A lyophilization process for phosphophol disodium for injection

Abstract

This invention discloses a lyophilization process for disodium fospropofol for injection, comprising sequential pre-freezing, sublimation drying, and desorption drying, wherein the pre-freezing process employs an annealing process. The lyophilization process for disodium fospropofol of this invention effectively solves the problems of low lyophilization efficiency caused by surface concentration and uneven crystal structure during pre-freezing through the annealing step in the pre-freezing process. The resulting lyophilized product has a good appearance, good reconstitution properties, and stable quality.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and specifically to a lyophilization process for injectable disodium propofol. Background Technology

[0002] Disodium propofol is a water-soluble propofol prodrug that is metabolized in the body into the active substance propofol, which produces an anesthetic effect. It does not require a fat emulsion carrier for propofol preparations, thus reducing the risks of infusion syndrome, bacterial contamination, and lipid metabolism disorders in clinical applications.

[0003] Currently, the 0.5g specification of fosprofen disodium for injection used clinically in China is manufactured by Humanwell Healthcare Co., Ltd. (according to C... 13 H 19 The main component is Na2O5P. This injectable disodium phosphoprothiol is composed of injectable disodium phosphoprothiol and mannitol. Existing lyophilization processes for disodium phosphoprothiol typically require two processes: sublimation drying and desorption drying. These processes are time-consuming, and the lyophilized disodium phosphoprothiol produced suffers from appearance defects and inconsistent quality.

[0004] Chinese patent CN101716149 B discloses a lyophilized formulation of a water-soluble propofol precursor compound and its preparation method. The lyophilization process disclosed in this patent is as follows: pre-freezing: the sterilized drug solution is pre-frozen at -10~-60℃ for 1~4 hours under aseptic conditions; sublimation drying: sublimation drying is carried out at a temperature of -30~0℃ for 24 hours; secondary drying: drying is continued at 0~40℃ for 12 hours. This lyophilization process has a long drying time and the appearance quality of the product is poor.

[0005] Therefore, it is still necessary to study a freeze-drying process for injectable disodium propofol with a short drying time, good appearance of freeze-dried products, and stable product quality. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a freeze-drying process for injectable disodium fosprophenol. The freeze-drying process provided by this invention, without changing the formulation of the already marketed product, has obtained an injectable disodium fosprophenol with good appearance, good reconstitution, and stable quality through research on the pre-freezing process of injectable disodium fosprophenol.

[0007] To achieve the above-mentioned objectives, the technical solution adopted by the present invention is as follows: A lyophilization process for disodium propofol for injection includes the following steps: (1) pre-freezing; (2) sublimation drying; (3) desorption drying; characterized in that the pre-freezing step (1) includes the following steps: (1a) Cool the drug solution from room temperature to -50~-30℃ and maintain it for 2~4 hours; (1b) Heat the sample obtained in step (1a) to -20~-5℃ and maintain it for 2~6 hours; (1c) Cool the sample obtained in (1b) to -50~-30℃ and keep it for 2~4 hours.

[0008] (1d) Repeat steps (1b) and (1c) 1 to 3 times.

[0009] The liquid solution mentioned in (1a) is a liquid preparation for preparing disodium fosprophenol for injection, and the solvent system of the liquid preparation is water for injection and excipients.

[0010] Step (1a) is the pre-freezing crystallization process, in which the temperature of the drug solution is rapidly reduced to below its glass transition temperature (-50~-30℃) and maintained at this temperature for 2~4 hours, resulting in a crystal structure with uniform crystal size and a good particle skeleton structure. Step (1b) is the pre-freezing annealing step, in which the annealing process in step (1b) raises the temperature of the drug solution from the final pre-freezing temperature to between the eutectic point and the glass transition temperature of the drug solution (-20~-5℃), which enables the crystals obtained in (1a) to crystallize more completely and thoroughly, making their structure more uniform. Step (1c) is the cooling after annealing, the function of which is the same as in step (1a) and will not be repeated here. The lyophilization process for disodium propofol for injection of the present invention employs a combination of cooling crystallization (steps (1a) and (1c)) in the pre-freezing stage and annealing during the cooling crystallization process (step (1b)). This process can obtain uniform crystal particles and a good crystal skeletal structure, effectively reducing the formation of amorphous substances and avoiding problems such as poor product appearance, long reconstitution time, low drying efficiency, and poor stability caused by uneven crystallization and solute migration. The resulting lyophilized powder formulation has better quality. Step (1d) involves one to multiple annealing steps. Performing multiple annealing steps can effectively improve the efficiency of converting glassy solutes into crystalline solutes.

[0011] As a preferred embodiment of the present invention, step (2) sublimation drying includes the following steps: (2a) Under a vacuum of 0.10~0.30 mbar, the sample obtained in step (1c) is heated to -25~0℃ and held for 8~36 hours; In the above-mentioned freeze-drying process of disodium propofol for injection, the sublimation drying in step (2) involves precisely controlling the relationship between the drying temperature, heating rate, and vacuum degree during the drying process. This controls the vapor flux in the crystal skeleton during water sublimation, which can avoid bottle spraying and collapse, improve sublimation efficiency, shorten drying process time, and reduce production costs. By precisely controlling the vacuum degree, the efficiency of sublimation drying can be improved. In the early stage of sublimation drying, the product temperature is relatively low, and heating generates a large amount of water vapor. At this stage, the sublimation of the product solvent is less dependent on heat conduction. This invention uses a higher vacuum degree to sublimate the product, which can improve the drying rate of the product and better control the gas flux in the freeze dryer chamber, reducing the occurrence of bottle spraying, collapse, melting, and other phenomena during the drying process. In the later stage of sublimation drying, the vapor amount in the chamber is low, and about 90% of the free water has been sublimated. At this time, reducing the vacuum degree in the chamber and increasing the sample temperature can improve the heat transfer efficiency and effectively remove bound water.

[0012] As a preferred embodiment of the present invention, the analytical drying in step (3) includes the following steps: (3a) Under a vacuum of 0~0.20 mbar, the sample obtained in step (2a) is heated to 20~40℃; and kept at 20~40℃ for 4~12 hours; In the above-mentioned drying process, the combination of low vacuum and high drying temperature can remove bound water from the product to the greatest extent while maintaining a good crystal skeleton structure. The resulting injectable disodium fosprophenol can have a moisture content as low as 1% or less.

[0013] Compared with existing freeze-drying processes, the advantages of this invention are as follows: (1) The lyophilization process of disodium propofol for injection of the present invention adds an annealing process (i.e. steps (1b, 1c, 1d)) in the pre-freezing stage. After annealing, the size and shape of the crystals are changed, so that the gaps of the lyophilized cake formed after drying are more uniform, which effectively improves the drying efficiency, reduces the formation of glassy state during the pre-freezing process, and avoids problems such as poor appearance, long reconstitution time and poor stability caused by uneven crystallization and solute migration. The resulting lyophilized formulation has a better appearance, shorter reconstitution time and better stability. (2) In the sublimation drying process in step (2), the drying temperature, vacuum degree and other process parameters are precisely controlled. There is no bottle spraying, collapse and shrinkage during the freeze drying process. The freeze-dried product with a complete skeleton can be obtained at the end of the sublimation drying process. (3) In the analytical drying process of step (3), by combining low vacuum and drying temperature, the bound water in the product can be removed to the greatest extent while maintaining a good crystal skeleton structure. The water content in the final injectable disodium propofol preparation can be as low as 1.0% or less. At the same time, by setting the vacuum degree to 0.20 mbar to the limit vacuum condition, compared with the initial stage of sublimation drying, the higher temperature and lower vacuum degree can effectively remove the bound water, effectively improve the drying efficiency, and are suitable for standardized industrial production. Detailed Implementation

[0014] The present invention will be further described in detail below with reference to the embodiments, but it should not be construed as the scope of the above subject matter of the present invention being limited to the following embodiments. All technologies implemented based on the content of the present invention are within the scope of the present invention.

[0015] The preparation processes of the drug solutions used in the various embodiments and comparative examples of this invention are as follows: Example 1

[0016] Dissolve the prescription fosetyl-propofol disodium and dextran in an appropriate amount of water for injection, and then add water for injection to the total batch preparation volume. Mix well, sterilize and filter the solution, and fill into injection vials, partially stoppering; (1a) Cool the drug solution from room temperature to -40°C and maintain it for 4 hours; (1b) Heat the sample obtained in step (1a) to -15°C and hold for 4 hours; (1c) Cool the sample obtained in (1b) to -40°C and keep it there for 4 hours; (2a) Under a vacuum of 0.30 mbar, the sample obtained in step (1c) was heated to -10°C and held for 12 hours; (3a) Under a vacuum of 0.20 mbar, the sample obtained in step (2a) was heated to 20°C and held for 12 hours; (3b) Under extreme vacuum conditions, the sample obtained in step (3a) is heated to 20°C and held for 4 hours; Example 2

[0017] Dissolve the prescription fosetyl-propofol disodium and sucrose in an appropriate amount of water for injection, and then add water for injection to the total batch preparation volume. Mix well, sterilize and filter the solution, and fill into injection vials, partially stoppering; (1a) Cool the drug solution from room temperature to -40°C and maintain it for 4 hours; (1b) Heat the sample obtained in step (1a) to -15°C and hold for 4 hours; (1c) Cool the sample obtained in (1b) to -40°C and keep it there for 4 hours; (2a) Under a vacuum of 0.30 mbar, the sample obtained in step (1c) was heated to -5°C and held for 12 hours; (3a) Under extreme vacuum conditions, the sample obtained in step (2a) is heated to 20°C and held for 4 hours; Example 3

[0018] Dissolve the prescription phosphopropofol disodium and mannitol in an appropriate amount of water for injection, and then add water for injection to the total batch preparation volume. Mix well, sterilize and filter the solution, and fill into injection vials, partially stoppering; (1a) Cool the drug solution from room temperature to -40°C and maintain it for 4 hours; (1b) Heat the sample obtained in step (1a) to -15°C and hold for 4 hours; (1c) Cool the sample obtained in (1b) to -40°C and keep it there for 4 hours; (2a) Under a vacuum of 0.30 mbar, the sample obtained in step (1c) was heated to -10°C and held for 12 hours; (3a) Under a vacuum of 0.20 mbar, the sample obtained in step (2a) was heated to 20°C and held for 12 hours; (3b) Under extreme vacuum conditions, the sample obtained in step (3a) is heated to 20°C and held for 4 hours; Example 4

[0019] Dissolve the prescription phosphopropofol disodium and mannitol in an appropriate amount of water for injection, and then add water for injection to the total batch preparation volume. Mix well, sterilize and filter the solution, and fill into injection vials, partially stoppering; (1a) Cool the drug solution from room temperature to -50°C and maintain it for 2 hours; (1b) Heat the sample obtained in step (1a) to -5°C and hold for 2 hours; (1c) Cool the sample obtained in (1b) to -50°C and keep it there for 2 hours; (2a) Under a vacuum of 0.20 mbar, the sample obtained in step (1c) was heated to -5°C and held for 12 hours; (3a) Under extreme vacuum conditions, the sample obtained in step (2a) is heated to 25°C and held for 6 hours;

[0020] Dissolve the prescription fosetyl-propofol disodium and sucrose in an appropriate amount of water for injection, and then add water for injection to the total batch preparation volume. Mix well, sterilize and filter the solution, and fill into injection vials, partially stoppering; (1a) Cool the drug solution from room temperature to -40°C and maintain it for 4 hours; (2a) Under a vacuum of 0.20 mbar, the sample obtained in step (1a) was heated to -20°C and held for 30 hours; (3a) Under a vacuum of 0.10 mbar, the sample obtained in step (2a) was heated to 20°C and kept at 20°C for 12 hours;

[0021] Dissolve the prescription fosetyl-propofol disodium and sucrose in an appropriate amount of water for injection, and then add water for injection to the total batch preparation volume. Mix well, sterilize and filter the solution, and fill into injection vials, partially stoppering; (1a) Cool the drug solution from room temperature to -50°C and maintain it for 2 hours; (2a) Under a vacuum of 0.20 mbar, the sample obtained in step (1a) was heated to -25°C and held for 36 hours; (3a) Under extreme vacuum conditions, the sample obtained in step (2a) is heated to 40°C and held for 10 hours; The lyophilized formulations obtained in each example and comparative example were analyzed as follows: The appearance results show that the lyophilized formulations of Examples 1, 2, 3 and 4 are relatively intact and blocky; while the lyophilized formulations of Comparative Examples 1 and 2, although blocky, are slightly layered, slightly shrunken and severely broken.

[0022] The reconstitution time results show that the reconstitution time of the lyophilized formulations in Examples 1, 2, 3 and 4 is shorter than that of the lyophilized formulations in Example 1 and Comparative Example 2.

[0023] The results regarding propofol show that the lyophilized formulations of Examples 1, 2, 3, and 4 have better initial values ​​and stability regarding propofol than the lyophilized formulations of Comparative Examples 1 and 2.

[0024] The moisture results show that the lyophilized formulations of Examples 1, 2, 3 and 4 have lower moisture content than the lyophilized formulations of Comparative Examples 1 and 2.

[0025] As can be seen from the above description, the embodiments of the present invention achieve the following technical effects: Annealing during the pre-freezing stage effectively controlled phenomena such as bottle spraying, collapse, and solute migration during the freeze-drying process, resulting in freeze-dried formulations with good stability.

[0026] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for lyophilization of phosphopholipid propofol disodium for injection, which annealing process is used in the freeze drying process. Wherein, The annealing temperature is between -20°C and -5°C, the number of annealing cycles is 1 to 3, and the annealing time is no less than 1 hour.

2. The lyophilization process of claim 1, wherein, Annealing temperature is -15~-5℃.

3. The lyophilization process of claim 1, wherein, The annealing process is repeated 1 to 2 times.

4. The lyophilization process of claim 1, wherein, Annealing time is 2 to 6 hours.

5. In the pre-freezing step of the disodium fosprophenol for injection according to any one of claims 1 to 4, the temperature of the drug solution is lowered to -30 to -50°C and kept at that temperature for 2 to 4 hours before annealing, and the temperature of the sample is lowered to -30 to -50°C and kept at that temperature for 2 to 4 hours after annealing.

6. The freeze-drying process according to claims 1 to 5, wherein step (2) of sublimation drying comprises the following steps: (a1) Under a vacuum of 0.10~0.30mbar, the sample obtained in step (1) is heated to -25~0℃ and kept for 8~36 hours.

7. The freeze-drying process according to claims 1 to 6, wherein step (3) of the analytical drying comprises the following steps: (b1) Under a vacuum of 0~0.20 mbar, the sample obtained in step (2) is heated to 20~40℃; Keep at 20~40℃ for 4~12 hours.

8. The lyophilized formulation of disodium fospropofol for injection used in the lyophilization process according to claims 1 to 7 comprises disodium fospropofol, excipients, and water for injection.

9. The excipient according to claim 8, comprising one or more of mannitol, dextran, sucrose, lactose, trehalose, and glucose.

10. The sample preparation method for the freeze-drying process according to claims 1 to 9 comprises: (1) Dissolve the prescribed amount of disodium propofol and excipients in an appropriate amount of water for injection, and then add water for injection to the total batch preparation amount; (2) Mix well, sterilize and filter the solution, fill into injection bottles, and partially stopper.

11. A lyophilized formulation of disodium fosprophenol for injection obtained by the lyophilization process according to claims 1 to 10.

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