CN101332191B - Stable perindopril tert-butylamine salt tablets and preparation method thereof - Google Patents
Stable perindopril tert-butylamine salt tablets and preparation method thereof Download PDFInfo
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- CN101332191B CN101332191B CN 200810012251 CN200810012251A CN101332191B CN 101332191 B CN101332191 B CN 101332191B CN 200810012251 CN200810012251 CN 200810012251 CN 200810012251 A CN200810012251 A CN 200810012251A CN 101332191 B CN101332191 B CN 101332191B
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- butylamine salt
- perindopril tert
- perindopril
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Abstract
The present invention belongs to the medical technical field and discloses a stable perindopril tert-butylamine salt troche and a preparation method thereof. The perindopril tert-butylamine salt troche mainly consists of 0.1 percent to 10 percent of perindopril tert-butylamine salt, 3 percent to 30 percent of disintegrant, 20 percent to 90 percent of filling agent, 2 percent to 70 percent of stabilizing agent and 0.5 percent to 5 percent of lubricant. The perindopril tert-butylamine salt troche is prepared by a method of adding the disintegrant internally and externally at the same time. The perindopril tert-butylamine salt troche prepared by the present invention can improve the stability of the perindopril tert-butylamine salt obviously and can be used for preparing the medicines for remedying the cardiovascular disease, the hypertension and the heart failure, etc. The preparation method does not have special requirement on equipment and is fit for mass production.
Description
Technical field:
The invention belongs to medical technical field, relate to a kind of stable perindopril tert-butylamine salt tablets and preparation method thereof.
Background technology:
Perindopril and its esters belong to angiotensin-convertion enzyme inhibitor, are widely used in the treatment of cardiovascular disease, especially have good effect in fields such as hypertension and heart failure.Perindopril is that the form with sodium salt is synthesized in US4508729, EP0049658 the earliest, but because its stability existing problems, EP-A 0308341 and WO 03/087050A2 have prepared respectively perindopril tert-butylamine salt and arginine salt, have improved the stability of medicine.What be widely used at present treating cardiovascular disease is its tert-butylamine salt form.Although tert-butylamine salt increases than the stability of sodium salt, this class medicine intrinsic weakness on its structure relatively still is easy to degrade under exacting terms at some.Medicine self deficient in stability, the diluting effect of adjuvant in the preparation, the easier degraded so that principal agent becomes, generally, commercially available tablet need to be deposited in the airtight packing of drying, this improves production cost virtually, reduced the profit margin of producer, but problem does not lie in this, even because preparation is not having oxygen, do not have under the condition of moisture, only at high temperature also can degrade, therefore we must be limited on its storage environment again, require low tempertaure storage, but in the area of some sweltering heats or national, such condition is to be difficult to reach, in transportation, preparation can be exposed under the high temperature constantly especially, and this has brought hidden danger with regard to the safety of giving medicine.
In order to improve the stability of preparation, new discovery continues to bring out.WO 03/087050A2 has synthesized perindopril arginine salt, under 40 ℃, the condition of RH75%, accelerated to test 6 months, medicament contg is 98.6%, and in the stability experiment of the perindopril tert-butylamine salt preparation that under similarity condition, carries out, the content to 67.2% of principal agent, so perindopril arginine salt significantly improves than the stability of tert-butylamine salt.WO2005/068490A1 attempts improving by the cyclodextrin clathrate of preparation perindopril and its esters the stability of preparation, but only brief introduction preparation method, whether it is had the effect that improves medicine stability is not done and illustrates, studies show that among the WO2007/025695A1, the stability of perindopril tert-butylamine salt preparation and crude drug size are closely related, for the medicine of large particle diameter, the easier degraded of the medicine of small particle diameter, therefore, in order to improve the stability of preparation, the author advises that the mean diameter of the crude drug in the preparation should be more than 7 μ m, WO20061014-62 A2 is the generation that the alkaline matter of 7-14 reduces impurity F by add some pH values in preparation, these alkaline matters comprise: sodium bicarbonate, sodium citrate, oxygen potassium oxide etc., although do not improve stability-enhanced foundation, also without any the raising of data show preparation stability, but patent GB2394660A mentions the acidic excipient with bigger serface, can accelerate the degraded of principal agent in the preparation such as silicon dioxide, therefore say that the generation of basic species mass-energy inhibition of impurities F is that certain basis is arranged.In order to solve the stability problem of perindopril in the preparation, a lot of people did research, but in these researchs, some people does not provide sufficient evidence to prove that preparation stability increases really, although another part people data show that the stability of principal agent is strengthened to some extent in the preparation, but these experiments only limit to again carry out under closed environment, and packing is still had very large dependency, and the stability when at high temperature being exposed in the air when preparation is not done discussion.
Summary of the invention:
The object of the present invention is to provide a kind of stable perindopril tert-butylamine salt tablets and preparation method thereof, compare with commercially available product, the stability of perindopril tert-butylamine salt sheet is significantly strengthened, and the foundation of invention is at repercussion study between medicine and the adjuvant.The present invention also provides the preparation method of perindopril tert-butylamine salt tablets, and the method without specific (special) requirements, is fit to the large production of scale to equipment.
The weight percentage composition of perindopril tert-butylamine salt tablets prescription of the present invention is: perindopril tert-butylamine salt 0.1%-10%, disintegrating agent 3%-30%, filler 20%-90%, stabilizing agent 2%-70%, lubricant 0.5%-5%.The adjuvant that wherein plays disintegration is a kind of, two or more compositions that forms with certain proportion of low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone.The adjuvant that wherein plays filling effect is a kind of, two or more compositions that forms with certain proportion of lactose, mannitol, xylitol, maltose alcohol, dextrin, pregelatinized Starch, microcrystalline Cellulose.The adjuvant that wherein plays Stabilization is starch, polyvidone, copolyvidone etc. or their various combinations.Wherein the adjuvant of lubricate is a kind of, two or more compositions that forms with certain proportion of magnesium stearate, zinc stearate, Polyethylene Glycol, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, Pulvis Talci, silicon dioxide.Also can select other filleies with filling effect, other disintegrating agent, other stabilizing agents with Stabilization and other lubricants with lubrication with disintegration to use in the present invention.
Preparation method of the present invention comprises the step of following order:
(1) with perindopril tert-butylamine salt and stabilizing agent mix homogeneously.
(2) with binding agent above-mentioned mixed-powder is mediated, granulated, granulate after the oven dry;
(3) with gained particle and rest materials mix homogeneously, tabletting.
Or take the step of following order to be prepared
(1) it is for subsequent use perindopril tert-butylamine salt and stabilizing agent to be dissolved in binding agent.
(2) mediate with disintegrating agent, filler in above-mentioned binding agent and the prescription, granulate, the rear granulate of oven dry;
(3) add lubricant, mix homogeneously, tabletting.
Or take the step of following order to be prepared
(1) after being prepared into solid dispersion, perindopril tert-butylamine salt and stabilizing agent pulverize.
(2) after being mixed with rest materials, solid dispersion prepares tablet with conventional wet granulation technology or direct compression technique.
The prepared perindopril tert-butylamine salt tablets of the present invention can be used for preparing Cardiovarscular, the medicine of hypertension and heart failure etc.
Advantage of the present invention is: can significantly strengthen the stability of perindopril tert-butylamine salt, its preparation method without specific (special) requirements, is fit to the large production of scale to equipment.
The specific embodiment:
Can further understand the present invention by instantiation of the present invention given below and application example, but they not limitation of the invention.
The interactional research of medicine and adjuvant
Research method:
Respectively with ratio and the magnesium stearate of perindopril crude drug with 4: 1, respectively with 1: 15 ratio and MCC, L-HPC, starch, lactose, with 1: 9 ratio and PVPK 30, behind the PVP VA64 mix homogeneously, following operation:
1. get 7 cillin bottles, respectively to the mixed-powder of wherein pack into an amount of various adjuvant and crude drug, uncovered being placed in 60 ℃ of baking ovens.
2. respectively to crude drug and MCC, L-HPC, starch adds an amount of water and mediated 5 minutes in the mixed-powder of lactose, granulate with 40 mesh sieves, and is rear with 30 mesh sieve granulate, for subsequent use 40 ℃ of lower oven dry.
3. get five cillin bottles, be respectively charged into an amount of as stated above medicine of preparation and the stuff and other stuff of various adjuvants, uncovered being placed in 60 ℃ of baking ovens.
4. with crude drug and PVP K30, the mixed-powder of PVP VA64 filters after with an amount of water dissolution, and lyophilization formed white powder after 24 hours, and is for subsequent use.
5. get two cillin bottles, be respectively charged into two kinds of powder of an amount of said method preparation, uncovered being placed in 60 ℃ of baking ovens.
4. after sample places, respectively at 0 day, with high performance liquid chromatogram each sample was carried out assay and related substance inspection in 10 days, and with material powder in similarity condition stability inferior result relatively.
Assay and related substance chromatographic condition:
Assay:
Chromatographic column: XTerra C-18 (250 * 4.6mm, 5 μ m)
Mobile phase: acetonitrile-0.05M potassium phosphate buffer (33: 67), phosphoric acid is transferred PH=2.5
Detect wavelength: 215nm
Flow velocity: 1ml/min column temperature: 40 ℃.
Related substance:
Chromatographic column: Xterra-C18 (250 * 4.6mm, 5 μ m)
Mobile phase: acetonitrile-7mmol/L heptanesulfonic acid sodium water solution (27: 73), perchloric acid is transferred pH=2
Detect wavelength: 215nm
Flow velocity: 1.0ml/min column temperature: 40 ℃.
The result:
Table 1: content and the related substance amount of zero day sample of various adjuvants and medicinal mixture
Table 2: content and the related substance amount of various adjuvants and 10 days samples of medicinal mixture powder
Medicine and adjuvant are interactional to be studies show that, perindopril tert-butylamine salt and MCC, L-HPC, lactose, starch, serious degraded all occurs in magnesium stearate mixed-powder according to a certain percentage after 60 ℃ of lower open mouths are placed 10 days, and carries out same experiment after other mixture water beyond the magnesium stearate is granulated, discovery is except lactose, compare with mixture of powders, the degraded of medicine in hybrid particles all is suppressed, and be wherein minimum with the degraded of starch hybrid particles Chinese medicine.Medicine and PVP K30, PVP VA64 mixed-powder after 10 days palliating degradation degree all less than crude drug, prove that these two kinds of adjuvants can improve its stability, particularly the sample that carries out the lyophilization gained after the mixture dissolving is further reduced in the degraded of high temperature experiment Chinese medicine, experimental result indication: if add starch at preparation, PVPK30, in three kinds of adjuvants of PVP VA64 one or more are as stabilizing agent, and adopt wet granulation technology that medicine dissolution and dispersion are fixed in these stabilizing agents, namely can improve the stability of perindopril tert-butylamine salt.
Embodiment 1:
MCC 30g
Lactose 30.5g
Starch 30g
L-HPC 7g
Perindopril tert-butylamine salt 2g
35% appropriate amount of ethanol
Magnesium stearate 0.5g
1000
With MCC, lactose, starch, perindopril tert-butylamine salt behind the L-HPC mix homogeneously, with 35% ethanol soft material processed, is granulated with 40 mesh sieves, 40 ℃ of dryings, 30 mesh sieve granulate add mix homogeneously after the magnesium stearate, tabletting and get final product.
Embodiment 2:
MCC 30g
Lactose 34.5g
Starch 20g
PVP K30 3g
L-HPC 10g
Perindopril tert-butylamine salt 2g
50% appropriate amount of ethanol
Magnesium stearate 0.5g
1000 amounts
With MCC, lactose, starch, PVP K30, L-HPC, behind the perindopril tert-butylamine salt mix homogeneously, with 50% ethanol soft material processed, 40 mesh sieves are granulated, 40 ℃ of dryings, 30 mesh sieve granulate, add the magnesium stearate mix homogeneously after, tabletting gets final product.
Embodiment 3:
MCC 30g
Lactose 34.5g
Starch 20g
L-HPC 10g
Perindopril tert-butylamine salt 2g
(50%) alcoholic solution of 5%PVP K30 is an amount of
Magnesium stearate 0.5
1000 amounts
With MCC, lactose, starch, L-HPC, behind the perindopril tert-butylamine salt mix homogeneously, with 5%PVPK30 solution soft material processed, 40 mesh sieve granulate, 40 ℃ of dryings, 30 mesh sieve granulate, behind the adding magnesium stearate mix homogeneously, tabletting and get final product.
Embodiment 4:
Powder 1:
MCC 15g
Lactose 34.5g
Starch 10g
L-HPC 5g
35% appropriate amount of ethanol
1000 amounts
Powder 2:
MCC 15g
Starch 5g
L-HPC 5g
Perindopril 2g
PVP K30 8g
Appropriate amount of ethanol
1000 amounts
With the MCC in powder 1 prescription, lactose, starch, behind the L-HPC mix homogeneously, with 35% alcoholic solution soft material processed, 40 mesh sieve granulate, 40 ℃ of dryings, 30 mesh sieve granulate, for subsequent use as particle 1.MCC, starch, L-HPC mix homogeneously with in powder 2 prescription are dissolved in perindopril and PVP K30 in an amount of ethanol, with this solution as binding agent, with the mixed-powder soft material processed in the above-mentioned powder 2,40 orders are granulated, 40 ℃ of dryings, 30 mesh sieve granulate, for subsequent use as particle 2.Particle 1 and particle 2 are mixed in proportion, add the 0.5g magnesium stearate, mixing, tabletting and get final product.
Embodiment 5:
Powder 1:
MCC 15g
Lactose 34.5g
Starch 10g
L-HPC 5g
35% appropriate amount of ethanol
1000 amounts
Powder 2:
MCC 15g
Starch 5g
L-HPC 5g
Perindopril 2
PVP VA64 8
Appropriate amount of ethanol
1000 amounts
With the MCC in powder 1 prescription, lactose, starch, behind the L-HPC mix homogeneously, with 35% alcoholic solution soft material processed, 40 mesh sieve granulate, 40 ℃ of dryings, 30 mesh sieve granulate, for subsequent use as particle 1.With the MCC in powder 2 prescriptions, starch, L-HPC, perindopril, PVP VA64 mix homogeneously, with ethanol soft material processed, 40 mesh sieves are granulated, and 40 ℃ of dryings are with 30 mesh sieve granulate, for subsequent use as particle 2.Particle 1 and particle 2 are mixed in proportion, add the 0.5g magnesium stearate, mixing, tabletting and get final product.
Embodiment 6: investigate the stability of each prescription, and compare with commercially available product.
In order to investigate tablet stability, above-mentioned tablet and the marketed tablet of respectively writing out a prescription placed 10 days at 60 ℃ of lower open mouths, respectively at the 0th, 10 day content and the related substance amount with perindopril tert-butylamine salt in the liquid chromatography for measuring tablet, the result was as follows:
60 ℃ of lower open mouths of table 3 perindopril tert-butylamine salt tablets are placed 10 days Stability Determination results
Result of the test shows, 60 ℃ of lower placements after 10 days, marketed tablet degraded 78.8%, and only degrade about 5% by the preparation that this patent provides, related substance also is starkly lower than marketed tablet, therefore prepares the tablet stability that contains perindopril tert-butylamine salt with prescription provided by the present invention and technique and is significantly strengthened than marketed tablet.
Claims (1)
1. stable perindopril tert-butylamine salt tablets, it is characterized in that: its weight percentage composition is:
Perindopril tert-butylamine salt 0.1%-10%
Disintegrating agent 3%-30%
Filler 20%-90%
Stabilizing agent 2%-70%
Lubricant 0.5%-5%
Binding agent is an amount of;
Described stabilizing agent be in starch, polyvidone or the copolyvidone a kind of, two kinds or three kinds;
And adopt the step of following order to prepare:
(1) with perindopril tert-butylamine salt and stabilizing agent mix homogeneously;
(2) with binding agent above-mentioned mixed-powder is mediated, granulated, granulate after the oven dry;
(3) with gained particle and rest materials mix homogeneously, tabletting;
Or take the step of following order to be prepared
(1) it is for subsequent use perindopril tert-butylamine salt and stabilizing agent to be dissolved in binding agent;
(2) mediate with disintegrating agent, filler in above-mentioned binding agent and the prescription, granulate, the rear granulate of oven dry;
(3) add lubricant, mix homogeneously, tabletting;
Or take the step of following order to be prepared
(1) after being prepared into solid dispersion, perindopril tert-butylamine salt and stabilizing agent pulverize;
(2) after being mixed with rest materials, solid dispersion prepares tablet with conventional wet granulation technology or direct compression technique.
2.Perindopril tert-butylamine salt tablets according to claim 1 is characterized in that: wherein disintegrating agent is a kind of, two or more the compositions of low-substituted hydroxypropyl cellulose, starch, carboxymethyl starch sodium, sodium carboxymethyl cellulose or polyvinylpolypyrrolidone.
3, perindopril tert-butylamine salt tablets according to claim 1 is characterized in that: wherein filler is a kind of, two or more compositions of lactose, mannitol, xylitol, maltose alcohol, dextrin, pregelatinized Starch or microcrystalline Cellulose.
4, perindopril tert-butylamine salt tablets according to claim 1 is characterized in that: wherein lubricant is magnesium stearate, zinc stearate, Polyethylene Glycol, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, Pulvis Talci, a kind of, two or more compositions in the silicon dioxide.
5, perindopril tert-butylamine salt tablets according to claim 1 is characterized in that: binding agent is a kind of, two or more mixture of water, ethanol, hydroxypropyl emthylcellulose, ethyl cellulose, polyvidone or starch.
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| CN 200810012251 CN101332191B (en) | 2008-07-10 | 2008-07-10 | Stable perindopril tert-butylamine salt tablets and preparation method thereof |
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| CN 200810012251 CN101332191B (en) | 2008-07-10 | 2008-07-10 | Stable perindopril tert-butylamine salt tablets and preparation method thereof |
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| CN101332191B true CN101332191B (en) | 2013-01-09 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI23149A (en) * | 2009-09-21 | 2011-03-31 | Silverstone Pharma | New benzatin salts of ace inhibitors, procedure for their preparationand their application for treatment of cardiovascular diseases |
| 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 |
| 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 |
| CN104586800B (en) * | 2015-01-27 | 2018-05-04 | 江苏嘉逸医药有限公司 | A kind of direct tablet compressing technique of perindopril tablets and its powder |
| CN106937943A (en) * | 2017-04-20 | 2017-07-11 | 上药东英（江苏）药业有限公司 | The soluplus composite solids dispersion of a kind of Perindopril and its salt and its preparation |
| CN112697935B (en) * | 2020-12-10 | 2021-09-28 | 湖南泰新医药科技有限公司 | Method for simultaneous determination of perindopril and perindopril A concentration in human plasma |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1738830A (en) * | 2002-11-18 | 2006-02-22 | 希普拉有限公司 | Perindopril |
| CN1883477A (en) * | 2006-05-30 | 2006-12-27 | 石家庄欧意药业有限公司 | Pharmaceutical composition for treating hypertension and cardiovascular disease |
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2008
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1738830A (en) * | 2002-11-18 | 2006-02-22 | 希普拉有限公司 | Perindopril |
| CN1883477A (en) * | 2006-05-30 | 2006-12-27 | 石家庄欧意药业有限公司 | Pharmaceutical composition for treating hypertension and cardiovascular disease |
Non-Patent Citations (1)
| Title |
|---|
| 崔福德.第四章 固体制剂-1（散剂、颗粒剂、片剂的包衣）.《药剂学》.人民卫生出版社,2004,(第5版),113-118. * |
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