High-stability isavuconazole sulfate freeze-drying agent and preparation method thereof

Abstract

The invention provides a high-stability isavuconazole sulfate freeze-drying agent and a preparation method thereof, and the high-stability isavuconazole sulfate freeze-drying agent comprises the following components in parts by weight: 350-400 parts of isavuconazole sulfate, 20-30 parts of mannitol, 35-40 parts of glucose and 5-10 parts of glycine. The isavuconazole sulfate freeze-drying agent prepared by the invention does not have the phenomena of color change, layering, caking and the like in the storage process, the stability of the isavuconazole sulfate in the physical form is reflected, and the uniformity and effectiveness of the isavuconazole sulfate are ensured. Through related substance detection and moisture detection, the isavuconazole sulfate prepared by the invention meets the specification.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and relates to a highly stable isavuconazole sulfate lyophilized agent and a preparation method thereof. Background Art

[0002] Isavuconazole sulfate is an odorless, bitter, amorphous, white to yellow-white powder. It is easily soluble in water and slightly soluble in ethanol. The aqueous solution of isavuconazole sulfate has poor stability. It has better stability under acidic conditions, and is prone to produce degradation impurities under alkaline conditions. Therefore, most of the injectable isavuconazole sulfate on the market has a pH value of 1 to 3. In clinical use, if the patient has other underlying diseases (such as renal insufficiency, etc.), the use of isavuconazole sulfate with a pH value of 1 to 3 for treatment will cause excessive burden on the kidneys. Therefore, in order to expand the scope of use of isavuconazole sulfate and reduce the probability of adverse reactions during use, a highly stable isavuconazole sulfate lyophilized agent and a preparation method thereof are proposed. Summary of the invention

[0003] In view of this, the present invention discloses a highly stable isavuconazole sulfate lyophilized agent and a preparation method thereof to solve the above problems.

[0004] The technical solution of the present invention is achieved in this way:

[0005] A highly stable isavuconazole sulfate lyophilized agent comprises, by weight, 350-400 parts of isavuconazole sulfate, 20-30 parts of mannitol, 35-40 parts of glucose and 5-10 parts of glycine.

[0006] Furthermore, it also includes a pH regulator, which is an acidic regulator and an alkaline regulator.

[0007] Furthermore, the acidic regulator is one of hydrochloric acid, phosphoric acid and sulfuric acid.

[0008] Furthermore, the alkaline regulator is a sodium hydroxide solution or a potassium hydroxide solution.

[0009] Furthermore, the concentration of the pH regulator is 0.1 wt% to 10 wt%.

[0010] Furthermore, a method for preparing a highly stable isavuconazole sulfate lyophilized agent comprises the following steps:

[0011] (1) adding isavuconazole sulfate, mannitol, glucose and glycine to water, adjusting the pH value to 1 to 1.5 with an acidic regulator, and mixing to prepare a mixed solution 1;

[0012] (2) adjusting the pH value of the mixed solution 1 to 7-8 using an alkaline regulator to obtain a mixed solution 2;

[0013] (3) Filter, package and freeze-dry the mixed solution 2 to obtain a finished product.

[0014] Furthermore, in step (1), 3 to 5 times the weight of isavuconazole sulfate is added with water.

[0015] Furthermore, in step (2), an alkaline regulator with a concentration of 0.1wt% to 1wt% is used to adjust the pH of the mixed solution 1 to 2.5 to 3, and then an alkaline regulator with a concentration of 2wt% to 3wt% is used to adjust the pH of the mixed solution 1 to 5.5 to 6, and finally an alkaline regulator with a concentration of 5wt% to 10wt% is used to adjust the pH of the mixed solution 1 to 7 to 8.

[0016] Furthermore, in step (2), when the pH value of the mixed solution 1 is adjusted using an alkaline regulator, the stirring speed is 80 to 200 r / min.

[0017] Furthermore, in step (3), the freeze-drying process includes pre-freezing, sublimation drying and analytical drying.

[0018] Furthermore, in step (3), the freeze-drying process comprises the following steps:

[0019] Prefreezing: Place the drug solution at -45 to -50°C for 4 to 6 hours.

[0020] Primary sublimation drying: heat up to -20--25℃ at 3-5℃ / h and keep warm for 5-7h;

[0021] Secondary sublimation drying: Raise the temperature to -5-0°C at 8-10°C / h and keep warm for 12-15h.

[0022] Primary analytical drying: heat up to 15-20℃ at 1-3℃ / h and keep warm for 4-6h;

[0023] Secondary analytical drying: heat at 4-6°C / h to 30-35°C and keep warm for 2-4h.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] In the present invention, isavuconazole sulfate, mannitol, glucose and glycine are used as raw materials to prepare an isavuconazole sulfate for injection with a pH value of 7 to 8. The isavuconazole sulfate for injection prepared by the present invention does not show discoloration, stratification, agglomeration and the like during storage. This reflects the stability of isavuconazole sulfate in physical form and ensures the uniformity and effectiveness of isavuconazole sulfate. Through relevant substance detection and moisture detection, the isavuconazole sulfate prepared by the present invention meets the regulations.

[0026] In the preparation process of the present invention, various raw materials are firstly mixed uniformly under acidic conditions, and then the pH value of the solution is adjusted with alkaline regulators of different concentrations, which can not only improve the solubility of the raw materials, but also reduce the risk of generating degradation impurities in the preparation process. DETAILED DESCRIPTION

[0027] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0028] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0029] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0030] Example 1

[0031] (1) Weigh 380 parts of isavuconazole sulfate, 25 parts of mannitol, 38 parts of glucose and 7 parts of glycine by weight.

[0032] (2) Weigh 4 times the weight of isavuconazole sulfate in water, cool to 6° C., add isavuconazole sulfate, mannitol, glucose and glycine, adjust the pH value of the solution to 1.3 with 3 wt % sulfuric acid solution, stir at 110 r / min for 8 min, and prepare an acidic solution.

[0033] (3) The acidic liquid was stirred with a stirrer at a speed of 55 r / min, the pH value of the acidic liquid was adjusted to 2.8 with a sodium hydroxide solution having a concentration of 0.5 wt %, the speed of the stirrer was adjusted to 90 r / min, the pH value of the acidic liquid was adjusted to 5.8 with a sodium hydroxide solution having a concentration of 2.5 wt %; the speed of the stirrer was adjusted to 130 r / min, and finally the pH value of the acidic liquid was adjusted to 7.5 with a sodium hydroxide solution having a concentration of 8 wt %, to obtain a liquid.

[0034] (4) The drug solution is initially filtered using a 0.45 μm PES filter element, and sterilized by filtration using a 0.22 μm PES filter element. The filtrate is filled into a vial and half-stoppered. The subpackaged drug solution is transferred to a freeze-drying box for freeze drying.

[0035] The freeze-drying process is:

[0036] Prefreeze: Prefreeze the drug solution at -45℃ for 5 hours.

[0037] Primary sublimation drying: heat at 4°C / h to -25°C and keep warm for 6h;

[0038] Secondary sublimation drying: heat at 9°C / h to 0°C and keep warm for 14h.

[0039] Primary drying: heating at 2℃ / h to 20℃ and keeping warm for 5h;

[0040] Secondary desorption drying: heat up to 35°C at 5°C / h and keep warm for 3h.

[0041] Example 2

[0042] (1) Weigh 350 parts of isavuconazole sulfate, 20 parts of mannitol, 35 parts of glucose and 5 parts of glycine by weight.

[0043] (2) Weigh 3 times the amount of water based on the weight of isavuconazole sulfate, cool to 2° C., add isavuconazole sulfate, mannitol, glucose and glycine, adjust the pH value of the solution to 1 with 3 wt % sulfuric acid solution, stir at 100 r / min for 5 min, and prepare an acidic solution.

[0044] (3) The acidic liquid was stirred with a stirrer at a speed of 50 r / min, the pH value of the acidic liquid was adjusted to 2.5 with a sodium hydroxide solution having a concentration of 0.1 wt %, the speed of the stirrer was adjusted to 80 r / min, the pH value of the acidic liquid was adjusted to 5.5 with a sodium hydroxide solution having a concentration of 2 wt %; the speed of the stirrer was adjusted to 120 r / min, and finally the pH value of the acidic liquid was adjusted to 7 with a sodium hydroxide solution having a concentration of 5 wt %, to obtain a liquid.

[0045] (4) The drug solution is initially filtered using a 0.45 μm PES filter element, and sterilized by filtration using a 0.22 μm PES filter element. The filtrate is filled into a vial and half-stoppered. The subpackaged drug solution is transferred to a freeze-drying box for freeze drying.

[0046] The freeze-drying process is:

[0047] Prefreeze: Prefreeze the drug solution at -45℃ for 4 hours.

[0048] Primary sublimation drying: heat at 3℃ / h to -20℃ and keep warm for 5h;

[0049] Secondary sublimation drying: Raise the temperature to -5°C at 8°C / h and keep warm for 12h.

[0050] Primary drying: heating at 1°C / h to 15°C and keeping warm for 4h;

[0051] Secondary drying: heat at 4°C / h to 30°C and keep warm for 2h.

[0052] Example 3

[0053] (1) Weigh 400 parts of isavuconazole sulfate, 30 parts of mannitol, 40 parts of glucose and 10 parts of glycine by weight.

[0054] (2) Weigh 5 times the weight of isavuconazole sulfate in water, cool to 8° C., add isavuconazole sulfate, mannitol, glucose and glycine, adjust the pH value of the solution to 1.5 with 5 wt % sulfuric acid solution, stir at 120 r / min for 10 min, and prepare an acidic solution.

[0055] (3) The acidic liquid was stirred with a stirrer at a speed of 60 r / min, the pH value of the acidic liquid was adjusted to 3 with a sodium hydroxide solution having a concentration of 1 wt%, the speed of the stirrer was adjusted to 100 r / min, the pH value of the acidic liquid was adjusted to 6 with a sodium hydroxide solution having a concentration of 3 wt%; the speed of the stirrer was adjusted to 140 r / min, and finally the pH value of the acidic liquid was adjusted to 8 with a sodium hydroxide solution having a concentration of 10 wt%, thereby obtaining a liquid.

[0056] (4) The drug solution is initially filtered using a 0.45 μm PES filter element, and sterilized by filtration using a 0.22 μm PES filter element. The filtrate is filled into a vial and half-stoppered. The subpackaged drug solution is transferred to a freeze-drying box for freeze drying.

[0057] The freeze-drying process is:

[0058] Prefreeze: Place the drug solution at -50℃ for 6 hours.

[0059] Primary sublimation drying: heat at 5℃ / h to -25℃ and keep warm for 7h;

[0060] Secondary sublimation drying: Raise the temperature to 0°C at 10°C / h and keep warm for 15h.

[0061] Primary drying: heating at 3℃ / h to 20℃ and keeping warm for 6h;

[0062] Secondary drying: heat at 6°C / h to 35°C and keep warm for 4h.

[0063] Comparative Example 1

[0064] (1) Weigh 380 parts of isavuconazole sulfate, 50 parts of mannitol, 20 parts of glucose and 4 parts of glycine by weight.

[0065] (2) Weigh 4 times the weight of isavuconazole sulfate in water, cool to 6° C., add isavuconazole sulfate, mannitol, glucose and glycine, adjust the pH value of the solution to 1.3 with 3 wt % sulfuric acid solution, stir at 110 r / min for 8 min, and prepare an acidic solution.

[0066] (3) The acidic liquid was stirred with a stirrer at a speed of 55 r / min, the pH value of the acidic liquid was adjusted to 2.8 with a sodium hydroxide solution having a concentration of 0.5 wt %, the speed of the stirrer was adjusted to 90 r / min, the pH value of the acidic liquid was adjusted to 5.8 with a sodium hydroxide solution having a concentration of 2.5 wt %; the speed of the stirrer was adjusted to 130 r / min, and finally the pH value of the acidic liquid was adjusted to 7.5 with a sodium hydroxide solution having a concentration of 8 wt %, to obtain a liquid.

[0067] (4) The drug solution is initially filtered using a 0.45 μm PES filter element, and sterilized by filtration using a 0.22 μm PES filter element. The filtrate is filled into a vial and half-stoppered. The subpackaged drug solution is transferred to a freeze-drying box for freeze drying.

[0068] The freeze-drying process is:

[0069] Prefreeze: Prefreeze the drug solution at -45℃ for 5 hours.

[0070] Primary sublimation drying: heat at 4°C / h to -25°C and keep warm for 6h;

[0071] Secondary sublimation drying: heat at 9°C / h to 0°C and keep warm for 14h.

[0072] Primary drying: heating at 2℃ / h to 20℃ and keeping warm for 5h;

[0073] Secondary desorption drying: heat up to 35°C at 5°C / h and keep warm for 3h.

[0074] Comparative Example 2

[0075] (1) Weigh 380 parts of isavuconazole sulfate, 25 parts of mannitol, 38 parts of glucose and 7 parts of glycine by weight.

[0076] (2) Weigh 4 times the weight of isavuconazole sulfate in water, cool to 6° C., add isavuconazole sulfate, mannitol, glucose and glycine, adjust the pH value of the solution to 1.3 with 3 wt % sulfuric acid solution, stir at 110 r / min for 8 min, and prepare an acidic solution.

[0077] (3) The acidic liquid was stirred with a stirrer at a stirring speed of 100 r / min, and the pH value of the acidic liquid was adjusted to 7.5 with a sodium hydroxide solution having a concentration of 3 wt %, to obtain a liquid.

[0078] (4) The drug solution is initially filtered using a 0.45 μm PES filter element, and sterilized by filtration using a 0.22 μm PES filter element. The filtrate is filled into a vial and half-stoppered. The subpackaged drug solution is transferred to a freeze-drying box for freeze drying.

[0079] The freeze-drying process is:

[0080] Prefreeze: Prefreeze the drug solution at -45℃ for 5 hours.

[0081] Primary sublimation drying: heat at 4°C / h to -25°C and keep warm for 6h;

[0082] Secondary sublimation drying: heat at 9°C / h to 0°C and keep warm for 14h.

[0083] Primary drying: heating at 2℃ / h to 20℃ and keeping warm for 5h;

[0084] Secondary desorption drying: heat up to 35°C at 5°C / h and keep warm for 3h.

[0085] Comparative Example 3

[0086] (1) Weigh 380 parts of isavuconazole sulfate, 25 parts of mannitol, 38 parts of glucose and 7 parts of glycine by weight.

[0087] (2) Weigh 4 times the amount of water based on the weight of isavuconazole sulfate, cool to 6° C., add isavuconazole sulfate, mannitol, glucose and glycine, and stir at 110 r / min for 8 minutes to prepare a premixed solution.

[0088] (3) The premixed liquid was stirred with a stirrer at a speed of 55 r / min, and the pH value of the premixed liquid was adjusted to 2.8 with a sodium hydroxide solution having a concentration of 0.5 wt %, the speed of the stirrer was adjusted to 90 r / min, and the pH value of the premixed liquid was adjusted to 5.8 with a sodium hydroxide solution having a concentration of 2.5 wt %; the speed of the stirrer was adjusted to 130 r / min, and finally, the pH value of the premixed liquid was adjusted to 7.5 with a sodium hydroxide solution having a concentration of 8 wt %, to prepare a drug solution.

[0089] (4) The drug solution is initially filtered using a 0.45 μm PES filter element, and sterilized by filtration using a 0.22 μm PES filter element. The filtrate is filled into a vial and half-stoppered. The subpackaged drug solution is transferred to a freeze-drying box for freeze drying.

[0090] The freeze-drying process is:

[0091] Prefreeze: Prefreeze the drug solution at -45℃ for 5 hours.

[0092] Primary sublimation drying: heat at 4°C / h to -25°C and keep warm for 6h;

[0093] Secondary sublimation drying: heat at 9°C / h to 0°C and keep warm for 14h.

[0094] Primary drying: heating at 2℃ / h to 20℃ and keeping warm for 5h;

[0095] Secondary desorption drying: heat up to 35°C at 5°C / h and keep warm for 3h.

[0096] Comparative Example 4

[0097] (1) Weigh 380 parts of isavuconazole sulfate, 25 parts of mannitol, 38 parts of glucose and 7 parts of glycine by weight.

[0098] (2) Weigh 4 times the weight of isavuconazole sulfate in water, cool to 6° C., add isavuconazole sulfate, mannitol, glucose and glycine, adjust the pH value of the solution to 1.3 with 3 wt % sulfuric acid solution, stir at 110 r / min for 8 min, and prepare an acidic solution.

[0099] (3) The acidic liquid was stirred with a stirrer at a stirring speed of 100 r / min, and the pH of the acidic liquid was adjusted to 2.8 with a sodium hydroxide solution having a concentration of 0.5 wt %, and then the pH of the acidic liquid was adjusted to 5.8 with a sodium hydroxide solution having a concentration of 2.5 wt %; finally, the pH of the acidic liquid was adjusted to 7.5 with a sodium hydroxide solution having a concentration of 8 wt %, to obtain a liquid.

[0100] (4) The drug solution is initially filtered using a 0.45 μm PES filter element, and sterilized by filtration using a 0.22 μm PES filter element. The filtrate is filled into a vial and half-stoppered. The subpackaged drug solution is transferred to a freeze-drying box for freeze drying.

[0101] The freeze-drying process is:

[0102] Prefreeze: Prefreeze the drug solution at -45℃ for 5 hours.

[0103] Primary sublimation drying: heat at 4°C / h to -25°C and keep warm for 6h;

[0104] Secondary sublimation drying: heat at 9°C / h to 0°C and keep warm for 14h.

[0105] Primary drying: heating at 2℃ / h to 20℃ and keeping warm for 5h;

[0106] Secondary desorption drying: heat up to 35°C at 5°C / h and keep warm for 3h.

[0107] Test Example 1:

[0108] The finished products obtained in Examples 1-3 and Comparative Examples 1-4 were tested for appearance, moisture, and total impurities according to the Chinese Pharmacopoeia.

[0109] name Appearance Moisture (%) Total impurities (%) Example 1 White loose lumps 0.63 0.11 Example 2 White loose lumps 0.69 0.12 Example 3 White loose lumps 0.74 0.10 Comparative Example 1 White loose lumps 0.93 0.13 Comparative Example 2 White loose lumps 0.82 0.21 Comparative Example 3 White loose lumps 0.86 0.18 Comparative Example 4 White loose lumps 0.79 0.14

[0110] The experimental results show that the finished product prepared by the present invention has a white loose block appearance and a low moisture content.

[0111] In Comparative Example 1, the amount of raw materials was changed, resulting in an increase in the moisture content and total impurities of the finished product relative to the comparative example. The reasonable ratio of raw materials in the present invention can improve the stability of the finished product. In Comparative Example 2, a single concentration of alkaline regulator was used to adjust the pH value, resulting in an increase in the total impurity content. In the present invention, multiple concentrations of alkaline regulators were used to adjust the pH value, which can avoid the production of degradation impurities in the finished product during the preparation process. In Comparative Example 3, the pH value of the solution was not adjusted to 1-1.5, resulting in a slight increase in the total impurities of the finished product relative to the comparative example. In the present invention, the pH value of the solution was adjusted to 1-1.5, which can promote the dissolution of raw materials and reduce the generation of degradation impurities. In Comparative Example 4, only a single stirring rate was used when adjusting the alkalinity of the solution, resulting in a slight increase in the total impurities of the finished product relative to the comparative example. In the present invention, different rates are used to adjust the alkalinity of the solution, which can make the alkaline regulator evenly mixed and avoid the production of degradation impurities in the finished product during the preparation process.

[0112] Test Example 2

[0113] The finished products obtained in Examples 1-3 and Comparative Examples 1-4 were subjected to accelerated testing under the experimental conditions of 40°C ± 2°C and 90% ± 10%. Samples were taken for testing in March and June, respectively. The appearance, moisture content, total impurities and content of the finished products were tested in accordance with the Chinese Pharmacopoeia.

[0114] Name (Accelerated March) Appearance Moisture (%) Total impurities (%) Example 1 White loose lumps 0.70 0.17 Example 2 White loose lumps 0.81 0.22 Example 3 White loose lumps 0.78 0.20 Comparative Example 1 White loose mass, slightly agglomerated 1.14 0.29 Comparative Example 2 White loose mass, slightly agglomerated 1.35 0.42 Comparative Example 3 White loose lumps 1.21 0.33 Comparative Example 4 White loose mass, slightly agglomerated 1.19 0.26

[0115] Name (Accelerated June) Appearance Moisture (%) Total impurities (%) Example 1 White loose lumps 0.85 0.56 Example 2 White loose lumps 0.96 0.60 Example 3 White loose lumps 0.98 0.62 Comparative Example 1 White block 1.49 1.08 Comparative Example 2 White block 1.87 1.24 Comparative Example 3 White block 1.55 1.14 Comparative Example 4 White block 1.47 0.97

[0116] The experimental results show that the finished product prepared by the embodiment of the present invention has good stability.

[0117] 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 highly stable isavuconazole sulfate lyophilized agent, characterized in that: Calculated by weight, the invention comprises 350-400 parts of isavuconazole sulfate, 20-30 parts of mannitol, 35-40 parts of glucose and 5-10 parts of glycine.

2. A highly stable isavuconazole sulfate lyophilized agent according to claim 1, characterized in that: The pH regulator is also included, and the pH regulator is an acid regulator and an alkaline regulator.

3. A highly stable isavuconazole sulfate lyophilized agent according to claim 2, characterized in that: The acidic regulator is one of hydrochloric acid, phosphoric acid and sulfuric acid.

4. A highly stable isavuconazole sulfate lyophilized agent according to claim 2, characterized in that: The alkaline regulator is a sodium hydroxide solution or a potassium hydroxide solution.

5. The highly stable isavuconazole sulfate lyophilized agent according to claim 2, characterized in that: The concentration of the pH adjuster is 0.1 wt% to 10 wt%.

6. A method for preparing a highly stable isavuconazole sulfate lyophilized agent according to any one of claims 1 to 5, characterized in that: The following steps are involved: (1) adding isavuconazole sulfate, mannitol, glucose and glycine to water, adjusting the pH value to 1 to 1.5 with an acidic regulator, and mixing to prepare a mixed solution 1; (2) adjusting the pH value of the mixed solution 1 to 7-8 using an alkaline regulator to obtain a mixed solution 2; (3) Filter, package and freeze-dry the mixed solution 2 to obtain a finished product.

7. The method for preparing a highly stable isavuconazole sulfate lyophilized agent according to claim 6, characterized in that: In step (1), 3 to 5 times the weight of isavuconazole sulfate is added with water.

8. The method for preparing a highly stable isavuconazole sulfate lyophilized agent according to claim 6, characterized in that: In step (2), an alkaline regulator with a concentration of 0.1 wt% to 1 wt% is used to adjust the pH of the mixed solution 1 to 2.5 to 3, and then an alkaline regulator with a concentration of 2 wt% to 3 wt% is used to adjust the pH of the mixed solution 1 to 5.5 to 6, and finally an alkaline regulator with a concentration of 5 wt% to 10 wt% is used to adjust the pH of the mixed solution 1 to 7 to 8.

9. The method for preparing a highly stable isavuconazole sulfate lyophilized agent according to claim 6, characterized in that: In step (2), when the pH value of the mixed solution 1 is adjusted using an alkaline regulator, the stirring speed is 80 to 200 r / min.

10. The method for preparing a highly stable isavuconazole sulfate lyophilized agent according to claim 6, characterized in that: In step (3), the freeze-drying includes pre-freezing, sublimation drying and analytical drying; The freeze-drying comprises the following steps: Prefreezing: Place mixed solution 2 at -45 to -50°C for 4 to 6 hours; Primary sublimation drying: heat up to -20--25℃ at 3-5℃ / h and keep warm for 5-7h; Secondary sublimation drying: heat up to -5-0℃ at 8-10℃ / h and keep warm for 12-15h; Primary analytical drying: heat up to 15-20℃ at 1-3℃ / h and keep warm for 4-6h; Secondary analytical drying: heat at 4-6°C / h to 30-35°C and keep warm for 2-4h.