Isavuconazole sulfate preparation and preparation method thereof

Abstract

The invention relates to a preparation method of an isavuconazole sulfate preparation, and belongs to the technical field of medicament preparation, by adding a dissolution-promoting stabilizer prepared from a mixture of water-soluble cellulose and chitosan, the solubility of isavuconazole sulfate in the preparation is improved, and rapid dissolution and absorption of a medicament in a body are facilitated, so that the bioavailability is improved. And mixing and unfreezing treatment are carried out at the low temperature of 0-10 DEG C, so that the stability of active ingredients of the medicine is favorably maintained, degradation or denaturation caused by high temperature is reduced, and the purity and curative effect of the product are ensured. Through pre-freezing and multiple unfreezing treatments and in combination with filter membrane filtration, impurities and particles in the solution can be effectively removed, and the clarity and purity of the preparation are improved. Then moisture is rapidly removed at low temperature, active ingredients and stability of the medicine are reserved, and meanwhile damage of high temperature to the medicine is avoided.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparation, and more specifically, to an isavuconazole sulfate preparation and a preparation method thereof. Background Art

[0002] In the field of antifungal drugs, isavuconazole sulfate has become a research hotspot in recent years due to its excellent antifungal activity and good therapeutic prospects. However, despite its significant clinical value, the stability of isavuconazole sulfate preparations during storage and the control of insoluble matter content have always been key factors restricting its widespread application.

[0003] First, storage stability is an important aspect of drug preparation quality assurance. As a highly active drug, isavuconazole sulfate preparations are easily affected by environmental factors such as temperature, humidity, and light during storage, resulting in reduced drug activity, impurity generation, or changes in physical properties, thereby affecting the efficacy and safety of the drug. Therefore, developing an isavuconazole sulfate preparation that can maintain high stability under various storage conditions is of great significance for ensuring drug quality and extending drug shelf life.

[0004] Secondly, the control of the content of insoluble substances is directly related to the purity and safety of drug preparations. Insoluble substances may come from APIs, excipients or impurities in the preparation process. Their presence not only affects the solubility and bioavailability of the drug, but may also cause adverse reactions in patients. Especially in the case of injection, insoluble substances may cause serious problems such as vascular irritation, pain and even thrombosis. Therefore, reducing the content of insoluble substances in isavuconazole sulfate preparations is the key to improving drug safety and patient medication experience.

[0005] Based on the above statements, the present application provides an isavuconazole sulfate preparation and a preparation method thereof. Summary of the invention

[0006] In order to solve the problems raised in the background technology, the present application provides an isavuconazole sulfate preparation and a preparation method thereof. By adding a dissolution-promoting stabilizer made from a mixture of water-soluble cellulose and chitosan, the solubility of isavuconazole sulfate in the preparation is improved, which helps the rapid dissolution and absorption of the drug in the body, thereby improving bioavailability. By mixing and thawing at a low temperature of 0-10°C, it helps to maintain the stability of the active ingredients of the drug, reduce degradation or denaturation caused by high temperature, and ensure the purity and efficacy of the product. By pre-freezing and multiple thawing processes, combined with membrane filtration, impurities and particles in the solution can be effectively removed, and the clarity and purity of the preparation can be improved. Subsequently, the water is quickly removed at a low temperature to retain the active ingredients and stability of the drug while avoiding the damage to the drug by high temperature.

[0007] The present application provides an isavuconazole sulfate preparation and a preparation method thereof, which adopts the following technical scheme: A method for preparing an isavuconazole sulfate preparation comprises the following preparation steps: S1. Mix the isavuconazole sulfate prodrug, excipients and solubility-promoting stabilizer with water for injection under sterile conditions at 0-10°C, and then adjust the pH value of the system to 1-2 to obtain a basic solution; S2. Pre-freeze the basic solution obtained in step S1, and then thaw it at 0-10°C for 30-60 minutes; then filter it once with a filter membrane, and freeze the filtered system twice; thaw the basic solution after the second freezing at 0-10°C for 30-60 minutes; then filter it twice with a filter membrane to obtain a pre-treated solution; S3, sublimation drying and analytical drying of the pretreated solution, followed by plugging and capping to obtain an isavuconazole sulfate preparation.

[0008] Furthermore, in step S1, the mass ratio of isavuconazole sulfate prodrug, excipient, and dissolution stabilizer is (1-3):(0.1-1):(0.1-0.2).

[0009] Furthermore, in step S1, the dissolution-promoting stabilizer is obtained by mixing water-soluble cellulose and chitosan in a mass ratio of (1-3):(1-5).

[0010] Furthermore, in step S1, the excipient is mannitol and sorbitol mixed in a mass ratio of (1-10):(1-3).

[0011] Furthermore, in step S2, the pore size of the filter membrane used for the primary filtration and the secondary filtration is 0.22 μm.

[0012] Furthermore, in step S2, the pre-freezing process specifically includes the following operations: After the basic solution obtained in step S1 is balanced at 0-4°C for 5-10 minutes, the temperature of the system is reduced to -30°C to -40°C at a rate of 5-10°C / hour for 60-90 minutes.

[0013] Furthermore, the specific operation of secondary freezing is: The basic solution after the primary filtration is cooled to -20°C to -30°C at a rate of 5-10°C / hour and treated for 30-60 minutes.

[0014] Furthermore, in step S3, the specific operation of sublimation drying is: The pretreatment solution obtained in step S2 is placed in a freeze dryer, the vacuum system is started, the vacuum degree is set to 0.04-0.2 mbar, the drying temperature is set to 20-30°C, the heating rate is set to 10-20°C / hour during the process, and the drying time is set to 3-10 hours.

[0015] Furthermore, in step S3, the specific operation of analytical drying is: The pre-treated solution after sublimation drying is dried at 35-40°C, the heating rate is set to 5-10°C / hour, and the drying time is 1-3 hours.

[0016] In summary, this application has the following beneficial effects: In the technical solution of the present invention, a dissolution-promoting stabilizer for isavuconazole sulfate preparation is prepared by compounding water-soluble cellulose and chitosan. Chitosan has good water absorption, moisture retention and hygroscopicity, which helps to improve the solubility of the drug. At the same time, chitosan, as a natural polysaccharide, has biocompatibility and non-antigenicity, which helps to stabilize the preparation. Water-soluble cellulose can increase the viscosity of the solution, help the dispersion and stability of the drug in the solution, and prevent the aggregation and precipitation of drug particles. The mixed system of water-soluble cellulose and chitosan can affect the release rate of the drug by adjusting their proportion and characteristics. This adjustment helps to achieve controlled release and sustained release of the drug, and improves the efficacy and safety of the drug. The combination of the two, the hydrophilicity of chitosan and the thickening effect of water-soluble cellulose cooperate with each other to jointly improve the solubility and stability of isavuconazole sulfate preparation. In addition, chitosan has good film-forming properties and lubricity, which can improve the taste and appearance of the preparation.

[0017] In the technical solution of the present invention, mannitol and sorbitol are compounded to prepare an excipient for the preparation of the excipient. Mannitol and sorbitol are both polyols with good solubility and stability. The compounding of the two can help isavuconazole sulfate to be evenly dispersed in the preparation, improve the solubility and stability of the drug, and the release rate of the drug can be adjusted by the ratio of the two, which is conducive to maintaining the effective concentration of the drug in the body and improving the efficacy and safety of the drug.

[0018] In the technical solution of the present invention, mixing and thawing at a low temperature of 0-10°C helps to maintain the stability of the active ingredients of the drug, reduce degradation or denaturation caused by high temperature, and ensure the purity and efficacy of the product. Pre-freezing and multiple thawing processes combined with membrane filtration can effectively remove impurities and particles in the solution, improving the clarity and purity of the preparation. Subsequently, water is quickly removed at low temperature to retain the active ingredients and stability of the drug, while avoiding damage to the drug by high temperature. DETAILED DESCRIPTION

[0019] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0020] The specific implementation methods of this application involve: Chitosan: provided by Shaanxi Panier Biotechnology Co., Ltd., CAS No. 9012-76-4, purity 99%; Water-soluble cellulose: Hydroxypropyl methylcellulose, CAS number is 9004-65-3; Isavuconazole sulfate prodrug: provided by Hubei Weideli Chemical Reagent Co., Ltd., CAS No. 946075-13-4, purity ≧99%.

[0021] Example 1 A method for preparing an isavuconazole sulfate preparation, comprising the following steps: S1. Mixing isavuconazole sulfate prodrug, excipients and dissolution-promoting stabilizers with water for injection under sterile conditions at 0°C, and then adjusting the pH value of the system to 1 with sulfuric acid solution to obtain a basic solution; Among them, the mass ratio of isavuconazole sulfate prodrug, excipient, and dissolution stabilizer is 1:0.1:0.1; The dissolution-promoting stabilizer is obtained by mixing water-soluble cellulose and chitosan in a mass ratio of 1:1; Wherein, the excipient is mannitol and sorbitol mixed in a mass ratio of 1:1. S2. Pre-freeze the basic solution obtained in step S1, and then thaw the pre-frozen basic solution at 0°C for 30 minutes; then filter once using a filter membrane, freeze the filtered system twice, and then thaw the secondary frozen basic solution at 0°C for 30 minutes; then filter twice using a filter membrane to obtain a pre-treated solution; Among them, the pre-freezing process specifically includes the following operations: After the basic solution obtained in step S1 was balanced at 0°C for 5 minutes, the temperature of the system was lowered to -30°C at a rate of 5°C / hour for 60 minutes; Among them, the specific operation of secondary freezing is: The basic solution after the primary filtration was cooled down to -20°C at a rate of 5°C / hour for 30 minutes; Among them, the filter membrane used for primary filtration and secondary filtration is 0.22μm polyethersulfone filter membrane; S3, performing sublimation drying and analytical drying on the pretreated solution, then stopping the vacuum pump, taking out the container, starting the plugging machine, lowering the plugging head and pressing it into the bottle mouth, and using a capping device to press the aluminum cap onto the mouth of the penicillin bottle, thereby obtaining an isavuconazole sulfate preparation; Among them, the specific operation of sublimation drying is: The pretreatment solution obtained in step S2 was placed in a freeze dryer, and the vacuum system was started. The vacuum degree was set to 0.04 mbar, the drying temperature was set to 20°C, the heating rate was set to 10°C / hour, and the drying time was set to 3 hours; Among them, the specific operation of analytical drying is: The pre-treated solution after sublimation drying was dried at 35° C. and a vacuum degree of 0.04 mbar, with a heating rate of 5° C. / hour and a drying time of 1 hour.

[0022] Example 2 A method for preparing an isavuconazole sulfate preparation, comprising the following steps: S1. Mixing isavuconazole sulfate prodrug, excipients and dissolution-promoting stabilizers with water for injection under sterile conditions at 0-10° C., and then adjusting the pH value of the system to 1-2 with sulfuric acid solution to obtain a basic solution; Among them, the mass ratio of isavuconazole sulfate prodrug, excipient, and dissolution stabilizer is 2:0.5:0.15; The dissolution-promoting stabilizer is obtained by mixing water-soluble cellulose and chitosan in a mass ratio of 2:3; Wherein, the excipient is mannitol and sorbitol mixed in a mass ratio of 5:2; S2, pre-freezing the basic solution obtained in step S1, and then thawing the pre-frozen basic solution at 4°C for 45 minutes; then filtering once using a filter membrane, freezing the filtered system twice, and then thawing the secondary frozen basic solution at 4°C for 45 minutes; then filtering twice using a filter membrane to obtain a pretreated solution; Among them, the pre-freezing process specifically includes the following operations: After the basic solution obtained in step S1 was balanced at 0°C for 8 minutes, the temperature of the system was lowered to -35°C at a rate of 8°C / hour for 75 minutes; Among them, the specific operation of secondary freezing is: The filtered basic solution was cooled to -25°C at a rate of 8°C / hour for 45 minutes; Among them, the filter membrane used for primary filtration and secondary filtration is 0.22μm polyethersulfone filter membrane; S3, performing sublimation drying and analytical drying on the pretreated solution, then stopping the vacuum pump, taking out the container, starting the plugging machine, lowering the plugging head and pressing it into the bottle mouth, and using a capping device to press the aluminum cap onto the mouth of the penicillin bottle, thereby obtaining an isavuconazole sulfate preparation; Among them, the specific operation of sublimation drying is: The pretreatment solution obtained in step S2 was placed in a freeze dryer, and the vacuum system was started. The vacuum degree was set to 0.1 mbar, the drying temperature was set to 25°C, the heating rate was set to 15°C / hour, and the drying time was set to 6 hours; Among them, the specific operation of analytical drying is: The pre-treated solution after sublimation drying was dried at 38° C. and a vacuum degree of 0.1 mbar, with a heating rate of 8° C. / hour and a drying time of 2 hours.

[0023] Example 3 A method for preparing an isavuconazole sulfate preparation, comprising the following steps: S1. Mixing isavuconazole sulfate prodrug, excipients and dissolution-promoting stabilizers with water for injection under sterile conditions at 10° C., and then adjusting the pH value of the system to 2 with sulfuric acid solution to obtain a basic solution; Among them, the mass ratio of isavuconazole sulfate prodrug, excipient, and dissolution stabilizer is 3:1:0.2; The dissolution-promoting stabilizer is obtained by mixing water-soluble cellulose and chitosan in a mass ratio of 3:5; Wherein, the excipient is mannitol and sorbitol mixed in a mass ratio of 10:3; S2, pre-freezing the basic solution obtained in step S1, and then thawing the pre-frozen basic solution at 10°C for 60 minutes; then filtering once using a filter membrane, freezing the filtered system twice, and then thawing the secondary frozen basic solution at 10°C for 60 minutes; then filtering twice using a filter membrane to obtain a pretreated solution; Among them, the pre-freezing process specifically includes the following operations: After the basic solution obtained in step S1 was balanced at 4°C for 10 minutes, the temperature of the system was reduced to -40°C at a rate of 10°C / hour for 90 minutes; Among them, the specific operation of secondary freezing is: The basic solution after the primary filtration was cooled down to -30°C at a rate of 10°C / hour for 60 minutes; Among them, the filter membrane used for primary filtration and secondary filtration is 0.22μm polyethersulfone filter membrane; S3, performing sublimation drying and analytical drying on the pretreated solution, then stopping the vacuum pump, taking out the container, starting the plugging machine, lowering the plugging head and pressing it into the bottle mouth, and using a capping device to press the aluminum cap onto the mouth of the penicillin bottle, thereby obtaining an isavuconazole sulfate preparation; Among them, the specific operation of sublimation drying is: The pretreatment solution obtained in step S2 was placed in a freeze dryer, and the vacuum system was started. The vacuum degree was set to 0.2 mbar, the drying temperature was set to 30°C, the heating rate was set to 20°C / hour, and the drying time was set to 10 hours; Among them, the specific operation of analytical drying is: The pre-treated solution after sublimation drying was dried at 40° C. and a vacuum degree of 0.2 mbar, with a heating rate of 10° C. / hour and a drying time of 3 hours.

[0024] Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that in step S1, the dissolution-promoting stabilizer is chitosan.

[0025] Comparative Example 2 The difference between this comparative example and Example 1 is that in step S1, the dissolution-promoting stabilizer is water-soluble cellulose.

[0026] Comparative Example 3 The difference between this comparative example and Example 1 is that in step S1, the excipient is mannitol.

[0027] Comparative Example 4 The difference between this comparative example and Example 1 is that in step S1, the excipient is sorbitol.

[0028] Comparative Example 5 The difference between this comparative example and Example 1 is that step S2 is: The basic solution obtained in step S1 is filtered once using a filter membrane, the filtered system is frozen twice, and then the twice-frozen basic solution is thawed at 0° C. for 30 minutes; then, the filter membrane is used for secondary filtration to obtain a pre-treated solution; Among them, the specific operation of secondary freezing is: The basic solution after the primary filtration was cooled down to -20°C at a rate of 5°C / hour for 30 minutes; The filter membrane used for the primary filtration and the secondary filtration is a 0.22 μm polyethersulfone filter membrane.

[0029] Performance Testing The isavuconazole sulfate preparations prepared in Examples 1-3 and Comparative Examples 1-5 of the present application were prepared into samples with a specification of 200 mg, and quality tests were performed on the samples prepared in different groups.

[0030] The appearance of isavuconazole sulfate preparations is tested and judged based on their color, shape and texture. The specific criteria for judging the grade of preparations are as follows: A: White or off-white, the preparation has uniform color; the preparation is in the form of small and uniform crystalline particles, without large pieces or irregular particles; the preparation powder feels fine, has no granular feel, and has no impurities visible to the naked eye.

[0031] B: Off-white to beige, with slight color deviation; the preparation is powdery as a whole, but with a small amount of tiny lumps; the powder of the preparation feels slightly rough, but without large particles or hard objects.

[0032] C: Light yellow to light brown; there are large lumps or lumps in the preparation; there are palpable particles or obvious impurities in the preparation.

[0033] D: Dark color or with obvious mixed colors; the preparation is in the form of blocks, flakes or other non-powdered forms; the preparation feels moist, sticky, or has formed obvious lumps.

[0034] The reconstitution effect of the isavuconazole sulfate preparations prepared in different groups was tested. The samples were diluted to 30 mL with ultrapure water. The reconstitution time and the insoluble content were recorded during the process. Each sample was tested 5 times and the average value was recorded. The specific test results are shown in Table 1.

[0035] Table 1 Quality test of isavuconazole sulfate preparations prepared in Examples 1-3 and Comparative Examples 1-5 Group Preparation grade Reconstitution time (s) Insoluble matter content (wt%) Example 1 A 14 Example 2 A 12 0.1 Example 3 A 15 Comparative Example 1 A 19 Comparative Example 2 A 23 Comparative Example 3 B 18 Comparative Example 4 B 17 Comparative Example 5 B 16 From the results in Table 1, it can be seen that the isavuconazole sulfate preparations prepared in Examples 1-3 have the best re-dissolution effect and quality. From the results in the comparative examples, it can be seen that the dissolution-promoting stabilizer obtained by compounding water-soluble cellulose and chitosan helps to improve the solubility of the drug. The excipient prepared by compounding mannitol and sorbitol can also improve the solubility of the drug.

[0036] The isavuconazole sulfate preparations prepared in Examples 1-3 and Comparative Examples 1-5 of the present application were prepared into samples with a specification of 200 mg, and the samples prepared in different groups were tested for storage stability.

[0037] The samples prepared in different groups were stored for 3 months at a temperature of 40°C ± 2°C, a relative humidity of 60% ± 5% and protected from light. Subsequently, the growth rate of the maximum single impurity and total impurity in the sample and the loss rate of the isavuconazole prodrug were detected, wherein the chromatographic column was LP-C18 4.6mm × 150mm, 3μm; acetonitrile-trifluoroacetic acid-water solution (volume ratio 5:0.05:95) mobile phase was used for elution, the flow rate was 1.5mL / min, the column temperature was 40°C, the autosampler temperature was 4°C, and the injection volume was 20μL. Each sample was tested 5 times, and the average value was recorded. The specific test results are shown in Table 2 below.

[0038] Table 2 Storage stability test of isavuconazole sulfate preparations prepared in Examples 1-3 and Comparative Examples 1-5 Group Maximum single impurity growth rate (%) Total miscellaneous growth rate (%) Prodrug loss rate (%) Example 1 1.0 2.0 3.9 Example 2 0.8 1.8 3.2 Example 3 0.9 1.9 3.5 Comparative Example 1 1.6 3.3 4.6 Comparative Example 2 1.5 3.3 4.4 Comparative Example 3 1.2 2.3 5.1 Comparative Example 4 1.3 2.6 5.0 Comparative Example 5 1.1 2.2 4.2 From the results shown in Table 1 above, it can be seen that the comprehensive performance of the isavuconazole sulfate preparations prepared in Examples 1-3 of the present application is significantly better than that of the isavuconazole sulfate preparations prepared in Comparative Examples 1-5, that is, within the technical solution defined in the present application, the comprehensive performance of the isavuconazole sulfate preparations prepared is excellent.

[0039] In the description of the specification, the description with reference to the terms "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0040] The above contents are merely examples and explanations of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in a similar manner. As long as they do not deviate from the invention or exceed the scope defined by the claims, they shall all fall within the protection scope of the present invention.

Claims

1. A method for preparing an isavuconazole sulfate preparation, characterized in that: The method comprises the following preparation steps: S1. Mixing isavuconazole sulfate prodrug, excipients and dissolution-promoting stabilizers with water for injection under sterile conditions at 0-10° C., and then adjusting the pH value of the system to 1-2 to obtain a basic solution; S2, pre-freezing the basic solution obtained in step S1, and then thawing it at 0-10° C. for 30-60 minutes; Filter once more using the filter membrane, and freeze the filtered system twice; thaw the twice-frozen basic solution at 0-10° C. for 30-60 minutes; Then, secondary filtration is performed using a filter membrane to obtain a pretreated solution; S3, sublimation drying and analytical drying of the pretreated solution, followed by plugging and capping to obtain an isavuconazole sulfate preparation.

2. The method for preparing an isavuconazole sulfate preparation according to claim 1, characterized in that: In step S1, the mass ratio of isavuconazole sulfate prodrug, excipient, and dissolution stabilizer is 1-3:0.1-1:0.1-0.

2.

3. The method for preparing an isavuconazole sulfate preparation according to claim 1, characterized in that: In step S1, the dissolution-promoting stabilizer is obtained by mixing water-soluble cellulose and chitosan in a mass ratio of 1-3:1-5.

4. The method for preparing an isavuconazole sulfate preparation according to claim 1, characterized in that: In step S1, the excipient is mannitol and sorbitol mixed in a mass ratio of 1-10:1-3.

5. The method for preparing an isavuconazole sulfate preparation according to claim 1, characterized in that: In step S2, the pore size of the filter membrane used for the primary filtration and the secondary filtration is 0.22 μm.

6. The method for preparing an isavuconazole sulfate preparation according to claim 1, characterized in that: In step S2, the pre-freezing process specifically includes the following operations: After the basic solution obtained in step S1 is balanced at 0-4°C for 5-10 minutes, the temperature of the system is reduced to -30°C to -40°C at a rate of 5-10°C / hour for 60-90 minutes.

7. The method for preparing an isavuconazole sulfate preparation according to claim 1, characterized in that: In step S2, the specific operation of secondary freezing is: The basic solution after the primary filtration is cooled to -20°C to -30°C at a rate of 5-10°C / hour and treated for 30-60 minutes.

8. The method for preparing an isavuconazole sulfate preparation according to claim 1, characterized in that: In step S3, the specific operation of sublimation drying is as follows: The pretreatment solution obtained in step S2 is placed in a freeze dryer, the vacuum system is started, the vacuum degree is set to 0.04-0.2 mbar, the drying temperature is set to 20-30°C, the heating rate is set to 10-20°C / hour during the process, and the drying time is set to 3-10 hours.

9. The method for preparing an isavuconazole sulfate preparation according to claim 1, characterized in that: In step S3, the specific operation of analytical drying is as follows: The pre-treated solution after sublimation drying is dried at 35-40°C, the heating rate is set to 5-10°C / hour, and the drying time is 1-3 hours.

10. An isavuconazole sulfate preparation obtained by the method for preparing the isavuconazole sulfate preparation according to any one of claims 1 to 9.