WO2009046632A1 - Composition pharmaceutique contenant un bloquant du récepteur ii de l'angiotensine et des vitamines b, et son utilisation - Google Patents

Composition pharmaceutique contenant un bloquant du récepteur ii de l'angiotensine et des vitamines b, et son utilisation Download PDF

Info

Publication number
WO2009046632A1
WO2009046632A1 PCT/CN2008/001682 CN2008001682W WO2009046632A1 WO 2009046632 A1 WO2009046632 A1 WO 2009046632A1 CN 2008001682 W CN2008001682 W CN 2008001682W WO 2009046632 A1 WO2009046632 A1 WO 2009046632A1
Authority
WO
WIPO (PCT)
Prior art keywords
vitamin
daily dosage
angiotensin
folic acid
receptor antagonist
Prior art date
Application number
PCT/CN2008/001682
Other languages
English (en)
Chinese (zh)
Inventor
Xiping Xu
Xianhui Qin
Guangliang Chen
Ping Liu
Wenyan Wang
Duo Yu
Yan Wang
Original Assignee
Beijing Huaanfo Biomedical Research Center, Inc
Shenzhen Ausa Pharma Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Huaanfo Biomedical Research Center, Inc, Shenzhen Ausa Pharma Co., Ltd. filed Critical Beijing Huaanfo Biomedical Research Center, Inc
Publication of WO2009046632A1 publication Critical patent/WO2009046632A1/fr

Links

Classifications

    • 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
    • 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
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • composition containing angiotensin II receptor antagonist 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 II receptor antagonist (ARB) and a B vitamin and its use for treating hyperhomocysteinemia.
  • ARB angiotensin II receptor antagonist
  • Hcy homocysteine
  • CVD cardiovascular disease
  • Hcy The increase in plasma Hcy by 5 ⁇ increases the risk of stroke by 59% (OR (odds ratio), 1.59; 95% CI (confidence interval) ), 1.30- 1.95), a 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 risk increased by 33% (OR, 1.33; 95% CI, 1.22- 1.46); Hcy level decreased by 3 ⁇ /L, stroke risk decreased by 24%, deep vein thrombosis risk decreased by 25%, ischemic heart disease risk Reduce 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 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 ⁇ /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.
  • Hcyemia is considered to be not only an independent risk factor for AD, but also associated with the progression and severity of AD
  • ccycy in AD dementia or impaired cognitive function
  • Possible mechanisms of action of ccycy in AD, dementia or impaired cognitive function include: direct damage of neurons by Hcy; enhancement of neurotoxic effects of amyloid ⁇ ; Affect brain function by damaging microcirculation.
  • Hcy The mechanism of damage caused by high Hcy is generally thought to be related to the damage of endothelial cells, oxidative stress, destruction of blood 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 ⁇ /L.
  • Hcy levels greater than or equal to 10 ⁇ /L are defined as high Hcyemia or elevated Hcy [Circulation, 2006; 113: e409-e449; Clin Chem Med 2003; 41 : 1392-1403]
  • Hcy levels greater than or equal to 10 ⁇ /L are defined as high Hcyemia or elevated Hcy [Circulation, 2006; 113: e409-e449; Clin Chem Med 2003; 41 : 1392-1403]
  • 0 Hughes et al found that Chinese males had an average Hcy level of 15.3 ⁇ /L and females of 12.2 mol/L [J Epidemiol Community Health. 2000; 54(1): 31-34.], If the plasma Hcy>14 mol/L is used as the criterion, the incidence of high Hcy in Chinese men is 57%, and that in women is 31%.
  • Hcy levels in Chinese population are significantly higher, with Hcy greater than or equal to ⁇ /L.
  • Hcy As a standard, the incidence of hyperhomocysteinemia in the South is about 32%, and in the 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.
  • Angiotensin II receptor antagonist directly blocks angiotensin type 1 (ATI) receptors, which have a specific effect on ACEI.
  • the ATI receptor is blocked, Angll contractes blood vessels and stimulates the release of aldosterone from the adrenal gland, which results in lower blood pressure and can treat congestive heart failure by reducing the load on the heart.
  • ACEI can not completely block the production of Angll
  • ARB blocks Angll more completely than ACEI. It is one of its advantages, but it lacks the slow-kein peptide of ACEI- Cardioprotective effects of the NO pathway. It can be seen that the mechanism of action of ACEI and ARB is very different.
  • ARB Commonly used drugs for ARB include losartan, valsartan, irbesartan, cantesartan, telmisartan, toxasartan, eprosartan, olmesartan, etc.; ARB has been used clinically for many years. Many large-scale clinical studies such as VALUE and LIFE have shown that there is no serious safety hazard in ARB clinical application. 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 diseases, and to provide a composition containing ARB and B vitamins in the preparation of lowering homocysteine level, effectively antagonizing The use of high homocysteine levels for damage, thereby treating drugs for high homocysteinemia.
  • B vitamins such as folic acid
  • ARB and B vitamins in the preparation of lowering homocysteine level
  • Hyperhomocysteinemia in the present invention is indicated by elevated plasma homocysteine levels, including body damage due to elevated levels of homocysteine. Elevated homocysteine levels Body damage is characterized by vascular smooth muscle hyperplasia, thrombosis, neuronal damage, microcirculation disturbance, etc.
  • the mechanism is generally considered to be related to oxidative stress, damage to endothelial cells, destruction of coagulation and fibrinolysis in the body, resulting in 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), Alz Alzheimer's disease (AD), dementia, cognitive dysfunction, osteoporosis, fracture, depression, bipolar disorder, Parkinson's disease (PD), schizophrenia, death, neonatal defects , habitual abortion and other related diseases.
  • ischemic heart disease including coronary heart disease, angina pectoris, arrhythmia, myocardial infarction, heart failure and sudden death
  • AD Alz Alzheimer's disease
  • dementia cognitive dysfunction
  • osteoporosis fracture
  • depression depression
  • bipolar disorder Parkinson's disease
  • Parkinson's disease schizophrenia, death, neonatal defects , habitual abortion and other related
  • the pharmaceutical composition provided by the present invention comprises one of a therapeutically effective amount of an angiotensin receptor antagonist and a therapeutically effective amount of one or more of the B vitamins and a pharmaceutically acceptable carrier.
  • the angiotensin II receptor antagonist (ARB) in the composition is selected from the group consisting of irbesartan (irbesartan), losartan, valsartan, telmisartan
  • angiotensin II receptor antagonist metabolite or a salt such as an angiotensin II receptor antagonist active derivative derivative, a metabolite, a precursor or an angiotensin II receptor antagonist in vivo active metabolite, It is included within the scope of the present disclosure.
  • angiotensin II receptor antagonists are: irbesartan 75 ⁇ 600mg, losartan 25 ⁇ 200mg, valsartan 40 ⁇ 300mg, telmisartan 20 ⁇ 160mg, candesartan 4 ⁇ 64mg, hesolartan 10 ⁇ 300mg, eprosartan 200 ⁇ 800mg, olmesartan 20 ⁇ 40mg.
  • the daily amount 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 angiotensin II receptor antagonists are: irbesartan 150 ⁇ 300mg, losartan 50 ⁇ 100mg, valsartan 80 ⁇ 160mg, telmisartan 20 ⁇ 80mg, candesartan 8 ⁇ 32mg, he oxasartan 25 ⁇ 300mg, eprosartan 400 ⁇ 800mg, olmesartan 20 ⁇ 40mg.
  • 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 B vitamin in the composition is selected from the group consisting of vitamin B1 (vitamin B1 ), Vitamin B2 vitamin B, vitamin B6, vitamin B 12 , vitamin B, folic acid, vitamin B9 and pantothenate, vitamin One or more of B5) or their derivatives and substances which can release/generate such compounds in vivo.
  • the B vitamins are preferably vitamin B6, vitamin B 12 and folic acid, more preferably folic acid.
  • 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.
  • vitamin B12 is selected from the group consisting of cobalamin, mecobalamin, 5,-deoxyadenosylcobalamin, hydroxocobalamin, cyanocobalamin and other cobalamin derivatives and can be released/generated in vivo.
  • Cobalamin substance is selected from the group consisting of cobalamin, mecobalamin, 5,-deoxyadenosylcobalamin, hydroxocobalamin, cyanocobalamin and other cobalamin derivatives and can be released/generated in vivo.
  • 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 can release/form folic acid in vivo.
  • the daily dosage of B vitamins is: folic acid 0.2 ⁇ 15mg, vitamin B12 is 0.1 ⁇ 2mg, and vitamin B6 is 0.5 ⁇ 50mg.
  • the preferred daily dosage is: folic acid 0. 2 ⁇ 5 mg, vitamin B12 1 ⁇ g ⁇ 2 mg, vitamin B6 5 ⁇ 50 mgo Folic acid daily dosage is more preferably 0. 4 mg or 0.8 mg.
  • the preferred combination is:
  • the angiotensin II receptor antagonist is irbesartan, and the daily dosage is 150 to 300 mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 to 5 mg.
  • the angiotensin II receptor antagonist is irbesartan, and the daily dose is 150 mg; the B group vitamin is folic acid, and the daily dose is 0.8 mg.
  • the angiotensin receptor antagonist is irbesartan, the daily dosage is 150 ⁇ 300mg; the B vitamin is vitamin B6, and the daily dosage is 5 ⁇ 50mg.
  • the angiotensin II receptor antagonist is irbesartan, the daily dosage is 150 ⁇ 300 mg; the B vitamin is vitamin B12, and the daily dosage is l g ⁇ 2 mg.
  • the angiotensin II receptor antagonist is losartan or losartan potassium, and the daily dosage is 50 to 100 mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 to 5 mg.
  • the angiotensin II receptor antagonist is losartan or losartan potassium, the daily dosage is 50 ⁇ 100 mg; the B vitamin is vitamin B6, and the daily dosage is 5 ⁇ 50 mg.
  • the angiotensin II receptor antagonist is losartan or losartan potassium, and the daily dosage is 50 ⁇ LOOmg; B vitamins are vitamin B12, the daily dosage is lg ⁇ 2mg.
  • the angiotensin II receptor antagonist is valsartan, and the daily dosage is 80 to 160 mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 to 5 mg.
  • the angiotensin II receptor antagonist is valsartan, the daily dosage is 80 ⁇ 160mg; the B vitamin is vitamin B6, and the daily dosage is 5 ⁇ 50mg.
  • the angiotensin II receptor antagonist is valsartan, the daily dosage is 80 ⁇ 160mg; the B vitamin is vitamin B12, and the daily dosage is ⁇ g ⁇ 2mg.
  • the angiotensin II receptor antagonist is telmisartan, and the daily dosage is 20 to 80 mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 to 5 mg.
  • the angiotensin II receptor antagonist is candesartan, the daily dosage is 8 ⁇ 32mg; the B vitamin is folic acid or calcium leucovorin, and the daily dosage is 0.2 ⁇ 5mg.
  • the active ingredient is an essential component in the composition, wherein one active ingredient is derived from one of an angiotensin II receptor antagonist and the other active ingredient is derived from one or several B groups.
  • the content of vitamins and active ingredients can be determined according to the daily dosage determined above.
  • the pharmaceutical composition includes, but is not limited to, ordinary tablets, double-layered tablets, multi-layered tablets, sustained-release tablets, single-chamber controlled-release tablets, dual-chamber controlled-release tablets, and 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, containing micro Pills or small pieces of capsules, pH-dependent capsules containing micropellets or tablets, oral liquids, films or patches, and particularly, pharmaceutical compositions containing angiotensin II receptor antagonists and B vitamins Made into tablets or capsules.
  • 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 separately 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 of one of the angiotensin II receptor antagonists and one of the B vitamins is preferably used.
  • the present invention also provides a pharmaceutical composition comprising an angiotensin II receptor antagonist and one or more of the B vitamins for treating a disease of elevated homocysteine, wherein angiotensin converting enzyme inhibits Agents and B vitamins are as defined above.
  • the angiotensin II receptor antagonist is irbesartan in an amount of 150 to 300 parts by weight; and the B vitamin is folic acid or calcium leucovorin. It is 0.2 to 5 parts by weight.
  • the angiotensin II receptor antagonist is irbesartan in an amount of 150 parts by weight; the B group vitamin is folic acid in an amount of 0.8 part by weight.
  • the angiotensin receptor antagonist is irbesartan in an amount of 150 to 300 parts by weight; the B group vitamin is vitamin B6 in an amount of 5 to 50 parts by weight.
  • the angiotensin II receptor antagonist is irbesartan in an amount of 150 to 300 parts by weight; the B group vitamin is vitamin B12 in an amount of 0.001 to 2 parts by weight.
  • the angiotensin receptor antagonist is losartan or losartan potassium in an amount of 50 to 100 parts by weight; and the B vitamin is folic acid or calcium leucovorin in an amount of 0.2 to 5 parts by weight.
  • the angiotensin receptor antagonist is losartan or losartan potassium in an amount of 50 to 100 parts by weight;
  • the B group vitamin is vitamin B6 in an amount of 5 to 50 parts by weight.
  • the angiotensin II receptor antagonist is losartan or losartan potassium in an amount of 50 to 100 parts by weight;
  • the B group vitamin is vitamin B12 in an amount of 0.001 to 2 parts by weight.
  • the angiotensin II receptor antagonist is valsartan in an amount of 80 to 160 parts by weight; and the B vitamin is folic acid or calcium leucovorin in an amount of 0.2 to 5 parts by weight.
  • the angiotensin II receptor antagonist is valsartan in an amount of 80 to 160 parts by weight; the B vitamin is vitamin B6 in an amount of 5 to 50 parts by weight.
  • the angiotensin II receptor antagonist is valsartan in an amount of 80 to 160 parts by weight; the B vitamin is vitamin B12 in an amount of 0.001 to 2 parts by weight.
  • the angiotensin II receptor antagonist is telmisartan in an amount of 20 to 80 parts by weight; and the B vitamin is folic acid or calcium leucovorin in an amount of 0.2 to 5 parts by weight.
  • the angiotensin II receptor antagonist is candesartan, and the content is 8 to 32 parts by weight; the B vitamin is folic acid or calcium leucovorin, and the content is 0.2 to 5 parts by weight.
  • the compound composition of irbesartan folic acid The agent can be used for the treatment of hyperhomocysteinemia.
  • irbesartan 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 irbesartan folic acid compound preparation is 150 parts by weight of irbesartan and 0.8 parts by weight of folic acid.
  • a combination preparation of valsartan folic acid can be used for the treatment of hyperhomocysteinemia.
  • valsartan folic acid compound preparation can significantly reduce the level of homocysteine in rats with hyperhomocysteinemia, protect the damage caused by elevated homocysteine, and its effect is excellent. Use either drug alone and show statistical differences.
  • the valsartan folic acid compound preparation is 80 parts by weight of valsartan and 0.4 parts by weight of folic acid.
  • the compound preparation composed of irbesartan folate 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 irbesartan folate compound preparation can be significantly inhibited further
  • the irbesartan folic acid compound preparation is 200 parts by weight of irbesartan 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 and they are inactive as pharmaceutical agents. Handbook of Pharmaceutical Excipients (A. Wade and PJ Weller, Second Edition, American Pharmaceutical Society, Washington and Pharmacy Press, London Press, 1994) Edited pharmaceutically acceptable carriers and excipients.
  • lactose, starch, cellulose derivatives and the like, and mixtures thereof are useful as carriers for the active ingredients of the compositions of the present invention.
  • the present invention will be further described in conjunction with the specific embodiments, which are not intended to limit the invention. Any equivalent substitutions in the art in accordance with the teachings of the present invention are within the scope of the invention. detailed description
  • Example 1 Efficacy of irbesartan folic acid compound in a rat model of hyperhomocysteinemia
  • Animal and high Hcy model were established: 60 male rats of 250 ⁇ 300g were randomly divided into 6 groups, .10/group. The blank group was given normal feed, and the other groups were given high methionine feed for 12 weeks.
  • Grouping and administration Oral administration of irbesartan in low dose group, high dose irbesartan group, folic acid group and irbesartan + folic acid group were given to irbesartan daily.
  • 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
  • Irbesartan + folic acid group significantly increased SOD, NO levels, decreased MDA levels, and its effect was significantly better than model family, irbesartan low dose group, irbesartan high dose group and folic acid group, indicating Besartan + folic acid in Antagonism against high Hcy levels induced SOD, MDA, NO damage also has significant synergy as shown in Table 1
  • 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.
  • the SOD level of the model group was significantly reduced, and the MDA level was significantly increased, indicating oxidation.
  • Injury is one of the main damage pathways of hyperhomocysteinemia; one of the most important markers of vascular endothelial injury and dysfunction is the decrease of NO level.
  • NO level in the model group is significantly reduced, indicating that endothelial cell injury is also high Hcy blood. An important way to cause damage to the body.
  • the data in Table 1 shows that the low-dose irbesartan group, the high-dose irbesartan group and the folic acid group have insufficient protective effects on high Hcy injury; however, the combination of irbesartan and folic acid has significant improvement on each index. And its effect is significantly better than the low-dose irbesartan group, the high-dose irbesartan group or the folic acid group; meanwhile, the irbesartan folate compound can synergistically reduce the level of Hcy in this study, and its effect on folic acid The effect has significant statistical differences.
  • irbesartan folic acid acts on multiple pathways and links of hyperhomocysteinemia, synergistically reduces Hcy levels, and effectively antagonizes 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.
  • Example 2 Efficacy of valsartan folic acid compound in a rat model of hyperhomocysteinemia
  • valsartan (8 mg/kg) was administered daily from the fifth week of modeling, low dose valsartan, high dose of valsartan, folic acid group and valsartan + folic acid group. ), valsartan (16mg kg), folic acid (0.08mg/kg), valsartan + folic acid (8mg + 0.08mg / kg), the model group and the normal group were given the same amount of normal saline for 8 weeks. Blood samples from the abdominal aorta after the last administration were measured for homocysteine (Hcy), nitric oxide (NO), superoxide dismutase (SOD), malondialdehyde (MDA), etc. (Detection method is the same as in Example 1) ).
  • Hcy homocysteine
  • NO nitric oxide
  • SOD superoxide dismutase
  • MDA malondialdehyde
  • the NO and SOD levels in the model group decreased significantly, and the MDA level increased significantly.
  • the low dose group, the high dose group of valsartan and the folic acid group had no significant effect on SOD, MDA and NO.
  • Folic acid could significantly increase NO and SOD, and had no significant effect on MDA.
  • the valsartan + folic acid group significantly increased the levels of SOD and NO, and decreased the level of MDA, which was significantly better than the model group and the single drug group, indicating that valsartan and folic acid also had significant synergistic effects in antagonizing high Hcy damage.
  • valsartan folic acid acts on multiple pathways and links of hyperhomocysteinemia, effectively reduces Hcy levels, and effectively antagonizes the damage caused by elevated 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.
  • Example 3 Inhibition of irbesartan folic acid on Hcy-induced proliferation of vascular smooth muscle cells (VSMC)
  • the DEME medium was cultured for 24 h, and after adherence, the DEME medium with a volume fraction of 0.5% calf serum was replaced for another 24 hours, and then the different drugs were added in the following groups for the experiment.
  • Control group only PBS;
  • Hcy group ⁇ -1 Hcy;
  • Irbesartan group 20 ⁇ 1 ⁇ -1 irbesartan;
  • Folic acid group OJ moLI/ 1 folic acid (5) Hcy+irbesartan group; (6) Hcy + folic acid group; (7) Hcy + folic acid + irbesartan group.
  • Each compound group used the same drug dose as the above unilateral group.
  • ⁇ ' ⁇ can significantly increase the proliferation of VSMC induced by Hcy-induced VSMC 3H-TdR in cultured rat VSMC 3H-TdR.
  • the combination of folic acid and irbesartan can induce Hcy-induced VSMC 3H-TdR incorporation.
  • Lowering, superior to the use of either drug alone, indicates that folic acid and irbesartan have additive or synergistic effects in inhibiting Hcy-induced VSMC proliferation. The results are shown in Table 3.
  • Proliferation of VSMC is also one of the important pathological features of body damage caused by high Hcy levels.
  • In vitro cell culture can exclude other interfering factors and specifically observe the protective effect of the drug Hcy.
  • the results showed that both folic acid and irbesartan could significantly inhibit the proliferation of VSMC, but the combination of folic acid and irbesartan could significantly inhibit the proliferation of VSMC, and its effect was significantly better than that of any single drug, and it showed significant Statistical difference, indicating folic acid and irbesartan in delay/treatment
  • Hcy acts on different pathways and links, and has a synergistic effect.
  • Irb irbesartan; %%P ⁇ 0.01 vs control; **P ⁇ 0.01 vs Hcy;
  • High Hcyemia and various diseases have oxidative damage, endothelial cell damage, cell proliferation and other major damage pathways.
  • folic acid alone or compound B vitamins are not satisfactory in the treatment of high Hcy, and there is a safety hazard in large doses.
  • the invention acts on multiple pathways and links of high Hcyemia, effectively reduces Hcy level, reduces high Hcy level damage, and has high safety, which is a better choice and provides more effective treatment for hyperhomocysteinemia. Treatment programs.
  • Example 4 Preparation of a compound irbesartan folic acid tablet containing 150 mg of irbesartan and 0.8 mg of folic acid irbesartan 150 g folic acid 0.8 g lactose 50 g microcrystalline cellulose 50 g starch 10 g sodium carboxymethyl starch 30 g magnesium stearate ig
  • Preparation method 150 g of irbesartan, 0.8 g of citric acid, 50 g of lactose, 50 g of vitamin cellulose and 10 g of starch are pulverized and uniformly mixed, and made into a soft material by 10% povidone ethanol solution, granulated and dried.
  • the whole granules are mixed with granules having a water content of about 3% and magnesium stearate, and compressed into tablets by a tableting machine.
  • Each of the prepared 1000 tablet tablets contained irbesartan 150 mg and folic acid 0.8 mg in a mass ratio of 150:0.8.
  • Example 5 Preparation of a compound benazepril folate tablet containing 80 mg of valsartan and 0.4 mg of folic acid Formula: valsartan folate lactose microcrystalline cellulose starch carboxymethyl starch sodium magnesium stearate
  • the preparation method was the same as in Example 4.
  • Each of the prepared 1000 tablet tablets contained 80 mg of valsartan and 0.4 mg of folic acid, and the mass ratio thereof was 80:0.4.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composition pharmaceutique contenant un bloquant du récepteur II de l'angiotensine (ARB) et des vitamines B, et utilisation de cette compositions dans le traitement de l'hyperhomocystéinémie. Le mélange d'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, ce qui permet de faire ressortir l'effet synergique important d'un bloquant du récepteur II de l'angiotensine et des vitamines B sur la diminution du taux élevé d'homocystéine et sur l'atténuation des dommages provoqués par un taux élevé d'homocystéine.
PCT/CN2008/001682 2007-09-28 2008-09-28 Composition pharmaceutique contenant un bloquant du récepteur ii de l'angiotensine et des vitamines b, et son utilisation WO2009046632A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710175284.8 2007-09-28
CNA2007101752848A CN101396562A (zh) 2007-09-28 2007-09-28 含有arb的组合物在制备治疗高同型半胱氨酸血症损伤及其相关疾病的药物中的用途

Publications (1)

Publication Number Publication Date
WO2009046632A1 true WO2009046632A1 (fr) 2009-04-16

Family

ID=40515560

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2008/001682 WO2009046632A1 (fr) 2007-09-28 2008-09-28 Composition pharmaceutique contenant un bloquant du récepteur ii de l'angiotensine et des vitamines b, et son utilisation

Country Status (2)

Country Link
CN (1) CN101396562A (fr)
WO (1) WO2009046632A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1383829A (zh) * 2001-05-08 2002-12-11 肖钢 用于预防或治疗高同型半胱氨酸血症及其相关疾病的复方叶酸制剂
CN1587269A (zh) * 2004-07-28 2005-03-02 安徽省生物医学研究所 含有血管紧张素ⅱ受体拮抗剂和b族维生素的药物组合物
CN1688305A (zh) * 2002-08-10 2005-10-26 贝塞斯达药物股份有限公司 不会引起液体潴流、水肿或充血性心力衰竭的新ppar配体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1383829A (zh) * 2001-05-08 2002-12-11 肖钢 用于预防或治疗高同型半胱氨酸血症及其相关疾病的复方叶酸制剂
CN1688305A (zh) * 2002-08-10 2005-10-26 贝塞斯达药物股份有限公司 不会引起液体潴流、水肿或充血性心力衰竭的新ppar配体
CN1587269A (zh) * 2004-07-28 2005-03-02 安徽省生物医学研究所 含有血管紧张素ⅱ受体拮抗剂和b族维生素的药物组合物

Also Published As

Publication number Publication date
CN101396562A (zh) 2009-04-01

Similar Documents

Publication Publication Date Title
US20210100813A1 (en) Combination therapy for cancer using bromodomain and extra-terminal (bet) protein inhibitors
EP4321157B1 (fr) Nouvelle utilisation d'une combinaison d'un bloqueur des récepteurs de l'angiotensine (arb) avec un inhibiteur de l'endopeptidase neutre (nepi)
JP7066679B2 (ja) 認知症の処置
US20090118211A1 (en) Compositions and Methods for Enhancement of Sexual Function
EP2838517B1 (fr) Formulation pharmaceutique disponible sous forme orale apte pour le traitement amélioré des troubles de la mobilite
WO2005084392A2 (fr) Formulations a base de 4-methylpyrazole destinees a inhiber l'intolerance a l'ethanol
WO2022062223A1 (fr) Application de l'auranofine dans la préparation d'un médicament pour le traitement du cancer de la prostate résistant à la castration
WO2010009618A1 (fr) Composition pharmaceutique pour traiter l’hypertension et le syndrome métabolique et utilisation de celle-ci
TW202214242A (zh) 西奧羅尼或其衍生物在製備用於預防和/或治療非霍奇金淋巴瘤的藥物之用途
Hazell et al. Treatment of rats with the JAK-2 inhibitor fedratinib does not lead to experimental Wernicke’s encephalopathy
CN111246851A (zh) 双层药物片剂制剂
JP2009102248A (ja) 血中尿酸を急速に低減させるための医薬組成物およびパッケージならびに血中尿酸を急速に低減させるためのアンセリンの使用
PT1643999E (pt) Piridoxamina para utilização no tratamento de nefropatia diabética na diabetes tipo ii
AU2004283047B2 (en) Pharmaceutical composition comprising a selective I1 imidazoline receptor agonist and an angiotensin II receptor blocker
AU2011339150B2 (en) Complex formulation comprising lercanidipine hydrochloride and valsartan and method for the preparation thereof
WO2010097501A2 (fr) Traitement combiné
JP2011037722A (ja) 小胞体ストレスによる神経細胞死の予防又は抑制剤
US20230277523A1 (en) Methods for inhibiting phosphate transport
US20040214802A1 (en) Dipyridamole, acetylsalicylic acid, and angiotensin II antagonist pharmaceutical compositions
CN106310278A (zh) 一种含叶酸的多联降压药物组合物
WO2009143662A1 (fr) Composition pharmaceutique comprenant un agent bloquant du canal de calcium et des vitamines de la famille b et utilisation de celle-ci
WO2009046631A1 (fr) Composition pharmaceutique contenant un inhibiteur d'enzyme de conversion de l'angiotensine et des vitamines b, et son utilisation
US20110117070A1 (en) Compositions and methods for treating headache
WO2009046632A1 (fr) Composition pharmaceutique contenant un bloquant du récepteur ii de l'angiotensine et des vitamines b, et son utilisation
EP4082549A1 (fr) Médicament de prévention du décès par séance de dialyse ou par maladie rénale

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08837134

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08837134

Country of ref document: EP

Kind code of ref document: A1