CN101406472A - Pharmaceutical composition of atenolol/amlodipine/folacin compound and uses thereof - Google Patents
Pharmaceutical composition of atenolol/amlodipine/folacin compound and uses thereof Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition containing atenolol, amlodipine, or folic acid compounds and application thereof. The pharmaceutical composition contains an officinal dosage of the atenolol, an officinal dosage of the amlodipine or levamlodipine, an officinal dosage of the folic acid compounds, and a pharmaceutical acceptable carrier. The dosage of the atenolol is between 5 and 50 milligrams, the dosage of the amlodipine or the levamlodipine is between 0.5 and 5.0 milligrams, and the dosage of the folic acid type compounds is between 0.2 and 1.6 milligrams. The pharmaceutical composition has the following advantages: the pharmaceutical composition enhances the hypertension curative effect through multi-target synergistic hypotensive action, and reduces the taking dosage of the amlodipine simultaneously, that is, just about one fourth of the original dosage can achieve the same hypotensive effect and reduce the side effects and medical expenses; and more importantly, the pharmaceutical composition can effectively prevent and treat or delay various complications of high blood pressure cardiovascular and cerebrovascular diseases such as cerebrovascular disorder and the like through dual targets (Hcy and blood pressure) on the basis of reducing toxic side effects. Besides, the pharmaceutical composition ensures that patients can take medicine conveniently.
Description
Technical field
The present invention relates to a kind of medical composition and its use of atenolol/amlodipine/folacin compound, belong to pharmaceutical technology.
Background technology
Hypertension is divided into essential hypertension (hypertension accounts for 90%) and secondary hypertension (symptomatic hypertension).Hypertensive sickness rate is approximately 20% the adult.Hypertensive direct complication has cerebrovascular accident, renal failure, heart failure etc., and these complication can disable mostly or cause death.Generally speaking, Hypertensive Population average life shortens 15～20 years than normal person group.Malignant hypertension, as without treatment, can be dead in 1 year.The line antihypertensive drug that WHO and China hypertension therapeutic guide are recommended is respectively: calcium antagonists, RAS depressant (comprising AT1 receptor antagonist and ACE inhibitor), receptor, blocking agent, diuretic antihypertensive medicine, the perhaps composite antihypertensive preparation of the fixed dosage of being made up of said medicine.There are some researches show to have only patient's blood pressure of 50% to obtain control preferably clinically when single medicine is treated, on the contrary, during two or more medication combined application, patient's blood pressure of 80%～90% can be effectively controlled.Wherein the synergism of receptor, blocking agent and calcium antagonists use in conjunction may be the strongest.The compound antihypertensive drug of compatriots' independent development in recent years is based on the coupling of this two classes medicine, as atenolol and amlodipine (Ling G, Liu AJ, Shen FM, et al.Effects of combination therapy with atenolol andamlodipine on blood pressure control and stroke prevention in stroke-prone spontaneouslyhypertensive rats.Acta Pharmacol Sin.2007; 28:1755-1760.).
Atenolol is just brought into use from 1976 as the receptor, blocking agent, and it also is that doctor's evolution is the most a kind of in the similar medicine by the development and sale of Pharmaceutical giant AstraZeneca pharmaceutcal corporation, Ltd.The atenolol efficacy of antihypertensive treatment is better, and is more suitable with tachycardia person to hypertension.Atenolol and other depressor use in conjunction scope are more extensive, have synergism, can improve curative effect, reduce side effect.Most clinical trials show, the total untoward reaction compliance light, the patient of atenolol good (Wang Xiaoming. antihypertensive clinical efficacy of atenolol and untoward reaction. Chinese Journal of New Drugs and Clinical Remedies .1988; 7:294-296.).
Calcium antagonists has just become a class antihypertensive drug of wide clinical application as far back as the eighties in 20th century, and its curative effect aspect controlling blood pressure and angina pectoris is unquestionable.Although there is the arguement that can cause gastrointestinal hemorrhage, cancer and suicide risk increase in calcium antagonists, calm down substantially at present in default of ample evidence, but because calcium antagonists may increase relevantly with cardiovascular event, so its safety still is under suspicion.Even more noteworthy, dihydropyridines calcium antagonists nifedipine is in the treatment of patients of acute myocardial infarction, to patient's prognosis may be unfavorable (Wang Ping, Sun Anyang. calcium antagonist cardiovascular system study on adverse reactions recent developments. Chinese clinical pharmacy magazine .1996; 2:69-73.).
The non-cardiovascular system untoward reaction of calcium antagonists is uncommon.Modal untoward reaction is a flushing, headache, hypotension and podedema.Calcium antagonists uses the excessive physiological reaction that other occurs, discharges as the insulin from pancreas to be subjected to press down, and reduces the utilization of myocardium free fatty etc.And these can cause hyperglycemia, lactic acidosis and can weaken myocardial contraction.Research prompting is arranged, calcium antagonists, especially dihydropyridines medicine, relevant with the death risk increase of tumor and gastrointestinal hemorrhage and a variety of causes, but do not obtain the confirmation of several large-scale researchs.
The arguement of at present relevant calcium antagonists mainly concentrates on the danger whether it increases cardiovascular event.The retrospective study prompting that Psaty etc. carry out, compare with the diuretic antihypertensive medicine, calcium antagonists can make the dangerous 58% (PsatyBM of increasing of myocardial infarction, Heckbert SR, Koepsell TD, et al.The risk of myocardial infarction associated withantihypertensive drug therapies.JAMA.1995; 274:620-625.), and have number of mechanisms can explain related between increasing of calcium antagonists and myocardial infarction.Negative inotropic action can cause the reduction of cardiac output and coronary flow, and some calcium antagonists also has the tendency that potential arrhythmogenic effect maybe can cause bleeding, and some can cause that arteria coronaria robs the blood phenomenon.The large-scale Macro or mass analysis result of reports such as Pahor in 2000 has comprised 9 relevant research (Pahor M, Psaty BM, Alderman MH, et al.Health outcomes associated with calcium antagonists compared withother first-line antihypertensive therapies:a meta-analysis of randomised controlled trials.Lancet.2000; 356:1949-1954.), relate to 8 kinds of calcium antagonistss, amount to 27743 routine patients and participate in.Discover: compare the myocardial infarction of each group of calcium antagonists, heart failure, the dangerous obviously increase of serious cardiovascular incident with ACE inhibitor, receptor, blocking agent, diuretic antihypertensive medicine or clonidine.Randomized, double-blind ALLHAT research (Anon.Major outcomes in high-risk hypertensive patients randomized toangiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic:TheAntihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) .JAMA.2002 that relates to 3338 routine patients; 288:2981-2997), estimated the safety of calcium antagonists.The patient age that participates in this clinical research has hypertension and more than one coronary risk factors more than 55 years old.The patient accepts diuretic antihypertensive medicine (chlortalidone at random in the research, one day 12.5～25mg), long-acting calcium antagonists (amlodipine, one day 2.5～10mg) or ACE inhibitor (lisinopril, one day 10～40mg), on average followed up a case by regular visits to 4.9 years, studying main terminal point is lethal coronary heart disease and non-lethality myocardial infarction, and secondary endpoints is mortality rate, apoplexy and other cardiovascular adverse events of a variety of causes, found that 6 years heart failure incidence rates of amlodipine group are higher.
Make a general survey of in recent years the multinomial large-scale researchs such as ALLHAT, INVEST, CONVINCE of report, there is the dispute that causes the cardiovascular system untoward reaction in calcium antagonists, and its safety receives much concern.This pharmaceutical composition has utilized the synergism between the medicine, in the optimal dose scope, by the collaborative hypotensive effect of many target spots, antihypertensive effect in the time of not only can reaching independent use amlodipine/folacin compound coupling, but also reduced the wherein taking dose of amlodipine, and only need original about 1/4 dosage just can reach equal antihypertensive effect, reduce side effect, improve curative effect, reduce medical expense.
Homocysteine (homocysteine, Hcy) be independent risk factor (the Wang X of the multiple cardiovascular and cerebrovascular disease complication of hypertension, Qin X, Demirtas H, et al.Efficacy of folic acid supplementation in strokeprevention:a meta-analysis.Lancet.2007; 369:1876-1882.), and receptor, blocking agent and calcium antagonists all can not reduce the level of homocysteine in blood plasma, its curative effect just has been subjected to limitation so clinically, especially in prevention, treat or delay aspect the multiple cardiovascular and cerebrovascular disease complication of hypertension.
Hcy is as the independent risk factor of the multiple cardiovascular and cerebrovascular disease complication of hypertension, proposed first by Epidemiological study in 1976 by people such as Wilcken, after this massive epidemiology has all confirmed that with clinical and experimentation Hcy is the independent risk factor of morbidities such as apoplexy, atherosclerosis, acute myocardial infarction, coronary artery pathological changes and peripheral blood vessel pathological changes in different regions, different crowd in succession.The every rising 5 μ mol/L of Hcy, the danger of coronary artery disease increases by 60%～80%, and the danger of cerebrovascular increases by 50%.There are some researches show, accompany the hypertension of high Hcy, in Chinese Hypertensive Population, accounted for 75%.If hypertension raises with Hcy simultaneously, the risk that apoplexy takes place will be 12 times of healthy population.The general higher reason of Chinese Hcy is many-sided, and Supplement of folic acid can significantly make it to reduce (McCully KS.Homocysteine, vitamins, and prevention of vascular disease.Mil Med.2004; 169:325-329.).
Summary of the invention
The present invention reduces the taking dose of calcium antagonists amlodipine in the pharmaceutical composition simultaneously in order to overcome atenolol/amlodipine in the deficiency aspect the generation of prophylaxis of hypertension crowd apoplexy, to reduce the untoward reaction of the cardiovascular system that amlodipine causes.Provide a kind of in efficacy of antihypertensive treatment, reduce side effect, reduce aspect medical expense, the target-organ protection, delay the multiple cardiovascular and cerebrovascular disease complication of hypertension (especially apoplexy) aspect and obviously be better than the pharmaceutical composition of atenolol/amlodipine or amlodipine/folacin compound.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition of atenolol/amlodipine/folacin compound contains the atenolol of pharmaceutical dosage, the amlodipine of pharmaceutical dosage or Levamlodipine, acceptable carrier on the folacin compound of pharmaceutical dosage and the pharmaceutics.
Above-mentioned " pharmaceutical dosage " main reference " Chinese hypertension prevention and control guide (2005) " and " The Seventh Reportof the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of HighBlood Pressure (JNC-7) " in the recommended dose of corresponding various concrete antihypertensives, or the dosage range of each package insert regulation.
The dosage of described atenolol is 5～50mg; Described amlodipine or Levamlodipine are one or more of benzene sulfonate, maleate and pharmaceutically acceptable other salt apoplexy due to endogenous wind, and dosage is 0.5～5.0mg.
Described folacin compound is one or more in folic acid, calcium folinate or the levoleucovorin calcium, and dosage is 0.2～1.6mg.
We use pharmaceutical composition of the present invention in the experiment of resisting hypertension drug effect, protection and the reduction cardiovascular and cerebrovascular vessel incident aspect of re-detection to target organ.This be because: if can not effectively control the multiple cardiovascular and cerebrovascular disease complication of hypertension independence risk factor (Hcy, blood pressure), continue several Nian Houke and cause important organs such as the heart, brain, kidney, eye to damage, and then develop into cardiovascular and cerebrovascular vessel incident such as apoplexy.Therefore, treating hypertensive main purpose is to reduce the independent risk factor (Hcy, blood pressure) that causes the multiple cardiovascular and cerebrovascular disease complication of hypertension to greatest extent, to reduce the disability rate and the mortality rate of Hypertensive Population.Blood pressure lowering, target-organ protection and control cardiovascular and cerebrovascular disease complication be the final core objective of hypertension therapeutic.
Originally discover, when atenolol and amlodipine/folate coupling time spent, antihypertensive effect in the time of not only can reaching independent use amlodipine/folacin compound, but also reduced the wherein taking dose of amlodipine, only need original about 1/4 dosage just can reach equal antihypertensive effect, reduce side effect, improve curative effect, reduce medical expense.
This research finds that also folacin compound is taken slight hypotensive effect for a long time separately, during with the atenolol/amlodipine coupling, can strengthen its hypotensive effect.When folacin compound and atenolol/amlodipine coupling, can also work in coordination with its target organ protection function of enhancing.Make that we are pleasantly surprised to be, this protective effect significantly is better than and only uses atenolol/amlodipine, also significantly is better than and only uses amlodipine/folic acid, and difference has statistical significance.
Therefore, the invention provides pharmaceutical composition that atenolol, amlodipine or the Levamlodipine of above-mentioned pharmaceutical dosage and folacin compound form is used for preventing, treating or delay hypertensive medicine in preparation purposes; Also provide aforementioned pharmaceutical compositions to be used for preventing, treat or delay the purposes of the medicine of the target organ damage that hypertension causes in preparation, described target organ damage comprises left ventricular hypertrophy, aortic hypertrophy, renal failure, optimum arteriolar nephrosclerosis, pernicious arteriolar nephrosclerosis, retinal arteriosclerosis disease or hypertension retinopathy.
Further, we find pleasantly surprisedly in experiment, when folacin compound and atenolol/amlodipine coupling, can also work in coordination with the danger that reduces the cardiovascular and cerebrovascular vessel incident, and effect significantly is better than only uses atenolol/amlodipine, also significantly be better than and only use amlodipine/folic acid, difference has statistical significance.
And then, the present invention also provides this pharmaceutical composition to be used for reducing the purposes of the medicine of the cardiovascular and cerebrovascular vessel incident danger that hypertension causes in preparation, wherein reduces cardiovascular and cerebrovascular vessel incident danger and is meant the incidence rate that reduces apoplexy (cerebral infarction or cerebral hemorrhage), angina pectoris, myocardial infarction, heart failure etc.
The dosage form of pharmaceutical composition of the present invention be conventional tablet, conventional capsule, soft capsule, granule, slow releasing tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, slow releasing capsule, controlled release capsule, contain micropill or small pieces capsule, contain the pH dependent form capsule or the oral liquid of micropill or small pieces.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into common oral preparation, comprise conventional tablet, conventional capsule etc., described pharmaceutically acceptable carrier includes excipient and the adjuvant 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, Icing Sugar, glucose, sodium chloride, cysteine, 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 tablet, comprise excipient and adjuvant etc.Described excipient and adjuvant have comprised that the adjuvant of slow releasing function is solubility/insoluble salt and/or other adjuvant that plays slow releasing function of hypromellose and/or ethyl cellulose and/or polyacrylic resin class and/or polycarboxy ethene and/or alginic acid, 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 the polyacrylic resin class adopts and includes polyacrylic resin II, the acrylic resin of III class or analog such as all size (Eudragit).Above-mentioned adjuvant is porogen, binding agent, lubricant, emulsifying agent, membrane material, solvent or other adjuvant, and porogen can adopt sucrose, mannitol, starch, Pulvis Talci, silicon dioxide etc.; Binding 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, Pulvis Talci, starch, paraffin etc.; Solubilizing agent can be adopted tartaric acid, citric acid etc.; Emulsifying agent can adopt span80 span85 etc.; Membrane material can adopt polyvinyl alcohol, hydroxyl methylcellulose, hydroxyl second fibre object, hymetellose, methylcellulose etc.; Foaming agent can adopt basic magnesium carbonate, sodium bicarbonate etc.; Bleach activator can adopt hexadecanol, octadecanol, Cera Flava 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 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 and/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, Glyceryl Behenate class etc.; Permeation-promoter can adopt sodium chloride, lactose, mannitol, fructose, glucose, sucrose etc.; Solubilizing agent can be adopted sodium lauryl sulphate or poloxamer etc.; Binding 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, Pulvis Talci, starch, paraffin etc.; Coloring agent can adopt iron oxide red, iron oxide yellow etc.; Porogen can adopt sucrose, mannitol, Polyethylene Glycol, titanium dioxide, Pulvis Talci, silicon dioxide etc.; Membrane 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 excipient and adjuvant etc.Described excipient and adjuvant have low substituted hydroxy-propyl methylcellulose, microcrystalline Cellulose, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, processing agar and mannitol, lactose 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; sucrose; dextrin; lactose; Icing Sugar; glucose; 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; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with various medicaments adjuvant such as porogen (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 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; sucrose; dextrin; lactose; Icing Sugar; glucose; 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; hydroxypropylmethylcellulose acetate methylcellulose phthalate ester, and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; triethyl citrate; tributyl citrate; CitroflexA-2; acetylated monoglycerides of Oleum Ricini and percentage or the like) with various medicaments adjuvant such as porogen (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 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; sucrose; dextrin; lactose; Icing Sugar; glucose; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., coating material comprises Lac; cellulose acetate; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit series); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; hydroxypropylmethylcellulose acetate methylcellulose phthalate ester; glyceryl monostearate; and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; triethyl citrate; tributyl citrate; CitroflexA-2; acetylated monoglycerides of Oleum Ricini and percentage or the like) with various medicaments adjuvant such as porogen (as PEG6000 etc.).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into dosage forms such as granule, oral liquid.Described diluent has starch, sucrose or lactose etc. when making granule, and disintegrating agent has starch, cellulose derivative etc., and binding agent has water 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 every day, perhaps with slow release or controlled release mode every day or a few days takes once every other day or at interval.
According to the present invention, pharmaceutical composition also can be meant the medicine box that contains two or three independent medicines.When " pharmaceutical composition " was meant the medicine box that contains two independent medicines, above-mentioned " Combined drug box " was a kind of box-packed container, the drug regimen of built-in multiple dosage form, and take description, " Combined drug box " more is applicable to personalized medicine; Contain atenolol/amlodipine in first medicine, second medicine is folacin compound.When " pharmaceutical composition " was meant the medicine box that contains three independent medicines, above-mentioned " Combined drug box " was a kind of box-packed container, the drug regimen of built-in multiple dosage form, and take description; First and second medicine contain atenolol and amlodipine respectively, contain folacin compound in the 3rd medicine.In this medicine box two or three independently medicine can concomitant dosing, also can be in a kind of pharmaceutical preparation or in different pharmaceutical preparation sequential administration.
The invention has the beneficial effects as follows: the efficacy of antihypertensive treatment when 1. this pharmaceutical composition can significantly improve the atenolol/amlodipine coupling; 2. this pharmaceutical composition is by the collaborative hypotensive effect of many target spots, antihypertensive effect in the time of not only can reaching independent use amlodipine/folacin compound, but also reduced the wherein taking dose of amlodipine, only need original about 1/4 dosage just can reach equal antihypertensive effect, reduce side effect, improve curative effect, reduce medical expense; 3. this pharmaceutical composition can significantly strengthen the protective effect to the hypertension target organ of atenolol/amlodipine or amlodipine/folate coupling time spent; 4. the more important thing is, this pharmaceutical composition is on the basis that reduces toxic and side effects, can effectively prevent, treat or delay the multiple cardiovascular and cerebrovascular disease complication of hypertension (comprising apoplexy, angina pectoris, myocardial infarction, heart failure, renal failure etc.) by two target spots (Hcy, blood pressure), this aspect significantly is better than atenolol/amlodipine or amlodipine/folic acid; The patient is taken medicine conveniently.
The specific embodiment
The invention will be further described below in conjunction with specific embodiment and test case, 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 preparation of embodiment 1 atenolol 20mg/ Amlodipine Besylate Tablet 2.0mg/ folic acid 0.4mg sheet
Prescription
Atenolol 20g
Amlodipine Besylate Tablet 2.0g
Folic acid 0.4g
Starch 45g
Microcrystalline Cellulose 45g
Sodium carboxymethyl cellulose (CMS.Na) 5.0g
5% polyvidone k-30 (solvent is a dehydrated alcohol) 1.0g
Magnesium stearate is an amount of
Make 1000
Preparation technology:
(1) atenolol, Amlodipine Besylate Tablet and the folic acid of getting recipe quantity is crossed behind 100 mesh sieves standby by equivalent incremental method mix homogeneously;
(2) other adjuvant is crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively;
(3) press behind the starch, microcrystalline Cellulose, CMS.Na mixing of recipe quantity again and mixed crude drug equivalent incremental method mix homogeneously;
(4) add binding agent and make soft material in right amount, 24 mesh sieves are granulated, 20 mesh sieve granulate, 40～75 ℃ of dryings.
(5) dry grain adds an amount of magnesium stearate mixing, tabletting behind the assay, packing.
Every day 1 time, each 1～2.
The capsular preparation of embodiment 2 atenolol 25mg/ amlodipine maleate 2.5mg/ calcium folinate 0.8mg
Prescription
Atenolol 25g
Amlodipine maleate 2.5g
Calcium folinate (by folinic acid) 0.8g
Lactose 30g
Microcrystalline Cellulose 15g
Starch 20g
Carboxymethylstach sodium 5.0g
Magnesium stearate is an amount of
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 crude drug crossed 100 mesh sieves, increase progressively mixing with above-mentioned adjuvant by equivalent, the capsule fill.
Every day 1 time, each 1～2.
The preparation of embodiment 3 atenolol 50mg/ Amlodipine Besylate Tablet 5mg//folic acid 0.8mg/ calcium folinate 0.8mg slow releasing tablet
Prescription
Atenolol 50g
Amlodipine Besylate Tablet 5g
Folic acid 0.8g
Calcium folinate 0.8g
Citric acid 10g
Hypromellose (K4M) 160g
Lactose 180g
Magnesium stearate is an amount of
Make 1000
Preparation technology:
By the prescription proportioning, with crude drug and hypromellose mixing, citric acid is dissolved in the ethanol makes soft material as wetting agent, granulate, and drying, granulate adds the magnesium stearate mixing, and tabletting is promptly.
The next day 1 time, each 1.
The preparation of embodiment 4 atenolol 10mg/ maleic acid levo amido chloro diping 0.25mg/ Amlodipine Besylate Tablet 0.25mg/ levoleucovorin calcium 0.2mg granules
Preparation technology:
With crude drug and the abundant mixing of proper starch, add an amount of water system soft material.With soft material with mechanical presses by screen cloth system wet granular, box-type drying granule, granulate and classification.
Every day 1 time, each 2～3 bags.
Test case 1 atenolol+amlodipine/folic acid---collaborative hypotensive effect
10～12 all spontaneous hypertensive rats in age (SHR) are available from The 2nd Army Medical College.The arteria caudalis method is measured twice of rat blood pressure (the 1st, 6 day) in one week, and the rat of getting blood pressure stabilization is used for experiment.Rat is pressed blood pressure grouping, totally 10 groups.After around the gastric infusion, administration, animal action arteries and veins, venous cannulation.Stablized 2 hours systolic pressures of continuous record 6 hours after recovering after 24～30 hours rat and computer system being connected.
Systolic pressure variation＞20mmHg thinks treatment effectively before and after the treatment, and it is invalid that blood pressure≤20mmHg thinks.Computing formula q=P
A+B/ (P
A+ P
B-P
A* P
B).A and B represent A medicine and B medicine; P is the percentage ratio that effecting reaction takes place.P
A+BEffecting reaction percentage ratio when referring to drug combination, P
A+ P
BBe two prescriptions when solely using effecting reaction and, P
A* P
BBe two prescriptions effecting reaction long-pending when solely using.Q＜0.85 represents that two medicines become antagonism, and q＞1.15 represent that two medicines become synergism, and q represents summation action between 0.85 and 1.15 the time.
Statistical analysis: measurement data mean+SD (X ± SD) expression, t check between relatively employing group of data between two groups.With P＜0.05 is the significance standard.
The result: with model control group relatively, folic acid group rat blood pressure makes moderate progress, atenolol/amlodipine group, amlodipine/folic acid group, and atenolol/amlodipine/folic acid group rat blood pressure all significantly reduce; With atenolol/amlodipine group or amlodipine/folic acid group (1.0/0.08) relatively, the blood pressure lowering amplitude of atenolol/amlodipine/folic acid group (10/1.0/0.08) rat further increases, and this comparison there were significant differences (seeing Table 1).Another one result is that this pharmaceutical composition can be by the collaborative blood pressure lowering (seeing Table 2) of many target spots.
With amlodipine/folic acid group (2.0/0.08) relatively, atenolol/amlodipine/folic acid group (10/0.5/0.08) is that 1/4 o'clock of original dosage just can reach equal antihypertensive effect (seeing Table 1) at the dosage of amlodipine.So, the antihypertensive effect when both having reached independent use amlodipine/folacin compound has also reduced side effect, improves curative effect, reduces medical expense.
Conclusion: atenolol and amlodipine/folate coupling time spent in blood pressure lowering intensity, reduce significantly to be better than aspect the side effect and only use amlodipine/folic acid, this be the upright topic of this compositions according to one of.Reduce side effect and be meant the cardiovascular system untoward reaction that reduces amlodipine.In addition, also can improve the efficacy of antihypertensive treatment of atenolol/amlodipine when folic acid and atenolol/amlodipine coupling.
Table 1. atenolol, amlodipine, folic acid list with or during coupling to the influence of spontaneous hypertensive rat systolic pressure (X ± SD)
Compare * P＜0.05, * * P＜0.01 with model control group; Compare with the atenolol/amlodipine group
△P＜0.05; Compare with amlodipine/folic acid (1.0/0.08) group
▲P＜0.05
Table 2. atenolol+amlodipine/folic acid is to the synergism of spontaneous hypertensive rat blood pressure lowering
Test case 2 folic acid+atenolol/amlodipine---collaborative target organ protection function
The grouping and the dosage of 10～12 week spontaneous hypertensive rats in age (SHR) see Table 3.Medicine is mixed in the rat standard feed by the foodstuff amount of animal every day, make animal edible voluntarily, the then edible rat standard feed that does not add medicine of model control group animal.Animal freely drinks water, and the indoor temperature of every treated animal, relative humidity and light application time are all identical.Be 4 months the course of treatment.Observation index is left ventricle index, aortic index and kidney index.The concrete operations step is as follows:
With 4 months rat anesthesia of treatment, open thoracic cavity and abdominal cavity, take out heart, thoracic aorta and right side kidney rapidly, clean with pre-cold saline.Separate left ventricle (comprising interventricular septum),, claim left ventricle heavy, calculate the heavy and weight ratio (LVW/BW) of left ventricle with the filter paper suck dry moisture; Remove adherent fatty tissue of thoracic aorta and connective tissue, from the excision of aortic arch left subclavian artery far-end branch, the length of getting thoracic aorta 30mm, the filter paper suck dry moisture is also weighed, and calculates the heavy and length ratio (AW/length) of thoracic aorta; With right kidney suck dry moisture, weigh, cut kidney along the center coronalplane, be the boundary with the medullary ray, measure renal cortex and medullary substance thickness respectively, calculate the thick ratio (RCT/RMT) of the thick and right medullary substance of right cortex.
It serves as effective that the synergism investigation relatively improves greater than 20% with pathological index and model control group.Computing formula q=P
A+B/ (P
A+ P
B-P
A* P
B).A and B represent A medicine and B medicine; P is the percentage ratio that effecting reaction takes place.P
A+BEffecting reaction percentage ratio when referring to drug combination, P
A+ P
BBe two prescriptions when solely using effecting reaction and, P
A* P
BBe two prescriptions effecting reaction long-pending when solely using.Q＜0.85 represents that two medicines become antagonism, and q＞1.15 represent that two medicines become synergism, and q represents summation action between 0.85 and 1.15 the time.
Statistical analysis: measurement data mean+SD (X ± SD) expression, t check between relatively employing group of data between two groups.With P＜0.05 is the significance standard.
The result: the folic acid list is used spontaneous hypertensive rat left ventricle index, thoracic aorta exponential sum kidney index is not made significant difference; The atenolol/amlodipine group has in various degree improvement effect to These parameters, and the improvement effect stronger (table 3) of folic acid+atenolol/amlodipine group also demonstrates good synergism (table 4) with q primary system meter.
Conclusion: only use atenolol/amlodipine significantly being better than aspect the Hypertensive Rats target-organ protection when folic acid and atenolol/amlodipine coupling, this is two of the upright topic of this a compositions foundation.
The table 3. folic acid+atenolol/amlodipine successive administration influence to the spontaneous hypertensive rat organ injury in 4 months (n=17～20)
Compare * P＜0.05, * * P＜0.01 with model control group; Compare with the atenolol/amlodipine group
△P＜0.05; Compare with amlodipine/folic acid (1.0/0.08) group
▲P＜0.05
Table 4. folic acid+atenolol/amlodipine is to the coordinating protection effect of spontaneous hypertensive rat target organ
Test case 3 atenolol/amlodipines/folic acid long term administration is to the influence of susceptible type spontaneously hypertensive (SHR-SP) rat brain stroke incidence
8～10 week spontaneous hypertensive rats in age (SHR) are divided into model control group group, atenolol/amlodipine group, amlodipine/folic acid group, atenolol/amlodipine/folic acid group, every group 30, medicine is mixed in the rat standard feed by the foodstuff amount of animal every day, make animal edible voluntarily, be 4 months the course of treatment.The then edible rat standard feed that does not add medicine of model control group animal.Observation index is as follows:
(1) observes animal diet followed, survival condition and behavioral activity every day.
(2) each treated animal cerebral seizure number.
The result:
(1) overview.In the experimentation, obvious lethargy appears after the model control group rat apoplexy, drowsiness, hair is fluffy, withered or come off, tarnish, weight loss, active movement obviously reduces, be slow in action, limbs are in various degree paralysis, and with symptoms such as tic, diarrhoea, urinary incontinence, eyeball are hemorrhage, the person of being in a bad way is dead in a few hours simultaneously for the morbidity of part rat.Most of animal nerve functional impairment of treatment group is slight than model group, and the mental status obviously is better than model group, and autonomic activities increases, and initiatively looks for food, drinks water, and weight loss is not obvious, and hair is also glossy along sliding than model group.
(2) apoplexy incidence rate.Atenolol/amlodipine/folic acid group rat brain stroke incidence significantly reduces, and relatively there were significant differences (P＜0.05) with the atenolol/amlodipine group, with amlodipine/more also there were significant differences for the folic acid group (P＜0.05).See table 5 for details.
Conclusion: only use atenolol/amlodipine significantly being better than aspect the generation of prevention SHR-SP rat brain apoplexy when folic acid and atenolol/amlodipine coupling, also significantly be better than and only use amlodipine/folic acid, this is three of the upright topic of this a compositions foundation.
The table 5. atenolol/amlodipine/folic acid successive administration influence to SHR-SP rat brain apoplexy in 4 months
X
2Check is compared with model control group
*P＜0.01; Compare with the atenolol/amlodipine group
△P＜0.05; Compare with amlodipine/folic acid group
▲P＜0.05
Test case 4 atenolol/Levamlodipine/calcium folinate is to the protective effect of spontaneous hypertensive rat (SHR) target organ damage
The concrete grouping and the dosage of 10～12 week spontaneous hypertensive rats in age (SHR) see Table 6.Medicine is mixed in the rat standard feed by the foodstuff amount of animal every day, make animal edible voluntarily, the then edible rat standard feed that does not add medicine of control animals.Animal freely drinks water, and the indoor temperature of every treated animal, relative humidity and light application time are all identical.Treated 4 months.Observation index is a left ventricle exponential sum thoracic aorta index.
Statistical analysis: measurement data mean+SD (X ± SD) expression, t check between relatively employing group of data between two groups.With P＜0.05 is the significance standard.
The result: atenolol/Levamlodipine/calcium folinate can effectively prevent SHR rat heart muscle plumpness and aortic hypertrophy, relatively there were significant differences (P＜0.05) with atenolol/Levamlodipine group, with Levamlodipine/more also there were significant differences for the calcium folinate group (P＜0.05).See Table 6.
Conclusion: only use atenolol/Levamlodipine significantly being better than aspect the Hypertensive Rats target-organ protection when calcium folinate and atenolol/Levamlodipine coupling, also significantly be better than and only use Levamlodipine/calcium folinate.
The table 6. atenolol/Levamlodipine/calcium folinate administration target organ coordinating protection effect to the SHR rat in 4 months
Compare with model control group
*P＜0.05,
*P＜0.01; Compare with atenolol/Levamlodipine group
△P＜0.05; Compare with Levamlodipine/calcium folinate group
▲P＜0.05.
Claims (10)
1. the pharmaceutical composition of an atenolol/amlodipine/folacin compound, it is characterized in that: the atenolol that contains pharmaceutical dosage, the amlodipine of pharmaceutical dosage or Levamlodipine, acceptable carrier on the folacin compound of pharmaceutical dosage and the pharmaceutics.
2. pharmaceutical composition according to claim 1 is characterized in that: the dosage of described atenolol is 5～50mg.
3. pharmaceutical composition according to claim 1 is characterized in that: described amlodipine or Levamlodipine are one or more of benzene sulfonate, maleate and pharmaceutically acceptable other salt apoplexy due to endogenous wind, and dosage is 0.5～5.0mg.
4. pharmaceutical composition according to claim 1 is characterized in that: described folacin compound is one or more in folic acid, calcium folinate or the levoleucovorin calcium, and dosage is 0.2～1.6mg.
5. according to arbitrary described pharmaceutical composition in the claim 1～4, it is characterized in that: the dosage form of described pharmaceutical composition be conventional tablet, conventional capsule, soft capsule, granule, slow releasing tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, slow releasing capsule, controlled release capsule, contain micropill or small pieces capsule, contain the pH dependent form capsule or the oral liquid of micropill or small pieces.
6. arbitrary described pharmaceutical composition is used for preventing, treating or delay the purposes of hypertensive medicine in the claim 1～4 in preparation.
7. arbitrary described pharmaceutical composition is used for preventing, treat or delay the purposes of the medicine of the target organ damage that hypertension causes in the claim 1～4 in preparation.
8. purposes according to claim 7 is characterized in that: described target organ damage comprises left ventricular hypertrophy, aortic hypertrophy, renal failure, optimum arteriolar nephrosclerosis, pernicious arteriolar nephrosclerosis, retinal arteriosclerosis disease or hypertension retinopathy.
9. arbitrary described pharmaceutical composition is used for reducing the purposes of the medicine of the cardiovascular and cerebrovascular vessel incident danger that hypertension causes in the claim 1～4 in preparation.
10. purposes according to claim 9 is characterized in that: the cardiovascular and cerebrovascular vessel incident danger that described reduction hypertension causes is meant the incidence rate that reduces apoplexy, angina pectoris, myocardial infarction or heart failure.
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Cited By (7)
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| CN101890165A (en) * | 2009-05-22 | 2010-11-24 | 北京奥萨医药研究中心有限公司 | Composition for lowering blood pressure and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101890165A (en) * | 2009-05-22 | 2010-11-24 | 北京奥萨医药研究中心有限公司 | Composition for lowering blood pressure and application thereof |
| CN101897973A (en) * | 2009-05-27 | 2010-12-01 | 北京奥萨医药研究中心有限公司 | Application of pharmaceutical composition containing calcium antagonists and B vitamins to preparing medicines for treating peripheral arterial diseases |
| CN103272236A (en) * | 2013-05-27 | 2013-09-04 | 深圳奥萨医药有限公司 | Beta-adrenergic receptor retarder and vitamins B-containing pharmaceutical composition and applications thereof |
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| CN110237258A (en) * | 2018-03-09 | 2019-09-17 | 深圳奥萨制药有限公司 | For treating the pharmaceutical composition of hypertension |
| CN111481554A (en) * | 2019-01-29 | 2020-08-04 | 深圳奥萨医药有限公司 | Tablet containing amlodipine and folic acid and preparation method thereof |
| EP4023221A4 (en) * | 2019-11-08 | 2023-09-27 | Shihuida Pharmaceuticals Group (Jilin) Ltd. | Composition containing legoamodipine besylate hydrate and preparation method therefor |
| CN116407495A (en) * | 2023-03-09 | 2023-07-11 | 北京梅尔森医药技术开发有限公司 | Atenolol oral solution and preparation method and application thereof |
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