CN101816655A - Medicinal preparation containing repaglinide and ligustrazine and application thereof in diabetic complications - Google Patents
Medicinal preparation containing repaglinide and ligustrazine and application thereof in diabetic complications Download PDFInfo
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- CN101816655A CN101816655A CN200910263427A CN200910263427A CN101816655A CN 101816655 A CN101816655 A CN 101816655A CN 200910263427 A CN200910263427 A CN 200910263427A CN 200910263427 A CN200910263427 A CN 200910263427A CN 101816655 A CN101816655 A CN 101816655A
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Abstract
The invention relates to a unit dosage combination preparation used for the combined delivery of repaglinide and ligustrazine or salts thereof. The preparation can be used for treating diabetic complications such as diabetic nephropathy, diabetic cardiomyopathy and aortic pathological changes, diabetic retinopathy and lenticular pathological changes, diabetic peripheral neuropathy, and the like. The invention also relates to a preparation method of the combined unit dosage preparation and an application of the combination preparation in the treatment of the diabetic complications.
Description
Technical field
The present invention relates to be used for the unit dose combination formulations sent uniting of repaglinide and ligustrazine or its salt.This class preparation can be used for treating diabetic complication.The invention still further relates to the preparation method and the purposes of this class combination formulations in the diabetic complication treatment of this class unit of association dosage particles.
Background technology
The non-insulin that perspective diabetes study confirms new diagnosis is according to patience diabetes (NIDDM) patient the 9th year after morbidity, and the incidence rate of macroangiopathy and microangiopathies is respectively 20% and 9%.Macroangiopathic accounts for 59% of all diabetes (DM) patient cause of the death, is that microangiopathies causes death 70 times that die.Therefore people recognize that gradually in comprehensive control of NIDDM, except that blood sugar control, the early prevention and treatment cardiovascular complication is significant.NIDDM is because of forming the generation that atherosclerosis (AS) finally causes complication such as the heart, cerebrovascular disease easily.Diabetic neuropathy can involve peripheral nerve and vegetative nerve.In recent years studies show that on the basis of carbohydrate metabolism disturbance, multiple factor combined effect, making glucose be converted into by polyhydric alcohol formula metabolic pathway that sorbitol excessively accumulates in tissue by the more activated activity of organizing aldose reductase of hyperglycemia is the major reason that causes some chronic complicating diseases of diabetes.Think that at present continuing hyperglycemia causes basement membrane of blood vessel to thicken, the hemoglobin degeneration, blood viscosity increases, and directly the influence perfusion causes the tissue ischemia anoxia, and hemorheology is unusual, plays an important role in the character process takes place.Diabetic nephropathy (DN) is the chronic microangiopathies of diabetes.In a single day early stage onset concealment easily by clinical ignorance, as developing into the clinical nephropathy phase, will cause the irreversible pathological change of kidney, thereby cause last renal failure eventually.Modern medicine thinks that the pathogeny of DN comprises that mainly multiple metabolism and endocrine regulation, hemodynamics change and microvascular structural damage.Glycolated hemoglobin increases and causes histanoxia, and hematocrit value obviously increases, and saccharifying such as plasma fibrinogen, low density lipoprotein, LDL, platelet are increased hyperamization liquid viscosity and increased, platelet aggregation.Hyperglycemia, hyperlipidemia influence, the anionic Heparan sulfate content of glomerular basement membrane band reduces, the electrostatic barrier miopragia, and excessively the albumen nonenzymatic glycosylation causes the unusual crosslinked increase of glomerular basement membrane composition, the filter membrane aperture changes, and can make urine protein output increase.
Repaglinide is a kind of non-sulfonylurea Drugs Promoting Insulin Secretion that amino acid structure is arranged, it combines with 36KDA protein-specific on the potassium-channel of the outer dependency ATP of insulin cell film, potassium channel is closed, cell depolarization, calcium channel is open, and flow of calcium ions promotes insulin secretion, its effect is faster than sulfonylurea, so hypoglycemic activity is very fast after the meal.In recent years discover that after 1 year, carotid artery intima middle level thickness obviously reduces NIDDM patient through the repaglinide treatment.Some studies show that repaglinide can better alleviate NIDDM patient's inflammatory reaction on the basis of better blood sugar control, improve vascular endothelial function and oxidative stress status, thereby prevents the heart, the generation of cerebrovascular complication, development.Ligustrazine is a kind of alkaloid monomer, by antagonism blood plasma ET, TNF level, reduces ICAM-1 and expresses, the propagation that suppresses GMCs stops the proliferative cell growth, simultaneously energy nephrectasia blood vessel, improve renal blood flow, improve the kidney microcirculation, reduce platelet aggregation, reduce blood viscosity and high blood clotting, reduce the thrombosis of kidney, alleviate the damage of glomerular basement membrane, thereby alleviate albuminuria, increase glomerular filtration rate, thereby improve renal function.Ligustrazine can effectively reduce the albuminuria of diabetic nephropathy; and can significantly reduce plasma ET; may be by the reparation of protection vascular endothelial cell, the impaired function of promotion endotheliocyte; reduce the synthetic of kidney endothelin level and to improve kidney local blood kinetics unusual, and then delay diabetes.
Because diabetic complication is to be brought out by multiple factor, drug combination embodies greater advantage at present.We studies show that, there are obvious synergism in repaglinide and ligustrazine drug combination in diabetes cardiovascular and cerebrovascular disease complication, diabetic peripheral neuropathy complication, diabetic nephropathy complication and diabetic retinopathy treatment.
The not good patient of control during for independent use repaglinide and ligustrazine can provide the repaglinide of therapeutic dose and the chemistry of ligustrazine and the dosage form of physically stable extremely to be of value to its generation of control and development in the treatment of clinical diabetes complication by the same unit dosage preparation in the mode of similar commercially available each stand-alone product.
Summary of the invention
The present invention relates to be used for the unit dose formulations of sending of uniting of repaglinide and ligustrazine or its salt, this class preparation can be used for treating diabetic complication.The invention still further relates to the preparation method and the purposes of this class combination formulations in the diabetic complication treatment of this class unit of association dosage particles.
The present invention is achieved through the following technical solutions: repaglinide 1～10 weight portion, ligustrazine or its salt 5～100 weight portions.In embodiments, the present invention relates to the unit dosage forms pharmaceutical composition, comprise and the bonded ligustrazine of repaglinide or its salt; With choose any one kind of them or multiple pharmaceutically acceptable excipient; Be prepared into oral liquid, capsule, soft gelatin capsule, tablet, drop pill, sustained-release preparation, powder pin, liquid drugs injection.
The unit dose formulations of sending the uniting of repaglinide of the present invention and ligustrazine or its salt has the better healing effect through laboratory observation to diabetic complication.Repaglinide and ligustrazine or its salt unite utilization, can potentiation and/or complementation.
(1) heightens sugar under repaglinide associating ligustrazine is worked in coordination with and cultivate the short fibrosis factor expression of myocardium fibroblast
Cardiac muscle fibroblast I type, normal sugared cultivation group of III collagen mRNA expression ratio (DMEM5 contains glucose 5mmol/L) after high sugar is cultivated (containing glucose 25mmol/L in the DMEM25 culture medium) significantly raise, high sugar+repaglinide+ligustrazine group significantly descends (P＜0.001) than height sugar group, and ratio is single with repaglinide group or ligustrazine group reduction effect more obvious (seeing Table 1).Repaglinide and ligustrazine drug combination are than single usefulness, and the fibrosis factor (TGF β is urged in also more obvious reduction
1) and the expression of CTGFmRNA, reduce Angiotensin II-1 receptor (AT
1-R) mRNA and proteic expression.
Table 1 repaglinide associating ligustrazine is collaborative to be heightened myocardium fibroblast I, the III collagen mRNA that sugar cultivates down and expresses (x ± s)
(2) the collaborative diabetic cardiomyopathy that reduces of repaglinide associating ligustrazine becomes Ca in the rat myocardial cell
2+The overload effect
The calcium ion overload is one of pathogenesis of diabetic cardiomyopathy in the myocardial cell, and it is again the main cause that causes its intracellular calcium overload that while abnormal carbohydrate metabolism makes the calmodulin (as the sarcoplasmic reticulum calcium pump) of some myocardial cell that unusual glycosylation take place.Table 2 experimentation shows, adopts STZ to inject modeling 8 all diabetic cardiomyopathys and becomes rat myocardial cells, and through repaglinide and ligustrazine associating or single with treating relatively, the collaborative diabetic cardiomyopathy that reduces of The combined becomes the interior Ca of rat myocardial cell
2+The overload effect is more single with stronger than both.
The collaborative diabetic cardiomyopathy that reduces of table 2 repaglinide associating ligustrazine becomes Ca in the rat myocardial cell
2+The overload effect (x ± s)
(3) collaborative type 2 diabetes mellitus (T2DM) the patient vessel endothelial function that improves of repaglinide associating ligustrazine
The type 2 diabetes mellitus patient gets blood and surveys VonW illebrand (VW F) and high quick C-reactive protein (HS-CRP) concentration through repaglinide and ligustrazine associating or single with 2 weeks of treatment.Table 3 result shows that repaglinide and ligustrazine therapeutic alliance improve the effect of infringement of T2DM patient vessel inner skin cell function and chronic inflammatory reaction and use by force than both are single.
The treatment of table 3 repaglinide+ligustrazine is to the influence of type 2 diabetes mellitus patient VWF and HS-CRP (x ± s)
(4) repaglinide associating ligustrazine is to the therapeutical effect of rat diabetes nephropathy
Injection STZ brings out rat diabetes, and 12 weeks back formation diabetic nephropathy (DN) is a pathological characters with the broadening of glomerular mesangium district, thin matrix build-up, basement membrane thickened and glomerular sclerosis.Table 4 shows early stage (modeling grouping back) repaglinide and ligustrazine use in conjunction are treated and can be obtained better curative effect, than single with the blood glucose that more can reduce the diabetic nephropathy model rat, glycolated hemoglobin (HbAlc), 24h urine protein, endogenous creatinine clearance rate (creatinine clearance, Ccr), matter monocyte chemoattractant protein-1 (MCP-1) and iuntercellular adhesion molecule-1 (ICAM-1) mRNA expression between kidney.
The treatment of table 4 repaglinide+ligustrazine is to the therapeutical effect of type 2 diabetes mellitus rat nephropathy (x ± s)
(5) repaglinide associating ligustrazine is to the protective effect of rat diabetes retinopathy
Rat disposable celiac injection STZ brings out diabetes model, then GP TH.Table 5 result shows, the model group rat forms diabetic renal papillary necrosis (diabeticretinopathy after 90 days, DR), show as the increase of retinal microvascular area density, retinal tissue type activator of plasminogen (tissue-typeplasminogenactivator, TPA) and VEGF (vascular endothelial growth factor, VEGF) level all significantly raises, repaglinide and ligustrazine use in conjunction are treated and can be obtained better curative effect, more can with effect than single.
Table 5 repaglinide+ligustrazine is to the protective effect of type 2 diabetes mellitus rat retina pathological changes (x ± s)
(6) repaglinide associating ligustrazine treatment diabetic peripheral neuropathy observation of curative effect
Diabetic peripheral neuropathy (diabetic peripheral neuropathy, DPN) patient adopts repaglinide and ligustrazine associating or single with 8 weeks of treatment, table 6～8 results show repaglinide associating ligustrazine treatment routine number (rate) of group produce effects and total effective rate than list with group better, more can obviously improve the motor conduction velocity (MNCV) and the sensation conduction velocity (SNCV) of median nerve, ulnar nerve, common peroneal nerve and tibial nerve.
Table 6 repaglinide+the ligustrazine treatment to the diabetic peripheral neuropathy clinical efficacy relatively
MNCV changes before and after table 7 repaglinide+ligustrazine treatment comparison (x ± s, ms
-1)
SNCV changes before and after table 8 repaglinide+ligustrazine treatment comparison (x ± s, ms
-1)
Claims (4)
1. treat the unit dose combination formulations of sending uniting of diabetic complication for one kind, it is characterized in that wherein containing repaglinide and ligustrazine or its salt and both pharmaceutically acceptable excipient of effective dose.
2. the unit dose combination formulations of sending of uniting according to claim 1, it comprises: 1～10 weight portion repaglinide, 5～100 weight portion ligustrazine or its salt.
3. according to the described unit dose combination formulations of sending of uniting of claim 1-2, it is characterized in that and choose any one kind of them or multiple pharmaceutically acceptable excipient, be prepared into oral liquid, capsule, soft gelatin capsule, tablet, drop pill, sustained-release preparation, powder pin, liquid drugs injection.
4. according to the described unit dose combination formulations of sending of uniting of claim 1-3, it is characterized in that being used for diabetic nephropathy, diabetic cardiomyopathy change and diabetic complications treatments such as large artery trunks pathological changes, diabetic renal papillary necrosis and crystalline lens pathological changes, diabetic peripheral neuropathy.
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| Application Number | Priority Date | Filing Date | Title |
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| CN200910263427A CN101816655A (en) | 2009-12-16 | 2009-12-16 | Medicinal preparation containing repaglinide and ligustrazine and application thereof in diabetic complications |
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| CN200910263427A CN101816655A (en) | 2009-12-16 | 2009-12-16 | Medicinal preparation containing repaglinide and ligustrazine and application thereof in diabetic complications |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8507451B1 (en) | 2011-03-07 | 2013-08-13 | Zhili Wang | Method for the treatment of type II diabetes |
| CN115887460A (en) * | 2017-05-27 | 2023-04-04 | 青岛海蓝医药有限公司 | Application of ligustrazine nitrone derivative in preventing and treating diabetic complication diseases |
-
2009
- 2009-12-16 CN CN200910263427A patent/CN101816655A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8507451B1 (en) | 2011-03-07 | 2013-08-13 | Zhili Wang | Method for the treatment of type II diabetes |
| CN115887460A (en) * | 2017-05-27 | 2023-04-04 | 青岛海蓝医药有限公司 | Application of ligustrazine nitrone derivative in preventing and treating diabetic complication diseases |
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Application publication date: 20100901 |