CN1587269A - Medicinal composition containing angiotensin II receptor antagonist and vitamin B - Google Patents

Medicinal composition containing angiotensin II receptor antagonist and vitamin B Download PDF

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Publication number
CN1587269A
CN1587269A CN 200410071055 CN200410071055A CN1587269A CN 1587269 A CN1587269 A CN 1587269A CN 200410071055 CN200410071055 CN 200410071055 CN 200410071055 A CN200410071055 A CN 200410071055A CN 1587269 A CN1587269 A CN 1587269A
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China
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vitamin
group
content
receptor antagonist
pharmaceutical composition
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CN1286844C (en
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陈光亮
徐希平
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Shandong OSA Pharmaceutical Co.,Ltd.
Shenzhen Ausa Pharmaceutical Co ltd
Shenzhen Ausa Pharmed Co ltd
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ANHUI BIOLOGICAL MEDICAL SCIENCE INST
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Abstract

The medicine composition consists of one of AT1 receptor antagonist, its active metabolism product, ester and salt in treating effective amount of 4-800 mg, one or several kinds one B family vitamins in treating effective amount of 0.1-50 mg, and pharmaceutically acceptable carrier. The medicine composition of the present invention has the beneficial effects of raising the treating effect of blood pressure lowering AT1 receptor antagonist, strengthening the protecting effect of blood pressure lowering AT1 receptor antagonist on target organ and reducing the incidence rate of hemorrhage of the ocular fundus, angina pectoris, myocardial infarction and other complications.

Description

The pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group
Technical field
The present invention relates to a kind of pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group, refer to a kind of treatment especially, prevent or delay the chemical drug composition of hypertension and relative disease thereof, belong to pharmaceutical field.
Background technology
Essential hypertension is one of modal chronic disease, is to cause serious cardiovascular diseases such as myocardial infarction, cerebral apoplexy, and the major cause of kidney disease etc.Essential hypertension is 27.2% in China's morbidity, at present existing patient more than 1.3 hundred million, and the increase of hypertension morbidity (is compared with investigation in 1991) rapidly, crowd's hypertension morbidity rate of increase male sex was 74% in 35～44 years old, and the women is 62% (Gu Dongfeng, Jiang He, Wu Xigui, et al. Chinese adult hypertension morbidity, awareness, treatment and control situation. Chinese Journal of Preventive Medicine, 2003,37 (2): 84～89).Elevation of blood pressure is the independent hazard factor of cerebral apoplexy and incidence of coronary heart disease, and elevation of blood pressure increases the danger of in heart failure and kidney disease.Treatment hypertensive patient's main purpose is to reduce the death of cardiovascular diseases and invalid total danger to greatest extent, medicine brings high blood pressure down and can reduce the M ﹠ M of cardiovascular complication effectively, prevents the generation and the development of cerebral apoplexy, coronary heart disease, heart failure and kidney disease.
The current medicine that is used for step-down is mainly: hydragog(ue), beta-blocker, angiotensin converting enzyme inhibitor (ACEI), angiotensin-ii receptor (AT 1) antagonist, calcium antagonist and alpha-blocking agent.Most hyperpietics need two or more antihypertensive drug to reach the controlling blood pressure target, two kinds of medicines can write out a prescription separately or for the compound preparation of fixed dosage (Chinese hypertension prevention and control guide Drafting Committee. Chinese hypertension prevention and control guide. hypertension magazine, 2000; 8 (1): 94～102,103～112).International extensive clinical trial proof drug combination has it to need and is worth, and the dosage of every kind of medicine is little, and the therapeutic action of medicine should have collaborative or the effect of addition at least, and its undesirable action can be cancelled out each other or not overlapping at least or addition.
Hypertensive treatment rate is respectively 28.2% and 59% in the China and the U.S., inverse amplification factor only is respectively 8.1% and 34% (Li Yanfang, Hu Yixin, Guo Guanghong etc. enalapril and losartan are to the influence of spontaneous hypertensive rat homocysteine and nitric oxide level. Chinese circulation magazine, 2002; 17 (5): 392～4).As seen, the hypotensive effect of hypertensive pharmacological agent still can not be fully up to expectations.In addition, to reach the target blood pressure be crucial though bring high blood pressure down, and target-organ protection is the ultimate aim of hypertension therapeutic.Be used for the treatment of hypertensive drug main at present and will be conceived to antihypertensive effect, and pay close attention to not enough the effect of target-organ protection.
Angiotensin-ii receptor (AT 1Acceptor) antagonist is the most frequently used medicine of clinic control hypertension, mainly by blocking Angiotensin II and AT specifically 1The combination of acceptor, thus the vasoconstriction of blocking-up Angiotensin II and aldosterone secretion reach the effect of step-down and protection target organ.Irbesartan (Irbesartan, irbesartan, Irb) is a kind of AT 1Receptor antagonist, only need once oral every day, and common dose is 75～300mg/d, the clinical treatment essential hypertension that is widely used in.Other clinical AT commonly used 1Receptor antagonist comprises: losartan (Losartan), valsartan (Valsartan), telmisartan (Telmisartan/Micardis, telmisartan), Candesartan (Candesartan, Kang Deshatan), eprosartan (Eprosartan, Eprosartan), Olmesartan (Olmesartan Medoxomil, olmesartan medoxomill), Tasosartan (Tasosartan/Verdia) etc.
There is certain problem in the AT receptor antagonist in clinical application, at first its efficacy of antihypertensive treatment has certain limit, light to 3700 examples, in, the severe hypertension patient.Carry out at random, double blinding, multiple center clinical study, found that and take losartan 50mg that efficient only is 41%～54%.Secondly, AT 1The receptor antagonist target organ protection function is still limited; LIFE research (in November, 2003 AHA's academic conference report) is found; the treatment plan that contains the angiotensin II receptor antagonists losartan is compared with the treatment plan that contains the beta-blockers atenolol USP 23, and the danger of two groups of crowd's myocardial infarctions and cardiovascular death there is no the significance difference.U.S.'s prevention, detection, assessment and the treatment hypertension whole nation the 7th report of joint committee (JNC 7) be not also with AT 1Receptor antagonist is as the recommendation medicine of high-risk diseases such as myocardial infarction, coronary heart disease.Homocysteine is the independent risk factor of hypertension incidence, AT 1Receptor antagonist can not reduce the level of homocysteine.
In recent years studies show that, the folic acid deficiency diet can cause rat hyperhomocysteinemiainjury and arterial injury (Gao Fen, Li Jing plum, Xiao Chuanshi. hyperhomocysteinemiainjury influences the experimental study of left ventricular function.China's cardiovascular diseases magazine, 2002; 30 (5): 312).Serum folic acid level and coronary heart disease have remarkable negative correlation, increase the folic acid intake and can reduce homocysteine level, reduce the mortality ratio of cardiovascular diseases, low serum folic acid salt level and dangerous relevant (the McCully KS.Homocysteine that raises of lethality coronary heart disease, vitamins, and prevention of vascular disease.Mil Med, 2004:169 (4): 325～9).
Summary of the invention
The objective of the invention is to overcome AT 1The receptor agonist hypotensor above shortcomings provide a kind of and all are being better than AT aspect efficacy of antihypertensive treatment and the target-organ protection 1Receptor antagonist, and the pharmaceutical composition that toxicity does not increase.
For achieving the above object, the present invention is by the following technical solutions:
The pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group, this pharmaceutical composition is by the AT of treatment significant quantity 1One or more and pharmaceutically acceptable carrier in the vitamin B group of a kind of, the treatment significant quantity in receptor antagonist and active metabolite thereof or the salt are formed; AT wherein 1The content of receptor antagonist and active metabolite thereof, ester class or salt is 4～800mg, and the content of vitamin B group is 0.1～50mg.
Described AT 1Receptor antagonist and active metabolite thereof or salt are selected from losartan (Losartan), valsartan (Valsartan), irbesartan (Irbesartan, irbesartan, Irb), telmisartan (Telmisartan/Micardis, telmisartan), Candesartan (Candesartan, Kang Deshatan), eprosartan (Eprosartan, Eprosartan), a kind of in Olmesartan (Olmesartan Medoxomil, olmesartan medoxomill), Tasosartan (Tasosartan/Verdia) and meta-bolites, ester class or the salt.
AT 1The content of receptor antagonist is respectively: losartan (25～200mg), valsartan (40～320mg), irbesartan (75～600mg), telmisartan (20～160mg), Candesartan (4～64mg), eprosartan (200～800mg), Olmesartan (20～80mg), (10～300mg), the active metabolite of above-mentioned substance, ester class or salt content are equal to corresponding above-mentioned substance content Tasosartan.
The better in the present invention content of these medicines is respectively: losartan (50～100mg), valsartan (80～160mg), irbesartan (150～300mg), telmisartan (20～80mg), Candesartan (8～32mg), eprosartan (400～800mg), Olmesartan (20～40mg), (25～300mg), the active metabolite of above-mentioned substance, ester class or salt content are equal to corresponding above-mentioned substance content Tasosartan.
Described vitamin B group is selected from one or more in vitamin B6, vitamin B12, folic acid or the calcium leucovorin.
Described vitamin B6 comprises the derivative of pyridoxol, pyridoxal, Pyridoxamine, pyridoxal phosphate, phosphoric acid Pyridoxamine and above-mentioned substance and can discharge/generate the material of this compounds in vivo.
Described vitamin B12 comprises the derivative of cobalami, mecobalamin element, 5 ' deoxyadenosyl cobalamin, hydroxocobalamine, cyanocobalamin and other cobalamis and can discharge/generate the material of cobalami in vivo.
Described folic acid class material comprises the active metabolite of folic acid, calcium leucovorin, L methopterin, folate, folic acid or folate and can discharge/generate the material of folic acid in vivo.
Vitamin B group class material treatment significant quantity in the present invention is respectively: the content of folic acid class material is 0.2～10mg, and vitamin B12 content is 0.1～2mg, and vitamin B6 content is 0.5～50mg.Its better treatment significant quantity is respectively: folic acid class material 0.2～5mg, vitamin B12 0.25～2mg, vitamin B6 5～50mg.
The present invention is preferably by the component of the following content pharmaceutical composition as activeconstituents: AT wherein 1Receptor antagonist be selected from losartan (50～100mg), valsartan (80～160mg), irbesartan (150～300mg), telmisartan (20～80mg), Candesartan (8～32mg) and active metabolite, ester class or salt in a kind of; Vitamin B group class material be selected from folic acid class material (0.2～5mg), vitamin B12 (0.25～2mg) and vitamin B6 (one or more in 5～50mg).
Described AT 1Receptor antagonist is selected from losartan or Losartan Potassium, and vitamin B group is folic acid or calcium leucovorin; AT wherein 1The content of receptor antagonist is 50～100mg, and the content of vitamin B group is 0.2～5mg.
Described AT 1Receptor antagonist is selected from losartan or Losartan Potassium, and vitamin B group is a vitamin B6; AT wherein 1The content of receptor antagonist is 50～100mg, and the content of vitamin B group is 5～50mg.
Described AT 1Receptor antagonist is selected from losartan or Losartan Potassium, and vitamin B group is a vitamin B12; AT wherein 1The content of receptor antagonist is 50～100mg, and the content of vitamin B group is 0.25～2mg.
Described AT 1Receptor antagonist is a valsartan, and vitamin B group is folic acid or calcium leucovorin; Wherein valsartan content is 80～160mg, and the content of vitamin B group is 0.2～5mg.
Described AT 1Receptor antagonist is a valsartan, and vitamin B group is a vitamin B6; Wherein valsartan content is 80～160mg, and the content of vitamin B group is 5～50mg.
Described AT 1Receptor antagonist is a valsartan, and vitamin B group is a vitamin B12; Wherein valsartan content is 80～160mg, and the content of vitamin B group is 0.25～2mg.
Described AT 1Receptor antagonist is an irbesartan, and vitamin B group is folic acid or calcium leucovorin; Wherein irbesartan content is 150～300mg, and the content of vitamin B group is 0.2～5mg.
Described AT 1Receptor antagonist is an irbesartan, and vitamin B group is a vitamin B6; Wherein irbesartan content is 150～300mg, and the content of vitamin B group is 5～50mg.
Described AT 1Receptor antagonist is an irbesartan, and vitamin B group is a vitamin B12; Wherein irbesartan content is 150～300mg; The content of vitamin B group is 0.25～2mg.
Described AT 1Receptor antagonist is a telmisartan, and vitamin B group is a folic acid; Wherein telmisartan content is 20～80mg, and the content of vitamin B group is 0.2～5mg.
Described AT 1Receptor antagonist is a Candesartan, and vitamin B group is a folic acid; Wherein Candesartan content is 8～32mg, and the content of vitamin B group is 0.2～5mg.
Originally discover that the vitamin B group list is with there being slight hypotensive effect, when with AT 1When receptor antagonist share, can strengthen AT 1The hypotensive effect of receptor antagonist.Vitamin B group and AT 1Receptor antagonist share and can strengthen it causes target organ damage to hypertension provide protection.
Described pharmaceutical composition can be made into conventional tablet, conventional capsule, granule, slow releasing tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coated tablet, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, slow releasing capsule, controlled release capsule, contain micropill or small pieces capsule, contain the formulations such as pH dependent form capsule, granule, oral liquid, film or patch of micropill or small pieces.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into common oral preparation, comprise conventional tablet, conventional capsule, granule etc., described pharmaceutically acceptable carrier includes vehicle and the adjuvant that helps active compound is mixed with medicinal preparations when making tablet, composition as one or more materials of starch, Microcrystalline Cellulose, inorganic salts, sucrose, dextrin, lactose, Icing Sugar, glucose, sodium-chlor, halfcystine, citric acid and S-WAT etc. belongs to this area general knowledge.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into slow releasing tablet, comprise vehicle and auxiliary material etc.Described vehicle and adjuvant have comprised that the auxiliary material of slow releasing function is solubility/insoluble salt and/or other auxiliary material that plays slow releasing function of hypromellose and/or ethyl cellulose and/or polyacrylic resin class and/or polycarboxy ethene and/or Lalgine, the hypromellose employing includes the extensive stock of HPMC (HPMC) such as U.S. many elegant (Methocel) of all size, ethyl cellulose adopts the extensive stock that includes ethyl cellulose (EC), and the polyacrylic resin class adopts and includes polyacrylic resin II, the acrylic resin of III class or analogue such as all size (Eudragit).Above-mentioned auxiliary material is pore-creating agent, tackiness agent, lubricant, emulsifying agent, mould material, solvent or other auxiliary material, and pore-creating agent can adopt sucrose, N.F,USP MANNITOL, starch, talcum powder, silicon-dioxide etc.; Tackiness agent can adopt polyvinylpyrrolidone, hypromellose etc.; Wetting agent can adopt the ethanol-water solution of water, dehydrated alcohol, various concentration; Lubricant can adopt stearic acid, Magnesium Stearate, talcum powder, starch, paraffin etc.; Solubilizing agent can adopt tartrate, citric acid etc.; Emulsifying agent can adopt span80 span85 etc.; Mould material can adopt polyvinyl alcohol, hydroxyl methylcellulose, hyetellose, hymetellose, methylcellulose gum etc.; Whipping agent can adopt magnesium basic carbonate, sodium bicarbonate etc.; Bleach activator can adopt hexadecanol, stearyl alcohol, beeswax etc.; Solvent can adopt dehydrated alcohol, ethanol, water etc.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into controlled release tablet, comprise that active medicine has reached the auxiliary material of controlled release effect.The above-mentioned auxiliary material that plays the controlled release effect is polyoxyethylene and/or hypromellose and/or ethyl cellulose and/or sodium-chlor and/or lactose and/or N.F,USP MANNITOL and/or fructose and/or glucose and/or sucrose/or low-substituted hydroxypropyl cellulose and/or croscarmellose sodium and/or cross-linked polyvinylpyrrolidone and/or cellulose acetate.Above-mentioned auxiliary material is pharmaceutical carrier, expanding material, penetration-assisting agent, solubilizing agent, tackiness agent, wetting agent, lubricant, tinting material, pore-creating agent, mould material, antisticking agent, softening agent, lucifuge agent, solvent.Pharmaceutical carrier, expanding material can adopt polyoxyethylene, hypromellose, ethyl cellulose, Glyceryl Behenate class etc.; Penetration-assisting agent can adopt sodium-chlor, lactose, N.F,USP MANNITOL, fructose, glucose, sucrose etc.; Solubilizing agent can adopt sodium lauryl sulphate or poloxamer etc.; Tackiness agent can adopt polyvinylpyrrolidone, hypromellose etc.; Wetting agent can adopt the ethanol-water solution of water, dehydrated alcohol, various concentration; Lubricant can adopt stearic acid, Magnesium Stearate, talcum powder, starch, paraffin etc.; Tinting material can adopt red iron oxide, iron oxide yellow etc.; Pore-creating agent can adopt sucrose, N.F,USP MANNITOL, polyoxyethylene glycol, titanium dioxide, talcum powder, silicon-dioxide etc.; Mould material can adopt cellulose acetate, ethyl cellulose etc.; Solvent can adopt acetone, dehydrated alcohol, ethanol, water etc.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into sublingual lozenge, oral cavity quick disintegrating slice or dispersible tablet etc., comprise vehicle and auxiliary material etc.Described vehicle and auxiliary material have low substituted hydroxy-propyl methylcellulose gum, Microcrystalline Cellulose, sodium starch glycolate, cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, processing agar and N.F,USP MANNITOL, lactose etc.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into enteric coated tablet or enteric coated capsule etc.; comprise vehicle and auxiliary material etc.; described vehicle and auxiliary material have starch; Microcrystalline Cellulose; inorganic salts; Vltra tears; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of Lalgine/insoluble salt; stearyl alcohol; stearic acid; sucrose; dextrin; lactose; Icing Sugar; glucose; sodium-chlor; halfcystine; the composition of one or more materials of citric acid and S-WAT etc.; enteric-coating material comprises: shellac; the cellulose acetate phthalate; crylic acid resin (as Eudragit L and S type etc.); the Vinyl Acetate Copolymer phthalic acid ester; phthalic acid hypromellose ester; succsinic acid acetic acid HPMC, and softening agent is (as diethyl phthalate; polyoxyethylene glycol; propylene glycol; triacetin; dimethyl phthalate; Uniflex DBS; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Viscotrol C and percentage etc.) with various medicaments auxiliary material such as pore-creating agent (as PEG6000 etc.).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into delayed-release tablet or timing (position) releasing piece; comprise vehicle and auxiliary material; described vehicle and auxiliary material have starch; Microcrystalline Cellulose; inorganic salts; Vltra tears; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of Lalgine/insoluble salt; stearyl alcohol; stearic acid; sucrose; dextrin; lactose; Icing Sugar; glucose; sodium-chlor; halfcystine; the composition of one or more materials of citric acid and S-WAT etc.; described coating material that postpones release or regularly (position) release comprises: shellac; the cellulose acetate phthalate; ethyl cellulose; Vltra tears; hydroxypropylcellulose; crylic acid resin (as Eudragit L and S type etc.); the Vinyl Acetate Copolymer phthalic acid ester; phthalic acid hypromellose ester; succsinic acid acetic acid HPMC; hydroxypropylmethylcellulose acetate methylcellulose gum phthalate, and softening agent is (as diethyl phthalate; polyoxyethylene glycol; propylene glycol; triacetin; dimethyl phthalate; Uniflex DBS; triethyl citrate; tributyl citrate; CitroflexA-2; acetylated monoglycerides of Viscotrol C and percentage or the like) with various medicaments auxiliary material such as pore-creating agent (as PEG6000 etc.).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into slow releasing capsule; controlled release capsule; the capsule that contains micropill or small pieces; contain the pH dependent form capsule of micropill or small pieces etc.; comprise vehicle and auxiliary material; described vehicle and auxiliary material have starch; Microcrystalline Cellulose; inorganic salts; Vltra tears; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of Lalgine/insoluble salt; stearyl alcohol; stearic acid; sucrose; dextrin; lactose; Icing Sugar; glucose; sodium-chlor; halfcystine; the composition of one or more materials of citric acid and S-WAT etc.; coating material comprises shellac; cellulose acetate; the cellulose acetate phthalate; ethyl cellulose; Vltra tears; hydroxypropylcellulose; crylic acid resin (as Eudragit series); the Vinyl Acetate Copolymer phthalic acid ester; phthalic acid hypromellose ester; succsinic acid acetic acid HPMC; hydroxypropylmethylcellulose acetate methylcellulose gum phthalate; the single-stearic acid glyceride, and softening agent is (as diethyl phthalate; polyoxyethylene glycol; propylene glycol; triacetin; dimethyl phthalate; Uniflex DBS; triethyl citrate; tributyl citrate; CitroflexA-2; acetylated monoglycerides of Viscotrol C and percentage or the like) with various medicaments auxiliary material such as pore-creating agent (as PEG6000 etc.).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into formulations such as granule, oral liquid, film, patch.Make patch; described pharmaceutically acceptable carrier includes vehicle and the adjuvant that helps active compound is mixed with medicinal preparations during film; as polyvinyl alcohol, cellulosetri-acetate, ethylene-vinyl acetate copolymer, polyvinylpyrrolidone, polyacrylamide, polyisobutene class pressure sensitive adhesive, crylic acid resin pressure sensitive adhesive, silicone pressure sensitive adhesive etc.; and back lining materials such as polyvinyl chloride, polyethylene, aluminium foil, polypropylene, polyester, the composition of one or more materials of protective membranes such as polyethylene, polystyrene, polypropylene etc.
Preparation of the present invention can use or use in turn with any order simultaneously, and is best to use simultaneously.Comprise in the above-mentioned use simultaneously that best uses with fixed combination with fixed combination and on-fixed combination.
Preparation of the present invention can be taken once or twice every day, perhaps with slowly-releasing or controlled release mode every day or a few days takes once every other day or at interval.Take once wherein preferred every day.
Described pharmaceutical composition can flexible using with " Combined drug box " form.Above-mentioned " Combined drug box " is a kind of case type container, the drug regimen of built-in multiple dosage form, and take specification sheets." Combined drug box " more is applicable to personalized medicine.
Pharmaceutical composition of the present invention is used for prevention, treats and delays hypertension and relative disease thereof, the target organ damage that hypertension causes comprises left ventricular hypertrophy, stenocardia, myocardial infarction, heart failure, optimum arteriolar nephrosclerosis, pernicious arteriolar nephrosclerosis, renal failure, retinal arteriosclerosis, hypertension ocular fundus pathology, cerebral apoplexy etc., and and the closely-related disease of hypertension, atherosclerosis, coronary heart disease, dissection of aorta and diabetes.
The invention has the beneficial effects as follows: the invention provides a kind of pharmaceutical composition, this pharmaceutical composition can improve AT 1The curative effect of receptor antagonist depressor strengthens AT 1The target organ protection function of receptor antagonist depressor, the incidence of complication such as minimizing retinal hemorrhage, stenocardia, myocardial infarction, cerebral apoplexy, heart failure, renal failure.The patient is taken medicine conveniently, reduce medical expense.
The present invention will be further described below in conjunction with embodiment, is not limitation of the invention, all any this areas of carrying out according to content of the present invention be equal to replacement, all belong to protection scope of the present invention.
Embodiment
Embodiment 1. preparation of pharmaceutical compositions
Prescription
Losartan 50.0g
Folic acid 0.2g
Starch 45.0g
Microcrystalline Cellulose 45.0g
Carboxymethylstach sodium (CMSNa) 5.0g
5% polyvidone k-30 (solvent is a dehydrated alcohol) QS
Magnesium Stearate (MS) QS
Make 1000
Preparation technology:
(1) mix standby by the equivalent incremental method after losartan, the folic acid of getting recipe quantity is crossed 100 mesh sieves;
(2) other auxiliary materials are crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively;
(3) by mixing with mixed bulk drug equivalent incremental method again behind the starch of recipe quantity, Microcrystalline Cellulose, the CMSNa mixing;
(4) add tackiness agent and make softwood in right amount, 24 mesh sieves are granulated, the whole grain of 20 mesh sieves, 40～45 ℃ of dryings;
(5) dried particle adds an amount of Magnesium Stearate mixing, compressing tablet behind the assay.
Embodiment 2. preparation of pharmaceutical compositions
Prescription:
Valsartan 80.0g
Calcium leucovorin 5.0g
Starch 45.0g
Microcrystalline Cellulose 35.0g
Carboxymethylstach sodium (CMSNa) 5.0g
5% polyvidone k-30 (solvent is a dehydrated alcohol) QS
Magnesium Stearate (MS) QS
Make 1000
Preparation technology:
(1) mix standby by the equivalent incremental method after valsartan, the calcium leucovorin of getting recipe quantity crossed 100 mesh sieves;
(2) other auxiliary materials are crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively;
(3) by mixing with mixed bulk drug equivalent incremental method again behind the starch of recipe quantity, Microcrystalline Cellulose, the CMSNa mixing;
(4) add tackiness agent and make softwood in right amount, 24 mesh sieves are granulated, the whole grain of 20 mesh sieves, 40～45 ℃ of dryings;
(5) dried particle adds an amount of Magnesium Stearate mixing, compressing tablet behind the assay.
Embodiment 3. preparation of pharmaceutical compositions
Prescription:
Irbesartan 150.0g
Folic acid 0.4g
Starch 45.0g
Microcrystalline Cellulose 35.0g
Carboxymethylstach sodium (CMSNa) 5.0g
5% polyvidone k-30 (solvent is a dehydrated alcohol) QS
Magnesium Stearate (MS) QS
Make 1000
Preparation technology:
(1) mix standby by the equivalent incremental method after irbesartan, the folic acid of getting recipe quantity is crossed 100 mesh sieves;
(2) other auxiliary materials are crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively;
(3) press behind the starch, Microcrystalline Cellulose, CMSNa mixing of recipe quantity dark even with mixed bulk drug equivalent incremental method again;
(4) add tackiness agent and make softwood in right amount, 24 mesh sieves are granulated, the whole grain of 20 mesh sieves, 40～45 ℃ of dryings;
(5) dried particle adds an amount of Magnesium Stearate mixing, compressing tablet behind the assay.
Embodiment 4. preparation of pharmaceutical compositions
Prescription:
Irbesartan 150.0g
Folic acid 0.8g
Starch 45.0g
Microcrystalline Cellulose 35.0g
Carboxymethylstach sodium (CMSNa) 5.0g
5% polyvidone k-30 (solvent is a dehydrated alcohol) QS
Magnesium Stearate (MS) QS
Make 1000
Preparation technology:
(1) mix standby by the equivalent incremental method after irbesartan, the folic acid of getting recipe quantity is crossed 100 mesh sieves:
(2) other auxiliary materials are crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively;
(3) press behind the starch, Microcrystalline Cellulose, CMSNa mixing of recipe quantity dark even with mixed bulk drug equivalent incremental method again;
(4) add tackiness agent and make softwood in right amount, 24 mesh sieves are granulated, the whole grain of 20 mesh sieves, 40～45 ℃ of dryings;
(5) dried particle adds an amount of Magnesium Stearate mixing, compressing tablet behind the assay.
Embodiment 5. preparation of pharmaceutical compositions
Prescription:
Losartan 50.0g
Vitamin B6 10.0g
Lactose 30.0g
Microcrystalline Cellulose 15.0g
Starch 20.0g
Carboxymethylstach sodium 5.0g
Magnesium Stearate QS
Make 1000
Preparation technology:
By the prescription proportioning, get lactose, Microcrystalline Cellulose, starch, carboxymethylstach sodium in about 100 ℃ dry about 2 hours respectively, cross 100 mesh sieves; After bulk drug crossed 100 mesh sieves, increase progressively mixing with above-mentioned auxiliary material by equivalent, the capsule can.
Embodiment 6. preparation of pharmaceutical compositions
Prescription:
Valsartan 80.0g
Vitamin B12 1.0g
Lactose 30.0g
Microcrystalline Cellulose 15.0g
Starch 20.0g
Carboxymethylstach sodium 5.0g
Magnesium Stearate QS
Make 1000
Preparation technology:
By the prescription proportioning, get lactose, Microcrystalline Cellulose, starch, carboxymethylstach sodium in about 100 ℃ dry about 2 hours respectively, cross 100 mesh sieves; After bulk drug crossed 100 mesh sieves, mix the capsule can by the equivalent incremental method with above-mentioned auxiliary material.
Embodiment 7. preparation of pharmaceutical compositions
Prescription:
Telmisartan 20.0g
Folic acid 0.8g
Starch 45.0g
Microcrystalline Cellulose 25.0g
Carboxymethylstach sodium (CMSNa) 5.0g
5% polyvidone k-30 (solvent is a dehydrated alcohol) QS
Magnesium Stearate (MS) QS
Make 1000
Preparation technology:
(1) mix standby by the equivalent incremental method after telmisartan, the folic acid of getting recipe quantity is crossed 100 mesh sieves;
(2) other auxiliary materials are crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively;
(3) press behind the starch, Microcrystalline Cellulose, CMSNa mixing of recipe quantity dark even with mixed bulk drug equivalent incremental method again;
(4) add tackiness agent and make softwood in right amount, 24 mesh sieves are granulated, the whole grain of 20 mesh sieves, 40～45 ℃ of dryings;
(5) dried particle adds an amount of Magnesium Stearate mixing, compressing tablet behind the assay.
Embodiment 8. preparation of pharmaceutical compositions
Prescription:
Candesartan 8.0g
Folic acid 0.4g
Starch 45.0g
Microcrystalline Cellulose 35.0g
Carboxymethylstach sodium (CMSNa) 5.0g
5% polyvidone k-30 (solvent is a dehydrated alcohol) QS
Magnesium Stearate (MS) QS
Make 1000
Preparation technology:
(1) mix standby by the equivalent incremental method after Candesartan, the folic acid of getting recipe quantity is crossed 100 mesh sieves;
(2) other auxiliary materials are crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively;
(3) press behind the starch, Microcrystalline Cellulose, CMSNa mixing of recipe quantity dark even with mixed bulk drug equivalent incremental method again;
(4) add tackiness agent and make softwood in right amount, 24 mesh sieves are granulated, the whole grain of 20 mesh sieves, 40～45 ℃ of dryings;
(5) dried particle adds an amount of Magnesium Stearate mixing, compressing tablet behind the assay.
Embodiment 9. preparation of pharmaceutical compositions
Prescription:
Irbesartan 150.0g
Folic acid 0.4g
HPMC?K15M(Methocel?K15MCR) 30g
Lactose 20g
Microcrystalline Cellulose 20g
5% polyvidone k-30 (solvent is a dehydrated alcohol) QS
Talcum powder QS
Magnesium Stearate (MS) QS
Make 1000
HPMCK15M is a hydrophilic polymer, it in said preparation framework material, meet the expansion of water or Digestive system and form the gel barrier, the diffusion of control active medicine, reach the slowly-releasing purpose, wherein HPMCK15M can be replaced by the HPMCK4M or the HPMCK100M of different amounts, or is used in combination with K100LV, to adjust the release curve.
Embodiment 10. irbesartans+folic acid-collaborative hypotensive effect
Spontaneous hypertensive rat is available from Chinese Academy of Sciences's Shanghai Experimental Animal Center, and rat blood pressure raises after 6 ages in week, significantly raises after 8～10 ages in week, measures 1 week of rat blood pressure (the 1st, 6 day), and the rat of getting blood pressure stabilization is used for experiment.With the spontaneous hypertensive rat random packet, be respectively model group (giving solvent), irbesartan group (10mg/kg), 1 group of (10+0.04) mg/kg of irbesartan+folic acid, 2 groups of (10+0.1) mg/kg of irbesartan+folic acid, 3 groups of (10+0.5) mg/kg of irbesartan+folic acid, 4 groups of (10+1) mg/kg of irbesartan+folic acid, folic acid group (0.5mg/kg), other establishes the normal control group.Gastric infusion, continuous 2 weeks.Measure before the administration respectively and administration after the different time blood pressure, calculate the step-down percentage: (SBP Before the administration-SBP After the administration)/SBP Before the administration* 100, the results are shown in Table 1.
Irbesartan has significant hypotensive effect to spontaneous hypertensive rat, average maximum reducing percentage is 13.3 ± 4.3%, the folic acid list is used has slight hypotensive effect to spontaneous hypertensive rat, average maximum reducing amplitude is 3.1 ± 2.2%, both share the hypotensive effect enhancing, and average maximum reducing amplitude is 18.5 ± 4.8%.
Analytical results shows that the step-down amplitude also there are differences between singly with irbesartan group and different levels drug combination group, singly with the irbesartan group more significant hypotensive effect is arranged the 10th, 14 day different levels drug combination group especially.After the 1st, 3,7,10 and 14 day step-down value merging, show same trend with the gauged linear regression analysis result of GEE, promptly the folic acid group has independently appropriate hypotensive effect, and drug combination group hypotensive effect is more remarkable.
Conclusion: folic acid and irbesartan share, and can strengthen the hypotensive effect of irbesartan, and folic acid dosage acts on close in 0.04～1.0mg/kg scope.
Continuous 2 weeks of table 1 irbesartan+various dose folic acid gastric infusion are to spontaneity
The hypotensive effect of Hypertensive Rats (step-down percentage) (x ± s, n=10)
Behind group and the dosage medicine
(mmHg) d1 d3 d7 d10 d14
Normal group-3.5 ± 2.9 2.1 ± 4.5-3.7 ± 4.8 2.8 ± 4.9 2.6 ± 3.7
Model group 2.5 ± 2.7 2.7 ± 3.8 4.6 ± 3.7-3.7 ± 3.1-1.9 ± 3.7
10+1 9.9±3.2 ** 10.4±4.3 ** 16.8±4.2 ** 17.2±4.3 18.5±4.8 **
10+0.5 9.1±3.8 ** 10.5±2. ** 16.2±4.5 ** 15.8±3.9 ** 17.9±5.3 **
10+0.1 6.7±4.5 * 8.4±3.3 ** 14.1±2.6 ** 15.7±3.7 ** 17.9±2.9 **
10+0.04 6.5±3.5 ** 9.1±3.6 ** 10.5±3.8 ** 13.8±2.6 ** 14.6±2.4 **
10 5.9±3.3 ** 6.9±4.6 ** 10.9±1.8 ** 9.2±1.6 ** 13.3±4.3 **
Folic acid 0.5 1.9 ± 2.8 3.0 ± 2.5 1.7 ± 0.8 3.1 ± 2.2 *2.8 ± 2.8 *
The synergy of embodiment 11. irbesartans+folic acid-target organ protection function
With the narrow Wistar rat of 0.2mm silver brain clip left renal artery, it is the hypertension artery model that the back rat blood pressure rising of 14～15 weeks surpasses 150mmHg above.Random packet, if model control group, irbesartan+folic acid (10+0.5mg/kg), irbesartan+folic acid (10+0.1mg/kg), irbesartan+folic acid (10+0.08mg/kg), irbesartan+folic acid (10+0.04mg/kg), irbesartan (10mg/kg) group, folic acid (0.08mg/kg) group, other gets 12 normal rats as the normal control group.Gastric infusion in continuous 13～15 weeks, is measured 24h urine α 1 microglobulin, left chamber end-diastolic pressure (LVEDP), isovolumic relaxation period time constant (T), the heavy index (left ventricle mg/ body weight g) in chamber respectively.The results are shown in Table 2.
Improving aspect the heart function, the LVEDP of irbesartan group and each horizontal drug combination group (reflection cardiac preload), T value (reflection ventricle isovolumetric relaxation function) all are lower than than model group (not administration group).Single have independently, moderately reduce LVEDP and the effect of T value with folic acid, and list can reduce LVEDP and T value significantly with irbesartan and drug combination.Aspect the effect that suppresses left ventricular hypertrophy, between each medication group, also observed similar result equally.
The index of Hypertensive Rats kidney injury represents that with twenty-four-hour urine α 1 microglobulin it is the marker of the early stage injury of renal tubular of reflection.Analytical results is supported equally: folic acid group, list all significantly reduce than the twenty-four-hour urine α 1 microglobulin content of model group with irbesartan group and each horizontal drug combination group.Wherein drug combination group improvement degree or reduction level are the most obvious.Conclusion: irbesartan and folic acid associating compatibility group has the effect of significant step-down and target-organ protection to renal hypertensive rat, and it is stronger to target organ protection function wherein to unite the compatibility group.
Continuous 13～15 weeks of table 2 irbesartan+folic acid gastric infusion are to the renal hypertensive rat target organ protection function
Group dosage LVEDP-dp/dtmax (T (ms) Zuo Xinchong/body weight 24h urine protein
Normal group-2.8 ± 2.0 10.0 ± 4.8 2.9 ± 2.2 2.11 ± 0.35 46.8 ± 13.1
Model group-15.3 ± 6.1 3.9 ± 2.9 8.6 ± 3.1 3.23 ± 0.25 110.3 ± 41.0
Irbesartan 10+0.5 6.1 ± 3.6 10.9 ± 3.8 3.3 ± 3.6 2.23 ± 0.43 66.9 ± 18.7
+ folic acid 10+0.1 5.9 ± 3.2 8.2 ± 3.2 3.6 ± 3.2 2.65 ± 0.68 50.3 ± 28.0
10+0.08 10.2±3.4 7.3±4.4 8.6±3.1 2.41±0.39 70.3±31.3
10+0.04 9.3±4.8 6.9±2.9 5.6±3.9 2.55±0.53 59.3±18.8
Irbesartan 10 8.8 ± 3.3 9.2 ± 4.8 5.6 ± 4.4 2.65 ± 0.34 70.9 ± 21.9
Folic acid 0.08 16.3 ± 8.1 8.9 ± 4.3 8.9 ± 4.7 3.01 ± 0.43 89.3 ± 34.8
Embodiment 12. telmisartans+folic acid-collaborative hypotensive effect
Spontaneous hypertensive rat is available from Chinese Academy of Sciences's Shanghai Experimental Animal Center, and rat blood pressure raises after 6 ages in week, significantly raises after 8～10 ages in week, measures 1 week of rat blood pressure (the 1st, 6 day), and the rat of getting blood pressure stabilization is used for experiment.Spontaneous hypertensive rat, random packet, every group 10, be respectively model group (0.5%CMC-Na solution), telmisartan group (4mg/kg), folic acid group (0.5mg/kg), 1 group of (4+0.5) mg/kg of telmisartan+folic acid, 2 groups of (4+0.08) mg/kg of telmisartan+folic acid, 3 groups of (4+0.04) mg/kg of telmisartan+folic acid,, other establishes normal control group (n=10).Medicine is prepared with 0.5%CMC-Na solution, 1ml/100g, gastric infusion, every day 1 time, continuous 2 weeks.Measure after the administration administration in the 1st, 3,7,10,14 days 2 hours respectively and measure rat blood pressure.The results are shown in Table 3.
Telmisartan has significant hypotensive effect to spontaneous hypertensive rat, average maximum reducing percentage is 14.9 ± 4.3%, the folic acid list is used has slight hypotensive effect to two kidneys, one folder type Hypertensive Rats, average maximum reducing percentage is 3.1 ± 2.2%, both share the hypotensive effect enhancing, and average maximum reducing percentage is 20.3 ± 5.8%.Folic acid dosage acts on close in 0.04～0.5mg/kg scope.
Continuous 2 weeks of the folic acid gastric infusion of table 3 telmisartan+various dose are to spontaneity
The hypotensive effect of Hypertensive Rats (step-down percentage) (x ± s, n=10)
Behind group and the dosage medicine
(mmHg) d1 d3 d7 d10 d14
Normal group 3.5 ± 4.6 4.3 ± 2.1-3.7 ± 1.8-3.8 ± 2.5 3.6 ± 3.1
Model group 2.5 ± 2.8-2.7 ± 3.3-4.6 ± 3.3-2.7 ± 2.2 1.9 ± 2.7
4+0.5 10.1±3.5 ** 12.5±2.4 ** 15.2±3.5 ** 16.7±4.4 ** 17.9±5.1 **
4+0.08 9.9±4.5 * 12.9±3.9 ** 14.4±2.2 ** 17.7±3.7 ** 20.3±5.8 **
4+0.04 7.5±5.5 ** 9.6±2.6 ** 12.3±3.8 ** 13.8±2.6 ** 16.6±2.4 **
4 6.9±3.3 ** 10.0±3.8 ** 12.1±4.8 ** 9.9±2.6 ** 14.9±4.3 **
Folic acid 0.5 2.8 ± 2.8 1.6 ± 2.5 2.7 ± 2.8 3.1 ± 2.2 *2.6 ± 2.6 *
Compare * P＜0.05, * * P＜0.01 with model group;
Embodiment 13. irbesartans+vitamin B6-collaborative step-down, target organ protection function
Spontaneous hypertensive rat is available from Chinese Academy of Sciences's Shanghai Experimental Animal Center, and rat blood pressure raises after 6 ages in week, significantly raises after 8～10 ages in week, and measure 1 week of rat blood pressure (the 1st, 6 day) 15 ages in week, and the rat of getting blood pressure stabilization is used for experiment.Random packet, every group 12, be respectively model group, irbesartan group (10mg/kg), vitamin B6 group (1mg/kg), 1 group of (10+5) mg/kg of irbesartan+vitamin B6,2 groups of (10+1) mg/kg of irbesartan+vitamin B6,3 groups of (10+0.5) mg/kg of irbesartan+vitamin B6, other establishes normal control group (n=12).Medicine is prepared with 0.5%CMC-Na solution, 1ml/100g, gastric infusion, every day 1 time, continuous 14 weeks.The 5th, 9,14 all blood pressures before measuring administration respectively, after the administration are collected twenty-four-hour urine liquid after the last administration, measure 24h urine α 1 microglobulin, the heavy index (left ventricle mg/ body weight g) in chamber.The results are shown in Table 4, table 5.
With compare before the administration, the model group rat blood pressure slightly increases, and irbesartan+vitamin B6 group and single irbesartan group of using, the 5th week of administration, 9 weeks, 14 week the back blood pressures significantly descend, there were significant differences (P＜0.01) than model group.Single more remarkable with the antihypertensive effect of irbesartan and different levels drug combination.In addition, the drug combination group is single has more obvious hypotensive effect with the irbesartan group.
Rat twenty-four-hour urine α 1 microglobulin of irbesartan group and each horizontal drug combination group, left ventricular hypertrophy all are lower than than model group (not administration group).
Table 4 irbesartan+vitamin B6 gastric infusion is to the step-down percentage (%) of spontaneous hypertensive rat blood pressure
(x±s，n＝10～12)
The dosage successive administration
Group
(mg/kg) 9 all 14 weeks of 5 weeks
Normally-1.8 ± 4.1-2.3 ± 5.9 1.3 ± 4.3
Model--3.5 ± 3.1-10.6 ± 5.6-14.8 ± 4.4
10+5 18.2±4.3 ** 13.9±4.5 ** 13.2±5.8 **
Irbesartan+1,0+1 13.6 ± 2.4 *14.2 ± 5.8 *15.7 ± 5.1 *
Vitamin B6
10+0.5 10.0±5.3 ** 12.1±4.9 ** 14.4±3.2 **
Irbesartan 10 13.1 ± 3.7 *10.6 ± 3.5 *11.3 ± 3.8 *
Vitamin B6 1-2.8 ± 4.3-6.8 ± 6.9 *-8.3 ± 5.8 *
Compare with model group: * P＜0.05, * * P＜continuous 14 weeks of 0.01 table 5 irbesartan+vitamin B6 gastric infusion are to spontaneous hypertensive rat
Target organ protection function (leading indicator velocity of variation %)
Dosage left side heart weight/body weight 24h urine protein
Group
(mg/kg) (mg/g) (μg)
Normal group-2.32 ± 0.53 19.3 ± 6.8
Model group-3.33 ± 0.49 84.8 ± 34.2
10+5 38.2↓ 44.3↓
Irbesartan+
10+1 37.9↓ 40.2↓
Vitamin B6
10+0.05 26.9↓ 40.1↓
Irbesartan 10 20.0 ↓ 30.8 ↓
Vitamin B6 1 6.9 ↓ 8.3 ↓
Embodiment 14. irbesartans+vitamin B12-collaborative step-down, target organ protection function
With the narrow Wistar rat of 0.2mm silver brain clip left renal artery, it is the hypertension artery model that the back rat blood pressure rising of 14～15 weeks surpasses 150mmHg above.Random packet, every group 12, if model control group, irbesartan (10mg/kg) group, irbesartan+vitamin B12 1 group of (10+0.2mg/kg), irbesartan+vitamin B12 2 groups of (10+0.1mg/kg), irbesartan+vitamin B12 3 groups of (10+0.05mg/kg), vitamin B12 group (0.1mg/kg) groups, other gets 12 normal rats as the normal control group.Gastric infusion, continuous 13 weeks.The 5th, 9,13 all blood pressures before measuring administration respectively, after the administration are collected twenty-four-hour urine liquid after the last administration, measure 24h urine α 1 microglobulin, the heavy index (left ventricle mg/ body weight g) in chamber.The results are shown in Table 6, table 7.
With compare before the administration, the model group rat blood pressure slightly increases, and irbesartan+vitamin B12 group and single irbesartan group of using, the 5th week of administration, 9 weeks, 13 week the back blood pressures significantly descend, there were significant differences (P＜0.01) than model group.Single more remarkable with the antihypertensive effect of irbesartan and different levels drug combination.In addition, the drug combination group is single has more obvious hypotensive effect with the irbesartan group.
Rat twenty-four-hour urine α 1 microglobulin of irbesartan group and each horizontal drug combination group, left ventricular hypertrophy all are lower than than model group (not administration group).
Table 6 irbesartan+vitamin B12 gastric infusion is to the step-down percentage (%) of renal hypertensive rat blood pressure
(x±s，n＝10～12)
The dosage successive administration
Group
(mg/kg) 9 all 13 weeks of 5 weeks
Normally-2.0 ± 6.5 3.3 ± 4.5 2.9 ± 4.0
Model-2.3 ± 4.0-2.3 ± 4.3-3.0 ± 3.9
10+0.2 10.2±4.7 ** 14.9±4.9 ** 16.3±5.2 **
Irbesartan+
10+0.1 8.2±4.2 ** 10.9±3.3 ** 15.7±5.2 **
Vitamin B12
10+0.05 9.3±3.5 ** 14.0±3.8 ** 15.6±2.2 **
Irbesartan 10 7.7 ± 4.3 *9.6 ± 4.3 *10.3 ± 4.2 *
Vitamin B12 0.1 3.3 ± 3.2-2.8 ± 3.9 *-5.9 ± 2.3 *
Compare with model group: * P＜0.05, * * P＜0.01
Continuous 13 weeks of table 7 irbesartan+vitamin B12 gastric infusion are to renal hypertensive rat
Target organ protection function (leading indicator velocity of variation %)
Dosage left side heart weight/body weight 24h urine protein
Group
(mg/kg) (mg/g) (μg)
Normal group-2.28 ± 0.37 45.8 ± 10.5
Model group-3.50 ± 0.25 99.1 ± 33.8
10+0.2 33.5↓ 53.5↓
Irbesartan
10+0.1 36.1↓ 49.2↓
+ vitamin B12
10+0.05 40.0↓ 35.7↓
Irbesartan 10 26.8 ↓ 33.8 ↓
Vitamin B12 0.1 5.1 ↓ 8.4 ↓

Claims (18)

1. a compound is characterized in that: have following structure.
2. pharmaceutical composition, it is characterized in that: this pharmaceutical composition is by AT 1The described compound of receptor antagonist class material and claim 1 is formed.
3. pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group, this pharmaceutical composition is by the AT of treatment significant quantity 1One or more and pharmaceutically acceptable carrier in the vitamin B group of a kind of, the treatment significant quantity in receptor antagonist and active metabolite thereof or the salt are formed: AT wherein 1The content of receptor antagonist and active metabolite thereof, ester class or salt is 4～800mg, and the content of vitamin B group is 0.1～50mg.
4. the pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist and active metabolite thereof, ester class or salt are selected from a kind of in losartan, valsartan, irbesartan, telmisartan, Candesartan, eprosartan, Olmesartan, Tasosartan and active metabolite thereof, ester class or the salt.
5. the pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described vitamin B group is selected from one or more in vitamin B6, vitamin B12, folic acid or the calcium leucovorin.
6. the pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist is selected from losartan or Losartan Potassium; Vitamin B group is folic acid or calcium leucovorin; AT wherein 1The content of receptor antagonist is 50～100mg, and the content of vitamin B group is 0.2～5mg.
7. the pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist is selected from losartan or Losartan Potassium, and vitamin B group is a vitamin B6; AT wherein 1The content of receptor antagonist is 50～100mg, and the content of vitamin B group is 5～50mg.
8. the pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist is selected from losartan or Losartan Potassium; Vitamin B group is a vitamin B12; AT wherein 1The content of receptor antagonist is 50～100mg, and the content of vitamin B group is 0.25～2mg.
9. the pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist is a valsartan, and vitamin B group is folic acid or calcium leucovorin; Wherein valsartan content is 80～160mg; The content of vitamin B group is 0.2～5mg.
10. the pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist is a valsartan; Vitamin B group is a vitamin B6; Wherein valsartan content is 80～160mg; The content of vitamin B group is 5～50mg.
11. the pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist is a valsartan; Vitamin B group is a vitamin B12; Wherein valsartan content is 80～160mg; The content of vitamin B group is 0.25～2mg.
12. the pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist is an irbesartan; Vitamin B group is folic acid or calcium leucovorin; Wherein irbesartan content is 150～300mg; The content of vitamin B group is 0.2～5mg.
13. the pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist is an irbesartan; Vitamin B group is a vitamin B6; Wherein irbesartan content is 150～300mg; The content of vitamin B group is 5～50mg.
14. the pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist is an irbesartan; Vitamin B group is a vitamin B12; Wherein irbesartan content is 150～300mg; The content of vitamin B group is 0.25～2mg.
15 pharmaceutical compositions that contain angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist is a telmisartan, and vitamin B group is a folic acid; Wherein telmisartan content is 20～80mg, and the content of vitamin B group is 0.2～5mg.
16 pharmaceutical compositions that contain angiotensin II receptor antagonists and vitamin B group according to claim 3 is characterized in that: described AT 1Receptor antagonist is a Candesartan, and vitamin B group is a folic acid; Wherein Candesartan content is 8～32mg, and the content of vitamin B group is 0.2～5mg.
17., it is characterized in that according to any one described pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group in the claim 3 to 16: described pharmaceutical composition can be made into conventional tablet, conventional capsule, granule, slow releasing tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coated tablet, enteric coated capsule, delayed-release tablet, regularly/formulations such as position releasing piece, slow releasing capsule, controlled release capsule, the capsule that contains micropill or small pieces, the pH dependent form capsule that contains micropill or small pieces, granule, oral liquid, film, patch.
18. according to any one described pharmaceutical composition that contains angiotensin II receptor antagonists and vitamin B group in the claim 3 to 17, it is characterized in that: described pharmaceutical composition is used for prevention, treatment and delay hypertension and relative disease thereof, the target organ damage that hypertension causes comprises left ventricular hypertrophy, stenocardia, myocardial infarction, heart failure, optimum arteriolar nephrosclerosis, pernicious arteriolar nephrosclerosis, renal failure, retinal arteriosclerosis, the hypertension ocular fundus pathology, cerebral apoplexy etc., and and closely-related disease of hypertension such as atherosclerosis, coronary heart disease, dissection of aorta and diabetes.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009046632A1 (en) * 2007-09-28 2009-04-16 Beijing Huaanfo Biomedical Research Center, Inc Pharmaceutical composition containing angiotensin ii receptor blocker and b family vitamins and use thereof
CN101869710A (en) * 2009-04-24 2010-10-27 北京奥萨医药研究中心有限公司 Antihypertensive medical composite
CN101199847B (en) * 2006-11-11 2011-10-12 深圳奥萨医药有限公司 Drug compound for AT1 receptor antagonist/diuretic/folate coupling and uses thereof
CN101199848B (en) * 2006-11-11 2012-05-23 深圳奥萨医药有限公司 Drug compound for Ca channel retarder/diuretic/ folate coupling and function
CN101683526B (en) * 2008-05-29 2013-01-02 北京奥萨医药研究中心有限公司 Pharmaceutical composition containing angiotensin II receptor antagonist, B vitamins and gingo biloba extract
CN106310267A (en) * 2015-09-23 2017-01-11 深圳奥萨制药有限公司 Composition of enkephalinase inhibitor, angiotensin receptor blocker and folic acid
CN109799304A (en) * 2019-03-27 2019-05-24 苏州旭辉检测有限公司 The detection method of a variety of smooth hypotensors of sand in a kind of urine specimen

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101199847B (en) * 2006-11-11 2011-10-12 深圳奥萨医药有限公司 Drug compound for AT1 receptor antagonist/diuretic/folate coupling and uses thereof
CN101199848B (en) * 2006-11-11 2012-05-23 深圳奥萨医药有限公司 Drug compound for Ca channel retarder/diuretic/ folate coupling and function
WO2009046632A1 (en) * 2007-09-28 2009-04-16 Beijing Huaanfo Biomedical Research Center, Inc Pharmaceutical composition containing angiotensin ii receptor blocker and b family vitamins and use thereof
CN101683526B (en) * 2008-05-29 2013-01-02 北京奥萨医药研究中心有限公司 Pharmaceutical composition containing angiotensin II receptor antagonist, B vitamins and gingo biloba extract
CN101869710A (en) * 2009-04-24 2010-10-27 北京奥萨医药研究中心有限公司 Antihypertensive medical composite
CN106310267A (en) * 2015-09-23 2017-01-11 深圳奥萨制药有限公司 Composition of enkephalinase inhibitor, angiotensin receptor blocker and folic acid
CN109799304A (en) * 2019-03-27 2019-05-24 苏州旭辉检测有限公司 The detection method of a variety of smooth hypotensors of sand in a kind of urine specimen

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