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

Abstract

The invention discloses an isavuconazole sulfate freeze-dried powder for injection and a preparation method thereof, the isavuconazole sulfate freeze-dried powder comprises isavuconazole sulfate, a freeze-drying protective additive and a pH regulator, the freeze-drying protective additive is mannitol, chitosan modified polyvinyl alcohol and L-cysteine hydrochloride, and the pH regulator is sulfuric acid; the isavuconazole sulfate freeze-drying protective agent is prepared from the following components in parts by weight: 35-45 parts of isavuconazole sulfate and 7-9 parts of freeze-drying protective agent. Chitosan modified polyvinyl alcohol, L-cysteine hydrochloride and mannitol cooperate to form a multi-element auxiliary carrier, so that the water solubility and dispersity of mannitol at low temperature are improved, the light resistance, high temperature resistance and high humidity environment resistance of active ingredients are improved, the stability is enhanced, the storage safety of medicines is facilitated, and the quality of the medicines is ensured.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an injectable isaconazole sulfate lyophilized powder and its preparation method. Background Technology

[0002] Isaconazole sulfate is a prodrug of isaconazole. Isaconazole is an azole antifungal drug that works by inhibiting cell division. The cytochrome P-450-dependent enzyme lanosterol 14-α-demethylase inhibits ergosterol synthesis, which is a key enzyme in fungal cells. A key component of the cell membrane, this enzyme is responsible for converting lanosterol to ergosterol. Methylated sterol precursors within the fungal cell membrane. The accumulation of ergosterol and its depletion weaken the structure and function of the cell membrane. Mammalian cell demethylation is associated with isaconazole. The inhibitory effect is not very sensitive.

[0003] The molecular formula of isaconazole sulfate for injection is C35H35F2N8O5S·HSO4. The original drug is a sterile powder for injection, developed by Basilea Pharmaceuticals in Switzerland. Currently, there are no approved isaconazole sulfate for injection products in China.

[0004] Isaconazole sulfate for injection is prepared using a lyophilization process. The main preparation process includes: solution preparation, filtration, and filling. The product is prepared by lyophilization and packaging. Patent document CN117064858A discloses a preparation process for injectable isaconazole sulfate, using mannitol as an excipient. Before dispensing, activated carbon is used for adsorption, followed by the addition of vitamin E and further adsorption with activated carbon. This process improves the clarity of the solution after reconstitution of the finished injectable isaconazole sulfate by controlling the clarity of the solution during dispensing. However, while this patent improves solution clarity, for lyophilized isaconazole sulfate powder for injection, improving product stability and reducing impurities generated during storage and transportation remain more critical issues.

[0005] Therefore, this patent application is filed. Summary of the Invention

[0006] To address the above issues, the purpose of this patent application is to provide an injectable isoconazole sulfate lyophilized powder and its preparation method, which can provide long-term stable protection for isoconazole sulfate.

[0007] This invention is achieved through the following technical solution: The first objective of this invention is to provide an injectable isaconazole sulfate lyophilized powder, comprising isaconazole sulfate, a lyophilization protectant, and a pH adjuster, wherein the lyophilization protectant is mannitol, chitosan-modified polyvinyl alcohol, and L-cysteine ​​hydrochloride, and the pH adjuster is sulfuric acid, wherein the pH is adjusted to 1-2 using the pH adjuster. Based on weight, isoconazole sulfate and lyophilization protectant are 35-45 parts and 7-9 parts, respectively.

[0008] Currently available injectable isaconazole sulfate lyophilized powder often uses mannitol as an excipient and adjusts the pH with sulfuric acid solution during preparation. However, when dissolving mannitol in water, the low water temperature during dissolution leads to low solubility of mannitol in cold water, easily resulting in particulate matter and affecting its use. In this invention, chitosan-modified polyvinyl alcohol, L-cysteine ​​hydrochloride, and mannitol synergistically form a multi-component auxiliary carrier. The interaction between chitosan-modified polyvinyl alcohol, L-cysteine ​​hydrochloride, and mannitol improves the water solubility and dispersibility of mannitol at low temperatures. The addition of chitosan-modified polyvinyl alcohol also improves the bioavailability of isaconazole sulfate, enhances drug safety, and increases the drug's light tolerance, thus improving storage safety.

[0009] The addition of L-cysteine ​​hydrochloride promotes pH regulation, working synergistically with sulfuric acid to adjust pH and providing antioxidant effects, thus improving the stability of lyophilized powders during storage and transportation. Chitosan is used to modify polyvinyl alcohol, forming a network three-dimensional structure. The combination of L-cysteine ​​hydrochloride and this modified network polyvinyl alcohol further helps to form a stable interface structure with antioxidant properties, ensuring the stability of the drug formulation crystal interface during preparation. This amplifies and enhances the antioxidant effect of L-cysteine ​​hydrochloride, improving the environmental adaptability of the crystal form during storage, especially in response to crystal transformation under high humidity and high temperature conditions, resulting in stronger drug stability.

[0010] As a preferred design, the mass ratio of mannitol, chitosan-modified polyvinyl alcohol, and L-cysteine ​​hydrochloride is (6~9):(0.2~0.4):(0.5~1.0). This invention rationally designs the proportions of the excipients formed by mannitol, chitosan-modified polyvinyl alcohol, and L-cysteine ​​hydrochloride, especially the ratio of chitosan-modified polyvinyl alcohol to L-cysteine ​​hydrochloride. If the amount of chitosan-modified polyvinyl alcohol is too large, it can easily affect the dispersibility of mannitol and L-cysteine ​​hydrochloride in cold water. Conversely, if the amount of chitosan-modified polyvinyl alcohol is too small, the improvement in the bioavailability of the drug is limited, and the antioxidant stability of the interface structure formed by its combination with L-cysteine ​​hydrochloride is weakened, thus reducing the enhancement of antioxidant performance and decreasing resistance to high humidity and high temperatures.

[0011] As a preferred design, a pH adjuster is used to adjust the pH to 1-2.

[0012] A second objective of this invention is to provide a method for preparing the lyophilized powder of isaconazole sulfate for injection as described in any of the above claims, comprising the following steps: (1) Solution preparation: Dissolve mannitol, chitosan-modified polyvinyl alcohol and L-cysteine ​​hydrochloride in water for injection, then add activated carbon, filter to remove activated carbon, and obtain the first product; (2) Add isaconazole sulfate to the first product, stir to dissolve, and obtain a clear solution. Then add sulfuric acid to adjust the pH to 1~2 to obtain the second product. (3) The second product is filled and freeze-dried to obtain isaconazole sulfate for injection.

[0013] In this invention, activated carbon is used for adsorption during the solution preparation stage, which improves the clarity of the solution and thus enhances the clarity of the solution during reconstitution. Furthermore, vitamin E is not required after adding isaconazole sulfate because the presence of chitosan-modified polyvinyl alcohol and L-cysteine ​​hydrochloride protects the active pharmaceutical ingredient from adsorption by the adsorbent.

[0014] As a preferred design, the preparation method of the chitosan-modified polyvinyl alcohol is as follows: Under the action of epichlorohydrin, chitosan and polyvinyl alcohol react to obtain chitosan-modified polyvinyl alcohol. The mass ratio of chitosan to polyvinyl alcohol is 1:2.

[0015] As a preferred design, the water temperature for dissolving mannitol, chitosan-modified polyvinyl alcohol, and L-cysteine ​​hydrochloride is 8~10℃, and the dissolved solution is placed in a constant temperature tank. The adsorption time for activated carbon is 5-15 minutes, and isaconazole sulfate is added 10-20 minutes after the activated carbon is added.

[0016] As a preferred design, the amount of activated carbon added is 0.10% to 0.15% of the aqueous solution containing mannitol, chitosan-modified polyvinyl alcohol, and L-cysteine ​​hydrochloride.

[0017] As a preferred design, the isaconazole sulfate added to the first product in step (2) was dried and roughened at a temperature of 180-200°C and roughened by using a blower.

[0018] As a preferred design, the drying process is carried out in a drying chamber filled with diatomaceous earth, and dry ice is added to the diatomaceous earth.

[0019] In this invention, dry ice is added to the diatomaceous earth desiccant, and the drying efficiency can be improved by utilizing the drying sublimation of the dry ice. The drying process increases the bulkiness of isaconazole sulfate, and the roughening treatment by blowing air alters the wettability of the isaconazole sulfate powder surface, accelerating the dissolution of isaconazole sulfate, reducing drug precipitation and crystallization, and minimizing the loss of the active pharmaceutical ingredient isaconazole sulfate.

[0020] As a preferred design, the freeze-drying process is as follows: First stage: pre-freezing at -45 to -40°C for 0.5 to 2 hours; Second stage: Then raise the temperature to -5℃~0℃ and evacuate to a vacuum degree of more than 50%, and perform low-temperature sublimation drying for 4~6 hours; Third stage: raise the temperature to 30-40℃ and evacuate to a vacuum degree of 35-40%, then desorb and dry for 6-7 hours; Fourth stage: Cool down to 5-10℃ and keep warm for 1-3 hours.

[0021] As a preferred design, the mass ratio of the active pharmaceutical ingredient, isaconazole sulfate, to the dry ice added in the first stage is (35~45):(4~10). The mass ratio of the active pharmaceutical ingredient, isaconazole sulfate, to the dry ice added in the second and third stages is (35~45):(1~2). The mass ratio of the active pharmaceutical ingredient isaconazole sulfate to L-cysteine ​​added in the second and third stages is (35~45):(0.5~2).

[0022] In this embodiment of the invention, the addition of dry ice in the first stage helps to shorten the pre-freezing time, reduce the operating time of the freeze-drying equipment, and facilitate industrialization. Simultaneously, the combined effect of mannitol allows the system to reach its eutectic point temperature in a shorter time, significantly shortening the pre-freezing time at low temperatures of -45 to -40°C in the first stage. The dry ice added in the second and third stages increases the rate of moisture desorption at higher temperatures. The addition of L-cysteine ​​hydrochloride prevents oxidation in the second and third stages. Furthermore, since chitosan-modified polyvinyl alcohol experiences some loss during drying and moisture desorption, the addition of L-cysteine ​​in the second and third stages reduces this loss, achieving long-term protection. The polar side chain of L-cysteine ​​interacts with isaconazole sulfate, preventing crystal changes under subsequent strong light exposure, long-term storage, and high temperature and humidity conditions, resulting in good stability.

[0023] Compared with the prior art, the present invention has the following advantages and beneficial effects: In this invention, chitosan-modified polyvinyl alcohol, L-cysteine ​​hydrochloride, and mannitol synergistically form a multi-component auxiliary carrier. The interaction between chitosan-modified polyvinyl alcohol, L-cysteine ​​hydrochloride, and mannitol improves the water solubility and dispersibility of mannitol at low temperatures. The addition of chitosan-modified polyvinyl alcohol also improves the bioavailability of isaconazole sulfate, enhances drug safety, and increases the drug's light tolerance, thus improving storage safety.

[0024] The addition of L-cysteine ​​hydrochloride promotes pH regulation, working synergistically with sulfuric acid to adjust pH and providing antioxidant effects, thus improving the stability of the lyophilized powder during storage and transportation. Furthermore, the combination of L-cysteine ​​hydrochloride and chitosan-modified polyvinyl alcohol helps form a stable interface structure with antioxidant properties, ensuring the stability of the drug formulation crystal interface during preparation. This amplifies and enhances the antioxidant effect of L-cysteine ​​hydrochloride, improving the crystal form's environmental adaptability during storage, especially in response to crystal transformation under high humidity (75%) and high temperature (25℃) conditions. This results in stronger drug stability and is expected to increase the storage temperature of injectable isaconazole sulfate, reducing storage costs. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the embodiments. The illustrative embodiments and descriptions of this invention are only used to explain this invention and are not intended to limit this invention.

[0026] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60–120 and 80–110 are listed for a specific parameter, it is understood that ranges of 60–110 and 80–120 are also expected. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1–3, 1–4, 1–5, 2–3, 2–4, and 2–5. In this application, unless otherwise stated, the numerical range "a–b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0~5" have been listed in this article; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0027] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0028] Unless otherwise specified, all technical features and optional technical features of this application may be combined to form new technical solutions.

[0029] Unless otherwise specified, all steps in this application may be performed sequentially or randomly, preferably sequentially. The process is performed sequentially. For example, the method includes steps (a) and (b), indicating that the method may include step (a) performed sequentially. (b) may also include steps (b) and (a) performed sequentially. For example, the method may also include step (c). This indicates that step (c) can be added to the method in any order; for example, the method may include steps (a), (b), and (c). It may also include steps (a), (c) and (b), or steps (c), (a) and (b), etc.

[0030] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0031] Example 1: A preparation process for isaconazole sulfate for injection includes the following steps: 1. Solution preparation: Six parts by weight of mannitol, 0.4 parts by weight of chitosan-modified polyvinyl alcohol, and 1.0 parts by weight of L-cysteine ​​hydrochloride were dissolved in water for injection at 10°C to obtain a mixed solution. Then, granular activated carbon was added for adsorption. The amount of granular activated carbon was 0.10% of the weight of the mixed solution, and the adsorption time was 10 minutes. The activated carbon was then filtered out to obtain the first product at about 10°C. The obtained first product was placed in a constant temperature tank for heat preservation.

[0032] 2. After heat treatment for 15 minutes, add 40 parts by weight of isaconazole sulfate to the first product, stir to dissolve and obtain a clear solution. Then add sulfuric acid to adjust the pH of the solution to 1.5 to obtain the second product.

[0033] Isaconazole sulfate underwent pretreatment, specifically as follows: First, isaconazole sulfate is placed in a drying oven at 200°C and dried. The drying oven is filled with diatomaceous earth, which contains dry ice. Then, the dried isaconazole sulfate is placed in a rotating cylinder connected to the drying oven. The airflow that has been drying and removing impurities from the drying oven enters the cylinder and carries away the impurities in the cylinder.

[0034] The preparation method of chitosan-modified polyvinyl alcohol is as follows: (1) Dissolve 0.5g of chitosan solution in acetic acid solution, then weigh 1.0g of polyvinyl alcohol and dissolve it in water, and then mix the chitosan acetic acid solution and the polyvinyl alcohol aqueous solution. (2) Add epichlorohydrin to sodium hydroxide solution, then add the above mixed solution, react at 40°C for 10 hours, and rinse with pure water until neutral after the reaction to obtain chitosan modified polyvinyl alcohol.

[0035] 3. The second product is then filled and freeze-dried.

[0036] The second product from step 2 is then filled into containers and freeze-dried. The freeze-drying process is as follows: First stage: Pre-freeze at -40℃ for 0.5 hours; Second stage: Heat to -5℃ and evacuate to a vacuum degree of 60%, then perform low-temperature sublimation drying for 4 hours; Third stage: Heat to 30℃ and evacuate to a vacuum degree of 35%, then desorb and dry for 6 hours; Fourth stage: Cool down to 5℃ and keep warm for 1 hour to obtain isaconazole sulfate.

[0037] Example 2: A preparation process for isaconazole sulfate for injection includes the following steps: 1. Solution preparation: Six parts by weight of mannitol, 0.4 parts by weight of chitosan-modified polyvinyl alcohol, and 1.0 parts by weight of L-cysteine ​​hydrochloride were dissolved in water for injection at 10°C to obtain a mixed solution. Then, granular activated carbon was added for adsorption. The amount of granular activated carbon was 0.10% of the weight of the mixed solution, and the adsorption time was 10 minutes. The activated carbon was then filtered out to obtain the first product at about 10°C. The obtained first product was placed in a constant temperature tank for heat preservation.

[0038] 2. After heat treatment for 15 minutes, add 40 parts by weight of isaconazole sulfate to the first product, stir to dissolve and obtain a clear solution. Then add sulfuric acid to adjust the pH of the solution to 1.5 to obtain the second product.

[0039] Isaconazole sulfate underwent pretreatment, specifically as follows: First, isaconazole sulfate is placed in a drying oven at 200°C and dried. The drying oven is filled with diatomaceous earth, which contains dry ice. Then, the dried isaconazole sulfate is placed in a rotating cylinder connected to the drying oven. The airflow that has been drying and removing impurities from the drying oven enters the cylinder and carries away the impurities in the cylinder.

[0040] The preparation method of chitosan-modified polyvinyl alcohol is the same as in Example 1.

[0041] 3. The second product is then filled and freeze-dried.

[0042] The second product from step 2 is then filled into containers and freeze-dried. The freeze-drying process is as follows: First stage: Add 5 parts by weight of dry ice and pre-freeze at -40℃ for 0.5 hours; Second stage: Add 2 parts by weight of dry ice and 1 part by weight of L-cysteine, then heat to -5°C and evacuate to a vacuum degree of 60%, and perform low-temperature sublimation drying for 4 hours; Third stage: Add 2 parts by weight of dry ice and 1 part by weight of L-cysteine, then raise the temperature to 30°C and evacuate to a vacuum degree of 35%, and desorb and dry for 6 hours. Fourth stage: Cool down to 5℃ and keep warm for 1 hour to obtain isaconazole sulfate.

[0043] Example 3: A preparation process for isaconazole sulfate for injection includes the following steps: 1. Solution preparation: Nine parts by weight of mannitol, 0.4 parts by weight of chitosan-modified polyvinyl alcohol, and 0.5 parts by weight of L-cysteine ​​hydrochloride were dissolved in water for injection at 8°C to obtain a mixed solution. Then, granular activated carbon was added for adsorption. The amount of granular activated carbon was 0.15% of the weight of the mixed solution, and the adsorption time was 15 minutes. The activated carbon was then filtered off to obtain the first product at about 8°C. The obtained first product was placed in a constant temperature tank for heat preservation.

[0044] 2. After heat treatment for 10 minutes, add 45 parts by weight of isaconazole sulfate to the first product, stir to dissolve and obtain a clear solution. Then add sulfuric acid to adjust the pH of the solution to 1.5 to obtain the second product.

[0045] Isaconazole sulfate underwent pretreatment, specifically as follows: First, isaconazole sulfate is dried in a drying oven at 180°C. The drying oven is filled with diatomaceous earth, which contains dry ice. Then, the dried isaconazole sulfate is placed in a rotating cylinder connected to the drying oven. The airflow that has been drying and removing impurities from the drying oven enters the cylinder and carries away the impurities in the cylinder.

[0046] The preparation method of chitosan-modified polyvinyl alcohol is the same as in Example 1.

[0047] 3. The second product is then filled and freeze-dried.

[0048] The second product from step 2 is then filled into containers and freeze-dried. The freeze-drying process is as follows: First stage: Add 8 parts by weight of dry ice and pre-freeze at -45℃ for 0.5 hours; Second stage: Add 2 parts by weight of dry ice and 2 parts by weight of L-cysteine, then heat to -5°C and evacuate to a vacuum degree of 70%, and perform low-temperature sublimation drying for 5 hours; Third stage: Add 2 parts by weight of dry ice and 2 parts by weight of L-cysteine, then raise the temperature to 40°C and evacuate to a vacuum degree of 38%, and desorb and dry for 6 hours; Fourth stage: Cool down to 6℃ and keep warm for 2 hours to obtain isaconazole sulfate.

[0049] Comparative Example 1: The difference between this comparative example and comparative example 1 is that chitosan-modified polyvinyl alcohol is not added.

[0050] Comparative Example 2: The difference between this comparative example and comparative example 1 is that L-cysteine ​​hydrochloride is not added.

[0051] Comparative Example 3: The difference between this comparative example and Comparative Example 1 is that chitosan-modified polyvinyl alcohol is replaced with polyethylene glycol.

[0052] Comparative Example 4: The difference between this comparative example and Example 1 is that the amount of chitosan-modified polyvinyl alcohol added is 1 part by weight.

[0053] The lyophilized powder of isaconazole sulfate for injection obtained in each example and comparative example was tested. The relevant properties were investigated under different treatment conditions, such as long-term storage at 2~8℃, strong light exposure for 15 days, and accelerated treatment (25℃ / 75%RH). The test results are shown in Table 1.

[0054] Table 1

[0055] As shown in Table 1 above, the lyophilized isaconazole sulfate for injection prepared by the method of the present invention exhibits excellent drug stability. After 6 months of storage, the isaconazole sulfate lyophilized powder content remains at a high level, above 99.0%, while the moisture content remains low, and the total impurities and maximum single impurities are also at low levels. The isaconazole sulfate lyophilized powder of the present invention also shows excellent performance against light, humidity, and high temperature environments, especially under high temperature (25°C) and high humidity (75%) conditions, where the moisture, maximum single impurity, and total impurity contents are all low.

[0056] The product obtained in Example 1 also exhibited excellent stability, maintaining a high content of active ingredients even under high temperature and humidity conditions and long-term storage, with minimal impurity formation. In contrast, Examples 2, 3, and 4 showed improved drying and moisture removal efficiency and better final product stability due to the addition of dry ice or L-cysteine ​​in the first, second, and third stages of the freeze-drying process.

[0057] In Comparative Examples 1 and 2, the absence of chitosan-modified polyvinyl alcohol and L-cysteine ​​hydrochloride significantly reduced resistance to light, high temperature, and high humidity, resulting in poor stability. In Comparative Example 3, where chitosan-modified polyvinyl alcohol was replaced with polyethylene glycol, it failed to synergistically enhance antioxidant properties with L-cysteine ​​hydrochloride, and its product also exhibited low stability. In Comparative Example 4, the large amount of chitosan-modified polyvinyl alcohol affected the dispersibility of mannitol and L-cysteine ​​hydrochloride in cold water, leading to a lower content of isaconazole sulfate and a weaker synergistic effect with L-cysteine ​​hydrochloride, adversely impacting product stability. Therefore, a reasonable and skillful design of the ratio of L-cysteine ​​hydrochloride to chitosan-modified polyvinyl alcohol is crucial.

[0058] The above specific embodiments further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above are merely specific embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A lyophilized powder of isaconazole sulfate for injection, characterized in that, The product includes isaconazole sulfate, a lyophilization protectant, and a pH adjuster. The lyophilization protectant is mannitol, chitosan-modified polyvinyl alcohol, and L-cysteine ​​hydrochloride. The pH adjuster is sulfuric acid. The pH is adjusted to 1-2 using the pH adjuster. Based on weight, isoconazole sulfate and lyophilization protectant are 35-45 parts and 7-9 parts, respectively.

2. The isoconazole sulfate lyophilized powder for injection according to claim 1, characterized in that, The mass ratio of mannitol, chitosan-modified polyvinyl alcohol, and L-cysteine ​​hydrochloride is (6~9):(0.2~0.4):(0.5~1.0).

3. A method for preparing an injectable isaconazole sulfate lyophilized powder according to any one of claims 1 to 2, characterized in that, Includes the following steps: (1) Solution preparation: Dissolve mannitol, chitosan-modified polyvinyl alcohol and L-cysteine ​​hydrochloride in water for injection, then add activated carbon, filter to remove activated carbon, and obtain the first product; (2) Add isaconazole sulfate to the first product, stir to dissolve, and obtain a clear solution. Then add sulfuric acid to adjust the pH to 1~2 to obtain the second product. (3) The second product is filled and freeze-dried to obtain isaconazole sulfate for injection.

4. The method for preparing an injectable isaconazole sulfate lyophilized powder according to claim 3, characterized in that, The preparation method of the chitosan-modified polyvinyl alcohol is as follows: Under the action of epichlorohydrin, chitosan and polyvinyl alcohol react to obtain chitosan-modified polyvinyl alcohol. The mass ratio of chitosan to polyvinyl alcohol is 1:

2.

5. The method for preparing an injectable isaconazole sulfate lyophilized powder according to claim 3, characterized in that, The water temperature for dissolving mannitol, chitosan-modified polyvinyl alcohol, and L-cysteine ​​hydrochloride is 8~10℃, and the dissolved solution is placed in a constant temperature container. The adsorption time for activated carbon is 5-15 minutes, and isaconazole sulfate is added 10-20 minutes after the activated carbon is added.

6. The method for preparing an injectable isaconazole sulfate lyophilized powder according to claim 3, characterized in that, The amount of activated carbon added is 0.10% to 0.15% of the aqueous solution containing mannitol, chitosan-modified polyvinyl alcohol, and L-cysteine ​​hydrochloride.

7. The method for preparing an injectable isaconazole sulfate lyophilized powder according to claim 3, characterized in that, In step (2), the isaconazole sulfate added to the first product was dried and roughened. The drying temperature was 180-200℃, and the roughening treatment was carried out by a blower.

8. The method for preparing an injectable isaconazole sulfate lyophilized powder according to claim 3, characterized in that, The drying process is carried out in a drying chamber filled with diatomaceous earth, and dry ice is added to the diatomaceous earth.

9. The preparation process of isaconazole sulfate for injection according to claim 4, characterized in that, The freeze-drying process is as follows: First stage: Pre-freezing at -45 to -40°C for 0.5 to 2 hours; Second stage: Then raise the temperature to -5℃~0℃ and evacuate to a vacuum degree of more than 50%, and perform low-temperature sublimation drying for 4~6 hours; Third stage: raise the temperature to 30-40℃ and evacuate to a vacuum degree of 35-40%, then desorb and dry for 6-7 hours; Fourth stage: Cool down to 5-10℃ and keep warm for 1-3 hours.

10. The method for preparing an injectable isaconazole sulfate lyophilized powder according to claim 9, characterized in that, Dry ice was added in the first stage, and L-cysteine ​​and dry ice were added in both the second and third stages; The mass ratio of the active pharmaceutical ingredient, isaconazole sulfate, to the dry ice added in the first stage is (35~45):(4~10). The mass ratio of the active pharmaceutical ingredient, isaconazole sulfate, to the dry ice added in the second and third stages is (35~45):(1~2). The mass ratio of the active pharmaceutical ingredient isaconazole sulfate to L-cysteine ​​added in the second and third stages is (35~45):(0.5~2).

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