CN103417972A - Cholesterol uptake inhibitor and vitamin-B composition and application thereof - Google Patents
Cholesterol uptake inhibitor and vitamin-B composition and application thereof Download PDFInfo
- Publication number
- CN103417972A CN103417972A CN2013103671164A CN201310367116A CN103417972A CN 103417972 A CN103417972 A CN 103417972A CN 2013103671164 A CN2013103671164 A CN 2013103671164A CN 201310367116 A CN201310367116 A CN 201310367116A CN 103417972 A CN103417972 A CN 103417972A
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- China
- Prior art keywords
- vitamin
- ezetimibe
- folic acid
- group
- pharmaceutical composition
- Prior art date
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Links
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- 229930003270 Vitamin B Natural products 0.000 title claims abstract description 30
- 235000019156 vitamin B Nutrition 0.000 title claims abstract description 30
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- 235000012000 cholesterol Nutrition 0.000 title abstract description 17
- 239000003112 inhibitor Substances 0.000 title abstract 5
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Abstract
The invention relates to cholesterol uptake inhibitor and vitamin-B composition and applications thereof. Preferably, Ezetimibe serves as the selective cholesterol uptake inhibitor, 1-30mg; vitamin-B is folates, vitamin B6 or vitamin B12, 0.01-50mg. The invention further provides the application of the composition in the preparation of drugs for treating hypercholesteremia and preventing atherosclerosis. The cholesterol uptake inhibitor and vitamin-B composition has the advantages that the composition is better in cholesterol reduction and is able to protect blood vessel endothelium to effectively prevent atherosclerosis accordingly; clinical application benefit of the composition is significantly better than that of the sole use of the selective cholesterol update inhibitor; in addition, the composition is convenient for patients to take, and costs in medical treatment are reduced.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition containing selective cholesterol absorption inhibitor and vitamin B group, espespecially a kind of pharmaceutical composition for the treatment of hypercholesterolemia, atherosclerosis formation and relevant disease.The invention belongs to pharmaceutical field.
Background technology
Cardiovascular and cerebrovascular disease is one of mankind's main causes of death, and comprising coronary atherosclerotic heart disease (be called for short coronary heart disease, myocardial infarction is its serious type) and apoplexy, the latter also causes mostly on the cerebral arteriosclerosis basis.Arteriosclerosis is a kind of non-inflammation pathological changes of tremulous pulse, can make that ductus arteriosus wall thickens, hardening, follows the string, luminal stenosis, and atherosis is topmost type (85% coronary heart disease is by atherosis causing coronarius) wherein.Dyslipidemia, especially hypercholesterolemia are to cause atherosclerotic main cause, and therefore adjusting blood lipid metabolism can prevent and treat atherosclerosis.One or more levels that dyslipidemia shows as in triglyceride in blood (TG), T-CHOL (TC), low-density lipoprotein cholesterol (LDL-C) raise or the reduction of HDL-C (HDL-C) level.The epidemiological study confirmation, the rising of TC level becomes positive correlation with the risk factor of coronary heart disease death.
Clinically, the drug main for the treatment of hypercholesterolemia or hyperlipemia will comprise cholesterol synthetic inhibitor (as Statins), clofibrate and phenoxy acetic acid class, bile acid intercalating agent and other (as the nicotinic acid class) etc.The selectivity cholesterol absorption inhibitor is that in recent years occur, novel anti-cholesterol drugs, Ezetimibe (ezetimibe, have another name called " ezetimibe ") be first, be also that a unique approval at present is for such clinical medicine, still have in addition several medicines be in development [angiocardiology branch of Chinese Medical Association. selectivity cholesterol absorption inhibitor clinical practice China Consensus of experts (2013 editions). CHINESE JOURNAL OF INTERNAL MEDICINE, 2013,52 (7): 617-620].Ezetimibe is a kind of 2-azetidinones, by Schering-Plough and Merck company cooperation research and development, obtained FDA approval listing in 2002, commodity are called Ai Zeting (Zetia), and chemical name is 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-aza cyclo-butanone.Ezetimibe is combined by memebrane protein on intestinal brush border film vesicles, suppresses small intestinal in diet and through bile, being transported to the absorption of the cholesterol in intestinal, reduces the cholesterol level in serum and liver.Clinical trial shows, Ezetimibe no matter alone or with the Statins use in conjunction, can receive good lipid-lowering effect, and can reduce LDL-C level [Toth PP when falling TC, et al.Update on the efficacy and safety of combination ezetimibe plus statin therapy.Lipidology.2010,5:655-684].Ezetimibe also has good curative effect to some intractable heritability hypercholesterolemias as familial homozygote hyperlipidemia; Ezetimibe also has good safety and toleration.But; because mechanism of action is single; also there are some defects in Ezetimibe; as lower by approximately 20%～40% than statins as the effect of cholesterol reducing effect; active in impact on ec-sod; can not improve the anti-oxidation function of endotheliocyte, in other words, Ezetimibe lacks the protective effect to blood vessel endothelium.
Vitamin B group comprises vitamin B
1, vitamin B
2, vitamin PP, vitamin B
6, vitamin B
12, folic acid, pantothenic acid and biotin etc., to body metabolism, erythrocyte, form, keep nervous system and function of immune system to there is important function.Vitamin B group belongs to water soluble vitamins, through human body intestinal canal, absorbs, and by urine, is excreted, and retention time is of short duration in vivo, seldom accumulate, so must be often from external picked-up to meet body nutrition and metabolism needs.Vitamin B group lacks can cause many adverse consequencess, comprises myasthenia, nerve problems, gastricism, wrinkled skin, serious anemia and heart damage etc.Wherein, folic acid, vitamin B
6, vitamin B
12Affect the metabolism of homocysteine during shortage, it is believed that homocysteine may be a kind of cardiovascular risk factor.
Although atherosclerotic pathomechanism is illustrated at present not yet fully, Most scholars support " endothelial injury reaction " theory, i.e. early stage endarterium damage is the basis of lipid infiltration, fibroplasia reaction and atherosclerosis plaque forming afterwards.Therefore, when carrying out cholesterol lowering therapeutic, how for atherosclerotic pathogenesis, strengthen the intervention to other link (as endothelial injury), thereby the effectively formation of atherosclerosis, this is one is worth our further investigated, and needs the problem solved very much.
Summary of the invention
The objective of the invention is to overcome the deficiency that the clinical practice of selectivity cholesterol absorption inhibitor exists; a kind of pharmaceutical composition for the treatment of more efficiently hypercholesterolemia is provided; the present said composition of this active isomer is except having better Lowering cholesterol effect; thereby the more effectively formation of atherosclerosis of blood vessel endothelium protection can also be provided simultaneously, and its clinical value is better than alone cholesterol absorption inhibitor.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition comprises:
(1) a kind of in the selectivity cholesterol absorption inhibitor of pharmaceutical dosage and active pharmaceutical precursor, active metabolite, salt or esters;
(2) one or more of the vitamin B group of pharmaceutical dosage;
(3) acceptable carrier on pharmaceutics.
In compositions of the present invention, the selectivity cholesterol absorption inhibitor is selected from Ezetimibe, SCH48461, SCH58053 etc., preferred Ezetimibe, comprise the phenol glucosiduronic acid of Ezetimibe or the mixture of its stereoisomer, isomer that be rich in to its non-mapping, that non-mapping ground is pure, that be rich in to mapping or mapping ground is pure, or the prodrug of this compounds, its mixture or isomer, or the pharmaceutically acceptable salt of described compound, mixture, isomer or prodrug.
In compositions of the present invention, the content of selectivity cholesterol absorption inhibitor is 1～30mg, preferably 5～20mg.
In compositions of the present invention, vitamin B group is selected from vitamin B
6, vitamin B
12, one or more in folic acid class material.Wherein, folic acid class material comprises the active metabolite of folic acid, formyl tetrahydrofolic acid, 5-methyltetrahydrofolate (metafolin), folate, folic acid or folate and can discharge in vivo the material that generates folic acid; Vitamin B
6Comprise the derivant of pyridoxol, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., pyridoxamine, pyridoxal 5-phosphate, phosphopyridoxamine and above-mentioned substance and can discharge in vivo/generate the material of this compounds; Vitamin B
12Comprise the derivant of cobalamine, mecobalamin element, 5 '-deoxyadenosyl cobalamin, hydroxocobalamine, cyanocobalamin and other cobalamine and can discharge in vivo/generate the material of cobalamine.
In compositions of the present invention, the content of folic acid class material is 0.2～5mg, vitamin B
6Content be 5～50mg, vitamin B
12Content be 0.01～1mg, its better treatment effective dose is: folic acid class material 0.2～1.2mg, vitamin B
610～40mg, vitamin B
120.01～0.5mg.
Above-mentioned pharmaceutical composition also can further comprise a kind of active component of effective therapeutic dose, and this active component is selected from a kind of in Hydroxymethylglutaryl list acyl coenzyme A (HMG-CoA) reductase inhibitor (being Statins) or clofibrate lipid-regulation medicine.
Be to be understood that medicament contg provided by the invention is not limitation of the present invention, but, to of the present invention preferred, generally, in this content range, this medicine can produce effective therapeutic effect to diseased individuals.Diseased individuals refers to the self-existent life entity of suffering from disease, and in the present invention, life entity is the mankind espespecially.Should be appreciated that in prior art, human pharmaceutical use content or medicinal content range can with mammal, as rat, mice etc., converted to draw to be applicable to corresponding animal applicable medicinal content or content range.
Therefore, the present invention also provides the application of aforementioned pharmaceutical compositions in preparing prevention, treat and delaying hyperlipemia or atherosclerosis relevant disease; Wherein relevant disease comprises coronary heart diseases and angina pectoris, myocardial infarction, acute coronary syndrome, apoplexy, arteriolar nephrosclerosis, abdominal aortic aneurysm, non-alcoholic fatty liver disease etc.
The dosage form of this pharmaceutical composition includes but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, the single chamber controlled release tablet, two chambers controlled release tablet, the pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, the capsule that contains micropill or small pieces, the pH dependent form capsule that contains micropill or small pieces, oral liquid, membrane or patch, what should particularly point out is, by the selectivity cholesterol absorption inhibitor, the vitamin B group compositions is made tablet or capsule.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into common oral preparation, comprise conventional tablet, conventional capsule, granule etc., while making tablet, described pharmaceutically suitable carrier comprises excipient and the accessory drugs that contributes to reactive compound is mixed with pharmaceutical formulation, compositions as one or more materials of starch, microcrystalline Cellulose, inorganic salts, sucrose, dextrin, lactose, sodium chloride, citric acid and sodium sulfite etc., belong to this area general knowledge.
Compound in compositions provided by the invention can be granted diseased individuals in identical preparation simultaneously, also in succession grants discriminably diseased individuals.If in succession grant diseased individuals, the delay that second (or additional) active component granted should not cause the active component to combine the loss of the beneficial effect brought.If grant diseased individuals simultaneously, the compound in compositions can mix and be present in same pharmaceutical dosage forms, also can independently exist respectively with same dosage form.If independently exist respectively with same dosage form, compositions can flexible existing with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of built-in one or more dosage forms and operation instructions thereof.
The invention has the beneficial effects as follows: the invention provides a kind of compositions and the application in preparing cholesterol reducing, Antiatherosclerosis medicine thereof; said composition not only can improve the cholesterol reducing curative effect of selectivity cholesterol absorption inhibitor; and aspect blood vessel endothelium protection and atherosclerosis formation, obviously be better than using separately cholesterol absorption inhibitor, and toxicity does not increase.Can also make in addition the patient take medicine conveniently, reduce medical expense, improve patient's compliance.The experiment support of its pharmacological action refers to the following specific embodiment.
Below in conjunction with the specific embodiment, the present invention will be further described, limitation of the invention not, all any this areas of carrying out according to content of the present invention be equal to replacement, all belong to protection scope of the present invention.
The specific embodiment
The preparation of embodiment 1. Ezetimibe 10mg/ folic acid 0.8mg sheets
Formula forms:
Make 1000
Preparation method: supplementary material was pulverized to 80 mesh sieves, drying for standby.Get Ezetimibe 10g and folic acid 0.8g according to equivalent incremental method mix homogeneously, add carboxymethyl starch sodium 25g, microcrystalline Cellulose 115g, calcium hydrogen phosphate 80g, according to the equivalent incremental method, evenly mix, add suitable amount of adhesive 10% polyvidone aqueous solution soft material processed, 30 orders are granulated, 40～45 ℃ of dry 3h; 30 order granulate, finally add 1% magnesium stearate to mix, after assay, and tabletting, packing.Note lucifuge in preparation process, after product inspection is qualified, aluminium-plastic bubble plate packing, keep in Dark Place.In the compound tablet of making, every contains Ezetimibe 10mg, folic acid 0.8mg.
The preparation of embodiment 2. Ezetimibe 10mg/5-methyl tetrahydrofolate 0.2mg capsules
Formula forms:
Make 1000
Preparation method: supplementary material was pulverized to 80 mesh sieves, drying for standby.Get Ezetimibe 10g, 5-methyltetrahydrofolate 0.2g according to equivalent incremental method mix homogeneously, add starch 80g, microcrystalline Cellulose 40g, carboxymethyl starch sodium 40g, evenly mix, make soft material with 50% ethanol, 20 mesh sieves are granulated, 60 ℃ of about 2h of drying, 20 mesh sieve granulate, the water content of controlling granule is 2-3%, dried granule is mixed homogeneously with 1% magnesium stearate of recipe quantity, and semi-finished product are detected, and measure content, the Capsules of packing into, obtain 1000 capsules.Note lucifuge in preparation process.The qualified rear aluminium-plastic bubble plate packing of product inspection, keep in Dark Place.In the compound capsule of making, every contains Ezetimibe 10mg, 5-methyltetrahydrofolate 0.2mg.
Embodiment 3. Ezetimibe phenol glucosiduronic acid 15mg/ calcium leucovorin 1mg/ vitamin Bs
65.0mg the preparation of granule
Formula forms:
Make 1000 bags
Preparation method: former, adjuvant were pulverized to 120 mesh sieves, get Ezetimibe phenol glucosiduronic acid 15g, calcium leucovorin 1.0g, vitamin B
65g, lactose 800g, starch 40g, arabic gum 5g, orange flavor 2g, Polyethylene Glycol 5g, carboxymethyl starch sodium 27g, sieve, mix homogeneously is made soft material, granulates, 40-60 ℃ drying, water content is 3% left and right, take out, granulate, be filled to according to a conventional method granule and get final product.In the compound tablet of making, every bag contains Ezetimibe phenol glucosiduronic acid 15mg, calcium leucovorin 1mg, vitamin B
65.0mg.
Embodiment 4. Ezetimibe 5mg/ vitamin Bs
120.1mg the preparation of sheet
Formula forms:
Make 1000
Preparation method reference example 1.
The preparation of embodiment 5.SCH4846120mg/5-methyl tetrahydrofolate 1.2mg sheet
Formula forms:
Make 1000
Preparation method reference example 1.
The preparation of embodiment 6. Ezetimibe phenol glucosiduronic acid 5mg/ vitamin B sheets
Formula forms:
Make 1000
Preparation method reference example 1.
The preparation of embodiment 7. Ezetimibe 10mg/ simvastatin 80mg/ folic acid 0.4mg double-layer tablet
Formula forms:
Make 1000
Above-mentioned composition is divided into to different two-layer of active component type separately.Every layer is composed as follows:
The Ezetimibe layer:
The simvastatin layer:
Preparation method: intimate mixing Ezetimibe, microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose and silica sol.Add magnesium stearate, mixture is mixed again, then be filled in the second funnel of double-layer tablet machine.Intimate mixing simvastatin, folic acid, microcrystalline Cellulose, lactose, cross-linking sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose and silica sol.Add magnesium stearate, mixture is mixed again, then be filled in the first funnel of double-layer tablet machine.Be prepared as follows double-layer tablet: the ground floor that at first will contain the mixture boil down to double-layer tablet of simvastatin, then the Ezetimibe mixture is compressed on described ground floor, thereby produces double-layer tablet, the every heavy 500mg of sheet, containing Ezetimibe 10mg, simvastatin 80mg and folic acid 0.4mg.
The impact of embodiment 8. Ezetimibes+folic acid use in conjunction on Atherosclerosis in Rabbits (AS)
One, method
(1) modeling, grouping and administration: healthy male New Zealand large ear rabbit (1.8～2.2kg), after adaptability is raised 1 week, be divided at random 6 groups by body weight, every group 7, be respectively: Normal group, model group, Ezetimibe group (0.5mg/kg), Ezetimibe+folic acid low dose group (0.5mg/kg+0.01mg/kg), Ezetimibe+folic acid high dose group (0.5mg/kg+0.06mg/kg) and folic acid (0.06mg/kg) group.Normal group is raised and is given normal feedstuff, common drinking-water, model group and each administration group are raised with high lipid food (containing 96% normal feedstuff, 0.5% cholesterol, 3.5% Adeps Sus domestica), 0.5% methionine drinking-water, after feeding 4 weeks, start gastric infusion, continuous 12 weeks, during administration, model group and administration group continue high fat diet, homomethionin drinking-water, feed altogether 16 weeks.After administration finishes, use etherization, cut off carotid artery and put to death animal, detect each index.
(2) index detects: total plasma cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), endothelin-1 (ET-1), nitric oxide (NO), homocysteine (Hcy) concentration.Observe the general pathology of respectively organizing AS speckle in Aortic Wall in Rabbits, utilize image analytical method to measure atherosclerotic plaques.
(3) date processing: experimental result is used
Mean, the statistical procedures of data adopts the SPSS10.0 statistical package, and group difference adopts the ANOVA variance analysis.
Two, result
(1) impact of Ezetimibe+folic acid on rabbit blood fat and Hcy: test and show, with normal group, compare, the baseline TC of model group animal and LDL-C and the equal tool of Hcy level significantly raise (P<0.01), prompting modeling success.After treatment, with model group, compare, Ezetimibe group TC and LDL-C level obviously reduce, but Hcy is had no significant effect; Ezetimibe+folic acid group blood fat reducing and fall Hcy alone group of the Ezetimibe that is better than evident in efficacy.The folic acid group is not obvious to lipid, but can significantly reduce Plasma Hcy.Refer to table 1.
The impact of table 1 Ezetimibe+folic acid on Hyperlipidemia Rabbits blood fat and Hcy
##P<0.01, model group is compared with matched group;
*P<0.05,
*P<0.01, administration group and model group are relatively;
ΔP<0.05,
The Δ ΔP<0.01, the compound recipe group is compared with Ezetimibe list medicine group.
(2) impact of Ezetimibe+folic acid on rabbit AS speckle and ET-1, NO level: experimental result shows, with matched group, compares, and the aorta AS speckle of model group animal obviously, the ET-1 level is increased significantly, the NO level obviously reduces.After drug treatment, with model group, compare, the equal showed different ET-1 level of folic acid group and Ezetimibe+folic acid group reduces and the NO level raises, and aorta wall plaque area (%) average of Ezetimibe+folic acid (height) group reduces obviously; Ezetimibe alone group of ET, NO are without significant change, and the aorta wall plaque area decreases, but not as Ezetimibe+folic acid group remarkable (table 2).Above result shows, folic acid has effect on protecting vascular endothelium, share to work in coordination with Ezetimibe and suppresses AS and form.
The impact of table 2 Ezetimibe+folic acid on rabbit AS
##P<0.01, model group and matched group are relatively;
*P<0.05,
*P<0.01, administration group and model group are relatively;
ΔP<0.05,
The Δ ΔCompare with the Ezetimibe group P<0.01
Pathological anatomy: perusal finds that the aorta wall of matched group rabbit is comparatively smooth, be canescence, and model group and each administration group Aortic Wall in Rabbits all are attached with faint yellow Lipid Plaque in various degree; the lighter rabbit of pathological changes is only at the visible Lipid Plaque of aorta or aortic arch place, and become the kitchen range shape to distribute; Heavier its lipid accumulation of rabbit of pathological changes goes out diffusivity to downward-extension from ascending aorta, aortic arch, and extends to thoracic aorta, ventral aorta and crotch thereof, is streak or reaches strip to distribute; Model group rabbit AS situation is the most serious; The AS situation of each administration group all is improved in varying degrees: Ezetimibe+folic acid compound recipe group rabbit AS condition improved is obvious, especially containing high dose folic acid group, obviously is better than alone Ezetimibe group.Examining under a microscope the aorta Lipid Plaque of pathological changes finds: the endotheliocyte of aorta wall sustains damage, inflammatory cell infiltration, and foam cell is assembled, fibroblast and smooth muscle cell proliferation, lesion degree and perusal are basically identical.
Conclusion: folic acid and Ezetimibe share can work in coordination with to reduce blood fat, protection blood vessel endothelium and suppress atherosclerotic plaque and form, and pharmaceutical composition of the present invention has the pharmacological action that collaborative control AS forms.
The collaborative cholesterol reducing of embodiment 9. Ezetimibe congener SCH48461+5-methyl tetrahydrofolates and effect on protecting vascular endothelium
One, method
(1) modeling, grouping and administration: healthy male SD rat (150～180g), after adaptability is raised 1 week, be divided at random 4 groups by body weight, every group 14, be respectively: Normal group, model group, SCH48461 group (1mg/kg), SCH48461+5-methyl tetrahydrofolate group (1mg/kg+0.08mg/kg).Normal group is raised and is given normal feedstuff, common drinking-water, model group and each administration group are raised with high lipid food (containing 96% normal feedstuff, 0.5% cholesterol, 3.5% Adeps Sus domestica), 0.5% methionine drinking-water, feed gastric infusion after 4 weeks, continuous 12 weeks, during administration, model group and administration group continued high fat diet, homomethionin drinking-water, feed altogether 16 weeks.Administration is got blood and is put to death animal after finishing.(2) index detects: plasma TC, Hcy, ET-1, NO and malonaldehyde (MDA) level, superoxide dismutase (SOD) vigor.(3) statistical analysis: experimental result is used
Mean, the statistical procedures of data adopts the SPSS10.0 statistical package, and group difference adopts the ANOVA variance analysis.
Two, result
(1) impact of SCH48461+5-methyl tetrahydrofolate on hyperlipidemia rats TC, Hcy: experiment shows, with normal group, compares, and the TC of model group animal, Hcy level all significantly raise (P<0.01), prompting modeling success.With model group, compare, SCH48461 group TC level obviously reduces, but Hcy is had no significant effect; SCH48461+5-methyl tetrahydrofolate group is fallen the TC curative effect and slightly is better than alone group of SCH48461 (but no statistical significance), falls the Hcy effect remarkable, refers to table 3.
The impact of table 3SCH48461+ folic acid on rats cholesterol and Hcy level
##P<0.01, model group and matched group are relatively; * P<0.01, administration group and model group are relatively;
The Δ ΔP<0.01 compound recipe group and single medicine group are relatively.
(2) impact of SCH48461+5-methyl tetrahydrofolate on rat endotheliocyte and anti-oxidation function: with matched group, compare, model group rat ET-1, MDA level obviously raise, and NO level, SOD vigor obviously reduce (P<0.01); With model group, compare; SCH48461+5-methyl tetrahydrofolate group ET-1, MDA obviously reduce, the NO level obviously raises; the SOD vigor increases; substantially there is no significant change and organize these indexs at SCH48461 except indivedual; the prompting 5-methyltetrahydrofolate has the effect of antioxidation, protection blood vessel endothelium, in Table 4.
The impact of table 4SCH48461+5-methyl tetrahydrofolate on rat endotheliocyte and anti-oxidation function
##P<0.01, model group is compared with matched group; * P<0.05, * * P<0.01, administration group and model group are relatively;
ΔP<0.05,
The Δ ΔP<0.01, Ezetimibe analog+5-methyltetrahydrofolate is compared with corresponding single medicine group
Hypercholesterolemia is the principal element that causes AS, and high Hcy can promote lipid peroxidation and cause vascular endothelial injury.The prompting of this result of study: the similar chemical substance SCH48461 of Ezetimibe and 5-methyltetrahydrofolate share by collaborative cholesterol reducing, fall Hcy, improve the oxidation resistance of body blood vessel, improve blood vessel inner skin cell function, thereby effectively prevent the formation of AS.
The effect that the collaborative anti-AS of embodiment 10. Ezetimibe phenol glucosiduronic acids and vitamin B group forms
Experimental technique is with embodiment 8, and 36 of rabbit, be divided into 6 groups at random, is respectively Normal group, model group, Ezetimibe phenol glucosiduronic acid group (0.8mg/kg), Ezetimibe phenol glucosiduronic acid+vitamin B
6Group (0.8mg/kg+2mg/kg), Ezetimibe phenol glucosiduronic acid+vitamin B
12Group (0.8mg/kg+0.01mg/kg) and Ezetimibe phenol glucosiduronic acid+vitamin B
6+ vitamin B
12+ folic acid group ((0.8mg/kg+2mg/kg+0.01mg/kg+0.04mg/kg).
Found that, descending aorta wall plaque area and endothelial function index ET and NO horizontal aspect, Ezetimibe phenol glucosiduronic acid and vitamin B
6, B
12Or compound vitamin B
6+ B
12The compound recipe group curative effect that+folic acid forms all significantly is better than alone Ezetimibe phenol glucosiduronic acid group.Ezetimibe phenol glucosiduronic acid and vitamin B group use in conjunction have coordinating protection endothelial function and anti-AS formation effect (table 5).
The impact of table 5 Ezetimibe phenol glucosiduronic acid+B group vitamin on rabbit AS
##P<0.01, model group and matched group are relatively;
*P<0.05,
*P<0.01, administration group and model group are relatively;
ΔP<0.05,
The Δ ΔP<0.01 compound recipe and Ezetimibe phenol glucosiduronic acid group are relatively.
Claims (8)
1. a pharmaceutical composition comprises:
(1) a kind of in the selectivity cholesterol absorption inhibitor of pharmaceutical dosage and active pharmaceutical precursor, active metabolite, salt or esters;
(2) one or more in the vitamin B group of pharmaceutical dosage and active pharmaceutical precursor, active metabolite, salt or esters;
(3) acceptable carrier on pharmaceutics.
2. pharmaceutical composition according to claim 1, it is characterized in that: described selectivity cholesterol absorption inhibitor comprises Ezetimibe, SCH48461 and SCH58053 etc., and content is 1～30mg.
3. according to claim 1 and 2 described pharmaceutical compositions, it is characterized in that, the phenol glucosiduronic acid of the preferred Ezetimibe of described selectivity cholesterol absorption inhibitor, Ezetimibe or the mixture of its stereoisomer, isomer that be rich in to its non-mapping, that non-mapping ground is pure, that be rich in to mapping or mapping ground is pure, or the prodrug of this compounds, its mixture or isomer, or the pharmaceutically acceptable salt of described compound, mixture, isomer or prodrug.
4. pharmaceutical composition according to claim 1, is characterized in that: described vitamin B group preferred vitamin B
6, vitamin B
12, one or more in folic acid class material; Wherein, vitamin B
6Content is 5～50mg, vitamin B
12Content is 0.01～1mg, and folic acid class content of material is 0.2～5mg.
5. pharmaceutical composition according to claim 4 is characterized in that: described folic acid class material comprises the active metabolite of folic acid, 5-methyltetrahydrofolate, formyl tetrahydrofolic acid, folinic acid, calcium levofolinate, folic acid officinal salt, folic acid or folic acid officinal salt and metabolism and/or generate the material of folic acid in vivo.
6. pharmaceutical composition according to claim 1 is characterized in that: also can further comprise a kind of active component of effective therapeutic dose in described pharmaceutical composition, this active component is selected from a kind of in Statins or clofibrate lipid-regulation medicine.
7. the described pharmaceutical composition of any one in claim 1～6, it is characterized in that: the pharmacy dosage form of described pharmaceutical composition is oral formulations, comprises tablet, capsule or granule etc.
8. the purposes of the described pharmaceutical composition of any one in the medicine formed for the preparation for the treatment of hypercholesterolemia and hyperlipemia, atherosclerosis in claim 1～7.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1803144A (en) * | 2005-01-13 | 2006-07-19 | 安徽省生物医学研究所 | Pharmaceutical composition containing clofibrate compound and B family vitamin |
| WO2007054975A1 (en) * | 2005-11-08 | 2007-05-18 | Panacea Biotec Ltd | Pharmaceutical compositions for the treatment of cardiovascular and other associated disorders |
| CN102143743A (en) * | 2008-09-05 | 2011-08-03 | 奎尔塞根医药有限责任公司 | Reducing cholesterol levels with combined use of querceting and statin |
| CN102349909A (en) * | 2011-08-19 | 2012-02-15 | 北京阜康仁生物制药科技有限公司 | Pharmaceutical composition for lowering blood lipid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1803144A (en) * | 2005-01-13 | 2006-07-19 | 安徽省生物医学研究所 | Pharmaceutical composition containing clofibrate compound and B family vitamin |
| WO2007054975A1 (en) * | 2005-11-08 | 2007-05-18 | Panacea Biotec Ltd | Pharmaceutical compositions for the treatment of cardiovascular and other associated disorders |
| CN102143743A (en) * | 2008-09-05 | 2011-08-03 | 奎尔塞根医药有限责任公司 | Reducing cholesterol levels with combined use of querceting and statin |
| CN102349909A (en) * | 2011-08-19 | 2012-02-15 | 北京阜康仁生物制药科技有限公司 | Pharmaceutical composition for lowering blood lipid |
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