CN101103993B - Hypoglycemic medicine composition - Google Patents

Hypoglycemic medicine composition Download PDF

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CN101103993B
CN101103993B CN2006100990276A CN200610099027A CN101103993B CN 101103993 B CN101103993 B CN 101103993B CN 2006100990276 A CN2006100990276 A CN 2006100990276A CN 200610099027 A CN200610099027 A CN 200610099027A CN 101103993 B CN101103993 B CN 101103993B
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vitamin
diabetes
rosiglitazone
folic acid
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CN101103993A (en
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戴成祥
王文艳
李华
陈明侠
王燕
于多
陈光亮
徐希平
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Shenzhen Ausa Pharmed Co ltd
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HUA'ANFO MEDICINE RESEARCH CENTER Co Ltd BEIJING
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Abstract

The invention relates to a newly-developed medicine compound for diabetes which contains sulfonylureas drug for diabetes or a bioactive metabolite of the sulfonylureas drug for diabetes or pharmaceutical salt of the sulfonylureas drug for diabetes, and thiazolidinedione drug for diabetes or pharmaceutical salt and vitamin B of the thiazolidinedione drug for diabetes. The compound contains the sulfonylureas drug for diabetes of therapy dose or the bioactive metabolite of the sulfonylureas drug for diabetes or the pharmaceutical salt of the sulfonylureas drug for diabetes, the thiazolidinedione drug for diabetes of therapy dose or the pharmaceutical salt and therapy dose of vitamin B of the thiazolidinedione drug for diabetes or compound which is related to the thiazolidinedione drug for diabetes and has similar bioactivity and pharmaceutical carrier or excipient. The invention also relates to the purpose of the compound in preparation of drug for treating diabetes or preventing diabetes complication, belonging to the pharmaceutical field.

Description

Hypoglycemic medicine composition
Technical field
The present invention relates to a kind of pharmaceutical composition that contains sulfonylureas drugs for diabetes thing, thiazolidinediones hypoglycemic medicine and vitamin B group, and the purposes of said composition in the medicine of preparation treatment diabetes or prevent diabetes complication.The invention belongs to field of medicaments.
Background technology
Diabetes are metabolic diseases of a kind of multi-pathogenesis, are characterized in chronic hyperglycemia, follow because of insulin secretion and/or effect the defective sugar, fat and the protein metabolism disorder that cause.Diabetes are seriously spread unchecked at present, 2003, the whole world had 1.94 hundred million people to suffer from diabetes, and the age was not waited from 20 years old to 79 years old, may increase by 72% and reach 3.33 hundred million to this numeral in 2025, and about 80% case will be distributed in country in the poor industrial development.China is one of 3 maximum countries of diabetes total number of persons.Point out in the report on October 12nd, 2004 " Chinese residents nutrition and Health Situation " that Ministry of Public Health, the Department of Science and Technology and State Statistics Bureau announce: China 18 years old and above resident's diabetes prevalence are 2.6%, and the impaired fasting glucose (IFG) rate is 1.9%.Estimate the existing number of patients more than 2,000 ten thousand of national diabetes, other has nearly 2,000 ten thousand people's impaired fasting glucose (IFG).The city prevalence is compared with diabetes sampling survey data in 1996 apparently higher than the rural area, the big city more than 20 years old diabetes prevalence by 4.6% rise to 6.4%, small and medium-sized cities rise to 3.9% by 3.4%.Diabetes are still serious public health problem of China.
Diabetes can betide any age, along with the course of disease prolongs, the infringement of histopathologies such as easy concurrent whole body nerve, blood capillary and macroangiopathy, and can cause histoorgans such as the heart, brain, kidney, nerve and eye chronic, carry out the sexually transmitted disease (STD) change.The patient enters diabetes from glucose carbohydrate tolerance normal (NGT) through impaired glucose tolerance (IGT), often through the subclinical stage in one period of quite growing (reckoning is 7～11 years), then transfers the dominance clinical stage to.Owing to hyperglycemia does not over a long time have clinical symptoms, existing about half patient has chronic complicating diseases of diabetes in various degree to exist when treating clinical definite.It is generally acknowledged, though chronic complicating diseases of diabetes does not take place in IGT patient, but the phenomenon that has macroangiopathy and mortality of hypertension to increase, and in case enter the diabetes stage, trunk, blood capillary and neuropathy incidence rate can not reach ideal standard along with course of disease delay and blood glucose, blood fat control and develop rapidly [the auspiciousness star of Zhu. modern diabetology. Shanghai: the .2000 of publishing house of Fudan University in May 299-371 page or leaf].The harm of diabetes is mainly from the complication of diabetes.To 30 provinces of China, the city, (1 day to 2000 January in 1991, on December 31) are analyzed in autonomous region's inpatient chronic complicating diseases of diabetes end-decade review, find that the diabetic complication prevalence is respectively: hypertension 31.9%, cerebrovascular complication 12.2%, cardiovascular complication 15.9%, lower limb vascular complication 5.0%, ocular complications 34.3%, renal complication 33.6%, neuropathy 60.3%, total prevalence rate is the .1991-2000 of chronic complicating diseases investigation team of diabetes branch of 73.2%[Chinese Medical Association whole nation diabetics chronic complicating diseases and relevant macroangiopathy retrospective analysis in hospital. Chinese Academy of Medical Sciences's journal, 2002,24 (5): 447-451].
The prevalence of diabetes is ascendant trend year by year.Diabetes are a kind of non-infectious chronic diseases, need control all the life.Because the human at present cause of disease and the pathogenesis to diabetes fully do not understood, and still lacks etiotropic effective treatment means.Emphasize the principle of early treatment, long-term treatment and Comprehensive Treatment at present.The target of treatment is blood glucose to be reached or near normal level, corrects metabolism disorder, eliminates diabetic symptom, prevents or delays complication, keeps health, work and learning capacity, ensures upgrowth and development of children, and life-saving reduces case fatality rate.Concrete measure gives medicine (oral antidiabetic, insulin) treatment based on treatment and the suitable physical training of keeping on a diet according to the different state of an illness.Be type 2 diabetes mellitus more than 90% in the diabetic, 70%～85% patient need use oral hypoglycemic drug therapy at the initial stage of a disease, only has 15%～30% patient to add the standard that exercise therapy reaches Satisfactory Control with simple diet.In afterwards 1～3 year of the latter, also need add mostly with the orally-taken blood sugar reducing medicine just can make glycemic control satisfied [Li Chunlin. the oral hypoglycemic drug therapy of diabetes. the medical officer people, 2004,47 (9): 544-547].Therefore, the importance of orally-taken blood sugar reducing medicine in treating diabetes is self-evident.Clinical oral antidiabetic thing commonly used comprises sulfonylurea hypoglycemic agent, biguanides antidiabetic drug, alpha-glucosidase inhibitor, thiazolidinediones (glitazone) antidiabetic drug, non-sulfonylurea Drugs Promoting Insulin Secretion etc. at present.
Studies show that in recent years, (Homocysteine, Hcy) level is closely related for diabetes and blood plasma homocysteine.Study the high Hcy mass formed by blood stasis of report diabetes merging nephrotic first as far back as Japanese Ohtsuka in 1992 and can obviously descend, think that the high Hcy level of diabetes and blood plasma is relevant in the well back Hcy level of glycemic control.Afterwards, many researchs all confirm the diabetics person that particularly is associated with the chronic complicating diseases, and its Plasma Hcy obviously raises.People [Montalescot G such as Montalescot G, et al.Plasma homocysteine and the extent of atherosclerosis in patients with coronaryartery disease.Int J Cardiol.1997,60 (3): 295-300] level of discovering the total Hcy of type 2 diabetes mellitus patient blood plasma that merges macroangiopathy, free Hcy thinks that all apparently higher than no macroangiopathy group and normal healthy controls group Hcy also is the independent hazard factor of diabetictrunk angiopathy.People such as Stabler SP study [Stabler SP, et al.Totalhomocysteine is associated with nephropathy in non-insulin-dependent diabetesmellitus.Metabolism.1999,48 (9): 1096-1101] think that homocysteine is relevant with diabetic neuropathy.[Hofmann MA such as Hofmann MA, et al.Hyperhomocyst (e) inemia and endothelialdysfunction in IDDM.Diabetes Care.1997,20 (12): 1880-1886] got rid of smoking, fat, hypertension, hyperlipidemia, glycolated hemoglobin important risk factor such as (HbA1c), studied the relation of Hcy and microangiopathies, find to merge the diabetics urine protein (Alb) of high Hcy mass formed by blood stasis, thrombomodulin (thrombomodulin TM) is all than the normal diabetics height of Hcy, diabetic nephropathy (75% pair 33%), retinopathy (69% pair 51%), the sickness rate of neuropathy (57% pair 41%) significantly increases, and thinks that high Hcy mass formed by blood stasis may be the important risk factor of diabetic microvascular complication.Other research also draws same conclusion [Araki A, et al.Plasma homocysteine concentrationsin Japanese patients with non-insulin-dependent diabetes mellitus:effect of parenteral methylcobalamin treatment.Atherosclerosis.1993,103 (2): 149-157; Robillon J F, et al.Type 1 diabetes mellitus and homocyst (e) ine.Diabete Metab.1994 Sep-Oct, 20 (5): 494-496; Hultberg B, et al.Poor metabolic control, early ageatonset, and marginal folate deficiency are associated with increas2ing levels ofplasma homocysteine in insulin-dependent diabetesmellitus.A five-year follow-upstudy.Scand J Clin Lab Invest.1997,57 (7): 595-600].
In a word, high tHcy mass formed by blood stasis is not only the independent hazard factor of cardiovascular and cerebrovascular disease, also be present in the diabetics, attention is to the monitoring of diabetics tHcy level, take intervening measure prevention and reduce the level of Plasma Hcy, to postpone type 2 diabetes mellitus patient multiple complications particularly vascular lesion time of taking place, reduce complication the order of severity significant.
The sulfonylureas drugs for diabetes thing is a kind of Drugs Promoting Insulin Secretion, year surplus clinical practice existing 50.For the type 2 diabetes mellitus patient of the new diagnosis of great majority, the sulfonylureas drugs for diabetes thing can make fasting glucose decline 50～80mg/dl, makes glycolated hemoglobin (HbA1c) descend 1.0%～2.5%.Because type 2 diabetes mellitus patient's β cell function is decayed in time, the sulfonylureas drugs for diabetes thing reduces very effective to the diabetics blood glucose of new diagnosis clinically.If various sulfonylureas drugs for diabetes owners are by closing adenosine triphosphate sensitive potassium (K on the β cell membrane ATP) passage increases endogenous insulin secretion.Sulfonylureas drugs for diabetes thing and K ATPThe sulphur urea receptor 1 (SUR1) of passage is in conjunction with closing K +Passage makes the subregion depolarization on the cell membrane cause voltage-dependent L-type Ca 2+Channel opener, Ca 2+Enter in the cell Ca in the endochylema 2+Concentration raises, thereby stimulates insulin secretion.The sulfonylureas drugs for diabetes thing is just as a line medication of non-overweight or non-fat type 2 diabetes mellitus patient treatment.The sulfonylureas drugs for diabetes thing of extensive use comprises glibenclamide (Glibenclamide) clinically, glibornuride (Glibornuride), glycyclamide (Glycyclamide), glyhexamide (Glyhexamide), glisamuride (Glisamuride), Glisentide (Glisentide), glisolamide (Glisolamide), glyoctamide (Glyoctamide), gliclazide (Gliclazide), glipizide (Glipizide), gliquidone (Gliquidone) and glimepiride (Glimepiride).
The thiazolidinediones hypoglycemic medicine also claims euglycemic agent, comprise rosiglitazone (rosiglitazone), pioglitazone (pioglitazone, pioglitazone), troglitazone (troglitazone), englitazone (englitazone), ciglitazone (cightazone) etc.Such medicine is the part of nucleus peroxisome multiplicaiton factor activated receptor (PPAR-γ), can increase the ability that peripheral tissues removes glucose, reduce glycogen output, the glycogen picked-up when increasing glucose load, thereby effectively blood sugar lowering improves insulin sensitivity.The blood sugar reducing function of thiazolidinediones medicine is to realize by the effect that strengthens insulin, so be difficult for producing hypoglycemia.Such medicine can be used separately, also can share with the oral antidiabetic drug and the insulin of other types.
Vitamin B group comprises folic acid, vitamin B12 (cobalamin), vitamin B6 (pyridoxol), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (nicotinic acid), pantothenic acid and biotin, all is the indispensable micronutrient of health.For the research of vitamin B group, what receive much attention at present is folic acid, vitamin B12 and vitamin B6.Vitamin B group forms, keeps nervous system and function of immune system to have important function to metabolism, erythrocyte, the shortage of vitamin B group can cause many bad consequences, comprises muscle weakness, paralysis, confusion, nerve problems, gastricism, wrinkled skin and firecoat, serious anemia and heart damage.
Folic acid, vitamin B12, the vitamin B6 that body is taken in can not cause vitamin folic acid deficiency in the body completely, and vitamin B12, vitamin B6 are respectively the coenzyme of cystathionine beta synzyme and methionine synthase, folic acid is the indirect donor of methyl in the body, both shortages had both hindered the resynthesis of methionine, also cause simultaneously accumulating of Hcy, homocysteine in plasma raises, thereby causes the generation of homocysteine mass formed by blood stasis and cardiovascular related diseases, and serious threat is to the health of life entity; Exogenous an amount of Supplement of folic acid can reduce the Hcy in the blood plasma, and its effective dose is 0.4～5mg/day.One comprises 12 researchs, 1114 routine experimenters the analysis showed that, the blood plasma folic acid concentration is that 12nmol/L and Hcy level are under the prerequisite of 12 μ mol/L before the markization treatment, 0.5～5mg folic acid has similar reducing homosysteine effect, approximately can reduce by 1/5～1/3 (as 12 μ mol/L to 8～9 μ mol/L) [Homocysteine Lowering Trialists ' Collaboration.Lowering bloodhomocysteine with folic acid based supplements:meta-analysis of randomized trials.BMJ.1998,316:894-898].John P Forman[Forman JP, et al.Folate intake and the riskof incident hypertension among US women.JAMA.2005 Jan 19,293 (3): 320-329] Bao Dao data is observed 93803 young woman and 62260 elderly womans altogether, in 2 years questionnaires once, having the report of 7373 young woman (NHSII) and 12347 elderly womans (NHSI) has hypertension (by clinician's diagnosis), takes the photograph the hypertension dangerous low 46% that folic acid 〉=1000 μ g/ days person's ratio is taken the photograph folic acid＜200 μ g/ days persons among the young woman; Elderly woman, the homofolic acid amount of taking the photograph person's hypertension danger is lower than the amount of taking the photograph person 18%, and the folic acid amount of taking the photograph＞1000 μ g/ days person's hypertension danger is lower than the suggestion 400 μ g/ days persons 40% that take the photograph the quantity not sufficient current American.There are some researches show, low-level folic acid and VB6 promote development of atherosclerosis [Robinson K, et al.Low circulating folate and vitamin B6 concentrations:riskfactors for stroke, peripheral vascular disease, and coronary artery disease:uropeanCOMAC Group.Circulation.1998,97:437-443].
Sulfonylureas drugs for diabetes thing and thiazolidinediones hypoglycemic medicine share the type 2 diabetes mellitus good effect, U.S. FDA has been ratified novel compound product A vandaryl (rosiglitazone maleate/glimepiride) list marketing of GlaxoSmithKline PLC company (GSK), be used for the treatment of type 2 diabetes mellitus, this compound product obviously is better than single with sulphanylureas group and placebo group, and also fine to old-aged diabetic's curative effect and safety.In addition, the document of two class drug combinations and patent report are also a lot: for the type 2 diabetes mellitus patient who suffers from metabolism syndrome, thiazolidinediones and glimepiride therapeutic alliance can obviously improve long-term controlling of blood pressure, reduce insulin resistant [Derosa G, et al.Thiazolidinedione effects on blood pressure in diabeticpatients with metabolic syndrome treated with glimepiride.Hypertens Res.2005,28 (11): 917-924]; Glimepiride and pioglitazone use in conjunction can significantly be improved the most of metabolic index of metabolism syndrome patient of type 2 diabetes mellitus: blood pressure, triglyceride and LDL-C all have obvious reduction under fasting glucose, the early morning quiescent condition, HDL-C obviously raises, waistline and Body Mass Index have reduction trend [Tian Jinglun etc. glimepiride and pioglitazone therapeutic alliance metabolism syndrome merge the type 2 diabetes mellitus clinical observation. practical hospital clinical magazine, 2005,2 (4): 33-34]; Rosiglitazone and gliclazide are united use and are more singly used gliclazide blood sugar control better, reduce glycolated hemoglobin (HbA 1C), TG, do not increase simultaneously fasting insulin (FIN) level [Gu Qin etc. the clinical efficacy of rosiglitazone and gliclazide therapeutic alliance type 2 diabetes mellitus. Chinese clinical pharmacy magazine, 2003,12 (3): 144-146]; Every day, 1 time Avandia and gliclazide use in conjunction had good tolerability, and Avandia can reduce the opposing of insulin, so Avandia can be worked in coordination with gliclazide blood sugar control effectively, find no untoward reaction such as liver function injury, have good safety [Sun Xiaohui. the 38 routine clinical observations of rosiglitazone and gliclazide use in conjunction treatment type 2 diabetes mellitus. Central China medical journal, 2004,28 (2): 129]; In addition, the compositions of open rosiglitazone and glimepiride among the patent CN200410022514.3, the two has synergism to hyperglycemia; The compositions that discloses sulfonylureas drugs for diabetes thing and thiazolidinediones hypoglycemic medicine and biguanide antidiabetic medicament among the patent CN98807319.6 is used for the treatment of diabetes; Or the like.
Yet share of sulfonylureas drugs for diabetes thing and thiazolidinediones hypoglycemic medicine can not alleviate the harm that Hcy brings diabetics.In clinical practice or the scientific research document of having delivered, we still do not find the research report of sulfonylureas drugs for diabetes thing, thiazolidinediones hypoglycemic medicine and three kinds of medication combined application of vitamin B group.We find through a large amount of experimental studies, sulfonylureas drugs for diabetes thing, thiazolidinediones hypoglycemic medicine and three kinds of medication combined application of vitamin B group are blood sugar control effectively, alleviate insulin resistant, alleviating the diabetics homocysteine in plasma that diabetics particularly is associated with chronic complicating diseases raises, and can work in coordination with or the generation of the minimizing chronic complicating diseases of diabetes of addition the protection inner skin cell function; Simultaneously also can alleviate patient economy burden, improve the compliance of patient treatment, thus the quality of life of further improving diabetics.
Summary of the invention
The object of the present invention is to provide the pharmaceutical composition of a kind of effective treatment diabetes or prevent diabetes complication; said composition is blood sugar lowering effectively; prevent that diabetics particularly is associated with the diabetics homocysteine in plasma rising of chronic complicating diseases; reduce the incidence rate of chronic complicating diseases of diabetes; protect inner skin cell function, have the effect of effective treatment diabetes or prevent diabetes chronic complicating diseases.
Pharmaceutical composition provided by the invention contain a kind of or this thiazolidinediones hypoglycemic medicine in the thiazolidinediones hypoglycemic medicine of officinal salt, pharmaceutical dosage of the active metabolite of a kind of or this sulfonylureas drugs for diabetes thing in the sulfonylureas drugs for diabetes thing of pharmaceutical dosage or this sulfonylureas drugs for diabetes thing officinal salt, pharmaceutical dosage vitamin B group or relatively have similar bioactive chemical compound, and pharmaceutically suitable carrier or excipient.
Sulfonylureas drugs for diabetes thing in the pharmaceutical composition provided by the invention is selected from glibenclamide, glibornuride, glycyclamide, glyhexamide, glimepiride, glypinamide, glisamuride, Glisentide, glisolamide, glyoctamide, gliclazide, glipizide and gliquidone, preferred glibenclamide, glimepiride, gliclazide, gliquidone or glipizide are more preferably glimepiride.
Thiazolidinediones hypoglycemic medicine in the pharmaceutical composition provided by the invention is selected from rosiglitazone (rosiglitazone), pioglitazone (pioglitazone, pioglitazone), troglitazone (troglitazone), englitazone (englitazone), ciglitazone (cightazone) etc., preferred rosiglitazone or pioglitazone.
The officinal salt of the thiazolidinediones hypoglycemic medicine in the pharmaceutical composition provided by the invention includes but not limited to rosiglitazone maleate, Tartraric rosiglitazone, Rosiglitazone sodium, Luogelie ketone hydrochloride, pioglitazone hydrochloride etc., preferred rosiglitazone maleate or pioglitazone hydrochloride.
Vitamin B group in the pharmaceutical composition provided by the invention is selected from folic acid, vitamin B12 (cobalamin), vitamin B6 (pyridoxol), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (nicotinic acid), pantothenic acid and biotin, preferred folic acid, vitamin B12 or vitamin B6 are more preferably folic acid.
In the present invention, relevant with vitamin B group have similar bioactive chemical compound and be meant the different subunit substituents of vitamin B group salt, vitamin B group or material with bioequivalence of metabolism or generation and vitamin B group in vivo, above-mentioned substance has similar biological activity to vitamin B group, but has the different existence or the form of expression with vitamin B group.Wherein, relevant with folic acid have a similar bioactive chemical compound, as the active metabolite of formyl tetrahydrofolic acid, methyl tetrahydrofolate, methylene tetrahydrofolate, folate, folic acid or folate and metabolism and/or generate the material etc. of folic acid in vivo; Relevant with vitamin B12 have a similar bioactive chemical compound, as the derivant of cobalamine, mecobalamin element, 5 '-deoxyadenosyl cobalamin, hydroxocobalamine and above-mentioned substance and metabolism and/or generate the material of this compounds in vivo; Relevant with vitamin B6 have a similar bioactive chemical compound, as the derivant of 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 in vivo.
Will be appreciated that; above-mentioned explanation is not a limitation of the present invention; everyly comprise glibenclamide with the sulfonylureas drugs for diabetes thing; glibornuride; glycyclamide; glyhexamide; glimepiride; glypinamide; glisamuride; Glisentide; glisolamide; glyoctamide; gliclazide; glipizide and gliquidone; or be that the chemical compound of active component is a constituent with the sulfonylureas drugs for diabetes thing; comprise rosiglitazone with the thiazolidinediones hypoglycemic medicine; pioglitazone; troglitazone; englitazone; or ciglitazone etc.; or be that the chemical compound of active component is another constituent with the thiazolidinediones hypoglycemic medicine; with vitamin B group or relative to have similar bioactive chemical compound be the 3rd pharmaceutical composition that constituent was constituted, all be the scope of protection of the invention.
In the pharmaceutical composition provided by the invention, the preferred glimepiride of sulfonylureas drugs for diabetes thing, glibenclamide, gliclazide, gliquidone or glipizide, wherein the content of above-mentioned substance when existing is respectively: glimepiride 1mg～4mg, glibenclamide 1mg～15mg, gliclazide 20mg～160mg, gliquidone 15mg～60mg, glipizide 1mg～15mg; Thiazolidinediones hypoglycemic medicine or the preferred rosiglitazone of its officinal salt, pioglitazone, rosiglitazone maleate or pioglitazone hydrochloride, wherein the content of above-mentioned substance when existing is respectively: rosiglitazone 1mg～8mg, pioglitazone 7.5mg～45mg, the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg; The preferred folic acid of vitamin B group, vitamin B12 or vitamin B6, wherein the content of above-mentioned substance when existing is respectively: folic acid 0.1mg～7.5mg, vitamin B12 0.005mg～2mg, vitamin B6 2mg～75mg.
More precisely, the preferred glimepiride of pharmaceutical composition provided by the invention, the combination of rosiglitazone and folic acid, glimepiride, the combination of pioglitazone and folic acid, glibenclamide, the combination of rosiglitazone and folic acid, glibenclamide, the combination of pioglitazone and folic acid, gliclazide, the combination of rosiglitazone and folic acid, gliclazide, the combination of pioglitazone and folic acid, gliquidone, the combination of rosiglitazone and folic acid, gliquidone, the combination of pioglitazone and folic acid, glipizide, the combination of rosiglitazone and folic acid, glipizide, a kind of in the combination of pioglitazone and folic acid.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a folic acid.In said composition, the content of glimepiride is 1mg～4mg, and the content of rosiglitazone is 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a folic acid.In said composition, the content of glimepiride is 1mg～4mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a folic acid.In said composition, the content of glimepiride is 1mg～4mg, and the content of pioglitazone is 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a folic acid.In said composition, the content of glimepiride is 1mg～4mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a vitamin B12.In said composition, the content of glimepiride is 1mg～4mg, and the content of rosiglitazone is 1mg～8mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a vitamin B12.In said composition, the content of glimepiride is 1mg～4mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a vitamin B12.In said composition, the content of glimepiride is 1mg～4mg, and the content of pioglitazone is 7.5mg～45mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a vitamin B12.In said composition, the content of glimepiride is 1mg～4mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a vitamin B6.In said composition, the content of glimepiride is 1mg～4mg, and the content of rosiglitazone is 1mg～8mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a vitamin B6.In said composition, the content of glimepiride is 1mg～4mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a vitamin B6.In said composition, the content of glimepiride is 1mg～4mg, and the content of pioglitazone is 7.5mg～45mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a vitamin B6.In said composition, the content of glimepiride is 1mg～4mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a folic acid.In said composition, the content of glibenclamide is 1mg～15mg, and the content of rosiglitazone is 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a folic acid.In said composition, the content of glibenclamide is 1mg～15mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a folic acid.In said composition, the content of glibenclamide is 1mg～15mg, and the content of pioglitazone is 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a folic acid.In said composition, the content of glibenclamide is 1mg～15mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a vitamin B12.In said composition, the content of glibenclamide is 1mg～15mg, and the content of rosiglitazone is 1mg～8mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a vitamin B12.In said composition, the content of glibenclamide is 1mg～15mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a vitamin B12.In said composition, the content of glibenclamide is 1mg～15mg, and the content of pioglitazone is 7.5mg～45mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a vitamin B12.In said composition, the content of glibenclamide is 1mg～15mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a vitamin B6.In said composition, the content of glibenclamide is 1mg～15mg, and the content of rosiglitazone is 1mg～8mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a vitamin B6.In said composition, the content of glibenclamide is 1mg～15mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a vitamin B6.In said composition, the content of glibenclamide is 1mg～15mg, and the content of pioglitazone is 7.5mg～45mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a vitamin B6.In said composition, the content of glibenclamide is 1mg～15mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a folic acid.In said composition, the content of gliclazide is 20mg～160mg, and the content of rosiglitazone is 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a folic acid.In said composition, the content of gliclazide is 20mg～160mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a folic acid.In said composition, the content of gliclazide is 20mg～160mg, and the content of pioglitazone is 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a folic acid.In said composition, the content of gliclazide is 20mg～160mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a vitamin B12.In said composition, the content of gliclazide is 20mg～160mg, and the content of rosiglitazone is 1mg～8mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a vitamin B12.In said composition, the content of gliclazide is 20mg～160mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a vitamin B12.In said composition, the content of gliclazide is 20mg～160mg, and the content of pioglitazone is 7.5mg～45mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a vitamin B12.In said composition, the content of gliclazide is 20mg～160mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a vitamin B6.In said composition, the content of gliclazide is 20mg～160mg, and the content of rosiglitazone is 1mg～8mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a vitamin B6.In said composition, the content of gliclazide is 20mg～160mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a vitamin B6.In said composition, the content of gliclazide is 20mg～160mg, and the content of pioglitazone is 7.5mg～45mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a vitamin B6.In said composition, the content of gliclazide is 20mg～160mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a folic acid.In said composition, the content of gliquidone is 15mg～60mg, and the content of rosiglitazone is 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a folic acid.In said composition, the content of gliquidone is 15mg～60mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a folic acid.In said composition, the content of gliquidone is 15mg～60mg, and the content of pioglitazone is 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a folic acid.In said composition, the content of gliquidone is 15mg～60mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a vitamin B12.In said composition, the content of gliquidone is 15mg～60mg, and the content of rosiglitazone is 1mg～8mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a vitamin B12.In said composition, the content of gliquidone is 15mg～60mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a vitamin B12.In said composition, the content of gliquidone is 15mg～60mg, and the content of pioglitazone is 7.5mg～45mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a vitamin B12.In said composition, the content of gliquidone is 15mg～60mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a vitamin B6.In said composition, the content of gliquidone is 15mg～60mg, and the content of rosiglitazone is 1mg～8mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a vitamin B6.In said composition, the content of gliquidone is 15mg～60mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a vitamin B6.In said composition, the content of gliquidone is 15mg～60mg, and the content of pioglitazone is 7.5mg～45mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a vitamin B6.In said composition, the content of gliquidone is 15mg～60mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a folic acid.In said composition, the content of glipizide is 1mg～15mg, and the content of rosiglitazone is 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a folic acid.In said composition, the content of glipizide is 1mg～15mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a folic acid.In said composition, the content of glipizide is 1mg～15mg, and the content of pioglitazone is 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a folic acid.In said composition, the content of glipizide is 1mg～15mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a vitamin B12.In said composition, the content of glipizide is 1mg～15mg, and the content of rosiglitazone is 1mg～8mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a vitamin B12.In said composition, the content of glipizide is 1mg～15mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a vitamin B12.In said composition, the content of glipizide is 1mg～15mg, and the content of pioglitazone is 7.5mg～45mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a vitamin B12.In said composition, the content of glipizide is 1mg～15mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of vitamin B12 is 0.005mg～2mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a vitamin B6.In said composition, the content of glipizide is 1mg～15mg, and the content of rosiglitazone is 1mg～8mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a vitamin B6.In said composition, the content of glipizide is 1mg～15mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a vitamin B6.In said composition, the content of glipizide is 1mg～15mg, and the content of pioglitazone is 7.5mg～45mg, and the content of vitamin B6 is 2mg～75mg.
In the pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a vitamin B6.In said composition, the content of glipizide is 1mg～15mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of vitamin B6 is 2mg～75mg.
According to the present invention, pharmaceutical composition comprises three solvents, one of them component comes from a kind of medicine or the active metabolite of this sulfonylureas drugs for diabetes thing or the officinal salt of this sulfonylureas drugs for diabetes thing in the sulfonylureas drugs for diabetes thing, component comes from a kind of medicine in the thiazolidinediones hypoglycemic medicine or the officinal salt of this thiazolidinediones hypoglycemic medicine, and another component comes from a kind of or a kind of relevant with vitamin B group in the vitamin B group and has similar bioactive chemical compound.This pharmaceutical composition can be made and comprise the pharmaceutically any dosage form of acceptable, for example will contain the active metabolite of sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing or the officinal salt of this sulfonylureas drugs for diabetes thing, the officinal salt of thiazolidinediones hypoglycemic medicine or this thiazolidinediones hypoglycemic medicine and vitamin B group or relatively have similar bioactive compound compositions and make 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 etc.What should particularly point out is, the officinal salt that will contain the officinal salt of the active metabolite of sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing, contains thiazolidinediones hypoglycemic medicine or this thiazolidinediones hypoglycemic medicine simultaneously and vitamin B group or relatively have similar bioactive compound compositions and make tablet or capsule.
In the present invention, term " pharmaceutical dosage " is the Essential Terms of this area, be meant with the treatment of diseases to be the dosage of the medicine that uses of purpose, as disclosed general knowledge, the pharmaceutical dosage of sulfonylureas drugs for diabetes thing and thiazolidinediones hypoglycemic medicine is a prior art, every kind of drug dose can be with reference to " new pharmacology ", " newly organized hospital medicine complete works ", " clinical application guide ", " the two-way guide of clinical application ", " clinical practice new drug handbook, " new drug clinical practice handbook and " newly organized clinical application handbook etc.
In the present invention, term " pharmaceutically suitable carrier or excipient " is meant known in the art and can serves as those materials of filler or support material in tablet, pill, capsule etc.Usually these materials are to obtain the approval of sanitary administration mechanism to be used for this purpose, and they are non-activities as pharmaceutical agents." pharmaceutical excipient handbook (A.Wade and P.J.Weller chief editor, second edition, American Pharmaceutical Association, Washington and pharmacy publishing house, london publishing, 1994) has been edited pharmaceutically suitable carrier and excipient.Particularly, lactose, starch, cellulose derivative or the like, and their mixture can be used as the carrier of present composition active component.
In the present invention, pharmaceutically suitable carrier or excipient can be made into common oral preparation, comprise conventional tablet, conventional capsule, granule etc., described pharmaceutically suitable carrier includes excipient and the adjuvant that helps reactive compound is mixed with pharmaceutical formulation when making tablet, as microcrystalline Cellulose, inorganic salts, lactose, sodium chloride, citric acid, sodium sulfite, starch, cellulose derivative, pregelatinized Starch, carboxymethyl starch sodium, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl fecula sodium, crospolyvinylpyrrolidone, sucrose, dextrin, Icing Sugar, the compositions of one or more materials of glucose etc. belongs to this area general knowledge.
In the present invention, pharmaceutically suitable carrier or excipient can be made into slow releasing preparation, comprise excipient and adjuvant etc.Described excipient and adjuvant have comprised that the adjuvant of slow releasing function is that the solubility/insoluble salt of hydroxypropyl methylcellulose and/or ethyl cellulose and/or polyacrylic resin class and/or polycarboxy ethene and/or alginic acid and/or ethyl cellulose and/or other play the adjuvant of slow releasing function, hypromellose adopts the extensive stock that includes hydroxypropyl methylcellulose (HPMC), ethyl cellulose adopts the extensive stock that includes ethyl cellulose (EC), and polyacrylic resin adopts and includes polyacrylic resin II, the acrylic resin of III class or analog such as all size (Eudragit).Above-mentioned adjuvant is porogen, binding agent, lubricant, emulsifying agent, membrane material, foaming agent, bleach activator, solvent or other adjuvants, and porogen can adopt sucrose, mannitol, starch, Pulvis Talci, silicon dioxide etc.; Binding agent can adopt ethanol-water solution; Lubricant can adopt stearic acid, magnesium stearate, Pulvis Talci, starch, paraffin etc.; Solubilizing agent can be adopted tartaric acid, citric acid etc.; Emulsifying agent can adopt span80 span85 etc.; Membrane material can adopt polyvinyl alcohol, hydroxyl methylcellulose, hyetellose, hymetellose, methylcellulose etc.; Foaming agent can adopt basic magnesium carbonate, sodium bicarbonate etc.; Bleach activator can adopt hexadecanol, octadecanol, Cera Flava etc.; Solvent can adopt dehydrated alcohol, ethanol, water etc.
In the present invention, pharmaceutically suitable carrier or excipient can be made into controlled release preparation, comprise that active medicine has reached the adjuvant of controlled release effect.The above-mentioned adjuvant that plays the controlled release effect is polyoxyethylene and/or hypromellose and/or ethyl cellulose and/or sodium chloride and/or lactose and/or mannitol and/or fructose and/or glucose and/or sucrose or low-substituted hydroxypropyl cellulose and/or cross-linking sodium carboxymethyl cellulose and/or crospolyvinylpyrrolidone and/or cellulose acetate.Above-mentioned adjuvant is pharmaceutical carrier, expanding material, permeation-promoter, solubilizing agent, binding agent, wetting agent, lubricant, coloring agent, porogen, membrane material, antiplastering aid, plasticizer, lucifuge agent, solvent.Pharmaceutical carrier, expanding material can adopt polyoxyethylene, hypromellose, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, Glyceryl Behenate class etc.; Permeation-promoter can adopt sodium chloride, lactose, mannitol etc.; Solubilizing agent can be adopted sodium lauryl sulphate or poloxamer etc.; Binding agent can adopt polyvinylpyrrolidone, hypromellose, chitosan, sodium alginate, methylcellulose, ethyl cellulose, starch slurry, arabic gum, gelatin, sucrose, polyvinyl alcohol etc.; Wetting agent can adopt the ethanol-water solution of dehydrated alcohol, water, various concentration; Lubricant can adopt stearic acid, magnesium stearate, Pulvis Talci, starch, paraffin etc.; Coloring agent can adopt natural pigment such as carmine, amaranth, lemon yellow, bright orchid, indigo, brownish red ferrum oxide and synthetic dyestuff or the like; Porogen can adopt sucrose, mannitol, Polyethylene Glycol, titanium dioxide, Pulvis Talci, silicon dioxide etc.; Membrane material can adopt cellulose acetate, ethyl cellulose, hydroxypropyl emthylcellulose acetic acid succinate, cellulose acetate-phthalate, poly-phthalic acid vinyl acetate cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose etc.; Solvent can adopt acetone, dehydrated alcohol, ethanol, water etc.
In the present invention, pharmaceutically suitable carrier or excipient can be made into sublingual lozenge, oral cavity quick disintegrating slice or dispersible tablet etc.; Comprise excipient and adjuvant etc.Described excipient and adjuvant are by mannitol, xylitol, low substituted hydroxy-propyl methylcellulose, microcrystalline Cellulose, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, processing agar, cyclodextrin, glycyrrhizic acid, stevioside, citric acid, Oleum menthae, eucalyptus oil, Oleum Caryophylli, Fructus Citri Limoniae oil, citrus seed oil and some other correctives that wraps up with microcapsule etc.
In the present invention; pharmaceutically suitable carrier or excipient can be made into enteric coatel tablets or enteric coated capsule etc.; comprise excipient and adjuvant etc.; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc.; enteric-coating material comprises: Lac; the cellulose acetate phthalate ester; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose, and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen various medicaments adjuvants such as (as PEG6000).
In the present invention; pharmaceutically suitable carrier or excipient can be made into delayed-release tablet or timing (position) releasing piece; comprise excipient and adjuvant; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., described coating material that postpones release or regularly (position) release comprises: Lac; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; the polyvinyl acetate phthalic acid ester; and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen (as PEG1000; PEG4000; various medicaments adjuvant such as PEG6000).
In the present invention; pharmaceutically suitable carrier or excipient can be made into slow releasing capsule; controlled release capsule; the capsule that contains micropill or small pieces; contain the pH dependent form capsule of micropill or small pieces etc.; comprise excipient and adjuvant; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., coating material comprises: Lac; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; the polyvinyl acetate phthalic acid ester; and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen various medicaments adjuvants such as (as PEG6000).
In the present invention, pharmaceutically suitable carrier or excipient can be made into dosage forms such as oral liquid, membrane, patch.Described pharmaceutically acceptable carrier includes excipient and the adjuvant that helps reactive compound is mixed with pharmaceutical formulation when making the patch membrane; give a tongue-lashing pyrrolidone, polyacrylamide, polybutene class pressure sensitive adhesive, crylic acid resin pressure sensitive adhesive, silicone pressure sensitive adhesive etc. as polyvinyl alcohol, Triafol T, ethylene-acetate ethylene copolymer, polyethylene; and back lining materials such as polrvinyl chloride, polyethylene, aluminium foil, polypropylene, polyester, the compositions of one or more materials of protecting film such as polyethylene, polystyrene, polypropylene etc.
According to the present invention, the officinal salt of the officinal salt of the active metabolite of sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing, thiazolidinediones hypoglycemic medicine or this thiazolidinediones hypoglycemic medicine and vitamin B group or relatively have three constituents of similar bioactive chemical compound and also can make preparation respectively in the pharmaceutical composition are made the packaged in combination form administration; Or the packaged in combination form of preparation and the 3rd preparation that constituent is made is made in any two constituents.
Chemical compound in the pharmaceutical composition provided by the invention can be granted diseased individuals simultaneously with identical dosage form, also grants diseased individuals discriminably in succession.If grant diseased individuals in succession, then the delay of granting of latter two (or additional) active component should not cause 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.The vitamin B group of the officinal salt of a kind of or this thiazolidinediones hypoglycemic medicine in the thiazolidinediones hypoglycemic medicine of the officinal salt of the active metabolite of a kind of or this sulfonylureas drugs for diabetes thing in the sulfonylureas drugs for diabetes thing of preferred described pharmaceutical dosage or this sulfonylureas drugs for diabetes thing, pharmaceutical dosage, pharmaceutical dosage or relatively have a compound tablet that similar bioactive chemical compound is formed in the present invention.
Chemical compound in the pharmaceutical composition provided by the invention can be granted diseased individuals simultaneously with dosage form inequality, also grants diseased individuals discriminably in succession.If grant diseased individuals in succession, then the delay of granting of latter two (or additional) active component should not cause active component to unite the loss of the beneficial effect that brings.If grant diseased individuals simultaneously, the chemical compound in the compositions independently exists with different dosage forms, and pharmaceutical composition also 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.
In experimentation, we are surprised to find, and with the vitamin B group of the officinal salt of the thiazolidinediones hypoglycemic medicine of the officinal salt of the active metabolite of the sulfonylureas drugs for diabetes thing of above-mentioned pharmaceutical dosage or this sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing, pharmaceutical dosage or this thiazolidinediones hypoglycemic medicine and pharmaceutical dosage or the relative pharmaceutical composition that to have similar bioactive chemical compound be component treatment diabetes or prevent diabetes complication are had significant effect.
One of component in the pharmaceutical composition provided by the invention is the sulfonylureas drugs for diabetes thing.For the type 2 diabetes mellitus patient of the new diagnosis of great majority, the sulfonylureas drugs for diabetes thing can make fasting glucose decline 50～80mg/dl, makes glycolated hemoglobin (HbA1c) descend 1.0%～2.5%.Because type 2 diabetes mellitus patient's β cell function is decayed in time, the sulfonylureas drugs for diabetes thing reduces very effective to the diabetics blood glucose of new diagnosis clinically.If various sulfonylureas drugs for diabetes owners are by closing adenosine triphosphate sensitive potassium (K on the β cell membrane ATP) passage increases endogenous insulin secretion.Sulfonylureas drugs for diabetes thing and K ATPThe sulphur urea receptor 1 (SUR1) of passage is in conjunction with closing K +Passage makes the subregion depolarization on the cell membrane cause voltage-dependent L-type Ca 2+Channel opener, Ca 2+Enter in the cell Ca in the endochylema 2+Concentration raises, thereby stimulates insulin secretion.The sulfonylureas drugs for diabetes thing is just as a line medication of non-overweight or non-fat type 2 diabetes mellitus patient treatment.Two of component in the pharmaceutical composition provided by the invention is thiazolidinediones hypoglycemic medicines, is used for the treatment of type 2 diabetes mellitus clinically.Such medicine also claims euglycemic agent, is the part of nucleus peroxisome multiplicaiton factor activated receptor (PPAR-γ), can increase the ability that peripheral tissues removes glucose, reduce glycogen output, glycogen picked-up when increasing glucose load, thus effective blood sugar lowering improves insulin sensitivity.The blood sugar reducing function of thiazolidinediones medicine is to realize by the effect that strengthens insulin, so this medicine of use can not blood sugar lowering separately when insulin deficit.Three of component in the pharmaceutical composition provided by the invention is a kind of in the vitamin B group, vitamin B group is the nutrient of needed by human, form, keep nervous system and function of immune system to have important function to life entity metabolism, erythrocyte, what is more important has the reduction effect to homocysteine.
In clinical practice or the document delivered, we still do not find the active metabolite of sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing officinal salt, thiazolidinediones hypoglycemic medicine or this thiazolidinediones hypoglycemic medicine officinal salt and vitamin B group or relatively have a report that three kinds of component use in conjunction of similar bioactive chemical compound are used for the treatment of diabetes or prevent diabetes complication.In experimentation, we are surprised to find, sulfonylureas drugs for diabetes thing or the active metabolite of this sulfonylureas drugs for diabetes thing or the officinal salt of this sulfonylureas drugs for diabetes thing with pharmaceutical dosage, the vitamin B group of the thiazolidinediones hypoglycemic medicine of pharmaceutical dosage or the officinal salt of this thiazolidinediones hypoglycemic medicine and pharmaceutical dosage or the relative pharmaceutical composition that to have similar bioactive chemical compound be active component can obviously reduce type 2 diabetes mellitus patient's blood glucose, vitamin levels such as folic acid and B12 in the while added body, effectively improve type 2 diabetes mellitus patients with insulin resistance state and Plasma Homocysteine, and the only application of three prescriptions all can not reach the effect of these three kinds of material use in conjunction.Result of the test shows; the officinal salt of the active metabolite of sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing; the officinal salt of thiazolidinediones hypoglycemic medicine or this thiazolidinediones hypoglycemic medicine and vitamin B group or relatively have three kinds of material use in conjunction of similar bioactive chemical compound except that effective control of diabetes patient blood glucose; but coordinating protection inner skin cell function; and can reduce the generation of chronic complicating diseases of diabetes; be better than arbitrary medicine list and use or any two drug combinations effect (seeing embodiment) with effective treatment diabetes or prevent diabetes complication.
The function of endotheliocyte be endowed special clinical meaning be because: (1) endotheliocyte participates in each phase that atherosclerosis forms; (2) risk factor of many typical risk factors and atypical cardiovascular disease is relevant with the endothelial function imbalance; (3) the endothelial function imbalance takes place before large artery trunks is atherosis, and can indicate atherosclerotic generation.The generation of endothelial cell damage and hypertension, diabetes, the development closely related; There is the scholar to classify hypertension, coronary heart disease, cerebral infarction (cerebral arteriosclerosis), diabetes etc. as " vascular endotheliocyte disfunction type disease ", though think that clinical change, pathogeny, pathological change and the Therapeutic Method of these four kinds of diseases are not quite similar, but all there is the vascular endothelial cell obstacle, mainly shows as serum NO level and lower.Pharmaceutical composition provided by the invention can be worked in coordination with and be improved inner skin cell function; reduce the generation of complication; better protection patient target organ; said composition also can alleviate patient economy burden simultaneously; improve the compliance of patient, thereby the deep exploitation of said composition is had great social significance and economic worth treatment.
According to the present invention, in the Its Mechanisms of said composition to treatment diabetes or prevent diabetes complication, we find: pharmaceutical composition medicinal effects provided by the invention is not to be the simple addition of constituent drug effect, brings into play drug effect but interaction by three active components and life entity changes original useful effect.Its mechanism of action it be unclear that, may with can better bring into play antioxidation after the three share, to act on mechanism such as different links of inner skin cell function relevant.The purposes of disclosed pharmaceutical composition is the medicine that is used to prepare treatment diabetes or prevent diabetes complication among the present invention.
In the present invention, described diabetes are meant one group because defect of insulin secretion and/or its biological action obstacle cause is the metabolic disease of feature with the hyperglycemia, comprise insulin dependent diabetes mellitus (IDDM) (IDDM, 1 type), non-insulin-dependent diabetes mellitus (NIDDM, 2 types), dystrophic diabetes (MRDM, 3 types), secondary diabetes, impaired glucose tolerance (IGT) and gestational diabetes (GDM), refer to type 2 diabetes mellitus especially.
In the present invention, described diabetic complication comprises chronic complicating diseases and acute complications, refers to chronic complicating diseases especially; Described chronic complicating diseases comprises diabetes cardiovascular complication, diabetic nephropathy, diabetic neuropathy, diabetic renal papillary necrosis, diabetic foot, diabetic dermopathy etc.
Life entity of the present invention is meant a kind of description to the individuality that has life, especially refers to mammal, refers in particular to the mankind.
Another object of the present invention is to provide the purposes of pharmaceutical composition in the medicine of preparation treatment diabetes; The 3rd purpose of the present invention is to provide the purposes of pharmaceutical composition in the medicine of preparation prevent diabetes complication.
One of component of the pharmaceutical composition that relates in the purposes provided by the invention is the sulfonylureas drugs for diabetes thing, comprise glibenclamide, glibornuride, glycyclamide, glyhexamide, glimepiride, glypinamide, glisamuride, Glisentide, glisolamide, glyoctamide, gliclazide, glipizide and gliquidone, preferred glibenclamide, glimepiride, gliclazide, gliquidone or glipizide are more preferably glimepiride; Two of component is thiazolidinediones hypoglycemic medicines, comprise rosiglitazone, pioglitazone, troglitazone, englitazone, ciglitazone, rosiglitazone maleate, Tartraric rosiglitazone, Rosiglitazone sodium, Luogelie ketone hydrochloride, pioglitazone hydrochloride etc., preferred rosiglitazone, rosiglitazone maleate, pioglitazone or pioglitazone hydrochloride; Three of component is at least a in the vitamin B group, described vitamin B group comprises folic acid, vitamin B12 (cobalamin), vitamin B6 (pyridoxol), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (nicotinic acid), pantothenic acid and biotin, preferred folic acid, vitamin B12 and vitamin B6 are more preferably folic acid.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a folic acid.In said composition, the content of glimepiride is 1mg～4mg, and the content of rosiglitazone is 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a folic acid.In said composition, the content of glimepiride is 1mg～4mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a folic acid.In said composition, the content of glimepiride is 1mg～4mg, and the content of pioglitazone is 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glimepiride, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a folic acid.In said composition, the content of glimepiride is 1mg～4mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a folic acid.In said composition, the content of glibenclamide is 1mg～15mg, and the content of rosiglitazone is 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a folic acid.In said composition, the content of glibenclamide is 1mg～15mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a folic acid.In said composition, the content of glibenclamide is 1mg～15mg, and the content of pioglitazone is 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glibenclamide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a folic acid.In said composition, the content of glibenclamide is 1mg～15mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a folic acid.In said composition, the content of gliclazide is 20mg～160mg, and the content of rosiglitazone is 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a folic acid.In said composition, the content of gliclazide is 20mg～160mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a folic acid.In said composition, the content of gliclazide is 20mg～160mg, and the content of pioglitazone is 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliclazide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a folic acid.In said composition, the content of gliclazide is 20mg～160mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a folic acid.In said composition, the content of gliquidone is 15mg～60mg, and the content of rosiglitazone is 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a folic acid.In said composition, the content of gliquidone is 15mg～60mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a folic acid.In said composition, the content of gliquidone is 15mg～60mg, and the content of pioglitazone is 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a gliquidone, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a folic acid.In said composition, the content of gliquidone is 15mg～60mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the thiazolidinediones hypoglycemic medicine is a rosiglitazone, and vitamin B group is a folic acid.In said composition, the content of glipizide is 1mg～15mg, and the content of rosiglitazone is 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a rosiglitazone maleate, and vitamin B group is a folic acid.In said composition, the content of glipizide is 1mg～15mg, and the content of rosiglitazone maleate is the rosiglitazone that is equivalent to 1mg～8mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the thiazolidinediones hypoglycemic medicine is a pioglitazone, and vitamin B group is a folic acid.In said composition, the content of glipizide is 1mg～15mg, and the content of pioglitazone is 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
In the purposes of pharmaceutical composition provided by the invention, the sulfonylureas drugs for diabetes thing is a glipizide, and the officinal salt of thiazolidinediones hypoglycemic medicine is a pioglitazone hydrochloride, and vitamin B group is a folic acid.In said composition, the content of glipizide is 1mg～15mg, and the content of pioglitazone hydrochloride is the pioglitazone that is equivalent to 7.5mg～45mg, and the content of folic acid is 0.1mg～7.5mg.
Beneficial effect of the present invention:
The invention provides the officinal salt and vitamin B group or relative pharmaceutical composition of officinal salt, thiazolidinediones hypoglycemic medicine or this thiazolidinediones hypoglycemic medicine of the active metabolite that contains sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing or this sulfonylureas drugs for diabetes thing with similar bioactive chemical compound.The sulfonylureas drugs for diabetes thing; the effect of three kinds of material use in conjunction of thiazolidinediones hypoglycemic medicine and vitamin B group be not each active substance each self-applying simply add and; this pharmaceutical composition is blood sugar control effectively; the coordinating protection inner skin cell function; alleviating the diabetics homocysteine in plasma that diabetics particularly is associated with chronic complicating diseases raises; and can reduce the generation of diabetic complication; the test explanation that the specific embodiment provides; three kinds of material use in conjunction are on the basis of technique effect separately; can bring into play the technique effect that three kinds of materials do not have separately, thereby reach synergism.Pharmaceutical composition provided by the invention is on the effective therapeutic effect of diabetes, beneficial effect with tangible prevent diabetes complication, therefore be antidiabetic medicine preferably, provide a kind of feasible, safe therapeutic scheme for treating diabetes or prevent diabetes complication.
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 formulation preparation process of following pharmaceutical preparation embodiment and 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 1Preparation compound recipe glimepiride rosiglitazone folic acid (0.4mg) sheet (1000 amounts)
Prescription: glimepiride 1g
Rosiglitazone 4g
Folic acid 0.4g
Starch 20g
Microcrystalline Cellulose 40g
Carboxymethyl starch sodium 40g
Low-substituted hydroxypropyl cellulose 20g
The polyvidone alcoholic solution is an amount of
Magnesium stearate 0.5%
Preparation method: adjuvant was pulverized 80 mesh sieves, drying for standby.Get 1g glimepiride, 4g rosiglitazone, 0.4g folic acid according to equivalent incremental method mix homogeneously, add starch, microcrystalline Cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose respectively according to recipe quantity, by equivalent incremental method uniform mixing, make soft material with 5% 30 POVIDONE K 30 BP/USP 29/30-95% alcoholic solution, 20 mesh sieves are granulated, 40 ℃ of dry about 2h, 18 mesh sieve granulate, controlling particulate water content is 2-3%, with dried granule and magnesium stearate mix homogeneously, semi-finished product detect, and measure content, are pressed into 1000 with tablet machine.The tablet of making needs aluminium-plastic bubble plate packing, keeps in Dark Place.Every contains glimepiride 1mg, rosiglitazone 4mg, folic acid 0.4mg in the compound tablet of making, and its mass ratio is 1: 4: 0.4.
Embodiment 2～embodiment 8Preparation contains the glimepiride rosiglitazone YESUAN PIAN of different content proportioning
Preparation method is identical with embodiment 1, makes tablet according to the granule that prescription shown in the table 1 obtains.
Embodiment 9Preparation compound recipe glimepiride rosiglitazone vitamin B12 (2mg) sheet (1000 amounts)
Embodiment 10Preparation compound recipe glimepiride rosiglitazone vitamin B6 (10mg) sheet (1000 amounts)
The preparation method of embodiment 9～10 is identical with embodiment 1, makes tablet according to the granule that prescription shown in the table 1 obtains.
Table 1 embodiment 2～10 tablet formulations are formed
Figure G06199027620060718D000231
Every contains glimepiride 2mg, rosiglitazone 4mg, folic acid 0.4mg in the compound recipe glimepiride rosiglitazone folic acid tablet that embodiment 2 makes, and its mass ratio is 2: 4: 0.4.
Every contains glimepiride 4mg, rosiglitazone 4mg, folic acid 0.4mg in the compound recipe glimepiride rosiglitazone folic acid tablet that embodiment 3 makes, and its mass ratio is 4: 4: 0.4.
Every contains glimepiride 1mg, rosiglitazone 4mg, folic acid 0.8mg in the compound recipe glimepiride rosiglitazone folic acid tablet that embodiment 4 makes, and its mass ratio is 1: 4: 0.8.
Every contains glimepiride 1mg, rosiglitazone 4mg, folic acid 1.0mg in the compound recipe glimepiride rosiglitazone folic acid tablet that embodiment 5 makes, and its mass ratio is 1: 4: 1.0.
Every contains glimepiride 4mg, rosiglitazone 2mg, folic acid 0.4mg in the compound recipe glimepiride rosiglitazone folic acid tablet that embodiment 6 makes, and its mass ratio is 4: 2: 0.4.
Every contains glimepiride 4mg, rosiglitazone 1mg, folic acid 0.4mg in the compound recipe glimepiride rosiglitazone folic acid tablet that embodiment 7 makes, and its mass ratio is 4: 1: 0.4.
Every contains glimepiride 4mg, rosiglitazone 8mg, folic acid 0.4mg in the compound recipe glimepiride rosiglitazone folic acid tablet that embodiment 8 makes, and its mass ratio is 4: 8: 0.4.
Every contains glimepiride 1mg, rosiglitazone 4mg, vitamin B12 2mg in the compound recipe glimepiride rosiglitazone vitamin B12 tablet that embodiment 9 makes, and its mass ratio is 1: 4: 2.
Every contains glimepiride 1mg, rosiglitazone 4mg, vitamin B6 10mg in the compound recipe glimepiride rosiglitazone vitamin B6 tablet that embodiment 10 makes, and its mass ratio is 1: 4: 10.
Embodiment 11～15Preparation contains the glimepiride pioglitazone YESUAN PIAN of different content proportioning
Preparation method is identical with embodiment 1, makes tablet according to the granule that prescription shown in the table 2 obtains.
Embodiment 16Preparation compound recipe glimepiride pioglitazone vitamin B12 (2mg) sheet (1000 amounts)
Embodiment 17Preparation compound recipe glimepiride is given a tongue-lashing lattice row ketone vitamin B6 (10mg) sheet (1000 amounts)
The preparation method of embodiment 16,17 is identical with embodiment 1, makes tablet according to the granule that prescription shown in the table 2 obtains.
Table 2 embodiment 11～17 tablet formulations are formed
Every contains glimepiride 1mg, pioglitazone 15mg, folic acid 0.4mg in the compound recipe glimepiride pioglitazone folic acid tablet that embodiment 11 makes, and its mass ratio is 1: 15: 0.4.
Every contains glimepiride 2mg, pioglitazone 15mg, folic acid 0.4mg in the compound recipe glimepiride pioglitazone folic acid tablet that embodiment 12 makes, and its mass ratio is 2: 15: 0.4.
Every contains glimepiride 4mg, pioglitazone 15mg, folic acid 0.4mg in the compound recipe glimepiride pioglitazone folic acid tablet that embodiment 13 makes, and its mass ratio is 4: 15: 0.4.
The compound recipe glimepiride that embodiment 14 makes is given a tongue-lashing in the lattice row ketone folic acid tablet every and is contained glimepiride 1mg, gives a tongue-lashing lattice row ketone 15mg, folic acid 0.8mg, and its mass ratio is 1: 15: 0.8.
Every contains glimepiride 1mg, pioglitazone 15mg, folic acid 1.0mg in the compound recipe glimepiride pioglitazone folic acid tablet that embodiment 15 makes, and its mass ratio is 1: 15: 1.0.
Every contains glimepiride 1mg, pioglitazone 15mg, vitamin B12 2mg in the compound recipe glimepiride pioglitazone vitamin B12 tablet that embodiment 16 makes, and its mass ratio is 1: 15: 2.
Every contains glimepiride 1mg, pioglitazone 15mg, vitamin B6 10mg in the compound recipe glimepiride pioglitazone vitamin B6 tablet that embodiment 17 makes, and its mass ratio is 1: 15: 10.
Embodiment 18Preparation compound recipe glimepiride rosiglitazone folic acid (0.4mg) capsule (1000 amounts)
Prescription: glimepiride 1g
Rosiglitazone 4g
Folic acid 0.4g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 20g
The polyvidone alcoholic solution is an amount of
Micropowder silica gel 1%
Magnesium stearate 1%
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get 4g rosiglitazone, 0.4g folic acid, microcrystalline Cellulose, carboxymethyl starch sodium according to equivalent incremental method mix homogeneously, make soft material with 5% polyvidone alcoholic solution, 30 mesh sieves are granulated, 18 mesh sieve granulate, and controlling particulate water content is 2-3%; With granule and the glimepiride mix homogeneously that makes, add micropowder silica gel and the abundant mix homogeneously of magnesium stearate, measure content, pack Capsules into promptly.The capsule of making needs aluminium-plastic bubble plate packing, keeps in Dark Place.Every contains glimepiride 1mg, rosiglitazone 4mg, folic acid 0.4mg in the capsule of making, and its mass ratio is 1: 4: 0.4.
Embodiment 19～embodiment 25Preparation contains the glimepiride rosiglitazone folic acid capsule of different content proportioning
Preparation method is identical with embodiment 18, makes capsule according to the granule that prescription shown in the table 3 obtains.
Embodiment 26Preparation compound recipe glimepiride rosiglitazone vitamin B12 (2mg) capsule (1000 amounts)
Embodiment 27Preparation compound recipe glimepiride rosiglitazone vitamin B6 (10mg) capsule (1000 amounts)
The preparation method of embodiment 26,27 is identical with embodiment 18, makes capsule according to the granule that prescription shown in the table 3 obtains.
Table 3 embodiment 19～27 capsule prescriptions are formed
Every contains glimepiride 2mg, rosiglitazone 4mg, folic acid 0.4mg in the compound recipe glimepiride rosiglitazone folic acid capsule that embodiment 19 makes, and its mass ratio is 2: 4: 0.4.
Every contains glimepiride 4mg, rosiglitazone 4mg, folic acid 0.4mg in the compound recipe glimepiride rosiglitazone folic acid capsule that embodiment 20 makes, and its mass ratio is 4: 4: 0.4.
Every contains glimepiride 1mg, rosiglitazone 4mg, folic acid 0.8mg in the compound recipe glimepiride rosiglitazone folic acid capsule that embodiment 21 makes, and its mass ratio is 1: 4: 0.8.
Every contains glimepiride 1mg, rosiglitazone 4mg, folic acid 1.0mg in the compound recipe glimepiride rosiglitazone folic acid capsule that embodiment 22 makes, and its mass ratio is 1: 4: 1.0.
Every contains glimepiride 4mg, rosiglitazone 2mg, folic acid 0.4mg in the compound recipe glimepiride rosiglitazone folic acid capsule that embodiment 23 makes, and its mass ratio is 4: 2: 0.4.
Every contains glimepiride 4mg, rosiglitazone 1mg, folic acid 0.4mg in the compound recipe glimepiride rosiglitazone folic acid capsule that embodiment 24 makes, and its mass ratio is 4: 1: 0.4.
Every contains glimepiride 1mg, rosiglitazone 8mg, folic acid 0.4mg in the compound recipe glimepiride rosiglitazone folic acid capsule that embodiment 25 makes, and its mass ratio is 1: 8: 0.4.
Every contains glimepiride 1mg, rosiglitazone 4mg, vitamin B12 2mg in the compound recipe glimepiride rosiglitazone vitamin B12 capsule that embodiment 26 makes, and its mass ratio is 1: 4: 2.
Every contains glimepiride 1mg, rosiglitazone 4mg, vitamin B6 10mg in the compound recipe glimepiride rosiglitazone vitamin B6 capsule that embodiment 27 makes, and its mass ratio is 1: 4: 10.
Embodiment 28～32Preparation contains the glimepiride pioglitazone folic acid capsule of different content proportioning
Preparation method is identical with embodiment 18, makes capsule according to the granule that prescription shown in the table 4 obtains.
Embodiment 33Preparation compound recipe glimepiride pioglitazone vitamin B12 (2mg) capsule (1000 amounts)
Embodiment 34Preparation compound recipe glimepiride is given a tongue-lashing lattice row ketone vitamin B6 (10mg) capsule (1000 amounts)
The preparation method of embodiment 33,34 is identical with embodiment 18, makes capsule according to the granule that prescription shown in the table 4 obtains.
Table 4 embodiment 28～34 capsule prescriptions are formed
Figure G06199027620060718D000271
Every contains glimepiride 1mg, pioglitazone 15mg, folic acid 0.4mg in the compound recipe glimepiride pioglitazone folic acid capsule that embodiment 28 makes, and its mass ratio is 1: 15: 0.4.
Every contains glimepiride 2mg, pioglitazone 15mg, folic acid 0.4mg in the compound recipe glimepiride pioglitazone folic acid capsule that embodiment 29 makes, and its mass ratio is 2: 15: 0.4.
Every contains glimepiride 4mg, pioglitazone 15mg, folic acid 0.4mg in the compound recipe glimepiride pioglitazone folic acid capsule that embodiment 30 makes, and its mass ratio is 4: 15: 0.4.
Every contains glimepiride 1mg, gives a tongue-lashing lattice row ketone 15mg, folic acid 0.8mg in the compound recipe glimepiride pioglitazone folic acid capsule that embodiment 31 makes, and its mass ratio is 1: 15: 0.8.
Every contains glimepiride 1mg, pioglitazone 15mg, folic acid 1.0mg in the compound recipe glimepiride pioglitazone folic acid capsule that embodiment 32 makes, and its mass ratio is 1: 15: 1.0.
Every contains glimepiride 1mg, pioglitazone 15mg, vitamin B12 2mg in the compound recipe glimepiride pioglitazone vitamin B12 capsule that embodiment 33 makes, and its mass ratio is 1: 15: 2.
The compound recipe glimepiride that embodiment 34 makes is given a tongue-lashing in the lattice row ketone vitamin B6 capsule every and is contained glimepiride 1mg, pioglitazone 15mg, vitamin B6 10mg, and its mass ratio is 1: 15: 10.
Embodiment 35Preparation compound recipe glibenclamide rosiglitazone folic acid (0.4mg) sheet (1000 amounts)
Embodiment 36Preparation compound recipe glibenclamide pioglitazone folic acid (0.4mg) sheet (1000 amounts)
Embodiment 37Preparation compound recipe gliclazide rosiglitazone folic acid (0.4mg) sheet (1000 amounts)
Embodiment 38Preparation compound recipe gliclazide pioglitazone folic acid (0.4mg) sheet (1000 amounts)
Embodiment 39Preparation compound recipe gliquidone rosiglitazone folic acid (0.4mg) sheet (1000 amounts)
Embodiment 40Preparation compound recipe gliquidone pioglitazone folic acid (0.4mg) sheet (1000 amounts)
Embodiment 41Preparation compound recipe glipizide rosiglitazone folic acid (0.4mg) sheet (1000 amounts)
Embodiment 42Preparation compound recipe glipizide pioglitazone folic acid (0.4mg) sheet (1000 amounts)
The preparation method of embodiment 35～42 is identical with embodiment 1, makes tablet according to the granule that prescription shown in the table 5 obtains.
Table 5 embodiment 35～42 tablet formulations are formed
Figure G06199027620060718D000281
Every contains glibenclamide 2.5mg, rosiglitazone 4mg, folic acid 0.4mg in the compound recipe glibenclamide rosiglitazone folic acid tablet that embodiment 35 makes, and its mass ratio is 2.5: 4: 0.4.
Every contains glibenclamide 2.5mg, pioglitazone 15mg, folic acid 0.4mg in the compound recipe glibenclamide pioglitazone folic acid tablet that embodiment 36 makes, and its mass ratio is 2.5: 15: 0.4.
Every contains gliquidone 30mg, rosiglitazone 4mg, folic acid 0.4mg in the compound recipe gliquidone rosiglitazone folic acid tablet that embodiment 37 makes, and its mass ratio is 30: 4: 0.4.
Every contains gliquidone 30mg, pioglitazone 15mg, folic acid 0.4mg in the compound recipe gliquidone pioglitazone folic acid tablet that embodiment 38 makes, and its mass ratio is 30: 15: 0.4.
Every contains gliclazide 50mg, rosiglitazone 4mg, folic acid 0.4mg in the compound recipe gliclazide rosiglitazone folic acid tablet that embodiment 39 makes, and its mass ratio is 50: 4: 0.4.
Every contains gliclazide 50mg, pioglitazone 15mg, folic acid 0.4mg in the compound recipe gliclazide pioglitazone folic acid tablet that embodiment 40 makes, and its mass ratio is 50: 15: 0.4.
Every contains glipizide 5mg, rosiglitazone 4mg, folic acid 0.4mg in the compound recipe glipizide rosiglitazone folic acid tablet that embodiment 41 makes, and its mass ratio is 5: 4: 0.4.
Every contains glipizide 5mg, pioglitazone 15mg, folic acid 0.4mg in the compound recipe glipizide pioglitazone folic acid tablet that embodiment 42 makes, and its mass ratio is 5: 15: 0.4.
Embodiment 43Glimepiride, rosiglitazone and folate composition are to the influence of blood glucose in diabetic rats, homocysteine, inner skin cell function and nephropathy
Streptozotocin solution: take by weighing the 1200mg streptozotocin face with the citrate buffer solution that before is dissolved in the new preparation of 200ml (0.1mmol/L, pH4.5) in, be made into the solution of 6mg/ml.
Get healthy rat, 10 rats of picked at random are as blank, all the other rat tail vein fast injection streptozotocin solution (60mg/kg), and blank group rat gives normal diet, and rats in test groups gives high lipid food and feeds and induce insulin resistant.The socket of the eye venous blood collection is measured fasting blood sugar after 2 weeks, and the screening blood glucose value is made the diabetes model rat above the rat of 16.7mmol/L and is used for subsequent experimental.
Diabetes rat is divided into model group, glimepiride group, rosiglitazone group, folic acid group, glimepiride+folic acid group, rosiglitazone+folic acid group, glimepiride+rosiglitazone group, glimepiride+rosiglitazone+folic acid group at random, irritate stomach every day respectively and give equivalent the corresponding thing that tried, once a day.Successive administration is after 6 weeks, carry out lactic acid dehydrogenase (LDH) in blood glucose (GLU), homocysteine in plasma (Hcy), the cardiac muscular tissue, malonaldehyde (MDA), nitric oxide (NO) mensuration, and creatinine (Cr), blood urea nitrogen (BUN) and 24h urine protein index are measured.The The above results that every group of 10 rat record is with (mean+SD) Expression, the multiple comparisons between sample average adopts one factor analysis of variance, uses SPSS10.0 software and carries out statistical analysis, sees table 6 for details.
Table 6 glimepiride, rosiglitazone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000301
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and glimepiride+rosiglitazone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Continuous table 6 glimepiride, rosiglitazone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000303
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and glimepiride+rosiglitazone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Conclusion: The above results shows, glimepiride, rosiglitazone and folate composition can significantly reduce blood glucose, the homocysteine level of diabetes rat, endothelial cell damage and nephropathy (p＜0.01 or 0.001) that the protection diabetes cause, glimepiride+rosiglitazone+folate composition blood sugar reducing function is better than folk prescription glimepiride and folic acid (p＜0.05 or 0.001); The reducing homosysteine level is better than folk prescription glimepiride and rosiglitazone (p＜0.01 or 0.001); The inner skin cell function damage that diabetes are caused and the protective effect of nephropathy also obviously are better than the combination (p＜0.05 or 0.01) of folk prescription or any two components.Illustrate that glimepiride, rosiglitazone and folate composition all have excellent curative to blood glucose in diabetic rats, homocysteine, inner skin cell function and nephropathy.
Embodiment 44Glimepiride, pioglitazone and folate composition are to the influence of blood glucose in diabetic rats, homotype half Guang oxygen acid, inner skin cell function and nephropathy
Experimental technique is with embodiment 43.The results are shown in Table 7.
Table 7 glimepiride, pyrroles's row ketone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000311
Figure G06199027620060718D000312
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and glimepiride+pyrroles's row ketone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Continuous table 7 glimepiride, pyrroles's row ketone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000313
Figure G06199027620060718D000314
Figure G06199027620060718D000321
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and glimepiride+pyrroles's row ketone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Conclusion: The above results shows, glimepiride, pyrroles's row ketone and folate composition can significantly reduce blood glucose, the homocysteine level of diabetes rat, endothelial cell damage and nephropathy (p＜0.01 or 0.001) that the protection diabetes cause, glimepiride+pyrroles's row ketone+folate composition blood sugar reducing function is better than folk prescription glimepiride and folic acid (p＜0.05 or 0.001); The reducing homosysteine level is better than folk prescription glimepiride and pyrroles's row ketone (p＜0.01 or 0.001); The inner skin cell function damage that diabetes are caused and the protective effect of nephropathy also obviously are better than the combination (p＜0.05 or 0.01) of folk prescription or any two components.Illustrate that glimepiride, pyrroles's row ketone and folate composition all have excellent curative to blood glucose in diabetic rats, homocysteine, inner skin cell function and nephropathy.
Embodiment 45Glibenclamide, rosiglitazone and folate composition are to the influence of blood glucose in diabetic rats, homocysteine, inner skin cell function and nephropathy
Experimental technique is with embodiment 43.The results are shown in Table 8.
Table 8 glibenclamide, rosiglitazone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000322
Figure G06199027620060718D000323
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and glibenclamide+rosiglitazone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Continuous table 8 glibenclamide, rosiglitazone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000331
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and glibenclamide+rosiglitazone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Conclusion: The above results shows, glibenclamide, rosiglitazone and folate composition can significantly reduce blood glucose, the homocysteine level of diabetes rat, endothelial cell damage and nephropathy (p＜0.01 or 0.001) that the protection diabetes cause, glibenclamide+rosiglitazone+folate composition blood sugar reducing function is better than folk prescription glibenclamide and folic acid (p＜0.05 or 0.001); The reducing homosysteine level is better than folk prescription glibenclamide and rosiglitazone (p＜0.01 or 0.001); The inner skin cell function damage that diabetes are caused and the protective effect of nephropathy also obviously are better than the combination (p＜0.05 or 0.01) of folk prescription or any two components.Illustrate that glibenclamide, rosiglitazone and folate composition all have excellent curative to blood glucose in diabetic rats, homocysteine, inner skin cell function and nephropathy.
Embodiment 46Gliquidone, rosiglitazone and folate composition are to the influence of blood glucose in diabetic rats, homocysteine, inner skin cell function and nephropathy
Experimental technique is with embodiment 43.The results are shown in Table 9.
Table 9 gliquidone, rosiglitazone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000341
Figure G06199027620060718D000342
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and gliquidone+rosiglitazone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Continuous table 9 gliquidone, rosiglitazone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000343
Figure G06199027620060718D000344
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and gliquidone+rosiglitazone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Conclusion: The above results shows, gliquidone, rosiglitazone and folate composition can significantly reduce blood glucose, the homocysteine level of diabetes rat, endothelial cell damage and nephropathy (p＜0.01 or 0.001) that the protection diabetes cause, gliquidone+rosiglitazone+folate composition blood sugar reducing function is better than folk prescription gliquidone and folic acid (p＜0.05 or 0.001); The reducing homosysteine level is better than folk prescription gliquidone and rosiglitazone (p＜0.01 or 0.001); The inner skin cell function damage that diabetes are caused and the protective effect of nephropathy also obviously are better than the combination (p＜0.05 or 0.01) of folk prescription or any two components.Illustrate that gliquidone, rosiglitazone and folate composition all have excellent curative to blood glucose in diabetic rats, homocysteine, inner skin cell function and nephropathy.
Embodiment 47Gliclazide, rosiglitazone and folate composition are to the influence of blood glucose in diabetic rats, homocysteine, inner skin cell function and nephropathy
Experimental technique is with embodiment 43.The results are shown in Table 10.
Table 10 gliclazide, rosiglitazone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000351
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and gliclazide+rosiglitazone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Continuous table 10 gliclazide, rosiglitazone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000353
Figure G06199027620060718D000354
Figure G06199027620060718D000361
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and gliclazide+rosiglitazone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Conclusion: The above results shows, gliclazide, rosiglitazone and folate composition can significantly reduce blood glucose, the homocysteine level of diabetes rat, endothelial cell damage and nephropathy (p＜0.01 or 0.001) that the protection diabetes cause, gliclazide+rosiglitazone+folate composition blood sugar reducing function is better than folk prescription gliclazide and folic acid (p＜0.05 or 0.001); The reducing homosysteine level is better than folk prescription gliclazide and rosiglitazone (p＜0.01 or 0.001); The inner skin cell function damage that diabetes are caused and the protective effect of nephropathy also obviously are better than the combination (p＜0.05 or 0.01) of folk prescription or any two components.Illustrate that gliclazide, rosiglitazone and folate composition all have excellent curative to blood glucose in diabetic rats, homocysteine, inner skin cell function and nephropathy.
Embodiment 48Glipizide, rosiglitazone and folate composition are to the influence of blood glucose in diabetic rats, homocysteine, inner skin cell function and nephropathy
Experimental technique is with embodiment 43.The results are shown in Table 11.
Table 11 glipizide, rosiglitazone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000362
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and glipizide+rosiglitazone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Continuous table 11 glipizide, rosiglitazone and folate composition are to the effect of diabetes rat
Figure G06199027620060718D000371
Figure G06199027620060718D000372
Annotate: matched group and model group compare, #P＜0.05, ##P＜0.01, ###P＜0.001; Each administration group and model group compare, *P＜0.05, *P＜0.01, * *P＜0.001; Each administration group and glipizide+rosiglitazone+folic acid group compares, △P＜0.05, △ △P＜0.01, △ △ △P＜0.001.
Conclusion: The above results shows, glipizide, rosiglitazone and folate composition can significantly reduce blood glucose, the homocysteine level of diabetes rat, endothelial cell damage and nephropathy (p＜0.01 or 0.001) that the protection diabetes cause, glipizide+rosiglitazone+folate composition blood sugar reducing function is better than folk prescription glipizide and folic acid (p＜0.05 or 0.001); The reducing homosysteine level is better than folk prescription gliclazide and rosiglitazone (p＜0.01 or 0.001); The inner skin cell function damage that diabetes are caused and the protective effect of nephropathy also obviously are better than the combination (p＜0.05 or 0.01) of folk prescription or any two components.Illustrate that glipizide, rosiglitazone and folate composition all have excellent curative to blood glucose in diabetic rats, homocysteine, inner skin cell function and nephropathy.

Claims (5)

1. hypoglycemic medicine composition, form by a kind of and pharmaceutically suitable carrier or excipient in the vitamin B group of a kind of, the pharmaceutical dosage in the thiazolidinediones hypoglycemic medicine of a kind of, the pharmaceutical dosage in the sulfonylureas drugs for diabetes thing of pharmaceutical dosage, it is characterized in that: described thiazolidinediones hypoglycemic medicine is a rosiglitazone, and content is 1mg～8mg; Described vitamin B group is a folic acid, and content is 0.1mg～7.5mg; Described sulfonylureas drugs for diabetes thing is glimepiride, glibenclamide, gliclazide, gliquidone or glipizide, wherein, the content of glimepiride is 1mg～4mg, the content of glibenclamide is 1mg～15mg, the content of gliclazide is 20mg～160mg, the content of gliquidone is 15mg～60mg, and the content of glipizide is 1mg～15mg.
2. hypoglycemic medicine composition, form by a kind of and pharmaceutically suitable carrier or excipient in the vitamin B group of a kind of, the pharmaceutical dosage in the thiazolidinediones hypoglycemic medicine of a kind of, the pharmaceutical dosage in the sulfonylureas drugs for diabetes thing of pharmaceutical dosage, it is characterized in that: described thiazolidinediones hypoglycemic medicine is a pioglitazone, and content is 7.5mg～45mg; Described vitamin B group is a folic acid, and content is 0.1mg～7.5mg; Described sulfonylureas drugs for diabetes thing is a glimepiride, and content is 1mg～4mg.
3. any one described pharmaceutical composition of claim 1 to 2, it is characterized in that: the dosage form of described pharmaceutical composition is tablet or capsule.
4. the purposes of any one described pharmaceutical composition in the medicine of preparation treatment diabetes in the claim 1 to 3.
5. the purposes of any one described pharmaceutical composition in the medicine of preparation prevent diabetes complication in the claim 1 to 3.
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