CN101849940A - Medicinal composition for treating hypertension - Google Patents
Medicinal composition for treating hypertension Download PDFInfo
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- CN101849940A CN101849940A CN200910128391A CN200910128391A CN101849940A CN 101849940 A CN101849940 A CN 101849940A CN 200910128391 A CN200910128391 A CN 200910128391A CN 200910128391 A CN200910128391 A CN 200910128391A CN 101849940 A CN101849940 A CN 101849940A
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- losartan
- levamlodipine
- medicinal composition
- pharmaceutical composition
- hypertension
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Abstract
The invention relates to a medicinal composition for treating hypertension, in particular to a medicinal composition containing low-dose Losartan, and belongs to the field of medicaments. The medicinal composition of hypertension resistance contains the following effective doses of medicaments: Levamlodipine or medicinal salts thereof and the Losartan, wherein the Levamlodipine is based on free alkali, the Losartan is based on free acid, and the weight ratio of the Levamlodipine to the Losartan is 1:0.2-9. The medicinal composition provided by the invention enhances the treatment effect, and reduces the treatment risks of patients.
Description
Technical field
The invention belongs to field of medicaments, relate to the hypertensive pharmaceutical composition of a kind of treatment, be specifically related to a kind of pharmaceutical composition that contains the low dosage losartan.
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, domestic and international medical circle is generally tended to the antihypertensive use in conjunction with two kinds of different mechanism of action.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 use in conjunction report of amlodipine and losartan at present, the weight ratio that following document discloses the amlodipine losartan is 1: 10 a clinical use in conjunction 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 use in conjunction 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 for the treatment of 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 make tablet, granule, capsule, injection, slow releasing agent, yet its example of formulations only discloses irbesartan, valsartan and Levamlodipine proportioning, and pharmacodynamics embodiment only discloses the pharmacodynamics effect of irbesartan and Levamlodipine.
Though had the use in conjunction 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 use in conjunction 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 to the further investigation of Levamlodipine losartan, has filtered out a kind of resisting hypertension compound medicament composition that contains the low dosage losartan by a large amount of zooperies.
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: 0.2～9, preferred 1: 0.5～5.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 5mg, and the content of losartan is 1～40mg; Further preferably, the content of Levamlodipine is 5mg, and the content of losartan is 2.5～25mg
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 the different depressor of application mechanism of action and often can strengthen therapeutic effect, look 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 alleviate the impaired of carbohydrate tolerance in the hypertensive while of treatment, reduces insulin resistant, alleviates the rising (seeing embodiment 8) of change of serum C RP.
The specific embodiment
Now further specify content of the present invention by following embodiment, wherein embodiment 1～7 is the preparation embodiment, and embodiment 8 is the pharmacodynamics embodiment, but range of application of the present invention is not limited only to the following example.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 5g
Losartan Potassium 45g
Starch 60g
Microcrystalline Cellulose 110g
L-HPC 30g
10% starch slurry is an amount of
Magnesium stearate 2g
Preparation technology:
Levamlodipine besylate, Losartan Potassium, starch, microcrystalline Cellulose and L-HPC in the prescription are crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 50 ℃, 18 mesh sieve granulate, add the magnesium stearate mixing of recipe quantity, tabletting promptly.
The preparation of embodiment 2 compound tablet
Maleic acid levo amido chloro diping 5g
Losartan 1g
Lactose 20g
Microcrystalline Cellulose 60g
Crospolyvinylpyrrolidone 5g
10% starch slurry is an amount of
Magnesium stearate 1g
Preparation technology:
Maleic acid levo amido chloro diping, losartan, lactose, microcrystalline Cellulose and crospolyvinylpyrrolidone in the prescription are crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 60 ℃, 18 mesh sieve granulate, add the magnesium stearate mixing of recipe quantity, tabletting promptly.
The preparation of embodiment 3 compound tablet
Levamlodipine besylate 5g
Losartan Potassium 25g
Microcrystalline Cellulose 180g
Starch 15g
Carboxymethyl starch sodium 20g
Magnesium stearate 1.5g
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, add carboxymethyl starch sodium, microcrystalline Cellulose mix homogeneously successively, add 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.
The preparation of embodiment 4 compound tablet
Maleic acid levo amido chloro diping 5g
Losartan Potassium 2.5g
Amylum pregelatinisatum 150g
Beta-schardinger dextrin-12g
Carboxymethyl starch sodium 10g
Micropowder silica gel 1.0g
The ethanol solution of 5%PVP is an amount of
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, add carboxymethyl starch sodium, amylum pregelatinisatum mix homogeneously successively, add the Olmesartan mixing at last, making binding agent with the ethanol solution of 5%PVP granulates, 40 ℃ of dryings, granulate adds the micropowder silica gel mixing, tabletting, promptly.
The preparation of embodiment 5 compound capsules
Levamlodipine besylate 5g
Losartan Potassium 5g
Microcrystalline Cellulose 210g
Beta-schardinger dextrin-15g
Micropowder silica gel 1.2g
Preparation technology: it is even earlier Levamlodipine besylate and beta-schardinger dextrin-to be put into the mortar ground and mixed, adds microcrystalline Cellulose, micropowder silica gel mix homogeneously successively, adds the Olmesartan mixing at last, the filling capsule shell, promptly.
Embodiment 6 compound granular agent preparation
Levamlodipine besylate 5g
Losartan Potassium 20g
Cross-linking sodium carboxymethyl cellulose 25g
Beta-schardinger dextrin-20g
Microcrystalline Cellulose 220g
Aspartame 1.2g
Sodium lauryl sulphate 50g
5% polyvidone ethanol liquid is an amount of
Orange flavor 5g
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.
The preparation of embodiment 7 compound recipe effervescent granules
Levamlodipine besylate 5g
Losartan Potassium 10g
Sodium carboxymethyl cellulose 10g
Saccharin sodium 2.5g
Microcrystalline Cellulose 180g
Aspartame 1.5g
Malic acid 150g
Sodium bicarbonate 50g
Natrium carbonicum calcinatum 15g
Sodium lauryl sulphate 50g
5% polyvidone ethanol liquid is an amount of
Orange flavor 5g
Preparation technology: after Levamlodipine besylate, Losartan Potassium, microcrystalline Cellulose, sodium carboxymethyl cellulose, malic acid crossed 16 mesh sieves, after the mixing again with saccharin sodium, aspartame mix homogeneously.Mixture is granulated with 5% polyvidone ethanol liquid, and drying is crossed 30 mesh sieve granulate and mixed with residue prescription adjuvant.Before the mixing, sodium bicarbonate, natrium carbonicum calcinatum sodium lauryl sulphate and orange flavor are crossed 60 mesh sieves.Mix homogeneously, packing, promptly.
Embodiment 8 Levamlodipine losartan compound recipes are to the influence of hypertension model rat
1. grouping
8 week spontaneous hypertensive rat in age (SHR) totally 70 are divided into model group, Levamlodipine group (ammonia group), losartan group (chlorine group), Levamlodipine+losartan group (ammonia chlorine group) at random, amount to 7 groups, 10 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, continues for 10 weeks with Levamlodipine, losartan, and dosage is as follows respectively:
Model group: with volume 0.9% normal saline;
Levamlodipine group: 0.5mg/ (kg.d) Levamlodipine
Losartan high dose group: 5mg/ (kg.d) losartan
Losartan low dose group: 0.25mg/ (kg.d) losartan
1 group of compound recipe: 0.5mg/ (kg.d) Levamlodipine+5mg/ (kg.d) losartan
2 groups of compound recipes: 0.5mg/ (kg.d) Levamlodipine+2.5mg/ (kg.d) losartan
3 groups of compound recipes: 0.5mg/ (kg.d) Levamlodipine+0.25mg/ (kg.d) losartan
3 detect index
3.1 compound recipe is to the influence of SHR rat blood pressure
Carrying out arteria caudalis systolic pressure mensuration the 2nd, 6,8,10 weeks one time respectively, experimental data is carried out statistical analysis with the Excel system.The result shows, from 6 weekends, 2 groups of compound recipes, 3 groups of compound recipes and model group relatively have significant difference, on antihypertensive effect, reached the effect of 1 group of the compound recipe that the higher dosage losartan is arranged, illustrated after the losartan of low dosage very and Levamlodipine are formed compound recipe and obtained good beyond thought hypotensive effect; Last in 10 weeks of administration, each group of compound recipe relatively has significant difference with Levamlodipine group, losartan high dose group, illustrates that the losartan Levamlodipine compound recipe of low dosage has well collaborative antihypertensive effect for hypertensive treatment; Even the losartan of low dosage very when use does not have antihypertensive effect substantially separately, and but has beyond thought collaborative antihypertensive effect after the Levamlodipine use in conjunction.
Table 1 compound recipe is to the influence (kPa) of SHR rat blood pressure
Compare with model group,
#P＜0.05; Compare with model group,
##P＜0.01
Compare with the Levamlodipine group,
*P＜0.05;
Compare with the losartan high dose group,
3.2 compound recipe is to the influence of SHR rat carbohydrate tolerance
After administration finishes, give about rat fasting 12h, get the fasting blood sugar of hematometry rat.After mensuration finishes, the glucose solution of lumbar injection 50%, dosage is 2g/kg, and the ophthalmic corner of the eyes is got blood behind the 2h, and centrifuging and taking blood plasma in the 30min utilizes biochemical instruments to measure blood glucose value.Experimental data is carried out statistical analysis with the Excel system.Concrete outcome sees Table 2.
Table 2 compound recipe is to the influence (mmol/L) of SHR rat carbohydrate tolerance
Compare with model group,
#P＜0.05; Compare with model group,
##P＜0.01
3.3 compound recipe is to the influence of SHR rat CRP
After administration finishes, measure the CRP value of respectively organizing rat, adopt Finland TURBOX analyser and original-pack matched reagent, cuvette, CV in crowd＜6.5%, CV＜8% between batch with immune scattering turbidimetry method.
Concrete outcome sees Table 3, and the losartan Levamlodipine compound recipe of low dosage is having beyond thought good result and synergism aspect the alleviation SHR rat CRP rising.
Table 3 compound recipe is to the influence (mg/L) of SHR rat CRP
Compare with model group,
#P＜0.05; Compare with model group,
##P＜0.01;
Compare for 1 group with compound recipe,
*P＜0.05.
Claims (6)
1. treat hypertensive pharmaceutical composition for one kind, described compositions contains 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: 0.2～9.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, Levamlodipine is in free alkali, and losartan is in free acid, and the weight ratio of Levamlodipine and losartan is 1: 0.5～5.
3. pharmaceutical composition as claimed in claim 1 is characterized in that, the content of Levamlodipine is 5mg in the per unit preparation, and the content of losartan is 1～40mg.
4. pharmaceutical composition as claimed in claim 3 is characterized in that, the content of Levamlodipine is 5mg in the per unit preparation, and the content of losartan is 2.5～25mg.
5. pharmaceutical composition as claimed in claim 1 is characterized in that, the Levamlodipine officinal salt is benzene sulfonate or maleate.
6. 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 |
|---|---|---|---|
| CN2009101283914A CN101849940B (en) | 2009-04-02 | 2009-04-02 | Medicinal composition for treating hypertension |
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| CN2009101283914A CN101849940B (en) | 2009-04-02 | 2009-04-02 | Medicinal composition for treating hypertension |
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| CN101849940B CN101849940B (en) | 2012-02-01 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110215455A (en) * | 2019-03-26 | 2019-09-10 | 山东省药学科学院 | A kind of pharmaceutical formulation for blood pressure lowering |
| CN114917224A (en) * | 2022-03-16 | 2022-08-19 | 黄山中皇制药有限公司 | Production and batching process and batching equipment for valsartan levamlodipine composition |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100364532C (en) * | 2004-09-30 | 2008-01-30 | 江苏恒瑞医药股份有限公司 | Composition containing amlodipine and angiotensin II receptor inhibitor |
| 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 |
-
2009
- 2009-04-02 CN CN2009101283914A patent/CN101849940B/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110215455A (en) * | 2019-03-26 | 2019-09-10 | 山东省药学科学院 | A kind of pharmaceutical formulation for blood pressure lowering |
| CN114917224A (en) * | 2022-03-16 | 2022-08-19 | 黄山中皇制药有限公司 | Production and batching process and batching equipment for valsartan levamlodipine composition |
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| CN101849940B (en) | 2012-02-01 |
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