Preparation method of triamcinolone acetonide injection

Abstract

The application relates to a preparation method of a final sterilization process of triamcinolone acetonide injection, which comprises the following steps: (1) mixing auxiliary materials with triamcinolone acetonide raw materials to prepare triamcinolone acetonide injection intermediate products, wherein the volume mode particle size distribution of the triamcinolone acetonide raw materials in the triamcinolone acetonide injection intermediate products meets the following conditions: D(0.9)=13.5-24.0 mu m, D(0.5)=6.0-8.0 mu m, and D(0.1)=1.1-1.4 mu m, and the viscosity of the triamcinolone acetonide injection intermediate products is 30.0-50.0 mPa.s; (2) filling and sealing the triamcinolone acetonide injection intermediate products to obtain triamcinolone acetonide injection pre-sterilization intermediate products; and (3) performing final sterilization on the triamcinolone acetonide injection pre-sterilization intermediate products, wherein the triamcinolone acetonide injection after the final sterilization meets the following conditions: the volume mode particle size distribution is D(0.9)=14.0-26.0 mu m, D(0.5)=6.0-9.0 mu m, and D(0.1)=1.1-1.6 mu m; and the viscosity is 9.0-16.0 mPa.s. The triamcinolone acetonide injection obtained according to the application meets the quality attributes of a reference preparation, and the sterile guarantee level is improved.

Description

Technical Field

[0001] The present application relates to the technical field of drug preparation, and in particular to a method for preparing triamcinolone acetonide injection. Background Art

[0002] Triamcinolone acetonide injection is an injection (suspension). The legal drug standards include a sterility test item, which strictly requires the complete absence of any viable microorganisms. However, due to the limitations of current testing methods, the concept of absolute sterility cannot be applied to the sterility evaluation of an entire batch of products. Therefore, the concept of "sterility" currently used is a probabilistic one. The sterility of a batch of drugs can only be characterized by the probability of the presence of viable microorganisms in the batch being low to an acceptable level, namely the Sterility Assurance Level (SAL).

[0003] Common sterilization methods are divided into terminal sterilization process (sterilizing process) and aseptic production process (aseptic processing) according to different processes. The terminal sterilization process refers to the process of properly sterilizing the product that has completed the final seal. The sterile preparations produced in this way are called terminally sterilized sterile drugs. Aseptic production process refers to the method of producing sterile drugs through aseptic operations under aseptic environmental conditions. Sterile filtration and aseptic production are both aseptic production processes. Drugs that use aseptic production processes for some or all of the processes are called non-terminally sterilized sterile drugs. The sterility assurance level of terminally sterilized sterile products is the probability of residual microbial contamination ≤ 10 -6 The sterility assurance level of non-terminally sterilized sterile products should at least reach a contamination probability of <0.1% under the 95% confidence limit. This shows that the probability of microbial contamination in non-terminally sterilized sterile products is much higher than that of terminally sterilized sterile products.

[0004] Furthermore, triamcinolone acetonide injection is a suspension. Non-Patent Document 1 states that suspensions cannot be terminally sterilized, as static sterilization may lead to problems such as clumping and wall adhesion. Therefore, sterile APIs and aseptic processes should be used for production. Given the above, aseptic processing is currently the mainstream method for preparing triamcinolone acetonide injection. For example, Patent Document 1 discloses a method for preparing triamcinolone acetonide acetate injection using a sterilization process, wherein the suspension is sterilized and then dispensed into sterile bottles. Patent Document 2 also discloses a method for preparing triamcinolone acetonide injection, wherein the suspension is sterilized under conditions such as stirring that allow for uniform drug dispersion, and then aseptically dispensed into sterile bottles. While both of these methods can improve the level of sterility assurance, neither employs a terminal sterilization process and falls short of the sterility assurance level of terminally sterilized sterile products, posing significant risks to consumers.

[0005] Prior art literature:

[0006] Non-patent technical literature

[0007] Non-Patent Document 1: Pharmaceutical Dosage Forms and Drug Delivery (Third Edition: Revised and Expanded) p. 389

[0008] Patent Literature

[0009] Patent Document 1: CN114206348A

[0010] Patent Document 2: US20190269616A1 Summary of the Invention

[0011] In view of this, the main purpose of the present application is to provide a preparation method of triamcinolone acetonide injection, by which triamcinolone acetonide injection with a higher sterility assurance level can be prepared.

[0012] To this end, the present application provides a method for preparing triamcinolone acetonide injection, comprising the following steps:

[0013] (1) mixing an excipient with a triamcinolone acetonide API to prepare a triamcinolone acetonide injection intermediate product, wherein the volume mode particle size distribution of the triamcinolone acetonide API in the triamcinolone acetonide injection intermediate product satisfies the following conditions: D(0.9)=13.5-24.0 μm, D(0.5)=6.0-8.0 μm, D(0.1)=1.1-1.4 μm, and the viscosity of the triamcinolone acetonide injection intermediate product is 30.0-50.0 mPa·s;

[0014] (2) filling and sealing the intermediate product of triamcinolone acetonide injection to obtain the intermediate product of triamcinolone acetonide injection before sterilization; and

[0015] (3) The intermediate product before sterilization of the triamcinolone acetonide injection is terminally sterilized, and the triamcinolone acetonide injection after terminal sterilization meets the following conditions: volume mode particle size distribution is: D(0.9)=14.0~26.0μm, D(0.5)=6.0~9.0μm, D(0.1)=1.1~1.6μm; viscosity is 9.0~16.0mPa·s.

[0016] In some embodiments, in step (1), the excipient contains 0.60% to 0.66% sodium carboxymethyl cellulose, 0.038% to 0.042% polysorbate 80, 0.94% to 1.04% benzyl alcohol and 0.63% to 0.69% sodium chloride.

[0017] In some embodiments, the 0.60% to 0.66% sodium carboxymethyl cellulose contained in the excipient is composed of sodium carboxymethyl cellulose with high, medium and low viscosity in different proportions.

[0018] In some embodiments, in step (1), the triamcinolone acetonide API is pretreated using a jet mill.

[0019] In some embodiments, before the triamcinolone acetonide injection intermediate product is filled, the preparation method further comprises: suspending the triamcinolone acetonide injection intermediate product to obtain a suspension of triamcinolone acetonide injection.

[0020] In some embodiments, the suspension time is 60 minutes to 80 minutes.

[0021] In some embodiments, in step (3), the terminal sterilization is performed in a static manner.

[0022] In some embodiments, in step (3), the terminal sterilization is performed using a steam sterilizer or a water bath sterilizer.

[0023] In some embodiments, the terminal sterilization conditions are 121° C., 12 minutes to 30 minutes; or 115° C., 30 minutes to 60 minutes.

[0024] The preparation method of triamcinolone acetonide injection provided in the present application controls the particle size distribution and viscosity range of triamcinolone acetonide raw materials and injection intermediates, and performs terminal sterilization on the products. The triamcinolone acetonide injection thus obtained meets the quality attributes of the reference preparation and improves the sterility assurance level. DETAILED DESCRIPTION

[0025] The following will be combined with the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of this application. Throughout the specification, unless otherwise specified, the terms used herein should be understood as meanings commonly used in the art.

[0026] The preparation method of triamcinolone acetonide injection of the present application comprises the following steps:

[0027] (1) mixing the excipients with the triamcinolone acetonide API to prepare a triamcinolone acetonide injection intermediate, wherein the volume mode particle size distribution of the triamcinolone acetonide API in the obtained triamcinolone acetonide injection intermediate satisfies the following conditions: D(0.9)=13.5-24.0 μm, D(0.5)=6.0-8.0 μm, D(0.1)=1.1-1.4 μm, and the viscosity of the triamcinolone acetonide injection intermediate is 30.0-50.0 mPa·s;

[0028] (2) filling and sealing the above-mentioned intermediate product of triamcinolone acetonide injection to obtain the intermediate product of triamcinolone acetonide injection before sterilization; and

[0029] (3) The intermediate product before sterilization of the triamcinolone acetonide injection is terminally sterilized. The triamcinolone acetonide injection after terminal sterilization meets the following conditions: volume mode particle size distribution is: D(0.9) = 14.0 to 26.0 μm, D(0.5) = 6.0 to 9.0 μm, D(0.1) = 1.1 to 1.6 μm; and viscosity is 9.0 to 16.0 mPa·s.

[0030] During the research process, the inventors discovered that the terminal sterilization process affects the particle size distribution and viscosity of triamcinolone acetonide injection. When the reference preparation of triamcinolone acetonide injection is directly subjected to terminal sterilization, the particle size distribution increases slightly, while the viscosity decreases after terminal sterilization. In order to ensure that the particle size and viscosity of the product obtained after terminal sterilization are consistent with the range of the reference preparation, the inventors controlled the particle size distribution (volume mode) and viscosity of the triamcinolone acetonide API and the injection intermediate product to meet D(0.9) = 13.5 to 24.0 μm, D(0.5) = 6.0 to 8.0 μm, D(0.1) = 1.1 to 1.4 μm, and the viscosity is between 30.0 and 50.0 mPa·s.

[0031] In some embodiments, the triamcinolone acetonide API can be pretreated so that the particle size distribution (volume mode) of the triamcinolone acetonide API in the intermediate product satisfies D(0.9) = 13.5-24.0 μm, D(0.5) = 6.0-8.0 μm, and D(0.1) = 1.1-1.4 μm. For example, a jet mill can be used to pretreat the triamcinolone acetonide API. The jet mill uses high-speed airflow to cause particles to impact, collide, and frictional shear forces to achieve ultrafine grinding. By adjusting the vibration frequency of the hopper, the pressure of the feed airflow, and the pressure of the grinding airflow, for example, setting the vibration frequency of the hopper to 10 Hz to 30 Hz, the pressure of the feed airflow to 0.45 MPa to 0.85 MPa, and the pressure of the grinding airflow to 0.30 MPa to 0.70 MPa, a triamcinolone acetonide API with a particle size distribution (volume mode) that meets the above requirements can be obtained.

[0032] In some embodiments, the excipients are mixed with the triamcinolone acetonide API to prepare a triamcinolone acetonide injection intermediate. This can be accomplished by slowly adding the excipients to water for injection cooled to 20°C to 60°C while stirring; then, adding the triamcinolone acetonide API obtained by pretreatment in the above step and stirring until uniformly mixed. If necessary, dilute hydrochloric acid or sodium hydroxide solution is added to the mixture to adjust the pH to 5.0 to 7.5, thereby preparing the triamcinolone acetonide injection intermediate. To minimize particle size distribution, stirring is performed at 600 to 5000 rpm. In some embodiments, each mL of triamcinolone acetonide injection contains 40 mg of triamcinolone acetonide, and the excipients include 0.60% to 0.66% sodium carboxymethylcellulose, 0.038% to 0.042% polysorbate 80, 0.94% to 1.04% benzyl alcohol, and 0.63% to 0.69% sodium chloride. Sodium carboxymethyl cellulose is used as a thickener. By adjusting the proportion of different types of sodium carboxymethyl cellulose (such as high, medium and low viscosity sodium carboxymethyl cellulose) (but the proportion of the total amount of sodium carboxymethyl cellulose in the prescription remains at 0.60% to 0.66%), a triamcinolone acetonide injection intermediate product with a viscosity of 30.0 to 50.0 mPa·s is obtained.

[0033] In one embodiment, before the triamcinolone acetonide injection intermediate product is filled, the preparation method further comprises suspending the triamcinolone acetonide injection intermediate product so that the triamcinolone acetonide API is uniformly dispersed in the intermediate product to obtain a triamcinolone acetonide suspension. In some embodiments, the triamcinolone acetonide injection intermediate product prepared in step (1) is transferred to a suspension tank for suspension. The suspension is carried out under stirring, and the rotation speed is set within 600 rpm to 5000 rpm without destroying the particle size distribution of the triamcinolone acetonide injection intermediate product. In some embodiments, the suspension time is 60 minutes to 80 minutes.

[0034] In step (2), the filling step is to place the above-mentioned triamcinolone acetonide injection intermediate product or triamcinolone acetonide suspension into a vial and seal it to obtain the pre-sterilized triamcinolone acetonide injection intermediate product. In some embodiments, the filling step is performed under stirring at a stirring speed within a range of 200 rpm to 5000 rpm, without destroying the particle size distribution of the triamcinolone acetonide injection intermediate product.

[0035] In some embodiments, prior to the filling process, the preparation method further comprises cleaning and sterilizing the vials, stoppers, and aluminum caps. The cleaning and sterilization process for the vials specifically comprises: ultrasonically cleaning the vials, then rinsing with water for injection, with the cleaning qualification standard being that visible foreign matter is not present; and then sterilizing at 320±15°C. The cleaning and sterilization process for the stoppers specifically comprises: rinsing the stoppers with water for injection, with the cleaning qualification standard being that visible foreign matter is not present; and then sterilizing with moist heat at 121°C for 20 minutes. The cleaning and sterilization process for the aluminum caps specifically comprises: rinsing the aluminum caps with purified water, with the cleaning qualification standard being that visible foreign matter is not present; and then sterilizing with moist heat at 121°C for 20 minutes.

[0036] In some embodiments, the filling volume is adjusted to between 1.10 ml and 1.30 ml, and the filling is performed. During the filling process, the filling volume and visible foreign matter are regularly checked. After the filling is completed, the bottle is sealed with the above-mentioned rubber stopper, and the above-mentioned aluminum cap is used for the capping process. During the capping process, the seal integrity is regularly checked to obtain the intermediate product of triamcinolone acetonide injection before sterilization.

[0037] In step (3), the intermediate product before sterilization of the above-mentioned triamcinolone acetonide injection is subjected to terminal sterilization. In some embodiments, the above-mentioned terminal sterilization is carried out in a static manner. Those skilled in the art generally believe that the terminal sterilization of the suspension needs to be carried out using a rotary or swinging sterilizer or a vibrating sterilizer, which is equivalent to a device with stirring action, to ensure the uniformity of sterilization. However, when a rotary or swinging sterilizer is used, the suspension is prone to form a wall hanging phenomenon due to rapid evaporation of the liquid film. When a vibrating sterilizer is used, the suspension is also prone to splashing onto the wall of the vial, causing wall hanging, and when the vibration frequency is high, the bottle is prone to breakage. In order to avoid the above-mentioned problems, the present invention adopts a static sterilization equipment during the final sterilization, such as a steam sterilizer or a water bath sterilizer. On the one hand, this can avoid the above-mentioned wall hanging and bottle breakage caused by factors such as swinging or vibration; on the other hand, the steam sterilizer or the water bath sterilizer can ensure the uniformity of sterilization, further simplifying the final sterilization process operation of the suspension and significantly reducing the production cost.

[0038] In some embodiments, the terminal sterilization conditions in step (3) above are: moist heat sterilization at 121°C for 12 to 30 minutes; or moist heat sterilization at 115°C for 30 to 60 minutes. Moist heat sterilization mainly includes overkill method and residual probability method. The selection of sterilization process is usually carried out according to the sterilization process decision tree. The intermediate product before sterilization of triamcinolone acetonide injection can withstand the high temperature of moist heat sterilization, and the thermal stability of the product is acceptable. Therefore, the moist heat sterilization process (overkill method) is preferably used for terminal sterilization.

[0039] In some embodiments, after the final sterilization process in step (3), the preparation method of the present application may further include a light inspection process, through which unqualified products such as broken bottles, damaged caps, missing caps, and abnormal filling volumes are removed.

[0040] The terminally sterilized triamcinolone acetonide injection obtained according to the preparation method of the present application meets the key quality attribute requirements of the reference preparation and is pharmaceutically equivalent to the reference preparation. In addition, the triamcinolone acetonide injection of the present application is prepared using a terminal sterilization process. Compared with products prepared using an aseptic process in the prior art, the present application obtains a terminally sterilized sterile triamcinolone acetonide injection with a higher sterility assurance level, which can minimize the risk of contamination of the injection.

[0041] Example

[0042] Critical Quality Attributes Test Methods for Pharmaceutical Products

[0043] (1) Properties: Take the test sample for visual observation. The standard is a suspension of fine particles. The fine particles sink after standing and become a uniform milky white suspension after shaking.

[0044] (2) Visible foreign matter: Take the test sample and use the method described in the fourth part of the 2020 edition of the Chinese Pharmacopoeia (General Chapter 0904). The standard is that no obvious visible foreign matter such as metal chips, glass chips, color blocks, fibers, etc. should be detected.

[0045] (3) Bacterial endotoxins: Take the test sample and test it using the method described in the fourth part of the 2020 edition of the Chinese Pharmacopoeia (General Chapter 1143). The standard is that the amount of endotoxin in every 1 mg of triamcinolone acetonide should be less than 3.0EU.

[0046] (4) Sterility: Take the test sample and test it using the Chinese Pharmacopoeia 2020 edition Part IV (General Rule 1101), and the standard is that there should be no sterile growth.

[0047] (5) Sedimentation volume ratio: Use a standardized (verified or calibrated) dry stoppered measuring cylinder to measure a certain volume of the test sample suspension, shake it vigorously, and read the initial height of the suspension. Let it stand until the volume of the sediment no longer changes, and then read the final height of the sediment. The ratio of the final height to the initial height is the sedimentation volume ratio.

[0048] (6) pH value: Take the test sample and test it using the method described in the fourth part of the 2020 edition of the Chinese Pharmacopoeia (General Chapter 0631), with the standard being 5.0-7.5.

[0049] (7) Related substances: Detection was carried out using the method described in Part IV of the 2020 edition of the Chinese Pharmacopoeia (General Chapter 0512).

[0050] Among them, the test solution is prepared as follows: take the test sample, shake it well, accurately measure an appropriate amount, add mobile phase B to dissolve it, and sonicate it to dissolve it if necessary, and quantitatively dilute it to make a solution containing about 1 mg of triamcinolone acetonide per 1 mL, which is used as the test solution.

[0051] Preparation of reference solution: Accurately measure an appropriate amount of the test solution, add mobile phase B to dissolve it, and dilute it to make a solution containing approximately 1 μg of triamcinolone acetonide per 1 mL as the reference solution.

[0052] Chromatographic conditions: octadecylsilane bonded silica gel was used as the filler (applicable to end-capped chromatographic columns); acetonitrile-water (32:68) was used as the mobile phase A, and water-acetonitrile (35:65) was used as the mobile phase B; gradient elution was performed according to Table 1 below; the detection wavelength was 254 nm; the column temperature was 40°C; the flow rate was 1.5 mL / min; and the injection volume was 20 μl.

[0053] Table 1

[0054] Time (min) Mobile phase A (%) Mobile phase B (%) 0 100 0 20 100 0 40 0 100 45 100 0 60 100 0

[0055] Determination method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, measure under the above chromatographic conditions and record the chromatogram.

[0056] Limits: Except for the benzyl alcohol chromatographic peak (relative retention time is about 0.3), if there are impurity peaks in the chromatogram of the test solution, the impurity peak area shall not exceed 2.0 times (0.2%) the main peak area of ​​the reference solution chromatogram, and the sum of the impurity peak areas shall not exceed 8 times (0.8%) the main peak area of ​​the reference solution chromatogram. Peaks in the chromatogram that are less than 0.5 times (0.05%) the main peak area of ​​the reference solution are ignored.

[0057] (8) Content determination: The method described in Part IV of the 2020 edition of the Chinese Pharmacopoeia (General Chapter 0512) was used for detection.

[0058] The test solution was prepared by taking the test sample, shaking it well, accurately measuring an appropriate amount, dissolving it with 70% methanol, sonicating it if necessary, and quantitatively diluting it to prepare a solution containing approximately 30 μg of triamcinolone acetonide per 1 mL as the test solution.

[0059] Preparation of reference solution: Accurately weigh triamcinolone acetonide reference substance, dissolve it in 70% methanol, sonicate it if necessary, and quantitatively dilute it to make a solution containing approximately 30 μg of triamcinolone acetonide per 1 mL as the reference solution.

[0060] Preparation of system suitability solution: Dissolve and dilute triamcinolone acetonide and triamcinolone separately in 70% methanol solution to prepare a solution containing approximately 5 μg triamcinolone acetonide and 5 μg triamcinolone per 1 mL, respectively, as the system suitability solution.

[0061] Chromatographic conditions: octadecylsilane bonded silica gel was used as the filler; methanol-water (58:42) was used as the mobile phase; the detection wavelength was 240 nm; and the injection volume was 20 μl.

[0062] System suitability requirements: The number of theoretical plates calculated based on the triamcinolone acetonide peak should be no less than 5000, and the separation degree between the triamcinolone acetonide peak and the triamcinolone peak should be greater than 15.

[0063] Determination method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, detect under the above chromatographic conditions and record the chromatogram.

[0064] Limit: Contains triamcinolone acetonide (C 24 H 31 FO6) should be 90.0%~110.0%.

[0065] (9) Benzyl alcohol content: Detected using the method described in Part IV of the 2020 edition of the Chinese Pharmacopoeia (General Chapter 0512).

[0066] Among them, the test solution was prepared as follows: take the test sample, shake it well and accurately measure 1 mL, place it in a 10 mL volumetric flask, first add 8 mL of methanol to dissolve it, sonicate to dissolve it if necessary, add water to make up the volume, shake it well, filter it, and take the filtrate as the test solution.

[0067] Preparation of reference solution: Accurately weigh an appropriate amount of benzyl alcohol reference substance, add methanol to make a solution containing 0.9 mg of benzyl alcohol per 1 mL, and take the filtrate as the reference solution.

[0068] Preparation of system suitability solution: Dissolve and dilute benzyl alcohol, triamcinolone acetonide, and triamcinolone separately in 70% methanol to prepare a solution containing approximately 0.9 mg of benzyl alcohol, 5 μg of triamcinolone acetonide, and 5 μg of triamcinolone per 1 mL, as the system suitability solution.

[0069] Chromatographic conditions: octadecylsilane bonded silica gel was used as the filler; methanol-water (525:475) was used as the mobile phase; the detection wavelength was 240 nm; and the injection volume was 20 μL.

[0070] System suitability requirements: In the system suitability solution chromatogram, the number of theoretical plates calculated based on the benzyl alcohol peak should be no less than 2000, and the separation degree between benzyl alcohol and triamcinolone should be greater than 1.5.

[0071] Determination method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, detect under the above chromatographic conditions and record the chromatogram.

[0072] Limit: The amount of benzyl alcohol in each 1 mL of injection should be 0.9 mg to 1.1 mg.

[0073] (10) Dissolution: The dissolution was tested using the method described in Part IV of the 2020 edition of the Chinese Pharmacopoeia (General Chapter 0931 Method 2).

[0074] Among them, the preparation of the test solution: take the test sample, use phosphate buffer (0.05 mol / l of sodium dihydrogen phosphate, 0.0391 mol / l of sodium hydroxide, add 0.1% SDS surfactant, dissolve in 1000 mL of water, pH 7.3±0.1) as the dissolution medium, the volume of the dissolution medium is 900 mL, the rotation speed is 50 revolutions per minute, operate according to the method, after 60 minutes, take an appropriate amount of the solution, filter, and use it as the test solution.

[0075] Preparation of reference solution: Accurately weigh triamcinolone acetonide reference substance and use 70% methanol as solvent to prepare a solution with a concentration of about 40 μg / mL as the reference solution.

[0076] System suitability solutions, chromatographic conditions and system suitability requirements refer to those specified in the above (8) content determination.

[0077] Determination method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph, and perform the test according to the chromatographic conditions specified in (8) above. Record the chromatogram. Calculate the amount of dissolution per bottle by the peak area according to the external standard method.

[0078] Limit: The dissolution rate is 80%, which complies with the provisions of Part IV of the 2020 edition of the Chinese Pharmacopoeia (0931 Dissolution and Release Determination Method).

[0079] (11) Particle size distribution: The particle size and particle size distribution determination method of Part IV of the 2020 edition of the Chinese Pharmacopoeia (General Chapter 0982 Method 3) was used for determination.

[0080] Specifically, a laser particle size analyzer (Malvern Mastersizer 2000 or equivalent) is used; approximately two bottles of the test sample are placed in a 100 mL beaker, and approximately 60 mL of polysorbate 80 solution (prepared to a concentration of approximately 0.4% (g / mL) polysorbate 80 solution, gently stirred, sonicated, and filtered through a 0.45 μm filter) is added. Stir thoroughly and sonicate for 10 minutes, with intervals of 2 to 3 minutes during the sonication process to stir the sample thoroughly. This serves as a reserve test solution. Approximately 600 mL of the polysorbate 80 solution is added to a 1000 mL beaker, and an appropriate amount of the reserve test solution is added. Gently stir and mix carefully to avoid foaming, ensuring that the detector light shielding is within the range of 5% to 15%. Inspection was carried out in accordance with the law. Specifically, the scanning time of the background and the sample was 15 s, the stirring rate was (1200 rpm), and ultrasound was performed simultaneously; the Fraunhofer mode was used for measurement (the refractive index of the particles was 0; the absorptivity of the particles was 0), and three consecutive measurements were made. The average value was calculated according to the volume mode (the results can be rounded to one decimal place according to the rounding rules of the Chinese Pharmacopoeia).

[0081] (12) Viscosity: A rheometer (Anton Paar MCR72) was used with a 50 mm diameter plate, a 0.7 mm gap, and a shear rate of 700 s. -1 The measurement temperature is 20℃, the measurement is 3 minutes, and the average value is taken.

[0082] Comparative Example 1 (Key Quality Attributes of Reference Preparation)

[0083] Multiple batches of the reference preparation (purchased from the United States, licensed by Apothecon Inc Div Bristol Myers Squibb, NDC: 003-0293-05, packaging specification: 40 mg / ml, 1 ml / bottle / box) were tested according to the above-mentioned quality attribute test method. The results are shown in Table 2.

[0084] Table 2

[0085]

[0086] Preparation Example 1

[0087] The preparation method provided in this application was used to prepare a triamcinolone acetonide injection sample. The specific operation of the raw material pretreatment included: using a jet mill (model: MQP10) from Shandong Elpa Powder Technology Co., Ltd., setting the vibration frequency of the hopper to 20 Hz, the pressure of the feed airflow to 0.70 MPa, and the pressure of the pulverizing airflow to 0.50 MPa to obtain triamcinolone acetonide raw materials in the following particle size range: D(0.9) = 13.5 μm, D(0.5) = 6.0 μm, and D(0.1) = 1.1 μm.

[0088] Specifically, the materials used in this product must comply with the quality standards of the Chinese Pharmacopoeia. The specific requirements are as follows:

[0089] Polysorbate 80 shall comply with the quality standards of Polysorbate 80 (II) in Part IV of the Chinese Pharmacopoeia; sodium carboxymethyl cellulose shall comply with the quality standards of sodium carboxymethyl cellulose in Part IV of the Chinese Pharmacopoeia; sodium chloride shall comply with the quality standards of sodium chloride (for injection) in Part IV of the Chinese Pharmacopoeia; benzyl alcohol shall comply with the quality standards of benzyl alcohol in Part IV of the Chinese Pharmacopoeia.

[0090] When weighing triamcinolone acetonide API, it is necessary to purify it. When weighing excipients, there is no need to consider moisture. Just weigh it according to the prescription amount. The specific weighing amounts are as follows.

[0091] Table 3

[0092] Components Prescription ratio (w / v) Triamcinolone acetonide (pure) 400.1 grams Sodium chloride 66.0 grams Benzyl alcohol 99.0 grams Sodium carboxymethylcellulose 63.0 grams Polysorbate 80 4.0 grams Water for injection 10000ml hydrochloric acid appropriate amount Sodium hydroxide appropriate amount

[0093] The specific preparation steps include: adding the excipients sodium carboxymethylcellulose, polysorbate 80, benzyl alcohol, and sodium chloride in the amounts listed in Table 3 to 10,000 ml of water for injection cooled to 35°C while stirring; then adding the triamcinolone acetonide API obtained from the above pretreatment and stirring evenly at 1,000 rpm; the pH value of the solution was measured to be 5.63, which met the pH requirement (5.0-7.5), and no pH adjustment with dilute hydrochloric acid or sodium hydroxide solution was required. The resulting triamcinolone acetonide injection intermediate had a viscosity of 44.5 mPa·s. The triamcinolone acetonide intermediate was transferred to a suspension tank and suspended for 60 minutes.

[0094] The resulting triamcinolone acetonide injection suspension was filled under the following conditions: filling was performed while stirring at a stirring speed of 2000 rpm to ensure that the particle size distribution of the triamcinolone acetonide in the intermediate product of triamcinolone acetonide injection was not disrupted. The suspension was then stoppered and capped to obtain the intermediate product of triamcinolone acetonide injection before sterilization.

[0095] The specific cleaning operations of the vials include: ultrasonic cleaning and rinsing with injection water until visible foreign matter is qualified.

[0096] Sterilization conditions for vials: temperature 320±15℃.

[0097] The specific operation of cleaning the rubber stopper includes: cleaning with injection water until visible foreign matter is qualified.

[0098] Sterilization conditions for rubber stoppers: 121°C, moist heat sterilization for 20 minutes.

[0099] The aluminum cover cleaning operation specifically includes: cleaning with purified water until visible foreign matter is qualified.

[0100] Aluminum cap sterilization conditions: 121℃, moist heat sterilization for 20 minutes.

[0101] Finally, the obtained intermediate product before sterilization of triamcinolone acetonide injection was terminally sterilized under the following terminal sterilization conditions: wet heat sterilization was adopted: 121° C., wet heat sterilization for 15 minutes.

[0102] Thus, a sterilized triamcinolone acetonide injection was obtained, which was used as sample 1.

[0103] Preparation Example 2

[0104] Based on Preparation Example 1, triamcinolone acetonide injection intermediates with different particle size distributions and viscosities were obtained by changing the preparation conditions of the triamcinolone acetonide API and the injection intermediate. The particle size distribution and viscosity are shown in Table 4. Otherwise, terminally sterilized triamcinolone acetonide injections were prepared in the same manner as in Preparation Example 1. These were used as Samples 2 to 9 and Comparative Samples 1 to 6.

[0105] Table 4

[0106] Sample number D(0.9) D(0.5) D(0.1) Viscosity (mPa·s) Sample 1 13.5 6.0 1.1 44.5 Sample 2 20.0 6.8 1.2 44.7 Sample 3 24.0 7.3 1.2 44.5 Sample 4 15.3 6.0 1.1 45.1 Sample 5 20.2 7.0 1.1 45.5 Sample 6 22.5 8.0 1.1 44.5 Sample 7 17.1 7.1 1.2 30.0 Sample 8 17.1 7.1 1.2 45.2 Sample 9 17.1 7.1 1.2 50.0 Comparative Sample 1 13.0 6.2 1.1 44.6 Comparative Sample 2 25.0 7.2 1.2 45.6 Comparative Sample 3 15.5 5.0 1.1 46.6 Comparative Sample 4 23.2 9.0 1.2 46.6 Comparative sample 5 20.0 6.8 1.2 29.0 Comparative Sample 6 20.0 6.8 1.2 51.0

[0107] Test Example 1

[0108] The above formulation critical quality attribute test method was used to test the critical quality attributes of each triamcinolone acetonide injection sample and the comparative sample in Table 4. The results are shown in Tables 5 and 6 below.

[0109] Table 5 Quality attribute test results of triamcinolone acetonide injection samples after terminal sterilization

[0110]

[0111] 2213085-I-CP-KMJDZY

[0112]

[0113] Table 6 Quality attribute test results of comparative samples after terminal sterilization

[0114]

[0115] From the above test results, it can be seen that when the particle size distribution of the triamcinolone acetonide injection intermediate product before terminal sterilization satisfies D(0.1) of 1.1-1.4, D(0.5) of 6.0-8.0, and D(0.9) of 13.5-24.0, and the viscosity of the triamcinolone acetonide injection intermediate product is 30-50 mPa·s, the final product obtained by the terminal sterilization process meets the quality attribute requirements of the reference preparation, and the sterility assurance level of the product obtained by the terminal sterilization process is higher, and the risk of product contamination is reduced. However, when the particle size distribution and viscosity of the triamcinolone acetonide injection intermediate product do not meet the ranges defined in this application, the particle size distribution and viscosity of the obtained terminally sterilized product do not meet the quality attribute requirements of the reference preparation.

[0116] Test Example 2

[0117] Sterilization uniformity testing

[0118] A batch of triamcinolone acetonide injection was prepared using the method described in Preparation Example 1 of the present invention. The particle size distribution of the triamcinolone acetonide API was 1.1 (D(0.1), 7.1 (D(0.5), and 18.3 (D(0.9)). The viscosity of the intermediate product was 45.7 mPa·s. Terminal sterilization was performed in a large waterbath sterilizer (Shandong Xinhua Medical Instrument Co., Ltd., ASMDF-4.0) at 121°C for 15 minutes. After sterilization, samples were taken from different spatial locations in the waterbath sterilizer and measured for viscosity and particle size. The results are shown in Table 7. Furthermore, a T-test was performed using the test results in the upper layer as a benchmark to obtain p-values. The results are shown in Table 8.

[0119] Table 7 Test results of samples at different positions of sterilizer

[0120]

[0121] Table 8 p-value table of the test results of samples at different positions of the sterilizer

[0122]

[0123] As can be seen from the above test results, under simulated full load conditions, the viscosity and particle size distribution of the samples measured at different spatial locations of the equipment were slightly different. A t-test analysis was performed, and the p-values ​​of the comparative analysis of the upper, middle, and lower layer sample test data were all greater than 0.05, indicating that there was no significant difference. This shows that there is no need to use a rotary or swing sterilizer or a vibrating sterilizer commonly used for suspensions. An ordinary steam sterilizer or water bath sterilizer can be used to achieve uniform sterilization of triamcinolone acetonide injection, and the key quality attributes (viscosity and particle size) are consistent with those of the reference preparation, simplifying the terminal sterilization operation and reducing production costs.

[0124] The above description is only a preferred embodiment of the present application and does not limit the patent scope of the present application. All equivalent structural transformations made using the contents of the present application specification under the inventive concept of the present application, or direct / indirect application in other related technical fields are included in the patent protection scope of the present application.

Claims

1. A method for preparing triamcinolone acetonide injection, wherein: The following steps are involved: (1) mixing an excipient with a triamcinolone acetonide API to prepare a triamcinolone acetonide injection intermediate, wherein the excipient contains 0.60% to 0.66% sodium carboxymethyl cellulose, 0.038% to 0.042% polysorbate 80, 0.94% to 1.04% benzyl alcohol, and 0.63% to 0.69% sodium chloride, and the volume mode particle size distribution of the triamcinolone acetonide API in the triamcinolone acetonide injection intermediate satisfies the following conditions: D(0.9)=13.5 to 24.0 μm, D(0.5)=6.0 to 8.0 μm, and D(0.1)=1.1 to 1.4 μm, and the viscosity of the triamcinolone acetonide injection intermediate is 30.0 to 50.0 mPa·s; (2) filling and sealing the intermediate product of triamcinolone acetonide injection to obtain the intermediate product of triamcinolone acetonide injection before sterilization; and (3) terminally sterilizing the intermediate product before sterilization of the triamcinolone acetonide injection, wherein the terminal sterilization conditions are 121° C. for 12 to 30 minutes; or 115° C. for 30 to 60 minutes, and the triamcinolone acetonide injection after terminal sterilization meets the following conditions: volume mode particle size distribution is: D(0.9)=14.0-26.0 μm, D(0.5)=6.0-9.0 μm, D(0.1)=1.1-1.6 μm; and viscosity is 9.0-16.0 mPa·s.

2. The preparation method according to claim 1, wherein The auxiliary material contains 0.60% to 0.66% of sodium carboxymethyl cellulose, which is composed of sodium carboxymethyl cellulose with high, medium and low viscosity in different proportions.

3. The preparation method according to claim 1, wherein In the step (1), the triamcinolone acetonide raw material is pretreated by a jet mill.

4. The preparation method according to claim 1, before the intermediate product of triamcinolone acetonide injection is filled, the preparation method further comprises: The triamcinolone acetonide injection intermediate product is suspended to obtain a suspension of triamcinolone acetonide injection.

5. The preparation method according to claim 4, wherein The suspension time is 60 to 80 minutes.

6. The preparation method according to claim 1, wherein In the step (3), the terminal sterilization is performed in a static manner.

7. The preparation method according to claim 6, wherein In step (3), the final sterilization is performed using a steam sterilizer or a water bath sterilizer.

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