WO2009143662A1

WO2009143662A1 - Pharmaceutical composition comprising calcium blocker and b family vitamins and the use thereof

Info

Publication number: WO2009143662A1
Application number: PCT/CN2008/001681
Authority: WO
Inventors: 徐希平; 秦献辉; 陈光亮; 王文艳; 于多; 王燕
Original assignee: 北京奥萨医药研究中心有限公司; 深圳奥萨医药有限公司
Priority date: 2008-05-30
Filing date: 2008-09-28
Publication date: 2009-12-03

Abstract

Pharmaceutical composition containing calcium channel blocker and B family vitamins and the use of the composition in treating hyperhomocysteinemia are provided. The combination of calcium channel blocker and B family vitamins can act on multiple paths and links of hyperhomocysteinemia, decrease organ damage effectively and reduce levels of homocysteine. It improves upon a single drug, and reavels the significant synergetic effect of calcium channel blocker and B family vitamins on the reduction of elevated levels of homocysteine and relief of the damage caused by elevated levels of homocysteine.

Description

Pharmaceutical composition containing calcium channel blocker and B vitamin and use thereof

The present invention relates to the treatment of hyperhomocysteinemia. In particular, the present invention relates to a pharmaceutical composition comprising a calcium channel blocker and a B vitamin and its use for the treatment of hyperhomocysteinemia. Background technique

As early as 1969, people hypothesized that homocysteine (Hcy) may be a risk factor for cardiovascular disease. Since then, a large number of studies have accumulated objective evidence that plasma Hcy levels and cardiovascular disease (Cadiovascular disease, CVD) is closely related to the risk of other systemic diseases.

Ye Deshou et al [Clinical Cardiology Journal, 2005; 21: 536-538] showed that the level of Hcy in Chinese patients with essential hypertension was significantly higher than that in the control group (P<0.05): the incidence of high Hcy in patients with essential hypertension (Hice concentration of Hice>15 μηιοΙ/L) was 36.6%, and that of the control group was 21.6%. The difference was 15%. The difference was statistically significant (P<0.05), indicating that Hcy was closely related to hypertension. At the same time, plasma Hcy levels can be independent of traditional risk factors such as hypertension and hyperlipidemia. The increase in plasma Hcy by 5 μιηοΙ/L increases the risk of stroke by 59% (OR (odds ratio), 1.59; 95% CI (contribution) Interval), 1.30-1.95), 60% increased risk of deep vein thrombosis (OR, 1.60; 95% CI, 1.15-2.22), ischemic heart disease (including coronary heart disease, angina pectoris, arrhythmia, myocardial infarction, heart failure) And sudden death) increased risk by 33% (OR, 1.33; 95% CI, 1.22-1.46); Hcy level decreased by 3 μιηοΙ/L, stroke risk decreased by 24%, deep vein thrombosis risk decreased by 25%, ischemic heart disease The risk is reduced by 16%. It indicates that Hcy is closely related to ischemic heart disease, stroke, and deep vein thrombosis [Wald DS, et al. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002; 325: 1202-1206.] .

In addition to its important role in the development of CVD, high Hcy is associated with other diseases such as Alzheimer's disease (AD), dementia, cognitive dysfunction, osteoporosis, fracture, depression, Parkinson's disease (PD). Various diseases such as schizophrenia, death, neonatal defects, and habitual abortion are closely related.

Since the 1990s, a large number of reports have suggested that high plasma Hcy is associated with decreased brain function and the development of AD. In 1998, Clarke et al. diagnosed 164 patients over 55 years old. A controlled study was performed in patients with AD and 148 elderly people of similar age [Clarke R, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998; 55: 1449-1455.], The results showed that the Cambridge Cognitive Examination (CAMCOG) score and the mini-mental state examination (MMSE) scores of AD patients were significantly lower than those of the control group, and plasma Hcy levels were significantly increased; The most characteristic feature was that 76 patients in the case had histologically confirmed after death. The difference in Hcy concentration between the confirmed AD patients and the control was more significant than that between the 164 clinically diagnosed patients and the control. Seshadri S et al. prospective trials of 1,092 volunteers with an average age of 76 years showed that for every 5 mol/L increase in Hcy levels, the risk of developing AD increased by 40%, and it is believed that at least 8 years ago Hcy levels are associated with the diagnosis of dementia and AD [Seshadri S, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002; 346: 476-483]; Postrglion et al. Patients not only have high plasma Hcy levels, but their progression is also directly proportional to Hcy levels, so Hcyemia is considered to be not only an independent risk factor for AD, but also associated with the progression and severity of AD [Postiglione A, et al. Plasma Folate, vitamin B12, and total homocysteine tetrahydrofolate reducase gene in patients with Alzheimer's dementia. A case-control study. Gerontolgy, 2001; 47: 324-349.]. More studies have shown that Hcy levels can be used independently to predict the upcoming decline in cognitive decline and decline in independence, independent of age, gender, education, kidney function, vitamin B6 levels, smoking history, and hypertension. [Morris MS, et al. Hyperhomocystinemia associated with poor recall in the third National Health and Nutrition Examination Survey. Am J Clin Nutr. 2001; 73: 927-933.]. The possible mechanisms of action of Hcy in AD, dementia or impaired cognitive function include: direct damage of neurons by Hcy; enhancement of neurotoxic effects of amyloid Αβ; affecting brain function by impairing microcirculation.

Studies have shown that patients with high Hcy PD have more severe depression and cognitive impairment [OpSuilleabhain PE, et al. Arch Neurol, 2004, 61: 865.]; Xin F et al's study of plasma Hcy levels in hospitalized patients with depression The incidence of high Hcy was significantly higher than that of the normal control group. The level of Hcy in the plasma of patients with depression was positively correlated with the degree of depression. As the condition improved, the level of Hcy in the plasma also decreased, indicating that Hcy is closely related to depression [Xin F, et Al. Relationship of Homocysteine and Folic acid with Depression. Heilongj iang Medical J. 2007; 31: 659-662]; In Zhao G et al., plasma Hcy levels were significantly higher in patients with bipolar disorder than in the normal group, indicating that blood cystic Hcy levels are closely related to bipolar disorder [Zhao G, et al. An association Analysis of methylenetetrahydrofolate dehydrogenase polymorphism, plasma homocysteine levels and bipolar affective disorder. Journal of Psychiatry, 2008; 21 : 130-132]. A study by Susser et al. compared Hcy levels in the schizophrenia group and the control group, and divided them into a normal folate level group and a low folic acid level group. It was found that there was a significant difference in Hcy levels in the low folate level group, suggesting a spirit There is an imbalance of Hcy metabolism in schizophrenia [Susser E, et al. Lindenbaum J: Schizophrenia and impaired homocysteine metabolism: a possible association. Biol Psychiatry, 1998; 44: 141]. Studies by Gonzalez S et al. have shown that high Hcy and mortality are closely related in the elderly population without any chronic disease [Gonzalez S, et al. Homocysteine increase the risk of mortality in elderly individuals. BJN. 2007; 1-7].

The mechanism of damage caused by high Hcy is generally thought to be related to the damage of endothelial cells, oxidative stress, destruction of coagulation and fibrinolysis, vascular smooth muscle cell proliferation and direct cytotoxicity. Numerous studies have confirmed that Hcy levels are positively correlated with the damage caused. The Hcy level of healthy people abroad is about 8-10 mol L. Currently, the Hcy level is greater than or equal to 10 μηιοΙ/L, which is defined as high Hcyemia or elevated Hcy [Circulation, 2006; 113: e409-e449; Clin Chem Med. 2003; 41 : 1392-1403]. Hughes et al found that Chinese male Hcy levels averaged 15.3 μΐΊΐοΙ/L, females 12.2 μηιοΙ/LtJ Epidemiol Community Health. 2000; 54(1): 31-34.], if plasma Hcy>14 mol/L The incidence of high Hcy in Chinese men is 57%, and that in women is 31%. Studies in Hao et al also show that Hcy levels in Chinese population are significantly higher. With Hcy greater than or equal to ΙΟμιηοΙ/L, the incidence of hyperhomocysteinemia in the South is about It is 32°/. North is about 58%, with an average of about 45% [J Nutr 2007; 137: 407- 413]. The above data indicate that high Hcyemia is widespread in China, causing serious social harm in many disease areas and must be actively intervened.

Most of the current use of B vitamins, mainly folic acid to reduce Hcy levels, in order to treat high Hcy disease. A meta-analysis indicates that folic acid dose is less than 1 mg/d

The effect of reducing Hcy levels was comparable (mean 0.5 mg), 1 -3 mg/d (mean 1.2 mg), and greater than 3 mg/d (average 5.7 mg) [BMJ. 1998; 316: 894-898]. Another study showed that taking 0.8 mg of folic acid daily can basically achieve the maximum effect of reducing Hcy levels, while adding vitamin B12.

(400 ig/day) can only reduce Hcy levels by 7%, while adding vitamin B6 or increasing Measures such as folic acid dose do not enhance its effect on reducing Hcy levels [Arch Intern Med. 2001; 161: 695-700; Am J Clin Nutr 2005; 82: 806-812.]. The above results indicate that the use of vitamins or multivitamins has a certain limit in reducing the effect of Hcy levels, and increasing the dose does not improve the effect of reducing Hcy.

Considering that most clinical studies have used large doses of compound B vitamins (folic acid, B6 and B12), and the previous data suggests that further increases in folic acid doses do not further reduce Hcy levels; meanwhile, studies have confirmed that large doses of folic acid are used in combination. B vitamins may present a safety hazard. In studies such as NORVIT (Norwegian Vitamin Trial) and H0PE2 (Heart Outcome Prevention Evaluation 2), patients have an increased risk of tumor prevalence. Therefore, it is of great medical value and social value to further seek ways and drugs that can safely and effectively reduce Hcy levels and antagonize the damage caused by high Hcy.

Calcium channel blockers, also known as calcium channel blockers, inhibit transmembrane Ca2+ influx and/or intracellular Ca2+ release, reduce intracellular free Ca2+ concentration and its utilization, inhibit ATPase activity, and reduce myocardial contractility It relaxes muscle cells, dilates blood vessels, and reduces peripheral vascular resistance, thereby lowering blood pressure. Clinically, calcium channel blockers are used to treat angina pectoris, hypertension, arrhythmias, congestive cardiomyopathy, and ischemic heart disease. At present, dozens of large-scale clinical studies, such as ASCOT, ACTION, ALLHAT, CAMLOT, etc., indicate that there is no serious safety hazard in the clinical use of calcium channel blockers.

Calcium channel blockers are mainly selected from nifedipine, amlodipine, nimodipine, nicardipine, lacidipine, nisoldipine, nitrendipine, felodipine, nilvadipine, isradipine, bani Dipine, benidipine, nirudipine, adipine, diltiazem, verapamil, cinnarizine, flunarizine and the like. Summary of the invention

The object of the present invention is to overcome the deficiency of B vitamins such as folic acid in the treatment of hyperhomocysteinemia, and to provide a composition containing a calcium channel blocker and a B vitamin in the preparation of reducing homocysteine, The use of a comprehensive and effective antagonism of high homocysteine damage, thereby safely and effectively treating drugs with high homocysteinemia.

Hyperhomocysteinemia in the present invention is indicated by an increase in plasma homocysteine levels, including Body damage caused by elevated levels of homocysteine. The damage caused by elevated levels of homocysteine is characterized by vascular smooth muscle hyperplasia, thrombosis, neuronal damage, and microcirculatory disorders. The mechanism is generally believed to be related to oxidative stress, damage to endothelial cells, and destruction of the body. Balance between coagulation and fibrinolysis, causing vascular smooth muscle cell proliferation, cytotoxicity, etc., can eventually cause stroke, deep vein thrombosis, hypertension, ischemic heart disease (including coronary heart disease, angina pectoris, arrhythmia, myocardial infarction , heart failure and sudden death), Alzheimer's disease (AD), dementia, cognitive dysfunction, osteoporosis, fracture, depression, bipolar disorder, Parkinson's disease (PD), spirit A variety of related diseases such as schizophrenia, death, neonatal defects, habitual abortion.

The pharmaceutical compositions provided herein comprise one or more of a therapeutically effective amount of a calcium channel blocker and a therapeutically effective amount of a B vitamin and a pharmaceutically acceptable carrier.

The calcium channel blocker in the composition is selected from the group consisting of nifedipine^ amlodipine, levamlodipine, nimodepine, nicardipine, lacidipine (lacidipine), nisoldipine (nitoldipine), nitrendipine, felodipine, nilvadipine, isradipine, bamidipine, benidipine ( Benidipine), niludipine. azelnidipine, diltiazem, verapamil

( verapamil ), cinnarizine, flunarizine, preferably schopenthalide, amlodipine, levamlodipine, nitrendipine, more preferably amlodipine, levoammonium chloride Adipine and nifedipine are more preferred amlodipine. Metabolites or salts of calcium channel blockers, such as derivative, metabolite, precursor or calcium channel blocker active metabolites with calcium channel blockers as active ingredients, are also included in the scope of the present disclosure. .

Through experimental research, the daily dosage of calcium channel blockers is: nifedipine 20~120mg, amlodipine 2.5~20mg, levamlodipine 2.5~10mg, nicardipine 30~240mg, lacidipine 2~8mg Nitrodipine 5~60mg, nitrendipine 10~60mg, felodipine 2.5~40mg, isradipine 2.5~20mg, diltiazem 30~240mg, verapamil 40~480mg, etc. The content of the derivative, precursor, active metabolite or salt of the above substance can be obtained by equivalent conversion of the above substances. The daily amount of the derivative, precursor, active metabolite or salt of the above substance can be determined by equivalent conversion of the above substance.

The preferred daily dosages of calcium channel blockers are: nifedipine 20~60mg, amlodipine 2.5~10mg, levamlodipine 2.5~5mg, nicardipine 60~: L20mg, lacidipine 4~6mg, nisoldipine 10~60mg, nitrendipine 20~60mg, felodipine 2.5~20mg, yira Level 2.5~10mg, diltiazem 90~240mg, verapamil 80~360mg, etc. The daily usage of the derivatives, precursors, active metabolites or salts of the above substances can be determined by equivalent conversion of the above substances.

In the present invention, the B vitamin in the composition is selected from the group consisting of vitamin B1 (vitamin B1), vitamin B2 (vitamin B2), vitamin PP, vitamin B6 (vitamin B6), vitamin B12 (vitamin B 12), biotin ( One or more of D-biotin, vitamin H), folic acid (vitamin B9) and pantothenate (vita B5) or their derivatives and substances which can release/generate such compounds in vivo.

The B vitamins are preferably vitamin B6, vitamin B12 and folic acid, more preferably folic acid. Among them, vitamin B6 is selected from the group consisting of pyridoxine, pyridoxal, pyridoxamine, pyridoxal phosphate, pyridoxamine phosphate, derivatives of the above, and substances which can release/produce such compounds in vivo.

Among them, vitamin B12 is selected from the group consisting of cobalamin, mecobalamin, 5'-deoxyadenosylcobalamin, hydroxocobalamin, cyanocobalamin and other cobalamin derivatives and can release/form cobalt in vivo. Amine substance.

Among them, folic acid is selected from the group consisting of active metabolites of folic acid, formyltetrahydrofolate, L-methylfolate, folate, folic acid or folate, and substances which release/form folic acid in vivo.

For the treatment of mammals including human hyperhomocysteinemia, the daily dose of B vitamins is: folic acid 0. 2~15 mg, vitamin B12 0. 1~2 mg, vitamin B6 0. 5~50 mg. The preferred daily dosage is: folic acid 0. 2~5 mg, vitamin B12 1 μg~2 mg, vitamin B6 5~50 m o The daily dose of folic acid is more preferably 0. 4 mg or 0.8 mg.

When used to treat hyperhomocysteinemia in mammals, including humans, the preferred combination is:

The calcium channel blocker is amlodipine, the daily dosage is 2.5~10mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2~5mg.

The calcium channel blocker is amlodipine, and the daily dosage is 5 mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.8 mg.

The calcium channel blocker is amlodipine, and the daily dosage is 5 mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.4 mg.

The calcium channel blocker is amlodipine, the daily dosage is 2.5~10mg; the B vitamin is Vitamin B6, daily dosage is 5~50mg.

The calcium channel blocker is amlodipine, the daily dosage is 2.5~10mg _{; the} B vitamin is vitamin B12, and the daily dosage is ^g~2mg.

The calcium channel blocker is levamlodipine, and the daily dosage is 25 mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 to 5 mg.

The calcium channel blocker is levamlodipine, the daily dosage is 25 mg; the B vitamin is vitamin B6, and the daily dosage is 5 to 50 mg.

The calcium channel blocker is levamlodipine, the daily dosage is 25 mg; the B vitamin is vitamin B12, and the daily dosage is l g~2 mg.

The calcium channel blocker is nifedipine, the daily dosage is 20~60mg _{; the} B vitamin is folic acid or calcium tetrahydrofolate, and the daily dosage is 0.2~5mg.

The calcium channel blocker is nifedipine, the daily dosage is 20~60m _{g; the} B vitamin is vitamin B6, and the daily dosage is 5~50mg.

The calcium channel blocker is nifedipine, the daily use I is 20~60mg; the B vitamin is vitamin B12, and the daily dosage is l g~2mg.

The calcium channel blocker is lacidipine, the daily use I is 4~6mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 -"5mgc

The calcium channel blocker is lacidipine, the daily use i: 4~6mg; the B vitamin is vitamin B6, and the daily dosage is 5~50mg.

The calcium channel blocker is lacidipine, the daily dosage is 4~6mg; the B vitamin is vitamin B12, and the daily dosage is l g~2mg.

The calcium channel blocker is felodipine, the daily use I is 4~6mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2~5mg _c

The calcium channel blocker is felodipine, the daily use I is 4~6mg; the B vitamin is vitamin B6, and the daily dosage is 5~50mg.

The calcium channel blocker is felodipine, the daily dosage is 4~6mg; the B vitamin is vitamin B12, and the daily dosage is l g~2mg.

In the pharmaceutical composition of the present invention, the active ingredient is an essential component in the composition, one active ingredient is derived from one of the calcium channel blockers, and the other active ingredient is derived from one or more B vitamins, active The amount of the ingredients can be determined in accordance with the daily amount determined above. The drug The composition may be in the form of a pharmaceutical preparation, including but not limited to common tablets, bilayer tablets, multi-layer tablets, sustained release tablets, single-chamber controlled release tablets, dual-chamber controlled release tablets, micropores Controlled release tablets, sublingual tablets, orally disintegrating tablets, dispersible tablets, enteric coated tablets, granules, pills, enteric capsules, delayed release tablets, timed/release tablets, ordinary capsules, sustained release capsules, controlled Capsules, capsules containing pellets or tablets, pH-dependent capsules containing micropellets or tablets, oral liquids, films or patches. Special mention should be made of drugs containing calcium channel blockers and B vitamins. The composition is made into a tablet or capsule.

For the treatment of hyperhomocysteinemia, the compounds in the pharmaceutical composition may be administered to the affected individual simultaneously in the same preparation, or may be administered to the affected individual separately. In the case of sequential administration to a diseased individual, the delay in the administration of the second (or additional) active ingredient should not result in a loss of beneficial effects resulting from the combination of the active ingredients. In the case of simultaneous administration to a diseased individual, the compounds in the composition may be present in the same pharmaceutical preparation form, or may be independently present in the same preparation form. If they are independently present in the same formulation, the pharmaceutical composition may be modified in the form of a "combination kit". A "combination kit" is a box-like container containing a combination of drugs in one or more dosage forms, and instructions for its use. In the present invention, a combination tablet of one of the calcium channel blockers and one of the B vitamins is preferred.

Meanwhile, the present invention also provides a pharmaceutical composition comprising one or more of a calcium channel blocker and a B vitamin for treating a disease of elevated homocysteine, wherein the angiotensin converting enzyme inhibitor and B Family vitamins are as defined above.

In a preferred embodiment, in the composition of the present invention: the calcium channel blocker is amlodipine in a content of 2.5 to 10 parts by weight; the B group vitamin is folic acid or calcium leucovorin, and the content is 0.2 to 5 Parts by weight.

The calcium channel blocker is amlodipine in an amount of 5 parts by weight; the B group vitamin is folic acid or calcium leucovorin, and the daily amount is 0.8 parts by weight.

The calcium channel blocker is amlodipine at a daily dosage of 5 parts by weight; the B group vitamin is folic acid or calcium leucovorin, and the daily amount is 0.4 parts by weight.

The calcium channel blocker is amlodipine, and the daily dosage is 2.5 to 10 parts by weight; the B group vitamin is vitamin B6, and the daily dosage is 5 to 50 parts by weight.

The calcium channel blocker is amlodipine, and the daily dosage is 2.5 to 10 parts by weight; It is a vitamin B12, and the daily dosage is 0.001 to 2 parts by weight.

The calcium channel blocker is levamlodipine, and the daily dosage is 2.5 to 5 parts by weight; the B group vitamin is folic acid or calcium leucovorin, and the daily amount is 0.2 to 5 parts by weight.

The calcium channel blocker is levamlodipine, and the daily dosage is 2.5 to 5 parts by weight; the B group vitamin is vitamin B6, and the daily amount is 5 to 50 parts by weight.

The calcium channel blocker is levamlodipine, and the daily dose is 2.5 to 5 parts by weight; the B group vitamin is vitamin B12, and the daily dosage is 0.001 to 2 parts by weight.

The calcium channel blocker is nifedipine, and the daily dosage is 20 to 60 parts by weight; the B group vitamin is folic acid or calcium tetrahydrofolate, and the daily amount is 0.2 to 5 parts by weight.

The calcium channel blocker is nifedipine, and the daily dosage is 20 to 60 parts by weight; the B group vitamin is vitamin B6, and the daily amount is 5 to 50 parts by weight.

The calcium channel blocker is nifedipine, and the daily dosage is 20 to 60 parts by weight; the B group vitamin is vitamin B12, and the daily dosage is 0.001 to 2 parts by weight.

The calcium channel blocker is lacidipine, and the daily dosage is 4 to 6 parts by weight; the B group vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 to 5 parts by weight.

The calcium channel blocker is lacidipine, and the daily dosage is 4 to 6 parts by weight; the B group vitamin is vitamin B6, and the daily dosage is 5 to 50 parts by weight.

The calcium channel blocker is lacidipine, and the daily dosage is 4 to 6 parts by weight; the B group vitamin is vitamin B12, and the daily dosage is 0.001 to 2 parts by weight.

The calcium channel blocker is felodipine, and the daily dosage is 4 to 6 parts by weight; the B group vitamin is folic acid or calcium leucovorin, and the daily amount is 0.2 to 5 parts by weight.

The calcium channel blocker is felodipine, and the daily dosage is 4 to 6 parts by weight; the B group vitamin is vitamin B6, and the daily dosage is 5 to 50 parts by weight.

The calcium channel blocker is felodipine, and the daily dosage is 4 to 6 parts by weight; the B group vitamin is vitamin B12, and the daily dosage is 0.001 to 2 parts by weight.

As a preferred mode provided by the embodiments of the present invention, a combination preparation of amlodipine folic acid can be used for the treatment of hyperhomocysteinemia. As a preferred combination preparation, the amlodipine folic acid compound preparation can significantly reduce the homocysteine level in rats with hyperhomocysteinemia and protect the damage caused by the increase of homocysteine. The drug was used alone and showed statistical differences. Wherein, the amlodipine folic acid compound preparation is 5 parts by weight of amlodipine, Folic acid 0.8 parts by weight.

A method of treating hyperhomocysteinemia comprising providing a pharmaceutical composition provided by a patient of the present invention.

As another preferred mode provided by the embodiment of the present invention, a combination preparation of amlodipine folic acid VB12 can be used for the treatment of hyperhomocysteinemia. As a preferred combination preparation, amlodipine folic acid VB12 compound preparation can significantly reduce the level of homocysteine in rats with hyperhomocysteinemia, and protect the damage caused by elevated homocysteine. Better than single-use drugs, and showed statistical differences. Among them, the amlodipine folic acid VB12 compound preparation was 5 parts by weight of amlodipine, 0.8 parts by weight of folic acid, and 0.1 part by weight of VB12.

As still another preferred mode provided by the embodiment of the present invention, a combination preparation of nifedipine folic acid can be used for the treatment of hyperhomocysteinemia. As a preferred compound preparation, the nifedipine folic acid compound preparation can significantly reduce the homocysteine level in rats with high homocysteineemia, and protect the damage caused by the increase of homocysteine. The drug was used alone and showed statistical differences. Among them, the nifedipine folic acid compound preparation is 5 parts by weight of nifedipine and 0.8 parts by weight of folic acid.

The pharmaceutical composition of the present invention can be prepared by adding a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers or excipients refer to those materials known in the art that can act as a filler or carrier material in tablets, pills, capsules and the like. Usually these substances are approved by the health administration for this purpose and they are inactive as pharmaceutical agents. Handbook of Pharmaceutical Excipients (A. Wade and P. J. Weller, 2nd ed., American Pharmaceutical Society, Washington and Pharmacy Press, London Press, 1994) Edited pharmaceutically acceptable carriers and excipients. In particular, lactose, starch, cellulosic derivatives and the like, and mixtures thereof, are useful as carriers for the active component of the compositions of the present invention.

The invention is further described in conjunction with the specific embodiments, which are not intended to limit the invention, and any equivalent substitutions in the art in accordance with the present invention are within the scope of the invention. detailed description

Example 1: Efficacy of amlodipine besylate folic acid compound in a rat model of hyperhomocysteinemia

1, method

Establishment of animal and high Hcy model: 60 male rats of 250~300g were randomly divided into 6 Group, 10/group. The blank group was given normal feed, the model group, the high dose group of amlodipine, the low dose group of amlodipine, the folic acid group and the amlodipine + folic acid group were given high methionine words, continuous

12 weeks.

Grouping and administration: Oral administration was started from the 5th week of modeling, amlodipine low dose group, amlodipine high dose group, folic acid group and amlodipine + folic acid group were given amlodipine daily.

(0.5mg/kg), amlodipine (1mg/kg), folic acid (0.08mg/kg), amlodipine + folic acid (0.5mg+0.08mg/kg), the model group and the blank group were given the same amount of normal saline. . For 8 consecutive weeks. The blood was collected from the abdominal aorta after the last administration. The relevant index homocysteine (Hcy) (Hcy test kit purchased from Beijing Zhongshan Biotechnology Engineering Co., Ltd.) and nitric oxide (NO) Nitrogen Synthase (NOS) test kit purchased from Nanjing Bio-Building Bioengineering Research Institute), superoxide dismutase (SOD) (superoxide dismutase (SOD) (extraction method) test box purchased from Nanjing Bio-built Bioengineering Institute), determination of malondialdehyde (MDA) (malondialdehyde (MDA) test kit purchased from Nanjing Bio-Building Bioengineering Institute)).

2, the result

The results showed (see Table 1) that the Hcy of the methionine feed group was significantly higher than that of the normal group. Low dose of amlodipine and high dose of amlodipine (0.5mg, lmg) had no significant effect on Hcy, folic acid group can reduce Hcy level; amlodipine + folic acid group can significantly reduce Hcy level, its effect is better than ammonia The low dose group of clodipine, the high dose group of amlodipine and the folic acid group showed significant statistical differences, indicating that amlodipine + folic acid has a significant synergistic effect on reducing Hcy.

At the same time, the levels of NO and SOD in the model group decreased significantly, and the level of MDA increased significantly. The low dose group of amlodipine and the high dose group of amlodipine had no significant effect on SOD, MDA and NO. Folic acid can increase NO and SOD, and has no obvious effect on MDA. The amlodipine + folic acid group significantly increased the levels of SOD and NO, and decreased the level of MDA. The effect was better than the low dose of amlodipine, the high dose of amlodipine and the folic acid group, and showed significant statistical differences. Amlodipine + folic acid also has a significant synergistic effect in antagonizing high Hcy damage.

Changes in detection indicators of each group

Hcy SOD MDA NO Group

(μπιοΐ丄^-1 ) (U.mL- ' ) (nmol.mL" ¹ ) (μη οΙΧ" ¹ ) Blank group 7.5±2.9** 133.2±20.1** 1.7±0.6** 45.4±13.2** Model group 19.8 ± 6.9 54.5 ± 20.7 5.8 ± 2.0 16.2 ± 8.8 high dose of amlodipine

19.3±7.5 62.4士17.4 5.8±1.8 19.0±8.1 Group

Low dose of amlodipine

19.4±8.3 63.9±18.5 5.6±1.7 18.6±5.0 Group o Folic acid group 14.4±3.6* 74.2±20.0* 5.2±1.7 23.8±7.2: ¹ : Amlodipine + folic acid

103.7±15.4** ^@@## 3 ±1.0**@® ^##

Group

*P<0.05, **P<0.01, compared with the model group; ^@P <0.05, ^@@ P<0.01, compared with the folic acid group; ^## P<0.01, compared with the amlodipine group (low or high dose)

3. Conclusion

Clinical studies have confirmed that the use of B vitamins alone can not effectively treat the body damage, while the use of B vitamins such as folic acid alone to reduce the level of Hcy has a certain limit, 0. 8 mg / d dose of folic acid has basically reached its maximum efficacy, and further Increasing the dose of B vitamins such as folic acid has a safety hazard.

In this study, the SOD level in the model group was significantly reduced, and the MDA level was significantly increased, indicating that oxidative damage is one of the major damage pathways of high Hcy. One of the most important markers of vascular endothelial injury and dysfunction is the decrease in NO levels. In this study, the level of NO in the model group was significantly reduced, indicating that endothelial cell injury is also an important pathway for high Hcyemia leading to body damage.

The data in Table 1 shows that the low-dose amlodipine group, the high-dose amlodipine group, and the folic acid monotherapy group have insufficient protective effects on high Hcy injury; however, the combination of amlodipine and folic acid has significant effects on each index. Moreover, in this study, the amlodipine folic acid compound can synergistically reduce the level of Hcy, and its effect has a statistically significant difference with the effect of folic acid. The results fully indicate that amlodipine folic acid acts on multiple pathways and links of hyperhomocysteinemia, further reducing Hcy, and comprehensively antagonizing the damage caused by high Hcy levels, and the two interact. The pharmaceutical composition provided by the present invention has high safety and is therefore a better choice for treating hyperhomocysteinemia. Example 2: Efficacy of amlodipine behenate VB12 compound in a rat model of sputum Hcyemia 1. Method Establishment of animal and high Hcy model: 60 male rats of 250~300g were randomly divided into 6 groups, 10 rats/group. The blank group was given normal vocabulary, and the model group, amlodipine high-dose group, clopidogpine low-dose group, folic acid VB12 group and amlodipine folic acid VB12 group were given high methionine feed for 12 weeks.

Grouping and administration: Gastric administration was started from the 5th week of modeling, amlodipine low dose group, amlodipine high dose group, folic acid + VB12 group and amlodipine folic acid VB12 group were given amlodipine every day (0.5 Mg/kg), amlodipine (lmg/kg), folic acid + VB12 (0.08mg+0.01mg/kg), amlodipine + folic acid + VB12 (0.5mg+0.08mg+0.01mg/kg), model group and The blank group was given an equal amount of physiological saline. For 8 consecutive weeks, the abdominal aorta was blood stasis after the last administration, and the required index was measured (detection method is the same as in Example 1).

2, the result

The results showed (see Table 2) that the Hcy of the methionine feed group was significantly higher than that of the normal group. Low dose of amlodipine and high dose of amlodipine (0.5mg, lmg) had no significant effect on Hcy. Folic acid + VB12 group could significantly reduce Hcy level; Amlodipine folate VB 12 group significantly decreased Hcy level, better than ammonia Low dose of clodipine, high dose of amlodipine, and folic acid + VB12 group showed that amlodipine folic acid VB12 had a significant synergistic effect on reducing Hcy.

Table 2 Changes in Hcy levels in each group

Letter ~ Hcy/ ol丄 blank group 7.5±2.9** model group 19.8±6.9

High dose group of amlodipine 19.3±7.5

Low dose group of amlodipine 19.4±8.3

Folic acid B12 group 12.5±3.0**

Amlodipine folic acid VB12 group 9.6±1.9**@ ^##

**P<0.01, compared with the model group; ^@P <0.05, compared with the folic acid B12 group; ^## P<0.01, compared with the amlodipine group (low or high dose)

Example 3: Efficacy of nifedipine folic acid compound in a rat model of hyperhomocysteinemia

1, method Establishment of animal and high Hcy model: 60 male rats of 250~300g were randomly divided into 6 groups, 10 rats/group. The blank group was given normal feed, and the model group, nifedipine high dose group, nifedipine low dose group, folic acid group and amlodipine + folic acid group were given high methionine feed for 12 weeks.

Grouping and administration: Oral administration from the 5th week of modeling, nifedipine low-dose group, nifedipine high-dose group, folic acid group and nifedipine + folic acid group were given nifedipine daily

(3mg/kg), nifedipine (6mg/kg), folic acid (0.08mg/kg), nifedipine + folic acid (3mg + 0.08mg/kg), the model group and the blank group were given the same amount of normal saline. For 8 consecutive weeks. After the last administration, the abdominal aorta blood stasis was measured with the same indicators of homocysteine (Hcy), nitric oxide (NO), superoxide dismutase (SOD), malondialdehyde (MDA), etc. Example 1).

2, the result

The results showed (see Table 3) that the Hcy of the methionine feed group was significantly higher than that of the normal group. Nifedipine low-dose group and nifedipine high-dose group had no significant effect on Hcy, folic acid group could reduce Hcy level; nifedipine + folic acid group could significantly reduce Hcy level, and its effect was better than nifedipine low-dose group, Nifedipine high dose group, folic acid group, indicating that nifedipine + folic acid has a significant synergistic effect on reducing Hcy.

At the same time, the levels of NO and SOD in the model group decreased significantly, and the level of MDA increased significantly. The low dose group of nifedipine and the high dose group of nifedipine had no significant effect on SOD, MDA and NO. Folic acid can increase NO and SOD, and has no obvious effect on MDA. The nifedipine + folic acid group significantly increased the levels of SOD and NO, and decreased the level of MDA. The effect was better than that of the model group and the nifedipine low-dose group, the nifedipine high-dose group, and the folic acid group, and showed significant statistics. The difference indicates that nifedipine and folic acid also have significant synergistic effects in antagonizing high Hcy damage.

Table 3 Changes in detection indicators of each group

Hcy SOD MDA NO Group

(μιηοΙΧ" ¹ ) (U-mL" ¹ ) (nmol.mL" ¹ ) (μιτιοΙΧ" ¹ ) Blank group 7.5 ± 2.9** 133.2 ± 20.1** 1.7 ± 0.6** 45.4 ± 13.2** Model group 19.8 ± 6.9 54.5±20.7 5.8±2.0 16.2±8.8 Nifedipine

18.8±6.8 62.7±16.1 5.5±1.3 18.3±8.3 leveling agent Volume group

Nifedipine

Flat low dose 19.2±5.7 60.3士 16.8 5.4±1.5 17.5±3.8

Folic acid group 14.4±3.6* 74.2±20.0* 5.2±1.7 23.8±7.2'* Nifedipine

Flat + folic acid 3.5±1.3** ^@## 4 2±8 7**®® ^##组

*P<0.05, **P<0.01, compared with the model group; @P<0.05, ^@@ P<0.01 compared with the folic acid group''^##P<0.01, compared with the nifedipine group (low or high dose)

3. Conclusion

In this study, the SOD level of the model group was significantly decreased, and the MDA level was significantly increased, indicating that oxidative damage is one of the major damage pathways of high Hcy; one of the most important markers of vascular endothelial injury and dysfunction is the decrease of NO level in this study. The level of NO in the model group was significantly reduced, indicating that endothelial cell injury is also an important pathway for high Hcyemia leading to body damage.

The data in Table 3 show that: nifedipine low-dose group, nifedipine high-dose group, folic acid single-agent group have insufficient protective effect on high Hcy injury; but nifedipine folic acid combination has significant improvement on each index. Moreover, in this study, nifedipine folic acid compound can synergistically reduce Hcy, and its effect has significant statistical difference with folic acid. This result fully demonstrates that nifedipine folic acid can act on multiple pathways and links of hyperhomocysteinemia, further reducing Hcy, and comprehensively antagonizing the damage caused by high Hcy levels, and the two interact. The pharmaceutical compositions provided by the present invention are highly safe and thus are a better choice for the treatment of hyperhomocysteinemia.

Summary: High Hcyemia is associated with various diseases, oxidative damage, endothelial cell damage, etc. The main route of injury. At present, folic acid alone or compound B vitamins are not effective in the treatment of clinical high Hcy. The present invention acts on multiple pathways and links of high Hcyemia, effectively reduces high Hcy levels, reduces high Hcy damage, and has high safety. , will be a better choice, providing a more effective treatment for the treatment of hyperhomocysteinemia. Example 4 Preparation of a compound enalapril folic acid tablet containing 5 mg of amlodipine and 0.8 mg of folic acid: amlodipine 5 g folic acid 0.8 g lactose 50 g microcrystalline cellulose 50 g starch 10 g sodium carboxymethyl starch 30 g magnesium stearate lg Preparation method: 5g amlodipine, 0.8g folic acid, 50g lactose, 50g vitamin cellulose and 10g starch are pulverized and uniformly mixed, made into soft material with 10% povidone ethanol solution, granulated, dried, whole grain The granules having a water content of about 3% were uniformly mixed with magnesium stearate, and compressed into tablets by a tableting machine. Each of the prepared 1000 tablet tablets contained 5 mg of amlodipine and 0.8 mg of folic acid in a mass ratio of 5:0.8.

Example 5 Compound enalapril folic acid capsule formulation containing 5 mg amlodipine and 0.4 mg folic acid: amlodipine 5 g folic acid 0.4 g microcrystalline cellulose 15 g starch 35 g Sodium Carboxymethyl Starch 20g

PVP aqueous solution

Preparation method: 5g amlodipine, folic acid 0.4g, 15g microcrystalline cellulose, 35g starch pulverized, sieved and mixed evenly, mixed with an appropriate amount of povidone aqueous solution to make a soft material, granulated, dried, added about 1 The magnesium stearate is uniformly mixed, and 1000 capsules are obtained by a conventional method.

Claims

Rights request

A use of a pharmaceutical composition comprising a calcium channel blocker neutralizing a B vitamin in the preparation of a medicament for treating a hyperhomocysteinemia disease, wherein the calcium channel blocker is selected from the group consisting of nifedipine, amlodipine, Levamlodipine, nimodipine, nicardipine, lacidipine, nisoldipine, nitrendipine, felodipine, nilvadipine, isradipine, banitipine, cilnidipine, niludipine, Deflated, diltiazem, verapamil, and derivatives, precursors, active metabolites or salts thereof; the B vitamins are selected from the group consisting of folic acid, calcium leucovorin, vitamin B6, vitamin B12, vitamin B1, Vitamin B2, vitamin PP, biotin and pantothenic acid and their derivatives and substances which can release/generate such compounds in the body.

2. The use according to claim 1, wherein said hyperhomocysteinemia is an injury caused by elevated levels of homocysteine, including oxidative damage, cell proliferation, endothelial cell damage, thrombosis Forming pathological features.

3. Use according to claim 1, characterized in that said hyperhomocysteinemia is associated with hypertension.

4. The use according to claim 1, wherein the calcium channel blocker is selected from the group consisting of nifedipine, amlodipine, levamlodipine, lacidipine, felodipine, isradipine, diltiazem. One of verapamil, the daily dosage is: nifedipine 20~120mg, amlodipine 2.5~20mg, levamlodipine 2.5~10mg, lacidipine 2~8mg, felodipine 2.5~ 40mg, irradipine 2.5-20mg, diltiazem 30-240mg, verapamil 40-480mg _; the B vitamins are selected from one or more of folic acid, calcium leucovorin, vitamin B12, vitamin B6 , the daily dosage is: folic acid 0.2~5mg, calcium leucovorin 0.2~5mg, vitamin Β1 ² 1μ _§ ~ 2mg, vitamin B6 5~50mg, derivatives, precursors, active metabolites or salts of the above substances The daily dosage can be obtained by equivalent conversion of the above substances.

5. Use according to any of claims 1-3, characterized in that:

The calcium channel blocker is amlodipine, the daily dosage is 2.5~10mg; the B vitamin is vitamin B6, and the daily dosage is 5~50mg.

The calcium channel blocker is amlodipine, the daily dosage is 2.5~10mg; the B vitamin is vitamin B12, and the daily dosage is lg~2mg. The calcium channel blocker is levamlodipine, the daily dosage is 2.5~5mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2~5mg. The calcium channel blocker is levamlodipine, the daily dosage is 2.5~5mg; the B vitamin is vitamin B6, and the daily dosage is 5~50mg.

The calcium channel blocker is levamlodipine, the daily dosage is 2.5~5m _{g; the} B vitamin is vitamin B12, and the daily dosage is lg~2mg.

The calcium channel blocker is nifedipine, the daily use is 20~60mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2~5mg.

The calcium channel blocker is nifedipine, the daily use is 20~60mg; the B vitamin is vitamin B6, and the daily dosage is 5~50mg.

The calcium channel blocker is nifedipine, the daily use is 20~60mg; the B vitamin is vitamin B12, and the daily dosage is lg~2mg.

The calcium channel blocker is lacidipine, and the daily use is 4 to 6 mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 to 5 mg.

The calcium channel blocker is lacidipine, and the daily dosage is 4~6mg B vitamins are vitamin B6, and the daily dosage is 5~50mg.

The calcium channel blocker is lacidipine, the sputum is: 4~6mg; the B vitamin is vitamin B12, and the daily dosage is lg~2mg.

The calcium channel blocker is felodipine, which is used for daily use: 4 to 6 mg; the B vitamin is folic acid or calcium tetrahydrofolate, and the daily dose is 0.2 to 5 mg.

The calcium channel blocker is felodipine, which is used daily for 4~6mg; the B vitamin is vitamin B6, and the daily dosage is 5~50mg.

The calcium channel blocker is felodipine, the daily use is 4~6mg; the B vitamin is vitamin B12, and the daily dosage is lg~2mg.

6. The use according to claim 5, characterized in that the daily dose of amlodipine is 5 mg, and the daily dose of folic acid is 0.4 mg or 0.8 mg.

The use according to any of the preceding claims, wherein the pharmaceutical composition can be made into a common tablet, a common capsule, a granule, a sustained release tablet, a sublingual tablet, an orphan disintegrating tablet, a dispersible tablet. , enteric-coated tablets, enteric-coated capsules, delayed-release tablets, timed/release tablets, sustained-release capsules, controlled-release capsules, capsules containing pellets or tablets, pH-dependent capsules containing pellets or tablets, granules, orally A liquid, a film, a patch dosage form or a combination kit in which the two active components are separately present.

8. A pharmaceutical composition comprising a calcium channel blocker neutralizing a B vitamin, wherein the calcium channel blocker is selected from the group consisting of nifedipine, amlodipine, levamlodipine, nimodipine, and Nika Dipyridin, lacidipine, nisoldipine, nitrendipine, felodipine, nilvadipine, isradipine, banitipine, cilnidipine, nirudipine, adipine, diltiazem, verapamil and their a derivative, a precursor, an active metabolite or a salt; the B vitamin is selected from the group consisting of folic acid, calcium leucovorin, vitamin B6, vitamin B12, vitamin B1, vitamin B2, vitamin PP, biotin and pantothenic acid, and Their derivatives and substances which release/generate such compounds in the body.

The pharmaceutical composition according to claim 8, wherein the calcium channel blocker is amlodipine in an amount of 5 parts by weight, and the B group vitamin is folic acid in an amount of 0.4 or 0.8 parts by weight.

10. A method of treating hyperhomocysteinemia comprising administering a composition of claim 8 to a patient.