RU2451691C2 - Pharmaceutical substance, its production method and medication - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemistry and deals with a pharmaceutical substance based on hydroxiethylated starch, its production method and a pharmaceutical composition for production of a medication with volemic action. The invention may find application in chemistry and medicine. The pharmaceutical substance represents a water-soluble powder of amylopectin hydroxiethylated starch with ratio of substituted hydroxiethylated C₂/C₆ atom groups is equal to 2 - 20, average molecular weight (Mw) remaining within the range of 100-450 kDa and the substitution degree amounting to 0.25-0.75. For production of the pharmaceutical substance of hydroxiethylated starch one uses starch with amylopectin content equal to 60-98% that is hydrolysed in suspension with an acid until an inherent viscosity value [η]=0.10-0.2. The hydrolysed starch is dissolved in water at T=70-105°C, hydroxiethylated in an inert gas atmosphere an alkylating agent and a catalyst until substitution degree is 0,25-0.75. The reaction mixture is neutralised; the produced solution is cleared of low-molecular fractions of hydroxiethylated starch and impurities by ultrafiltration method, filtered in a sterile way and dried. Additionally, the invention deals with a pharmaceutical composition for production of a medication with volemic action using the above method.

EFFECT: development of a pharmaceutical substance volemic action as well as optimisation of the pharmaceutical substance production method enabling regulation of substitution degree within the interval required, obtaining a favourable ratio of substituted hydroxiethyl groups.

21 cl, 5 ex

Description

The invention relates to chemistry and relates to substances based on hydroxyethylated starch. The invention may find application in chemistry and medicine.

Hydroxyethylated starch is a high molecular weight compound consisting of polymerized glucose residues in which the free hydroxyl groups of glucose are partially replaced by hydroxyethyl groups, which helps to reduce the rate of hydrolysis of amylopectin by serum amylase and increase its duration in the blood. The similarity with the structure of glycogen explains the high level of tolerance of these agents.

Plasma substituting solutions based on hydroxyethylated starch are used mainly as a means of volemic action, including hemorrhagic, traumatic, burn and septic shock, during isovolemic hemodelution, they are used for massive blood loss, etc.

Of particular importance in these solutions is the average molecular weight, the degree of substitution of hydroxyl groups - the degree of hydroxyethylation, and the distribution of substituted groups, which determine the effectiveness of the action.

Researchers in this field continue to search for more effective drugs that can be in the bloodstream for a long time, providing anti-shock and anti-toxic effects.

Hydroxyethylated starch is known in the art for use as a substitute for blood plasma with an average molecular weight of 60-600 kDa, with a ratio of substituted hydroxyethylated C ₂ / C ₆ atom groups of 8 to 20 with a degree of substitution of 0.15 to 0.5 (US 5218108, 06/08/1993 - abstract, claims 1-7 of the claims).

The closest technical solution (prototype) is a substance - dried amylopectin hydroxyethylated starch, which is soluble in water with a ratio of substituted hydroxyethylated groups of C ₂ / C ₆ atoms from 4 to 6 and an average molecular weight of Mw in the range of 120-480 kDa with a degree of substitution of 0 , 35-0.7 and a medicine based on it (RU 2245714, 02/10/2005 - abstract, examples 1-5, claims).

The objective of the invention is to develop a new pharmaceutical substance of a volemic effect, quickly restoring pressure in the bloodstream of a patient who has lost a lot of blood, having fewer side effects, as well as optimizing the method of obtaining this pharmaceutical substance, which allows you to adjust the degree of substitution in the desired interval and obtain a favorable ratio of substituted hydroxyethyl groups.

The problem is solved by obtaining a new pharmaceutical substance of hydroxyethylated starch, which is a water-soluble powder of amylopectin hydroxyethylated starch with a ratio of substituted hydroxyethylated groups of C ₂ / C ₆ atoms from 6.1 to 20 and an average molecular weight Mw in the range of 100-450 kDa, degree of substitution 0.25-0.75. Advantageously, the amylopectin hydroxyethylated starch powder has a white or yellowish color (no more than standard B9 or BY6), an average value of 10% of the high molecular weight fraction is not more than 2000 kDa, an average value of 10% of the low molecular weight fraction is not less than 10 kDa, and the total microbiological purity is not more than 100 KBE / g, microbiological purity of mushrooms not more than 10, moisture not more than 8%, may contain ethylene glycol not more than 875 ppm, ethylene oxide not more than 1 ppm, chloroethanol not more than 5 ppm, bacterial endotoxins not more than 10 U / g.

The closest technical solution to the proposed method is a method for producing a substance of hydroxyethylated starch, in which corn starch or potato starch with an amylopectin content of at least 95% is used, which is subjected to acid hydrolysis to a given degree of substitution, and the hydrolyzed starch is dissolved in water at 85-90 ° C, the resulting paste is hydroxyethylated in an inert gas atmosphere using an alkylating agent and a catalyst, the reaction mass is neutralized, solution was purified by low molecular weight hydroxyethyl starch fractions and impurities by ultrafiltration, sterile filtration and dried (RU 2245714, 10.02.2005 - Examples 1-5).

The proposed method is characterized in that the pharmaceutical substance of hydroxyethylated starch is obtained by acid hydrolysis, hydroxyethylation, ultrafiltration, purification and drying, while starch is used as a raw material for the pharmaceutical substance of hydroxyethylated starch with amylopectin 60-98%, which is hydrolyzed in suspension with acid to values of intrinsic viscosity [η] = 0.10-0.25, dissolve hydrolyzed starch in water at T = 70-105 ° C, with amylopectin in the starch less than 95% of the starch is purified from amylose using a complexing agent, hydroxyethylated in an inert gas atmosphere using an alkylating agent and a catalyst to a degree of substitution of 0.25-0.75, the reaction mass is neutralized, the resulting solution is purified from low molecular weight fractions of hydroxyethylated starch and impurities by ultrafiltration, sterile filtered and dried. Advantageously, corn or potato starch is used as the raw material. It is preferable that the starch is hydrolyzed in an aqueous or alcoholic suspension with a starch content of 20-40%, at a concentration of acid, mainly hydrochloric, 0.2-1.0 M, at T = 40-60 ° C for 0.5-6 0 hours. Advantageously, the α-amylase enzyme is used as a catalyst for hydrolysis. Advantageously, purification from amylose involves the treatment of starch solution with a complexing agent in an amount of 0.5-10% by weight of starch at a temperature of 95-105 ° C for 0.5-1.5 hours, crystallization of the amylose complex with slow cooling to T = 10-25 ° C and subsequent removal of the formed amylose complex by centrifugation at 1.5-3.5 thousand rpm Advantageously, aliphatic or alicyclic alcohols with C> 4, preferably cyclohexanol, are used as the complexing agent. Advantageously, ethylene oxide or 2-chloroethanol (ethylene chlorohydrin) is used as the alkylating agent, while when using as the alkylating agent ethylene oxide or 2-chloroethanol (ethylene chlorohydrin), alkali metal salts or hydroxides, mainly sodium chloride or hydroxide, can be used as a catalyst. . Advantageously, if a fine suspension occurs after hydroxyethylation, the reaction mass is diluted to a concentration of 1-15% hydroxyethylated starch and passed through an adsorbent bed, using silica gel or perlite as the adsorbent. It is preferable that to obtain hydroxyethylated starch with a weight average molecular weight below 150 kDa after ultrafiltration, additional acid hydrolysis is carried out to the desired molecular weight, high molecular weight fractions of hydroxyethylated starch are removed by membrane filtration and the salts are treated with ion exchangers to remove residual salts. Advantageously, the ultrafiltration is carried out on hollow fibers with a cutoff limit of 10 kDa. Advantageously, a spray dryer is used to dry the substance, preferably by preconcentrating the hydroxyethylated starch solution in a vacuum evaporator, or a low temperature spray dryer is used to dry the substance.

A pharmaceutical composition for the preparation of a medication of a volemic effect includes a pharmaceutical substance obtained by the above method. Advantageously, the pharmaceutical composition is an aqueous solution or a colloidal aqueous solution, wherein the aqueous solution is clear (<RSIII), has an intrinsic viscosity [η] = 0.10-0.25 dl / g, specific rotation + 182 h + 202 ° and pH value 4.5-7.0.

The pharmaceutical composition allows you to get a drug that can quickly restore pressure in the bloodstream of a patient who has lost a lot of blood.

The claimed invention:

- allows the use of corn or potato starch;

- allows, when used in the process of hydroxyethylation as a catalyst of alkali metal hydroxides, to obtain a slightly colored product with high selectivity for the main product and a high degree of conversion;

- allows you to use one stage of hydrolysis;

- when using conventional varieties of starch with an amylopectin content of less than 95%, as a result of preliminary hydrolysis to the desired molecular weight and subsequent separation of the amylose fraction, it allows to free both low molecular weight and high molecular weight starch fractions and obtain a product with a narrow MMP range;

- the use of 2-chloroethanol (ethylene chlorohydrin) as an alkylating agent can significantly protect the process;

- passing a neutralized HES solution through a layer of sorbent allows you to lower the color of the solution and to separate hard-to-filter sediment.

Method implementation examples

Example 1

A mixture of 1411 ml of water and 174 ml of concentrated (36.5%) hydrochloric acid was charged into a three-necked round-bottom flask with a capacity of 3 L, equipped with a stirrer, thermometer and reflux condenser. With constant stirring, 424 g of air-dried corn starch (more than 70% amylopectin) is added in portions. The suspension is heated to 50 ° C and maintained at this temperature for 3.5 hours. After exposure, the suspension is cooled to a temperature of 20 ± 5 ° C and neutralized by the addition of 40% NaOH solution. Hydrolysis in suspension with acid goes up to the characteristic viscosity [η] = 0.201. The neutralized suspension is filtered off and 313 g of hydrolyzed starch is added portionwise to the 4-liter three-neck round-bottom flask equipped with a stirrer, thermometer and reflux condenser, into which 3218 ml of water are pre-charged. 90 ml of isoamyl alcohol is poured into a starch suspension and heated to a temperature of 97 ° C. The resulting starch paste is kept under stirring at this temperature for 1 hour, the heating is turned off and slowly cooled to a temperature of 20-25 ° C. The crystallized amylose complex is removed by centrifugation at a rotation speed of 2.5-3.5 thousand rpm.

To 2760 g of the mother liquor obtained by centrifugation, add 730 ml of acetone. The precipitate is centrifuged again at a rotation speed of 2.5-3.5 thousand rpm.

800 ml of acetone are added to the resulting mother liquor, the mixture is cooled to 5-15 ° C, after which amylopectin (130 g, calculated on the dry matter) is separated by decantation of the supernatant.

The amylopectin precipitate is dissolved in 600 ml of water containing 13.1 g of NaCl when heated to 70-80 ° C, and filtered through a polypropylene filter to remove solids.

The amylopectin solution is transferred to a stainless steel apparatus equipped with an anchor stirrer, thermocouple, pressure gauge and barbator. The apparatus is purged with nitrogen, heated with a thermostat to 70 ° C and liquid ethylene oxide is supplied dropwise. The supply of ethylene oxide is regulated so that the pressure in the apparatus does not exceed 2 atm. The total amount of ethylene oxide is 47 g. After loading the required amount of ethylene oxide, the reaction mass is maintained at 70 ° C for 1 hour.

At the end of the exposure, the reaction mass is cooled to 40-45 ° C and the apparatus is purged with nitrogen. After purging, the mixture was diluted by adding 1.6 L of distilled water and cooled with stirring to a temperature of 20-25 ° C. The reaction mass is neutralized with 2M HCl to a pH of 6.5-7.0 and filtered through a layer of alumina to remove water-insoluble products and solids.

Next, the solution is subjected to purification from low molecular weight compounds by ultrafiltration on hollow fibers with a cutoff limit of 10 kDa against water purified to achieve a chloride concentration of 0.05-0.07%. Upon reaching the desired degree of purification, HES is concentrated to a concentration of 5.5-6.5%.

The HES concentrate is dried in a spray dryer at a temperature of 170 ° C. 130 g of dried HES are obtained with the following characteristics: C ₂ / C ₆ ratio of 7.9; Mw = 210000 Yes; Mn = 67740 Yes; Mw / Mn = 3.10; [η] = 0.201; Sz = 0.51.

Example 2

A mixture of 1575 ml of water and 194 ml of concentrated (36.5%) hydrochloric acid was charged into a 3-neck round bottom flask with a capacity of 3 L, equipped with a stirrer, thermometer and reflux condenser. With constant stirring, 473 g of air-dried corn starch (more than 60% amylopectin) is added in portions. The suspension is heated to 50 ° C and maintained at this temperature for 3.5 hours. After exposure, the suspension is cooled to a temperature of 20 ± 5 ° C and neutralized by the addition of 40% NaOH solution. Hydrolysis in suspension with acid goes up to the characteristic viscosity [η] = 0.185. The neutralized suspension is filtered off and 350 g of hydrolyzed starch with constant stirring are added portionwise to a 4-liter three-neck round-bottom flask equipped with a stirrer, thermometer and reflux condenser, into which 1534 ml of water are pre-charged. 50 ml of isoamyl alcohol are poured into a starch suspension and heated to a temperature of 97 ° C. The resulting starch paste is kept under stirring at this temperature for 1 hour, the heating is turned off and slowly cooled to a temperature of 20-25 ° C. The crystallized amylose complex is removed by centrifugation at a rotation speed of 2.5-3.5 thousand rpm.

In 1245 ml of the mother liquor obtained by centrifugation, 18.6 g of NaCl are dissolved. The resulting solution is filtered through a layer of aluminum oxide and transferred to a stainless steel apparatus equipped with an anchor stirrer, a thermocouple, a manometer and a hydroxyethylation bubbler.

The apparatus is purged with nitrogen, heated with a thermostat to 50 ° C and liquid ethylene oxide is supplied dropwise. The supply of ethylene oxide is regulated so that the pressure in the apparatus does not exceed 2 atm. The total amount of ethylene oxide is 62 g. After loading the required amount of ethylene oxide, the reaction mass is maintained at 50 ° C for 3 hours. At the end of the exposure, the reaction mass is cooled to 30-40 ° C and the apparatus is purged with nitrogen.

After purging, the mixture is diluted by adding 2 l of distilled water and cooled with stirring to a temperature of 20-25 ° C.

The reaction mass is neutralized with 2M HCl to a pH of 6.5-7.0 and filtered through a layer of alumina to remove water-insoluble products and solids.

Next, the solution is subjected to purification from low molecular weight compounds by ultrafiltration on hollow fibers with a cutoff limit of 10 kDa against water purified to achieve a chloride concentration of 0.05-0.07%. Upon reaching the desired degree of purification, HES is concentrated to a concentration of 5.5-6.5%.

The HES concentrate is dried in a spray dryer at a temperature of 170 ° C.

162 g of HES are obtained with the following characteristics: C ₂ / C ₆ ratio of 11.0; Mw = 190,000 Yes; Mn = 65520 Yes; Mw / Mn = 2.90; [η] = 0.185; Sz = 0.5.

Example 3

A mixture of 1068 ml of water and 132 ml of concentrated (36.5%) hydrochloric acid was charged into a 3-neck round-bottomed flask with a capacity of 2 L, equipped with a stirrer, thermometer and reflux condenser. With constant stirring, 382 g of dry amylopectin starch is added in portions. The suspension is heated to 50 ° C and maintained at this temperature for 4.5 hours. After exposure, the suspension is cooled to a temperature of 25 ± 5 ° C and neutralized by the addition of 40% NaOH solution. Hydrolysis in suspension with acid goes up to a characteristic viscosity [η] = 0.162. The neutralized suspension is filtered off and 275 g of the obtained starch are portioned into a 4 L three-necked round-bottom flask equipped with a stirrer, thermometer and reflux condenser, into which 1534 ml of water is pre-charged.

The suspension is heated to 85-90 ° C and maintained at this temperature for 20-25 minutes. The resulting paste is cooled with stirring to a temperature of 20-25 ° C and 50 ml of a 40% NaOH solution are added. The alkaline solution of hydrolyzed amylopectin starch is transferred to a stainless steel apparatus equipped with an anchor stirrer, a thermocouple, a manometer and a barbator.

The apparatus is purged with nitrogen, heated with a thermostat to 40 ° C and liquid ethylene oxide is supplied dropwise. The supply of ethylene oxide is regulated so that the pressure in the apparatus does not exceed 2 atm. The total amount of ethylene oxide is 47 g. After loading the required amount of ethylene oxide, the reaction mass is maintained at 40 ° C for 2 hours. At the end of the exposure, the reaction mass is cooled to 20-25 ° C and the apparatus is purged with nitrogen.

After purging, the mixture was diluted by adding 3 L of distilled water, and neutralized with 2M HCl to pH 6.5-7.0, and filtered through a layer of silica gel to remove water-insoluble products and solids.

Next, the solution is subjected to purification from low molecular weight compounds by ultrafiltration on hollow fibers with a cutoff limit of 10 kDa against water purified to achieve a chloride concentration of 0.05-0.07%. Upon reaching the desired degree of purification, HES is concentrated to a concentration of 5.5-6.5%.

The HES concentrate is dried in a spray dryer at a temperature of 170 ° C. 130 g of HES are obtained with the following characteristics: C ₂ / C ₆ 6.1 ratio; Mw = 180,000 Yes; SZ = 0.51; [η] = 0.162.

Example 4

A mixture of 1134 ml of n-butanol and 66 ml of concentrated (36.5%) hydrochloric acid was charged into a 3-neck round bottom flask with a capacity of 2 L, equipped with a stirrer, a thermometer and a reflux condenser. With constant stirring, 350 g of dry amylopectin starch is added in portions. The suspension is heated to 50 ° C and maintained at this temperature for 1 hour. After exposure is cooled to 25 ± 5 ° C, the hydrolyzed starch is filtered off. The precipitate is stirred in 1200 ml of distilled water and neutralized by adding 40% NaOH solution to a pH of 6.9-7.1. Hydrolysis in suspension with acid goes up to a characteristic viscosity [η] = 0.150. The neutralized suspension is filtered off and 269 g of hydrolyzed starch is added portionwise to a 2-liter three-necked round-bottom flask equipped with a stirrer, thermometer and reflux condenser, in which 1000 ml of distilled water are pre-charged. The suspension is heated to 85-90 ° C and maintained at this temperature for 20-25 minutes. The resulting paste is cooled with stirring to a temperature of 20-25 ° C and 32 ml of a 40% NaOH solution are added. The alkaline solution of hydrolyzed amylopectin starch is transferred to a stainless steel apparatus equipped with an anchor stirrer, a thermocouple, a manometer and a barbator.

The apparatus is purged with nitrogen, heated with a thermostat to 30 ° C and liquid ethylene oxide is supplied dropwise. The supply of ethylene oxide is regulated so that the pressure in the apparatus does not exceed 2 atm. The total amount of ethylene oxide is 48 g. After loading the required amount of ethylene oxide, the reaction mass is maintained at a temperature of 30 ° C for 6 hours. At the end of the exposure, the reaction mass is cooled to 20-25 ° C and the apparatus is purged with nitrogen.

After purging, the reaction mass is diluted by adding 3 l of distilled water, and neutralized with 2M HCl to a pH of 6.5-7.0, and filtered through a layer of alumina to remove water-insoluble products and solids.

Next, the solution is subjected to purification from low molecular weight compounds by ultrafiltration on hollow fibers with a cutoff limit of 10 kDa against water purified to achieve a chloride concentration of 0.05-0.07%. Upon reaching the desired degree of purification, HES is concentrated to a concentration of 5.5-6.5%.

The HES concentrate is dried in a spray dryer at a temperature of 170 ° C.

Obtain 127 g of HES with the following characteristics: ratio of C ₂ / C ₆ 6.3; Mw = 172,000 Yes; SZ = 0.52; [η] = 0.150.

Example 5

A mixture of 1068 ml of water and 132 ml of concentrated (36.5%) hydrochloric acid was charged into a 3-neck round-bottomed flask with a capacity of 2 L, equipped with a stirrer, thermometer and reflux condenser. With constant stirring, 384 g of air-dried amylopectin starch are added in portions. The suspension is heated to 50 ° C and maintained at this temperature for 4.5 hours. After exposure, the suspension is cooled to a temperature of 25 ± 5 ° C and neutralized by the addition of 40% NaOH solution. Hydrolysis in suspension with acid goes up to the characteristic viscosity [η] = 0.159. The neutralized suspension is filtered off and 275 g of hydrolyzed starch is added portionwise to a 2-liter three-necked round-bottom flask equipped with a stirrer, thermometer and reflux condenser, into which 925 ml of distilled water is pre-charged.

The suspension is heated to 85-90 ° C and maintained at this temperature for 20-25 minutes. The resulting paste is cooled with stirring to a temperature of 20-25 ° C and 275 ml of a 40% NaOH solution are added.

The alkaline solution of hydrolyzed amylopectin starch is transferred to a stainless steel apparatus equipped with an anchor stirrer, a thermocouple, a manometer and a barbator.

The apparatus is purged with nitrogen, heated with a thermostat to 60 ° C, and 2-chloroethanol is added dropwise. The supply of 2-chloroethanol is controlled so that the pressure in the apparatus does not exceed 2 atm. The total amount of 2-chloroethanol is 160 g. After loading the required amount of 2-chloroethanol, the reaction mass is maintained at a temperature of 60 ° C for 1 hour. At the end of the exposure, the reaction mass is cooled to 20-25 ° C and the apparatus is purged with nitrogen.

After purging, the reaction mass is diluted by adding 3 l of distilled water, and neutralized with 2M HCl to a pH of 6.5-7.0, and filtered through a layer of alumina to remove water-insoluble products and solids.

Next, the solution is subjected to purification from low molecular weight compounds by ultrafiltration on hollow fibers with a cutoff limit of 10 kDa against water purified to achieve a chloride concentration of 0.05-0.07%. Upon reaching the desired degree of purification, HES is concentrated to a concentration of 5.5-6.5%.

The HES concentrate is dried in a spray dryer at a temperature of 170 ° C.

125 g of HES are obtained with the following characteristics: C ₂ / C ₆ ratio of 14.2; Mw = 185,000 Yes; SZ = 0.45; [η] = 0.159.

The proposed pharmaceutical substance and the pharmaceutical composition including it make it possible to obtain a medicine that quickly restores pressure in the bloodstream of a patient who has lost a lot of blood, and the method allows you to adjust the degree of substitution in the desired interval and obtain a favorable ratio of substituted hydroxyethyl groups.

Claims (21)

1. A pharmaceutical substance, which is a water-soluble powder of amylopectin hydroxyethylated starch with a ratio of substituted hydroxyethylated groups of C ₂ / C ₆ atoms from 2 to 20 and an average molecular weight of Mw in the range of 100-450 kDa, with a degree of substitution of 0.25-0 , 75. 2. The pharmaceutical substance according to claim 1, characterized in that the amylopectin hydroxyethylated starch powder has a white or yellowish color (not more than standard B9 or BY6), an average value of 10% of a high molecular weight fraction of not more than 2000 kDa, an average value of 10% of a low molecular weight fraction of not less than 10 kDa, total microbiological purity of not more than 100 KBE / g, microbiological purity of mushrooms not more than 10, moisture - not more than 8%, contains ethylene glycol - not more than 875 ppm, ethylene oxide - not more than 1 ppm, chloroethanol - not more than 5 ppm, bacterial endotoxins - not more 10 it EdE / g. 3. A method of obtaining a pharmaceutical substance of hydroxyethylated starch by acid hydrolysis, hydroxyethylation, ultrafiltration, purification and drying, characterized in that as a raw material for the preparation of a pharmaceutical substance of hydroxyethylated starch, starch is used with an amylopectin content of 60-98%, which is hydrolyzed in suspension with acid to a value intrinsic viscosity [η] = 0.10-0.25, hydrolyzed starch is dissolved in water at T = 70-105 ° C, hydroxyethylated in an inert gas atmosphere using m alkylating agent and the catalyst to a degree of substitution of 0.25-0.75, the reaction mixture is neutralized, the resulting solution is purified from the low molecular weight fractions of HES and impurities by ultrafiltration, sterile-filtered and dried. 4. The method according to claim 3, characterized in that the raw materials use corn or potato starch. 5. The method according to claim 3, characterized in that the hydrolysis of starch is carried out in an aqueous or alcohol suspension with a starch content of 20-40%, at a concentration of acid, mainly hydrochloric, 0.2-1.0 M, at T = 40-60 ° C for 0.5-6.0 hours 6. The method according to claim 3, characterized in that the enzyme α-amylase is used as a catalyst for hydrolysis. 7. The method according to claim 3, characterized in that when the content of amylopectin in the starch is less than 95%, the starch is purified from amylose using a complexing agent. 8. The method according to claim 7, characterized in that the purification from amylose includes the treatment of starch solution with a complexing agent in an amount of 0.5-10% by weight of starch at a temperature of 95-105 ° C for 0.5-1.5 h, by crystallization of the amylose complex with slow cooling to T = 10-25 ° C, followed by removal of the formed amylose complex by centrifugation at 1.5-3.5 thousand rpm. 9. The method according to claim 7, characterized in that aliphatic or alicyclic alcohols with C> 4, preferably cyclohexanol, are used as complexing agent. 10. The method according to claim 3, characterized in that ethylene oxide or 2-chloroethanol (ethylene chlorohydrin) is used as the alkylating agent. 11. The method according to claim 10, characterized in that when using ethylene oxide or 2-chloroethanol (ethylene chlorohydrin) as an alkylating agent, alkali metal salts or hydroxides, mainly sodium chloride or hydroxide, can be used as a catalyst. 12. The method according to claim 3, characterized in that when a fine suspension occurs after hydroxyethylation in the reaction mass, the reaction mass is diluted to a concentration of 1-15% hydroxyethylated starch and passed through an adsorbent layer. 13. The method according to p. 12, characterized in that as the adsorbent use silica gel or perlite. 14. The method according to claim 3, characterized in that to obtain hydroxyethylated starch with a weight average molecular weight below 150 kDa after ultrafiltration, additional acid hydrolysis is carried out to the desired molecular weight, the high molecular weight fractions of hydroxyethylated starch are removed by membrane filtration and the salts are removed from the residues by ion exchange treatment. 15. The method according to claim 3, characterized in that the ultrafiltration is carried out on hollow fibers with a cutoff limit of 10 kDa. 16. The method according to claim 3, characterized in that a spray dryer is used to dry the substance. 17. The method according to claim 3, characterized in that for drying the substance using a low temperature spray dryer. 18. The method according to claim 3, characterized in that for drying the substance using a spray dryer with preliminary concentration of a solution of hydroxyethylated starch in a vacuum evaporator. 19. A pharmaceutical composition for producing a medication of a volemic effect, comprising the pharmaceutical substance according to claim 1, obtained by the method specified in claim 3. 20. The pharmaceutical composition according to claim 19, characterized in that it is an aqueous solution or a colloidal aqueous solution. 21. The pharmaceutical composition according to claim 20, characterized in that the aqueous solution is transparent (<RSIII), has a characteristic viscosity [η] = 0.10-0.25 dl / g, specific rotation + 182 ÷ + 202 ° and a hydrogen index pH 4.5-7.0.