CN102973592A

CN102973592A - Application of dextran sulfate in preparing medicament for treating diabetes mellitus

Info

Publication number: CN102973592A
Application number: CN2012104860277A
Authority: CN
Inventors: 董磊
Original assignee: Hefei Botai Pharmaceutical Biotechnology Development Co Ltd
Current assignee: Hefei Botai Pharmaceutical Biotechnology Development Co Ltd
Priority date: 2012-11-26
Filing date: 2012-11-26
Publication date: 2013-03-20

Abstract

The invention discloses novel application of dextran sulfate in preparing a medicament for treating diabetes mellitus. The medicament can protect a body from insulin resistance due to chronic inflammation caused by activated macrophage generated by fat and other reasons, so that attack or symptom worse of diabetes mellitus. Dextran sulfate has good curative effect in a high glucose and lysophosphatidylcholine induced animal model; and the medicaments used in the application can be easily acquired, low in price and stable in properties, are convenient to store and transport, and have wide application prospect.

Description

The application of dextran sulfate in preparation treatment diabetes medicament

Technical field

The invention belongs to the biological medicine technology field, be specifically related to the application of dextran sulfate in preparation treatment diabetes medicament.

Background technology

Diabetes are the diseases that have a strong impact on people's life health.In recent years along with people life style, the variation of dietary habit, the onset diabetes rate has continuous rising, and age of onset has the trend of continuous rejuvenation.Diabetes are divided into insulin-dependent (I type) and non-insulin-depending type (II type) two large classes generally, in the diabetics, are the type ii diabetes patient more than 90%.

Dextran sulfate Dextran sulfate, molecular weight 2KD ~ 600KD does not wait, and it is the polyanionically-derivatised thing of glucosan, is formed by the esterification of glucosan and chlorosulfonic acid, and at present, it is mainly used in blood fat reducing and antiatherosclerotic.

Nearest basic research proves, follow the fat lipid peroxidation that waits physiologic factor to produce to cause for a long time, low-level chronic inflammatory disease, the activated macrophage that wherein is distributed in the fatty tissue can cause significant insulin resistant by some inflammatory factor of long-term expression, make body to insulin insensitivity, then cause diabetic symptom.Therefore for this pathogenesis, can develop targetedly treatment means and medicine.

Summary of the invention

Purpose of the present invention namely is to provide the application of a kind of dextran sulfate in preparation treatment diabetes medicament, dextran sulfate of the present invention can demonstrate the character of strong inhibition macrophage activation in related experiment, suppress the expression of relevant inflammatory factors, thereby can alleviate the insulin resistant in the type ii diabetes pathogenic process, alleviate diabetic symptom.Therefore, dextran sulfate can develop into a kind of medicine for the treatment of diabetes on the principle.

The application of dextran sulfate of the present invention in preparation treatment diabetes medicament, wherein, described dextran sulfate is alpha-glucans, molecular weight is 3.6 kD ~ 300 kD.

Described dextran sulfate can be the commercially available prod, also can synthesize with commercial available dextran sulfate modification, the glucosan of modifying the different molecular weight size as passing through chlorosulfonic acid-pyridine method obtains, preparation method as: pyridine is added in the three-necked bottle with condensing tube and agitating device, place cryosel to bathe, dropwise add chlorosulfonic acid, 10 min dropwise, add again alpha-glucans, immediately it is moved in the oil bath of preheating in 400-1000 degree centigrade of isothermal reaction.React complete after, in reactant liquor impouring frozen water.Transfer to pH neutrality with 10 mol/LNaOH.With deionized water 48 h that dialyse, dialysis solution concentrates precipitate with ethanol, redissolution, lyophilizing, namely gets dextran sulfate (Richetts CR. Preparation of dextran sulphate and tracer experiments in the rabbit. Biochem J. 1954; 58:523. the favorable to the people pharmaceutical factory in Guangdong. dextran sulfate: pyridine-chlorosulfonic acid esterification process brief introduction. medical industry, 1975; 3:1.）。Control reaction temperature, can control the modification rate of glucosan, the different modifying rate is as follows with corresponding reaction temperature synopsis among the present invention:

Molecular weight and modification rate	Reaction temperature
		3.6 the KD dextran sulfate, 5% modifies	400 degrees centigrade
3.6 the KD dextran sulfate, 27% modifies	690 degrees centigrade
		40 KD dextran sulfates, 7% modifies	570 degrees centigrade
40 KD dextran sulfates, 22% modifies	750 degrees centigrade
		70 KD dextran sulfates, 8% modifies	630 degrees centigrade
70 KD dextran sulfates, 24% modifies	860 degrees centigrade
		70 KD dextran sulfates, 43% modifies	970 degrees centigrade
110 KD dextran sulfates, 6% modifies	790 degrees centigrade
		110 KD dextran sulfates, 18% modifies	940 degrees centigrade
300 KD dextran sulfates, 4% modifies	880 degrees centigrade
		300 KD dextran sulfates, 14% modifies	1000 degrees centigrade

Adopt dextran sulfate of the present invention to combine with multiple pharmaceutically acceptable carrier for soluble salt such as the dextran sulfate sodium salt of dextran sulfate, by such as oral cavity, vein, nasal cavity, rectum or other any administering modes that can carry the active substance of effective dose, can be prepared into various liquid preparations such as injection, oral liquid formulations etc., also can be prepared into various effectively and be easy to solid preparation such as capsule, the suppository etc. of administration.Wherein, be used for injection or liquid preparation for oral use, its required carrier can be the medically acceptable carriers such as sterilized water, Sterile Saline or water solublity organic carrier such as cyclodextrin, Semen Maydis oil, olive oil, ethyl oleate, glycols; The solid drug-delivery preparation can add solid preparation adjuvant commonly used such as excipient glucose, lactose, cellulose etc. in preparation, also can add lubricant Polyethylene Glycol, magnesium stearate etc., and the required adjunct ingredients of solid preparation such as binding agent, correctives, again by operation molding such as mixing, granulations.The effective dose of the active substance in above-mentioned these preparations is the amount that diabetic symptom is obviously reduced, research worker with routine techniques can be determined the most effective dosage and the time consideration administering mode of the reagent that this invention provides, drug metabolism, and some other pharmacokinetic parameter drug distribution for example, clearance rate etc.Reagent provided by the present invention can also and other reagent conventional antidiabetic drug medicine administering drug combinations for example so that the onset diabetes degree effectively reduces.

The present invention carries out illustration by the diabetes model of in the body high glucose and high fat being induced.Animal herein includes, but are not limited to: mice, rat, performing animal includes, but are not limited to cat, Canis familiaris L., and some other animal for example but be not limited to cattle, sheep, pig, horse, primate for example but be not limited to monkey and people.

The present invention proposes the new application of dextran sulfate in preparation treatment diabetes medicament; the insulin resistant that the chronic inflammatory disease that the activated macrophage that this medicine can protect body to avoid the reason generations such as obesity causes causes, thereby outbreak or the sx↑ of inhibition diabetes.Dextran sulfate is obtained good curative effect in the animal model that high glucose and high fat is induced, simultaneously, medicine used in the present invention is easy to obtain, and is cheap, and stable in properties is convenient to storage and transport, has broad application prospects.

The specific embodiment

The zoopery example

(treatment of the diabetes model that dextran sulfate injection solution preparation is induced high glucose and high fat)

It is for subsequent use that the dextran sulfate of different molecular weight and different modifying rate is made into the 2.0mg/ml injection with physiological saline solution, regulates pH value to 7.0 with 10 mol/L NaOH solution.Get 78 of female new zealand white rabbits, body weight 1.8 kg-2.0 kg are divided into 13 groups at random with animal, and 6 every group, i.e. Normal group, diabetic model group, respectively with the treatment group of the dextran sulfate treatment of different molecular weight and modification rate.Normal group utilizes common feedstuffs (rabbit standard common feedstuff, Standard Laboratory Chow for Rabbits, Shanghai Shengwang Experimental Animal Ranch (P.R.China) company) to raise.Model group animal and each treatment experimental group is supplied with the high lipolysaccharide feedstuff that contains the sucrose of 10% Adeps Sus domestica and 37% above-mentioned rabbit in the standard test feedstuff, and the lumbar injection dextran sulfate is treated, and the model group of drug treatment is not injected isopyknic normal saline.After (after 0 week), 4 weeks after the experiment beginning, after 8 weeks, after 12 weeks, after 16 weeks, after 20 weeks and after 24 weeks, make and respectively organize rabbit and go on a hunger strike a night, take a blood sample from arteria auricularis, use the commercially available glucose assays test kit that utilizes enzyme process (Glucose Determination Kit(Glucose oxidase-peroxidase method), Shanghai Rongsheng Biotech Inc.(P.R.China) company makes), measure the concentration of glucose (mg/dl) in the blood plasma, experimental result is as shown in table 1:

Table 1: the evaluation of pesticide effectiveness of dextran sulfate

Group	0 week	4 weeks	8 weeks	12 weeks	16 weeks	20 weeks	24 weeks
								Normal group	54	61	48	72	58	67	55
Model group	51	109	118	122	125	134	134
								3.6 the KD dextran sulfate, 5% modifies	57	81	82	78	74	68*	72*
3.6 the KD dextran sulfate, 27% modifies	57	78	73	71	74	65*	61*
								40 KD dextran sulfates, 7% modifies	62	90	85	89	83	78*	81*
40 KD dextran sulfates, 22% modifies	50	98	91	88	86	78*	87*
								70 KD dextran sulfates, 8% modifies	63	77	88	67	72	81*	62*
70 KD dextran sulfates, 24% modifies	41	87	73	66	74	72*	63*
								70 KD dextran sulfates, 43% modifies	59	61	85	71	73	63*	72*
110 KD dextran sulfates, 6% modifies	47	78	83	74	66	70*	72*
								110 KD dextran sulfates, 18% modifies	56	68	89	92	93	89*	83*
300 KD dextran sulfates, 4% modifies	72	98	101	94	81	93*	92*
								300 KD dextran sulfates, 14% modifies	67	78	89	86	86	84*	85*

Claims

1. the application of dextran sulfate in preparation treatment diabetes medicament.

2. application according to claim 1 is characterized in that: described dextran sulfate molecular weight is 3.6 kD ~ 300 kD.