A preparation process of cipemastat sodium lyophilized preparation for injection and lyophilization curve optimization technology

Abstract

The application discloses a preparation process and a freeze-drying curve optimization method of a sodium cevimeline freeze-dried preparation for injection. In view of the problems of poor solubility and insufficient stability of sodium cevimeline, a series of effective measures are taken. By precisely controlling the particle size of the raw material drug, the dissolution time is successfully shortened to within 20 minutes. In the aspect of formula optimization, mannitol is used as an excipient, and sodium hydroxide or phosphate is used to adjust the pH of the solution to 7.5-8.0, thereby effectively inhibiting the generation of hydrolysis impurities. In the freeze-drying stage, the optimized freeze-drying curve is selected, which covers the key stages of pre-freezing, sublimation drying and analytical drying. The freeze-drying curve can effectively shorten the freeze-drying cycle, significantly improve the production efficiency, reduce the production cost, and highly meet the needs of industrial large-scale production. The freeze-dried preparation prepared by the method has the appearance of white loose block, the high purity is greater than or equal to 99.5%, and the reconstitution speed is extremely fast, and the reconstitution can be completed within 30 seconds. The accelerated and long-term stability tests show that the degradation rate of the active ingredient is greatly reduced, the shelf life of the product is effectively prolonged, the storage and transportation are more convenient, and the market application value is extremely significant.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a preparation process for a lyophilized formulation of injectable cefelesat sodium and a corresponding lyophilization curve optimization technology, aiming to improve the solubility, stability and clinical applicability of the formulation. Background Technology

[0002] Cevelexostat sodium, a neutrophil elastase inhibitor, has demonstrated good efficacy in the clinical treatment of diseases such as acute respiratory distress syndrome. However, its poor solubility and inadequate stability make traditional formulations unsuitable for the stringent requirements of long-term storage and clinical application. Lyophilized formulations, with their advantages of improved drug stability, extended shelf life, and ease of storage and transportation, have become an ideal choice for cevelexostat sodium preparations. However, currently, the poor solubility of lyophilized injectable cevelexostat sodium significantly restricts production time during preparation; furthermore, unreasonable lyophilization profiles lead to unstable product quality, decreased purity, and poor reconstitution, severely hindering the clinical application and market promotion of this drug. Therefore, developing a method for efficiently preparing high-quality lyophilized injectable cevelexostat sodium and precisely optimizing its lyophilization profile is of significant practical importance. Summary of the Invention

[0003] The present invention aims to provide a method for preparing and optimizing the lyophilization curve of injectable cevelexta sodium lyophilized formulation, which effectively overcomes the defects in the prior art and prepares injectable cevelexta sodium lyophilized formulation with excellent stability, high purity and excellent reconstitution properties.

[0004] Technical solution

[0005] 1. Control of active pharmaceutical ingredient particle size distribution

[0006] By using mechanical pulverization or micronization technology, the particle size of cefilestat sodium raw material is precisely controlled within the range of 100μm, ensuring its rapid dissolution during the production process while inhibiting the growth of hydrolytic impurities.

[0007] 2. Formula Composition

[0008] Active ingredient: High-purity cevelexat sodium raw material with a purity of not less than 99% is selected to ensure the quality of the active ingredient from the source.

[0009] Excipients: excipients (mannitol, lactose, etc.), pH adjusters (sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate or a mixture of these solutions), solvents (water or water and organic alcohols). All excipients strictly comply with pharmaceutical standards.

[0010] 3. Solution preparation

[0011] The excipient was dissolved in water for injection, and then cefelestat sodium was added and stirred thoroughly to prepare a suspension. Subsequently, the pH of the solution was precisely adjusted to 7.5–8.5 using a pH adjuster, with the optimal range being 7.5–8.0, to ensure complete dissolution of the raw material.

[0012] 4. Preparation process

[0013] After the prepared solution has been pH adjusted and completely dissolved, it is quantitatively filled into vials, and then the freeze-drying operation is carried out according to the optimized freeze-drying curve.

[0014] 5. Optimization of freeze-drying curve

[0015] Using experimental design techniques and a multi-factor experimental approach, this study systematically investigated the effects of key factors such as cevelexostat sodium, excipient type, pre-freezing cooling rate, pre-freezing temperature, primary drying sublimation temperature, primary drying time, secondary drying desorption temperature, and secondary drying time on the quality of lyophilized formulations (covering appearance, purity, reconstitution, and stability). A mathematical model was constructed using statistical analysis methods (such as analysis of variance and response surface methodology) to optimize and derive the optimal lyophilization curve. The specific steps are as follows:

[0016] Pre-freezing stage: First, pre-freeze the solution at -5°C or below for 0.5 hours. This process ensures that no precipitation occurs and that the temperature of all parts of the solution is basically uniform. Then, continue pre-freezing at -40°C or below for 2 hours to ensure that the solution is completely frozen.

[0017] First drying: Turn on the vacuum system to rapidly reduce the pressure in the freeze-drying chamber to 20 Pa. Raise the shelf temperature to the range of -15°C to -5°C at a heating rate of 0.3°C / min and maintain it for 21 hours to remove most of the free water in the material through sublimation.

[0018] Secondary drying: Dry at 30°C for 15 hours to completely remove residual bound water from the material and ensure that the moisture content of the final formulation is less than 1.5%.

[0019] Beneficial effects

[0020] Significantly improved production efficiency: By controlling the particle size distribution of cevimestat sodium active pharmaceutical ingredient (API), the API can be completely dissolved in a short time, greatly improving the solubility of the formulation. Combined with the optimized freeze-drying curve, the freeze-drying cycle is effectively shortened, production efficiency is improved, and production costs are reduced, laying a solid foundation for large-scale industrial production.

[0021] Product quality has been significantly improved: Through the optimized preparation method and freeze-drying curve, the freeze-dried formulation of injectable cefilestat sodium has an ideal appearance, presenting as a white, loose, blocky substance without any adverse phenomena such as collapse or shrinkage; it has high purity and stable content of active ingredients; it has excellent resolubility and can be completely dissolved in a short time, fully meeting the requirements for clinical use.

[0022] Significantly enhanced stability: Under accelerated and long-term testing conditions, the lyophilized formulation prepared by this invention exhibits slow degradation of the active pharmaceutical ingredient, significantly improved stability, effectively extended product shelf life, and facilitates storage and transportation. Detailed Implementation

[0023] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0024] Example 1

[0025] The dissolution time of cevelexostat sodium raw material was studied by subjecting it to different processes using mechanical pulverization or micronization techniques. The results are as follows:

[0026] Effect of different particle sizes on the dissolution rate of cevelexostat sodium active pharmaceutical ingredient

[0027]

[0028] Note: API refers to cevelexta sodium raw material.

[0029] Experimental steps

[0030] 1. Raw material processing

[0031] The sodium cetylestradiol raw material was subjected to mechanical pulverization 10 times, mechanical pulverization 30 times, mechanical pulverization followed by sieving through an 80-mesh sieve, and air jet milling to obtain raw materials with different particle size distributions.

[0032] Determination of D in each batch of active pharmaceutical ingredient 50 (median particle size) and D 90 (90% cumulative particle size), and record its content and moisture.

[0033] 2. Solubility test

[0034] Add each batch of raw materials to water separately, control the preparation temperature to below 20℃, stir until completely dissolved, and record the dissolution time.

[0035] Experimental Results Analysis

[0036] 1. Effect of particle size on dissolution time

[0037] Untreated API-1 particles have a larger diameter (D) 50=300.5μm), the dissolution time exceeded 2 hours, and a large amount of API remained undissolved.

[0038] After mechanical pulverization 10 times, the particle size of the active pharmaceutical ingredient was significantly reduced (D). 50 =11.2μm), the dissolution time is shortened to 3 hours.

[0039] After mechanical pulverization 30 times, the particle size of the active pharmaceutical ingredient was further reduced (D). 50 =7.9μm), and the dissolution time is shortened to 1 hour.

[0040] After air jet milling, the particle size of the active pharmaceutical ingredient reaches the micrometer level (D). 50 =0.3μm), the dissolution time is shortened to 20 minutes.

[0041] 2. Process optimization effect

[0042] By using mechanical pulverization and air jet milling technologies, the particle size of the active pharmaceutical ingredient was significantly reduced, the dissolution time was shortened, and the production efficiency was improved.

[0043] The air jet milling process yields the best results and has the shortest dissolution time (20 minutes), fully meeting the needs of commercial production.

[0044] Conclusion: By controlling the particle size distribution of cevelexat sodium active pharmaceutical ingredient, dissolution time can be significantly shortened, the growth of hydrolytic impurities can be inhibited, and formulation stability and production efficiency can be improved. Air jet milling showed the best performance in optimizing solubility and is suitable for large-scale commercial production.

[0045] Example 2

[0046] Formula: Accurately weigh 2g of high-purity cevelexatol sodium, 4g of mannitol, and an appropriate amount of sodium hydroxide.

[0047] Preparation method: Dissolve mannitol in 100 ml of water for injection, add cetylestradiol sodium, stir until evenly dispersed, and adjust the pH value to 7.7 with 0.1 mol / L sodium hydroxide solution to completely dissolve it.

[0048] Pre-freezing: Dispense the solution into 20ml vials. Pre-freeze at -5℃ for 0.5 hours, then at -40℃ for 2 hours.

[0049] First drying: Turn on the vacuum system to reduce the pressure in the freeze-drying chamber to 20 Pa. Raise the shelf temperature to -15°C at a heating rate of 0.3°C / min and maintain it for 21 hours.

[0050] Secondary drying: Dry at 30℃ for 15 hours.

[0051] Product quality testing: The prepared lyophilized formulation was tested for appearance, purity, reconstitution, and stability. The results showed that the formulation appeared as a white, loose, blocky substance without collapse; the moisture content was 0.58%, and the purity reached 99.5%; the reconstitution was good, dissolving completely within 30 seconds; after 6 months of accelerated testing and 12 months of long-term testing, the content of the active pharmaceutical ingredient decreased significantly, while the content of related substances increased significantly.

[0052] Example 3

[0053] Raw material preparation: Accurately weigh 2g of high-purity cevelexatol sodium, 4g of mannitol, and an appropriate amount of sodium carbonate.

[0054] Preparation method: Dissolve mannitol in 100 ml of water for injection, add cetylestradiol sodium, stir until evenly dispersed, and adjust the pH to 7.8 with 0.1 mol / L sodium carbonate solution to ensure complete dissolution.

[0055] Pre-freezing: Dispense the solution into 20ml vials. Pre-freeze at -5℃ for 0.5 hours, then at -40℃ for 2 hours.

[0056] First drying: Turn on the vacuum system to reduce the pressure in the freeze-drying chamber to 20 Pa. Raise the shelf temperature to -15°C at a heating rate of 0.3°C / min and maintain it for 21 hours.

[0057] Secondary drying: Dry at 30℃ for 15 hours.

[0058] Product quality testing: The prepared lyophilized formulation was tested for appearance, purity, reconstitution, and stability. Results showed that the formulation had a slightly rough appearance and a moisture content of 0.9%. Accelerated and long-term testing indicated slightly poor product stability. Furthermore, varying degrees of precipitation occurred during prolonged storage (within 30 hours) of the prepared solution.

[0059] Example 4

[0060] Raw material preparation: Accurately weigh out 10g of high-purity cevelexatol sodium, 4g of mannitol, and an appropriate amount of sodium dihydrogen phosphate.

[0061] Preparation method: Dissolve mannitol and sodium dihydrogen phosphate in 100 ml of water for injection, add cevelexat sodium, stir until evenly dispersed, and adjust the pH value to 7.7 with 0.5 mol / L sodium hydroxide to completely dissolve it.

[0062] Pre-freezing: Dispense the solution into 20ml vials. Pre-freeze at -5℃ for 0.5 hours, then at -40℃ for 2 hours.

[0063] First drying: Turn on the vacuum system to reduce the pressure in the freeze-drying chamber to 20 Pa. Raise the shelf temperature to -15°C at a heating rate of 0.3°C / min and maintain it for 21 hours.

[0064] Secondary drying: Dry at 30℃ for 15 hours.

[0065] Product quality testing: The prepared lyophilized formulation was tested for appearance, purity, reconstitution, and stability. The results showed that the formulation appeared as a white, loose, blocky substance without collapse, and was dense and homogeneous; the moisture content was 0.45%, and the purity reached 99.5%; the reconstitution was good, and it dissolved completely within 30 seconds; after 6 months of accelerated testing and 12 months of long-term testing, the active pharmaceutical ingredient remained basically unchanged, and the increase trend of related substances was small.

[0066] Comparative Example 1

[0067] Preparation method: Modify the pH adjuster in this invention.

[0068] Formula: Accurately weigh 2g of high-purity cevelexatol sodium, 4g of mannitol, disodium hydrogen phosphate, and an appropriate amount of sodium hydroxide buffer.

[0069] Preparation method: Dissolve mannitol in 100ml of water for injection, add cetylestradiol sodium, stir until evenly dispersed, and adjust the pH to 8.0 using disodium hydrogen phosphate and sodium hydroxide buffer to dissolve it.

[0070] Pre-freezing: Freeze-dry according to the freeze-drying procedure of Example 4.

[0071] The prepared lyophilized formulation was tested for appearance, purity, reconstitution, and stability. The results showed that the formulation had a good appearance and a moisture content of 0.88%. After 6 months of accelerated testing and 12 months of long-term testing, the active pharmaceutical ingredient decreased by 3.5%. At the same time, the hydrolytic impurities in the related substances increased rapidly due to pH influence.

[0072] The comparison between the examples and comparative examples clearly shows that the method for preparing lyophilized formulations of injectable cefelestat sodium and optimizing the lyophilization curve provided by the present invention can produce lyophilized formulations with better quality and stability.

[0073] The above embodiments are only some implementations of the present invention, and the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a lyophilized formulation of cefelestat sodium for injection, characterized in that, Includes the following steps: Dissolve the excipient / cosolvent in water, add the active ingredient, and stir until evenly dispersed; The pH of the solution was adjusted to 7.5-8.0 using one or a mixture of both solutions, and then freeze-dried according to the optimized freeze-drying curve after filling.

2. The preparation method according to claim 1, characterized in that, The particle size of the cevelexat sodium active pharmaceutical ingredient is controlled within the range of 100 μm.

3. The preparation method according to claim 1, characterized in that, The co-solvent is a solution of sodium dihydrogen phosphate and sodium hydroxide, or a mixture thereof, etc.

4. The preparation method according to claim 1, characterized in that, The excipient is mannitol.

5. The preparation method according to claim 1, characterized in that, The freeze-drying curve includes a pre-freezing stage, a primary drying stage, and a secondary drying stage.

6. The preparation method according to claim 5, characterized in that, The pre-freezing stage involves pre-freezing at -5°C for 0.5 hours, followed by pre-freezing at -40°C for 2 hours. The first drying stage involves raising the shelf temperature to the range of -15°C to -5°C at a heating rate of 0.3°C / min, and drying under a vacuum of less than 20Pa for 21 hours. The temperature is then further increased, and the product is dried at 30°C for 15 hours to ensure that the final formulation has a water content of less than 1.5%.

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