SU1048987A3 - Method of producing polyglucane ester - Google Patents

Abstract

СП METHOD OF OBTAINING COMPLEX ETHER OF A POLYHYLUCANE by the esterification of a polyglucan with anhydride of glutaric or succinic acid in solution in the presence of a catalyst, so that in order to get a chemically cross-linked polyglucan ester having a high hemostatic function, you can use a sylphane-rich, hemostatic component. amylose, dextran or pullulan are used, and the esterification is carried out at pH 7-9 to the degree of substitution of polyglucan ester 0.324-2.43, followed by acidification to pH 4.0-5.2, drying and heat treatment at 60 and 120 s, respectively, 2, the method according to claim 1, consisting in the fact that, in order to obtain a networked polyglucan ester, obtained after acidification of 3.8-4, the polyglucan solution is frozen in the presence of 0.2 5 0.55 С CoC, formamide, N - methyl 2-pyrSP of rolidone or dimethyl sulfoxide per weight, h, of a polyglucan ester at a temperature below, 4 00 co oo

Description

The invention relates to the field of chemical technology, in particular to the preparation of hydrogel sponges based on cross-linked polyglucanesters of succinic or glutaric acids, which have high hemostatic activity.  A known method of producing polyglucan esters by esterifying a polyglucan with glutaric or succinic acid in solution in the presence of a catalyst. Starch pj is used as a polyglucan. The resulting products are not crosslinked, cannot be obtained in the form of sponge hydrogels, and does not have hemostatic activity. crosslinked ester of polyglucan with high hemostatic activity The goal is achieved by the fact that according to the method of obtaining difficult polyglucan ester by esterification of a polyglucan with glutaric or succinic acid in solution in the presence of a catalyst, amylose, dextran or pullulan is used as a polyglucan, and esterification is carried out at up to the degree of polyglucan ether substitution, 3, followed by acidification of the solution to pH 4.0- 5.2 by drying and heat treatment at 60 and, respectively, for the preparation of a polyglucan ester with a net structure obtained after acidification of 3.8, the polyglucan solution is frozen in the presence of 0.2-0.55% CoS formamide, N -met Il-2-pyrrolidone or dimethyl sulfoxide per 1 pound of Cho polyether ester at a temperature below Example 1 ° Amylose succinate, 400 g of amylose potatoes (Superlose, Stein Hall) with moisture 9.1 poured through a sieve into 400 ml of intensively stirred water to obtain a homogeneous milk mixture The mixture is cooled to 10 ° C and 595 g of a 50.6% sodium hydroxide solution and 1700 ml of water are added to it.  After the mixture is clarified and the temperature rises to 13 ° C, 685 g of succinic anhydride powder are poured into the reaction mixture through a sieve.  After the pH drops to about 8, a 5N sodium hydroxide solution (1000 ml of 1 872 pre-weighed solution is used) is added at a rate sufficient to maintain the pH of the reaction mixture between 8 and 9 ° 5 But the sodium hydroxide solution is weighed and the exact amount used the amount is 929.9 g or 788.0 ml. During the reaction, the reactor is cooled to maintain the temperature of the reaction mixture between 10 and 22 ° C. The degree of substitution (C3) of succinate groups is calculated according to the stoichiometric reaction equation g7 1b2 (20x-y) 7 where X is the weight of succinic anhydride, g; y is the amount of sodium hydroxide used, mmol; 2, - dry weight of amylose,  Therefore, SOC 162 (20-685 -114bb1 1000 363.6 Then the reaction mixture is filtered to remove all substances with a particle size. more than 5 µm. The pH of the solution is adjusted to 4.0 by addition of acetic acid in the filtered solution. The solution is dialyzed in cellulose tubes to remove low molecular weight salts until the electrical conductivity of the solution becomes constant.  Concentrate the solution in the evaporator to a solids concentration of 13.2. A solution of the resulting amylose succinate (solids concentration 13.2, NW 1.00 and pH 4, o) in the form of a partial sodium salt is poured in a film 1 mm thick onto the glass. these plates.  The films are dried for 2 hours at 60 ° C in a heating cabinet. with forced air ventilation and cross-linked with cross-bridges by immediately placing them in a heating cabinet with forced air ventilation heated to 120 ° C for about 20 minutes.  After cooling, the films and plates are soaked for 15 minutes in an aqueous solution of sodium bicarbonate.  The film is separated from the plate and collected on Segeh® fabric 28.8 g / m (Moncanto Corp), (Spunbonded non-woven nylon, Spunbonded nylon yarn). The film is then placed together with the cloth in distilled water and subjected to grinding in a homogenizer for 15 seconds. at high speed.  The pH of 7 is created by adding an aqueous solution of succinic acid to the mixture. The product, which is a powdered hydrogel, is collected on Segeh fabric and washed twice with 5 times the volume of distilled water relative to the volume of the hydrogel.  The gel is dried by immersion in a 10-fold volume of anhydrous acetone relative to its swollen volume.  The acetone is decanted and the product is dried in a vacuum heating cabinet for 1 hr. The product is subjected to mild abrasion with a mortar and pestle to destroy the aggregates and the resulting powder is separated by sequential sieving into three fractions of -50, 100 and 200 mesh. Salt retention is determined by swelling 5QO mg of powder with a predetermined moisture content retained on a sieve with a pore size of 100 Meso, in 50 ml of 0, an aqueous solution of sodium chloride at 23 ° C with stirring for 10 min. The powdered hydrogel is drawn into sushivaniem on preliminary but a piece of cloth suspended Segeh® until until no dripping from it.  The raw powder is weighed on a - fsi piece of Segeh tissue and the amount of salt supercooling (C |) is calculated by the equation. Wet weight of powder. Dry weight of powder. Salt retention is 19.5. Test of hemostatic effect is carried out by determining the ability of the material to stop bleeding that occurs in an adult dog. as a result of the amputation of the tissue of the village.  The animal is anesthetized with pontotal sodium.  An incision is made along the midline of the abdominal cavity and the spleen is exposed.  Part of the TC or spleen amputated.  The removed area is 2.5 x 0.95 cm with a wound depth determined by the scissors bend (approximately 0.32 cm).  After the occurrence of heavy bleeding, the area on which the amputation was performed is soaked with dry cotton gauze and some amount (about 300 mg) of the dry powdered hydrogel based on the neutral sodium salt of amylose succinate is immediately applied to the wound. , obtained in accordance with the present example, and kept on the wound 30 with the addition of a weak pressure effect on the powder using a dry cellulose gauze pad.  After the gauze pad is removed, the bleeding does not resume and most of the powder is not soaked with blood.  If no further bleeding is observed for the next 10 minutes, excess powder is removed by adding an isotonic saline solution to it.  Most of the powder swells in saline and is washed off, but the powder soaked in blood remains at the wound site, continues to exhibit a hemostatic effect, and its consistency acquires a rubber-like character.  Due to this consistency of the clot and its snug fit to the underlying tissue, the wound withstands significant movements and does not bleed.  Example 2, pH for crosslinked films.  Of. the masses of amylose succinate synthesized and prepared in accordance with the procedure of Example 1 were prepared by introducing sodium bicarbonate solution to pH 5.2 and 5.5 by introducing sodium bicarbonate solution.  Films (l mm thick) from these samples are heated for 2 hours at 60 ° C and then for 1-0.5 hours at, in heating cabinets with forced air ventilation.  The trial of the insolubility of a dense film when neutralized in sodium bicarbonate solution, good stitching occurred at pH 5.0; 5.2, The dissolving of the sample in this solution at pH 5 | 5 indicates that the crosslinking did not occur.  Example 3 Amylose succinate with a maximum degree of substitution.  According to the technology of Example 1, amylose succinate is obtained using 30 g of amylose dissolved in 200 ml of water, 200 g of succinic anhydride, 21.1 g of 50.6% NaOH and 78.9 g of 5N, NaOH. The degree of substitution of the obtained amylose succinate is 2, 43, The resulting product is filtered, dialyzed and crosslinked according to the procedure of Example 1 with the difference that some films are heated for 22 minutes and other films are heated at 35 minutes.  The salt retention values of these samples (powders per 100 mesh) are 16.0 and-15.6, respectively.  These powders (100 mesh) stop the bleeding of a dog's spleen wound in less than 30 seconds.  Example 4 Salts of amylose succinate, Calcium, magnesium, potassium and ammonium salts of the cross-linked powdered amylose succinate (SZ 1.1; SU 13.4, prepared according to the general procedure described in example 1) are obtained as follows. About 1.3 g 100 mesh powder in the form of sodium salt is stirred in 50 ml of water and acidified to pH 4.0 1 But HCE.  The gel is washed twice with water (100 ml portions) and then stirred for 4 minutes in 5 solutions of this salt — one of the listed in Table 1–. Then the gel is washed three times with water (100 ml portions), twice with acetone (portions 100 ml each) and heated for 1 hour in vacuum at 70 ° C Table 1 8.1 Less than 3 seconds acetone, 0 tat magnesium 10.6 potassium acetate 5% bicar 10.2 Less than 3 seconds ammonium booster Example 5 "Succinate dextran To 100 g of dextran in 1 l of water, succinic anhydride (100 g) and 5 N of NaOH are added alternately (314.8 g while maintaining the pH between 8 and 9 and the temperature in the range of 6-10 ° C. dextran succinate 1.14 ' The dextran succinate solution is acidified with glacial acetic acid to pH 4, dialyzed against distilled water until the conductivity is set constant and concentrated in an evaporator at 45-55 ° C to a concentration of solids 51 Polymer solution films 1 mm thick are applied to glass plates. An hour of plates is heated for 2 hours at 60 ° C and then for 1 hour at, and the rest at 60 ° C for 220 minutes and then 127 minutes at the Film is neutralized in% sodium bicarbonate solution , Aspirated for 15 seconds in 100 ml of water in a homogenizer, filtered and mixed with 600 ml of water. After adjusting the pH of this mixture with succinic acid to 7.0, the crushed film was washed twice more with water (600 4 parts each) and twice with acetone (portions 400 ml) and heated in a vacuum oven at for 1 h.  This dry sample is ground in a mortar and pestle and sieved through a sieve, extracting 100 fractions of a mesh (150 mm), 200 mesh (150-75 microns) and more than 200 mesh (less than 75 microns).  Salt retention of the sample fraction of 100 mesh, heated a shorter time, 85, salt retention of the sample of the same fraction, but heated a longer time, 15.4.  The samples of these powders exhibit a good hemostatic effect on the wound of the dog's spleen, stopping the bleeding in less than 30 seconds. Example 6 ° Pullulan succinate To 25 g of pullulan in 225 ml of water at 10 ° C is added 24.0, 6 wt. % NaOHo To the solution of pullulan according to the procedure of Example 5, succinic anhydride (35 g) and 5N NaOH (53.7 g) are added alternately.  Calculated degree of substitution of pullulan succinate 1.1 Such a solution of pullulan succinate is processed into a cross-linked powder according to Example 5 with the difference that film formation is made from PA. Z-solution by heating at 60 ° C for 90 minutes and then at 120 ° C for 40 minutes. Salt retention of the powder fraction 100 mesh 19 ° 9. A sample of the powder fraction 100 mesh has a good hemostatic effect on the wound of the dog's spleen, stopping the bleeding in less than 30 c. Example 7 Amylose Glutarate To 55 g of amylose in 500 ml of water at 10 ° C is added 25.8 g of 50.6 weight of NaOH.  Glutaraldehyde (Т14.1 g) and 5 N, NaOH (277 g) are alternately added to the amylose solution according to the procedure of Example 5. Calculated degree of substitution of amylose glutarate 1.6 The amylose glutarate solution is recycled into cross-linked powder according to an example 5 with the difference that film formation was carried out from a 27.1% solution by 1.5 hours heating at 60 ° C and heating for 25 minutes at.  14.3o salt retention A sample of this powder has a good hemostatic effect on a dog's spleen wound, stopping the bleeding in less than 30 seconds.  Example 8 Dextran amylosuccinato 44 g (52% solids) not cross-linked with dextran succinate prepared according to Example 5 was mixed with 156 g (14, solid content) also not treated for cross-linking amylose succinate obtained according to example 1, using a mechanical stirrer and creating sodium bicarbonate with a pH in a mixture of 4.2, the mixture of this solution 1 mm thick is heated at 60 ° C for 150 minutes and heated to 120 ° C for 100 minutes and powdered according to example 5 o Saline holding the powder of the 100 mesh fraction 11.5 A sample of the powder of the 100 mesh fraction has a good hemostatic effect, stopping bleeding on a dog's spleen wound in less than 30 s.  Example 9  Pullulan-amylo-zasuccinate, 5b g (with a solids content of 52) not cross-linked with pullulan succinate prepared according to Example 6 is mixed with 142 g (with a solids content of 14.5%) amylose succinate, also not treated for cross-linking, according to example 8, with the difference that the film is heated for 35 min. Salt retention is 16.1, the hemostatic effect is good, the bleeding stops in less than 30 seconds. Example 10 o Amylose glutarate – amylose succinate, 80 g (with solid content substances 21.7 not subjected to cross-linking glutarate amylose, obtained according to example 7, mixed with 120 g (solids 14.5) succin) amylose in accordance with example 8 with the fact that the film is heated at 120 C for 25 min.  Salt retention of 22.8, the product has a good hemostatic effect, stopping the bleeding in less than 30 seconds.  Example 11 Preparation of an amylose succinate sponge using a formamide, 400 g amylose potatoes (Superlose.  Stein Hall) with a moisture content of 12.2 is poured through a sieve in 4700 ml of rapidly stirred water at 23 ° C to obtain a homogeneous milk mixture. The mixture is cooled in an ice bath to 10 ° C and 1475.3 g of 4.94 N hydroxide solution is added on three .  After dissolving the amylose and setting the temperature to 8 ° C, 0 g of the succinic anhydride powder is added to the reaction mixture.  After the pH drops to 7 through the addition funnel, 4.94 N, sodium hydroxide solution (use 1000 ml of pre-weighed solution) is added at a rate sufficient to maintain the pH of the reaction at about 8il. Sodium hydroxide is added until pH 8 is adjusted. 5, The remaining sodium hydroxide solution is weighed and the exact amount of alkali used at this stage is 2257.2 g or 1912.9 ml.  During the reaction, the reactor is cooled to maintain the reaction temperature from 8 to 20 ° C. The degree of substitution of the anhydroglucose unit succinate groups is calculated based on the stoichiometry of the reaction using the equation of the example 1 st 1b2 (20x (585) - 9449,7), , 1000 X 351.2 Once the reaction is complete, the pH is shifted to 4.5 by the addition of acetic acid and the solution is filtered to remove all substances with a particle size greater than 5 µm.  The filtered solution is then dialyzed to remove low molecular weight substances.  Dialysis is carried out in a dialysis cell against distilled water until a constant conductivity is established at a pressure drop of 500 mmHg, St. During the dialysis process, the pH of the solution is maintained at 4.0, the Final solution of amylose succinate in the form of a partial sodium salt at pH 4.0 characterized by a solids content of 5.15%. .  A part of this solution with a concentration of k,% (126.2 g, which is equivalent to 6.5 g of the solid substances contained in the solution, is thoroughly mixed with 2.72 g of forms yes (oh, 41% of COPS per 1 ° C of polyglucan) and the amount of water is sufficient In order for the total weight of the mixture to be 1 О 0 Данный This solution is uniformly frozen on the inner stacks of the flask by rotating it and the solution horizontally in a bath filled with acetone with dry ice (-78 s) until the frozen solution is pressed from the glass walls ( this process is accompanied by a loud crash) o Immediately after you Immersing the flask from the bath with acetone and dry ice is immediately transferred to a round copper connecting sieve sleeve and connected to a freeze drying apparatus with an internal stainless steel pipe of 8 cm and an internal diameter of 16 mm. The pressure drop between the sample and the cooling trap is maintained at a level of 600 µm pToTo Copper sieve provides greater uniformity of thermal rioTOKa into the flask during the lyophilization process, thereby obtaining a more uniform hydrogel spongy product.  The flask is exposed to ambient atmospheric conditions at approximately relative humidity and, when possible, periodically rotates the flask in order to partially reduce the difference in heat transfer from different sides. To measure the temperature of the product during the lyophilization process, the thermocouple is frozen into the product mass. it is determined that the entire lyophilization process is about 4.5 hours) takes place between -10 and -9 ° C with a slight temperature drop to -13 C, just before the temperature rises rapidly to the environment level with End of Lyophilization Lyophilization is faster (almost 1 hour) against the walls of the flask. The flask is left in the apparatus for lyophilization for several hours after the internal temperature rises to room temperature.  Sponge with a spatula carefully removed from the flask, cut and put1 7. °  Spread on a flat surface, dry. It is heated in a heating cabinet with forced air ventilation for 2 hours at 60 ° C and then immediately cross-linked by heating in a heating cabinet with forced air ventilation for 25 minutes at.  To characterize the sponge treated for cross-linking, the following measurements were taken: specific gravity, thickness, apparent density, free volume, porosity with respect to airflow, salt retention 7 cm, aged for 48 hours or more at 21 ° C and relative humidity, except in the case of determining the value of salt retention.  The pitch weight of 0.0192 thickness (0.1–5 cm) is determined as the average of 13 measurements with a micrometer with an indicator head (without pressure), an apparent density of 0.116 The determination of free volume is based on the determination of the absolute density of the polymer 1.50 g / cm, found from the data so that the powder made from the sponge slowly sinks in chloroform (beats. weight is 1.498 g / ml and floats in chloroform containing 251 carbon tetrachloride (sp. “carbon tetrachloride weight is 1.595 g / ml).  The free volume is 92.3.  calculated by the formula apparent with a density of 1 -. . .  .  . -n X 100.  absolute density. The porosity with respect to the air flow is measured using a special adapter plate to reduce the surface area of the sponge through which air is supplied to 6.26. The measurement of the porosity with respect to the air flow is carried out in three areas of the sponge.  The average value is 238.8 m / m min at 76.2 cm, Hg, Hg, 21 ° C and relative humidity.  Salt retention is determined on a portion of a sample dried in a heating cabinet at 60 ° C to a brittle state J carefully ground into powder and sieved to obtain a fraction passing through a sieve with a pore of 50 Meiji and retained on the sieve of 100 mesh (from 0.30 up to 0.15 mm). This fraction is stirred in solution.

sodium bicarbonate (75 ml / g of powder), collected on a fabric — 28.8 g / m and washed three times with 5 times the volume of distilled water with respect to its swollen volume. 1) The solution of the body was dissolved in the gel in 10 times Compared with its swollen volume of anhydrous acetate, the product is dried to dry cobalt, stanni for 1 h at a vacuum temperature of 10 moshkaf at 60 Co 500 mg of powder (hot dry weight is stirred for 10 min in 50 ml of 0.9 aqueous solution sodium chloride at 23 ° C. The swollen powder is removed by drying is at the pred a weighted piece of cloth until it stops dripping. Raw powder is weighed on the cloth and the amount of salt retention (13.25) is calculated by the equation 2, Example 1,

For testing the hemostatic activity, the sponge is neutralized by gently stirring it in calcium acetate solution (7 ml / g sponge) with a-25 by the next addition of calcium hydroxide as a suspension until the pH remains constant for 10 minutes. 6.5 The sponge is removed from the solution, carefully squeezed out to remove excess solution, and washed three times with 1300 ml portions of distilled water. To remove water, the wet sponge is subjected to solvent change with dry acetone, which causes the sponge to compress to its original size. and dried between sheets of filter paper,

Hemostatic activity is determined by the ability of the neutralized sponge to stop bleeding in an adult dog, caused by amputation of spleen tissue. After the occurrence of heavy bleeding, the wound area is soaked with dry cotton gauze and immediately put on the wound a double layer of a sponge 2.5 x 3.7 cm (about 300 mg) and kept on the wound 30 with a weak pressure applied to the sponge through a wet cellulose tampon . After the gauze pad is removed when the bleeding is resumed, the pressing action is continued for another 30 ° C. A quantitative evaluation is carried out based on the number of required 30 second periods of pressing activity. If no subsequent bleeding is observed for at least 15 minutes of observation, the sponge is saturated with isotonic saline solution and is removed by force from the surface of the wound to assess its adhesive characteristics. To ensure hemostasis, only an initial 30 second period of exerting pressure is needed. The sponge adheres tightly to the wound, withstands pressure, movement, stretching of the spleen and friction.

Example 12, Microscopic characterization of Hia sponges based on amylose succinate,

Six sponges (A-F) are obtained in accordance with Example 11 with the difference that the following amounts of formamide are used, g: But no, B 2.15; C 2, A9; D2.72; E 3.17; F 3.6 (0; 0.33 0.38J 0.41 0.48; 0.55 weight, h, respectively, for 1 weight, h, polyglucan) “These sponges lie within the structural organization due to the absence of a mesh structure (A ), very fine structure (c) to a very coarse structure p). Comparison of the physical parameters measured on these sponges is found in Table 2,

table 2

0,01750,360

0,01900,163

0,01610,126

0,01650,123

39.07 19.54 15.13 15.20

13

1048987

V2

A sample of 100 measurements on a piece of sponge with an area of 100 cm was impossible to neutralize the sample from different dimensions in different positions without destroying the individual gel particles. Samples of sponges B, C, and E are poured into epoxy resin. Kra of filled-in sponges are then manually polished with coarse and fine emery paper, cloth with polishing powder and water aluminum paste. Smoothly polished cross-section shown in the micrograph of Fig.2 from 52 -fold magnification, examine in the dark field of the incident light. Different areas of this cross section are photographed and increased to a total magnification of 1BO. The number of micrographs taken on each of the four samples varies from 13 to 20 For each enlarged photograph see Figo 1-3) carried along and across the line of cut polished sides sponges, sponges 1arallelno plane of slice thickness is carried out on five lines,

And Continued table. 2 2.5 cm more spaced apart from each other A measuring line is applied to each line and the length of each free space captured by the line is measured with an accuracy of 0.1 cm (6.25 µm). Measurements of voids along line 1 (smooth the layer — the side that was in contact with the surface of the flask wall during the lyophilization process, as a rule, is thinner and has a more closed structure (see the lower cut surface in FIG. 2) and along the lines 3, 4 and 5 (combined) that make up the mass of the sponge , belong to classes of length 2 cm on enlarged photographs x (125 µm in Valid The, real sponge). The distribution by class of lengths of hollows as a percentage of the frequency is given in Table. 3. Table 3

15

The graphic characteristic of this data is shown in FIG. 4, “The data characterizing the polished side of the sponge is not shaded, and the data characterizing

The number of 30 second periods of pressure is necessary to stop the bleeding.

13

D F Example 13. An amylose succinate-based sponge, prepared using 55, as an agent for promoting the formation of a network of formamide.

sixteen

1048987 Continuation of the table. 3

the central mass of the sponge is shaded.

In example 11, the following data on hemostatic activity are presented in table. k

Table 4

Wound adhesion data

There is no adhesion, the blood does not penetrate into the sponge, but accumulates under it, forming a soft clot between the sponge and the bucket.

Good adhesion

Good adhesion, but when stretching and friction through large pores, bleeding is observed. A sponge is obtained in accordance with Example 1 with the difference that the lyophilized sample solution contains 12.0 g of solids, which corresponds to 8% (g, e, 12/250 ), SZ g 7 formamide and generally weighs 250 g, instead of 6.5 g, 2, ml and 1bO g, respectively. A piece of a sponge with an area of 100 cm is characterized by the following data Specific weight, Thickness, cm Apparently with density, g / cm 0.135 Free volume 91, 0 em,% Porosity with respect to air flow, MVM / min (average of 6 measurements) 180.88 Velich in salt 12.74 retention This sponge (in the form of calcium salt) is tested for hemostatic activity in accordance with example 11 o. To stop the bleeding, two 30-second periods of exerting pressure are required, adhesion to the wound is good, except for the edges of the wound. Example Sponge based on low degree of amylose succinate. In this example, I get a sponge according to Example 11 with the difference that to obtain amylose succinate with a degree of substitution of 0.3 instead of 1.01, the neck uses the amount of succinic anhydride and the amount used For the preparation of a sponge, formamide is 1.35 grams instead of 2.72 grams (0.20 VeC per 1 h of polyglucan). A piece of a sponge with an area of 100 cm is characterized by the following data. Thickness, cm Apparent c-density, g / cm Free volume, Porosity with respect to air flow, / / min (average of 180.88 6 measurements) Size of salt-soluble emulsion retention Sponge based on Example 15 high degree of amylose succinate with substitution 7 In this example, a sponge is prepared in accordance with Example 11 with the difference that more amylose anhydride is used to obtain amylose succinate with a degree of substitution of 2.08 instead of 1.04, and the amount of formamide used to make a sponge is 2.83 g instead of 2.72 g (0, 43 weight, h per 1 h of polyglucan. The resulting sponge is characterized by the following data: Specific gravity,, 018 Thickness, cm 0.133 Apparent to density, g / cm 0.138 Free volume,% 90.8 Porosity with respect to air flow, MV / m2 / (in 259.20 Salt retention value 15.49 This sponge (in the form of calcium salt) is tested for hemostatic activity in accordance with Example 11. To stop bleeding, three 30-second periods of suppressive effect are required, adhesion to the wound is excellent. Example 16 Sponge on the basis of amylose succinate, obtained from Using as formamide as a network-forming agent in this example, a hydrogel sponge is prepared in accordance with Example 11, with the difference that 2.9 g of formamide (0.4 per 1 weight per hour of polyglucan) is used and lyophilization using an aluminum vessel coated with Teflon (inner diameter of 8.6 cm; internal length 18.5 cm; wall thickness - 8 mm), which provides better conditions for supplying heat to the product than when using glass bottles. The vessel is sealed from above with a rubber stopper N ° 15 and connected to the freeze-dryer by a tube with an internal diameter of 8 mm. A sponge piece with an area of 100 cm characterized by the following data: Specific gravity, g / cm 20,021 Thickness, cm 0.086 Apparently with density, g / cm Free volume Porosity with respect to airflow, m VM / min (average of 6 measurements 151.39 Salt value 11, 97 th This sample sponge (in the form of calcium salt) are tested for hemostatic activity according to Example 1. To stop bleeding, three 30 second periods of pressure are required, the adhesion to the wound was good, except for the edges of the wound. Example 17 Amylose succinate sponge obtained using as an agent that promotes the formation of a mesh structure, formamide. In this example, a hydrogel gouk is obtained according to Example 11 with the difference that the solution contains 7.0 g of solids, which corresponds to 3.8% (7 / l80), 3, g formamide (About 52 vesoCh. on 1, p liglucan and has a total weight of l80 g; the solution is frozen on the walls of a Teflon-coated vessel (inner diameter 8.5 cm; inner length - 17.5 cm; - wall thickness 8 mm) and sealed from above with a rubber stopper No. 15 with a 1 cm hole in the center, freeze-dried water is used on a shelf dryer for freeze drying at a pressure difference between the pump and the refrigerator trap from 350 to kQO μm pTOSTo and the temperature of the shelves о The resulting sponge is characterized by the following data: Specific weight, g / cm0.022 Thickness, cm 0.187 Apparent density, g / cm 0,115 Volume of voids; .92.3 Porosity with respect to air flow, m. 231.95 Salt retention value 12.79 Example 18o Atyloxy succinate based sponge obtained using 7 ° as a network promoting agent, N-methyl-2- pyrrolidone. In this example, a hydrogel sponge is prepared in accordance with Example 11 with the difference that instead of formamide, N-methyl-2-pyrrolidone in the amount of 3.46 g (0.53 weight, h , on 1, polyglucan) and add so much water that about The volume of the solution is 220 ml. A sponge piece with an area of 100 cm is characterized by the following data: Specific gravity, 020 Thickness, cm 0.184 Apparently with density, g / cm 0.108 Free volume,% 92.8 Porosity with respect to air flow, m5 / mM ( average of 6 measures 144, 70 Salt retention 25.96 With the cross-linking of this sponge sample, heating is carried out for 20 minutes more so that the strength of the sample is sufficient to turn into calcium salt and to test for hemostatic activity in accordance with an example 11 o. To stop the bleeding, two 30-second periods of pressure are required, adhesion to the wound is excellent. Example 19 Amylose succinate-based sponge prepared using dimethyl sulfoxide (DMSO) as the agent promoting network formation. In this example, a sponge is prepared according to example 11 with the difference that instead of formamide as a network-forming agent , use DMSO in the amount of 2.9 g (o, 44 per 1 of the poly, polyglucan), 2 a piece of sponge with an area of 100 cm is characterized by the following data: Specific weight. g / cm Thickness, cm Apparent to density, g / cm 0.112 Free volume,% 92.5 Porosity with respect to air flow, / min (average of 6 measurements) 198.51 Salt retention value 21.68 This sponge (in the form calcium salt) are tested for hemostatic activity in accordance with clause 11. To stop the bleeding, two 30-second periods of exerting pressing effect are required, adhesion to the wound is excellent. Example 20 o Sponge on amylose. In this example, the sponge is obtained in accordance with Example 11, with the difference that instead of succinate amides, amylose glutarate is used. Me to produce amylose glutarate basically coincides with the method of example 1 with the difference that instead of succinic anhydride, glutaric anhydride 5regio5e (containing ; moisture content 11.5%) g-55.1 Water, ml 500 5 n. sodium hydroxide (added first), ml 65.0 Glutaric anhydride (anhydrous), g 114.1 5 n, sodium hydroxide (added during the reaction), ml 256.3 Total NaOH added (3379.2 g), ml 321.3 The equation by which the degree of substitution is determined is changed to (2000x 1G1.1 lOOOz where X is the weight of glutaric anhydride, y is the amount of sodium hydroxide used, mol; 7, is the dry weight of amylose, g Therefore, -162 IO-11M -5x321, З1 рт L IL -.- - - 100 X (8.8 1, ЗК 722 The resulting sponge is characterized by the following data: Specific gravity, g / cm 20.019 Thickness, cm 0.173 Cach lh with density, g / cm 3 0.111 Free volume ,% 9), 6 Porosity with respect to air flow, 153.22 Salt depth value 1b, b7 This sample sponge (in the form of calcium salt) is tested for hemostatic activity in accordance with example 1o. To stop bleeding, two 30-second periods are required. a period of exerting a pressing effect, adhesion to the wound is excellent. Example 21 Amylose succinate powder on an amylose succinate sponge Powder of amylose succinate obtained in accordance with Example 1 is sprinkled over the surface of a sponge made of cross-linked succinate am The powder obtained according to Example 11o. Powder is applied by finely spraying with water so as to moisten the surface sufficiently to ensure adhesion of the powder to the surface. The powder from the surface of the sponge is then dried by placing the sponge with powder between two sheets of fabric for about 15 minutes at 50 C in a heating cabinet with forced air ventilation Sponge with powder applied to one surface is tested for hemostatic activity, applying a sponge to the wound with a surface coated with powder in accordance with with example 11o. A good hemostatic effect and good adhesion to the wound is fixed in the case of 10 powder with a particle size of 50-100 mesh. When using 30 powdered additives with a particle size of 100-200 mesh, a hemostatic effect can be ensured and then, after wetting with isotonic saline, , the sponge can be removed by leaving a part of the powder that stops the bleeding on the wound. Thus, the present invention allows to obtain a spongy bioabsorbable material, which has fast and effective hemostatis. with cicomous activity, the ability to adhere firmly to bleeding wounds and completely and evenly dissolve

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in contact with the tissue without causing its irritation or toxic effect on

 -:

FIG.

Claims (3)

1. METHOD FOR PRODUCING COMPLEXATE POLYGlucane Ester by Esterification of Polyglucan with Glutaric or Succinic Anhydride in a Solution in the Presence of a Catalyst, characterized in that, in order to obtain a chemically cross-linked polyglucan ester with high hemostatic activity, amylose lulane, dextran, or amylose pulstan are used as polyglucan and the esterification is carried out at pH = 7 ^_ 9 and degree of substitution of ether polyglucans 0,324-2,43 followed by acidification to pH = 4,0-5,2, drying and heat treatment at 60 and 120 ° C, respectively, 2. The method according to p. 1, which consists in the fact that, in order to obtain a polyglucan ester with a mesh structure, obtained after acidification 3.8-4.8% polyglucan solution is frozen in the presence of 0.20.55 parts by weight formamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide per 1 weight, h, polyglucan ester at a temperature below ~ 30 ° C, ate FIG. 1