公司 | Measuring method of content of perindopril tert-butylamine salt |
| CN103861080A (en) * | 2014-03-20 | 2014-06-18 | 东英（江苏）药业有限公司 | Efficient perindopril tablet and production process thereof |
| CN105395497A (en) * | 2015-12-04 | 2016-03-16 | 杭州新诺华医药有限公司 | Stable alpha-crystalline form perindopril tert-butylamine tablet and preparation method thereof |
| CN113133977A (en) * | 2020-01-20 | 2021-07-20 | 鲁南制药集团股份有限公司 | Afatinib maleate tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1451656A (en) * | 2002-04-18 | 2003-10-29 | 瑟维尔实验室 | Novel salt of perindopril and pharmaceutical composition contg. same |
| CN101252915A (en) * | 2005-08-30 | 2008-08-27 | 力奇制药公司 | Pharmaceutical composition comprising perindopril or its salts |
-
2008
- 2008-12-31 CN CN200810242989A patent/CN101766598A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1451656A (en) * | 2002-04-18 | 2003-10-29 | 瑟维尔实验室 | Novel salt of perindopril and pharmaceutical composition contg. same |
| CN101252915A (en) * | 2005-08-30 | 2008-08-27 | 力奇制药公司 | Pharmaceutical composition comprising perindopril or its salts |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103822996A (en) * | 2014-03-20 | 2014-05-28 | 东英（江苏）药业有限公司 | Measuring method of content of perindopril tert-butylamine salt |
| CN103861080A (en) * | 2014-03-20 | 2014-06-18 | 东英（江苏）药业有限公司 | Efficient perindopril tablet and production process thereof |
| CN103861080B (en) * | 2014-03-20 | 2016-03-30 | 上药东英（江苏）药业有限公司 | A kind of perindopril tablet and production technology thereof efficiently |
| CN105395497A (en) * | 2015-12-04 | 2016-03-16 | 杭州新诺华医药有限公司 | Stable alpha-crystalline form perindopril tert-butylamine tablet and preparation method thereof |
| CN105395497B (en) * | 2015-12-04 | 2019-06-18 | 杭州新诺华医药有限公司 | A kind of stable alpha-crystal form perindopril tert-butylamine piece and preparation method |
| CN113133977A (en) * | 2020-01-20 | 2021-07-20 | 鲁南制药集团股份有限公司 | Afatinib maleate tablet and preparation method thereof |
| CN113133977B (en) * | 2020-01-20 | 2024-03-15 | 鲁南制药集团股份有限公司 | Afatinib maleate tablet and preparation method thereof |
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Application publication date: 20100707 |