WO2009046631A1 - Composition pharmaceutique contenant un inhibiteur d'enzyme de conversion de l'angiotensine et des vitamines b, et son utilisation - Google Patents

Composition pharmaceutique contenant un inhibiteur d'enzyme de conversion de l'angiotensine et des vitamines b, et son utilisation Download PDF

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WO2009046631A1
WO2009046631A1 PCT/CN2008/001680 CN2008001680W WO2009046631A1 WO 2009046631 A1 WO2009046631 A1 WO 2009046631A1 CN 2008001680 W CN2008001680 W CN 2008001680W WO 2009046631 A1 WO2009046631 A1 WO 2009046631A1
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Prior art keywords
vitamin
daily dosage
folic acid
enzyme inhibitor
converting enzyme
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PCT/CN2008/001680
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English (en)
Chinese (zh)
Inventor
Xiping Xu
Xianhui Qin
Guangliang Chen
Ping Liu
Wenyan Wang
Duo Yu
Yan Wang
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Beijing Huaanfo Biomedical Research Center, Inc
Shenzhen Ausa Pharma Co., Ltd.
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Publication of WO2009046631A1 publication Critical patent/WO2009046631A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • composition containing angiotensin converting enzyme inhibitor and B vitamin and use thereof
  • the present invention relates to the treatment of hyperhomocysteinemia.
  • the present invention relates to a pharmaceutical composition comprising an angiotensin converting enzyme inhibitor (ACEI) and a B vitamin and its use for the treatment of hyperhomocysteinemia.
  • ACEI angiotensin converting enzyme inhibitor
  • Hcycysteine As early as 1969, people hypothesized that homocysteine (Hcycysteine, 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.
  • Hcycysteine As early as 1969, people hypothesized that homocysteine (Hcycysteine, 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.
  • CVD cardiovascular disease
  • Hcy The increase in plasma Hcy is 5 ⁇ /L, which 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 nd/L, stroke risk decreased by 24%, deep vein thrombosis risk decreased by 25%, ischemic heart disease The risk is reduced by 16%.
  • 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.] .
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • schizophrenia death, neonatal defects, habitual abortion and other diseases are closely related.
  • Hcy concentration The difference in Hcy concentration between the AD patients after the diagnosis and the control was more significant than that between the 164 clinically diagnosed patients and the control.
  • Seshadri S et al. conducted a prospective trial of 1,092 volunteers with an average age of 76 years. The risk of AD increased by 40% for every 5 mol/L increase in Hcy levels, and it is believed to be at least 8 years old. 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.
  • 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 7_K can be used independently to predict the upcoming decline in cognitive ability and decline independently of age, gender, education, kidney function, vitamin ⁇ 6 level, smoking history and hypertension. Degree of page measurement [Morris MS, et al. Hyperhomocystinemia associated with
  • Hcy in AD dementia or impaired cognitive function
  • the possible mechanisms of action of Hcy in AD, dementia or impaired cognitive function include: direct damage of neurons by Hcy; enhancement of neurotoxicity of amyloid ⁇ ; affecting brain function by impairing microcirculation.
  • Hcy levels are positively correlated with the damage caused.
  • the Hcy level of healthy people abroad is about 8-10 ⁇ /L.
  • Hcy levels greater than or equal to 10 ⁇ /L are defined as high Hcyemia or elevated Hcy [Circulation, 2006; 113: e 409-e449; Clin Chem Med.
  • B vitamins may present a safety hazard.
  • studies such as NORVIT (Norwegian Vitamin Trial) and HOPE2 (Heart Outcome Prevention Evaluation 2) patients are at increased risk of tumor prevalence. Therefore, it is of great medical 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.
  • Angiotensin-converting enzyme inhibitors are a class of drugs that act by competitively inhibiting angiotensin converting enzyme (ACE).
  • ACE is a non-specific enzyme that, in addition to converting angiotensin I (Angl) to angiotensin II (Angll), also catalyzes the degradation of peptide-like vasodilators such as bradykinin. Therefore, under the action of ACE, the concentration of Angll in the circulation and tissues is increased, and the level of bradykinin is decreased.
  • ACEI competitively blocks the conversion of Angl to Angll, thereby reducing circulating and local Angll levels, increasing bradykinin levels, and increasing the release of nitric oxide and vasoactive prostaglandins (prostacyclin and prostaglandin E); At the same time, ACEI can block the degradation of angiotensin 1-7 and increase its level, thereby further expanding the blood vessels and anti-proliferative effects by strengthening the stimulation of angiotensin 1-7 receptor.
  • ACEI short-term use of ACEI treatment is accompanied by a decrease in the levels of Angll and aldosterone, which lowers the levels of plasma epinephrine, norepinephrine, and vasopressin in the pituitary.
  • Long-term use of ACEI due to the activation of non-angiotensin-converting enzyme-mediated alternative pathways (such as chymase), Angll and aldosterone levels have returned to pre-treatment trends (aldosterone "escape" phenomenon). Therefore, ACEI increases the levels of bradykinin, angiotensin 1-7, prostacyclin and nitric oxide, which may be the main factors for the persistence of dilated blood vessels and antithrombotic effects.
  • ACEI has been used clinically for many years, HOPE (Heart Outcome Prevention Evaluation), EUROPE (EURopean Trial on reduction of cardiac events with Perindopril in stable coronary Artery disease, European Perindopril for the treatment of stable coronary artery disease Large-scale clinical studies such as event studies), PEACE (Prevention of Events with Angiotensin-Converting Enzyme Inhibition), ANBP2 (Second Australian National Blood Pressure Study) There is no serious safety hazard in ACEI clinical application.
  • ACEI is widely used in the treatment of hypertension, congestive heart failure, diabetic nephropathy, etc.
  • Commonly used ACEI drugs include captopril, enalapril, ramipril, lisinopril, benazepril, fosump Lee et al. 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 pharmaceutical composition containing ACEI and B vitamins in the preparation for effectively antagonizing homocysteine (Hcy) Use of levels of body damage, reduction of Hcy levels, and thus treatment of drugs with high Hcy.
  • B vitamins such as folic acid
  • B vitamins such as folic acid
  • Hyperhomocysteinemia in the present invention is indicated by elevated plasma homocysteine levels, including body damage due to elevated levels of homocysteine.
  • the damage of the body 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.
  • ischemic heart disease including coronary heart disease, angina pectoris, arrhythmia, myocardial infarction , heart failure and sudden death
  • AD Alzheimer's disease
  • dementia cognitive dysfunction
  • osteoporosis fracture
  • depression bipolar disorder
  • Parkinson's disease PD
  • spirit Mitosis death, neonatal defects, habitual abortion and other related diseases.
  • compositions provided herein comprise one or more of a therapeutically effective amount of an angiotensin converting enzyme inhibitor (ACEI) and a therapeutically effective amount of a B vitamin and a pharmaceutically acceptable carrier.
  • ACEI angiotensin converting enzyme inhibitor
  • An angiotensin converting enzyme inhibitor (ACEI) in the composition is selected from the group consisting of enalapril, benazepril, captopril, lisinopril, lei Ramipril, fosinopril, cilazapril, perindopril, quinapril, trandolapril, dirap Delipril, imidapril, temocapril (temocapril) > spirapril, moexipril and alapril.
  • ACEI angiotensin converting enzyme inhibitor
  • an in vivo active metabolite of an angiotensin-converting enzyme inhibitor such as a metabolite or a salt of an angiotensin-converting enzyme inhibitor, which is an active component of an angiotensin-converting enzyme inhibitor, or an angiotensin converting enzyme inhibitor.
  • an angiotensin-converting enzyme inhibitor such as a metabolite or a salt of an angiotensin-converting enzyme inhibitor, which is an active component of an angiotensin-converting enzyme inhibitor, or an angiotensin converting enzyme inhibitor.
  • the daily dosage of ACEI in the treatment of high Hcyemia in mammals including humans is: enalapril 2.5 ⁇ 40 mg, benazepril 2.5 ⁇ 40 mg, ramipril 1.25 ⁇ 20 Mg, fosinopril 10 ⁇ 80 mg, lisinopril 2.5 ⁇ 80 mg, captopril 12.5 ⁇ 100 mg, quinapril 5 ⁇ 80 mg, cilazapril 1.2 ⁇ 5 mg, Peipu 2 ⁇ 16 mg, delaipril 15 ⁇ ; 120 mg, moxipril 3.75 ⁇ 30 mg, group Dopply 0.5 ⁇ 4 mg, midazolam 2.5 ⁇ 40 mg, sulpiride 3 ⁇ 30 mg Alapril 12.5 ⁇ : 100 mg.
  • the content of the derivative, precursor, active metabolite or salt of the above substance can be obtained by equivalent conversion of the above substance.
  • the preferred daily doses of ACEI drugs are: enalapril 5 ⁇ 40 mg, benazepril 5 ⁇ 40 mg, ramipril 2.5 ⁇ 20 mg, fosinopril 10 ⁇ 40 mg, lisinopril 5 ⁇ 40 mg, captopril 25 ⁇ 100 mg, quinapril 10 ⁇ 40 mg, cilazapril 2.5 ⁇ 5 mg, perindopril 4 ⁇ 8 mg, delaipril 15 ⁇ 60 mg, Moxipril 7.5 ⁇ 30 mg, group Dopply 0.5 ⁇ 2 mg, midazolam 2.5 ⁇ 10 mg, sulpiride 3 ⁇ 15 mg, alapril 25 ⁇ 100 mg.
  • the content of the derivative, precursor, active metabolite or salt of the above substance can be obtained by equivalent conversion of the above substance.
  • 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), and vitamin B12 (vitamin B 12 ) biotin (D).
  • vitamin B1 vitamin B1
  • vitamin B2 vitamin B2
  • vitamin PP vitamin B6
  • vitamin B12 vitamin B 12
  • biotin D
  • the B vitamins are preferably vitamin B6, vitamin B12 and folic acid, more preferably folic acid.
  • vitamin B6 includes pyridoxine, pyridoxal, pyridoxamine, pyridoxal phosphate, pyridoxamine phosphate, derivatives of the above substances, and substances which can release/produce such compounds in the body.
  • vitamin B12 includes cobalamin, mecobalamin, 5'-deoxyadenosylcobalamin, hydroxocobalamin, cyanocobalamin and other cobalamin derivatives and can release/form cobamine in the body. Substance.
  • folic acid includes active metabolites of folic acid, formyltetrahydrofolate, L-methylfolate, folate, folic acid or folate, and substances which can release/form folic acid in vivo.
  • B vitamins is: folic acid 0.2 ⁇ 15mg, vitamin B120.1 ⁇ 2mg, vitamin B60.5 ⁇ 50 mg.
  • the preferred daily dosage is: folic acid 0.2 ⁇ 5 mg, vitamin B121 g ⁇ 2 mg, vitamin B65 ⁇ 50 mg.
  • the daily dose of folic acid is more preferably 0.4 mg or 0.8 mg.
  • the preferred combination is:
  • the ACEI is enalapril maleate or enalapril, and the daily dosage is 5 ⁇ 40mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 ⁇ 5mg.
  • the ACEI is enalapril maleate, and the daily dose is 10 mg; the B vitamin is folic acid, and the daily dose is 0.8 mg.
  • the ACEI is enalapril maleate, and the daily dose is 10 mg; the B vitamin is folic acid, and the daily dose is 0.4 mg.
  • the ACEI is enalapril maleate, and the daily dosage is 5 mg; the B vitamin is folic acid, and the daily dosage is 0.4 mg.
  • the ACEI is enalapril maleate or enalapril, and the daily dosage is 5 to 40 mg; the B vitamin is vitamin B6, and the daily dosage is 5 to 50 mg.
  • the ACEI is enalapril maleate or enalapril, and the daily dosage is 5 ⁇ 40 mg; the B vitamin is vitamin B12, and the daily dosage is l g ⁇ 2 mg.
  • the ACEI is benazepril hydrochloride or benazepril, and the daily dosage is 5 to 40 mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 to 5 mg.
  • the ACEI is benazepril hydrochloride or benazepril, and the daily dosage is 5 to 40 mg; the B vitamin is B6, and the daily dosage is 5 to 50 mg.
  • the ACEI is benazepril hydrochloride or benazepril, the daily dosage is 5 ⁇ 40mg; the B vitamin is B12, and the daily dosage is lg ⁇ 2mg.
  • the ACEI is from fosinopril, the daily dosage is 10 ⁇ 40 mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 ⁇ 5 mg.
  • the ACEI is from fosinopril, the daily dosage is 10 ⁇ 40 mg; the B vitamin is B6, and the daily dosage is 5 ⁇ 50 mg.
  • the ACEI is from fosinopril, the daily dosage is 10 ⁇ 40mg; the B vitamin is B12, and the daily dosage is 1g ⁇ 2mg.
  • the ACEI is from ramipril, and the daily dosage is 2.5 to 20 mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 to 5 mg.
  • the ACEI is from ramipril, the daily dosage is 2.5 ⁇ 20 mg; the B vitamin is B6, and the daily dosage is 5 ⁇ 50 mg.
  • the ACEI is from ramipril, the daily dosage is 2.5 ⁇ 20 mg; the B vitamin is B12, and the daily dosage is l g ⁇ 2 mg.
  • the ACEI is from cilazapril, the daily dosage is 2.5 ⁇ 5 mg; the B vitamin is folic acid, and the daily dosage is 0.2 ⁇ 5 mg.
  • the ACEI is self-perindopril, the daily dosage is 4 ⁇ 8 mg; the B vitamin is folic acid, and the daily dosage is 0.2 ⁇ 5 mg.
  • the active ingredient is an essential component in the composition, wherein one active ingredient is derived from one of an angiotensin converting enzyme inhibitor and the other active ingredient is derived from one or several B vitamins.
  • the content of the active ingredient can be determined according to the daily dosage determined above.
  • the pharmaceutical 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, Microporous 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-release capsules, capsules containing pellets or tablets, pH-dependent capsules containing pellets or tablets, oral solutions, films or patches. It should be particularly noted that a pharmaceutical composition containing an angiotensin converting enzyme inhibitor and a B vitamin is made into a tablet or capsule.
  • 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.
  • 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.
  • 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.
  • a combination tablet consisting of one of the angiotensin converting enzyme inhibitors and one of the B vitamins is preferably used.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an angiotensin converting enzyme inhibitor and one or more of the B vitamins for treating hyperhomocysteinemia, wherein angiotensin is transformed Enzyme inhibitors and B vitamins are as defined above.
  • the angiotensin converting enzyme inhibitor is enalapril maleate or enalapril, and the content is 5 to 40 parts by weight; the B vitamin is folic acid or calcium leucovorin, and the content is 0.2 to 5
  • the content is 10 parts by weight; the B vitamin is folic acid, and the content is 0.8 parts by weight.
  • the ACEI is enalapril maleate in an amount of 10 parts by weight; the B vitamin is folic acid in an amount of 0.4 parts by weight.
  • the ACEI is enalapril maleate in an amount of 5 parts by weight; the B vitamin is folic acid in an amount of 0.4 part by weight.
  • a method of treating hyperhomocysteinemia comprising administering to a patient a pharmaceutical composition provided by the present invention.
  • a combination of enalapril and folic acid can be used for the treatment of hyperhomocysteinemia.
  • enalapril folic acid compound preparation can significantly reduce the level of homocysteine in rats with hyperhomocysteinemia and protect the damage caused by elevated homocysteine. It is superior to either drug alone and shows statistical differences.
  • the enalapril folic acid compound preparation was 10 parts by weight of enalapril and 0.8 parts by weight of folic acid.
  • a combination preparation of perindopril and folic acid can be used for the treatment of hyperhomocysteinemia.
  • the combination of perindopril folic acid can significantly reduce the level of homocysteine in rats with hyperhomocysteinemia and protect against damage caused by elevated homocysteine. It is superior to either drug alone and shows statistical differences.
  • the perindopril folic acid compound preparation was 4 parts by weight of perindopril and 0.4 parts by weight of folic acid.
  • the combination preparation of enalapril and folic acid has an inhibitory effect on the proliferation of vascular smooth muscle cells (VSMC) induced by high concentration of Hcy.
  • VSMC vascular smooth muscle cells
  • the enalapril folic acid compound preparation can significantly inhibit the proliferation of VSMC, and the effect is significantly better than either drug alone.
  • the enalapril folic acid compound preparation was 10 parts by weight of enalapril and 0.2 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. They are also inactive as pharmaceutical agents. Handbook of Pharmaceutical Excipients (A. Wade and
  • Example 1 Efficacy of enalapril folic acid in rats with hyperhomocysteinemia
  • enalapril was administered daily from the enalapril high dose group, the enalapril low dose group, the folic acid group, and the enalapril + folic acid group. 2mg/kg), enalapril (1mg/kg), folic acid (0.08mg/kg), enalapril + folic acid (1mg +0.08mg/kg), the model group and the blank control group were given the same amount of normal saline. , for 8 consecutive weeks.
  • Hcy homocysteine
  • Hcy detection kit was purchased from Beijing Zhongshan Biotechnology Engineering Co., Ltd.
  • NOS nitric oxide (NO) (-nitrogen oxide synthesis) Enzyme
  • SOD superoxide dismutase
  • SOD extraction method
  • the levels of NO and SOD in the model group were significantly decreased, and the level of MDA was significantly increased.
  • the high dose group of enalapril and the low dose group of enalapril had no significant effect on SOD, MDA and NO.
  • Folic acid could increase NO and SOD has no significant effect on MDA.
  • the enalapril + folic acid group significantly increased the levels of SOD and NO, and decreased the level of DA, which was significantly better than the model group and the single drug group, indicating that enalapril and folic acid also antagonize the high Hcy-induced SOD, MDA, and NO damage. Has a significant synergy.
  • 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, the 0.8 mg / d dose of folic acid has basically reached its maximum efficacy, and further increase
  • the dose of B vitamins such as folic acid has a safe and implicit study.
  • the SOD level of the model group is significantly decreased, and the MDA level is significantly increased, indicating that oxidative damage is one of the main damage pathways of hyperhomocysteinemia.
  • 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 to cause damage.
  • the intraperitoneal administration was started from the 5th week of modeling, and the perindopril high-dose group, the perindopril low-dose group, the folic acid group, and the perindopril + folic acid group were given perindopril daily.
  • the high-dose Puli group, the low-dose perindopril group, and the folic acid group showed that the combination of perindopril folic acid had a significant synergistic effect in reducing Hcy.
  • 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 hyperhomocysteinemia.
  • One of the most important markers of vascular endothelial injury and dysfunction is the decrease in NO levels.
  • the level of NO in the model group was significantly reduced, indicating that endothelial cell injury is also an important pathway for high Hcyemia to cause damage.
  • the cells were seeded in a 24-well plate at a cell size of 5 ⁇ 10 5 per well, and cultured in DEME medium containing 20% calf serum for 24 hours. After adherence, the cells were cultured in a DEME medium containing 0.5% calf serum. 24h, then add different drugs to the experiment in the following groups.
  • (1) blank control group only PBS; (2) Hcy group: ⁇ - 1 Hcy ; (3) enalapril group: ⁇ . ⁇ 1 enalapril; (4) folic acid group: 0.2 ⁇ ⁇ !; 1 folic acid; (5) Hcy + enalapril group; (6) Hcy + folic acid group; (7) Hcy + folic acid + enalapril group.
  • Each compound group used the same drug dose as the above unilateral group.
  • the cells were collected and washed, treated with 100 g of I / 3 trichloroacetic acid, the filter was placed in a scintillation vial, scintillation fluid was added, and the radioactivity of 3 H was measured on a liquid scintillation counter.
  • ⁇ - 1 Hcy can significantly increase the dysentery of cultured rat VSMC 3 H-TdR.
  • Folic acid and enalapril can inhibit Hcy-induced VSMC proliferation.
  • Combined use of folic acid and enalapril can further reduce Hcy-induced VSMC 3 H-TdR incorporation, which is superior to single drug, indicating folic acid and Naprilat has a superposition or synergistic effect on inhibiting the proliferation of VSMC caused by Hcy.
  • Table 3 The results are shown in Table 3.
  • VSMC proliferation of VSMC is also one of the important pathological features of high Hcy-induced injury. In vitro cell culture can exclude other interfering factors and specifically observe the protective effect of drugs on Hcy-induced damage.
  • Significant statistical differences indicate that folic acid and enalapril have different pathways and links in delaying/treating the mechanism of Hcy-induced damage to the body, with additive or synergistic effects.
  • High Hcyemia is associated with a variety of diseases, oxidative damage, cell proliferation, endothelial cell injury, etc. are the main path of injury.
  • 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 hyperhomocysteinemia, effectively reduces high Hcy levels, and reduces damage caused by high Hcy levels, and High safety will be a better choice and provide a more effective treatment for the treatment of hyperhomocysteinemia.
  • Example 4 Preparation of a compound enalapril folic acid tablet containing 10 mg of enalapril and 0.8 mg of folic acid
  • Magnesium stearate lg Preparation method: 10 g of enalapril, 0.8 g of folic acid, 50 g of lactose, 50 g of cellulose and 10 g of starch are pulverized and uniformly mixed, and made into a soft material by 10% povidone ethanol solution, granulated, dried, and finished. For the granules, the granules having a water content of about 3% were uniformly mixed with magnesium stearate, and pressed into tablets by a tableting machine. Each of the prepared 1000 tablet tablets contained 10 mg of enalapril and 0.8 mg of folic acid, and the mass ratio thereof was 10:0.8.
  • Example 5 Preparation of compound benazepril containing 10 mg of benazepril and 0.4 mg of folic acid: benazepril
  • the preparation method was the same as in Example 4.
  • Each of the prepared 1000 tablet tablets contained benazepril 10 mg and folic acid 0.4 mg in a mass ratio of 10:0.4.

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Abstract

Composition pharmaceutique contenant un inhibiteur de l'enzyme de conversion de l'angiotensine (ACEI) et des vitamines B, et utilisation de la composition dans le traitement de l'hyperhomocystéinémie. Le mélange d'un bloquant du récepteur II de l'angiotensine (ARB) et de vitamines B peut agir sur divers canaux et liaisons de l'hyperhomocystéinémie, diminuer le taux d'homocystéine et inhiber les dommages provoqués à l'organisme par un taux élevé d'homocystéine, et il présente des qualités meilleures que celles d'un médicament unique, ce qui permet de faire ressortir l'effet synergique important d'un bloquant du récepteur II de l'angiotensine et des vitamines B sur l'atténuation des dommages provoqués par un taux élevé d'homocystéine et sur la diminution du taux élevé d'homocystéine.
PCT/CN2008/001680 2007-09-28 2008-09-28 Composition pharmaceutique contenant un inhibiteur d'enzyme de conversion de l'angiotensine et des vitamines b, et son utilisation WO2009046631A1 (fr)

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TN2010000566A1 (en) * 2010-12-03 2012-05-24 Rekik Raouf Folic acid - ramipril combination : cell protective neuroprotective and retinoprotective ophtalmologic drugs
CN103386130A (zh) * 2013-06-27 2013-11-13 深圳奥萨医药有限公司 Ace抑制剂/噻嗪类利尿剂/5-甲基四氢叶酸药物组合物及用途

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CN1587270A (zh) * 2004-07-28 2005-03-02 安徽省生物医学研究所 含有血管紧张素转化酶抑制剂和b族维生素的药物组合物
CN1785196A (zh) * 2004-12-10 2006-06-14 张鹏 一种防治心脑血管疾病的复合制剂
CN1982471A (zh) * 2005-12-14 2007-06-20 北京华安佛医药研究中心有限公司 多态性位点基因型预测血管紧张素转换酶抑制剂类药物作用效果的用途、方法和试剂盒

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1587270A (zh) * 2004-07-28 2005-03-02 安徽省生物医学研究所 含有血管紧张素转化酶抑制剂和b族维生素的药物组合物
CN1785196A (zh) * 2004-12-10 2006-06-14 张鹏 一种防治心脑血管疾病的复合制剂
CN1982471A (zh) * 2005-12-14 2007-06-20 北京华安佛医药研究中心有限公司 多态性位点基因型预测血管紧张素转换酶抑制剂类药物作用效果的用途、方法和试剂盒

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