Freeze-drying process of isavuconazole sulfate

Abstract

The invention provides an isavuconazole sulfate freeze-drying process which comprises the following steps: (1) pre-freezing: placing a liquid medicine in a partition plate of-13 to-17 DEG C, preserving heat for 30-40 minutes, adjusting the temperature to-40 to-45 DEG C, and preserving heat for 1.5-2.5 hours; (2) sublimation drying: primary sublimation: adjusting the temperature to-33 DEG C to-37 DEG C, and keeping the temperature for 40-80 minutes; secondary sublimation: adjusting the temperature to-18 DEG C to-22 DEG C, and keeping the temperature for 5-7 hours; third sublimation: adjusting the temperature to 0-5 DEG C, and keeping the temperature for 1-1.5 hours; and (3) resolving: adjusting the temperature to 20-30 DEG C, and keeping the temperature for 4-6 hours. According to the freeze-drying process, moisture in the medicine can be fully removed, and the stability of the product is improved. The prepared product is loose, porous and spongy, and the redissolution time of the product is shortened.

Description

Technical Field

[0001] The invention relates to the field of drug preparation, and in particular to a freeze-drying process for isavuconazole sulfate. Background Art

[0002] Isavuconazole sulfate is a prodrug of the triazole antifungal drug isavuconazole. Isavuconazole blocks the synthesis of ergosterol, a key component of fungal cell membranes, by inhibiting the cytochrome P450-dependent enzyme lanosterol 14-α-demethylase, which is responsible for converting lanosterol to ergosterol. This leads to the accumulation of methylated sterol precursors and the loss of ergosterol in the cell membrane, thereby weakening the structure and function of the fungal cell membrane.

[0003] Freeze drying is a drying method that freezes the liquid medicine into a solid at low temperature, and then removes the water from the frozen state by sublimation under a certain vacuum and low temperature, achieving low-temperature dehydration. Prior art CN107661298B is a kind of isavuconazolium sulfate for injection and its freeze-drying process, providing a freeze-drying process that can reduce the water content in the finished product and improve the stability of the finished product. However, the re-dissolution time of the above scheme is 8-14s, which is relatively long. Summary of the invention

[0004] In view of this, the present invention proposes a freeze-drying process for isavuconazole sulfate to solve the above problems.

[0005] The technical solution of the present invention is achieved in this way:

[0006] A freeze-drying process for isavuconazole sulfate comprises the following steps:

[0007] (1) Prefreezing: Place the drug solution in a partition at -13 to -17°C for 30 to 40 minutes, adjust the temperature to -40 to -45°C, and keep it for 1.5 to 2.5 hours;

[0008] (2) Sublimation drying: primary sublimation: adjust the temperature to -33 to -37 °C and keep warm for 40 to 80 minutes;

[0009] Secondary sublimation: adjust the temperature to -18~-22℃, and keep warm for 5-7h;

[0010] Three sublimation: adjust the temperature to 0-5℃, and keep warm for 1-1.5h;

[0011] (3) Drying: Adjust the temperature to 20-30°C and keep warm for 4-6 hours.

[0012] Furthermore, in step (1), the temperature is adjusted to -40 to -45°C at a cooling rate of 10 to 15°C / h.

[0013] Furthermore, in step (2), the vacuum degree of the primary sublimation and the secondary sublimation is 40-60 Pa, and the vacuum degree of the tertiary sublimation is 10-20 Pa.

[0014] Furthermore, in step (2), the temperature of the first sublimation is adjusted to -33 to -37°C at a heating rate of 5 to 7°C / h; the temperature of the second sublimation is adjusted to -18 to -22°C at a heating rate of 5 to 7°C / h; and the temperature of the third sublimation is adjusted to 0 to 5°C at a heating rate of 10 to 12°C / h.

[0015] Furthermore, in step (3), the vacuum degree of the analytical drying is 8 to 10 Pa.

[0016] Furthermore, in step (3), the temperature is adjusted to 20-30°C using a heating rate of 7-10°C / h.

[0017] Furthermore, in step (1), the drug solution comprises isavuconazole sulfate, mannitol and water in a mass ratio of 6.5-8:0.9-1.1:16-20.

[0018] Furthermore, in step (1), the pH value of the drug solution is 1-2.

[0019] Furthermore, the pH value is adjusted using 1-10 wt % of an acidity regulator, and the acidity regulator is one of sulfuric acid, hydrochloric acid, and phosphoric acid.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The present invention can fully remove the moisture in the medicine through a specific freeze-drying process, thereby improving the stability of the product. The obtained finished product has a loose texture, is porous and spongy, and shortens the re-dissolution time of the product.

[0022] The present invention helps to reduce the content of particles and the chance of drug contamination during the freeze-drying process by pre-freezing and performing sublimation drying three times, combined with the adjustment of temperature and time, and helps to increase the drug content of isavuconazole sulfate.

[0023] In the present invention, isavuconazole sulfate, mannitol and water are prepared into a liquid medicine in a mass ratio of 6.5-8:0.9-1.1:16-20. Not only does the particle size of the prepared finished product after reconstitution become smaller, but also the adverse reaction of local pain caused by mannitol can be reduced during use. DETAILED DESCRIPTION

[0024] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0025] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0026] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0027] Example 1

[0028] (1) Preparation of liquid medicine

[0029] Weigh isavuconazole sulfate, mannitol and water for injection in a mass ratio of 7:1:18, cool the water for injection to 6°C, add isavuconazole sulfate and mannitol, stir at 200 rpm / min for 10 min, and adjust the pH value of the solution to 1.5 with 5wt% sulfuric acid solution to obtain a drug solution.

[0030] (2) Packaging

[0031] The drug solution was initially filtered through a 0.45um PES filter element, and then sterilized and filtered through two 0.22um PES filter elements. The filtrate was filled into a vial and half-stoppered.

[0032] (3) Freeze drying

[0033] (3.1) Prefreezing: Place the drug solution in a -15°C partition for 35 min, adjust the temperature to -43°C at a cooling rate of 13°C / h, and keep it for 2 h;

[0034] (3.2) Sublimation drying

[0035] Primary sublimation: adjust the vacuum degree to 50Pa, adjust the temperature to -35℃ at a heating rate of 6℃ / h, and keep warm for 60min;

[0036] Secondary sublimation: maintain the vacuum degree at 50Pa, adjust the temperature to -20℃ at a heating rate of 6℃ / h, and keep warm for 6h;

[0037] Three sublimation: adjust the vacuum degree to 15Pa, adjust the temperature to 3℃ at a heating rate of 11℃ / h, and keep warm for 1.3h;

[0038] (3.3) Desorption and drying: The vacuum degree was adjusted to 9 Pa, and the temperature was adjusted to 25° C. at a heating rate of 8° C. / h. The heat preservation time was 5 h to obtain isavuconazole sulfate preparation.

[0039] Example 2

[0040] (1) Preparation of liquid medicine

[0041] Weigh isavuconazole sulfate, mannitol and water for injection in a mass ratio of 6.5:0.9:16, cool the water for injection to 6°C, add isavuconazole sulfate and mannitol, stir at 200 rpm / min for 10 min, and adjust the pH value of the solution to 1.5 with 5wt% sulfuric acid solution to obtain a drug solution.

[0042] (2) Packaging

[0043] The drug solution was initially filtered through a 0.45um PES filter element, and then sterilized and filtered through two 0.22um PES filter elements. The filtrate was filled into a vial and half-stoppered.

[0044] (3) Freeze drying

[0045] (3.1) Prefreezing: Place the drug solution in a -13°C partition for 30 min, then adjust the temperature to -40°C at a cooling rate of 10°C / h for 1.5 h;

[0046] (3.2) Sublimation drying

[0047] Primary sublimation: adjust the vacuum degree to 50Pa, adjust the temperature to -35℃ at a heating rate of 6℃ / h, and keep warm for 60min;

[0048] Secondary sublimation: maintain the vacuum degree at 50Pa, adjust the temperature to -20℃ at a heating rate of 6℃ / h, and keep warm for 6h;

[0049] Three sublimation: adjust the vacuum degree to 15 Pa, adjust the temperature to 3 °C at a heating rate of 11 °C / h, and keep warm for 1.3 h.

[0050] (3.3) Desorption and drying: The vacuum degree was adjusted to 8 Pa, and the temperature was adjusted to 20° C. at a heating rate of 7° C. / h. The heat preservation time was 4 h to obtain isavuconazole sulfate preparation.

[0051] Example 3

[0052] (1) Preparation of liquid medicine

[0053] Weigh isavuconazole sulfate, mannitol and water for injection in a mass ratio of 8:1.1:20, cool the water for injection to 6°C, add isavuconazole sulfate and mannitol, and stir at 200 rpm / min for 10 minutes. Use 5wt% sulfuric acid solution to adjust the pH value of the solution to 1.5 to prepare a drug solution.

[0054] (2) Packaging

[0055] The drug solution was initially filtered through a 0.45um PES filter element, and then sterilized and filtered through two 0.22um PES filter elements. The filtrate was filled into a vial and half-stoppered.

[0056] (3) Freeze drying

[0057] (3.1) Prefreezing: Place the drug solution in a -17°C partition for 40 min, adjust the temperature to -45°C at a cooling rate of 15°C / h, and keep it for 2.5 h;

[0058] (3.2) Sublimation drying

[0059] Primary sublimation: adjust the vacuum degree to 60Pa, adjust the temperature to -33℃ at a heating rate of 7℃ / h, and keep warm for 80min;

[0060] Secondary sublimation: maintain the vacuum degree at 60Pa, adjust the temperature to -18℃ at a heating rate of 7℃ / h, and keep warm for 7h;

[0061] Three sublimation: adjust the vacuum degree to 20Pa, adjust the temperature to 5℃ at a heating rate of 12℃ / h, and keep warm for 1.5h;

[0062] (3.3) Desorption and drying: The vacuum degree was adjusted to 10 Pa, and the temperature was adjusted to 30° C. at a heating rate of 10° C. / h. The heat preservation time was 6 h to obtain an isavuconazole sulfate preparation.

[0063] Comparative Example 1

[0064] On the basis of Example 1, the vacuum degree of sublimation drying in the freeze-drying process was adjusted as follows:

[0065] (3) Freeze drying

[0066] (3.1) Prefreezing: Place the drug solution in a -15°C partition for 35 min, adjust the temperature to -43°C at a cooling rate of 13°C / h, and keep it for 2 h;

[0067] (3.2) Sublimation drying

[0068] Primary sublimation: adjust the vacuum degree to 15 Pa, adjust the temperature to -35 °C at a heating rate of 6 °C / h, and keep warm for 60 min;

[0069] Secondary sublimation: maintain the vacuum degree at 15Pa, adjust the temperature to -20℃ at a heating rate of 6℃ / h, and keep warm for 6h;

[0070] Three sublimation: maintain the vacuum degree at 15Pa, adjust the temperature to 3℃ at a heating rate of 11℃ / h, and keep warm for 1.3h;

[0071] (3.3) Desorption and drying: The vacuum degree was adjusted to 9 Pa, and the temperature was adjusted to 25° C. at a heating rate of 8° C. / h. The heat preservation time was 5 h to obtain isavuconazole sulfate preparation.

[0072] Comparative Example 2

[0073] On the basis of Example 1, the pre-freezing parameters in the freeze-drying process were adjusted, specifically:

[0074] (3) Freeze drying

[0075] (3.1) Prefreezing: Place the drug solution in a -43°C partition for 3 hours;

[0076] (3.2) Sublimation drying

[0077] Primary sublimation: adjust the vacuum degree to 50Pa, adjust the temperature to -35℃ at a heating rate of 6℃ / h, and keep warm for 60min;

[0078] Secondary sublimation: maintain the vacuum degree at 50Pa, adjust the temperature to -29℃ at a heating rate of 6℃ / h, and keep warm for 1.5h;

[0079] Three sublimation: adjust the vacuum degree to 15Pa, adjust the temperature to -20℃ at a heating rate of 3℃ / h, and keep warm for 1.3h;

[0080] (3.3) Desorption and drying: The vacuum degree was adjusted to 9 Pa, and the temperature was adjusted to 25° C. at a heating rate of 8° C. / h. The heat preservation time was 5 h to obtain isavuconazole sulfate preparation.

[0081] Comparative Example 3

[0082] Based on Example 1, the parameters of sublimation drying in the freeze-drying process were adjusted, specifically:

[0083] (3) Freeze drying

[0084] (3.1) Prefreezing: Place the drug solution in a -15°C partition for 35 min, adjust the temperature to -43°C at a cooling rate of 13°C / h, and keep it for 2 h;

[0085] (3.2) Sublimation drying

[0086] Primary sublimation: adjust the vacuum degree to 50Pa, adjust the temperature to -30℃ at a heating rate of 6℃ / h, and keep warm for 60min;

[0087] Secondary sublimation: maintain vacuum degree of 50Pa, adjust temperature to -10℃ with heating rate of 6℃ / h, and keep warm for 5h;

[0088] Three sublimation: adjust the vacuum degree to 15Pa, adjust the temperature to 3℃ at a heating rate of 11℃ / h, and keep warm for 1.3h;

[0089] (3.3) Desorption and drying: The vacuum degree was adjusted to 9 Pa, and the temperature was adjusted to 25° C. at a heating rate of 8° C. / h. The heat preservation time was 5 h to obtain isavuconazole sulfate preparation.

[0090] Comparative Example 4

[0091] On the basis of Example 1, the raw material ratio was adjusted, specifically:

[0092] Weigh isavuconazole sulfate, mannitol and water for injection in a mass ratio of 10:1:18, cool the water for injection to 6°C, add isavuconazole sulfate and mannitol, and stir at 200 rpm / min for 10 minutes. Use 5wt% sulfuric acid solution to adjust the pH value of the solution to 1.5 to prepare a drug solution.

[0093] Test Example 1

[0094] The moisture content and dissolution time of the isavuconazole sulfate preparations prepared in Examples 1-3 and Comparative Examples 1-4 were detected, wherein the specification of the isavuconazole sulfate preparation was 200 mg (calculated as isavuconazole).

[0095] The moisture content (%) was detected by a moisture titrator with reference to the moisture determination method in the Chinese Pharmacopoeia.

[0096] The dissolution time is determined by adding 5 mL of water for injection into a vial and shaking the vial to completely dissolve the contents. The reconstituted solution should be visually inspected and the concentrated solution after reconstitution should be clear and free of visible particles. The dissolution time is recorded.

[0097] name shape Moisture (%) Dissolution time(s) Example 1 White lumps, loose 0.27 5.3 Example 2 White lumps, loose 0.30 5.7 Example 3 White lumps, loose 0.31 5.6 Comparative Example 1 White block, slightly attached to the wall 0.74 9.4 Comparative Example 2 White lumps, slightly agglomerated 0.68 10.2 Comparative Example 3 White lumps, slightly collapsed 0.53 8.7 Comparative Example 4 White lumps, slightly agglomerated 0.62 11.5

[0098] The experimental results show that the finished product obtained by the freeze-drying process of the present invention is in the shape of a complete white block and is loose. The moisture content in the finished product is low, and the loose structure is conducive to the dissolution of the finished product, thereby achieving the purpose of shortening the dissolution time.

[0099] In comparative example 1, the vacuum degree in sublimation drying is adjusted, resulting in the finished product being slightly attached to the wall, indicating that the finished product is not thoroughly dried. In the present invention, by adjusting the vacuum degree, it is beneficial for the water to volatilize in the sublimation drying stage, so that the finished product is fully dried. In comparative example 2, the pre-freezing parameters are adjusted, resulting in the finished product being slightly lumped, the water content increases, and the re-dissolution time is extended. The same temperature pre-freezing is adopted, and the temperature distribution is uneven, resulting in the ice crystal structure being different in size, so the finished product is slightly lumped. In the present invention, the secondary temperature change method is adopted in the pre-freezing process to ensure that the medicinal liquid reaches the same temperature during the freezing process, further control the size of the ice crystal, and is conducive to the subsequent freeze-drying process. In comparative example 3, the parameters of sublimation drying in the freeze-drying process are changed, and the shape of the finished product is partially collapsed. In the present invention, reasonable vacuum degree and drying temperature are adopted in sublimation drying, which can not only remove moisture, but also maintain the pore structure of the sample. In comparative example 4, the amount of raw materials is adjusted, and mannitol is added to the drug preparation as an excipient to reduce the amount of mannitol, resulting in the finished product being slightly lumped.

[0100] Test Example 2

[0101] The finished products prepared in Examples 1-3 were stored at a temperature of 2-8° C. and a humidity of 35±5% for 12 months, and the moisture content, dissolution time and total impurities of the isavuconazole sulfate preparations prepared in Examples 1-3 were tested.

[0102] name shape Moisture (%) Dissolution time(s) Total impurities (%) Example 1 White lumps, loose 0.29 5.6 0.15 Example 2 White lumps, loose 0.33 5.8 0.16 Example 3 White lumps, loose 0.35 5.5 0.16

[0103] The finished product prepared by the present invention has been verified by long-term storage, and the experimental results show that the finished product prepared by the present invention has good stability.

[0104] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A freeze-drying process for isavuconazole sulfate, characterized in that: The following steps are involved: (1) Prefreezing: Place the drug solution in a partition at -13 to -17°C for 30 to 40 minutes, adjust the temperature to -40 to -45°C, and keep it for 1.5 to 2.5 hours; (2) Sublimation drying: primary sublimation: adjust the temperature to -33 to -37 °C and keep warm for 40 to 80 minutes; Secondary sublimation: adjust the temperature to -18~-22℃, and keep warm for 5~7h; Three sublimation: adjust the temperature to 0-5℃, and keep warm for 1-1.5h; (3) Drying: Adjust the temperature to 20-30°C and keep warm for 4-6 hours.

2. The freeze-drying process of isavuconazole sulfate according to claim 1, characterized in that: In step (1), the temperature is adjusted to -40 to -45°C at a cooling rate of 10 to 15°C / h.

3. The freeze-drying process of isavuconazole sulfate according to claim 1, characterized in that: In step (2), the vacuum degree of the primary sublimation and the secondary sublimation is 40-60 Pa, and the vacuum degree of the tertiary sublimation is 10-20 Pa.

4. The freeze-drying process of isavuconazole sulfate according to claim 1, characterized in that: In step (2), the temperature of the primary sublimation is adjusted to -33 to -37°C at a heating rate of 5 to 7°C / h; the temperature of the secondary sublimation is adjusted to -18 to -22°C at a heating rate of 5 to 7°C / h; and the temperature of the tertiary sublimation is adjusted to 0 to 5°C at a heating rate of 10 to 12°C / h.

5. The freeze-drying process of isavuconazole sulfate according to claim 1, characterized in that: In step (3), the vacuum degree of the analytical drying is 8-10Pa.

6. The freeze-drying process of isavuconazole sulfate according to claim 1, characterized in that: In step (3), the temperature is adjusted to 20-30°C using a heating rate of 7-10°C / h.

7. The freeze-drying process of isavuconazole sulfate according to claim 1, characterized in that: In step (1), the drug solution comprises isavuconazole sulfate, mannitol and water in a mass ratio of 6.5-8:0.9-1.1:16-20.

8. The freeze-drying process of isavuconazole sulfate according to claim 1, characterized in that: In step (1), the pH value of the drug solution is 1-2.

9. The freeze-drying process of isavuconazole sulfate according to claim 8, characterized in that: The pH value is adjusted by using 1wt% to 10wt% of an acidity regulator, and the acidity regulator is one of sulfuric acid, hydrochloric acid, and phosphoric acid.