CN103230594A - Medicine composition of alpha-glucosidase inhibitor and vitamin B - Google Patents
Medicine composition of alpha-glucosidase inhibitor and vitamin B Download PDFInfo
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Abstract
The invention relates to a medicine composition composed of one of a pharmaceutically acceptable dose of alpha-glucosidase inhibitor and active metabolite of salt thereof, one or more of pharmaceutically acceptable doses of vitamin B, and a pharmaceutically acceptable carrier. The invention belongs to the field of medicine. The invention also relates to an application of the composition in preparing diabetes-treating medicines. With a medicine prepared by using the medicine composition provided by the invention, blood sugar can be effectively reduced, and a beneficial effect of substantially controlling diabetes vascular lesion complications is provided. Therefore, the medicine is a more appropriate anti-diabetic medicine.
Description
Technical field
The present invention relates to contain a kind of pharmaceutical composition of one or more and pharmaceutically suitable carrier of vitamin B group of, pharmaceutical dosage of the alpha-glucosidase inhibitor class hypoglycemic drug of pharmaceutical dosage and active metabolite or salt apoplexy due to endogenous wind and said composition for the preparation of the purposes in treatment diabetes and the complication medicine thereof.The invention belongs to pharmaceutical field.
Background technology
Diabetes are a kind of common endocrine metabolism diseases, are characterized in that chronic hyperglycemia follows because of hypoinsulinism and/or effect the defective sugar, fat and the protein metabolism disorder that cause.According to Epidemiological study, China's diabetes prevalence is up to 9.7% (Yang W, et al.Prevalence of diabetes among men and women in China.N Engl J Med.2010; 362:1090-1101), calculate nearly 100,000,000 people of national diabetics sum.Therefore, diabetes have been a serious public health problem.Diabetes comprise macroangiopathy and microangiopathies with the normal vascular complication that takes place of course of disease progress, cause the chronic progressive external infringement of organs such as the heart, brain, kidney, eye, and the harm of diabetes is mainly from these complication.According to diabetes branch of Chinese Medical Association, the prevalence of diabetic vascular complications is: hypertension 31.9%, cerebrovascular 12.2%, cardiovascular diseases 15.9%, lower limb vascular disease 5.096, nephropathy (glomerular microangiopathy change) 33.6%, retinopathy 24.3%, total prevalence rate 73.2% (chronic complicating diseases investigation team of diabetes branch of Chinese Medical Association. the whole nation is diabetics chronic complicating diseases and 10 years Retrospective Analysis of hazard factor thereof in hospital. Chinese diabetes magazine, 2003; 11:232-237).
The treatment of diabetes target is blood glucose to be reached or near normal level, corrects metabolism disorder, eliminates diabetic symptom, prevents or delays complication, reduces case fatality rate.Alpha-glucosidase inhibitor (glueosidase inhibitor) is a class reaches the treatment diabetes to delay the intestinal carbohydrate absorption orally-taken blood sugar reducing medicine, be widely used in clinical, its mechanism of action is the various alpha-glucosidases that competitive inhibition is positioned at small intestinal, the speed that makes starch based be decomposed into glucose slows down, thereby slow down the absorption of glucose in the intestinal, reduce postprandial hyperglycemia.The theory significance that the control post-prandial glycemia raises is to stop the carbohydrate tolerance sufferer to develop into the danger of type 2 diabetes mellitus or reduction diabetics generation macroangiopathy, because postprandial hyperglycemia can cause that vasoconstriction and permeability increase, vascular endothelial cell adheres to increase, cause vascular lesion.The present alpha-glucosidase inhibitor that has gone on the market also clinical practice has 3 kinds, that is: acarbose (acarbose), voglibose (voglibose) and miglitol (miglitol).
Compare with traditional sulphanylureas, biguanide antidiabetic medicament, the sharpest edges of alpha-glucosidase inhibitor are to suppress post-prandial glycemia to raise, reduce blood glucose fluctuation, but still come with some shortcomings in other side.One is compared with other class hypoglycemic drug commonly used, and the clinical practice history of alpha-glucosidase inhibitor is not long, is still lacking enough evidence-based medicine EBM data aspect the control diabetic angiopathy complication, thereby is not having clear superiority; Its two, alpha-glucosidase inhibitor class types of drugs is few, based on import or foreign capitals production, drug cost is higher, is in the price inferior position in the market competition; They are three years old, use heavy dose of alpha-glucosidase inhibitor separately and also can produce some side effect, as gastrointestinal reactions such as abdominal distention, diarrhoea, crampy gastrointestinal pain, constipation, when share other antidiabetic drug (as insulin, sulphanylureas or biguanides) hypoglycemia might take place.
If on the market at the different blood sugar lowering of the various mechanism of action for the treatment of of diabetes drug main, pay attention to correcting pathoglycemia state and the metabolism disorder of diabetes, and ignored early prevention and treatment to diabetic complication, especially vascular lesion complication to a certain extent.Studies show that, homocysteine level raises or relevant [the Sun Y of danger rising of folate level reduction and angiopathys such as coronary heart disease, apoplexy in the blood, et al.Use of serum homocysteine to predict stroke, coronary heart disease and death in Ethnic Chinese:a 12-year prospective cohort study.Circ is J.2009; 73:1423-1430], Supplement of folic acid or composite B vitamin can reduce homocysteine level, reduce cardiovascular event danger.One of important goal for the treatment of diabetes namely is to prevent or delay various complication, especially vascular complication, thereby reduces case fatality rate, therefore needs treatment other and blood vessel injury factor or the clinical disease deposited.
On the other hand, clinical trial has proved that drug combination or compound preparation have it to need and value, and the dosage of every kind of medicine can reduce, and the therapeutical effect of medicine has concertedness or addition at least, and untoward reaction can be cancelled out each other or not overlapping at least or addition.
Summary of the invention
The objective of the invention is to overcome the alpha-glucosidase inhibitor above shortcomings, a kind of pharmaceutical composition (compound medicine and preparation) that toxic and side effects does not increase being better than alpha-glucosidase inhibitor aspect the pathoglycemia state of correcting diabetes and the control diabetic vascular complications is provided.
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 alpha-glucosidase inhibitor of pharmaceutical dosage and active metabolite thereof or its esters;
(2) one or more of the vitamin B group of pharmaceutical dosage;
(3) acceptable carrier on the pharmaceutics.
Above-mentioned " pharmaceutical dosage " refers to have amount collaborative, that prevent or treat the pharmacological action of effect.
Above-mentioned alpha-glucosidase inhibitor is selected from acarbose, voglibose or miglitol, and vitamin B group is selected from vitamin B
6, vitamin B
12With folic acid class material.Vitamin B among the present invention
6Comprise the derivant of pyridoxol, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., pyridoxamine, pyridoxin phosphate, pyridoxal 5-phosphate, phosphopyridoxamine and above-mentioned substance and metabolism and/or generate the material of this compounds, vitamin B among the present invention in vivo
6Dosage be selected from 1mg～50mg; Vitamin B among the present invention
12Comprise the derivant of cobalamine, mecobalamin element, 5 '-deoxyadenosyl cobalamin, hydroxocobalamine, cyanocobalamin and above-mentioned substance and metabolism and/or generate the material of this compounds, vitamin B among the present invention in vivo
12Dosage be selected from 0.01mg～0.1mg; Folic acid class material among the present invention comprises the active metabolite of folic acid, 5-methyl tetrahydrofolate, 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, and the dosage of middle period acid of the present invention is selected from 0.1mg～5mg.
In the pharmaceutical composition provided by the invention, alpha-glucosidase inhibitor is acarbose, and vitamin B group is folic acid class material.In said composition, the dosage of acarbose is selected from 50mg～200mg, and the dosage of folic acid class material is selected from 0.2mg～2mg.Wherein, the preferred 5-methyl tetrahydrofolate of folic acid class material or folic acid, the preferred 0.2mg～1mg of dosage of folic acid class material is more preferably 0.4 or 0.8mg.
In the pharmaceutical composition provided by the invention, alpha-glucosidase inhibitor is voglibose, and vitamin B group is folic acid class material.In said composition, the dosage of voglibose is selected from 0.1mg～0.5mg, and the dosage of folic acid class material is selected from 0.2mg～2mg.Wherein, the preferred 5-methyl tetrahydrofolate of folic acid class material or folic acid, the preferred 0.2mg～1mg of dosage of folic acid class material is more preferably 0.4 or 0.8mg.
In the pharmaceutical composition provided by the invention, alpha-glucosidase inhibitor is miglitol, and vitamin B group is folic acid class material.In said composition, the dosage of miglitol is selected from 25mg～100mg, and the dosage of folic acid class material is selected from 0.2mg～2mg.Wherein, the preferred 5-methyl tetrahydrofolate of folic acid class material or folic acid, the preferred 0.2mg～1mg of dosage of folic acid class material is more preferably 0.4 or 0.8mg.
In the pharmaceutical composition provided by the invention, alpha-glucosidase inhibitor is acarbose, and vitamin B group is vitamin B
6In said composition, the dosage of acarbose is selected from 50mg～200mg, vitamin B
6Dosage be selected from 3mg～30mg.
In the pharmaceutical composition provided by the invention, alpha-glucosidase inhibitor is voglibose, and vitamin B group is vitamin B
6In said composition, the dosage of voglibose is selected from 0.1mg～0.5mg, vitamin B
6Dosage be selected from 3mg～30mg.
In the pharmaceutical composition provided by the invention, alpha-glucosidase inhibitor is miglitol, and vitamin B group is vitamin B
6In said composition, the dosage of miglitol is selected from 25mg～100mg, vitamin B
6Dosage be selected from 3mg～30mg.
In the pharmaceutical composition provided by the invention, alpha-glucosidase inhibitor is acarbose, and vitamin B group is vitamin B
12In said composition, the dosage of acarbose is selected from 50mg～200mg, vitamin B
12Dosage be selected from 0.01mg～0.1mg.
In the pharmaceutical composition provided by the invention, alpha-glucosidase inhibitor is voglibose, and vitamin B group is vitamin B
12In said composition, the dosage of voglibose is selected from 0.1mg～0.5mg, vitamin B
12Dosage be selected from 0.01mg～0.1mg.
In the pharmaceutical composition provided by the invention, alpha-glucosidase inhibitor is miglitol, and vitamin B group is vitamin B
12In said composition, the dosage of miglitol is selected from 25mg～100mg, vitamin B
12Dosage be selected from 0.01mg～0.1mg.
The inventor finds under study for action; the compound medicine of being made up of alpha-glucosidase inhibitor and vitamin B group is except the diabetes model animal is had the better blood sugar reducing function; has remarkable reduction blood homocysteine level, improve vascular endothelial function, reduce effects such as urine protein; prompting is to the Additional Protection of diabetic animal blood vessel; and be better than and only use alpha-glucosidase inhibitor or singly use vitamin B group, namely shown synergism.Further, in experiment, find, when alpha-glucosidase inhibitor and vitamin B group are share, can work in coordination with the danger that reduces vascular events.
According to the present invention, active component in the pharmaceutical composition is the solvent in the compositions, one of them active component comes from a kind of in the alpha-glucosidase inhibitor, another active component is one or more of vitamin B group, and 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/the 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 that one or more pharmaceutical compositions that will contain alpha-glucosidase inhibitor and vitamin B group are 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., described pharmaceutically suitable carrier includes excipient and the accessory drugs that helps reactive compound is mixed with pharmaceutical formulation when making tablet, compositions as one or more materials of microcrystalline Cellulose, inorganic salts, lactose, sodium chloride, citric acid and sodium sulfite etc. belongs to this area general knowledge.
Chemical compound in the pharmaceutical composition provided by the invention can be granted diseased individuals simultaneously in identical preparation, also grant diseased individuals discriminably in succession.If grant diseased individuals in succession, the delay that then second (or additional) active component granted should not cause the active component to unite the loss of the beneficial effect that brings.If grant diseased individuals simultaneously, the chemical compound in the compositions can mix and be present in the same pharmaceutical dosage forms, also can independently exist respectively with same dosage form.If independently exist respectively with same dosage form, then pharmaceutical composition 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 compound tablet of one or more compositions of a kind of and vitamin B group in the preferred described alpha-glucosidase inhibitor in the present invention.
Another object of the present invention provides the purposes of pharmaceutical composition in the medicine of preparation treatment diabetes of one or more and pharmaceutically suitable carrier of the vitamin B group of a kind of, the pharmaceutical dosage in the alpha-glucosidase inhibitor that contains pharmaceutical dosage and active metabolite or its esters.Pharmaceutical composition provided by the invention is prevented and treated diabetic vascular complications because of remarkable, thereby becomes antidiabetic medicine preferably.Wherein, alpha-glucosidase inhibitor is selected from a kind of in acarbose, voglibose, the miglitol, and another active component is selected from vitamin B in the compositions
6, vitamin B
12With in the folic acid class material one or more.
In the pharmaceutical composition purposes provided by the invention, alpha-glucosidase inhibitor is acarbose, and vitamin B group is folic acid class material.In said composition, the dosage of acarbose is selected from 50mg～200mg, and the dosage of folic acid class material is selected from 0.2mg～2mg.Wherein, the preferred 5-methyl tetrahydrofolate of folic acid class material or folic acid, the preferred 0.2mg～1mg of dosage of folic acid class material is more preferably 0.4 or 0.8mg.
In the pharmaceutical composition purposes provided by the invention, alpha-glucosidase inhibitor is voglibose, and vitamin B group is folic acid class material.In said composition, the dosage of voglibose is selected from 0.1mg～0.5mg, and the dosage of folic acid class material is selected from 0.2mg～2mg.Wherein, the preferred 5-methyl tetrahydrofolate of folic acid class material or folic acid, the preferred 0.2mg～1mg of dosage of folic acid class material is more preferably 0.4 or 0.8mg.
In the pharmaceutical composition purposes provided by the invention, alpha-glucosidase inhibitor is miglitol, and vitamin B group is folic acid class material.In said composition, the dosage of miglitol is selected from 25mg～100mg, and the dosage of folic acid class material is selected from 0.2mg～2mg.Wherein, the preferred 5-methyl tetrahydrofolate of folic acid class material or folic acid, the preferred 0.2mg～1mg of dosage of folic acid class material is more preferably 0.4 or 0.8mg.
In the pharmaceutical composition purposes provided by the invention, alpha-glucosidase inhibitor is acarbose, and vitamin B group is vitamin B
6In said composition, the dosage of acarbose is selected from 50mg～200mg, vitamin B
6Dosage be selected from 3mg～30mg.
In the pharmaceutical composition purposes provided by the invention, alpha-glucosidase inhibitor is voglibose, and vitamin B group is vitamin B
6In said composition, the dosage of voglibose is selected from 0.1mg～0.5mg, vitamin B
6Dosage be selected from 3mg～30mg.
In the pharmaceutical composition purposes provided by the invention, alpha-glucosidase inhibitor is miglitol, and vitamin B group is vitamin B
6In said composition, the dosage of miglitol is selected from 25mg～100mg, vitamin B
6Dosage be selected from 3mg～30mg.
In the pharmaceutical composition purposes provided by the invention, alpha-glucosidase inhibitor is acarbose, and vitamin B group is vitamin B
12In said composition, the dosage of acarbose is selected from 50mg～200mg, vitamin B
12Dosage be selected from 0.01mg～0.1mg.
In the pharmaceutical composition purposes provided by the invention, alpha-glucosidase inhibitor is voglibose, and vitamin B group is vitamin B
12In said composition, the dosage of voglibose is selected from 0.1mg～0.5mg, vitamin B
12Dosage be selected from 0.01mg～0.1mg.
In the pharmaceutical composition purposes provided by the invention, alpha-glucosidase inhibitor is miglitol, and vitamin B group is vitamin B
12In said composition, the dosage of miglitol is selected from 25mg～100mg, vitamin B
12Dosage be selected from 0.01mg～0.1mg.
Diabetic vascular complications of the present invention mainly includes but not limited to atherosclerosis, coronary heart disease, cerebrovascular, lower limb gangrene, nephropathy, retinal microvascular pathological changes.
Advantage of the present invention: the pharmaceutical composition of one or more and pharmaceutically suitable carrier that the invention provides the vitamin B group of a kind of, the pharmaceutical dosage in the alpha-glucosidase inhibitor that contains pharmaceutical dosage and active metabolite or its esters.The combined effect of alpha-glucosidase inhibitor and vitamin B group is not the simple addition of each self-applying of each active substance, but causes type 2 diabetes mellitus patient's the generation that reduces diabetic vascular complications on the basis of significantly improving hyperglycemia.That is to say that alpha-glucosidase inhibitor and vitamin B group drug combination have been obtained synergistic therapeutic effect, is antidiabetic medicine preferably therefore.
The present invention will be further described below in conjunction with the specific embodiment, is not limitation of the invention, all any this areas of carrying out according to content of the present invention be equal to replacement, all belong to protection scope of the present invention.
The specific embodiment
The consumption of the preparation process of following pharmaceutical preparation embodiment and the used material of preparation or the used material of preparation is not limited to character express; all formulation methods that contains pharmaceutical composition provided by the invention; all belong to protection scope of the present invention; but concrete experimental technique reference drug preparation quick-reference book is as " pharmaceutical necessities is used and preparation ", " pharmaceutics ", " Biopharmaceutics and Pharmacokinetics " etc.
Embodiment 1 preparation compound recipe acarbose/YESUAN PIAN (1000 amounts)
Prescription:
Preparation method: supplementary material is crossed 80 mesh sieves, drying for standby.Get recipe quantity folic acid, acarbose according to equivalent incremental method mix homogeneously, take by weighing microcrystalline Cellulose, low-substituted hydroxypropyl cellulose (L-HPC), the carboxymethyl starch sodium of recipe quantity, press the abundant mixing of equivalent incremental method with the crude drug mixed powder, add an amount of 5% polyvidone, 95% alcoholic solution and make soft material, 20 mesh sieves are granulated, 50 ℃ of dry about 6h, 20 mesh sieve granulate, the water content of control granule is 2-3%, magnesium stearate mix homogeneously with dried granule and recipe quantity, intermediate detects, and is pressed into 1000.Note lucifuge in the preparation process, the tablet of making needs aluminium-plastic bubble plate packing, keeps in Dark Place.Every contains acarbose 50mg, folic acid 0.8mg in the compound tablet of making.
Embodiment 2 preparation compound recipe voglibose/YESUAN PIAN (1000 amounts)
Prescription:
Preparation method: supplementary material is crossed 80 mesh sieves, drying for standby.Get recipe quantity folic acid, voglibose according to equivalent incremental method mix homogeneously, take by weighing microcrystalline Cellulose, lactose, crospolyvinylpyrrolidone, the carboxymethyl starch sodium of recipe quantity, press the abundant mixing of equivalent incremental method with the crude drug mixed powder, add an amount of 10% starch slurry solution and make soft material, 20 mesh sieves are granulated, 50 ℃ of dry about 6h, 20 mesh sieve granulate, the water content of control granule is 2-3%, Glyceryl Behenate and magnesium stearate mix homogeneously with dried granule and recipe quantity, intermediate detects, and is pressed into 1000.Note lucifuge in the preparation process, the tablet of making needs aluminium-plastic bubble plate packing, keeps in Dark Place.Every contains voglibose 0.2mg, folic acid 0.8mg in the compound tablet of making, and its mass ratio is 1: 4.
Embodiment 3 preparation compound recipe miglitol/5-methyl tetrahydrofolate sheets (1000 amounts)
Prescription:
Preparation method: adjuvant is the vertical compression adjuvant, drying for standby.Get the 5-methyl tetrahydrofolate of recipe quantity and 10g microcrystalline Cellulose according to equivalent incremental method mix homogeneously, obtain mixing powder intermediate 1; Take by weighing residue microcrystalline Cellulose, lactose, the carboxymethyl starch sodium of recipe quantity, press the abundant mixing of equivalent incremental method with miglitol, obtain mixing powder intermediate 2; The magnesium stearate of mixing powder intermediate 1 and mixed powder intermediate 2 and recipe quantity according to equivalent incremental method mix homogeneously, is got and finally mixes the powder intermediate, detect and mix the powder intermediate, be pressed into 1000.Note lucifuge in the preparation process, the tablet of making needs aluminium-plastic bubble plate packing, keeps in Dark Place.Every contains miglitol 50mg, 5-methyl tetrahydrofolate 0.8mg in the compound tablet of making, and its mass ratio is 50: 0.8.
Embodiment 4 preparation compound recipe acarbose/vitamin Bs
6Sheet (1000 amounts)
Prescription:
Preparation method: adjuvant is the vertical compression adjuvant, drying for standby.Get vitamin B6 and the 10g microcrystalline Cellulose mix homogeneously of recipe quantity, obtain mixing powder intermediate 1; Take by weighing residue microcrystalline Cellulose, the low-substituted hydroxypropyl cellulose (L-HPC) of recipe quantity, press the abundant mixing of equivalent incremental method with acarbose, obtain mixing powder intermediate 2; Finally mix the powder intermediate with mixing powder intermediate 1 and the mixed powder intermediate 2 magnesium stearate mix homogeneously with recipe quantity, getting, detect and mix the powder intermediate, be pressed into 1000.Note lucifuge in the preparation process, the tablet of making needs aluminium-plastic bubble plate packing, keeps in Dark Place.Every contains acarbose 50mg, vitamin B in the compound tablet of making
610mg, its mass ratio are 5: 1.
Embodiment 5 preparation compound recipe voglibose/5-methyl tetrahydrofolate/vitamin Bs
12Capsule (1000 amounts)
Prescription:
Preparation method: supplementary material is crossed 80 mesh sieves, drying for standby.Get 5-methyl tetrahydrofolate 0.8g, vitamin B12 0.05g, voglibose 0.2g according to equivalent incremental method mix homogeneously, after increasing progressively mix homogeneously with microcrystalline Cellulose, carboxymethyl starch sodium equivalent again, it is an amount of to add 5% polyvidone ethanol solution, soft material processed, 50 ℃ of dry about 6h cross 24 mesh sieves granule processed, the water content of control granule is 2-3%, with dried granule and recipe quantity micropowder silica gel mix homogeneously, the granule intermediate that obtains detects, detect qualified after, pack Capsules into namely.Note lucifuge in the preparation process, the capsule of making needs aluminium-plastic bubble plate packing, keeps in Dark Place.Every contains voglibose 0.2mg, 5-methyl tetrahydrofolate 0.8mg, vitamin B12 50 μ g in the capsule of making.
Embodiment 6 preparation compound recipe acarbose folic acid double-layer tablet
Prescription: acarbose layer:
The preparation method of acarbose layer granule: supplementary material was pulverized 80 mesh sieves, drying for standby.Get acarbose 50g, 60g Celluloasun Microcrystallisatum and 10g carboxymethyl starch sodium, evenly mix according to the equivalent incremental method, make soft material with 5% 30 POVIDONE K 30 BP/USP 29/30-95% alcoholic solution, 20 mesh sieves are granulated, 50 ℃ of dry about 6h, 20 mesh sieve granulate, the water content of control granule is 2-3%, obtains acarbose layer granule A;
The folic acid layer:
The preparation method of folic acid layer granule: get folic acid 0.8g, 60g microcrystalline Cellulose and 10g low-substituted hydroxypropyl cellulose, evenly mix according to the equivalent incremental method, make soft material with 5% 30 POVIDONE K 30 BP/USP 29/30-95% alcoholic solution, 20 mesh sieves are granulated, 50 ℃ of dry about 6h, 20 mesh sieve granulate, the water content of control granule is 2-3%, obtains folic acid layer granule B;
The preparation method of double-layer tablet: with dried granule A, B respectively with the magnesium stearate mix homogeneously, semi-finished product detect respectively, measure content after, be respectively charged in the feed hopper, be pressed into 1000 with the double-layer tablet tablet machine.Note lucifuge in the preparation process, the tablet of making needs aluminium-plastic bubble plate packing, keeps in Dark Place.Every contains acarbose 50mg, folic acid 0.8mg in the compound tablet of making, and its mass ratio is 50: 0.8.
Embodiment 7 acarbose folate composition are to blood sugar lowering, the vascular protection effect of diabetes rat
Method: a) streptozotocin solution: take by weighing 600mg streptozotocin (STZ) and face with before being dissolved in the 200ml citric acid solution, be made into the solution of 3mg/ml.B) healthy rat is 80,10 rats of picked at random are as normal control, all the other rats by intraperitoneal injection STZ solution (30mg/kg), normal diet, blood sampling mensuration fasting glucose (FPG) value behind the socket of the eye after 2 weeks, screening blood glucose value are made hyperglycemic rat above the rat of 11.1mmol/L and are used for follow-up experiment.C) hyperglycemic rat is divided at random model group, acarbose group, folic acid group, acarbose+folic acid group (seeing Table 1), every group 13, irritate stomach every day respectively and give normal saline, acarbose 5mg/kg, folic acid 0.0gmg/kg, acarbose 5mg/kg+ folic acid 0.08mg/kg, make blank with normal rat in addition, give the equivalent normal saline, the filling gastric capacity is lml/100g, every day 1 time.Normal diet, successive administration are after 6 weeks, and each is organized the blood sampling of rat eye socket and surveys FPG and endothelin level-1 (ET-1).Remove dead rat midway, every group records the result and represents (table 1) with means standard deviation, statistical test method employing paired t-test.
Result: see Table 1.Model group rat fasting blood-glucose (FPG) level is significantly higher than rats in normal control group, shows that the model group rat blood sugar presents hyperglycemia state.Give with the hyperglycemic rat Drug therapy after, acarbose, acarbose folate composition group rat FPG significantly reduce (P＜0.01), folic acid group rat FPG slightly reduces, but difference does not have significance; The acarbose folate composition is better than the acarbose list with (P＜0.05) to the hypoglycemic activity of hyperglycemic rat, shows that the acarbose folate composition is a kind of antidiabetic medicine that more is applicable to application.Plasma ET is one of index of reflection diabetic angiopathy; this experiment is found; compare with model group, folic acid, acarbose folate composition group rat plasma ET-1 all have remarkable reduction (P＜0.05), and prompting folic acid is to the protective effect of blood vessel endothelium.
Table 1 acarbose folate composition is to the effect of rat
Annotate: compare * P＜0.05, * * P＜0.01 with model group; Compare with the acarbose group,
ΔP＜0.05.
Embodiment 8 miglitol folate composition are to blood sugar lowering and the vascular protection effect of diabetes rat
Method: (1) material: 80 of SD rats, body weight 200～230g, male and female half and half; Streptozotocin (STZ, U.S. sigma company product); Blood glucose meter (U.S. MediSense company product); Serum superoxide dismutases (SOD), catalase (CAT) test kit, serum endothelin (ET) radioimmunological kit are purchased in Nanjing and are built up biotech firm.(2) animal modeling and administration: the rat adaptability is randomly drawed 10 as the blank group after raising for 1 week, all the other 70 give the STZ30mg/kg single intraperitoneal injection respectively, blood sugar level is measured in the rat tail vein blood sampling behind the 14d, be defined as diabetes modeling success greater than 11.1mmoL/L, get 52, be divided into 4 groups at random, it is model control group, the miglitol group, the folic acid group, miglitol+folic acid group, every group 13,3 groups of fillings every days in back are fed and are given miglitol 5mg/kg, folic acid 0.04mg/kg, miglitol 5mg/kg+ folic acid 0.04mg/kg, blank group, model group gives the normal saline filling of equivalent and feeds, and each organizes medication or the processing time was 8 weeks.(3) collection of specimens, index detect: 10% chloral hydrate intraperitoneal injection of anesthesia animal after 8 weeks, abdominal aortic blood is surveyed blood glucose, and measures SOD in serum, CAT, ET level respectively by the test kit description.Remove dead rat midway, every group records the result and statistics sees Table 2.
Result and discussion: see Table 2.Give with the diabetes rat Drug therapy after 8 weeks, miglitol, miglitol folate composition group rat FPG significantly reduce, compare with model group, folic acid group rat FPG there was no significant difference, the miglitol folate composition is better than miglitol list usefulness to the blood sugar reducing function of rat, shows that miglitol and folic acid have share collaborative hypoglycemic activity.Compare with rats in normal control group, the rising of model group rat blood serum ET level, SOD, CAT level reduce, the prompting diabetes model merges vascular endothelial injury, miglitol, folic acid and miglitol folate composition all show the effect that reduces Serum ET, increased SOD, CAT, and prompting miglitol and folic acid share the collaborative effect that improves rat anti oxidation and anti-endothelial injury.
Diabetic angiopathy is main performance with arteriosclerosis, and vascular endothelial injury is the initiating link of diabetic vascular complications, and the generation of diabetic angiopathy simultaneously further promotes endothelial injury again, but the mechanism of vascular lesion is not illustrated as yet fully.ET is the active substance of vascular endothelial cell secretion in the blood, is strong vasoconstrictor, and is closely related with diabetic vascular complications.According to the literature, with the diabetes progress, the ET level raises gradually, is the good index of reflection diabetic angiopathy.Oxygen-derived free radicals is the key factor that causes endothelial injury, and SOD, CAT are the important protease of removing oxygen-derived free radicals in the blood.According to above-mentioned result of study, our Preliminary conclusion: folic acid and miglitol use in conjunction not only have good hypoglycemic activity, also have the remarkable effect that improves the diabetes rat vascular endothelial injury.
Table 2-1 miglitol folate composition is to the effect of rat blood sugar
Annotate: compare * P＜0.05, * * P＜0.01 with model group; Compare with the miglitol group,
ΔP＜0.05.
Table 2-2 miglitol folate composition is to the protective effect of rat aorta
Annotate: compare * P＜0.05, * * P＜0.01 with model group; Compare with the miglitol group,
ΔP＜0.05.
Embodiment 9 vogliboses/folic acid/vitamin B
12Compositions is to the effect of diabetes rat vasodilation function
Method: the SD rat is raised 4 all pneumoretroperitoneum injection streptozocins (30mg/kg) with high fat diet, and 4 weeks back survey FPG affirmation rat type 2 diabetes mellitus is induced successfully, continues to raise with high fat diet.56 diabetes rats are divided into 4 groups at random: model group, voglibose group, folic acid+vitamin B
12Group, voglibose+folic acid+vitamin B
12Group, treatment every day or processing should be mutually feeds equal-volume distilled water, 0.04mg/kg voglibose, 0.04mg/kg folic acid+0.05mg/kg vitamin B
12, 0.04mg/kg voglibose+0.04mg/kg folic acid+0.05mg/kg vitamin B
12Other establishes 10 of normal control rats (normal diet of taking food all the time).10 week of administration back repetition measurement FPG, lumbar injection 30mg/kg pentobarbital sodium anesthetized rat, open the abdominal cavity, separate ventral aorta and superior mesenteric artery, tell the above and below ligation respectively of superior mesenteric artery at ventral aorta, one " Y " shape pipe is inserted superior mesenteric artery, and the ligation tremulous pulse also is fixed on " Y " shape pipe, cuts mesentery is complete along intestinal tube then." Y " shape Guan Yiduan is connected in the peristaltic pump perfusion system of water bath with thermostatic control, can replace constant speed perfusion Krebs liquid (balance and flushing mesentery vascular bed) or contain the Krebs liquid (administration) of medicine.The other end of " Y " shape pipe is connected in four road physiology monitors, record mesentery vascular bed internal pressure (the reflection antiotasis changes).Mesentery vasodilation reaction assay: adding final concentration in Krebs liquid is the norepinephrine (NE) of 1 μ mol/L, the mesentery vasoconstriction reaches the highest and stable back (the intrinsic pressure rising of vascular bed), the sodium nitroprusside (SNP) that adds the acetylcholine that final concentration is 1 μ mol/L (ACh) or 1 μ mol/L again, drops in the vasodilation, mesentery vascular bed.With the mesentery blood vessel relaxation rate percentage ratio [(NE mesentery intravascular pressure-ACh or SNP mesentery intravascular pressure)/NE mesentery intravascular pressure * 100%] of ACh or SNP is represented that mesentery vascular bed is to the stretching reaction of ACh or SNP.Endothelium-denuded cell vasodilation reaction assay: adding final concentration in Krebs liquid is Saponin endothelium-denuded (about perfusion 20mL of 1 μ mol/L, Saponin is destroyed blood vessel endothelium and vascular smooth muscle is not had influence), with Krebs liquid perfusion flushing 30min, repeat above-mentioned steps again, the mesentery blood vessel is to the stretching reaction of ACh or SNP behind the observation endothelium-denuded cell.
Result and discussion: data see Table 3-1 and table 3-2.Compare with the normal control group, the model group rat blood sugar significantly raises, and shows the modeling success.After giving the diabetes rat Drug therapy, voglibose group, voglibose+folic acid+vitamin B
12Compositions group rat FPG all significantly reduces, folic acid+vitamin B
12The group rat blood sugar also has reduction (P＜0.05), voglibose+folic acid+vitamin B
12Compositions is better than voglibose group (P＜0.05) to the hypoglycemic activity of diabetes rat, prompting voglibose and folic acid, vitamin B
12Share collaborative blood sugar reducing function.
The initial reason of diabetic angiopathy is the vascular endothelial cell infringement.Whether this research and utilization myocardium vessel perfusion technology is observed this compositions has protective effect to diabetes rat mesentery vascular endothelial cell.The diastolic rate of ACh can reflect inner skin cell function.Found that diabetes model rat mesentery blood vessel ACh diastolic rate is (31.9 ± 6.8) %, normal matched group (79.4 ± 8.9) % obviously reduces voglibose group, folic acid+vitamin B
12Group, voglibose+folic acid+vitamin B
12Group blood vessel ACh diastolic rate all is significantly improved than model group, and voglibose+folic acid+vitamin B
12The improvement degree of group is better than voglibose group (P＜0.05), points out folic acid, vitamin B strongly
12The protection of ecs effect is arranged.Behind the Saponin endothelium-denuded, 3 treatment group mesentery blood vessels all obviously reduce there was no significant difference between group to the reactivity of ACh vasodilator.But before and after endothelium-denuded is handled, each is organized the mesentery blood vessel SNP (is discharged nitric oxide, directly relaxing smooth muscle belongs to non-endothelium-dependent relaxation) the no significant change of vasodilatory reactivity, the early stage vascular lesion of side light diabetes rat mainly is the infringement blood vessel endothelium.
According to above experimental result, we think voglibose/folic acid/vitamin B
12Compositions has remarkable protective effect to type 2 diabetes mellitus rat aorta endotheliocyte.
Table 3-1 voglibose/folic acid/vitamin B
12Compositions is to the effect of rat blood sugar
Annotate: compare * P＜0.05, * * P＜0.01 with model group; Compare with the voglibose group,
ΔP＜0.05.
Table 3-2 voglibose/folic acid/vitamin B
12Compositions is to the influence of rat aorta endothelial function
Annotate: compare * P＜0.05, * * P＜0.01 with model group; Compare with the voglibose group,
ΔP＜0.05.
Embodiment 10 acarbose 5-methyl tetrahydrofolate (5-MTHF) compositionss are to the influence of diabetes rat kidney, vascular endothelial function
Method: the Wistar rat is (male, body weight 200-250g) lumbar injection streptozotocin STZ (30mg/kg), be aided with normal feedstuff and feed, freely drink water, the survey blood glucose of taking a blood sample behind the socket of the eye after 2 weeks filters out 48 of diabetes rats, be divided into 4 groups at random, be respectively model control group, acarbose group (10mg/kg), 5-MTHF group (0.1mg/kg), acarbose+5-MTHF organizes (10mg/kg+0.1mg/kg), 12 every group, gastric infusion, every day 1 time, continuous 8 weeks; Other sets up 12 of normal control groups.Except the normal control group was fed normal diet, all the other each groups were all fed with the high heat feedstuff.Experimental session animal drinking-water and feedstuff do not add restriction, and blood glucose and nitric oxide (NO) content were surveyed in blood sampling when experiment finished, and the metabolic cage method accesses the 24h urine, measures the 24h urine albumen amount.Statistical method: data are represented with mean ± standard deviation, relatively more capable paired t-test between group.
Result and discussion: see Table 4.1. acarbose 5-MTHF compositions is to the influence of blood glucose: model group blood glucose significantly raises, and the acarbose list is with remarkable blood sugar lowering, and 5-MTHF singly uses has slight effect to blood glucose, and acarbose 5-MTHF compositions has remarkable blood sugar reducing function, is better than arbitrary single medicine.2. acarbose 5-MTHF compositions is to the influence of 24h urine protein: the model group urine protein significantly raises; acarbose group rat urine protein significantly descends; and 5-MTHF group rat urine protein has a declining tendency; acarbose 5-MTHF compositions urine protein decline effect is obvious; and effect is better than acarbose, and the protection that visible acarbose and 5-MTHF share renal function has significant synergism.3. acarbose 5-MTHF compositions is to the influence of vascular endothelial function: long-term hyperglycemia state easily causes vascular lesion, and early stage normal performance has vascular endothelial function to change, and plasma nitric oxide levels can reflect vascular endothelial function indirectly.In this experiment; model group blood plasma NO significantly reduces, and 5-MTHF group NO has slight rising, and prompting 5-MTHF self has certain protective role to endotheliocyte; acarbose 5-MTHF group NO significantly raises, and points out the blood vessel endothelium protective effect that has collaborative or addition between two medicines.
Table 4 acarbose 5-MTHF compositions is to the influence of blood glucose, 24h urine protein and blood plasma NO
Annotate: compare * P＜0.05, * * P＜0.01 with model control group; Compare with the acarbose group,
ΔP＜0.05.
Embodiment 11 vogliboses/5-MTHF/Vit B
6Compositions is to the protective effect of diabetic retinal tissue in rat
Method: the rat adaptability is raised the back and is surveyed fasting glucose and be lower than 10 of 7mmol/L person's picked at random as the normal control group, all the other rats streptozotocin (STZ, U.S. Sigma company product, 0.1mmol/L citrate buffer solution is made into 1% concentration, through the filtering with microporous membrane sterilization) bring out diabetes by the 30mg/kg lumbar injection, get tail blood after 72 hours and survey blood glucose, blood glucose value 〉=11.1mmoL/L is diabetes rat.Diabetes rat is divided into four groups at random, 14 every group: diabetes matched group, voglibose treatment group (0.03mg/kg), 5-MTHF+Vit B
6Treatment group (0.08+2mg/kg), voglibose+5-MTHF+Vit B
6Treatment group (0.03+0.08+2mg/kg).Every day gastric infusion.In the 12nd week behind the blood sugar increasing, get tail blood and survey blood glucose and glycosylated hemoglobin (HbAlc).Get 10 rats for every group, get the bilateral eyeball, place the ice normal saline, take out retinal tissue, precision balance is weighed, make 10% tissue homogenate under the ice bath, centrifugal 10 minutes of 3000r/min gets supernatant and carries out nitricoxide synthase (NOS) and aldose reductase (AR) determination of activity (it is that an enzyme activity unit is represented that NOS generates 1mmol NO with every milligram of histone per minute; The mensuration of AR activity ultraviolet determination method), protein determination Coomassie brilliant blue colorimetry.AR unit's enzymatic activity is that every mg homogenate albumen per minute consumes 1umolNADPH.The The above results that every group of 10 rat record is with means standard deviation
The t check is adopted in expression, statistical test method.
Result and discussion: see Table 5.
Table 5 voglibose/5-MTHF/Vit B
6Compositions to the protective effect of diabetic retina (
N=10)
Annotate: compare with model group,
*P＜0.01,
*P＜0.001; Compare with the voglibose group,
ΔP＜0.05
In the pathogenesis of diabetic renal papillary necrosis, the AR increased activity, NOS expresses enhancing.In this experiment, blood glucose in diabetic rats raises the 12nd week of back, and model group NOS and AR value all are significantly higher than the normal control group, shows that this diabetes rat suffered from early stage retinopathy.Voglibose group diabetes rat and 5-MTHF/Vit B
6The NOS of group diabetes rat and AR value and model group diabetes rat do not have significant difference, and voglibose/5-MTHF/Vit B
6No matter NOS and the AR value of group diabetes rat be to compare with model group, or compare with voglibose group rat, and significant significant difference is arranged, and shows voglibose/5-MTHF/Vit B
6Compositions has the effect of obvious synergistic prevention and treatment of DR.
Embodiment 12 miglitols/5-MTHF compositions is to blood vessel and the protection of ecs effect of diabetes rat
Method: Wistar rat (male, body weight 200-250g) high lipid food fed for 12 weeks.Fasting is 12 hours before the rat modeling, lumbar injection streptozotocin STZ (30mg/kg), adopt fasting blood behind the socket of the eye after 2 weeks, surveying blood glucose 〉=11.1mmoL/L is diabetes modeling success, and 52 diabetes rats are divided into 4 groups at random by blood glucose value, is respectively model control group, miglitol group (5mg/kg), 5-MTHF group (0.06mg/kg), miglitol+5-MTHF and organizes (5mg/kg+0.06mg/kg), every group 13, gastric infusion, every day 1 time, continuous 12 weeks; Other sets up 10 of rats in normal control group, feeds (model contrast and normal control rat are irritated the stomach distilled water every day) with normal diet.Each group of diabetes rat all continues to feed with the high heat feedstuff, experimental session animal drinking-water and feedstuff do not limit, test blood sampling when finishing in 12 weeks, survey blood glucose and press test kit description mensuration NO (nitrate reductase method), total nitric oxide synthetase (T-NOS) and total SOD vigor; Put the method for exempting from and measure thromboxane (TXB in the serum
2), prostaglandin (6-keto-PGFl α, be called for short PGFl α) and blood plasma ET.Data are represented with mean ± standard deviation, relatively more capable paired t-test between group.
Result and discussion: the results are shown in Table 6-1 and 6-2.
1. miglitol 5-MTHF compositions is to the influence of blood glucose: model group blood glucose significantly raises, and the miglitol list is with remarkable blood sugar lowering, and 5-MTHF singly uses has slight effect to blood glucose, and miglitol 5-MTHF compositions has remarkable blood sugar reducing function, is better than arbitrary single medicine.
2. miglitol 5-MTHF compositions is to the influence of NO, T-NOS, ET and NO/ET: with normal group relatively, model group blood plasma NO slightly reduces, serum T-NOS vigor has downward trend, ET content raises, and NO/ET ratio significantly reduces, and NO is respectively organized in administration all rising, the T-NOS energy value rises, ET content descends, and NO/ET ratio significantly increases, and with model group in various degree significant difference is arranged relatively.Wherein, compare with miglitol group or 5-MTHF group, miglitol 5-MTHF group NO, T-NOS raise more obvious, and NO/ET ratio increases also more remarkable, points out the blood vessel endothelium protective effect that has collaborative or addition between two medicines.
3. miglitol 5-MTHF compositions is to TXB
2, PGF1 α and both ratio influence: with normal group relatively, model group blood plasma TXB
2Significantly raise, PGFl α changes not obvious, TXB
2/ PGFl α ratio raises; Compare with model group, TXB is respectively organized in administration
2All have more obviously to descend, PGFl α amplitude of variation is little, TXB
2/ PGFl α ratio majority descends to some extent.Compare with miglitol group or 5-MTHF group, miglitol 5-MTHF organizes TXB
2It is more remarkable to descend, and points out two drug combinations to have the effect of collaborative treatment of vascular thromboembolism.
4. miglitol 5-MTHF compositions is to the influence of total SOD vigor in the serum: with normal group relatively, the total SOD vigor of model group serum significantly reduces, the SOD vigor is respectively organized in administration all to be had in various degree and rises.Wherein, compare with miglitol group or 5-MTHF group, miglitol 5-MTHF group SOD vigor raises more obvious, points out between two medicines to have collaborative vascular protection effect.
Table 6-1 miglitol 5-MTHF compositions is to the effect of rat blood sugar
Annotate: compare * P＜0.05, * * P＜0.01 with model group; Compare with the miglitol group,
ΔP＜0.05.
Table 6-2 miglitol 5-MTHF compositions is to the protective effect of rat aorta endothelium
Annotate: compare * P＜0.05, * * P＜0.01 with normal group; Compare with model group,
ΔP＜0.05,
The Δ ΔP＜0.01.
Table 6-3 miglitol 5-MTHF compositions is to the protective effect of rat aorta
Annotate: compare * P＜0.05, * * P＜0.01 with normal group; Compare with model group,
ΔP＜0.05,
The Δ ΔP＜0.01.
Diabetic angiopathy, especially microangiopathies are the pathologic basis of diabetes multiple complications, wherein vascular endothelial cell damage may be one of major reason, and nitric oxide/Endothelin (NO/ET) and thromboxane/prostaglandin are two groups of vaso-active substances, by vascular endothelial cell secretion, two groups of dynamic equilibrium plays an important role to the normal function of keeping endotheliocyte and to hemodynamics etc.The prompting of this result of study, compare with folk prescription, miglitol and 5-MTHF use in conjunction more are conducive to keep the homeostasis of NO/ET and thromboxane/prostaglandin, be conducive to assist to regulate microvascular easypro contracting, anticoagulant and thrombosis, therefore have the pharmacological action of control diabetic angiopathy.
Claims (12)
1. pharmaceutical composition, contain:
1) a kind of in the alpha-glucosidase inhibitor of pharmaceutical dosage, its active metabolite or its esters,
2) one or more in the vitamin B group of pharmaceutical dosage, and
3) pharmaceutically suitable carrier;
Wherein alpha-glucosidase inhibitor is selected from acarbose, voglibose and miglitol, and vitamin B group is selected from vitamin B
6, vitamin B
12With folic acid class material.
2. according to the compositions described in the claim 1, it is characterized in that: the content of described acarbose is 50mg～200mg, and the content of voglibose is 0.1mg～0.5mg, and the content of miglitol is 25mg～100mg.
3. according to the compositions described in the claim 1, it is characterized in that: described vitamin B
6Be selected from the derivant of pyridoxol, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., pyridoxamine, pyridoxin phosphate, pyridoxal 5-phosphate, phosphopyridoxamine and above-mentioned substance and metabolism and/or generate the material of this compounds, vitamin B in vivo
6Content be 1mg～50mg.
4. according to the compositions described in the claim 1, it is characterized in that: described vitamin B
12Be selected from the derivant of cobalamine, mecobalamin element, 5 '-deoxyadenosyl cobalamin, hydroxocobalamine, cyanocobalamin and above-mentioned substance and metabolism and/or generate the material of this compounds, vitamin B in vivo
12Content be 0.01mg～0.1mg.
5. according to the compositions described in the claim 1, it is characterized in that: described folic acid class material is selected from the active metabolite of 5-methyl tetrahydrofolate, formyl tetrahydrofolic acid, folinic acid, calcium levofolinate, folic acid, folic acid officinal salt, folic acid or folic acid officinal salt and metabolism and/or generate the material of folic acid in vivo, and the content of folic acid class material is 0.1mg～5mg.
6. compositions according to claim 5, it is characterized in that: described alpha-glucosidase inhibitor is acarbose, and described folic acid class material is 5-methyl tetrahydrofolate or folic acid, and its preferred dose is 0.2mg～1mg, is more preferably 0.4 or 0.8mg.
7. compositions according to claim 5, it is characterized in that: described alpha-glucosidase inhibitor is voglibose, described folic acid class material is 5-methyl tetrahydrofolate or folic acid, and its preferred dose is 0.2mg～1mg, is more preferably 0.4 or 0.8mg.
8. compositions according to claim 5, it is characterized in that: described alpha-glucosidase inhibitor is miglitol, and described folic acid class material is 5-methyl tetrahydrofolate or folic acid, and its preferred dose is 0.2mg～1mg, is more preferably 0.4 or 0.8mg.
The pharmacy dosage form of any one described compositions of claim 1 to 8 comprise conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, 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 etc.
10. the purposes of any one described compositions in the medicine of preparation treatment diabetes in the claim 1 to 8 is particularly useful for the diabetes with hyperhomocysteinemiainjury.
11. the purposes of any one described compositions in the medicine of preparation control diabetic angiopathy in the claim 1 to 8.
12. the described purposes of claim 11 is characterized in that: described diabetic angiopathy comprises atherosclerosis, coronary heart disease, cerebrovascular, lower limb gangrene, nephropathy and retinal microvascular pathological changes.
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| CN110327356A (en) * | 2019-08-12 | 2019-10-15 | 浙江养生堂天然药物研究所有限公司 | Combination product comprising limonoid and alpha-glucosidase inhibitor |
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