CN101590232A - The medical composition and its use of angiotensin-convertion enzyme inhibitor, lipid-lowering statins and nicotinic acid - Google Patents
The medical composition and its use of angiotensin-convertion enzyme inhibitor, lipid-lowering statins and nicotinic acid Download PDFInfo
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- CN101590232A CN101590232A CNA2008101139232A CN200810113923A CN101590232A CN 101590232 A CN101590232 A CN 101590232A CN A2008101139232 A CNA2008101139232 A CN A2008101139232A CN 200810113923 A CN200810113923 A CN 200810113923A CN 101590232 A CN101590232 A CN 101590232A
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Abstract
The present invention relates to the pharmaceutical composition of acceptable carrier on the nicotinic acid of stanin fat-reducing medicament, pharmaceutical dosage of a kind of angiotensin-convertion enzyme inhibitor (ACEI) that contains pharmaceutical dosage, pharmaceutical dosage and the pharmaceutics.Hypertension companion dyslipidemia can effectively be treated, prevents or be delayed to pharmaceutical composition provided by the invention, can the effect of coordinating protection inner skin cell function, collaborative antioxidation, coordinating protection cardiorenal function, collaborative prevention or delay atheromatous plaque formation effect, the collaborative apoplexy incidence rate that reduces.By enforcement of the present invention, offer the better therapeutic strategy of patient on the one hand, can improve patient's compliance simultaneously, the patient is taken medicine conveniently, reduce medical expense, have better market prospect.The invention belongs to pharmaceutical field.
Description
Technical field
The present invention relates to the pharmaceutical composition of acceptable carrier on the nicotinic acid of stanin fat-reducing medicament, pharmaceutical dosage of a kind of angiotensin-convertion enzyme inhibitor (ACEI) that contains pharmaceutical dosage, pharmaceutical dosage and the pharmaceutics.The invention still further relates to this pharmaceutical composition in preparation treatment, prevent or delay target organ damage or the hypertension companion's dyslipidemia relevant disease that hypertension companion dyslipidemia, hypertension companion dyslipidemia cause or reduce purposes in the dangerous medicine of cardiovascular and cerebrovascular vessel incident.The invention belongs to pharmaceutical field.
Background technology
Hypertension and dyslipidemia are two kinds of concurrent cardiovascular disease risk factor the most general, the hyperpietic greater than 50% be attended by dyslipidemia [O ' Meara JG, et al.Arch Intern Med.2004; 164:1313-1318].Studies show that recently, the adult of Britain 20% suffer from the hypertensive patients dyslipidemia [Williams B, et al.Eur Heart J.2004; 25:528-529].One of WHO analyzes and finds, has 30% adult to suffer from hypertensive patients dyslipidemia [Tunstall-Pedoe H, et al.Pharmacoepidemiol Drug Saf.2004 approximately in West Europe; 13 (Suppl 1): S307].Baseline blood pressure and serum cholesterol raise can sharply increase the incidence rate of cardiovascular disease and the danger of coronary heart disease.Therefore, develop a kind of effective hypertension and hyperlipemia medicine and have important clinical meaning and important social meaning.
Enalapril (enalapril) is that a kind of nothing is dredged basic, long-acting, oral ACEI inhibitor, and only need once oral every day, and common dose is 5-20mg, clinical be widely used in treatment gently, severe hypertension is sick.ACEI comprises: benazepril (benazepril), lisinopril (lisinopril), fosinopril (fosinopril), imidapril (imidapril), perindopril (perindopril), ramipril (ramipril), captopril (captopril) etc.
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor is called for short Statins (statins) medicine, is a class medicine of treatment hypercholesterolemia.A large amount of evidence-based medicine EBM evidences shows especially low-density lipoprotein cholesterol (LDL-C) level of the effective cholesterol reducing of statins, has significantly reduced various biliary sterol levels and cardiovascular diseases population at risk's Incidence of CHD, mortality rate.
(nicotinic acid NA) belongs to vitamin B group to nicotinic acid, is the cofactor in a kind of internal metabolism process.Nicotinic acid is applied to clinically had more than 40 year as lipid-regulation medicine, its main mechanism is for suppressing the formation of cAMP, cause glycerol three phytase activities to reduce, lipolysis in the fatty tissue slows down, the lowering of concentration of non-acidizing fatty acid (NE-FA) in the blood, the synthetic VLDL of liver reduces, and LDL is reduced.
Summary of the invention
The objective of the invention is provides a kind of pharmaceutical composition more efficiently at the hypertensive patients dyslipidemia.Hypertension companion dyslipidemia can effectively be treated, prevents or be delayed to pharmaceutical composition provided by the invention, and can the effect of coordinating protection inner skin cell function, collaborative antioxidation, coordinating protection cardiorenal function, collaborative prevention or delay atheromatous plaque formation effect, the collaborative apoplexy incidence rate that reduces.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition comprises:
(1) a kind of in the angiotensin-convertion enzyme inhibitor of pharmaceutical dosage, angiotensin-convertion enzyme inhibitor isomer, angiotensin-convertion enzyme inhibitor active metabolite or the angiotensin-convertion enzyme inhibitor officinal salt;
(2) a kind of in the stanin fat-reducing medicament of pharmaceutical dosage, stanin fat-reducing medicament isomer, stanin fat-reducing medicament active metabolite or the stanin fat-reducing medicament officinal salt;
(3) nicotinic acid of pharmaceutical dosage; And
(4) acceptable carrier on the pharmaceutics.
Among the present invention, described angiotensin converting enzyme inhibitor comprises enalapril (enalapril), benazepril (benazepril), lisinopril (lisinopril), fosinopril (fosinopril), imidapril (imidapril), ramipril (ramipril), captopril (captopril), quinapril (quinapril), cilazapril (cilazpril), perindopril (perindopril), delapril (delapril), moexipril (moexipril), spirapril (spirapril), trandolapril (trandolapril) and alacepril (alacepril).
Wherein, enalapril content is 5mg～40mg, benazepril content is 5mg～40mg, lisinopril content is 5mg～40mg, fosinopril content is 10mg～40mg, imidapril content is 2.5mg～10mg, ramipril content is 2.5mg～20mg, captopril content is 25mg～100mg, quinapril content is 10mg～40mg, cilazapril content is 2.5mg～5mg, perindopril content is 4mg～8mg, delapril content is 15mg～60mg, moexipril content is 7.5mg～30mg, spirapril content is 3mg～15mg, trandolapril content is 0.5mg～2mg, alacepril content is 25mg～100mg, and the active metabolite of above-mentioned substance or salt content are equal to corresponding above-mentioned substance content.
Among the present invention, described stanin fat-reducing medicament comprises that atorvastatin (atorvastatin), simvastatin (simvastatin), Pitavastatin (pitavastatin), pravastatin (pravastatin), lovastatin (lovastatin), fluvastatin (fluvastatin), cerivastatin (cerivastatin), Rosuvastatin (rosuvastatin), itavastatin (itavastatin), Buddhist nun cut down his spit of fland (nisvastatin), bervastatin (bervastatin), mevastatin (mevastatin) etc.
Wherein, atorvastatin content is that 5mg～80mg, simvastatin content are that 5mg～80mg, Pitavastatin content are that 1mg～4mg, lovastatin content are that 5mg～80mg, fluvastatin content are that 5mg～80mg, pravastatin content are that 5mg～80mg, Rosuvastatin content are 5mg～80mg, and the active metabolite of above-mentioned substance or salt content are equal to corresponding above-mentioned substance content.
Among the present invention, described nicotinic acid is also referred to as vitamin B3, or vitamin PP.It is one of 13 kinds of vitamin of needed by human, is a kind of water soluble vitamins, belongs to vitamin B complex.The content of nicotinic acid is 50mg-1000mg among the present invention.
In the pharmaceutical composition provided by the invention, described angiotensin converting enzyme inhibitor is an enalapril maleate, and content is 5mg-40mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is an enalaprilat, and content is 5mg-40mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a benazepril hydrochloride, and content is 5mg-40mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a lisinopril, and content is 5mg-40mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a fosinopril, and content is 10mg-40mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is an imidapril, and content is 2.5mg-10mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor ramipril, content are 2.5mg-20mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor captopril, content are 25mg-100mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a quinapril, and content is 10mg-40mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a perindopril, and content is 4mg-8mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a spirapril, and content is 3mg-15mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a trandolapril, and content is 0.5mg-2mg; Described stanin fat-reducing medicament is an Atorvastatin calcium, and content is the amount that is equivalent to the 5mg-80mg atorvastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin converting enzyme inhibitor is an enalapril maleate, and content is the amount that is equivalent to the 5mg-40mg enalapril; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor enalaprilat, content are 5mg-40mg; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a benazepril hydrochloride, and content is the amount that is equivalent to the 5mg-40mg benazepril; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a lisinopril, and content is 5mg-40mg; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a fosinopril, and content is 10mg-40mg; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is an imidapril, and content is 2.5mg-10mg; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a ramipril, and content is 2.5mg-20mg; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a captopril, and content is 25mg-100mg; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a quinapril, and content is 10mg-40mg; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a perindopril, and content is 4mg-8mg; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a spirapril, and content is 3mg-15mg; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a trandolapril, and content is 0.5mg-2mg; Described stanin fat-reducing medicament is a simvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin converting enzyme inhibitor is an enalapril maleate, and content is the amount that is equivalent to the 5mg-40mg enalapril; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is an enalaprilat, and content is 5mg-40mg; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a benazepril hydrochloride, and content is the amount that is equivalent to the 5mg-40mg benazepril; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a lisinopril, and content is 5mg-40mg; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a fosinopril, and content is 10mg-40mg; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is an imidapril, and content is 2.5mg-10mg; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a ramipril, and content is 2.5mg-20mg; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a captopril, and content is 25mg-100mg; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a quinapril, and content is 10mg-40mg; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a perindopril, and content is 4mg-8mg; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a spirapril, and content is 3mg-15mg; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a trandolapril, and content is 0.5mg-2mg; Described stanin fat-reducing medicament is a Pitavastatin Calcium, and content is the amount that is equivalent to the 1mg-4mg Pitavastatin; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin converting enzyme inhibitor is an enalapril maleate, and content is the amount that is equivalent to the 5mg-40mg enalapril; Described stanin fat-reducing medicament is a lovastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a benazepril hydrochloride, and content is the amount that is equivalent to the 5mg-40mg benazepril; Described stanin fat-reducing medicament is a lovastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a lisinopril, and content is 5mg-40mg; Described stanin fat-reducing medicament is a lovastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a fosinopril, and content is 10mg-40mg; Described stanin fat-reducing medicament is a lovastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is an imidapril, and content is 2.5mg-10mg; Described lipid-lowering statins is a lovastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin converting enzyme inhibitor is an enalapril maleate, and content is the amount that is equivalent to the 5mg-40mg enalapril; Described stanin fat-reducing medicament is a pravastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a benazepril hydrochloride, and content is the amount that is equivalent to the 5mg-40mg benazepril; Described stanin fat-reducing medicament is a pravastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a lisinopril, and content is 5mg-40mg; Described stanin fat-reducing medicament is a pravastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a fosinopril, and content is 10mg-40mg; Described stanin fat-reducing medicament is a pravastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is an imidapril, and content is 2.5mg-10mg; Described stanin fat-reducing medicament is a pravastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin converting enzyme inhibitor is an enalapril maleate, and content is the amount that is equivalent to the 5mg-40mg enalapril; Described stanin fat-reducing medicament is a fluvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a benazepril hydrochloride, and content is the amount that is equivalent to the 5mg-40mg benazepril; Described stanin fat-reducing medicament is a fluvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a lisinopril, and content is 5mg-40mg; Described stanin fat-reducing medicament is a fluvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a fosinopril, and content is 10mg-40mg; Described stanin fat-reducing medicament is a fluvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is an imidapril, and content is 2.5mg-10mg; Described stanin fat-reducing medicament is a fluvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin converting enzyme inhibitor is an enalapril maleate, and content is the amount that is equivalent to the 5mg-40mg enalapril; Described stanin fat-reducing medicament is a Rosuvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor benazepril hydrochloride, content are the amount that is equivalent to the 5mg-40mg benazepril; Described stanin fat-reducing medicament is a Rosuvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a lisinopril, and content is 5mg-40mg; Described stanin fat-reducing medicament is a Rosuvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is a fosinopril, and content is 10mg-40mg; Described stanin fat-reducing medicament is a Rosuvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
In the pharmaceutical composition provided by the invention, described angiotensin-convertion enzyme inhibitor is an imidapril, and content is 2.5mg-10mg; Described stanin fat-reducing medicament is a Rosuvastatin, and content is 5mg-80mg; Described nicotinic acid content is 50mg-1000mg.
According to the present invention, active component in the pharmaceutical composition is the solvent in the compositions, one of them active component comes from a kind of in the angiotensin-convertion enzyme inhibitor, a kind of from the stanin fat-reducing medicament of active component, and another active component is a nicotinic acid.The dosage form of this pharmaceutical composition includes but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, the single chamber controlled release tablet, two chambers controlled release tablet, the pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/the position releasing piece, conventional capsule, 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, oral liquid, membrane or patch, what should particularly point out is to contain angiotensin-convertion enzyme inhibitor, the pharmaceutical composition of stanin fat-reducing medicament and nicotinic acid is made tablet or capsule.
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 suitable carrier includes excipient and the accessory drugs that helps reactive compound is mixed with pharmaceutical formulation when making tablet, compositions as one or more materials of starch, microcrystalline Cellulose, inorganic salts, sucrose, dextrin, lactose, sodium chloride, citric acid and sodium sulfite etc. belongs to this area general knowledge.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into slow releasing preparation, comprise excipient and adjuvant etc.Described excipient and adjuvant have comprised that the adjuvant of slow releasing function is that the solubility/insoluble salt of hydroxypropyl methylcellulose and/or ethyl cellulose and/or polyacrylic resin class and/or polycarboxy ethene and/or alginic acid and/or ethyl cellulose and/or other play the adjuvant of slow releasing function, the hypromellose employing includes the extensive stock of hydroxypropyl methylcellulose (HPMC) such as U.S. many elegant (Methocel) of all size, ethyl cellulose adopts the extensive stock that includes ethyl cellulose (EC), and polyacrylic resin adopts and includes polyacrylic resin II, the acrylic resin of III class or analog such as all size (Eudragit).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into controlled release preparation, comprise that active medicine has reached the adjuvant of controlled release effect.The above-mentioned adjuvant that plays the controlled release effect is polyoxyethylene and/or hypromellose and/or ethyl cellulose and/or sodium chloride and/or lactose and/or mannitol and/or fructose and/or glucose and/or sucrose or low-substituted hydroxypropyl cellulose and/or cross-linking sodium carboxymethyl cellulose and/or crospolyvinylpyrrolidone and/or cellulose acetate.Above-mentioned adjuvant is pharmaceutical carrier, expanding material, permeation-promoter, solubilizing agent, binding agent, wetting agent, lubricant, coloring agent, porogen, membrane material, antiplastering aid, plasticizer, lucifuge agent, solvent.Pharmaceutical carrier, expanding material can adopt polyoxyethylene, hypromellose, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, Glyceryl Behenate class etc.; Permeation-promoter can adopt sodium chloride, lactose, mannitol etc.; Solubilizing agent can be adopted sodium lauryl sulphate or poloxamer etc.; Binding agent can adopt polyvinylpyrrolidone, hypromellose, chitosan, sodium alginate, methylcellulose, ethyl cellulose, starch slurry, arabic gum, gelatin, sucrose, polyvinyl alcohol etc.; Wetting agent can adopt the ethanol-water solution of dehydrated alcohol, water, various concentration; Lubricant can adopt stearic acid, magnesium stearate, Pulvis Talci, starch, paraffin etc.; Coloring agent can adopt natural pigment such as carmine, amaranth, lemon yellow, bright orchid, indigo, brownish red ferrum oxide and synthetic dyestuff or the like; Porogen can adopt sucrose, mannitol, Polyethylene Glycol, titanium dioxide, Pulvis Talci, silicon dioxide etc.; Membrane material can adopt cellulose acetate, ethyl cellulose, hydroxypropyl emthylcellulose acetic acid succinate, beautiful jade Cellulose Acetate Phthalate, poly-phthalic acid vinyl acetate cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose etc.; Solvent can adopt acetone, dehydrated alcohol, ethanol, water etc.
Also contain the pharmaceutics acceptable carrier in the said composition, can be made into sublingual lozenge, oral cavity quick disintegrating slice or dispersible tablet etc.; Comprise excipient and adjuvant etc.Described excipient and adjuvant have mannitol, sorbitol, maltose alcohol, low substituted hydroxy-propyl methylcellulose, microcrystalline Cellulose, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, processing agar, cyclodextrin, glycyrrhizic acid, stevioside, citric acid, Oleum menthae, eucalyptus oil, Oleum Caryophylli, Fructus Citri Limoniae oil, citrus seed oil and some other correctives that wraps up with microcapsule etc.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into enteric coatel tablets or enteric coated capsule etc.; comprise excipient and adjuvant etc.; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc.; enteric-coating material comprises: Lac; the cellulose acetate phthalate ester; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose, and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen various medicaments adjuvants such as (as PEG6000).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into delayed-release tablet or timing (position) releasing piece; comprise excipient and adjuvant; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., described coating material that postpones release or regularly (position) release comprises: Lac; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; the polyvinyl acetate phthalic acid ester; and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen (as PEG1000; PEG4000; various medicaments adjuvant such as PEG6000).
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 excipient and adjuvant; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., coating material comprises: Lac; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; the polyvinyl acetate phthalic acid ester; and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen various medicaments adjuvants such as (as PEG6000).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into dosage forms such as granule, oral liquid, membrane, patch.
Chemical compound in the pharmaceutical composition provided by the invention can be granted diseased individuals simultaneously in identical preparation, also grant diseased individuals discriminably in succession.If grant diseased individuals in succession, then the delay of granting of second (or additional) active component should not cause active component to unite the loss of the beneficial effect that brings.If grant diseased individuals simultaneously, the chemical compound in the compositions can mix and be present in the same pharmaceutical dosage forms, also can independently exist respectively with same dosage form.If independently exist respectively with same dosage form, then pharmaceutical composition can flexible existing with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of built-in one or more dosage forms, and operation instructions.In the present invention preferably with a kind of in a kind of, the stanin fat-reducing medicament in the described angiotensin-convertion enzyme inhibitor and compound tablet that nicotinic acid is formed.
Chemical compound in the pharmaceutical composition provided by the invention can be granted diseased individuals simultaneously in preparation inequality, also grant diseased individuals discriminably in succession.If grant diseased individuals in succession, then the delay of granting of second (or additional) active component should not cause active component to unite the loss that brings beneficial effect.If grant diseased individuals simultaneously, the chemical compound in the compositions independently exists with different dosage forms, and pharmaceutical composition also can flexible existing with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of built-in one or more dosage forms, and operation instructions.
Another object of the present invention provides angiotensin-convertion enzyme inhibitor and the isomer thereof that contains pharmaceutical dosage, a kind of in active metabolite or its officinal salt, the stanin fat-reducing medicament of pharmaceutical dosage and isomer thereof, a kind of in active metabolite or its officinal salt, the pharmaceutical composition of acceptable carrier is being treated in preparation on the nicotinic acid of pharmaceutical dosage and the pharmaceutics, prevention or delay hypertension half dyslipidemia, target organ damage that hypertension companion dyslipidemia causes or hypertension companion dyslipidemia relevant disease, or reduce purposes in the dangerous medicine of cardiovascular and cerebrovascular vessel incident that hypertension companion dyslipidemia causes.
In the purposes of the present invention, angiotensin converting enzyme inhibitor is selected from enalapril, benazepril, lisinopril, fosinopril, imidapril, ramipril, captopril, quinapril, cilazapril, perindopril, delapril, moexipril, spirapril, a kind of in trandolapril and the alacepril, wherein, enalapril content is 5mg～40mg, benazepril content is 5mg～40mg, lisinopril content is 5mg～40mg, fosinopril content is 10mg～40mg, imidapril content is 2.5mg～10mg, ramipril content is 2.5mg～20mg, captopril content is 25mg～100mg, quinapril content is 10mg～40mg, cilazapril content is 2.5mg～5mg, perindopril content is 4mg～8mg, delapril content is 15mg～60mg, moexipril content is 7.5mg～30mg, spirapril content is 3mg～15mg, trandolapril content is 0.5mg～2mg, alacepril content is 25mg～100mg, and the active metabolite of above-mentioned substance or its officinal salt content are equal to corresponding above-mentioned substance content.Stanin fat-reducing medicament is selected from atorvastatin, simvastatin, Pitavastatin, pravastatin, lovastatin, fluvastatin, cerivastatin, Rosuvastatin, itavastatin, the Buddhist nun cuts down his spit of fland, bervastatin, mevastatin and isomer thereof, a kind of in active metabolite or its officinal salt, wherein, atorvastatin content is 5mg-80mg, simvastatin content is 5mg-80mg, Pitavastatin content is 1mg-4mg, pravastatin content is 5mg-80mg, lovastatin content is 5mg-80mg, fluvastatin content is 5mg-80mg, Rosuvastatin content is 5mg-80mg.The medicinal content of nicotinic acid is 50mg-1000mg.
The target organ damage that hypertension companion dyslipidemia of the present invention causes, be meant because the heart that hypertension and/or dyslipidemia and other possible factors cause, brain, kidney, the secondary lesion of organs such as eye comprises apoplexy, atherosclerosis, coronary heart disease, left ventricular hypertrophy, angina pectoris, myocardial infarction, acute coronary syndrome, cardiac function goes down, optimum arteriolar nephrosclerosis, heart failure, arrhythmia, the primary cardiac all standing, renal function goes down, pernicious arteriolar nephrosclerosis, peripheral arterial disease, retinal arteriosclerosis or hypertension retinopathy.
The cardiovascular and cerebrovascular vessel incident danger that reduction hypertension companion dyslipidemia of the present invention causes is meant and reduces apoplexy, acute coronary syndrome, angina pectoris, myocardial infarction, heart failure, arrhythmia, primary cardiac all standing or the high-risk incidence rate of coronary heart disease.
Among the present invention, term " pharmaceutical dosage " is meant that the clinician grants the dosage of medicine to diseased individuals according to the diseased individuals degree that is in a bad way in order to reach effective treatment, prevent or to delay the purpose of disease.Be to be understood that medicine pharmaceutical dosage provided by the invention is not a limitation of the present invention, but to of the present invention preferred, generally, in this dosage preferable range, this medicine can effectively treat, prevent or delay effect disease that the patient takes a disease generation.Diseased individuals is meant the self-existent life entity of suffering from disease, and in the present invention, life entity refers to the mankind especially.Should be appreciated that in the prior art, human pharmaceutical use dosage or pharmaceutical dosage scope can with mammal, as rat, mice etc., converting is fit to pharmaceutical dosage or the dosage range that corresponding animal is suitable for to draw.
The invention has the beneficial effects as follows:
The combined effect of angiotensin converting enzyme inhibitor, stanin fat-reducing medicament and nicotinic acid be not each active substance each self-applying simply add and, the three share has obvious synergism.Studies show that pharmaceutical composition provided by the invention can effectively treat, prevents or delay hypertension companion dyslipidemia, can the effect of coordinating protection inner skin cell function, collaborative antioxidation, coordinating protection cardiorenal function, collaborative prevention or delay atheromatous plaque formation effect, the collaborative apoplexy incidence rate that reduces.By enforcement of the present invention, the pharmaceutical composition that offers this special-purpose of patient can improve patient's compliance, and the patient is taken medicine conveniently, reduces medical expense, has better market prospect.
The present invention will be further described below in conjunction with the specific 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.
The specific embodiment
Embodiment 1: enalapril+atorvastatin+nicotinic acid is to the target organ protection function of hypertension companion dyslipidemia rat
The SD rat, body weight 150～180g, chloral hydrate (320mg/kg) intraperitoneal injection of anesthesia is opened the abdominal cavity, separates left renal artery, the narrow left renal artery of 0.2mm silver brain clip, in 8～10 weeks of postoperative, getting contractive pressure 〉=140mmHg person rat is Hypertensive Rats.Irritate stomach to Hypertensive Rats by the accumulated dose of 600,000 U/kg and give vitamin D3, divide 3d to give, feed high lipid food (cholesterol 1.0% afterwards every day, propylthiouracil 0.2%, sodium cholate 0.5%, Adeps Sus domestica 5.0%, methionine 1.0%, normal feedstuff 92.3%) [Yen CH, Lau YT.Vascular responses in male and female hypertensive rats withhyperhomocysteinemia.Hypertension, 2002; 40 (3): 322-328.Robin S, et al.Oppositeeffect of methionine-supplemented diet, a model of hyperhomocysteinemia, on plasmaand liver antioxidant status in normotensive and spontaneously hypertensive rats.J Nutr Biochem.2004; 15 (2): 80-89. Wen Jinkun etc., a kind of experimental technique of setting up the atherosis model of rat artery fast, Chinese gerontology magazine, 2001,21 (1): 50-52], the rats in normal control group normal diet of feeding.After 4 weeks, measure rat blood pressure (systolic pressure), adopt tail blood and survey serum total cholesterol (TC), triglyceride (TG).
Get 80 of hypertension companion dyslipidemia rats, according to blood pressure and blood lipid level rat is divided into 4 groups, every group 20, be respectively model group, enalapril (1.0mg/kg) group, enalapril+atorvastatin+nicotinic acid (1.0+1.0+50mg/kg) group, atorvastatin+nicotinic acid (1.0+50mg/kg) group, other gets 20 normal rats as the normal control group.Hypertensive Rats continues the high lipid food of feeding, the normal rats normal diet of feeding.Normal control group, model group such as give at capacity 0.5%CMC solution, weigh weekly once, adjust dose, 20 weeks of successive administration according to body weight.
Detect index:
(1) measure before the administration respectively and different time blood pressure (179 type blood pressure determination instrument, American I ITC Life ScienceInc.) calculating blood pressure lowering amplitude (systolic pressure before the=administration-administration after-contraction is pressed) after the administration.
Get blood after (2) 20 weeks, measure serum total cholesterol (TC), triglyceride (TG), serum superoxide dismutases (SOD), malonaldehyde (MDA), nitric oxide (NO), Endothelin (ET) level according to the test kit description.
(3) collect urine, with the turbidimetry for Determination urine protein, put the method for exempting from and measure 24h and urinate α 1 microglobulin; Get blood, measure serum creatinine, calculate creatinine clearance rate (Ccr).
(4) myocardium hydroxyproline determination: get left ventricular free wall cardiac muscular tissue, be prepared into cardiac muscular tissue's homogenate of 10%, press hydroxyproline testing cassete description, digestion method is measured myocardium hydroxyproline content, press collagen content=hydroxyproline content * 7.46, be converted into collagen content.
(5) the conventional section of cardiac muscular tissue, Sirius is red-picric acid dyeing, measure myocardial collagen fraction by volume (CVF) and myocardial vascular area of collagen (PVCA) on every side.CVF is the ratio of the area of collagen and the myocardium gross area, and wherein area of collagen does not comprise PVCA, and its average is got in 5 visuals field of stochastic analysis.PVCA measures 4 ratios that are interior arteriolar surrounding area of cross section wall and tube chamber area for each specimen, gets its average.
(6) small artery is observed in the kidney: through abdominal aortic cannulation, 0.1mg/ml behind the abundant blood vessel dilating of sodium nitroprusside, formalin with 10% is poured into fixing under 10～12kPa, separate left kidney, the place cuts kidney from the hilus renalis, place 4% formaldehyde fixing, conventional dehydration, paraffin embedding, transverse section, HE dyeing.Choosing external diameter under the optical microscope is the interior small artery of kidney of 50～100 μ m, measures small artery internal diameter, wall thickness in the kidney, calculated wall thickness internal diameter ratio.Each specimen is measured 4 and is small artery in the cross section wall, gets its meansigma methods.
(7) gather the aorta sample, detect aorta lipid plaque area with image analytical method.
Measurement data represents that with x ± s data statistics is handled and adopted the SPSS10.0 statistical package, relatively adopts the t check between two groups.
Embodiment 2: enalapril+atorvastatin+nicotinic acid is to the protective effect of apoplexy susceptible type spontaneously hypertensive companion dyslipidemia rat target organ damage
8～10 week apoplexy susceptible type spontaneous hypertensive rats in age (SHRsp) are respectively available from Shanghai City hypertension institute, Fuwai Hospital's Experimental Animal Center, raising is in room temperature (23 ± 2) ℃, relative humidity (50 ± 10) %, each 12h of illumination light and shade, the high lipid food of feeding (prescription is with pharmacological evaluation 1).Measure blood pressure before the test, according to blood pressure values, SHRsp is divided into model group, nicotinic acid (50mg/kg) group, enalapril+atorvastatin (1.0+1.0mg/kg) group, enalapril+atorvastatin+nicotinic acid (50mg/kg) group, and other establishes the WKY matched group, 30 every group.Gastric infusion is weighed weekly once every day 1 time, adjusts dose, continuous 20 weeks according to body weight.
Observation index:
(1) observes animal diet followed, survival condition and behavioral activity every day, write down each treated animal cerebral seizure number.
(2) all rats of pathological observation are all got cerebral tissue, and cerebral hemorrhage, cerebral infarction or Combination apoplexy are observed in section, HE dyeing, calculate and respectively organize the rat brain stroke incidence.
(3) row aorta intubate behind the rat anesthesia, behind the abundant blood vessel dilating of 0.1mg/ml sodium nitroprusside, the perfusion of 2.5% glutaraldehyde is fixing, broken end is got brain, separates skull base arterial ring and intraparenchymatous small artery of brain and arteriole, and 2.5% glutaraldehyde is fixed, embedding, section, Toluidine blue staining.Computer pathology image analysis system is measured media thickness, the lumen diameter footpath of blood vessel, calculates the ratio of media thickness/lumen diameter, and 10 blood vessels are surveyed in every section.
Embodiment 3: benazepril+simvastatin+nicotinic acid is to the target organ protection function of hypertension companion dyslipidemia rat
The SD rat, body weight 150～180g, modeling method is with embodiment 1.According to blood pressure and blood lipid level rat is divided into model group then, benazepril+simvastatin (1.0+1.0mg/kg) group, benazepril+simvastatin+nicotinic acid (1.0+1.0+50mg/kg) group, nicotinic acid (50mg/kg) group, other establishes the normal control group.Hypertensive Rats continues the high lipid food of feeding, the normal rats normal diet of feeding.Normal control group, model group such as give at capacity 0.5%CMC solution, weigh weekly once, adjust dose, 20 weeks of successive administration according to body weight.
Measure administration front and back blood pressure; Get blood after 20 weeks, measure serum total cholesterol (TC), triglyceride (TG), serum superoxide dismutases (SOD), malonaldehyde (MDA), blood plasma nitric oxide (NO), Endothelin (ET) level according to the test kit description.20 weeks back collection urine is surveyed urine protein, 24h urine α 1 microglobulin; Get blood, measure serum creatinine, calculate creatinine clearance rate (Ccr).After 20 weeks, get left ventricular free wall cardiac muscular tissue, measure myocardium hydroxyproline content, and calculate collagen content; Myocardial collagen fraction by volume (CVF) and myocardial vascular area of collagen (PVCA) is on every side measured in the conventional section of cardiac muscular tissue.Separate left kidney, paraffin section is measured small artery internal diameter, wall thickness in the kidney, calculated wall thickness internal diameter ratio.Gather the aorta sample, detect aorta lipid plaque area with image analytical method.
Embodiment 4: preparation compound recipe enalapril/atorvastatin/nicotinic acid tablet
Following (1000) write out a prescription:
Enalapril 5g
Atorvastatin 10g
Nicotinic acid 50g
Carboxymethyl starch sodium 20g
Calcium hydrogen phosphate 180g
10% polyvidone aqueous solution is an amount of
Magnesium stearate 1%
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get the enalapril maleate that is equivalent to 5g enalapril amount, the Atorvastatin calcium that is equivalent to 10g atorvastatin amount and 50g nicotinic acid according to equivalent incremental method mix homogeneously, add carboxymethyl starch sodium 20g, calcium hydrogen phosphate 180g, according to equivalent incremental method uniform mixing, nicotinic acid is dissolved in the binding agent 10% polyvidone aqueous solution, add binding agent and make soft material in right amount, 30 orders are granulated, 40～45 ℃ of dry 3h; 30 order granulate add an amount of magnesium stearate mixing, behind the assay with No. 8 drifts, tabletting, promptly.Note lucifuge in the preparation process, after product inspection was qualified, aluminium-plastic bubble plate packing kept in Dark Place.Every contains enalapril 5mg, atorvastatin 10mg, nicotinic acid 50mg in the compound tablet of making.
Embodiment 5: the preparation compound tablet
Preparation method: with embodiment 4.The composition and the content of various compound tablet see Table 1.
Table 1 compound active pharmaceutical formulation is formed
| The compound recipe kind | Enalapril | Benazepril | Lisinopril | Fosinopril | Imidapril | Atorvastatin | Simvastatin | Pitavastatin | Nicotinic acid |
| 1 | 5mg | - | - | - | - | 10mg | - | - | 100mg |
| 2 | 5mg | - | - | - | - | 10mg | - | - | 300mg |
| 3 | 10mg | - | - | - | - | 10mg | - | - | 100mg |
| 4 | 10mg | - | - | - | - | 10mg | - | - | 300mg |
| 5 | 20mg | - | - | - | - | 10mg | - | - | 100mg |
| 6 | 20mg | - | - | - | - | 20mg | - | - | 100mg |
| 7 | 10mg | - | - | - | - | 40mg | - | - | 100mg |
| 8 | 20mg | - | - | - | - | 40mg | - | - | 300mg |
| 9 | - | 5mg | - | - | - | 10mg | - | - | 100mg |
| 10 | - | 5mg | - | - | - | 10mg | - | - | 300mg |
| 11 | - | 10mg | - | - | - | 10mg | - | - | 100mg |
| 12 | - | 10mg | - | - | - | 10mg | - | - | 300mg |
| 13 | - | 20mg | - | - | - | 10mg | - | - | 100mg |
| 14 | - | 20mg | - | - | - | 20mg | - | - | 100mg |
| 15 | - | 10mg | - | - | - | 40mg | - | - | 100mg |
| 16 | - | 20mg | - | - | - | 40mg | - | - | 300mg |
| 17 | - | - | 2.5mg | - | - | 10mg | - | - | 100mg |
| 18 | - | - | 5mg | - | - | 10mg | - | - | 100mg |
| 19 | - | - | 10mg | - | - | 20mg | - | - | 100mg |
| 20 | - | - | 20mg | - | - | 40mg | - | - | 100mg |
| 21 | - | - | - | 10mg | - | 10mg | - | - | 100mg |
| 22 | - | - | - | 20mg | - | 10mg | - | - | 100mg |
| 23 | - | - | - | - | 5mg | 10mg | - | - | 100mg |
| 24 | - | - | - | - | 10mg | 10mg | - | - | 100mg |
| 25 | 5mg | - | - | - | - | - | 10mg | - | 100mg |
| 26 | 10mg | - | - | - | - | - | 10mg | - | 100mg |
| 27 | 10mg | - | - | - | - | - | 10mg | - | 300mg |
| 28 | 20mg | - | - | - | - | - | 10mg | - | 100mg |
| 29 | 5mg | - | - | - | - | - | - | 1mg | 100mg |
| 30 | 10mg | - | - | - | - | - | - | 1mg | 100mg |
| 31 | 20mg | - | - | - | - | - | - | 2mg | 100mg |
| 32 | - | 10mg | - | - | - | - | 10mg | - | 100mg |
| 33 | - | - | 10mg | - | - | 10mg | - | - | 100mg |
Annotate: dosage shown in the dosage=table of various medicine officinal salts, isomer or its active metabolite * (officinal salt, isomer or its active metabolite molecular weight/drug molecule amount); During by 1000 slices// bags of preparation medicines, dosage shown in dosage=table * 1000.
Embodiment 6: preparation compound recipe enalapril/atorvastatin/nicotinic acid capsule
Following (1000) write out a prescription:
Enalapril 5g
Atorvastatin 10g
Nicotinic acid 50g
Lactose 100～200g
Carboxymethyl starch sodium 15～25g
10% polyvidone aqueous solution is an amount of
Magnesium stearate 1%
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get the enalapril maleate that is equivalent to 5g enalapril amount, be equivalent to the Atorvastatin calcium of 10g atorvastatin amount and 50g nicotinic acid according to equivalent incremental method mix homogeneously, add 100～200g lactose, 15～25g carboxymethyl starch sodium (the definite consumption of adjuvant is adjusted according to the active medicine consumption), according to equivalent incremental method uniform mixing, make soft material with 10% polyvidone alcoholic solution, 20 mesh sieves are granulated, 60 ℃ of dry about 2h, 20 mesh sieve granulate, controlling particulate water content is 2-3%, with dried granule and recipe quantity magnesium stearate mix homogeneously, semi-finished product detect, and measure content, the Capsules of packing into promptly gets 1000 capsules.Note lucifuge in the preparation process.The qualified back of product inspection aluminium-plastic bubble plate packing keeps in Dark Place.Every contains enalapril 5mg, Atorvastatin calcium 10mg, nicotinic acid 50mg in the compound capsule of making.
Embodiment 7: the preparation compound capsule
Preparation method: with embodiment 6.The composition and the content of various compound capsule agent see Table 1.
Embodiment 8: preparation compound recipe enalapril/atorvastatin/nicotinic acid granule
Write out a prescription following (1000 bags):
Enalapril 5g
Atorvastatin 10g
Nicotinic acid 50g
Lactose 850～950g
Carboxymethyl starch sodium 10～20g
Arabic gum 2g
10% polyvidone aqueous solution is an amount of
Orange flavor 2g
Aspartame 5g
Polyethylene Glycol 1%
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get the enalapril maleate that is equivalent to 5g enalapril amount, be equivalent to the Atorvastatin calcium of 10g atorvastatin amount and 50g nicotinic acid according to equivalent incremental method mix homogeneously, add 850～950g lactose, 10～20g carboxymethyl starch sodium (the definite consumption of adjuvant is adjusted according to the active medicine consumption), according to equivalent incremental method uniform mixing, make soft material with 10% polyvidone alcoholic solution, 18 mesh sieves are granulated, 60 ℃ of dry about 2h, 16 mesh sieve granulate, controlling particulate water content is below 2%, with dried granule and recipe quantity orange flavor, aspartame, the magnesium stearate mix homogeneously, semi-finished product detect, and measure content, and the aluminum bag of packing into promptly gets 1000 bags.Note lucifuge in the preparation process.Every bag contains enalapril 5mg, atorvastatin 10mg, nicotinic acid 50mg in the compound granular agent of making.
Embodiment 9: the agent of preparation compound granular
Preparation method: with embodiment 8.The composition and the content of various compound granular agent see Table 1.
Embodiment 10: preparation compound recipe enalapril/atorvastatin/niacin slow-release tablet
Following (1000) write out a prescription:
Enalapril 10g
Atorvastatin 10g
Nicotinic acid 500g
Hydroxypropyl emthylcellulose (K100M) 80g
Hydroxypropyl emthylcellulose (K15M) 40g
Octadecanol 40g
Magnesium stearate is an amount of
5% ethyl cellulose alcoholic solution is an amount of
Preparation method:
Metformin hydrochloride, hydroxypropyl emthylcellulose and the octadecanol of crossing 80 mesh sieves are pressed the recipe quantity mix homogeneously, add 5% ethyl cellulose alcoholic solution system soft material, granulate with 20 mesh sieves, in 60 ℃ of dryings 2 hours, with 18 mesh sieve granulate, add magnesium stearate then, quality inspection.
(1) enalapril, atorvastatin and the nicotinic acid of getting recipe quantity is crossed behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get hydroxypropyl emthylcellulose (K100M), hydroxypropyl emthylcellulose (K15M), octadecanol, the mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% ethyl cellulose alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay, aluminium-plastic bubble plate packing.
Embodiment 11: prepare compound sustained-released tablet
Preparation method: with embodiment 10.The composition and the content of various compound sustained-released tablets see Table 2.
Table 2 compound active pharmaceutical formulation is formed
| The compound recipe kind | Enalapril | Benazepril | Lisinopril | Fosinopril | Imidapril | Atorvastatin | Simvastatin | Pitavastatin | Nicotinic acid |
| 1 | 5mg | - | - | - | - | 10mg | - | - | 500mg |
| 2 | 10mg | - | - | - | - | 10mg | - | - | 750mg |
| 3 | 10mg | - | - | - | - | 10mg | - | - | 1000mg |
| 4 | 10mg | - | - | - | - | 20mg | - | - | 500mg |
| 5 | 20mg | - | - | - | - | 10mg | - | - | 500mg |
| 6 | 20mg | - | - | - | - | 20mg | - | - | 500mg |
| 7 | - | 5mg | - | - | - | 10mg | - | - | 500mg |
| 8 | - | 10mg | - | - | - | 10mg | - | - | 500mg |
| 9 | - | 10mg | - | - | - | 10mg | - | - | 750mg |
| 10 | - | 10mg | - | - | - | 20mg | - | - | 500mg |
| 11 | - | 20mg | - | - | - | 20mg | - | - | 500mg |
| 12 | - | - | 5mg | - | - | 10mg | - | - | 500mg |
| 13 | - | - | 10mg | - | - | 10mg | - | - | 500mg |
| 14 | - | - | 10mg | - | - | 10mg | - | - | 750mg |
| 15 | - | - | - | 10mg | - | 10mg | - | - | 500mg |
| 16 | - | - | - | 20mg | - | 40mg | - | - | 500mg |
| 17 | - | - | - | - | 5mg | 10mg | - | - | 1000mg |
| 18 | - | - | - | - | 10mg | 10mg | - | - | 500mg |
| 19 | 5mg | - | - | - | - | - | 10mg | - | 500mg |
| 20 | 10mg | - | - | - | - | - | 10mg | - | 500mg |
| 21 | 10mg | - | - | - | - | - | 10mg | - | 750mg |
| 22 | 20mg | - | - | - | - | - | 10mg | - | 1000mg |
| 23 | 5mg | - | - | - | - | - | - | 1mg | 500mg |
| 24 | 10mg | - | - | - | - | - | - | 1mg | 500mg |
| 25 | 20mg | - | - | - | - | - | - | 2mg | 750mg |
| 26 | - | 10mg | - | - | - | - | 10mg | - | 500mg |
| 27 | - | 10mg | - | - | - | - | 10mg | - | 750mg |
Annotate: dosage shown in the dosage=table of various medicine officinal salts, isomer or its active metabolite * (officinal salt, isomer or its active metabolite molecular weight/drug molecule amount); During by 1000 slices// bags of preparation medicines, dosage shown in dosage=table * 1000.
Embodiment 12: preparation compound recipe enalapril/atorvastatin/nicotinic acid controlled releasing tablet
Following (1000) write out a prescription:
Enalapril 10g
Atorvastatin 10g
Nicotinic acid 500g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 20g
Low-substituted hydroxypropyl cellulose 20g
Cellulose acetate 80g
PEG-1500 20g
Acetone 2000ml
5% 30 POVIDONE K 30 BP/USP-30 (95% alcoholic solution) is an amount of
Magnesium stearate 1%
Preparation method:
(1) enalapril, atorvastatin and the nicotinic acid of getting recipe quantity is crossed behind 100 mesh sieves standby by equivalent incremental method mix homogeneously respectively;
(2) other adjuvant is crossed 100 mesh sieves respectively after, in 75 ℃ of dry about 2h;
(3) get microcrystalline Cellulose, carboxymethyl starch sodium, the low-substituted hydroxypropyl cellulose mixing of recipe quantity, then with mixed crude drug by equivalent incremental method mix homogeneously;
(4) add 5% 30 POVIDONE K 30 BP/USP-3095% alcoholic solution and make soft material in right amount, 24 mesh sieves are granulated, 40 ℃ of dryings, and controlling particulate water content is 2-3%, 20 mesh sieve granulate;
(5) with dried granule and magnesium stearate mix homogeneously, tabletting behind the assay;
(6) cellulose acetate and PEG-1500 are dissolved in the acetone, become suspension, stir and make muddy coating;
(7) aluminium-plastic bubble plate packing.
Claims (8)
1. pharmaceutical composition comprises:
(1) a kind of in the angiotensin-convertion enzyme inhibitor of pharmaceutical dosage, angiotensin-convertion enzyme inhibitor isomer, angiotensin-convertion enzyme inhibitor active metabolite or the angiotensin-convertion enzyme inhibitor officinal salt;
(2) a kind of in the stanin fat-reducing medicament of pharmaceutical dosage, stanin fat-reducing medicament isomer, stanin fat-reducing medicament active metabolite or the stanin fat-reducing medicament officinal salt;
(3) nicotinic acid of pharmaceutical dosage; And
(4) acceptable carrier on the pharmaceutics.
Wherein, described angiotensin transaminase inhibitor is selected from a kind of in enalapril, benazepril, lisinopril, fosinopril, imidapril, ramipril, captopril, quinapril, cilazapril, PERINDOPRIL, delapril, moexipril, spirapril, trandolapril and the alacepril; Described stanin fat-reducing medicament is selected from atorvastatin, simvastatin, Pitavastatin, pravastatin, lovastatin, fluvastatin, Rosuvastatin, itavastatin, Buddhist nun and cuts down a kind of in his spit of fland, bervastatin, the mevastatin.
2. the described pharmaceutical composition of claim 1 is characterized in that: described angiotensin transaminase inhibitor is selected from a kind of in enalapril, enalapril maleate, enalaprilat, benazepril, benazepril hydrochloride, lisinopril, fosinopril, imidapril, ramipril, the quinapril; Described stanin fat-reducing medicament is selected from a kind of in Atorvastatin calcium, simvastatin, the Pitavastatin Calcium; The content of described nicotinic acid is 50mg-1000mg.
3. the described pharmaceutical composition of claim 2, it is characterized in that: the content that described enalapril content is 5mg-40mg, enalapril maleate or enalaprilat is that the amount, the benazepril content that are equivalent to the 5mg-40mg enalapril are that 5mg-40mg, benazepril hydrochloride content are that amount, the lisinopril content that is equivalent to the 5mg-40mg benazepril is that 5mg-40mg, fosinopril content are that 10mg-40mg, imidapril content are that 2.5mg-10mg, ramipril content are that 2.5mg-20mg, quinapril content are 10mg～40mg; Described atorvastatin calcium content is that the amount, the simvastatin content that are equivalent to the 5mg-80mg atorvastatin are that 5mg-80mg, Pitavastatin calcium content are the amount that is equivalent to the 1mg-4mg Pitavastatin.
4. each described pharmaceutical composition in the claim 1 to 3 is characterized in that: this pharmaceutical composition can be made into conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, single chamber controlled release tablet, two chambers controlled release tablet, pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, contain micropill or small pieces capsule, contain pH dependent form capsule, oral liquid, membrane or the patch of micropill or small pieces.
5. arbitrary described pharmaceutical composition is used for the treatment of, prevents in preparation or delays purposes in the medicine of hypertension companion dyslipidemia in the claim 1 to 4.
6. arbitrary described pharmaceutical composition is used for the treatment of, prevents or delay purposes in the medicine of the target organ damage that hypertension companion dyslipidemia causes in the claim 1 to 4 in preparation.
7. the described purposes of claim 4 is characterized in that: the target organ damage that described hypertension companion dyslipidemia causes is an apoplexy.
8. arbitrary described pharmaceutical composition is used for reducing the purposes of the medicine of the cardiovascular and cerebrovascular vessel incident danger that hypertension companion dyslipidemia causes in the claim 1 to 4 in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101139232A CN101590232A (en) | 2008-05-29 | 2008-05-29 | The medical composition and its use of angiotensin-convertion enzyme inhibitor, lipid-lowering statins and nicotinic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101139232A CN101590232A (en) | 2008-05-29 | 2008-05-29 | The medical composition and its use of angiotensin-convertion enzyme inhibitor, lipid-lowering statins and nicotinic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101590232A true CN101590232A (en) | 2009-12-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008101139232A Pending CN101590232A (en) | 2008-05-29 | 2008-05-29 | The medical composition and its use of angiotensin-convertion enzyme inhibitor, lipid-lowering statins and nicotinic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108853029A (en) * | 2018-09-07 | 2018-11-23 | 南通雅本化学有限公司 | A kind of preparation method of rosuvastatin |
| EP3955912A4 (en) * | 2019-04-17 | 2022-12-14 | Cardiopharma, Inc. | Anti-hypertensive and cholesterol-lowering fixed-dose combination and method of manufacture |
-
2008
- 2008-05-29 CN CNA2008101139232A patent/CN101590232A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108853029A (en) * | 2018-09-07 | 2018-11-23 | 南通雅本化学有限公司 | A kind of preparation method of rosuvastatin |
| EP3955912A4 (en) * | 2019-04-17 | 2022-12-14 | Cardiopharma, Inc. | Anti-hypertensive and cholesterol-lowering fixed-dose combination and method of manufacture |
| US11737988B2 (en) | 2019-04-17 | 2023-08-29 | CardioPharma, Inc. | Anti-hypertensive and cholesterol-lowering fixed-dose combination and method of manufacture |
| AU2019441241B2 (en) * | 2019-04-17 | 2023-11-23 | CardioPharma, Inc. | Anti-hypertensive and cholesterol-lowering fixed-dose combination and method of manufacture |
| IL287299B1 (en) * | 2019-04-17 | 2024-06-01 | Cardiopharma Inc | Anti-hypertensive and cholesterol-lowering fixed-dose combination and method of manufacture |
| IL287299B2 (en) * | 2019-04-17 | 2024-10-01 | Cardiopharma Inc | Anti-hypertensive and cholesterol-lowering fixed-dose combination and method of manufacture |
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Open date: 20091202 |