CN103393686B - The purposes of Thiazolidinediones and 5-methyltetrahydrofolate pharmaceutical composition - Google Patents
The purposes of Thiazolidinediones and 5-methyltetrahydrofolate pharmaceutical composition Download PDFInfo
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Abstract
The present invention relates to thiazolidinediones (TZDs) blood sugar lowering containing pharmaceutical dosage, drug induced hepatic injury that the pharmaceutical composition of 5-methyltetrahydrofolate of pharmaceutical dosage causes for preventing and treating TZDs; Wherein, the preferred agents of TZDs and dosage are rosiglitazone 1 ~ 8mg, pioglitazone 7.5 ~ 45mg, and the preferred dose of 5-methyltetrahydrofolate is 1.0 ~ 2.4mg.Advantage of the present invention is: on effective hypoglycemic basis, and this pharmaceutical composition can prevent, treats or alleviate the hepatic injury that TZDs causes, and therefore can improve the benefit/risk ratio of TZDs clinical practice.
Description
Technical field
The present invention relates to the thiazolidinediones blood sugar lowering of pharmaceutical dosage, pharmaceutical composition that 5-methyltetrahydrofolate forms is for preventing and treating the novelty teabag of Thiazolidinediones hepatic injury side effect.The invention belongs to field of medicaments.
Background technology
Diabetes are a kind of common endocrine metabolism diseases, are characterized in that chronic hyperglycemia is with the sugar, fat and the protein metabolism disorder that cause because of hypoinsulinism and/or effect defect.Diabetes have become the third-largest disease of the mankind after cardiovascular and cerebrovascular vessel, cancer.According to investigations, China's diabetes prevalence, up to 9.7%, calculates that national diabetics about has 9,240 ten thousand people [YangW, etal.PrevalenceofdiabetesamongmenandwomeninChina.NEnglJM ed.2010 accordingly; 362:1090-1101].Separately according to IDF (InternationalDiabetesFederation, IDF) statistics, within 2010, global diabetics has reached 2.85 hundred million, estimates that the year two thousand thirty whole world will have nearly 500,000,000 people to suffer from diabetes.Thus, effectiveness and the safety of diabetes drug treatment not only have clinical meaning, have more important social meaning.
Diabetes are mainly divided into I type (insulin-dependent) and two kinds, II type (non-insulin-depending type), and the latter accounts for more than 90% of diabetics sum.The dominant pathophysiology of type ii diabetes be characterized as insulin secretion that islet beta cell function defect causes reduce insulin that (or relatively reducing) or insulin resistant cause in body, regulate and control the decline of glucose ability or both jointly exist [diabetes branch of Chinese Medical Association edits. Type 2 Diabetes In China guideline of prevention and treatment (2010 editions). medical publishing society of Peking University, JIUYUE the 1st edition in 2011].Can be strengthened the effect of insulin by the sensitivity improving Insulin receptor INSR, this is the effective prevention approach for type ii diabetes, and therefore, exploitation euglycemic agent becomes study hotspot in recent years.On current antidiabetic medicine market, thiazolidinediones (thiazolidinediones, TZDs) medicine belongs to the main Types of euglycemic agent.
TZDs medicine generally has 5-substituted benzylthiazolidine-2, the basic structure of 4-diketone, represent medicine and have rosiglitazone (Rosiglitazone), pioglitazone (Pioglitazone), still there is Fa Gelie ketone (Farglitazar grinding medicine, GlaxoSmithKline PLC company), darglitazone (Darglitazoan, Japanese Takeda Pharmaceutical Company Limited) etc.Such medicine can activate core peroxidase paraphyte receptor (PPAR-γ), strengthens the effect of insulin from transcriptional level.PPAR-γ has higher expression at fatty tissue, skeletal muscle and liver, and namely it be activated after being combined with TZDs, and conformation changes, release corpresor, thus activated gene is transcribed.By this mechanism, TZDs significantly improves the insulin resistant of type ii diabetes patient peripheral target tissue, strengthens the picked-up to glucose, thus reduces fasting glucose and glycated hemoglobin level, and the feedback of plasma insulin can be suppressed to raise.
In clinical practice, people find that TZDs has obvious hepatotoxicity effect to human body gradually.Such as, troglitazone (Troglitazone) is first euglycemic agent for clinical treatment type ii diabetes in the world, gets permission listing, but find that this medicine has hepatotoxicity soon in 1996 ~ 1997 years, and have the report of death, therefore namely stopped in 2000 selling.What meet with same destiny also has ciglitazone (Cightazone) and englitazone (Englitazone), and because being subject to the impact of the serious adverse reaction comprising liver toxicity, two medicines are also successively eliminated or remove city.At present conventional TZDs only have pioglitazone. rosiglitazone two, although not yet find their serious liver toxicity, but owing to being similar drugs, the two still has the untoward reaction causing abnormal liver function, general ALT (alanine aminotransferase) is forbidden higher than the patient of normal more than 2.5 times, and 1 ~ 2.5 times of person is cautious use of.Before the treatment and treatment the 1st year every 1 ~ 2 month require to check liver function, also want later periodic review [Sun Jingfang, etc. the clinical practice of euglycemic agent and progress. Chinese medicinal application and monitoring .2007; (1): 24-26].In addition, the side effect that TZDs is common also has body weight increase, edema, brings out heart failure and fracture etc.
Diabetes are a kind of with lifelong disease, need Long-term taking medicine, therefore drug safety sex chromosome mosaicism can not be ignored.The side effect such as above-mentioned hepatic injury greatly limit the use of TZDs, reduce the benefit/risk ratio of TZDs clinical practice.In the patent (CN200510106553.6) of obtaining the authorization in our prior; the compositions disclosing euglycemic agent and vitamin B group is protected at vascular endothelial cell and prevents and treats the advantage in diabetic complication, but does not relate to the drug induced hepatic injury aspect of TZDs.5-methyltetrahydrofolate (5-methyltetrahydrofolate, 5-MTHF) be the natural activity form of folic acid, can absorb through human body intestinal canal, be excreted by urine, seldom accumulate in vivo, thus constantly from external picked-up to meet body nutrition and metabolism needs.We have significant liver function protective effect at the favorite outer discovery 5-MTHF of zoopery; therefore think that it and TZDs are formed compound medicine will have extra benefit; namely can prevent or alleviate the medicine hepatic injury that TZDs causes, improve the benefit/risk ratio of TZDs clinical practice.
Summary of the invention
The present invention is intended to the hepatic injury side effect overcoming the existence of thiazolidinediones (TZDs) antidiabetic medicine, 5. methyl tetrahydrofolates (5-MTHF) of pharmaceutical dosage and TZDs is selected to form compound medicine, be used for the treatment of type ii diabetes, and can prevent, treat or delay the drug induced hepatic injury that TZDs causes.This pharmaceutical composition improve blood sugar lowering treatment benefit/risk than in the obvious TZDs of being better than be used alone.
Described " pharmaceutical dosage " refers to the amount of pharmacological action with collaborative, prevention or treatment.
Described TZDs comprise gone on the market rosiglitazone, pioglitazone and Fa Gelie ketone, darglitazone etc. to be gone on the market, pharmaceutically preferably rosiglitazone maleate, pioglitazone hydrochloride.
In the present invention, according to clinical data and experimental data, the pharmaceutical dosage of TZDs is respectively rosiglitazone 1 ~ 8mg, pioglitazone 7.5 ~ 45mg; The pharmaceutical dosage of 5-MTHF is 0.1 ~ 5mg, and preferred dose is 1.0 ~ 2.4mg.
In zoopery, we find; the pharmaceutical composition of the TZDs of pharmaceutical dosage and the 5-MTHF composition of pharmaceutical dosage raises the transaminase that TZDs causes wonderful effect: this pharmaceutical composition not only makes the hypoglycemic effect of TZDs strengthen to some extent (5-MTHF has slight hypoglycemic activity); the more important thing is the rising that significantly can suppress transaminase; point out it to have Hepatocyte protection, can be used for the drug induced hepatic injury of preventing and treating TZDs.
The dosage form of pharmaceutical composition of the present invention includes but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, single chamber controlled release tablet, two rooms controlled release tablet, pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, capsule containing micropill or small pieces, pH dependent form capsule containing micropill or small pieces, oral liquid, membrane or patch.Should it is emphasized that the pharmaceutical composition containing TZDs and 5-MTHF be made tablet or capsule.
Term " pharmaceutical dosage " refers to that clinician grants the dosage of medicine to diseased individuals according to diseased individuals coincident with severity degree of condition in order to reach effectively control or disease therapy object.Be to be understood that medicine pharmaceutical dosage provided by the invention is not limitation of the present invention, but to preferably of the present invention, under normal circumstances, in this dosage preferable range, this medicine can produce effective therapeutic effect to diseased individuals.Diseased individuals refers to the self-existent life entity suffering from disease, and in the present invention, life entity is the mankind espespecially.Should be appreciated that in prior art, human pharmaceutical use dosage or pharmaceutical dosage scope can with mammal, as rat, mice etc., carry out the pharmaceutical dosage that converts to show that applicable corresponding animal is suitable for or dosage range.
Advantage of the present invention:
The invention provides the novelty teabag of the pharmaceutical composition of TZDs, the 5-MTHF containing pharmaceutical dosage.The combined effect of TZDs and 5-MTHF be not simply adding of each self-applying of each active substance and, but significantly can reduce the hepatic injury effect that TZDs brings out on the basis making type ii diabetes patient blood glucose obtain better control, thus improve the benefit/risk ratio of TZDs clinical practice.
Below in conjunction with detailed description of the invention, the present invention will be further described, not limitation of the invention, and the equivalent replacement of all any this areas of carrying out according to content of the present invention, all belongs to protection scope of the present invention.
Detailed description of the invention
Embodiment 1: the preparation of rosiglitazone maleate 4mg/5-methyl tetrahydrofolate (5-MTHF) 1.2mg sheet
Formula forms
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get rosiglitazone maleate 4.0g and 5-MTHF1.2g according to equal increments method mix homogeneously, add microcrystalline Cellulose 122g, carboxymethyl starch sodium 18g, add lactose 80g again, Homogeneous phase mixing, add suitable amount of adhesive 10% polyvidone aqueous solution soft material, 30 orders are granulated, 40 ~ 45 DEG C of dry 3h; 30 order granulate, finally add appropriate 1% magnesium stearate mixing, after assay, and tabletting, packaging.Note lucifuge in preparation process, after product inspection is qualified, aluminium-plastic bubble plate packing, keeps in Dark Place.In the compound tablet made, every sheet is containing rosiglitazone maleate 4mg, 5-MTHF1.2mg.
Embodiment 2: the preparation of pioglitazone hydrochloride 30mg/5-MTHF1.2mg capsule
Formula forms
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get pioglitazone hydrochloride 30g, 5-MTHF1.2g according to equal increments method mix homogeneously, add starch 80g, microcrystalline Cellulose 60g, carboxymethyl starch sodium 20g, mix homogeneously, soft material is made with 60% appropriate amount of ethanol, 20 mesh sieves are granulated, 60 DEG C of drying about 2h, 20 mesh sieve granulate, the water content controlling granule is 2-3%, mixed homogeneously with 1% magnesium stearate of recipe quantity by dried granule, semi-finished product detect, and measure content, load Capsules, obtain 1000 capsules.Lucifuge is noted in preparation process.The qualified rear aluminium-plastic bubble plate packing of product inspection, keeps in Dark Place.Every hydrochloric pioglitazone 30mg, 5-MTHF1.2mg in the compound capsule made.
Embodiment 3: the preparation of pioglitazone hydrochloride 15mg/5-MTHF1.0mg granule
Formula forms
Preparation technology: former, adjuvant were pulverized 80 mesh sieves, getting hydrochloric acid pyrrole lattice row. ketone 15g, 5-MTHF1.0g, lactose 800g, starch 40g, arabic gum 5g, orange flavor 2g, Polyethylene Glycol 5g pulverize and sieve, add carboxymethyl starch sodium mix homogeneously and make soft material, granulation, 40-60 DEG C drying, water content is about 3%, take out, granulate, is filled to granule agent according to a conventional method.Every bag of hydrochloric pioglitazone 15mg, 5-MTHF1.0mg in the compound tablet made.
Embodiment 4: the preparation of Luogelie ketone hydrochloride 2mg/5-MTIHF1.2mug sheet
Formula forms
Preparation technology's reference example 1.
Embodiment 5: the preparation of pioglitazone hydrochloride 15mg/5-MTHF1.0mg sheet
Formula forms
Preparation technology's reference example 1.
Embodiment 6: the impact that oral 5-MTHF causes diabetics transaminase to raise on TZDs
One, method:
Collect this city 3 hospitals meet following condition out-patient 42 example: (1) men and women do not limit, the range of age 30-65 year; (2) suffer from type ii diabetes, take TZDs medicine more than 1 month continuously in the recent period; (3) without known hepatic disease; (4) the front blood bio-chemistry checking ALT > 40IU/L of group is entered.Patient is divided into two groups: 1. matched group (21 example): continue to take TZDs medicine, dosage is constant; 2. test group (21 example): continue to take TZDs medicine, dosage is constant, simultaneously oral 5-MTHF (Merck product), and dosage is 1.2mg/ days, and two groups of other treatments or process keep equity substantially.More than treat/process and continue 8 weeks, detect the fasting glucose (FPG) into patient after group (baseline) and 8 weeks and liver function (ALT, AST) respectively.
Two, result:
Demographic data shows, matched group mean age 53.5 ± 9.4 (year), the ratio of male/female is 9/12, test group mean age 54.3 ± 10.2 (year), the ratio of male/female is 10/11, two groups of populations no significant differences generally.
Behind two groups of index of correlation baseline values and 8 weeks, results and statistics see the following form 1.We find, after treating 8 weeks, compare with its baseline value, matched group patients serum ALT still has slight rising (81.6 ± 23.2vs72.7 ± 16.9, P < 0.05), AST slightly rises, but no statistical significance: and treat the reduction of the equal showed different of test group patients serum ALT and AST after 8 weeks, especially more remarkable (53.8 ± 12.3vs75.5 ± 19.6, P < 0.01) is reduced with ALT.In addition, compared with matched group, it is larger that the fasting glucose (FPG) after test group treatment reduces amplitude, and prompting 5-MTHF has assistant hypoglycemic effect.
Conclusion: compared with alone TZDs, the liver function of the diabetics that conbined usage TZDs and 5-methyltetrahydrofolate make existing transaminase raise significantly improves, and prompting 5-methyltetrahydrofolate has hepatoprotective effect, and has assistant hypoglycemic effect.
Table 1 patient baseline feature and the rear index of correlation for the treatment of in 8 weeks compare
Note: compare with baseline (paired t-test) after 8 weeks,
*p < 0.05,
*p < 0.01.
Embodiment 7:5-MTHF is on the impact of the hepatic injury rat of tetrachloro-methane induction
One, method:
Adopting 20% carbon tetrachloride vegetable oil solution to be derivant, is 1.5ml/kg body weight to SD rat consumption, every 3 days lumbar injections 1 time, totally 8 weeks, cause rat chronic chemical liver injury [Zhang Haiyan, etc. practical hepatopathy magazine, 2009; 12 (3): 161 ~ 163)].Get modeling success rat 40, randomized grouping is: 5-MTHF high dose group (0.32mg/kg), dosage group (0.16mg/kg) in 5-MTHF, 5-MTHF low dose group (0.08mg/kg), model control group, separately establish Normal group (during the modeling stage lumbar injection equivalent vegetable oil) 10, front 3 groups of 5-MTHF dosage gavages every day by above-mentioned setting once, rear 2 matched group gavage every day 0.5% cmc solns, continuous use or process 8 weeks, within 9th week, get blood (standby survey serum liver function) and put to death animal afterwards, animal body quality regulating liver-QI is claimed to wet quality, perusal hepatic tissue also makes pathological section, HE dyeing is observed liver histopathology and is changed.
Two, result:
Model control group rat blood serum ALT and AST level are apparently higher than Normal group, liver enlargement is shown in perusal, claims liver weight in wet base to increase, and most of swelling of liver cell in lobules of liver is shown in pathology HE dyeing, balloon sample is had to become, occur that fat drips cavity in part kytoplasm, core occupies limit, and cell boundary is unclear, sinus hepaticus is narrow, in lobule and the inflammatory cell infiltration of portal area, and with liver cell regeneration, prompting modeling success.Compare with model control group, 5-MTHF high dose (0.32mg/kg) obviously reduces rat blood serum ALT and AST level: 59.08 ± 20.52v.s.168.37 ± 66.51, P < 0.01; 192.63 ± 67.41v.s.386.16 ± 92.63, P < 0.01; Compare with model group, in 5-MTHF, dosage (0.16mg/kg) also obviously reduces rat blood serum ALT and AST level: 108.32 ± 38.63v.s.168.37 ± 66.51, P < 0.01; 325.18 ± 86.47v.s.386.16 ± 92.63, P < 0.05.The enlargement of 5-MTHF high, medium and low dosage group hepatic tissue all has after the treatment and alleviates in various degree, in lobules of liver and portal area inflammatory cell infiltration be also improved in varying degrees.Key data is in table 2.
The chronic hepatic injury tool of conclusion: 5-MTHF to tetrachloro-methane induction is significantly improved, especially comparatively remarkable with the therapeutic effect of middle and high dosage (0.16 ~ 0.32mg/kg/d).
Table 2 respectively group rats'liver weight in wet base, the heavy index of liver and serum aminotransferase levels at commencement compares
Note: compare with model comparison,
ap < 0.01;
bp < 0.05; Compare with normal control,
tp < 0.01;
Embodiment 8: pioglitazone+5-MTHF is to blood sugar lowering, the hepatoprotective effect of diabetes rat
One, method:
SD rat 60, body weight 200 ~ 230g, male and female half and half, adaptability randomly draws 10 as blank group after raising 1 week, all the other 50 give streptozotocin (STZ) 30mg/kg single intraperitoneal injection respectively, after 14 days, rat tail vein blood sampling measures blood sugar level, is greater than 11.1mmoL/L and is defined as Glycemia Decline success; Get more than 40 diabetes rats, be divided into 3 groups at random, i.e. model control group, pioglitazone group, pioglitazone+5-MTF group, latter 2 groups give pioglitazone 3mg/kg/d, pioglitazone+5-MTF (3+0.12mg/kg/d) respectively every day, blank group, model group give normal saline, all feed by filling with for 1 time every day for each group, medication or processing time are 16 weeks.Get blood after 8 weeks and survey ALT, AST, Rat Fast 12 hours after 16 weeks, after anesthetized animal, blood glucose, ALT, AST are surveyed in ventral aorta blood-letting.Removing midway rat cadavers, each group experimental data and statistics (adopting SPSS10.0 statistical package) are in table 3.
Two, result:
(1) experimental result that affects of blood glucose in diabetic rats is shown: administration is after 16 weeks, and compared with model group, pioglitazone group, pioglitazone+5-MTF group can reduce blood glucose significantly.But compare with pioglitazone group, significantly (P < 0.05), prompting pioglitazone and 5-MTHF share has collaborative hypoglycemic effect to the blood sugar decreasing effect that pioglitazone+5-MTF organizes.Refer to table 3.
(2) affect rat administration after 8 weeks on diabetes rat transaminase, compared with model group, pioglitazone group Serum ALT, AST activity starts significantly to raise, and pioglitazone+5-MTF group also has slight rising.Administration is after 16 weeks, compared with model group, pioglitazone group Serum ALT, AST are active to be raised further, and pioglitazone+5-MTF organizes transaminase ALT and AST activity presents remarkable reduction (ALT is close to model group level), there were significant differences compared with pioglitazone group (P < 0.05).These results show the hepatic injury that 5-MTF can improve pioglitazone and causes.
The table 3 pioglitazone+5-MTHF administration impact on blood glucose in diabetic rats, transaminase in 16 weeks
Note: compare with Normal group,
#p < 0.01; Compare with model control group, * P < 0.05, * * P < 0.01;
Compound recipe group compares with single medicine group,
Δp < 0.05.
Claims (5)
1. the pharmaceutical composition that forms of the thiazolidinediones blood sugar lowering of pharmaceutical dosage, the 5-methyltetrahydrofolate of pharmaceutical dosage is for the preparation for the treatment of type ii diabetes and the purposes prevented, treat or delay in the medicine of the hepatic injury that Thiazolidinediones causes, and wherein thiazolidinediones blood sugar lowering is selected from rosiglitazone, pioglitazone, Fa Gelie ketone and darglitazone.
2. purposes according to claim 1, is characterized in that: described thiazolidinediones blood sugar lowering is the one in rosiglitazone, pioglitazone, and wherein the content of rosiglitazone is 1 ~ 8mg, the content of pioglitazone is 7.5 ~ 45mg.
3. purposes according to claim 1, is characterized in that: described 5-methyltetrahydrofolate content is 0.1 ~ 5mg.
4. purposes according to claim 3, is characterized in that: described 5-methyltetrahydrofolate content is 1.0 ~ 2.4mg.
5. purposes according to claim 1, is characterized in that: described hepatic injury effect shows as the rising of serum alanine aminotransferase, aspartate aminotransferase level.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1096785A (en) * | 1993-06-01 | 1994-12-28 | 阿尔巴诺化学工业股份公司 | Commercial run by chromatographic separation preparation (6S) folic acid derivatives |
| WO2006102788A1 (en) * | 2005-03-28 | 2006-10-05 | Pficker Pharmaceuticals Ltd. | The complex antihyperlipidemics |
| CN1939540A (en) * | 2005-10-01 | 2007-04-04 | 安徽省现代中药研究中心 | Medicine composition containing insulin sensibilizer and B-family vatamines |
| CN101069745A (en) * | 2006-05-12 | 2007-11-14 | 北京华安佛医药研究中心有限公司 | Sugar-reducing medicine composition |
| CN101103993A (en) * | 2006-07-14 | 2008-01-16 | 北京华安佛医药研究中心有限公司 | Hypoglycemic medicine composition |
| CN101897696A (en) * | 2009-05-27 | 2010-12-01 | 北京奥萨医药研究中心有限公司 | Sugar-lowering drug composition and application thereof |
-
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1096785A (en) * | 1993-06-01 | 1994-12-28 | 阿尔巴诺化学工业股份公司 | Commercial run by chromatographic separation preparation (6S) folic acid derivatives |
| WO2006102788A1 (en) * | 2005-03-28 | 2006-10-05 | Pficker Pharmaceuticals Ltd. | The complex antihyperlipidemics |
| CN1939540A (en) * | 2005-10-01 | 2007-04-04 | 安徽省现代中药研究中心 | Medicine composition containing insulin sensibilizer and B-family vatamines |
| CN101069745A (en) * | 2006-05-12 | 2007-11-14 | 北京华安佛医药研究中心有限公司 | Sugar-reducing medicine composition |
| CN101103993A (en) * | 2006-07-14 | 2008-01-16 | 北京华安佛医药研究中心有限公司 | Hypoglycemic medicine composition |
| CN101897696A (en) * | 2009-05-27 | 2010-12-01 | 北京奥萨医药研究中心有限公司 | Sugar-lowering drug composition and application thereof |
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