Medicinal agent with volemic effect and method for its preparing

FIELD: medicine, hematology, pharmaceutical technology, pharmacy.

SUBSTANCE: medicinal agent represents hydroxyethylated starch an aqueous solution containing 5-10% of hydroxyethylated starch with the optimal ratio of substituted hydroxyethyl groups at atoms C2/C6 up to 6:1 in glucose residue, average value of molecular mass 130-450 kDa, narrowed molecular-mass distribution at the substitution degree 0.35-0.70 and 0.80-1.00% of sodium chloride. Agent is prepared using maize or potato starch as the raw with the content of amylopectin 95%, not less. Starch is subjected for alkaline purification, acidic or enzymatic hydrolysis up to preparing products with molecular mass 400-900 kDa up to the required degree of substitution of hydroxyethyl groups. The solution is purified from impurities by ultrafiltration and/or reverse osmosis and purification is carried out using apyrogenic activated carbon and/or by sterilizing filtration and the following thermal sterilization of the end product. Invention provides preparing a new agent for rapid blood pressure recovery after blood loss.

EFFECT: improved preparing method, valuable medicinal properties of agent.

9 cl, 6 ex

 

The invention relates to the field of medicine and relates to fluid-based tools gidroksietilirovannogo starch (HES).

Gidroksietilirovanny starch is a high molecular compound consisting of polymerized residues of glucose, in which free hydroxyl groups of glucose partially substituted hydroxyethylene groups, which contributes to the reduction in the rate of hydrolysis of amylopectin serum amylase and increase the duration of its stay in the blood. The similarity with the structure of glycogen explains the high level of portability of these funds.

Plasma-substituting solutions based gidroksietilirovannogo starch are used mainly as a means volemic actions, including hemorrhagic, traumatic, burn and septic shock, when conducting izovolemicescuu hemodilution used with massive blood loss, etc.

For drugs in this group are of special importance in the average molecular weight, degree of substitution of hydroxyl groups is the degree of gidroksietilirovaniya, and the distribution of the substituted groups, which determine the effectiveness of actions.

There are various drugs on the basis of the SEC. However, researchers in this area continues the search for more effective means, capable of a long time to be in krovenosnaya, providing an anti-shock and anti-toxic effect.

A method of obtaining hydroxyalkyloxy, including hydroxyethylamine, with a degree of substitution MS of 0.14 to 0.24 by enzymatic hydrolysis of starch and subsequent hydroxyethylammonium ethylene oxide in the presence of a hydroxide of an alkali metal and an inhibitor of gelation at pH 10-13 and a temperature of 30-50°C for 16-18 h (WO 00/47629, 17.08.2000).

A well known substitute for blood plasma-based BSE, obtained by acid hydrolysis of the SEC at 70°s to the viscosity of 0.13 to 0.15 DL/g, treatment with activated charcoal at the same temperature for 30 minutes, fractionation hydrolyzed HES diafiltrate on membrane plant at a certain pressure to a concentration of 5.5 to 6.5% with a viscosity of 0.14 to 0.18 DL/g and pH 6,5-7,0 (RF 2136293 C1, 10.09.1999).

Known means on the basis of gidroksietilirovannogo starch with an average molecular weight 60-600 kDa, degree of substitution MS 0,115 to 0.5, the ratio of substitution of C2 to C6 substitution anhydroglucose units 8-20 and the degree of substitution DS of 0.2-0.5. HES obtained by extraction of starch with methanol, partial acid hydrolysis within 2-4 hours at a temperature of 30-50°With alkaline treatment, gidroksietilirovaniyu chloroethanol or ethylene oxide, followed by neutralization, purification and drying (US 5218108 And 08.06.1993).

A method of obtaining preparaton the basis of ethoxylated starch by oksietilirovannye amylopectin starch in the presence of sodium chloride or potassium by feeding ethylene oxide at a temperature of about 90° With, hydrolysis solution oke acid to the characteristic viscosity of 0.14-0.18 and the degree of substitution of 0.5-0.7, clarification, purification and ultrafiltration, get 6% solution with its subsequent sterilization (EN 2139294 C1, 10.10.1999).

Known gidroksietilirovanny starch with a molar ratio of ethoxylated C2 and C6 to about 1. The drug is produced by acid hydrolysis of starch, gidroksietilirovaniyu with ethylene oxide in nitrogen atmosphere, neutralizing the mixture by treatment with activated carbon, concentrated and drying, dissolving the product in extracting the solvent, by filtration, by precipitation with BSE, drying and cleaning (US 4167622 And 11.09.1979).

Known preparations of the above prior art does not provide an optimal level of finding funds in the blood. Methods for their preparation do not allow to establish a favorable ratio of substituted hydroxyethylene groups and the degree of substitution in the given interval, which are primarily responsible for the effectiveness of this operation.

The present invention is to develop a new means of volemic steps, quickly reducing the pressure in the blood stream of a patient who has lost a lot of blood, with fewer side effects, and optimization of the method of receiving the above-mentioned means to regulate the degree of substitution at the right interval and to obtain a favorable ratio of substituted hydroxyethylene groups.

The problem is solved with the medication, representing 5-10% solution gidroksietilirovannogo starch with an optimal ratio of substituted hydroxyethylene groups of atoms C2/C6, from 4:1 to 6:1 in the remainder of glucose (confirmed by NMR13C), the optimal value of the average molecular weight in the range from 120 to 480, mostly from 170 to 230 kDa and narrow molecular weight distribution when the degree of substitution of 0.35 to 0.7, and containing 0,80-1,00% sodium chloride solution.

Such characteristics of the main active start - gidroksietilirovannogo starch - provide rapid recovery of the pressure in the blood line of the patient who has lost a lot of blood, and accordingly microcirculation in organs and tissues, restoring their normal energy supply and removal of waste products, including endogenous toxins, and possible exogenous toxins.

In addition, the proposed tool is not as undesirable impurities of high-molecular compounds and, accordingly, reduced the risk of side effects.

The content of sodium chloride in the amount of 0.80 to 1.0% provides isotonicity biological body fluids injected solution.

The proposed method of obtaining funds is that a) Native amylopectin corn or potatoes the aqueous starch content of amylopectin at least 95%, compared with other polysaccharide starch - aminosol - longer resists the action of enzymes, which allows more time to be in the bloodstream, providing for shock action, with a molecular weight of up to 20 thousand kDa subjected to preliminary hydrolysis, acid or enzyme, with decreasing molecular weight of up to 400-1000 kDa, which allows subsequent gidroksietilirovaniya in a homogeneous phase with increasing homogeneity of the environment, ensuring the regularity of gidroksietilirovaniya along the entire chain of the polymer and reducing the color of the solution. Preferably the preliminary acid hydrolysis is performed at a content of starch in suspension 10-40%, the concentration of HCl 0.1-0.5 M, a temperature of 30-50°C. the Duration of 3-12 hours. The enzymatic hydrolysis is carried out using the type of enzymes amylases, glucosides and such at 35-40°s to the specified value of the molecular weight under control NMR C-13.

b) Spend alkaline cleaning. For example, when the content of starch in suspension 20-50%, the concentration of NaOH 0.1-0.5 M, the temperature of 30-50°With a duration of 0.5-3 hours

b) a Partially hydrolyzed starch will gidroksietiliden in an alkaline medium in the presence of a catalyst, which can be used inorganic salts, for example sodium chloride or potassium chloride, hydroxide of the metals, ninety. The synthesis conditions BSE may vary. The reaction temperature 50-90°C, the ratio of ethylene oxide to the starch 10-50% when the rate of feed, causing the pressure in the apparatus from 1.2 to 1.8 ATM, duration of 0.5 to 5 hours, the concentration of the catalyst is 0.5 to 5%. At the end of the process the mixture is cooled, neutralized and filtered.

In the case of use as a catalyst anion exchange pH of about 10.

g) carry out acid hydrolysis of an aqueous solution obtained BSE to a predetermined molecular weight at a pH of 0.4 to 1.5, a temperature of 50-80°C, the duration 2-6 hours. Specifications molecular mass and molecular mass distributions are controlled using the method of liquid chromatography and low-angle laser light scattering.

d) the Solution is clear of unwanted impurities and low molecular weight fractions gidroksietilirovannogo starch ultrafiltration and/or reverse osmosis. Upon reaching the desired degree of purification hold the concentration or dilution of BSE to a solution of 5-10% concentration.

e) is Added to a solution of sodium chloride to a concentration of 0.8-1.0%, pyrogen-free activated carbon, heat the mixture to 95-100°, then cooled to 70-80°and/or

g) Conduct sterilizing filtration with subsequent filling solution in appropriate containers, and of course thermal sterilization.

After ultrafiltration and/or reverse osmosis may conduct sterilizing filtration of the solution gidroksietilirovannogo starch, drying conditions, retains its composition and structure, freeze or spray drying plant.

When carrying out the sterilizing filtration substance gidroksietilirovannogo starch dissolved in water for injection in the amount of 50-70 g/l with the addition of 8-10 g/l of sodium chloride or in the amount of 90-100 g/l with the addition of 8-10 g/l sodium chloride solution, filtered through sterilizing filters with a pore diameter of ≤0.22 μm.

At all stages of the process is complete physico-chemical analysis of the reaction products.

Advantages of the claimed method:

- preliminary acid hydrolysis can improve the homogeneity of the environment, ensuring the regularity of gidroksietilirovaniya along the entire chain of the polymer, to reduce the coloration of the solution.

- conditions gidroksietilirovaniya partially hydrolyzed amylopectin allow you to set the degree of substitution in the desired interval: 0,35-0,70, and to obtain a favorable ratio of substituted hydroxyethylene groups of atoms C2/C6 from 4:1 to 6:1.

- conditions of controlled acid hydrolysis gidroksietilirovannogo starch allow pre-allocation of the polymer to the desired average value m is molecular weight in the range from 120 to 480 kDa, and, as mentioned above, the lack of as impurities undesirable high molecular weight compounds.

The following are specific examples of carrying out the invention.

Example 1.

In a flask with stirrer capacity of 5 litres pour 2 liters of 0.1 M sodium hydroxide solution in water treated (FS 42-2619-97) and under stirring load dry amylopectinosis starch in the amount of 1.0 kg of Starch suspension is heated on a mantle to 45°C and stirred for 1 hour

After alkaline treatment of the mixture to dilute the starch content of 10-20%, neutralized to pH 5.0-7.0 and separating the precipitate on the filter. The precipitate is washed with 5 volumes of purified water.

The residue is purified starch is transferred into a container with a stirrer with a capacity of 10 l, add 3 liters of purified water, heated to 40°add hydrochloric acid to a concentration of 0.1 M and carry out the hydrolysis at 40°C for 12 h with constant stirring.

After carrying out the hydrolysis, the suspension is neutralized to pH 6,0-7,0, to dilute the starch content of 10-20%, mix and separate the starch on the filter. Partially hydrolyzed starch on the filter is washed with 5 volumes of purified water.

In chetyrehosnuju round bottom flask with a capacity of 5 l pour purified water in an amount of 3.0 liters, add the sodium chloride in the amount of 0.15 kg and stirred at ambient temperature the re 20-25° With up to complete dissolution of sodium chloride. Then the flask was added with constant stirring purified partially hydrolyzed starch. At the end of the boot with the help of mantle temperature in the reaction mass is gradually raised to 85-90°and stir it at this temperature for 30 minutes the resulting paste was filtered at 60-70°through a polypropylene filter to remove solids.

Starch paste is transferred into the apparatus of stainless steel, equipped with anchor stirrer, thermometer, pressure gauge and barbaterom, and purge with nitrogen. Then in the device create excessive pressure 40-60 kPa, using an oil bath heated the reaction mixture to 75°and start drip feeding of liquid ethylene oxide. Gidroksietilirovaniya carried out at a temperature of 80°C. the Filing of ethylene oxide regulate so that the pressure in the apparatus was less than 2 ATM. The total quantity of ethylene oxide is 0.15 kg After loading the required amount of ethylene oxide, the reaction mixture is maintained at a temperature of 80°C for 30 minutes At the end of the process gidroksietilirovaniya the reaction mass is then cooled to 40-45°and conduct purge apparatus with nitrogen. After purging the mixture is diluted by addition of 8 l of purified water and stirred for 45-60 minutes, cooling the mixture to 20-25#x000B0; C. Then the device is added 2 M HCl to establish a pH of 6.5-7.0 and filtered off the solution from the solids.

The filtered solution BSE transferred into the apparatus with stirrer capacity of 30 litres, add 11 l of purified water and stirred for 20 minutes using mantle raise the temperature of the mixture up to 50°and with stirring, add 2 M HCl to a pH of 0.7. Control the degree of hydrolysis lead by viscometric method. The hydrolysis time is about 3 h until a relative viscosity of 3.0. When reaching a given value of the relative viscosity of the hydrolysate HES cooled to 50-60°and the solution is neutralized 1 M NaOH to a pH of 5.0-6.0.

Then, the solution purified from low molecular weight compounds by ultrafiltration hollow fibers with a tensile cut-off 30 kDa against purified water until the residual chloride concentration up to 0.05-0.07 per cent. Upon reaching the desired degree of purification spend the concentration of BSE in the solution to a concentration of 5.5-6.5 per cent.

The solution of the BSE is transferred into a flask, add sodium chloride to a concentration of 0.85 to 1.0%, pyrogen-free activated carbon in the amount of 8-10 g/l for the removal of pyrogens, stir the mixture to dissolve the sodium chloride, heating the mixture to 95-100°C and stirred at this temperature for 20 minutes At the end of processing is cooled mixture to 70-80°and filtered through a filter the seat reservation cleaning and sterilizing filter.

The filtered solution BSE in sterile conditions is poured into appropriate containers for pharmaceuticals (glass bottle or plastic container).

Bottle or plastic container with a solution of the HES is subjected to sterilization in a steam-autoclave at a temperature of 105-120°C for 20-40 minutes

Get 24 bottles of solution BSE 400 ml each, containing a total of 720 g of BSE with the following characteristics:

Mw- 234700 Yes.

The degree of substitution is about 0.53.

C2:C6 - 3,9:1.

Example 2.

In a flask with stirrer capacity of 5 litres pour 2 liters 0,0 5M sodium hydroxide solution in water treated (FS 42-2619-97) and under stirring load dry amylopectinosis starch in a quantity of 0.8 kg. of Starch suspension is heated on a mantle to 35°C and stirred for 2 hours

After alkaline treatment of the mixture to dilute the starch content of 10-20%, neutralized to pH 5.0-7.0 and separating the precipitate on the filter. The precipitate is washed with 5 volumes of purified water.

The residue is purified starch is transferred into a container with a stirrer with a capacity of 10 l, add 3 liters of purified water, heated to 50°add hydrochloric acid to a concentration of 0.05 M and carry out the hydrolysis at 50°C for 12 h with constant stirring.

After carrying out the hydrolysis, the suspension is neutralized to pH 6,0-7,0, dilute the content of starch 10-20%, mix and separate the starch on the filter. Partially hydrolyzed starch on the filter is washed with 5 volumes of purified water.

In chetyrehosnuju round bottom flask with a capacity of 5 l pour purified water in the amount of 3.0 liters, add the potassium chloride in the amount of 0.12 kg and stirred at a temperature of 20-25°to dissolve the potassium chloride. Then the flask was added with constant stirring purified partially hydrolyzed starch. At the end of the boot with the help of mantle temperature in the reaction mass is gradually raised to 85-90°C and stirred at this temperature for 30 minutes the resulting paste was filtered at 60-70°through a polypropylene filter to remove solids.

Starch paste is transferred into the apparatus of stainless steel, equipped with anchor stirrer, thermometer, pressure gauge and barbaterom, and purge with nitrogen. Then in the device creates a pressure of 40-60 kPa, using an oil bath heated the reaction mixture to 85°and begin to drip feeding of liquid ethylene oxide. Gidroksietilirovaniya carried out at a temperature of 85°C. the Filing of ethylene oxide regulate so that the pressure in the apparatus was less than 2 ATM. The total quantity of ethylene oxide is 0.12 kg After loading the required amount of ethylene oxide, the reaction mixture in the support at a temperature of 85° C for 1 h At the end of the process gidroksietilirovaniya the reaction mass is then cooled to 40-45°and conduct purge apparatus with nitrogen. After purging the mixture is diluted by adding 6 l of purified water and stirred for 45-60 minutes, cooling the mixture to 20-25°C. Then the device is added 2 M HCl to establish a pH of 6.5-7.0 and filtered off the solution from the solids.

The filtered solution BSE transferred into the apparatus with stirrer capacity of 30 litres, add 8 l of purified water and stirred for 20 minutes using mantle raise the temperature of the mixture to 60°and with stirring, add 2M HCl to a pH of 1.0. Control the degree of hydrolysis lead by viscometric method. The time of hydrolysis of about 2.5 h until a relative viscosity of 3.0. When reaching a given value of the relative viscosity of the hydrolysate HES cooled to 50-60°and the solution is neutralized 1 M NaOH to a pH of 5.0-6.0.

Then, the solution purified from low molecular weight compounds by ultrafiltration hollow fibers with a tensile cut-off 30 kDa against purified water to achieve a residual concentration of chlorides 0,05-0,07%. Upon reaching the desired degree of purification spend the concentration of the solution of the BSE to a concentration of 5.5 to 6.5%.

Concentrate BSE serves for the installation of spray drying, where the temperature is 170°conduct sushi is in the SEC.

Get 610 g of dried pyrogen-free and microbiologically pure BSE with the following characteristics:

Mw- 201000 Yes.

The degree of substitution - 0,49.

C2:C6 - 4,3:1.

Dry BSE in the amount of 306 g dissolved in 3.0 l of water for injection (FS 42-2620-97) at 50°With stirring for 30 minutes the solution is added to 45.9 g of sodium chloride and stirred for 30 minutes Then the solution is brought to a volume of 5.1 l by adding water for injection.

The solution is subjected to microfiltration using a sterilizing filter with an average pore diameter of not more than 0.22 μm.

Then, the solution is poured into 10 bottles with a capacity of 500 ml, sealed with rubber stoppers and rolled aluminum caps.

Bottle with a solution of the BSE subjected to heat sterilization in a steam-autoclave-sterilizer at a temperature of 121°C for 20 minutes

Get 10 bottles with pyrogen-free and sterile 6% solution of the SEC.

Example 3.

In a flask with stirrer with a capacity of 3 l pour 1.5 liters of 0.2 M sodium hydroxide solution in water treated (FS 42-2619-97) and under stirring load dry amylopectinosis starch in the amount of 0.65 kg of Starch suspension is heated on a mantle up to 40°C and stirred for 2 hours

After alkaline treatment of the mixture to dilute the starch content of 10-20%, neutralized to pH 5.0-7.0 and separate OSA is OK on the filter. The precipitate is washed with 5 volumes of purified water.

The residue is purified starch is transferred into a flask with a stirrer with a capacity of 5 l was added to 2.0 l of purified water, heated to 30°add hydrochloric acid to a concentration of 0.15 M and carry out the hydrolysis at 40°C for 6 h with constant stirring.

After carrying out the hydrolysis, the suspension is neutralized to pH 6,0-7,0, to dilute the starch content of 10-20%, mix and separate the starch on the filter. Partially hydrolyzed starch on the filter is washed with 5 volumes of purified water.

In a round bottom flask with a capacity of 3 l pour purified water in the amount of 2.5 liters, add potassium chloride and sodium chloride in an amount of 0.06 kg when the weight ratio of salt to 1:1 and stirred at a temperature of 20-25°until full dissolution. Then the flask was added with constant stirring purified partially hydrolyzed starch. At the end of the boot with the help of mantle temperature in the reaction mass is gradually raised to 85-90°C and stirred at this temperature for 30 minutes the resulting paste was filtered at 60-70°through a polypropylene filter to remove solids.

Starch paste is transferred into the apparatus of stainless steel, equipped with anchor stirrer, thermometer, pressure gauge and barbaterom, and purge with nitrogen. The ZAT is in the device create excessive pressure 40-60 kPa, using an oil bath heated the reaction mixture to 65°and start drip feeding of liquid ethylene oxide. Gidroksietilirovaniya carried out at a temperature of 65°C. the Filing of ethylene oxide regulate so that the pressure in the apparatus was less than 2 ATM. The total quantity of ethylene oxide is 0.09 kg After loading the required amount of ethylene oxide, the reaction mixture is maintained at a temperature of 65°C for 4 h At the end of the process gidroksietilirovaniya the reaction mass is then cooled to 40-45°and conduct purge apparatus with nitrogen. After purging the mixture is diluted by adding 4 l of purified water and stirred for 45-60 minutes, cooling the mixture to 20-25°C. Then the device is added 2 M HCl to establish a pH of 6.5-7.0 and filtered off the solution from the solids.

The filtered solution BSE transferred into a flask with a stirrer with a capacity of 10 l, add 5.0 litres of purified water and stirred for 20 minutes using mantle raise the temperature of the mixture to 60°and with stirring, add 2 M HCl to a pH of 1.5. Control the degree of hydrolysis HES lead by viscometric method to achieve a relative viscosity of 2.5-3.5. Upon reaching a given value of the relative viscosity of the hydrolysate HES cooled to 50-60°and the solution is neutralized to a pH of 5.0-6.0.

Then, the solution evaluation is to provide cleaning from low molecular weight compounds by ultrafiltration hollow fibers with a tensile cut-off 30 kDa against purified water to achieve a residual concentration of chlorides 0,05-0,07%. Upon reaching the desired degree of purification spend the concentration of the solution of the BSE to a concentration of 5.5 to 6.5%.

Concentrate HES quickly frozen at -40°C, kept at this temperature for 12 h and conduct of freeze-dried product.

Receive 541 g of dried HES with the following characteristics:

Mw- 197300 Yes.

The degree of substitution - 0,51.

C2:C6 - 4,4:1.

Example 4.

In a flask with stirrer with a capacity of 3 l pour 1.5 liters of 0.3 M solution of sodium hydroxide in purified water (FS 42-2619-97) and under stirring load dry amylopectinosis starch in the amount of 0.65 kg of Starch suspension is heated on a mantle up to 30°C and stirred for 1.0 hours

After alkaline treatment of the mixture to dilute the starch content of 10-20%, neutralized to pH 5.0-7.0 and separating the precipitate on the filter. The precipitate is washed with 5 volumes of purified water.

The residue is purified starch is transferred into a flask with a stirrer with a capacity of 5 l was added to 2.0 l of purified water, heated to 35°add hydrochloric acid to a concentration of 0.2m and carry out the hydrolysis at 35°C for 4 h with constant stirring.

After carrying out the hydrolysis, the suspension is neutralized to pH 6,0-7,0, to dilute the starch content of 10-20%, mix and separate the starch on the filter. Partially hydrolyzed starch on the filter is washed with 5 volumes in the purified water.

In a round bottom flask with a capacity of 3 l pour purified water in the amount of 2.0 liters, add the sodium chloride in the amount of 0.08 kg and stirred at a temperature of 20-25°until it dissolves. Then the flask was added with constant stirring purified partially hydrolyzed starch. At the end of the boot with the help of mantle temperature in the reaction mass is gradually raised to 85-90°C and stirred at this temperature for 30 minutes the resulting paste was filtered at 60-70°through a polypropylene filter to remove solids.

Starch paste is transferred into the apparatus of stainless steel, equipped with anchor stirrer, thermometer, pressure gauge and barbaterom, and purge with nitrogen. Then in the device create excessive pressure 40-60 kPa, using an oil bath heated the reaction mixture to 70°and start drip feeding of liquid ethylene oxide. Gidroksietilirovaniya carried out at a temperature of 70°C. the Filing of ethylene oxide regulate so that the pressure in the apparatus was less than 2 ATM. The total quantity of ethylene oxide is 0.06 kg After loading the required amount of ethylene oxide, the reaction mixture is maintained at a temperature of 70°C for 3 hours At the end of the process gidroksietilirovaniya the reaction mass is then cooled to 40-45°and Prov is completed with a blowing apparatus with nitrogen. After purging the mixture is diluted by adding 4 l of purified water and stirred for 45-60 minutes, cooling the mixture to 20-25°C. Then the device is added 2 M HCl to establish a pH of 6.5-7.0 and filtered off the solution from the solids.

The filtered solution BSE transferred into a flask with a stirrer with a capacity of 10 l, add 5.0 litres of purified water and stirred for 20 minutes using mantle raise the temperature of the mixture to 60°and with stirring, add 2 M HCl to a pH of 1.0. Control the degree of hydrolysis HES lead by viscometric method to achieve a relative viscosity of 1.5-2.0. Upon reaching a given value of the relative viscosity of the hydrolysate HES cooled to 50-60°and the solution is neutralized to a pH of 5.0-6.0.

Then, the solution purified from low molecular weight compounds by ultrafiltration hollow fibers with a tensile cut-off 30 kDa against purified water to achieve a residual concentration of chlorides 0,05-0,07%. Upon reaching the desired degree of purification spend the concentration of the solution of the BSE to a concentration of 5.5 to 6.5%.

Concentrate HES quickly frozen at -40°C, kept at this temperature for 12 h and conduct of freeze-dried product.

Get 585 g of dried HES with the following characteristics:

Mw- 132100 Yes.

The degree of substitution to 0.39.

C2:C6 - 5,2:1.

Example 5.

In a flask with stirrer with a capacity of 3 l pour 1.5 liters of 0.1 M sodium hydroxide solution in water treated (FS 42-2619-97) and under stirring load dry amylopectinosis starch in the amount of 0.65 kg of Starch suspension is heated on a mantle up to 50°C and stirred for 0.5 hours

After alkaline treatment of the mixture to dilute the starch content of 10-20%, neutralized to pH 5.0-7.0 and separating the precipitate on the filter. The precipitate is washed with 5 volumes of purified water.

The residue is purified starch is transferred into a flask with a stirrer with a capacity of 5 l was added to 2.0 l of purified water, heated to 35°add hydrochloric acid to a concentration of 0.15 M and carry out the hydrolysis at 35°C for 5 h under constant stirring.

After carrying out the hydrolysis, the suspension is neutralized to pH 6,0-7,0, to dilute the starch content of 10-20%, mix and separate the starch on the filter. Partially hydrolyzed starch on the filter is washed with 5 volumes of purified water.

In a round bottom flask with a capacity of 3 l pour purified water in the amount of 2.0 liters, add the potassium chloride in the amount of 0.09 kg and stirred at a temperature of 20-25°until it dissolves. Then the flask was added with constant stirring purified partially hydrolyzed starch. At the end of the boot with the help of mantle temperature in the PE klonoa weight gradually raised to 85-90° C and stirred at this temperature for 30 minutes the resulting paste was filtered at 60-70°through a polypropylene filter to remove solids.

Starch paste is transferred into the apparatus of stainless steel, equipped with anchor stirrer, thermometer, pressure gauge and barbaterom, and purge with nitrogen. Then in the device create excessive pressure 40-60 kPa, using an oil bath heated the reaction mixture to 70°and start drip feeding of liquid ethylene oxide. Gidroksietilirovaniya carried out at a temperature of 70°C. the Filing of ethylene oxide regulate so that the pressure in the apparatus was less than 2 ATM. The total quantity of ethylene oxide is 0,18 kg After loading the required amount of ethylene oxide, the reaction mixture is maintained at a temperature of 70°C for 3 hours At the end of the process gidroksietilirovaniya the reaction mass is then cooled to 40-45°and conduct purge apparatus with nitrogen. After purging the mixture is diluted by adding 4 l of purified water and stirred for 45-60 minutes, cooling the mixture to 20-25°C. Then the device is added 2 M HCl to establish a pH of 6.5-7.0 and filtered off the solution from the solids.

The filtered solution BSE transferred into a flask with a stirrer with a capacity of 10 l, add 5.0 litres of purified water and stirred for 20 minutes With the aid of the completion mantle raise the temperature of the mixture to 40° With and with stirring, add 2 M HCl to a pH of 0.5. Control the degree of hydrolysis HES lead by viscometric method to achieve a relative viscosity of 4.0 to 5.0. Upon reaching a given value of the relative viscosity of the hydrolysate HES cooled to 50-60°and the solution is neutralized to a pH of 5.0-6.0.

Then, the solution purified from low molecular weight compounds by ultrafiltration hollow fibers with a tensile cut-off 30 kDa against purified water to achieve a residual concentration of chlorides 0,05-0,07%. Upon reaching the desired degree of purification spend the concentration of the solution of the BSE to a concentration of 5.5 to 6.5%.

Concentrate HES quickly frozen at -40°C, kept at this temperature for 12 h and conduct of freeze-dried product.

Get 585 g of dried HES with the following characteristics:

Mw- 445700 Yes.

The degree of substitution is 0.71.

C2:C6 - 3,5:1.

Dry BSE in the number of 509 g dissolved in 4.0 l of water for injection (FS 42-2620-97) at 50°With stirring for 30 minutes the solution is added to 45.9 g of sodium chloride and stirred for 30 minutes and Then the solution is brought to volume with 5.2 liter by adding water for injection.

The solution is subjected to microfiltration using a sterilizing filter with an average pore diameter of not more than 0.22 μm.

Then, the solution is poured into 10 bottles with a capacity of 500 ml, ukup the mandate rubber plugs and rolled aluminum caps.

Bottle with a solution of the BSE subjected to heat sterilization in a steam-air autoclave-sterilizer at a temperature of 121°C for 20 minutes Get a pyrogen-free sterile 10% solution of the SEC.

Received stated the way the drug has an optimum composition, meets the standards that exist for this group of drugs showed high efficiency in testing and can be recommended for widespread use in clinical practice.

1. Drug volemic action, which is an aqueous solution gidroksietilirovannogo starch, characterized in that it contains 5-10% gidroksietilirovannogo starch with an optimal ratio of substituted gidroksietilirovanny groups of atoms With2/S6from 4:1 to 6:1 in the remainder of glucose, the average molecular weight within the 120 - 480 kDa, narrow molecular weight distribution when the degree of substitution of 0.35 to 0.70, and 0.80 to 1.0% sodium chloride solution.

2. The method of obtaining medicines volemic actions by gidroksietilirovaniya amylopectin, acid hydrolysis, sterilizing filtration and ultrafiltration, characterized in that is used as raw material of corn or potato starch containing amylopectin not less than 95%, which is subjected to alkaline cleaning, subsequent pre the preliminary acid or enzymatic hydrolysis to obtain products with a molecular mass of 400-900 kDa and the resulting partially hydrolyzed starch will gidroksietiliden to a predetermined degree of substitution hydroxyethylene groups from 0.35 to 0.70, in an alkaline medium and in the presence of 0.5 to 5% of catalyst at the reaction temperature 50-90°With ethylene oxide, the rate of feed, causing the pressure in the apparatus of 1.2 - 2 ATM, for 0.5-5 h, gidroksietilirovanny starch is subjected to controlled acid hydrolysis at a given molecular weight, 120 - 480 kDa, the solution is purified from unwanted impurities and low molecular weight fractions gidroksietilirovannogo starch ultrafiltration and/or reverse osmosis, get a 5-10% solution gidroksietilirovannogo starch, add in a sodium chloride solution to obtain 0,8-1,0% concentrations are cleaned using pyrogen-free activated carbon and/or sterilizing filtration with subsequent heat sterilization of the final product.

3. The method according to claim 2, characterized in that after ultrafiltration and/or reverse osmosis spend sterilizing filtration of the solution gidroksietilirovannogo starch, dried under conditions that preserve its composition and structure, freeze or spray drying plant.

4. The method according to claim 2, characterized in that the substance gidroksietilirovannogo starch dissolved in water for injection in the amount of 50-70 g/l with the addition of 8-10 g/l of sodium chloride, filtered through sterilizing filters pore diameter of not more than 0.22 μm, bottled in glass bottles or plastic the new containers, intended for drugs, and subjected to heat sterilization.

5. The method according to claim 2, characterized in that the substance gidroksietilirovannogo starch dissolved in water for injection in the amount of 90-100 g/l with the addition of 8-10 g/l of sodium chloride, filtered through sterilizing filters pore diameter of not more than 0.22 μm, bottled in glass bottles or plastic containers for medicines, and subjected to heat sterilization.

6. The method according to claim 1, characterized in that the pre-cleaning gidroksietilirovannogo starch is carried out in the presence of sodium hydroxide with a concentration of 0.1-0.5 M at a temperature of 30-50°and duration of 0.5-3 hours

7. The method according to claim 1, characterized in that the preliminary acid hydrolysis carried out with hydrochloric acid in a concentration of 0.1-0.5m HCl at a temperature of 30-50°and duration of 3-12 hours

8. The method according to any of claim 2 to 7, characterized in that the catalyst used is sodium chloride or potassium chloride.

9. The method according to any of claim 2 to 7, characterized in that the catalyst used anion exchange resin at pH process gidroksietilirovaniya equal to 10.



 

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