CN1587270A - Medicinal composition contaniing angiotensin invertase inhibitor and vitamin B - Google Patents
Medicinal composition contaniing angiotensin invertase inhibitor and vitamin B Download PDFInfo
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- CN1587270A CN1587270A CN 200410071056 CN200410071056A CN1587270A CN 1587270 A CN1587270 A CN 1587270A CN 200410071056 CN200410071056 CN 200410071056 CN 200410071056 A CN200410071056 A CN 200410071056A CN 1587270 A CN1587270 A CN 1587270A
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Abstract
The medicine composition consists of one of ACE1, its active metabolism product and salt in treating effective amount of 0.5-100 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 advantages of raising the treating effect of blood pressure lowering ACE1 medicine, strengthening the protecting effect of blood pressure lowering ACE1 medicine on target organ and reducing the incidence rate of hemorrhage of the ocular fundus, angina pectoris, myocardial infarction and other complications.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor 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 reach the controlling blood pressure target, and two kinds of medicines can be write out a prescription separately or are the compound preparation of fixed dosage (Chinese hypertension prevention and control guide Drafting Committee.China's 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-convertion enzyme inhibitor (ACEI) is the most frequently used medicine of clinic control hypertension, main by suppressing the activity of angiotensin-converting enzyme (ACE), reduce the content of Angiotensin II and aldosterone, can reduce simultaneously the bradykinin degraded, promote prostaglandin(PG) to discharge, also can suppress ACE in local organization such as kidney, vessel wall and the brain, vasodilator, reduce total peripheral resistance, bring high blood pressure down, be used for the treatment of essential hypertension.Enalapril (enalapril) is the long-acting ACE inhibitor of a kind of non-sulfydryl, and only need once oral every day, and common dose is 5～20mg, and clinical being widely used in treated light, moderate essential hypertension.Other clinical ACEI commonly used also comprise: captopril (captopril), Yipingshu (cilazapril), benazepril (benazepril), perindopril (perindopril), Ramipril (ramipril), fosinopril (fosinopril) etc.
Also there is certain problem in ACEI depressor in clinical application, at first its efficacy of antihypertensive treatment has certain limit, and lot of documents report total effective rate only is about 60%, 40% invalid or curative effect is not remarkable.Compare with other depressor; the target organ protection function of ACEI depressor does not have clear superiority; ESC's hypertension therapeutic guide report in 2003; to comprising 46553 at random in 5 experimental studies of patient; the curative effect that compares ACEI and conventional medicament; evaluation index comprises general mortality rate, cardiovascular death rate, all cardiovascular events, myocardial infarction and heart failure, and the result does not find that ACEI is better than old medicine aspect above-mentioned.Hyperhomocysteinemiainjury is the independent risk factor of hypertension incidence, and ACEI depressor 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. Chinese 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 ACEI depressor above shortcomings, provide a kind of and be better than ACEI aspect efficacy of antihypertensive treatment and the target-organ protection, and the pharmaceutical composition that toxicity does not increase.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group is made up of one or more and pharmaceutically acceptable carrier in the vitamin B group of a kind of, the treatment significant quantity in the treatment ACEI of significant quantity and active metabolite or the salt; Wherein the content of ACEI and active metabolite thereof or salt is 0.5～100mg, and the content of vitamin B group is 0.1～50mg.
Described ACEI and active metabolite thereof or salt are selected from captopril (Captopril), enalapril (Enalapril), quinapril (Quinapril), benazepril (Benarapril), Ramipril (ramipril), fosinopril (fosinopril), lisinopril (lisinopril), Yipingshu (Cilazpril), PERINDOPRIL (perindopril), delapril (Delapril), moexipril (Moexipril), spirapril (Spirapril), imidapril (Imidapril), a kind of in Trolapril (Trandolapril) and alacepril (Alacepril) and meta-bolites or the salt.
By experimental study, the content of ACEI is respectively: captopril (12.5～100mg), enalapril (2.5～40mg), quinapril (5～80mg), benazepril (2.5～40mg), Ramipril (1.25～20mg), fosinopril (10～80mg), lisinopril (2.5～80mg), Yipingshu (1.25～5mg), perindopril (2～16mg), delapril (15～120mg), moexipril (3.75～30mg), spirapril (3～30mg), imidapril (2.5～40mg), Trolapril (0.5～4mg), (12.5～100mg), the active metabolite of above-mentioned substance or salt content are equal to corresponding above-mentioned substance content alacepril.
The better in the present invention treatment significant quantity of these medicines is respectively: captopril (25～100mg), enalapril (5～40mg), quinapril (10～40mg), benazepril (5～40mg), Ramipril (2.5～20mg), fosinopril (10～40mg), lisinopril (5～40mg), Yipingshu (2.5～5mg), perindopril (4～8mg), delapril (15～60mg), moexipril (7.5～30mg), spirapril (3～15mg), imidapril (2.5～10mg), Trolapril (0.5～2mg), (25～100mg), the active metabolite of above-mentioned substance or salt content are equal to corresponding above-mentioned substance content alacepril.
Described vitamin B group is selected from one or more in vitamin B6, vitamin B12, folic acid and the calcium leucovorin.
Described vitamin B6 class material 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 class material 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 class substances content is 0.1～2mg, and vitamin B6 class substances content is 0.5～50mg.Its better treatment significant quantity is respectively: folic acid class material 0.2～5mg, vitamin B12 class material 0.25～2mg, vitamin B6 class material 5～50mg.
The present invention is preferably by the component of the following content pharmaceutical composition as activeconstituents: wherein ACEI be selected from enalapril (5～40mg), benazepril (5～40mg), fosinopril (10～40mg), Ramipril (2.5～20mg), Yipingshu (2.5～5mg), perindopril (4～8mg) and active metabolite or salt in a kind of; Vitamin B group be selected from folic acid (0.2～5mg), calcium leucovorin (0.2～5mg), vitamin B12 (0.25～2mg) and vitamin B6 (one or more in 5～50mg).
Described ACEI is enalapril maleate or enalaprilat, and vitamin B group is folic acid or calcium leucovorin; Wherein the content of ACEI is 5～40mg, and the content of vitamin B group is 0.2～5mg.
Described ACEI is enalapril maleate or enalaprilat, and vitamin B group is a vitamin B6; Wherein the content of ACEI is 5～40mg, and the content of vitamin B group is 5～50mg.
Described ACEI is enalapril maleate or enalaprilat, and vitamin B group is a vitamin B12; Wherein the content of ACEI is 5～40mg; The content of vitamin B group is 0.25～2mg.
Described ACEI is benazepril hydrochloride or benazeprilat, and vitamin B group is folic acid or calcium leucovorin; Wherein the content of ACEI is 5～40mg; The content of vitamin B group is 0.2～5mg.
Described ACEI is benazepril hydrochloride or benazeprilat, and vitamin B group is B6; Wherein the content of ACEI is 5～40mg, and the content of vitamin B group is 5～50mg.
Described ACEI is benazepril hydrochloride or benazeprilat, and vitamin B group is B12; Wherein the content of ACEI is 5～40mg, and the content of vitamin B group is 0.25～2mg.
Described ACEI is selected from fosinopril, and vitamin B group is folic acid or calcium leucovorin; Wherein the content of ACEI is 10～40mg, and the content of vitamin B group is 0.2～5mg.
Described ACEI is selected from fosinopril, and vitamin B group is B6; Wherein the content of ACEI is 10～40mg, and the content of vitamin B group is 5～50mg.
Described ACEI is selected from fosinopril, and vitamin B group is B12; Wherein the content of ACEI is 10～40mg; The content of vitamin B group is 0.25～2mg.
Described ACEI is selected from Ramipril, and vitamin B group is folic acid or calcium leucovorin; Wherein the content of ACEI is 2.5～20mg; The content of vitamin B group is 0.2～5mg.
Described ACEI is selected from Ramipril, and vitamin B group is B6, and wherein the content of ACEI is 2.5～20mg, and the content of vitamin B group is 5～50mg.
Described ACEI is selected from Ramipril, and vitamin B group is B12, and wherein the content of ACEI is 2.5～20mg; The content of vitamin B group is 0.25～2mg.
Described ACEI is selected from Yipingshu, and vitamin B group is selected from folic acid; Wherein the content of ACEI is 2.5～5mg; The content of vitamin B group is 0.2～5mg.
Described ACEI is selected from perindopril, and vitamin B group is selected from folic acid; Wherein the content of ACEI is 4～8mg; The content of vitamin B group is 0.2～5mg.
Originally discover that the vitamin B group list when share with ACEI, can strengthen the hypotensive effect of ACEI medicine with slight hypotensive effect is arranged.The vitamin B group list is used has slight provide protection to the target organ damage that is caused by hypertension, can strengthen it causes target organ damage to hypertension provide protection with the ACEI drug combination.
This 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.
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.
The present invention is applied to 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, 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 the curative effect of ACEI depressor; strengthen the target organ protection function of ACEI depressor, reduce the incidence of complication such as 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
Enalapril maleate 5.0g (enalapril maleate meter)
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 enalapril maleate, 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
Enalapril maleate 10.0g (enalapril maleate meter)
Folic acid 0.8g
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 enalapril maleate, 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 3. preparation of pharmaceutical compositions
Prescription:
Benazepril hydrochloride 10.0g (benazepril hydrochloride meter)
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 benazepril hydrochloride, 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 4. preparation of pharmaceutical compositions
Prescription:
Fosinopril 10.0g
Calcium leucovorin 1.0g
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 fosinopril, 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) 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:
Ramipril 10.0g
Folic acid 5.0g
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 by the equivalent incremental method with above-mentioned auxiliary material, with No. 3 capsule cans.
Embodiment 6. preparation of pharmaceutical compositions
Prescription:
Yipingshu 2.5g
Vitamin B6 5.0g
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 by the equivalent incremental method with above-mentioned auxiliary material, with No. 3 capsule cans.
Embodiment 7. preparation of pharmaceutical compositions
Prescription:
Perindopril 4.0g
Vitamin B12 1.0g
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 perindopril, the vitamin B12 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) 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:
Fosinopril 10.0g
Folic acid 1.0g
Vitamin B12 1.0g
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 fosinopril, folic acid, the vitamin B12 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) 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) add an amount of Magnesium Stearate mixing, compressing tablet behind the assay in particle.
Embodiment 9. preparation of pharmaceutical compositions
Prescription:
Enalapril maleate 10.0g
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.
The collaborative hypotensive effect of embodiment 10. enalapril maleates and folic acid compatibility
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 8～10 weeks surpasses 150mmHg above.With the Hypertensive Rats random packet, be respectively model group (giving solvent), enalapril group (1mg/kg), 1 group of (1+0.04) mg/kg of enalapril+folic acid, 2 groups of (1+0.1) mg/kg of enalapril+folic acid, 3 groups of (1+0.5) mg/kg of enalapril+folic acid, 4 groups of (1+1) mg/kg of enalapril+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.
The result shows: folic acid is used separately has slight hypotensive effect to two kidneys, one folder type Hypertensive Rats, and average step-down percentage rate is 0～3.2%.Enalapril 1mg/kg gastric infusion has remarkable hypotensive effect to two kidneys, one folder type Hypertensive Rats, and average step-down percentage is 17.6～24.9%; After share with folic acid, average step-down percentage rate is 17.6～29.6%.
Conclusion: folic acid and enalapril share, and can strengthen the hypotensive effect of enalapril, and folic acid dosage acts on close in 0.04～1.0mg/kg scope.
Embodiment 11. enalapril maleates+folic acid is worked in coordination with target organ protection function
With the narrow Wistar rat of 0.2mm silver brain clip left renal artery, it is hypertension animal model that the back rat blood pressure rising of 14～15 weeks surpasses 150mmHg above.Random packet, if model control group, enalapril+folic acid (1+0.5mg/kg), enalapril+folic acid (1+0.1mg/kg), enalapril+folic acid (1+0.08mg/kg), enalapril+folic acid (1+0.04mg/kg), enalapril (1mg/kg) group, folic acid (0.08mg/kg) group, other gets 12 normal rats as the normal control group.Gastric infusion, continuous 13～15 weeks.Measure 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.
The folic acid list suppresses left ventricular hypertrophy with the diastolic function that can independent, slightly improve the renal hypertensive rat heart.Improving aspect the heart function, folic acid group, single LVEDP (reflection cardiac preload) with enalapril maleate group and each horizontal drug combination group, T value (reflecting 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 enalapril maleate and drug combination.Aspect the effect that suppresses left ventricular hypertrophy, between each medication group, also observed similar result equally.
Continuous 2 weeks of table 1 enalapril maleate+various dose folic acid gastric infusion are to two kidneys, one folder type hypertension
The hypotensive effect of rat (step-down percentage) (x ± s, n=12)
Behind group and the dosage medicine
(mg/kg) d1 d3 d7 d10 d14
Normal group-1.1 ± 9.3-1.2 ± 7.8-0.3 ± 1.8 1.0 ± 7.8 0.6 ± 2.3
Model group-1.3 ± 5.4 1.2 ± 5.1 1.4 ± 4.4 1.9 ± 3.9 2.4 ± 5.2
1+1 17.6±4.2
** 19.7±3.7
** 23.3±3.7
** 25.4±4.2
** 29.2±5.1
**
1+0.5 18.6±2.7
** 19.7±4.2
** 24.7±4.0
** 24.6±2.7
** 29.6±2.5
**
1+0.1 17.1±4.7
** 20.1±2.9
** 25.7±3.3
** 24.5±4.5
** 28.4±3.1
**
1+0.04 19.5±2.4
** 18.2±3.0
** 24.3±3.2
** 23.6±3.6
** 26.4±4.5
**
1 18.3±4.1
** 17.6±3.3
** 22.5±4.6
** 24.9±4.9
** 23.3±5.8
**
Folic acid 0.5-1.6 ± 1.6-1.4 ± 2.3 1.3 ± 2.5 3.2 ± 1.7 2.5 ± 1.4
Compare * * P＜0.01 with model group;
Continuous 13～15 weeks of table 2 enalapril maleate+folic acid gastric infusion are to the renal hypertensive rat target organ protection function
Dosage LVEDP-dp/dtmax (Zuo Xinchong/body weight 24h urine protein
Group T (ms)
(mg/kg) (mmHg) ×103mmHg/s) (mg/g) (μg)
Normal group-1.0 ± 1.4 8.5 ± 1.2 4.8 ± 0.9 1.92 ± 0.23 17.3 ± 3.8
Model group-12.9 ± 4.0 6.1 ± 1.6 9.2 ± 1.3 2.87 ± 0.19 39.5 ± 11.9
Enalapril 1+0.5 3.6 ± 2.8 7.9 ± 1.1 5.0 ± 0.6 1.98 ± 0.34 24.7 ± 8.1
+ folic acid 1+0.1 1.3 ± 2.2 7.8 ± 1.2 5.5 ± 1.3 2.07 ± 0.27 22.9 ± 6.9
1+0.08 2.8±1.8 7.4±0.9 5.5±1.7 2.41±0.21 25.5±8.6
1+0.04 4.6±2.7 7.2±1.5 5.3±1.1 2.21±0.33 27.6±7.0
Enalapril 1 4.7 ± 4.0 6.9 ± 1.8 7.3 ± 3.4 2.33 ± 0.27 27.3 ± 7.0
Folic acid 0.08 6.9 ± 3.8 6.2 ± 3.6 8.1 ± 1.6 2.58 ± 0.30 30.9 ± 5.4
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 enalapril maleate group and each horizontal drug combination group.Wherein drug combination group improvement degree or reduction level are the most obvious.Conclusion: folic acid to renal hypertensive rat have independently, the appropriateness step-down and the effect of target-organ protection.Enalapril maleate and enalapril maleate 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.
The collaborative hypotensive effect of embodiment 12. benazepril hydrochloride and folic acid
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, be divided into 7 groups at random, every group 10, be respectively model group (0.5%CMC-Na solution), benazepril hydrochloride group (1mg/kg), folic acid group (0.5mg/kg), 1 group of (1+1) mg/kg of benazepril hydrochloride+folic acid, 2 groups of (1+0.5) mg/kg of benazepril hydrochloride+folic acid, 3 groups of (1+0.08) mg/kg of benazepril hydrochloride+folic acid, 4 groups of (1+0.04) mg/kg of benazepril hydrochloride+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.
Benazepril hydrochloride has significant hypotensive effect to spontaneous hypertensive rat, average maximum reducing percentage is 12.0 ± 2.3%, the folic acid list is used has slight hypotensive effect to two kidneys, one folder type Hypertensive Rats, average maximum reducing percentage is 2.9 ± 2.0%, both share the hypotensive effect enhancing, and average maximum reducing percentage is 15.9 ± 3.7%.Folic acid dosage acts on close in 0.04～1mg/kg scope.
Continuous 2 weeks of the folic acid gastric infusion of table 3 benazepril hydrochloride+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-2.5 ± 4.6-2.3 ± 5.7-1.7 ± 2.8-0.8 ± 4.1 0.6 ± 3.7
Model group-1.5 ± 2.2-1.7 ± 3.1-1.6 ± 3.0-1.7 ± 2.6-0.9 ± 2.2
1+1 6.9±3.3
** 8.4±3.8
** 13.8±2.7
** 15.9±3.7 14.5±3.0
**
1+0.5 7.1±2.8
** 8.5±3.4
** 12.2±2.5
** 14.7±2.3
** 15.8±3.3
**
1+0.08 7.1±4.5
* 7.9±3.1
** 14.4±2.2
** 15.7±3.7
** 14.9±2.0
**
1+0.04 7.5±2.5
** 9.6±2.6
** 7.5±2.8
** 11.8±2.6
** 12.6±2.4
**
1 7.3±2.3
** 8.0±1.6
** 11.1±1.8
** 9.7±1.6
** 12.0±2.3
**
Folic acid 0.5-0.8 ± 1.8-1.0 ± 1.5 0.7 ± 0.8 1.1 ± 1.2
*2.9 ± 2.0
*
Compare * P＜0.05, * * P＜0.01 with model group;
Embodiment 13. benazepril hydrochloride+folic acid is to the target organ coordinating protection effect of Hypertensive Rats
Spontaneous hypertensive rat is available from Chinese Academy of Sciences's Shanghai Experimental Animal Center, and rat blood pressure raises after 8 ages in week, significantly raises after 15 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, be divided into 7 groups at random, every group 10, be respectively model group (0.5%CMC-Na solution), benazepril hydrochloride group (1mg/kg), folic acid group (0.5mg/kg), 1 group of (1+1) mg/kg of benazepril hydrochloride+folic acid, 2 groups of (1+0.5) mg/kg of benazepril hydrochloride+folic acid, 3 groups of (1+0.08) mg/kg of benazepril hydrochloride+folic acid, 4 groups of (1+0.04) mg/kg of benazepril hydrochloride+folic acid, other establishes normal control group (n=10).Gastric infusion, every day 1 time, continuous 13～15 weeks.Measure 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 4.
The folic acid list suppresses left ventricular hypertrophy with the diastolic function that can independent, slightly improve the spontaneous hypertensive rat heart.Improving aspect the heart function, folic acid group, single LVEDP (reflection cardiac preload) with benazepril hydrochloride group and each horizontal drug combination group, T value (reflecting 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 benazepril hydrochloride 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 benazepril hydrochloride group and each horizontal drug combination group.Wherein drug combination group improvement degree or reduction level are the most obvious.Conclusion: folic acid to spontaneous hypertensive rat have independently, the appropriateness step-down and the effect of target-organ protection.Benazepril hydrochloride and benazepril hydrochloride compatibility folic acid group have the effect of significant step-down and target-organ protection to spontaneous hypertensive rat, and it is stronger to target organ protection function wherein to unite the compatibility group.
Continuous 13～15 weeks of table 4 benazepril hydrochloride+folic acid gastric infusion are to the spontaneous hypertensive rat target organ protection function
Dosage LVEDP-dp/dtmax (Zuo Xinchong/body weight 24h urine protein
Group T (ms)
(mg/kg) (mmHg) ×10
3mmHg/s) (mg/g) (μg)
Normal group--2.8 ± 2.4 10.5 ± 3.8 6.9 ± 3.8 2.12 ± 0.44 27.9 ± 8.6
Model group-9.9 ± 6.0 5.5 ± 3.7 12.2 ± 4.4 3.01 ± 0.25 95.9 ± 21.1
Benazepril 1+0.5 2.9 ± 3.6 8.2 ± 4.4 6.8 ± 3.6 2.42 ± 0.44 54.9 ± 18.2
+ folic acid 1+0.1 2.3 ± 3.4 6.8 ± 4.0 7.5 ± 3.0 2.38 ± 0.31 42.6 ± 20.1
1+0.08 4.1±2.3 7.0±3.9 6.9±3.7 2.31±0.21 50.8±18.9
1+0.04 3.9±6.7 6.2±4.5 5.3±2.0 2.41±0.33 67.4±17.0
Benazepril 1 5.7 ± 4.0 7.3 ± 3.8 7.3 ± 2.8 2.47 ± 0.27 60.3 ± 27.3
Folic acid 0.08 8.2 ± 4.0 9.0 ± 3.6 11.1 ± 6.2 2.66 ± 0.45 75.3 ± 25.4
The embodiment 14. fosinoprils+collaborative step-down of vitamin B6 compatibility, 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, fosinopril group (1mg/kg), vitamin B6 group (1mg/kg), 1 group of (1+5) mg/kg of fosinopril+vitamin B6,2 groups of (1+1) mg/kg of fosinopril+vitamin B6,3 groups of (1+0.5) mg/kg of fosinopril+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 5, table 6.
During 14 weeks of successive administration, add up to 6 Hypertensive Rats death, no significant difference between administration group and model group.With compare before the administration, the model group rat blood pressure slightly increases, and fosinopril+vitamin B6 group and single fosinopril 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.Model group, vitamin B6 1mg/kg, fosinopril 1mg/kg group, fosinopril+vitamin B6 group (1+0.5) mg/kg, (1+1) mg/kg, (1+5) mg/kg the 14th all average step-down percentage are respectively-11.0 ± 2.9% ,-2.3 ± 3.8%, 10.3 ± 3.8%, 12.8 ± 5.2%, 12.7 ± 3.1%, 15.3 ± 5.0%.Show that vitamin B6 has slight hypotensive effect, single more remarkable with the antihypertensive effect of fosinopril and different levels drug combination.In addition, the drug combination group is single has more obvious hypotensive effect with the fosinopril group.
Table 5 fosinopril+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--2.8 ± 9.2-5.3 ± 8.3-4.3 ± 5.9
Model--5.5 ± 2.8-8.1 ± 4.8-11.0 ± 2.9
Fosinopril+1+5 15.2 ± 5.0
*15.9 ± 6.7
*15.3 ± 5.0
*
Vitamin B6 1+1 14.2 ± 5.4
*14.2 ± 3.8
*12.7 ± 3.1
*
1+0.5 14.0±3.5
** 14.7±4.3
** 12.8±5.2
**
Fosinopril 1 13.1 ± 3.7
*10.6 ± 3.5
*10.3 ± 3.8
*
Vitamin B6 1-1.3 ± 4.1-0.8 ± 4.9
*-2.3 ± 3.8
*
Compare with model group: * P＜0.05, * * P＜0.01
The vitamin B6 list is with independent, slightly improving the spontaneous hypertensive rat renal function, suppressing left ventricular hypertrophy.Rat twenty-four-hour urine α 1 microglobulin of fosinopril group and each horizontal drug combination group, left ventricular hypertrophy all are lower than than model group (not administration group).
Continuous 14 weeks of table 6 fosinopril+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-2.12 ± 0.33 37.3 ± 8.8
Model group-3.17 ± 0.29 109.5 ± 31.9
1+5 33.2↓ 50.5↓
Fosinopril
1+1 37.9↓ 40.2↓
+ vitamin B6
1+0.05 26.0↓ 45.1↓
Fosinopril 1 26.4 ↓ 36.1 ↓
Vitamin B6 1 8.1 ↓ 11.9 ↓
The embodiment 15. Ramiprils+collaborative step-down of vitamin B12 compatibility, 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, Ramipril (1mg/kg) group, Ramipril+vitamin B12 1 group of (1+0.2mg/kg), Ramipril+vitamin B12 2 groups of (1+0.1mg/kg), Ramipril+vitamin B12 3 groups of (1+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 7, table 8.
With compare before the administration, the model group rat blood pressure slightly increases, and Ramipril+vitamin B12 group and single Ramipril 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.Show that vitamin B12 has slight hypotensive effect, single more remarkable with the antihypertensive effect of Ramipril and different levels drug combination.In addition, the drug combination group is single has more obvious hypotensive effect with the Ramipril group.
The vitamin B12 list is with independent, slightly improving the spontaneous hypertensive rat renal function, suppressing left ventricular hypertrophy.Rat twenty-four-hour urine α 1 microglobulin of Ramipril group and each horizontal drug combination group, left ventricular hypertrophy all are lower than than model group (not administration group).
Table 7 Ramipril+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--1.8 ± 7.3-4.3 ± 6.6-3.8 ± 6.4
Model--4.3 ± 3.2-5.3 ± 5.7-8.0 ± 3.2
Ramipril+1+0.2 12.2 ± 3.2
*11.9 ± 6.1
*13.3 ± 4.3
*
1+0.1 13.2±5.8
** 12.9±4.8
** 12.7±5.2
**
Vitamin B12 1+0.05 10.0 ± 2.5
*14.0 ± 3.3
*11.6 ± 2.2
*
Ramipril 1 10.1 ± 2.1
*9.6 ± 3.1
*9.3 ± 4.2
*
Vitamin B12 0.1-2.3 ± 3.2-6.8 ± 6.9
*-10.3 ± 4.3
*
Compare with model group: * P＜0.05, * * P＜0.01
Continuous 13 weeks of table 8 Ramipril+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-2.01 ± 0.45 10.3 ± 4.0
Model group-3.33 ± 0.49 129.1 ± 41.3
1+0.2 43.0↓ 40.1↓
Ramipril
1+0.1 30.4↓ 29.3↓
+ vitamin B12
1+0.05 36.3↓ 35.1↓
Ramipril 1 20.4 ↓ 26.3 ↓
Vitamin B12 0.1 3.1 ↓ 2.9 ↓
Claims (21)
1. a compound is characterized in that: have following structure.
2. pharmaceutical composition, it is characterized in that: this pharmaceutical composition is made up of ACEI material and the described compound of claim 1.
3. pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group is made up of one or more and pharmaceutically acceptable carrier in the vitamin B group of a kind of, the treatment significant quantity in the ACEI of treatment significant quantity and active metabolite or the salt; Wherein the content of ACEI and active metabolite thereof or salt is 0.5～100mg, and the content of vitamin B group is 0.1～50mg.
4. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group according to claim 3 is characterized in that: described ACEI and active metabolite thereof or salt are selected from a kind of in captopril, enalapril, quinapril, benazepril, Ramipril, fosinopril, lisinopril, Yipingshu, PERINDOPRIL, delapril, moexipril, spirapril, imidapril, Trolapril, alacepril and active metabolite thereof or the salt.
5. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor 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 and the calcium leucovorin.
6. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group according to claim 3 is characterized in that: described ACEI is enalapril maleate or enalaprilat, and vitamin B group is folic acid or calcium leucovorin; Wherein the content of ACEI is 5～40mg, and the content of vitamin B group is 0.2～5mg.
7. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group according to claim 3 is characterized in that: described ACEI is enalapril maleate or enalaprilat, and vitamin B group is a vitamin B6; Wherein the content of ACEI is 5～40mg; The content of vitamin B group is 5～50mg.
8. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group according to claim 3 is characterized in that: described ACEI is enalapril maleate or enalaprilat, and vitamin B group is a vitamin B12; Wherein the content of ACEI is 5～40mg, and the content of vitamin B group is 0.25～2mg.
9. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group according to claim 3 is characterized in that: described ACEI is benazepril hydrochloride or benazeprilat; Vitamin B group is folic acid or calcium leucovorin; Wherein the content of ACEI is 5～40mg; The content of vitamin B group is 0.2～5mg.
10. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group according to claim 3 is characterized in that: described ACEI is benazepril hydrochloride or benazeprilat; Vitamin B group is B6; Wherein the content of ACEI is 5～40mg; The content of vitamin B group is 5～50mg.
11. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group according to claim 3 is characterized in that: described ACEI is benazepril hydrochloride or benazeprilat; Vitamin B group is B12; Wherein the content of ACEI is 5～40mg; The content of vitamin B group is 0.25～2mg.
12. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group according to claim 3 is characterized in that: described ACEI is selected from fosinopril, vitamin B group is folic acid or calcium leucovorin; Wherein the content of ACEI is 10～40mg, and the content of vitamin B group is 0.2～5mg.
13. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group according to claim 3 is characterized in that: described ACEI is selected from fosinopril, vitamin B group is B6; Wherein the content of ACEI is 10～40mg, and the content of vitamin B group is 5～50mg.
14. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group according to claim 3 is characterized in that: described ACEI is selected from fosinopril, vitamin B group is B12; Wherein the content of ACEI is 10～40mg; The content of vitamin B group is 0.25～2mg.
15. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group class according to claim 3, it is characterized in that: described ACEI is selected from Ramipril, vitamin B group is folic acid or calcium leucovorin, and wherein the content of ACEI is 2.5～20mg; The content of vitamin B group is 0.2～5mg.
16. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group class according to claim 3, it is characterized in that: described ACEI is selected from Ramipril, and vitamin B group is B6, and wherein the content of ACEI is 2.5～20mg; The content of vitamin B group is 5～50mg.
17. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group class according to claim 3, it is characterized in that: described ACEI is selected from Ramipril, and vitamin B group is B12, and wherein the content of ACEI is 2.5～20mg; The content of vitamin B group is 0.25～2mg.
18. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group class according to claim 3, it is characterized in that: described ACEI is selected from Yipingshu, and vitamin B group is selected from folic acid; Wherein the content of ACEI is 2.5～5mg; The content of vitamin B group is 0.2～5mg.
19. the pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group class according to claim 3, it is characterized in that: described ACEI is selected from perindopril, and vitamin B group is selected from folic acid; Wherein the content of ACEI is 4～8mg; The content of vitamin B group is 0.2～5mg.
20., it is characterized in that according to any one described pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group in the claim 3 to 19: this 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.
21. according to any one described pharmaceutical composition that contains angiotensin-convertion enzyme inhibitor and vitamin B group in the claim 3 to 20, 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, and and the closely-related disease of hypertension, atherosclerosis, coronary heart disease, dissection of aorta and diabetes.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200410071056 CN1269529C (en) | 2004-07-28 | 2004-07-28 | Medicinal composition contaniing angiotensin invertase inhibitor and vitamin B |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200410071056 CN1269529C (en) | 2004-07-28 | 2004-07-28 | Medicinal composition contaniing angiotensin invertase inhibitor and vitamin B |
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| CN1587270A true CN1587270A (en) | 2005-03-02 |
| CN1269529C CN1269529C (en) | 2006-08-16 |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009046631A1 (en) * | 2007-09-28 | 2009-04-16 | Beijing Huaanfo Biomedical Research Center, Inc | Pharmaceutical composition containing angiotensin converting enzyme inhibitor 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 |
| CN101590084B (en) * | 2008-05-29 | 2012-12-05 | 北京奥萨医药研究中心有限公司 | Pharmaceutical composition containing angiotensin converting enzyme inhibitors, B vitamins and ginkgo biloba extracts |
| CN103222960A (en) * | 2013-05-15 | 2013-07-31 | 中国药科大学 | Oral enalapril maleate timed-release pellet and preparation method thereof |
| CN103386130A (en) * | 2013-06-27 | 2013-11-13 | 深圳奥萨医药有限公司 | ACE inhibitor/thiazide diuretic/5-methyltetrahydrofolate pharmaceutical composition and applications |
| CN106310218A (en) * | 2015-11-27 | 2017-01-11 | 深圳奥萨制药有限公司 | Tablet composition containing enalapril and folic acid and preparation method thereof |
| CN106963938A (en) * | 2016-09-30 | 2017-07-21 | 南京优科制药有限公司 | A kind of pharmaceutical composition of enalapril maleate folic acid and preparation method thereof |
| CN107007838A (en) * | 2016-09-30 | 2017-08-04 | 南京优科制药有限公司 | A kind of pharmaceutical composition containing enalapril maleate, folic acid and sour stabilizer |
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2004
- 2004-07-28 CN CN 200410071056 patent/CN1269529C/en active Active
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009046631A1 (en) * | 2007-09-28 | 2009-04-16 | Beijing Huaanfo Biomedical Research Center, Inc | Pharmaceutical composition containing angiotensin converting enzyme inhibitor and b family vitamins and use thereof |
| CN101590084B (en) * | 2008-05-29 | 2012-12-05 | 北京奥萨医药研究中心有限公司 | Pharmaceutical composition containing angiotensin converting enzyme inhibitors, B vitamins and ginkgo biloba extracts |
| 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 |
| CN103222960A (en) * | 2013-05-15 | 2013-07-31 | 中国药科大学 | Oral enalapril maleate timed-release pellet and preparation method thereof |
| CN103222960B (en) * | 2013-05-15 | 2016-06-15 | 中国药科大学 | Oral time controlled released micropill of a kind of enalapril maleate and preparation method thereof |
| CN103386130A (en) * | 2013-06-27 | 2013-11-13 | 深圳奥萨医药有限公司 | ACE inhibitor/thiazide diuretic/5-methyltetrahydrofolate pharmaceutical composition and applications |
| CN106310218A (en) * | 2015-11-27 | 2017-01-11 | 深圳奥萨制药有限公司 | Tablet composition containing enalapril and folic acid and preparation method thereof |
| CN106963938A (en) * | 2016-09-30 | 2017-07-21 | 南京优科制药有限公司 | A kind of pharmaceutical composition of enalapril maleate folic acid and preparation method thereof |
| CN107007838A (en) * | 2016-09-30 | 2017-08-04 | 南京优科制药有限公司 | A kind of pharmaceutical composition containing enalapril maleate, folic acid and sour stabilizer |
| CN106963938B (en) * | 2016-09-30 | 2021-04-30 | 南京优科制药有限公司 | Enalapril maleate folic acid pharmaceutical composition and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN1269529C (en) | 2006-08-16 |
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