CN103006650B - Compound hypotensive tablet containing sodium chloride medicine carrier - Google Patents
Compound hypotensive tablet containing sodium chloride medicine carrier Download PDFInfo
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- CN103006650B CN103006650B CN201210587763.1A CN201210587763A CN103006650B CN 103006650 B CN103006650 B CN 103006650B CN 201210587763 A CN201210587763 A CN 201210587763A CN 103006650 B CN103006650 B CN 103006650B
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- amlodipine
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- candesartan cilexetil
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Abstract
The invention relates to a compound hypotensive tablet containing a sodium chloride medicine carrier, which meets the requirement of a pharmaceutical enterprise in improving medicine quality. The disclosed tablet comprises sodium chloride, candesartan cilexetil, amlodipine salt, and pharmaceutically acceptable adjuvants. The sodium chloride is stable in property and good in water solubility and compressibility, and is well compatible with the candesartan cilexetil and the amlodipine salt. The sodium chloride is taken as the carrier for the candesartan cilexetil and the amlodipine salt; by injecting polyethylene glycol 6000 solution or polyethylene glycol 8000 solution, a medicine is loaded on sodium chloride and a mixed carrier containing other pharmaceutically acceptable adjuvants of the medicine; the adjuvants, such as a lubricant, are added to mix uniformly, and the mixture is subjected to tabletting and can be molded by compression under a pretty low pressure; and in addition, the use of the adjuvants, such as lactose and mannitol, aldose of which can react with primary amine of the amlodipine salt to produce impurity, can be prevented. The tablet disclosed by the invention has good stability and is released quickly.
Description
Technical field
The present invention relates to medical solid tablet, be specifically related to a kind of antihypertensive compound medicine tablet, belong to medical technical field.
Background technology
The < < Chinese residents nutrition of Ministry of Public Health announcement in 2004 and Health Situation > > show that China 18 years old and above prevalence of hypertension rate are 18.8%, estimate national number of patients more than 1.6 hundred million.The National archives > > of the < < Environmental Health of World Health Organization's announcement in 2005 shows, hypertension has become one of China's ten large chronic diseases, is also one of high disease of ten large fatality rate.
For many hyperpietics, use a kind of antihypertensive drugs to be often difficult to the antihypertensive effect that reaches satisfied, so antihypertensive drug is combined to use and is become the most frequently used treatment means.The < < Treatment Guidelines for Hypertension > > of European hypertension association issue in 2007～2009 years explicitly points out, in order to reach target blood pressure, most of patient has adopted combination medicine treatment.
Candesartan Cilexetil is angiotensin
-
receptor antagonist, is hydrolyzed to active metabolite Candesartan in vivo, by with vascular smooth muscle AT
1receptors bind and antagonizing vessel Angiotensin Converting Enzyme
vasoconstrictor effects, thereby reduce peripheral vascular resistance.Amlodipine is third generation calcium ion antagonist, can block calcium ion cross-film and enter cardiac muscle and vascular smooth muscle cell, by expansion periphery small artery and coronary artery, reduces total peripheral vascular resistance.The mechanism of action of these two kinds of medicines is different with action site, and use in conjunction can produce good synergy, is not improving under the prerequisite of drug dose, reaches the object of controlling patient's blood pressure.Meanwhile, drug combination not only can more effectively be controlled blood pressure, because the dosage using is only the lowest dose level of two kinds of medicines, can also more fully protect blood vessel and target organ, reduces side effect, thereby improves patient's compliance.
On pharmaceutical chemistry, often active component is modified, to improve stability, the dissolubility of medicine, thus the optimum medicine efficacy of performance active component.Amlodipine is water-soluble hardly, and its dissolubility is about 75mg/L, when therefore medicinal, is made into salt to improve its dissolubility, and for example the dissolubility of Amlodipine Besylate Tablet in water reaches 3.5mg/mL.Its pharmaceutically acceptable salt of amlodipine has hydrochlorate, hydrobromate, sulfate, phosphate, acetate, maleate, rich maleate, lactate, citrate, tartrate, gluconate, mesylate, toluene fulfonate, Salicylate, aspartate, benzene sulfonate and succinate.
In prior art, mostly candesartan Cilexetil amlodipine is to using that lactose, mannitol or starch are as major auxiliary burden (Chinese patent CN102670604, CN102688236, CN102743381A, CN102342837A, CN 102481248A).In fact, because lactose contains aldehyde radical, in mannitol and starch, all contain aldehyde radical reducing sugar impurity, and aldehyde radical can with amlodipine structure in primary amino radical there is Maillard condensation reaction, generate brown compound, so lactose, mannitol, starch and the amlodipine compatibility are bad, if this product is usingd lactose, mannitol, starch as major auxiliary burden, can produce new impurity, product colour can slowly deepen, and impurity level increases very fast.
The moisture that WO 2004075825 A2 disclose in preparation can cause amlodipine degraded, the moisture that EP0546 358B1 discloses in preparation can cause candesartan Cilexetil degraded, and when tabletting pressure is high, can affect the stability of candesartan Cilexetil, above documents and materials have disclosed the cellulose family that water content is high and water absorption is stronger, polyvinylpyrrolidone class adjuvant also should not be as the major auxiliary burden of this product, and when moisture is lower, needs the adjuvant that elevated pressures could molding also should not be as the major auxiliary burden of this product.At present, candesartan Cilexetil amlodipine besylate tablets only has the preparation of military field pharmaceutical manufacturing in Japan's listing (trade name: Unisia).Product description demonstration, pharmaceutical adjunct forms mannitol, microcrystalline Cellulose, hyprolose, cross-linked carboxymethyl cellulose sodium, magnesium stearate, from above analysis, can learn that these adjuvants are not the optimum formula of candesartan Cilexetil amlodipine besylate tablets.
Summary of the invention
The compound recipe blood pressure lowering tablet that the object of this invention is to provide sodium chloride-containing pharmaceutical carrier, this compound tablet good stability, and there is quick release.
In order to address the above problem, technical solution of the present invention is to have invented to comprise sodium chloride, candesartan Cilexetil, Amlodipine, and the tablet made of pharmaceutically acceptable adjuvant, and its stability is very good, and discharges very fast.
The compound tablet of sodium chloride-containing pharmaceutical carrier of the present invention, its every weight that contains candesartan Cilexetil is 4mg～32mg, the weight of Amlodipine is that 1.25mg～10mg(is in amlodipine), the weight ratio of sodium chloride is 40%～85%.
Its every weight ratio that contains sodium chloride of the present invention is 50%～85% above.
Amlodipine pharmaceutically acceptable salt of the present invention is Amlodipine Besylate Tablet, amlodipine maleate, Amlodipine mesylate, L-ASPARTIC ACID amlodipine, Levamlodipine besylate, maleic acid levo amido chloro diping; Can comprise polyethylene glycol 6000, PEG 8000, cross-linked carboxymethyl cellulose sodium, carboxymethyl starch sodium, magnesium stearate etc. by the upper acceptable adjuvant of drug of choice.
The present invention uses sodium chloride as major auxiliary burden and the pharmaceutical carrier of this product, because sodium chloride is the highly stable neutral compound of physicochemical property, all can there is not chemical reaction with candesartan Cilexetil and Amlodipine, the compatibility is very good, and sodium chloride is soluble in water, be conducive to stripping and the release of insoluble drug; Sodium chloride water content very low (pharmacopeia regulation loss on drying is no more than 0.5%) in addition, and under the production environment below 70%, it draws moist very low, and sodium chloride is cubic crystal at relative humidity, have very good can molded property, can compression molding under lower pressure.The compound tablet stability that adopts sodium chloride to make as candesartan Cilexetil and Amlodipine pharmaceutical carrier is very good, and discharges very fast.The sodium chloride of not usining is at present prepared the report of its sheet as candesartan Cilexetil and Amlodipine pharmaceutical carrier.
Tablet prepared by the present invention accelerated test under 40 ℃ of RH75% conditions is investigated 6 months, and tablet related substance prepared by result demonstration the present invention is few, and stripping is rapid.
Advantage of the present invention is the characteristic that the tablet of preparation has good stability and discharges fast.
The specific embodiment
Be below specific embodiments of the invention, but do not represent that the present invention only limits to following examples.
embodiment 1
Formula (1000 meters):
Note: * Amlodipine Besylate Tablet 3.48g, 6.96g are equivalent to amlodipine 2.5g, 5g;
* amlodipine maleate 1.6g, 12.8g are equivalent to amlodipine 1.25g, 10g.
1. preparation method:
(1) by formula ratio, take polyethylene glycol 6000, be heated to 70 ~ 75 ℃, be melted into liquid (I).
(2) by formula, take sodium chloride; after pulverizing, mix homogeneously with candesartan Cilexetil, Amlodipine, cross-linked carboxymethyl cellulose sodium; add in turbine granulator; open turbine granulator; control inlet temperature and make temperature of charge remain on 25 ℃ ~ 40 ℃, (I) is slowly sprayed onto on material by aerodynamic atomization, sprayed rear discharging; granulate, obtains candesartan Cilexetil amlodipine salt particle (II).
(3) by formula ratio, take magnesium stearate and mix homogeneously with (II), tabletting.
embodiment 2
1. fill a prescription by (1000 meters):
Note:
*amlodipine mesylate 6.18g is equivalent to amlodipine 5g;
*l-ASPARTIC ACID amlodipine 6.62g is equivalent to amlodipine 5g.
2. preparation method:
(1) by formula ratio, take polyethylene glycol 6000, be heated to 70 ~ 75 ℃, be melted into liquid (I).
(2) by formula, take sodium chloride; after pulverizing, mix homogeneously with candesartan Cilexetil, Amlodipine, carboxymethylstach sodium; add in turbine granulator; open turbine granulator; control inlet temperature and make temperature of charge remain on 25 ℃ ~ 40 ℃, (I) is slowly sprayed onto on material by aerodynamic atomization, sprayed rear discharging; granulate, obtains candesartan Cilexetil amlodipine salt particle (II).
(3) by formula ratio, take magnesium stearate and mix homogeneously with (II), tabletting.
embodiment 3
1. fill a prescription by (1000 meters)
Note:
*levamlodipine besylate 3.47g, 13.9g are equivalent to amlodipine 2.5g, 10g;
*maleic acid levo amido chloro diping 6.4g, 12.8g are equivalent to amlodipine 5g, 10g.
2. preparation method:
(1) by formula ratio, take PEG 8000, be heated to 70 ~ 80 ℃, be melted into liquid (I).
(2) by formula, take sodium chloride; after pulverizing, mix homogeneously with candesartan Cilexetil, Amlodipine, cross-linked carboxymethyl cellulose sodium; add in turbine granulator; open turbine granulator; control inlet temperature and make temperature of charge remain on 25 ℃ ~ 40 ℃, (I) is slowly sprayed onto on material by aerodynamic atomization, sprayed rear discharging; granulate, obtains candesartan Cilexetil amlodipine salt particle (II).
(3) by formula ratio, take magnesium stearate and mix homogeneously with (II), tabletting.
embodiment 4the study on the stability of candesartan Cilexetil Amlodipine sheet
The product Unisia of the tablet Yu Wu Tanabe Selyaku Co., Ltd listing of 1～10 preparation of filling a prescription in the embodiment of the present invention under being 40 ℃, the condition of RH75%, temperature is placed 6 months, carry out study on the stability contrast, measure the related substance separately by candesartan Cilexetil and Amlodipine.Adopt the impurity degradation amount of high effective liquid chromatography for measuring formula tablet, take octadecyl silane as filler, the methanol-acetonitrile-water (2.3g/L ammonium acetate) of take is (55:10:35) mobile phase, and wavelength is 237nm, the results are shown in Table 1.
The related substance of table 1 candesartan Cilexetil Amlodipine sheet under 40 ℃, RH75% condition changes
Note:
★the candesartan Cilexetil amlodipine besylate tablets of military Tanabe Selyaku Co., Ltd listing
At 40 ℃, the study on the stability result of placing under the condition of RH75% 6 months shows, 1～10 the tablet candesartan Cilexetil related substance of filling a prescription in the embodiment of the present invention becomes 0.6 left and right from 0.28 left and right, in the product Unisia of Er Wu Tanabe Selyaku Co., Ltd listing, candesartan Cilexetil related substance becomes 1.36 from 0.48, the Amlodipine in 1～10 of filling a prescription in embodiment becomes 0.2 left and right from 0.06 left and right, in Unisia, amlodipine becomes 0.42 left and right from 0. 12 left and right, show that its stability of tablet prepared by the present invention is significantly better than the candesartan Cilexetil amlodipine besylate tablets (Unisia) that military Tanabe Selyaku Co., Ltd goes on the market.
embodiment 5candesartan Cilexetil amlodipine
saltthe dissolution test of sheet
The tablet Yu Wu Tanabe Selyaku Co., Ltd listing product Unisia of 1～10 preparation of filling a prescription in the embodiment of the present invention is placed 6 months under 40 ℃, the condition of RH75%, carry out dissolution and investigate contrast, according to dissolution method (2010 editions two appendix XC of Chinese Pharmacopoeia), the 1% polysorbate 20 solution 900ml of take is dissolution medium, 37 ℃, slurry method, rotating speed is 50rpm, evaluates the dissolving out capability of active component.The results are shown in Table 2.
The dissolution of candesartan Cilexetil in table 2 candesartan Cilexetil Amlodipine sheet
Note:
★the candesartan Cilexetil Amlodipine Besylate Tablet salt sheet of military Tanabe Selyaku Co., Ltd listing
Dissolution determination result shows tablet candesartan Cilexetil and all strippings rapidly of Amlodipine that embodiment of the present invention formula 1～10 makes.Before keeping sample, the dissolution candesartan Cilexetil of 15min is all more than 80%, and Amlodipine is all more than 85%, and stripping is rapid, and the condition of 40 ℃ of RH75% keep sample 6 months after dissolution do not change; The candesartan Cilexetil amlodipine besylate tablets (Unisia) of Er Wu Tanabe Selyaku Co., Ltd listing is candesartan Cilexetil dissolution only 68% when 15min, amlodipine 15min only 72%, condition through 40 ℃ of RH75% kept sample after 6 months, during 15min, the dissolution of candesartan Cilexetil and amlodipine all presents decline, approximately declines 5%.Above result shows that tablet prepared by the present invention can discharge fast, and dissolution rate do not decline, and is significantly better than the candesartan Cilexetil amlodipine besylate tablets (Unisia) of military Tanabe Selyaku Co., Ltd listing.
Claims (3)
1. the compound recipe blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier, is characterized in that, contains sodium chloride, and its weight ratio in sheet is 40% ~ 85%; Candesartan Cilexetil, its weight in sheet is 4mg ~ 32mg; Amlodipine, its weight in sheet of amlodipine of take is 1.25mg ~ 10mg; And pharmaceutically acceptable adjuvant.
2. the compound recipe blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier according to claim 1, is characterized in that every weight ratio that contains sodium chloride is 50%～85%.
3. the compound recipe blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier according to claim 1, is characterized in that Amlodipine is Amlodipine Besylate Tablet, amlodipine maleate, Amlodipine mesylate, L-ASPARTIC ACID amlodipine, Levamlodipine besylate, maleic acid levo amido chloro diping.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210587763.1A CN103006650B (en) | 2012-12-31 | 2012-12-31 | Compound hypotensive tablet containing sodium chloride medicine carrier |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210587763.1A CN103006650B (en) | 2012-12-31 | 2012-12-31 | Compound hypotensive tablet containing sodium chloride medicine carrier |
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| Publication Number | Publication Date |
|---|---|
| CN103006650A CN103006650A (en) | 2013-04-03 |
| CN103006650B true CN103006650B (en) | 2014-07-23 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101433536A (en) * | 2007-11-12 | 2009-05-20 | 北京瑞康医药技术有限公司 | Therapeutic compositions containing amlodipine niacin and losartan medicament |
| CN102670603A (en) * | 2012-04-29 | 2012-09-19 | 浙江华海药业股份有限公司 | Oral tablet containing candesartan cilexetil and benzene sulfonate amlodipine and preparation method for oral tablet |
| CN102743381A (en) * | 2011-04-22 | 2012-10-24 | 重庆市力扬医药开发有限公司 | Stable candesartan cilexetil amlodipine pharmaceutical composition and its preparation method |
-
2012
- 2012-12-31 CN CN201210587763.1A patent/CN103006650B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101433536A (en) * | 2007-11-12 | 2009-05-20 | 北京瑞康医药技术有限公司 | Therapeutic compositions containing amlodipine niacin and losartan medicament |
| CN102743381A (en) * | 2011-04-22 | 2012-10-24 | 重庆市力扬医药开发有限公司 | Stable candesartan cilexetil amlodipine pharmaceutical composition and its preparation method |
| CN102670603A (en) * | 2012-04-29 | 2012-09-19 | 浙江华海药业股份有限公司 | Oral tablet containing candesartan cilexetil and benzene sulfonate amlodipine and preparation method for oral tablet |
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| CN103006650A (en) | 2013-04-03 |
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