Summary of the invention
Technical problem to be solved by this invention provides that a kind of toxicity is little, the vanadium complexes of the polysaccharide derivates of oral easy absorption.After polysaccharide is modified through carboxymethylation, because carboxymethyl has stronger complex ability with the vanadyl ion, the vanadyl complex of formation polysaccharide derivates, and make that the content of vanadium ion increases in the complex compound.
In order to address the above problem, the present invention specifically adopts following scheme:
The vanadium complexes of polysaccharide derivates, polysaccharide that at first NaOH has been alkalized and Monochloro Acetic Acid are at 40-80 ℃ of reaction 3-4 hour down, synthetic polysaccharide derivates; Then above-mentioned polysaccharide derivates and vanadium solution were at room temperature reacted 12-24 hour, obtain the vanadium complexes of polysaccharide derivates.
Polysaccharide comprises chitosan, carrageenin, synanthrin etc.;
The mass ratio of polysaccharide, NaOH and Monochloro Acetic Acid is 1: 1.2-1.5: 1.2-2;
The time of NaOH alkalization polysaccharide is 0.5-1.5h;
The mass ratio of polysaccharide derivates and vanadium ion is 100: 0.1-5;
Vanadium solution is VOSO
4The aqueous solution;
The temperature of reaction of polysaccharide and Monochloro Acetic Acid is 60 ℃.
The application of the vanadium complexes of this polysaccharide derivates in the treatment hypoglycemic drug.
Compared with prior art, the present invention has following advantage:
1, the present invention has the advantage of following three aspects: one, polysaccharide derivates itself has multiple pharmacological effect such as antitumor, anti-various cardiovascular diseasess, antiviral, anti-oxidant, hypoglycemic and strengthening immunity; Two, polysaccharide is modified through carboxymethylation, and at first, carboxymethylation strengthens the water-soluble of polysaccharide greatly, is easy to absorption and the utilization of organism; Secondly, the coordination of carboxymethylation polysaccharide and vanadium ion strengthens greatly, the content of the vanadium in the complex compound is raise, can give full play to the physiologically active of micro-vanadium and polysaccharide derivates, make both effect coordinate mutually and strengthen, improve vanadium utilizability in vivo, reach same curative effect required dosage and reduce, greatly reduce toxicity; Three, inorganic vanadium is converted into the organic vanadium of polysaccharide derivates as part, polysaccharide derivates itself is nontoxic, but also have certain prevention and reduce the ability of the toxic side effect of vanadium, the coordination environment that provides leaves certain room and becomes key position with weak when forming title complex, ligand exchange can take place, be convenient to combining of complex compound and substrate, improved the mode of vanadium absorption in vivo, distribution, metabolism and removing simultaneously.
2, the existing report of the complexing of transition metal ion and sugar, but the complexing of general Study transition metal and monose or disaccharides, and reaction medium is a methyl alcohol.It is raw material that the present invention adopts the derivative of polysaccharide, in aqueous medium, and the following and VOSO of neutrallty condition
4Reaction through filtration, dry, pulverizing, obtains the complex compound of vanadium and polysaccharide derivates.Among the present invention, the preparation of complex compound is carried out fully at ambient temperature, and technology is simple, is easy to realize suitability for industrialized production.
Embodiment
The present invention will be described in detail below in conjunction with embodiment:
Embodiment 1: with 50.0g chitosan swelling 20min in the 450ml Virahol, drip massfraction and be 50% NaOH solution 120.0g and alkalize, alkalize after 1 hour, the 60.0g Monochloro Acetic Acid is dissolved in is added drop-wise in the 75ml Virahol in the above-mentioned reaction solution, system is warmed up to 60 ℃ then, isothermal reaction 3.5 hours, after reaction finishes, treat that temperature drops to room temperature after, regulating pH value is neutrality, add 3 times of volume of ethanol sedimentations, filter washing, drying, pulverize, obtain the carboxymethylation chitosan; The 5.0g cm-chitosan is dissolved in the 130ml deionized water, it is neutral regulating the pH value, drip the 0.1609gVOSO4 solid simultaneously and be made into the aqueous solution of 20ml, reacted 12 hours, and added 4 times of volume of ethanol sedimentations, filter, with filtration cakes torrefaction, pulverize, promptly get the complex compound of lurid vanadium and cm-chitosan, the content of vanadium is 0.75% in the complex compound.
Fig. 1 is the characteristic infrared (cm of chitosan
-1): 3379.64,2879.2,1644.98,1421.28,1320.04,1083.80; Fig. 2 is the characteristic infrared (cm of cm-chitosan
-1): 3408.57,2918.74,1603.52,1421.28,1321.00,1066.44; Fig. 3 is the characteristic infrared (cm of cm-chitosan vanadyl complex
-1): 3371.92,2918.74,1599.66,1416.46,1324.86,1070.30.Fig. 2 compared to Figure 1, at 1603.52cm
-1The place new absorption peak, 1603.52cm have appearred
-1Corresponding is the stretching vibration peak of carboxyl in the cm-chitosan, has proved the formation of target compound cm-chitosan.Fig. 3 compares with Fig. 2, and certain displacement has all taken place some characteristic peaks, and peak width and absorption intensity weaken, and illustrates that these groups have all participated in and the complexing of vanadyl ionic.Illustrate that vanadium oxonium ion and cm-chitosan combine with the form of chemical bond and formed the complex compound with certain constitutional features.
Embodiment 2: with 50.0g carrageenin swelling 25min in the 750ml Virahol, drip massfraction and be 50% NaOH solution 120.0g and alkalize, alkalized 1.5 hours, the 60.0g Monochloro Acetic Acid is dissolved in is added drop-wise in the 75ml Virahol in the above-mentioned reaction solution, system is warmed up to 60 ℃ then, isothermal reaction 4 hours, after reaction finishes, treat that temperature drops to room temperature after, regulating pH value is neutrality, add 3 times of volume of ethanol sedimentations, filter washing, drying, pulverize, obtain the carboxymethylation carrageenin; 30.0g carboxymethyl carrageenin is dissolved in the 600.0ml deionized water, and it is neutral regulating the pH value, drips 0.966gVOSO simultaneously
4Solid is made into the aqueous solution of 100ml, reacts 24 hours, adds 4 times of volume of ethanol sedimentations, filters, and with filtration cakes torrefaction, pulverizes, and promptly gets the complex compound of milky vanadium and carboxymethyl carrageenin, and the content of vanadium is 0.43% in the complex compound.
Fig. 4 has shown the characteristic absorbance of carrageenin, 3409.53cm fully
-1The absorption peak of position is the stretching vibration characteristic peak of hydroxyl, 2962.13cm
-1The absorption peak of position is a C-H stretching vibration absorption peak, 1234.22cm
-1The absorption peak of position is the asymmetric stretching vibration peak of sulfur-to-oxygen double bond in the sulfate, 926.63cm
-1The absorption peak of position is the charateristic avsorption band of 3,6 inner ether semi-lactosis, 848.53cm
-1The absorption peak prompting sulfate of position is connected the C-4 position of galactosyl.
Fig. 5 compares with Fig. 4, at 1610.27cm
-1The place new absorption peak, 1610.27cm have appearred
-1Corresponding is the stretching vibration peak of carboxyl in the carboxymethyl carrageenin, has proved the formation of target compound carboxymethyl carrageenin.
Fig. 6 compares with Fig. 5, can find, is positioned at 1610.27cm
-1The absorption peak of carboxymethyl carrageenin vanadyl complex carboxyl obviously weaken, illustrate that complex reaction has taken place for carboxyl and vanadyl ion; Be positioned at 3443.28cm
-1The absorption peak of carboxymethyl carrageenin vanadyl complex hydroxyl obvious displacement taking place and absorbs obviously weakens, illustrated that complex reaction has taken place for part of hydroxyl and vanadyl ion; Be positioned at 1255.43cm
-1The vibration peak and the 927cm of sulfur-to-oxygen double bond
-1The charateristic avsorption band of 3,6 inner ether semi-lactosis compare with the carboxymethyl carrageenin, absorption intensity weakens, and illustrates that the Sauerstoffatom of two keys of S=O and ehter bond has also participated in and the complexing of vanadyl ionic.Illustrate that vanadium oxonium ion and carboxymethyl carrageenin combine with the form of chemical bond and formed the carboxymethyl carrageenin vanadyl complex with certain constitutional features.
Embodiment 3: with 50.0g synanthrin swelling 20min in the 400ml Virahol, drip massfraction and be 50% NaOH solution 120.0g and alkalize alkalization 45min, the 60.0g Monochloro Acetic Acid is dissolved in is added drop-wise in the 75ml Virahol in the above-mentioned reaction solution, system is warmed up to 60 ℃ then, isothermal reaction 4 hours, after reaction finishes, treat that temperature drops to room temperature after, regulating pH value is neutrality, add 3 times of volume of ethanol sedimentations, filter washing, drying, pulverize, obtain the carboxymethylation synanthrin; The 5.0g carboxymethyl inulin is dissolved in the 100.0ml deionized water, and it is neutral regulating the pH value, drips 0.1609gVOSO simultaneously
4Solid is made into the aqueous solution of 20ml, reacts 15 hours, adds 4 times of volume of ethanol sedimentations, filters, and with filtration cakes torrefaction, pulverizes, and promptly gets the white vanadium and the complex compound of carboxymethyl inulin, and the content of vanadium is 0.35% in the complex compound.
Embodiment 4: hypoglycemic activity experiment, and select for use the vanadium complexes of cm-chitosan and the vanadium complexes of carboxymethyl carrageenin to carry out hypoglycemic experiment, as a sample, mass concentration is 5% with the vanadium complexes of cm-chitosan; As No. two samples, mass concentration is 10% with the vanadium complexes of carboxymethyl carrageenin.At first, make the diabetes model of mouse, select the Kunming kind healthy male mice of body weight 20-24g for use, adapt to experimental situation after 5 days, fasting 20h, with 160mg/kg body weight dosage abdominal injection, fasting is 6 hours after 5 days with freshly prepared tetraoxypyrimidine, measure fasting plasma glucose, with 10mmol/L<blood sugar<25mmol/L as diabetic mice.
In the hypoglycemic experiment of diabetic mice, selecting the Kunming kind healthy male mice random packet of body weight 20-26g for use is the normal control group, it is model control group, glyburide (Glyburide) control group, low dose group, middle dosage group, high dose group that diabetic mice is divided into 5 groups at random by blood glucose value level disease, 10 every group.Normal control group and the isopyknic tap water of high sugared model control group gastric infusion, glyburide control group, low dose group, middle dosage group, the isopyknic finite concentration sample of high dose group gastric infusion, administration time is 21d, carries out fasting plasma glucose when experiment finishes and measures.
Table 1 is the influence to hyperglycemia model mouse body weight of sample
Table 2 is the influence to the mouse fasting plasma glucose of sample
Annotate: as shown in Table 2, compare P>0.05, * P<0.05, * * P<0.01 with normal control;
Compare P>0.05 with model, #P<0.05, ##P<0.01;
Compare P>0.05 with the Glyburide control group; P<0.05 , ﹠amp; ﹠amp; P<0.01
Can draw from the data of table 1, No. one sample does not have influence substantially to hyperglycemia model mouse body weight; From the data of table 2 as can be known, a sample basic, normal, high dosage group in the hypoglycemic experiment of diabetic mice therapeutic all has remarkable blood sugar reducing function (P<0.05) to fasting plasma glucose, and middle dosage group particularly significantly (P<0.01) does not have notable difference (P>0.05) with each dosage group blood sugar reducing function of Glyburide group comparison.
Table 3 is the influence to hyperglycemia model mouse body weight of No. two samples
Table 4 is the influence to the mouse fasting plasma glucose of No. two samples
Annotate: as shown in Table 4, compare P>0.05, * P<0.05, * * P<0.01 with normal control
Compare P>0.05 with model, #P<0.05, ##P<0.01
Compare P>0.05 with the Glyburide control group; P<0.05 , ﹠amp; ﹠amp; P<0.01
No. two samples do not have influence substantially to hyperglycemia model mouse body weight as can be seen from Table 3; As known from Table 4, No. two samples are in the hypoglycemic experiment of diabetic mice therapeutic, and basic, normal, high dosage group all has remarkable blood sugar reducing function (P<0.05) to fasting plasma glucose and diabetic mice sugar dosis tolerata, and high dose group particularly significantly (P<0.01).With Glyburide group comparison high dose group blood sugar reducing function notable difference (P<0.05) is arranged, other dosage group blood sugar reducing functions do not have notable difference (P>0.05).
Experimental result shows: the vanadium complexes of the vanadium complexes of cm-chitosan and carboxymethyl carrageenin all has significant blood sugar reducing function to fasting plasma glucose and the anti-sugar amount of diabetic mice in the hypoglycemic experiment of diabetic mice.