CN101849942B - Medicinal composition for treating hypertension - Google Patents
Medicinal composition for treating hypertension Download PDFInfo
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- CN101849942B CN101849942B CN2009101342081A CN200910134208A CN101849942B CN 101849942 B CN101849942 B CN 101849942B CN 2009101342081 A CN2009101342081 A CN 2009101342081A CN 200910134208 A CN200910134208 A CN 200910134208A CN 101849942 B CN101849942 B CN 101849942B
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Abstract
The invention discloses a medicinal composition for treating hypertension, and belongs to the field of medicaments. The antihypertensive medicinal composition comprises a pharmaceutically effective dose of levoamlodipine or a pharmaceutically acceptable salt thereof and losartanpotassium, wherein the levoamlodipine is weighed in free alkali; the losartan is weighed in free acid; and the weight ratio of the levoamlodipine to the losartan is 1 to 11-19. The medicinal composition does not damage the target organ while reducing the blood pressure so as to enhance the therapeutic effect and reduce the risk for therapy of a patient.
Description
Technical field
The invention belongs to field of medicaments, relate to the hypertensive pharmaceutical composition of a kind of treatment.
Background technology
Hypertension is modal cardiovascular disease, has become the great public health problem in the global range.Show that according to national hygiene department statistics to the end of the year 2006, China patients with hypertension crowd has reached 1.6 hundred million people, and annual newly-increased patient is more than 3,000,000.
Hypertension is a cause of disease and the very complicated syndrome of pathogenesis, once making a definite diagnosis, promptly needs lifelong medication.At present, medical circle is generally tended to the antihypertensive Combined application with two kinds of different effects mechanism both at home and abroad.According to U.S.'s prevention, the 6th report of the detection assessment and the treatment hypertension National Committee; The fixed compound preparation of these antihypertensive low doses not only can be used as the two wires medicine; Also can be used as a line medicine and be used for hypertensive treatment, more should be like this when especially the patient has other complication or complication to exist simultaneously." the Chinese hypertension prevention and control guide in 2004 " of China's revision in 2004 (originally practical) thought, adopts the fixed mixing ratio compound recipe, and its advantage is convenient, helps improving patient's compliance.
More about the clinical Combined application report of amlodipine and losartan at present; The weight ratio that following document discloses the amlodipine losartan is 1: 10 a clinical Combined application report: " practical medical journal " 2004 the 20th the 9th phases of volume, inscribeing one's name is " losartan, amlodipine and the two coupling treatment senile hypertension 232 routine efficacy analysis "; Roll up o. 11th " modern practical medical science " November the 18th in 2006, inscribes one's name to be " losartan and amlodipine therapeutic alliance are to the influence of hyperpietic's blood pressure left ventricle thickness and cardiac function "; Rolled up for the 1st phase " Fujian medical magazine " February the 30th in 2008, inscribes one's name to be " losartan and amlodipine therapeutic alliance senile hypertension complication with diabetes ".In addition; Following bibliographical information the weight ratio of amlodipine or Levamlodipine losartan be 1: 20 clinical Combined application report: " modern practical medical science " November the 18th in 2006 the volume o. 11th, inscribe one's name and be " losartan and amlodipine therapeutic alliance are to the influence of hyperpietic's blood pressure-left ventricle thickness and cardiac function "; " practical medical magazine " 2006 03 month the 23rd the 03rd phase of volume " Levamlodipine associating losartan treatment diabetic nephropathy complicated hypertension ".
PCT patent application WO2005070463 discloses a kind of pharmaceutical composition that contains Levamlodipine and angiotensin ii receptor antagonist; Wherein angiotensin ii receptor antagonist comprises irbesartan (Irbesartan), Olmesartan (Olmesartan), telmisartan (Telmisartan), Eprosartan (Eprosartan), Losartan Potassium (LosartanPotassium), and this patent application also discloses the tablet embodiment of Levamlodipine Losartan Potassium (weight ratio is 1: 20) in embodiment.
PCT patent application WO2006034631 discloses a kind of pharmaceutical composition; It contains the amlodipine or the pharmaceutically acceptable acid addition salts of medicine effective quantity; The angiotensin-ii receptor inhibitor of medicine effective quantity or its officinal salt; Wherein said angiotensin-ii receptor inhibitor is selected from irbesartan, telmisartan, valsartan, losartan, Candesartan, yet embodiment only discloses the specific embodiment of amlodipine irbesartan.
Chinese patent CN1883478 discloses a kind of pharmaceutical composition of treating hypertension and cardiovascular disease; Comprise a kind of in Levamlodipine and losartan, irbesartan, valsartan, Eprosartan, Candesartan or the Tasosartan; And disclose this pharmaceutical composition and can process tablet, granule, capsule, injection, slow releasing agent; Yet its FORMULATION EXAMPLE only discloses irbesartan, valsartan and Levamlodipine proportioning, and pharmacodynamics embodiment only discloses the pharmacodynamics effect of irbesartan and Levamlodipine.
Though had the Combined application of a lot of bibliographical information amlodipines and losartan to have synergy at present; Yet pertinent literature is the weight ratio of amlodipine losartan basically is the clinical Combined application report of 1: 10 or 1: 20; And the weight ratio of amlodipine losartan is 1: 10 or 1: 20 to be that (the common oral initial dose of amlodipine is 5mg for the proportioning of two medicines clinical consumption commonly used; Once a day, maximum is no more than 10mg, once a day; The common initial sum maintenance dose of Losartan Potassium is 50mg once a day, and in the part patient, dosage is increased to 100mg once a day).
Summary of the invention
The present invention is through a large amount of zooperies, to the further investigation of Levamlodipine losartan, filtered out a kind of not only can blood pressure lowering but also can protect the resisting hypertension compound medicament composition of target organ.
Combination antihypertensive of the present invention contains Levamlodipine or its officinal salt and the losartan of medicine effective quantity; Wherein, Levamlodipine is in free alkali, and losartan is in free acid; The weight ratio of Levamlodipine and losartan is 1: 11～19, be preferably 1: 13～and 17.Levamlodipine can be the benzene sulfonate or the maleate of amlodipine.
The active component preferred content is in the aforementioned pharmaceutical compositions per unit preparation: Levamlodipine is in free alkali, and losartan is in free acid, and the content of Levamlodipine is 4mg, and the content of losartan is 44～76mg; Preferably, Levamlodipine is in free alkali, and losartan is in free acid, and the content of Levamlodipine is 4mg, and the content of losartan is 52～68mg.
Aforementioned pharmaceutical compositions can be prepared into tablet, capsule, granule.
The advantage of combination antihypertensive of the present invention is embodied in following several aspect:
At first; In therapeutic process; Merge using the different depressor of mechanism of action often can enhancing treatment effect, looks after the different links in the hypertension incidence mechanism simultaneously, make multiple risk factor or and deposit disease and obtain Optimal Control; More help the protection of hypertension target organ 26S Proteasome Structure and Function, further reduce the incidence rate of cardiovascular event;
Secondly, because when forming immobilised compound, the dosage of each single medicine all has minimizing, especially the dosage of losartan reduces significantly, thereby the incidence rate of drug side effect reduces; About medical expense, reduce when using separately owing to used drug dose ratio, and production and packing cost reduction, therefore, medical expense not only can not increase, and has decline on the contrary, and the benefit/expense ratio of feasible treatment is significantly improved.Therefore patient's treatment compliance increases greatly, and quality of life also just obviously improves.
The 3rd, compound medicine of the present invention can also prevent the SHR rat that left ventricular hypertrophy takes place in the hypertensive while of treatment, in the prevention SHR rat chest aorta film thicken and thoracic aorta around fibrosis, thereby the target organ that watches for animals (seeing embodiment 5).
The specific embodiment
Further specify content of the present invention through following embodiment, wherein embodiment 1～4 is the preparation embodiment, and embodiment 5 is the pharmacodynamics embodiment, but range of application of the present invention is not limited only to the following example at present.The weight of Losartan Potassium all is in free acid in following examples, and the weight of Levamlodipine besylate and maleic acid levo amido chloro diping all is in free alkali.
The preparation of embodiment 1 compound tablet
Levamlodipine besylate 4g
Losartan 44g
Lactose 18g
Microcrystalline Cellulose 150g
Crospolyvinylpyrrolidone 10g
10% starch slurry is an amount of
Magnesium stearate 2.5g
Preparation technology: the Levamlodipine besylate in will writing out a prescription, losartan, lactose, microcrystalline Cellulose and crospolyvinylpyrrolidone are crossed 100 mesh sieves respectively; Mixing, add 10% starch slurry and granulate in right amount; Oven dry below 60 ℃; 18 mesh sieve granulate, the magnesium stearate mixing of adding recipe quantity, tabletting promptly gets.
The preparation of embodiment 2 compound tablet
Levamlodipine besylate 4g
Losartan Potassium 76g
Microcrystalline Cellulose 195g
Starch 25g
Carboxymethyl starch sodium 30g
Magnesium stearate 3g
The ethanol solution of 5%PVP is an amount of
Preparation technology: it is even earlier Levamlodipine besylate and starch to be put into the mortar ground and mixed, adds carboxymethyl starch sodium, microcrystalline Cellulose mix homogeneously successively, adds the Losartan Potassium mixing at last; Making binding agent with the ethanol solution of 5%PVP granulates; 40 ℃ of dryings, granulate adds the magnesium stearate mixing; Tabletting promptly gets.
The preparation of embodiment 3 compound capsules
Maleic acid levo amido chloro diping 4g
Losartan Potassium 60g
Microcrystalline Cellulose 190g
Beta-schardinger dextrin-20g
Micropowder silica gel 2g
Preparation technology: it is even earlier maleic acid levo amido chloro diping and beta-schardinger dextrin-to be put into the mortar ground and mixed, adds microcrystalline Cellulose, micropowder silica gel mix homogeneously successively, adds the Losartan Potassium mixing at last, and the filling capsule shell promptly gets.
Embodiment 4 compound granular agent preparation
Levamlodipine besylate 8g
Losartan Potassium 88g
Cross-linking sodium carboxymethyl cellulose 20g
Beta-schardinger dextrin-20g
Microcrystalline Cellulose 180g
Aspartame 2g
Sodium lauryl sulphate 45g
5% polyvidone ethanol liquid is an amount of
Orange flavor 6g
Preparation technology: earlier with Levamlodipine besylate and beta-schardinger dextrin-mix homogeneously; Add Losartan Potassium, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, sodium lauryl sulphate then and mix after crossing 16 mesh sieves, after again with orange flavor, aspartame mix homogeneously.Mixture is granulated with 5% polyvidone ethanol liquid, drying, and granulate, packing promptly gets.
Embodiment 5 Levamlodipine losartan compound recipes are to the influence of hypertension model rat
1. divide into groups
8 week spontaneous hypertensive rat in age (SHR) totally 60 are divided into model group, 1 group of compound recipe, 2 groups of compound recipes, 3 groups of compound recipes, 4 groups of compound recipes at random, amount to 5 groups, 12 every group.
2 medications
With an amount of purified water and swollen sodium carboxymethyl cellulose wiring solution-forming or suspension, each organizes the equal gastric infusion of rat with Levamlodipine, losartan, continues for 6 weeks, and dosage is distinguished as follows:
Model group: with the volume carboxymethylcellulose sodium solution;
1 group of compound recipe: 0.4mg/ (kg.d) Levamlodipine+4mg/ (kg.d) losartan
2 groups of compound recipes: 0.4mg/ (kg.d) Levamlodipine+8mg/ (kg.d) losartan
3 groups of compound recipes: 0.4mg/ (kg.d) Levamlodipine+5.2mg/ (kg.d) losartan
4 groups of compound recipes: 0.4mg/ (kg.d) Levamlodipine+6.8mg/ (kg.d) losartan
3 detect index
3.1 compound recipe is to the influence of SHR rat blood pressure
After administration finished, the arteria caudalis systolic pressure was measured and is averaged for 3 times when regaining consciousness with toy non-invasive blood pressure appearance measurement rat.Experimental data is carried out statistical analysis with the Excel system, and the result shows that each group of compound recipe relatively has utmost point significant difference with model group; In addition, 3 groups of compound recipes, 4 groups of compound recipes and 1 group of compound recipe, compound recipe compare there was no significant difference for 2 groups, and 3 groups of compound recipes of the present invention, 4 groups of antihypertensive effects that can reach prior art (1 group of compound recipe, 2 groups of compound recipes) of compound recipe are described.
Table 1 compound recipe is to the influence of SHR rat blood pressure
Compare with model group,
##P＜0.01
3.2 compound recipe is to the exponential influence of SHR rat left chamber
Administration with 1% pentobarbital sodium 3mL/kg intraperitoneal injection of anesthesia, is weighed after finishing, and opens the thoracic cavity, takes off heart, cuts off atrium and right ventricle tissue on ice, weighs in left chamber.Calculate left room index (left room index=left ventricular mass/body weight).Experimental data is carried out statistical analysis with the Excel system, and the result shows that each group of compound recipe relatively has utmost point significant difference with model group; In addition, 4 groups of 3 groups of compound recipes, compound recipe relatively have significant difference for 2 groups with 1 group of compound recipe, compound recipe, explain that 4 groups of 3 groups of compound recipes of the present invention, compound recipe can prevent the SHR rat that left ventricular hypertrophy takes place with respect to prior art better.
Table 2 compound recipe is to the exponential influence of SHR rat left chamber
Compare with model group,
##P＜0.01
Compare for 1 group with compound recipe,
*P＜0.05;
Compare for 2 groups with compound recipe,
$P＜0.05;
3.2 the influence that compound recipe is learned vascular morphology
Last 1/3,10% neutral formalin of getting the thoracic aorta section of falling is FFPE fixedly, and 5 μ m thickness serial section are carried out HE dyeing and the dyeing of Masson three-color process.Adopt film and internal diameter in the Axiovision software measurement, calculate both ratio; Measure perivascular fibrosis area and blood vessel area, calculate both ratio.Experimental data is carried out statistical analysis with the Excel system, and the result shows that 3 groups of compound recipes, 4 groups of compound recipes and model group relatively have utmost point significant difference; In addition; 3 groups of compound recipes, 4 groups of compound recipes and 1 group of compound recipe, compound recipe relatively have significant difference or utmost point significant difference for 2 groups; Explain that 4 groups of 3 groups of compound recipes of the present invention, compound recipe are with respect to prior art; Can prevent in the SHR rat chest aorta film to thicken better and thoracic aorta around fibrosis, thereby the target organ that watches for animals.
Table 3 compound recipe is to the influence of SHR rat chest aorta media thickness/internal diameter
Compare with model group,
##P＜0.01
Compare for 1 group with compound recipe,
*P＜0.05; Compare for 1 group with compound recipe,
*P＜0.01;
Compare for 2 groups with compound recipe,
$P＜0.05; Compare for 2 groups with compound recipe,
$$P＜0.01;
Table 4 compound recipe is to Fibrotic influence around the SHR rat chest aorta
Compare with model group,
##P＜0.01
Compare for 1 group with compound recipe,
*P＜0.01;
Compare for 2 groups with compound recipe,
$$P＜0.01.
Claims (1)
1. treat hypertensive pharmaceutical composition for one kind; Said compositions is made up of Levamlodipine or its officinal salt and losartan, it is characterized in that Levamlodipine is in free alkali; Losartan is in free acid, and the weight ratio of Levamlodipine and losartan is 1:11-17.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, the content of Levamlodipine is 4mg in the per unit preparation, and the content of losartan is 44～68mg.
3. pharmaceutical composition as claimed in claim 2 is characterized in that, the content of Levamlodipine is 4mg in the per unit preparation, and the content of losartan is 52～68mg.
4. pharmaceutical composition as claimed in claim 1 is characterized in that, the Levamlodipine officinal salt is benzene sulfonate or maleate.
5. pharmaceutical composition as claimed in claim 1 is characterized in that, it is tablet, capsule or granule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101342081A CN101849942B (en) | 2009-04-02 | 2009-04-02 | Medicinal composition for treating hypertension |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101342081A CN101849942B (en) | 2009-04-02 | 2009-04-02 | Medicinal composition for treating hypertension |
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| CN101849942A CN101849942A (en) | 2010-10-06 |
| CN101849942B true CN101849942B (en) | 2012-05-23 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102335172B (en) * | 2011-07-20 | 2012-12-12 | 海南锦瑞制药股份有限公司 | Amlodipine and losartan potassium medicinal composition and preparation method thereof |
| CN102266331B (en) * | 2011-08-19 | 2012-12-26 | 海南锦瑞制药股份有限公司 | Brand new medicinal composition containing levamlodipine and losartan potassium and preparation method thereof |
| CN102600146B (en) * | 2012-04-11 | 2014-10-08 | 兆科药业（合肥）有限公司 | Lercanidipine hydrochloride and losartan potassium compound preparation and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005070463A2 (en) * | 2004-01-12 | 2005-08-04 | Sepracor, Inc. | Compositions comprising (s)-amlodipine malate and an angiotensin receptor blocker and methods of their use |
| CN1883478A (en) * | 2006-05-30 | 2006-12-27 | 石家庄制药集团欧意药业有限公司 | Pharmaceutical composition for treating hypertension and cardiovascular disease |
| WO2008044862A1 (en) * | 2006-10-10 | 2008-04-17 | Hanall Pharmaceutical Co., Ltd. | Combined preparation for the treatment of cardiovascular diseases based on chronotherapy theory |
| WO2008069612A1 (en) * | 2006-12-08 | 2008-06-12 | Hanmi Pharm. Co., Ltd. | Pharmaceutical composition comprising amlodipine and losartan |
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2009
- 2009-04-02 CN CN2009101342081A patent/CN101849942B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005070463A2 (en) * | 2004-01-12 | 2005-08-04 | Sepracor, Inc. | Compositions comprising (s)-amlodipine malate and an angiotensin receptor blocker and methods of their use |
| CN1883478A (en) * | 2006-05-30 | 2006-12-27 | 石家庄制药集团欧意药业有限公司 | Pharmaceutical composition for treating hypertension and cardiovascular disease |
| WO2008044862A1 (en) * | 2006-10-10 | 2008-04-17 | Hanall Pharmaceutical Co., Ltd. | Combined preparation for the treatment of cardiovascular diseases based on chronotherapy theory |
| WO2008069612A1 (en) * | 2006-12-08 | 2008-06-12 | Hanmi Pharm. Co., Ltd. | Pharmaceutical composition comprising amlodipine and losartan |
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