Thermal method for sterilizing poloxamer comprising liquid drugs

Abstract

The invention relates to chemical and pharmaceutical industry, in particular to technologies of obtaining sterile drugs, drug substances and cosmetic products used in the form of solutions or emulsions, and comprising poloxamer. The thermal method for sterilizing aqueous poloxamer solutions is provided, the method including: dissolving a poloxamer in water for injection; performing the sterilizing filtration of the aqueous poloxamer solution simultaneously with filling sterile containers with the filtered poloxamer solution; sealing the containers containing the poloxamer solution; applying a thermal sterilization with steam under pressure to the containers containing the poloxamer solution, and cooling them, wherein the thermal sterilization of the containers containing the poloxamer solution with steam under pressure is performed under the pressure between 82.4 and 107.8 kPa.

Claims

1. A thermal method for sterilizing aqueous poloxamer solutions, the method including: dissolving a poloxamer in water for injection; performing a sterilizing filtration of the aqueous poloxamer solution simultaneously with filling sterile containers with the filtered poloxamer solution; sealing the containers containing the poloxamer solution; and applying a thermal sterilization with steam under pressure to the containers containing the poloxamer solution, and cooling the containers, characterized in that the thermal sterilization of the containers containing the poloxamer solution with steam under pressure is performed under a pressure between 82.4 and 107.8 kPa, and in that the containers containing the poloxamer solution are cooled to a temperature of 30-40° C. for at least 2 hours.

2. The method according to claim 1, characterized in that the thermal sterilization with steam under pressure is applied to the containers containing 2 to 100 ml of the poloxamer solution for 8-10 minutes.

3. The method according to claim 1, characterized in that containers containing 100 to 400 ml of the poloxamer solution are subjected to the thermal sterilization with steam under pressure for 12 minutes.

4. The method according to claim 1, characterized in that sterile ampoules or vials are used as the containers.

5. The method according to claim 4, characterized in that the vials containing the poloxamer solution are sealed by stoppering them with sterile stoppers, covering the vials with sterile aluminium caps and further rolling the caps on.

6. The method according to claim 4, characterized in that the ampoules containing the poloxamer solution are sealed by sealing them off.

7. The method according to claim 1, characterized in that the concentration of the poloxamer in the solution is between 0.1 wt %/1 and 40 wt %/1.

8. The method according to claim 1, characterized in that the poloxamer is dissolved in the water for injections at a temperature of the water between 5 and 25° C.

9. The method according to claim 1, characterized in that sodium chloride is further added to the aqueous poloxamer solution.

10. The method according to claim 1, characterized in that potassium chloride is further added to the aqueous poloxamer solution.

Description

EMBODIMENTS OF THE METHOD

Example 1. Preparation of a Sterile Aqueous Solution Containing 16% of the Poloxamer of Emuxol-268 of Grade “A”

(1) A metal reservoir with a capacity of 40 liters is filled with 15 liters of water for injection the temperature of which is 7° C., and is filled portionwise with 4.0 kg of the poloxamer. The contents of the reservoir are stirred with a laboratory mixer of a PW type having a “”-shaped stirring arm (the rotary speed of the stirring arm is in the range of 500÷700 rpm) until the poloxamer is completely dissolved. The volume of the poloxamer solution is adjusted with the water for injections of the same temperature to 25 liters.

(2) The sterilizing filtration is performed in aseptic conditions. The prepared poloxamer solution is filtered at a pressure of 68.6-147.1 kPa through a sterile hydrophilic membrane filter with a pore diameter of 0.2-0.22 μm. The poloxamer solution is dispensed simultaneously with the sterilizing filtration: 400 ml of the filtered poloxamer solution is fed directly to each of the sterile glass vials that have a volume of 450 ml and used for infusion preparations, then the vials containing the poloxamer solution are stoppered with sterile stoppers, and covered and rolled with sterile aluminium caps. The sterilization of the poloxamer solution in the vials is performed in a steam sterilizer VK-75 at a pressure of 88.3 kPa for 12 minutes. After the completion of the process of the thermal sterilization with steam under pressure, the vials containing the poloxamer solution are cooled to 35° C. for 2.5 hours. The insignificant gel formation of the poloxamer solution disappears after 30 minutes. The poloxamer solution treated this way is tested for sterility and pyrogenicity.

(3) The test results are shown in Table 1.

(4) TABLE-US-00001 TABLE 1 The comparison table of the testing of the poloxamer solution for sterility and pyrogenicity in the process of production Pyrogenicity Sterility Requirement Requirement Name of test of normative Analysis of normative Analysis object documentation results documentation results Poloxamer Must be Pyrogen- Must be sterile Sterile solution, pyrogen-free free 16%, 400 ml

Example 2. Preparation of a Sterile Aqueous Solution Containing 1% of the Poloxamer of Lutrol F68

(5) A metal reservoir with a capacity of 40 liters is filled with 16 liters of water for injection the temperature of which is 20° C., and then is filled portionwise with 0.25 kg of the poloxamer. The contents of the reservoir are stirred with a laboratory mixer of a PW type having a “”-shaped stirring arm (the rotary speed of the stirring arm is in the range of 500÷700 rpm) until the poloxamer is completely dissolved. The volume of the poloxamer solution is adjusted with the water for injections of the same temperature to 25 liters.

(6) The sterilizing filtration is performed in aseptic conditions. The prepared poloxamer solution is filtered at a pressure of 68.6-147.1 kPa through a sterile hydrophilic membrane filter with a pore diameter of 0.2-0.22 μm. The poloxamer solution is dispensed simultaneously with the sterilizing filtration: 200 ml of the filtered poloxamer solution is fed directly to each of the sterile glass vials that have a volume of 250 ml and used for infusion preparations, then the vials containing the poloxamer solution are stoppered with sterile stoppers, and covered and rolled with sterile aluminium caps. The sterilization of the poloxamer solution in the vials is performed in a steam sterilizer VK-75 at a pressure of 98.1 kPa for 12 minutes. After the completion of the process of the thermal sterilization with steam under pressure, the vials containing the poloxamer solution are cooled to 30° C. for 2 hours and 10 minutes. The insignificant gel formation of the poloxamer solution disappears after 20 minutes. The poloxamer solution treated this way is tested for sterility and pyrogenicity.

(7) The test results are shown in Table 2.

(8) TABLE-US-00002 TABLE 2 The comparison table of the testing of the poloxamer solution for sterility and pyrogenicity in the process of production Pyrogenicity Sterility Requirement Requirement Name of test of normative Analysis of normative Analysis object documentation results documentation results Poloxamer Must be Pyrogen- Must be sterile Sterile solution, pyrogen-free free 1%, 200 ml

Example 3. Preparation of a Sterile Aqueous Solution Containing 28% of the Poloxamer of Emuxol-268 of Grade “A”

(9) A metal reservoir with a capacity of 40 liters is filled with 16 liters of water for injection the temperature of which is 11° C., and is filled portionwise with 7.0 kg of the poloxamer. The contents of the reservoir are stirred with a laboratory mixer of a PW type having a “”-shaped stirring arm (the rotary speed of the stirring arm is in the range of 500÷700 rpm) until the poloxamer is completely dissolved. The volume of the poloxamer solution is adjusted with the water for injections of the same temperature to 25 liters.

(10) The sterilizing filtration is performed in aseptic conditions. The prepared poloxamer solution is filtered at a pressure of 68.6-147.1 kPa through a sterile hydrophilic membrane filter with a pore diameter of 0.2-0.22 μm. The poloxamer solution is dispensed simultaneously with the sterilizing filtration: 200 ml of the filtered poloxamer solution is fed directly to each of the sterile glass vials that have a volume of 250 ml and used for infusion preparations, then the vials containing the poloxamer solution are stoppered with sterile stoppers, and covered and rolled with sterile aluminium caps. The sterilization of the poloxamer solution in the vials is performed in a steam sterilizer VK-75 at a pressure of 83.4 kPa for 12 minutes. After the completion of the process of the thermal sterilization with steam under pressure, the vials containing the poloxamer solution are cooled to 40° C. for 3 hours. Gel formation of the poloxamer solution was not observed. The poloxamer solution treated this way is tested for sterility and pyrogenicity.

(11) The test results are shown in Table 3.

(12) TABLE-US-00003 TABLE 3 The comparison table of the testing of the poloxamer solution for sterility and pyrogenicity in the process of production Pyrogenicity Sterility Requirement Requirement Name of test of normative Analysis of normative Analysis object documentation results documentation results Poloxamer Must be Pyrogen- Must be sterile Sterile solution, pyrogen-free free 28%, 200 ml

Example 4. Preparation of a Sterile Aqueous Solution Containing 6% of the Poloxamer of Emuxol-268 of Grade “A” and 0.9% of Sodium Chloride

(13) A metal reservoir with a capacity of 40 liters is filled with 15 liters of water for injection the temperature of which is 18° C., and is filled portionwise with 1.5 kg of the poloxamer. The contents of the reservoir are stirred with a laboratory mixer of a PW type having a “”-shaped stirring arm (the rotary speed of the stirring arm is in the range of 500÷700 rpm) until the poloxamer is completely dissolved. 0.36 kg of sodium chloride is added to the resulting solution and stirred. The volume of the poloxamer solution is adjusted with the water for injections of the same temperature to 25 liters.

(14) The sterilizing filtration is performed in aseptic conditions. The prepared poloxamer solution is filtered at a pressure of 68.6-147.1 kPa through a sterile hydrophilic membrane filter with a pore diameter of 0.2-0.22 μm. The poloxamer solution is dispensed simultaneously with the sterilizing filtration: 10 ml of the filtered poloxamer solution is fed directly to each of the glass ampoules that have a capacity of 12 ml, and then the ampoules are sealed off The sterilization of the poloxamer solution in the ampoules is performed in a steam sterilizer VK-75 at a pressure of 85.0 kPa for 8 minutes. After completion of the process of the thermal sterilization with steam under pressure, the ampoules containing the poloxamer solution are cooled to 32° C. for 2 hours. Gel formation of the poloxamer solution was not observed. The poloxamer solution treated this way is tested for sterility and pyrogenicity.

(15) The test results are shown in Table 4.

(16) TABLE-US-00004 TABLE 4 The comparison table of the testing of the poloxamer solution for sterility and pyrogenicity in the process of production Pyrogenicity Sterility Requirement Requirement Name of test of normative Analysis of normative Analysis object documentation results documentation results Poloxamer Must be Pyrogen- Must be sterile Sterile solution, pyrogen-free free 10 ml, 6% with 0.9% of sodium chloride

Example 5. Preparation of a Sterile Aqueous Solution Containing 16% of the Poloxamer of Emuxol-268 of Grade “A” at a Pressure of 82.0 kPa Without Preliminary Sterilizing Filtration

(17) A metal reservoir with a capacity of 40 liters is filled with 17 liters of water for injection the temperature of which is 7° C., and is filled portionwise with 4.0 kg of the poloxamer. The contents of the reservoir are stirred with a laboratory mixer of a PW type having a “”-shaped stirring arm (the rotary speed of the stirring arm is in the range of 500÷700 rpm) until the poloxamer is completely dissolved. The volume of the poloxamer solution is adjusted with the water for injections of the same temperature to 25 liters.

(18) 400 ml of the poloxamer solution is dispensed simultaneously into each of the sterile glass vials that have a volume of 450 ml and used for infusion preparations, then the vials containing the poloxamer solution are stoppered with sterile stoppers, and covered and rolled with sterile aluminium caps. The sterilization of the poloxamer solution in the vials is performed in a steam sterilizer VK-75 at a pressure of 82.0 kPa for 12 minutes. After the completion of the process of the thermal sterilization with steam under pressure, the vials containing the poloxamer solution are cooled to 34° C. for 2 hours and 10 minutes. The insignificant gel formation of the poloxamer solution disappears after 20 minutes. The poloxamer solution treated this way is tested for sterility and pyrogenicity.

(19) The test results are shown in Table 5.

(20) TABLE-US-00005 TABLE 5 The comparison table of the testing of the poloxamer solution for sterility and pyrogenicity in the process of production Pyrogenicity Sterility Requirement Requirement Name of test of normative Analysis of normative Analysis object documentation results documentation results Poloxamer Must be Pyrogen- Must be sterile Not solution, pyrogen-free free sterile 16%, 400 ml, at a pressure of 82.0 kPa without preliminary sterilizing filtration

Example 6. Preparation of a Sterile Aqueous Solution Containing 6% of the Poloxamer of Emuxol-268 of Grade “A” and 0.9% of Sodium Chloride at a Pressure of 108.0 kPa

(21) A metal reservoir with a capacity of 40 liters is filled with 15 liters of water for injection the temperature of which is 18° C., and is filled portionwise with 1.5 kg of the poloxamer. The contents of the reservoir are stirred with a laboratory mixer of a PW type having a “”-shaped stirring arm (the rotary speed of the stirring arm is in the range of 500÷700 rpm) until the poloxamer is completely dissolved. 0.36 kg of sodium chloride is added to the resulting solution and stirred. The volume of the poloxamer solution is adjusted with the water for injections of the same temperature to 25 liters.

(22) The sterilizing filtration is performed in aseptic conditions. The prepared poloxamer solution is filtered at a pressure of 68.6-147.1 kPa through a sterile hydrophilic membrane filter with a pore diameter of 0.2-0.22 μm. The poloxamer solution is dispensed simultaneously with the sterilizing filtration: 10 ml of the filtered poloxamer solution is fed directly to each of the glass ampoules that have a capacity of 12 ml, and then the ampoules are sealed off. The sterilization of the poloxamer solution in ampoules is performed in a steam sterilizer VK-75 at a pressure of 108.0 kPa for 8 minutes. After completion of the process of the thermal sterilization with steam under pressure, the ampoules containing the poloxamer solution are cooled to 35° C. for 2 hours. The gel formation of the poloxamer solution disappears after 25 hours. The poloxamer solution treated this way is tested for sterility and pyrogenicity.

(23) The test results are shown in Table 6.

(24) TABLE-US-00006 TABLE 6 The comparison table of the testing of the poloxamer solution for sterility and pyrogenicity in the process of production Pyrogenicity Sterility Requirement Requirement Name of test of normative Analysis of normative Analysis object documentation results documentation results Poloxamer Must be Pyrogen- Must be sterile Sterile solution, pyrogen-free free 10 ml, 6% with 0.9% of sodium chloride at a pressure of 108.0 kPa

(25) Thus, provided is a technologically more simple method for obtaining a sterile solution containing a poloxamer, wherein a thermal sterilization method with steam under pressure is used, so that the achievement of the technical result which consists in reducing the time of recovering the poloxamer solution after the gel formation and the time of the thermal sterilization process is ensured. According to the invention, the obtained aqueous solutions containing, in particular, the poloxamer are subjected to preliminary sterilizing filtration and thermal sterilization with steam in conditions that ensure sterility and the absence of pyrogenic impurities, wherein the cooling time is controlled to preserve the properties of the poloxamer, as evidenced by the transparency of the solution.