Isavuconazole sulfate freeze-dried powder injection for injection and preparation method thereof

Abstract

The invention discloses an isavuconazole sulfate freeze-dried powder injection for injection, and belongs to the technical field of pharmaceutical preparations. The isavuconazole sulfate freeze-dried powder injection for injection is prepared from 70 to 80 weight percent of isavuconazole sulfate and the balance of excipient. By controlling the excipients to be sorbitol and cane sugar and controlling the mass ratio of the sorbitol to the cane sugar to be 1: (3-5), the problem that individual impurities grow rapidly and even exceed the limit after an intermediate product liquid medicine is placed at normal temperature for several hours is solved, the moisture content is controlled to be 0.06% or below after freeze-drying, and the problems that in the prior art, a freeze-dried product is high in moisture and rapid in impurity growth are solved; in addition, the freeze-dried powder injection is short in redissolution time and has remarkable advantages.

Description

Technical Field

[0001] The present application relates to a lyophilized powder of isavuconazole sulfate for injection, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Isavuconazonium sulfate is a broad-spectrum triazole antifungal drug, mainly used to treat severe fungal infections. Isavuconazonium sulfate is rapidly metabolized by esterases in the body, releasing the active form of isavuconazonium. Isavuconazonium inhibits the CYP51 enzyme on the fungal cell membrane, interferes with the synthesis of the fungal cell membrane, and causes cell membrane dysfunction and fungal death.

[0003] At present, the injection form of isavuconazole sulfate has at least the following problems: 1. The detection of the content and filling of the intermediate product of isavuconazole sulfate for injection need to be placed for a period of time. However, after the intermediate product of isavuconazole sulfate for injection is placed at room temperature for a period of time, the impurities grow rapidly and there is a problem of poor stability. 2. Isavuconazole sulfate is sensitive to temperature. High temperature conditions will accelerate the degradation of isavuconazole sulfate and affect product quality. 3. Isavuconazole sulfate is easily degraded under acidic and alkaline conditions. When the pH is adjusted during the preparation process, it is easy to cause degradation. 4. The moisture content of the freeze-dried product of isavuconazole sulfate is high, and the impurities grow rapidly. 5. The re-dissolution time is relatively long. Summary of the invention

[0004] According to one aspect of the present application, a lyophilized powder injection of isavuconazole sulfate for injection is provided, wherein the excipients include sorbitol and sucrose, and the mass ratio of the two is controlled to be 1:(3-5), thereby solving the problem that after the intermediate product liquid is left at room temperature for several hours, individual impurities grow rapidly or even exceed the limit, and after freeze-drying, the moisture content is controlled below 0.06%, thereby solving the problem of high moisture content and rapid impurity growth of the freeze-dried product in the prior art; in addition, the lyophilized powder injection has a short reconstitution time and has significant advantages.

[0005] The isavuconazole sulfate lyophilized powder for injection described in the present application comprises 70-80 wt % of isavuconazole sulfate and the remainder of excipients.

[0006] Optionally, the isavuconazole sulfate lyophilized preparation for injection comprises 75.5 wt % of isavuconazole sulfate and 24.5 wt % of excipients.

[0007] Optionally, the excipient is selected from one or more of mannitol, sorbitol and sucrose.

[0008] Optionally, the excipient is excipient A and / or excipient B;

[0009] The excipient A is mannitol;

[0010] The excipient B is sorbitol and sucrose.

[0011] Optionally, the weight ratio of sorbitol to sucrose is 1:(3-5); preferably, the weight ratio of sorbitol to sucrose is 1:4.2.

[0012] Optionally, when the excipients are excipient A and excipient B, the weight ratio of excipient A to excipient B is 0.5:(2-3); preferably, when the excipients are excipient A and excipient B, the weight ratio of excipient A to excipient B is 0.5:2.5.

[0013] A method for preparing a lyophilized isavuconazole sulfate preparation for injection comprises: mixing a mixture comprising isavuconazole sulfate and an excipient with water for injection, adding an acid-base regulator to adjust the pH, and preparing an intermediate product liquid; and then performing sterilization filtration, filling, semi-plugging, freeze drying, capping, and packaging.

[0014] Optionally, the temperature of the mixture and the water for injection is 15-25°C.

[0015] Optionally, the temperature at which the mixture and the water for injection are mixed is independently selected from any one of 15°C, 20°C, 25°C, or a range between any two of the above.

[0016] Optionally, the amount of the water for injection and the mixture added is 1L:(150-160)g; preferably, the amount of the water for injection and the mixture added is 1L:155g.

[0017] Optionally, the acid-base regulator is sulfuric acid.

[0018] Optionally, the concentration of the sulfuric acid is 0.1-1.8 mol / L; preferably, the concentration of the sulfuric acid is 1.3-1.8 mol / L; more preferably, the concentration of the sulfuric acid is 1.5 mol / L.

[0019] Optionally, the pH is adjusted to 1.2-1.8; preferably, the pH is adjusted to 1.5.

[0020] Optionally, freeze drying process is as follows:

[0021] Keep warm at 0-5℃ for 120-150min;

[0022] Cool down to -40--50℃ at a rate of 20-30℃ / h and keep warm for 120-150min;

[0023] Raise the temperature to 0-5°C at a rate of 10-20°C / h, keep warm for 720-750min, and control the vacuum at 15-25Pa;

[0024] Continue to raise the temperature to 30-35°C at a rate of 10-20°C / h, keep warm for 600-630 minutes, and control the vacuum at 3-5Pa.

[0025] Preferably, the freeze drying process is as follows:

[0026] Keep warm at 3℃ for 135min;

[0027] Cool down to -45°C at a rate of 25°C / h and keep warm for 135 min;

[0028] The temperature was raised to 3°C at a rate of 15°C / h, kept at that temperature for 735 min, and the vacuum was controlled at 20 Pa;

[0029] The temperature was continued to be raised to 32°C at a rate of 15°C / h, and kept at that temperature for 615 min. The vacuum was controlled at 4 Pa.

[0030] The beneficial effects of this application include:

[0031] 1. The intermediate product liquid of isavuconazole sulfate for injection needs to be placed for a period of time for content detection and filling. The inventor found in the experiment that after the intermediate product liquid was placed at room temperature for a few hours, some impurities grew rapidly and even exceeded the limit. When adjusting the prescription, the inventor unexpectedly found that when the excipients included sorbitol and sucrose, the growth of impurities in the intermediate product liquid was controllable and stable after being placed at room temperature for 24 hours, which actually solved the problem of rapid growth of impurities in the intermediate product liquid after being placed at room temperature for a period of time. The inventor searched for information and guessed that the possible reason was that sorbitol and sucrose could form a protective barrier on the surface of isavuconazole sulfate molecules, which could prevent the aggregation of isavuconazole sulfate molecules and prevent the thermal decomposition of isavuconazole sulfate. In addition, sorbitol and sucrose may also reduce the degradation of isavuconazole sulfate by regulating the surface tension of the solution and reducing the changes in external factors.

[0032] 2. The inventors found that in the process of preparing the intermediate product solution of isavuconazole sulfate, the concentration of sulfuric acid also causes the growth of impurities to a certain extent. Too low or too high a sulfuric acid concentration will cause the impurities to grow rapidly. The possible reasons are that on the one hand, it affects the barrier protection effect of sorbitol and sucrose at room temperature, increasing the sensitivity of isavuconazole sulfate to temperature; on the other hand, when sulfuric acid is used to adjust the pH, the acidity per unit volume is too low, resulting in drug degradation.

[0033] 3. The preparation of the present application is simple and easy to operate. Using the preparation process conditions of the present application, the moisture content is controlled below 0.06% after freeze-drying, which solves the problem of high moisture content and rapid growth of impurities in freeze-dried products in the prior art.

[0034] 4. The inventors found that the excipient of the present application was mixed with isavuconazole sulfate and water for injection, and the pH was adjusted before freeze-drying. The reconstitution time of the obtained freeze-dried product was less than 20 seconds, which has a significant advantage over the existing isavuconazole sulfate injection with a reconstitution time of more than 30 seconds. DETAILED DESCRIPTION

[0035] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0036] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0037] The relevant substances were tested using the import registration standard JX20220065 for isavuconazole sulfate for injection;

[0038] S29-3 was tested using the import registration standard JX20220065 for isavuconazole sulfate for injection;

[0039] 2-Butenal was tested using the import registration standard JX20220065 for isavuconazole sulfate for injection.

[0040] The impurity information is as follows:

[0041] S29-ZZ-3

[0042]

[0043] (2-(Methylamino)pyridin-3-yl)methyl-N-methylglycine

[0044] S29-ZZ-24

[0045]

[0046] 1-Methyl-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one

[0047] S29-ZZ-22

[0048]

[0049] 1-((2R,3R)-3-(4-(4-carbamoylphenyl)thiazol-2-yl)-2-(2,5-difluorophenyl)-2-hydroxybutyl)-4-(1-((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl)-1H-1,2,4-triazol-4-ium

[0050] S29-ZZ-26

[0051]

[0052] 1-((2R,3R)-3-(4-(4-cyanophenyl)thiazol-2-yl)-2-(2,5-difluorophenyl)-2-hydroxybutyl)-4-(1-(((3-(hydroxymethyl)pyridin-2-yl)(methyl)carbamoyl)oxy)ethyl)-1H-1,2,4-triazol-4-ium

[0053] S29-3

[0054]

[0055] 4-(2-((2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)thiazol-4-yl)benzonitrile

[0056] 2-Butenal

[0057]

[0058] 2-Butenal

[0059] Example 1

[0060] A lyophilized powder of isavuconazole sulfate for injection, prepared from the following raw materials (1000 bottles):

[0061]

[0062]

[0063] The excipients are sorbitol and sucrose in a weight ratio of 1:3.

[0064] The preparation method of the isavuconazole sulfate lyophilized preparation for injection is as follows:

[0065] At 20° C., a mixture including isavuconazole sulfate and excipients is mixed with water for injection, and an acid-base regulator is added to adjust the pH to 1.5 to prepare an intermediate product liquid; then, sterilization filtration, filling, semi-stoppering, freeze drying, capping and packaging are carried out.

[0066] The freeze drying process is as follows:

[0067] Keep warm at 0℃ for 120min;

[0068] Cool down to -40℃ at a rate of 20℃ / h and keep warm for 120min;

[0069] Raise the temperature to 0°C at a rate of 10°C / h, keep warm for 720 min, and control the vacuum at 15 Pa;

[0070] Continue to raise the temperature to 30°C at a rate of 10°C / h, keep warm for 600 min, and control the vacuum at 3Pa.

[0071] Example 2

[0072] A lyophilized powder of isavuconazole sulfate for injection, prepared from the following raw materials:

[0073]

[0074] The excipients are sorbitol and sucrose in a weight ratio of 1:5.

[0075] The preparation method of the isavuconazole sulfate lyophilized preparation for injection is as follows:

[0076] At 20° C., a mixture including isavuconazole sulfate and excipients is mixed with water for injection, and an acid-base regulator is added to adjust the pH to 1.5 to prepare an intermediate product liquid; then, sterilization filtration, filling, semi-stoppering, freeze drying, capping and packaging are carried out.

[0077] The freeze drying process is as follows:

[0078] Keep warm at 5℃ for 150min;

[0079] Cool down to -50°C at a rate of 30°C / h and keep warm for 150 min;

[0080] The temperature was raised to 5°C at a rate of 20°C / h, kept at that temperature for 750 min, and the vacuum was controlled at 25 Pa;

[0081] The temperature was continued to be raised to 35°C at a rate of 20°C / h, and kept at that temperature for 630 min. The vacuum was controlled at 5 Pa.

[0082] Example 3

[0083] A lyophilized powder of isavuconazole sulfate for injection, prepared from the following raw materials:

[0084]

[0085] The excipients are sorbitol and sucrose in a weight ratio of 1:4.2.

[0086] The preparation method of the isavuconazole sulfate lyophilized preparation for injection is as follows:

[0087] At 20° C., a mixture including isavuconazole sulfate and excipients is mixed with water for injection, and an acid-base regulator is added to adjust the pH to 1.5 to prepare an intermediate product liquid; then, sterilization filtration, filling, semi-stoppering, freeze drying, capping and packaging are carried out.

[0088] The freeze drying process is as follows:

[0089] Keep warm at 3℃ for 135min;

[0090] Cool down to -45°C at a rate of 25°C / h and keep warm for 135 min;

[0091] The temperature was raised to 3°C at a rate of 15°C / h, kept at that temperature for 735 min, and the vacuum was controlled at 20 Pa;

[0092] The temperature was continued to be raised to 32°C at a rate of 15°C / h, and kept at that temperature for 615 min. The vacuum was controlled at 4 Pa.

[0093] The shape, reconstitution time, moisture, content, related substances, S29-3 content and 2-butenal content of the freeze-dried products of Examples 1-3 were tested. The test results are shown in Table 1.

[0094] Table 1

[0095]

[0096]

[0097] It can be seen from the test results in Table 1 that the properties, moisture content and related substances of the isavuconazole sulfate lyophilized preparation for injection prepared using the prescription and process of the present application all meet the quality standards.

[0098] The intermediate product solutions of Examples 1-3 were placed at 20° C. for 0 h, 4 h, 8 h, and 24 h, respectively, and then their shapes, related substances, and S29-3 contents were tested. The test results are shown in Table 2.

[0099] Table 2

[0100]

[0101]

[0102]

[0103] From the test results in Table 2, it can be seen that after the intermediate product solution obtained in the present application is placed at 20°C for 24 hours, the impurities grow slowly and the impurity content is controllable, which solves the problem that the impurities of the intermediate product solution of isavuconazole sulfate for injection grow rapidly and have poor stability after being placed at room temperature for a period of time.

[0104] Example 4

[0105] The raw materials for preparing isavuconazole sulfate lyophilized powder injection are the same as those in Example 3, except that the excipients are mannitol and lactose in a weight ratio of 1:4.2.

[0106] Example 5

[0107] The raw materials for preparing isavuconazole sulfate lyophilized powder for injection are the same as those in Example 3, except that the excipient is sorbitol.

[0108] Example 6

[0109] The raw materials for preparing isavuconazole sulfate lyophilized powder injection are the same as those in Example 3, except that the excipient is mannitol.

[0110] Example 7

[0111] The raw materials for preparing isavuconazole sulfate lyophilized powder injection are the same as those in Example 3, except that the concentration of sulfuric acid is 2.5 mol / L.

[0112] Example 8

[0113] The raw materials for preparing isavuconazole sulfate lyophilized powder injection are the same as those in Example 3, except that the concentration of sulfuric acid is 0.1 mol / L.

[0114] After the intermediate product solutions of Examples 4 to 8 were placed at 20° C. for 24 hours, the impurity content was tested. The test results are shown in Table 3.

[0115] Table 3

[0116]

[0117] From the test results in Table 3, it can be seen that by adjusting the type of excipients and the concentration of sulfuric acid, impurities increase rapidly after 24 hours. In actual production, the controllability is poor and the quality and efficacy of the product cannot be guaranteed.

[0118] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A lyophilized powder of isavuconazole sulfate for injection, characterized in that: The invention comprises 70-80 wt % of isavuconazole sulfate and the balance of excipients; The excipient is selected from one or more of mannitol, sorbitol and sucrose.

2. The isavuconazole sulfate lyophilized powder for injection according to claim 1, characterized in that: The excipient is excipient A and / or excipient B; The excipient A is mannitol; The excipient B is sorbitol and sucrose.

3. The isavuconazole sulfate lyophilized powder for injection according to claim 2, characterized in that: The weight ratio of sorbitol to sucrose is 1:(3-5).

4. The isavuconazole sulfate lyophilized powder for injection according to claim 2, characterized in that: When the excipients are excipient A and excipient B, the weight ratio of excipient A to excipient B is 0.5:(2-3).

5. A method for preparing the isavuconazole sulfate lyophilized powder injection according to any one of claims 1 to 4, characterized in that: include: The mixture including isavuconazole sulfate and excipients is mixed with water for injection, and an acid-base regulator is added to adjust the pH to prepare an intermediate product liquid; Then sterilize and filter, fill, semi-stopper, freeze-dry, cap and package.

6. The method for preparing the isavuconazole sulfate lyophilized powder injection for injection according to claim 5, characterized in that: The temperature of the mixture and the water for injection is 15-25°C.

7. The method for preparing the isavuconazole sulfate lyophilized powder injection for injection according to claim 6, characterized in that: The acid-base regulator is sulfuric acid.

8. The method for preparing the isavuconazole sulfate lyophilized powder injection for injection according to claim 7, characterized in that: The concentration of the sulfuric acid is 0.1-1.8 mol / L.

9. The method for preparing the isavuconazole sulfate lyophilized powder injection for injection according to claim 5, characterized in that: Adjust pH to 1.2-1.

8.

10. The method for preparing the isavuconazole sulfate lyophilized powder injection according to any one of claims 5 to 9, characterized in that: The freeze drying process is as follows: Keep warm at 0-5℃ for 120-150min; Cool down to -40--50℃ at a rate of 20-30℃ / h and keep warm for 120-150min; Raise the temperature to 0-5°C at a rate of 10-20°C / h, keep warm for 720-750min, and control the vacuum at 15-25Pa; Continue to raise the temperature to 30-35°C at a rate of 10-20°C / h, keep warm for 600-630 minutes, and control the vacuum at 3-5Pa.

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