Ombalecycline tosylate preparation for injection and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an omagazines tosylate preparation for injection and a preparation method of the omagazines tosylate preparation. The omagazines tosylate preparation for injection is prepared from the following components: omagazines tosylate, a stabilizer, cane sugar, a pH regulator and water for injection, wherein the stabilizer is selected from sodium lactobionate, potassium chloride, sodium chloride, sodium citrate, mannitol, sodium pyrosulfite and anhydrous sodium sulfate. According to the invention, by introducing the stabilizer, the production process window is obviously widened, and the generation of impurities in the production process is effectively inhibited; meanwhile, the matched freeze-drying process is simple and easy to control, commercialized production is easy, and the prepared freeze-drying preparation is good in stability and excellent in quality.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an injectable omalicycline tosylate formulation and its preparation method. Background Technology

[0002] Omacycline tosylate is a novel aminomethyltetracycline antibiotic that effectively overcomes two major resistance mechanisms: efflux pump and ribosomal protection, providing a new option for treating drug-resistant bacterial infections. Currently, its injectable formulation is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).

[0003] Omacycline tosylate for injection was originally developed by Paratek Pharmaceuticals and approved for marketing in the United States in 2018, with a marketed strength of 0.1g (according to C). 29 H 40 (N4O7 calculation). Zai Lab obtained the license from Paratek Pharmaceuticals and was approved for marketing in China in 2021. According to the FDA's marketing information for omalicycline tosylate for injection, its single-vial formulation contains 131 mg of omalicycline tosylate (equivalent to 0.1 g of omalicycline), 100 mg of sucrose, sodium hydroxide for pH adjustment, and hydrochloric acid.

[0004] Tetracycline antibiotics contain acidic phenolic and enol hydroxyl groups and basic dimethylamino groups in their structure. These drugs are all amphoteric compounds. Therefore, tetracycline antibiotics are not stable under acidic or basic conditions and are prone to hydrolysis, producing isomer impurities. This leads to a significant decrease in the content of the preparation and affects clinical use. Therefore, the pH range of this product is strictly controlled, which is difficult to achieve in production.

[0005] Meanwhile, this product is sensitive to the solution temperature. Excessively high temperatures will significantly increase degradation impurities, while excessively low temperatures will easily cause the solution to freeze, significantly increasing energy consumption and production costs. Therefore, the preparation process must be strictly controlled within a narrow, specific range to avoid these problems.

[0006] Furthermore, the low collapse temperature of this product presents significant challenges in developing its freeze-drying process. Setting the primary drying temperature too high can easily lead to product collapse or result in substandard color and clarity after freeze-drying. Therefore, annealing is typically used to optimize the process. However, annealing significantly extends the pre-freezing time, thereby increasing energy consumption and prolonging the commercial production cycle.

[0007] CN118845678A discloses a lyophilized powder injection of omalicycline tosylate and its preparation method. The formulation has a high solid content, which, while beneficial for improving lyophilization efficiency, affects the solubility of raw materials and excipients during preparation and carries a high risk of poor reconstitution performance (reconstitution time, clarity and color, and insoluble particles). Furthermore, its high solution preparation temperature (15~30℃) may lead to a significant increase in degradation during the preparation process. Additionally, its preferred lyophilization process employs annealing, requiring multiple cooling rates of 5℃ / min, which places extremely high demands on the performance of the lyophilizer and is difficult to achieve in industrial production.

[0008] CN120000599A discloses a method for preparing omalicycline tosylate for injection. The solution preparation process requires controlling the temperature to 2-8℃ and the pH to be within the range of 4.0-4.4, which is difficult to control during production, indicating that the solution preparation and adjustment in this formula are quite demanding. Furthermore, this method requires controlling the vacuum level during freeze-drying to be relatively low and precisely controlled between 0.1-0.5 Pa, which places high demands on the performance of the freeze dryer and is not easily achieved in industrial production.

[0009] CN119258227A discloses an omalicycline tosylate formulation and its preparation method. The formulation mentions that pH adjusters include one or more of hydrochloric acid, acetic acid, citric acid, sodium hydroxide, sodium citrate, sodium phosphate, and sodium acetate. However, according to existing data, at pH 2-6, the dimethylamine at the C-4 position of tetracycline antibiotics readily undergoes reversible epimerization, generating a 4-position epimer (i.e., a 4-β isomer impurity). The presence of certain anions, such as phosphate, citrate, and acetate ions, can accelerate this isomerization. Therefore, this formulation carries a high risk of increasing isomer impurities, affecting drug quality. Furthermore, the freeze-drying process in this invention is complex, energy-intensive, and time-consuming, which is not conducive to commercial production.

[0010] In summary, the currently published patented formulations and freeze-drying processes have significant limitations: First, the pH and solution temperature control ranges are quite stringent, resulting in poor production reproducibility and posing a significant challenge to product quality and process control. Second, the freeze-drying process itself is complex, often requiring annealing, which is not only time-consuming and energy-intensive but also places higher demands on equipment performance, making it particularly unsuitable for commercial production. Summary of the Invention

[0011] One of the objectives of this invention is to provide a formulation of omalicycline tosylate for injection with better stability, which can maintain stability over a wider pH range and under mild solution preparation conditions, thereby significantly reducing the safety risks of clinical use.

[0012] The second objective of this invention is to provide a method for preparing an injectable omalicycline tosylate formulation. This method, by optimizing the freeze-drying process, effectively shortens the production cycle and reduces the stringent requirements on equipment performance (such as vacuum level).

[0013] The objective of this invention can be achieved through the following technical solutions:

[0014] In a first aspect, the present invention provides an injectable omalicycline tosylate formulation, comprising the following components by weight percentage (g / g):

[0015] Omacycline toluenesulfonate 3%~6%;

[0016] Stabilizer 0.1%~1.6%;

[0017] Sucrose 3%~8%;

[0018] pH adjuster to pH 3.0-6.0; and the remainder is water for injection.

[0019] The stabilizer is selected from sodium lactobionate, potassium chloride, sodium chloride, sodium citrate, mannitol, sodium metabisulfite, and anhydrous sodium sulfate.

[0020] In some specific embodiments of the present invention, sodium lactobionate, mannitol, potassium chloride, and sodium chloride are used.

[0021] In some specific embodiments of the present invention, the stabilizer is selected from sodium lactobionate and mannitol.

[0022] In some specific embodiments of the present invention, the stabilizer is sodium lactobionate; the amount of sodium lactobionate used is 0.2~1.6% by weight percentage (g / g).

[0023] In some specific embodiments of the present invention, the stabilizer is sodium lactobionate; the amount of sodium lactobionate used is 0.4~1.2% by weight percentage (g / g).

[0024] In some specific embodiments of the present invention, the stabilizer is sodium lactobionate; the amount of sodium lactobionate used is 0.4% by weight percentage (g / g).

[0025] In some specific embodiments of the present invention, the pH adjuster adjusts the pH to 4.0~5.5.

[0026] In this invention, the pH adjuster includes, but is not limited to, hydrochloric acid, sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate.

[0027] In some specific embodiments of the present invention, the pH adjuster is hydrochloric acid and / or sodium hydroxide.

[0028] In some specific embodiments of the present invention, the injectable omalicycline tosylate formulation comprises the following components, by weight percentage (g / g):

[0029] Omacycline tosylate 4.4%;

[0030] Sodium lactobionate 0.4%;

[0031] Sucrose 3.3%;

[0032] pH adjuster to pH 4.0-5.5; and the remainder is water for injection.

[0033] Secondly, the present invention also provides a method for preparing an injectable omalicycline tosylate formulation, comprising the following steps: under certain solution preparation temperature conditions, first mix omalicycline tosylate, stabilizer, sucrose, and water for injection, then adjust the pH, make up the volume, filter, and freeze dry to obtain the product.

[0034] In this invention, the solution preparation temperature is 5~25℃.

[0035] In some specific embodiments of the present invention, the solution preparation temperature is 8~20℃.

[0036] In this invention, the filtration includes using a filter membrane; the pore size of the filter membrane can be selected from 0.22 to 0.45 μm, preferably 0.22 μm.

[0037] In this invention, the freeze-drying process parameters used in the freeze-drying step are as follows:

[0038]

[0039] In some specific embodiments of the present invention, the freeze-drying process parameters used in the freeze-drying step are as follows:

[0040]

[0041] In some specific embodiments of the present invention, the freeze-drying process parameters used in the freeze-drying step are as follows:

[0042]

[0043] In some specific embodiments of the present invention, the freeze-drying process parameters used in the freeze-drying step are as follows:

[0044]

[0045] In some specific embodiments of the present invention, the freeze-drying process parameters used in the freeze-drying step are as follows:

[0046]

[0047] In some specific embodiments of the present invention, the preparation method of omalicycline tosylate for injection includes the following steps:

[0048] (1) Add 70% water for injection beforehand, and control the temperature of the water for injection to 5~25℃;

[0049] (2) Add stabilizer, omalicycline tosylate and sucrose to water for injection in sequence, and stir thoroughly until completely dissolved;

[0050] (3) Add a pH adjuster to (2) to adjust the pH to 3.0~6.0;

[0051] (4) Add water for injection to make up the volume, stir evenly, and then filter through a 0.22μm filter membrane. Maintain the temperature of the drug solution at 5~25℃.

[0052] (5) Fill the filtered solution from (4) into vials and partially stopper them;

[0053] (6) Perform freeze-drying according to the following freeze-drying process:

[0054]

[0055] (7) Pressurize the nitrogen gas to -0.04 MPa ~ -0.06 MPa, then plug and cap it.

[0056] The beneficial effects of this invention are:

[0057] (1) By optimizing the formulation of omalcycline tosylate for injection, this invention adds stabilizers such as sodium lactobionate, potassium chloride, sodium citrate, mannitol, sodium metabisulfite, and anhydrous sodium sulfate to the reference formulation, which can ensure better product quality properties at higher solution temperatures and a wider pH range, while also effectively reducing the generation of degradation impurities in the formulation.

[0058] (2) After adding stabilizers, the present invention can significantly improve the disadvantage of long freeze-drying cycle by optimizing the freeze-drying process. Moreover, the freeze-drying process is easy to reproduce and has low requirements for equipment performance. In commercial production, it can effectively shorten the freeze-drying cycle and save energy. Attached Figure Description

[0059] Figure 1 The image shows the appearance of the lyophilized formulation in sample group 23.

[0060] Figure 2 The image shows the appearance of the lyophilized formulation in sample group 25.

[0061] Figure 3 This is an image of the lyophilized formulation of sample group 27. Detailed Implementation

[0062] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. All features disclosed in this specification, or steps in all disclosed methods or processes, except for mutually exclusive features and / or steps, can be combined in any way.

[0063] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0064] Unless otherwise specified in the following embodiments, the techniques or conditions described in the literature in this field or in accordance with the product instructions shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products. Specific experimental methods not mentioned in the following embodiments are generally performed using conventional experimental methods.

[0065] In this application, the detection of related substances in the omalicycline tosylate product was performed using HPLC. The test conditions were as follows: HPLC determination was conducted using an Agilent 1260DAD (or Shimadzu LC 2030) liquid chromatograph. The determination was performed according to the high-performance liquid chromatography method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512):

[0066] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Phenomenex Gemini 4.6mm × 250mm, 5μm or equivalent column); mobile phase A was potassium dihydrogen phosphate buffer (13.6g potassium dihydrogen phosphate dissolved in 900mL water, pH adjusted to 6.45–6.50 with 10mol / L sodium hydroxide solution, diluted to 1000mL with water, then dissolved in 0.5g tetrabutylammonium hydrogen sulfate and 0.4g disodium ethylenediaminetetraacetate, and mixed well)-acetonitrile, and mobile phase B was potassium dihydrogen phosphate buffer-acetonitrile, with gradient elution according to the table below; flow rate was 1.5mL / min; column temperature was 35℃; detection wavelength was 280nm; injection volume was 10μL; sample tray temperature was 5℃.

[0067]

[0068] System suitability requirements: The signal-to-noise ratio of the main peak height in the chromatogram of the impurity reference solution should not be less than 100.

[0069] Limits: If impurity peaks are present in the chromatogram of the test solution, the content of each impurity shall be calculated based on the peak area and shall comply with the regulations.

[0070] Moisture determination: Take this product and determine the moisture content according to the method for moisture determination (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0832, Method 1). It should meet the requirements.

[0071] Example 1: Effect of stabilizer dosage on intermediate products of omalicycline tosylate lyophilized formulation

[0072] (1) Preparation of intermediate products of omalcycline tosylate lyophilized formulation

[0073] The preparation of the intermediate product of omalcycline tosylate lyophilized formulation includes the following steps: add water for injection to a dry and clean container, control the water temperature at 20℃, then add 1.31g of omalcycline tosylate, 1g of sucrose, and stabilizer (sodium lactobionate), and stir until completely dissolved. Adjust the pH to 4.6 with a pH adjuster, add water for injection to a final volume of 30mL, stir thoroughly to mix, and filter to obtain the final product.

[0074] The samples were divided into 6 groups according to the amount of sodium lactobionate used: control group (0g), sample group 1 (0.06g, 0.28mmol), sample group 2 (0.12g, 0.55mmol), sample group 3 (0.24g (1.10mmol), sample group 4 (0.36g (1.65mmol)) and sample group 5 (0.48g, 2.20mmol).

[0075] (2) Detection of intermediate products of omalcycline tosylate lyophilized formulation

[0076] The filtered drug solution (intermediate product) was placed at 20℃, and the relevant substances in the solution were tested at 0h and 10h respectively. The test results are shown in Table 1.

[0077] Table 1. Effect of stabilizer addition amount on intermediate products of omalicycline tosylate lyophilized formulation

[0078]

[0079] From Table 1, we can obtain:

[0080] (1) The effect of the presence or absence of stabilizer on stability

[0081] Comparing the control group 1 (without stabilizer) with the sample groups (1-5) with stabilizers: After 10 hours, the 4-β isomer increased by 0.37% and the total impurities increased by 0.37% in control group 1; while in all sample groups containing stabilizers, the increase values ​​of related substances were much lower than those in the control group. This indicates that adding stabilizers can significantly improve the stability of the intermediate product solution.

[0082] (2) The effect of stabilizer "addition amount" on stability

[0083] By observing sample groups with different amounts of stabilizer added (0.06g, 0.12g, 0.24g, 0.36g, 0.48g), it can be seen that:

[0084] ① The amount of stabilizer added affects the initial product quality of intermediate products: As the amount of stabilizer added increases, the initial levels of 4-β isomers and total impurities at 0h in sample groups (1-5) both show an increasing trend. When the amount of stabilizer added is ≤0.36g, the initial impurity level is basically the same as that of the control group without stabilizer, indicating that within this range of stabilizer addition, the stabilizer has almost no significant impact on the initial quality properties of the product. However, when the amount added is >0.36g (sample group 5), the initial impurity level (0h) of the stabilizer-added group is significantly higher than that of the control group without stabilizer, with 4-β isomers increasing by 0.29% and total impurities increasing by 0.26%, indicating a significant deterioration in product quality properties. Analysis suggests that this may be because sodium lactobionate itself is weakly alkaline, and as the amount added increases, the pH of the solution rises, which may lead to an increase in degradation impurities in the solution before pH adjustment.

[0085] ② The amount of stabilizer added affects the product's stability trend: To assess the impact of stabilizer addition on impurity levels, this invention compared the growth of product impurities under different stabilizer addition amounts. Based on the impurity growth of all sample groups within 10 hours, when the stabilizer addition amount was ≥0.12g, the growth values ​​of isomer impurities and total impurities in the intermediate product solution were both at low levels (≤0.09%). However, when the addition amount was 0.06g, isomer impurities and total impurities increased by 0.22% and 0.20% respectively, indicating poor product stability. This suggests that the stabilizer may not be effective due to insufficient concentration. Therefore, to ensure the stabilizer's effectiveness, the amount added should be at least 0.12g.

[0086] In summary, the addition of stabilizers can significantly improve stability. Considering the actual production conditions of pharmaceuticals, in order to obtain both a good initial product quality (0h) and a product with slower impurity growth and better stability during the production process, it was determined that the sample quality attributes are optimal when the amount of stabilizer added is in the range of 0.12g to 0.36g.

[0087] Example 2: Effect of different stabilizers on omalicycline tosylate formulation

[0088] (1) Preparation of lyophilized omalicycline tosylate for injection

[0089] The preparation of lyophilized omalicycline tosylate for injection includes the following steps: add water for injection to a dry and clean container, control the water temperature at 20℃, then add 1.31g of omalicycline tosylate, 1g of sucrose, and a certain amount of stabilizer, stir until completely dissolved, adjust the pH to 4.6 with a pH adjuster, add water for injection to a final volume of 30mL, filter, fill with half-stopper, and lyophilize to obtain the final product.

[0090] The samples were divided into 14 groups according to different stabilizers: Group 6 (containing 0.12g sodium lactobionate) before lyophilization / Group 13 after lyophilization; Group 7 (containing 0.10g mannitol) before lyophilization / Group 14 after lyophilization; Group 8 (containing 0.04g potassium chloride) before lyophilization / Group 15 after lyophilization; Group 9 (containing 0.14g sodium citrate) before lyophilization / Group 16 after lyophilization; Group 10 (containing 0.03g sodium chloride) before lyophilization / Group 17 after lyophilization; Group 11 (containing 0.11g sodium metabisulfite) before lyophilization / Group 18 after lyophilization; and Group 12 (containing 0.17g anhydrous sodium sulfate) before lyophilization / Group 19 after lyophilization.

[0091] No stabilizers were added to control group 2 (before freeze-drying) and control group 3 (after freeze-drying), and the rest of the formulation and process were the same as above.

[0092] The process parameters involved in the freeze-drying process are shown in Table 2.

[0093] Table 2 Freeze-drying process parameters

[0094]

[0095] (2) Detection of intermediate products of omalcycline tosylate lyophilized formulation

[0096] Before lyophilization, the drug solution was taken and placed at a temperature of 20℃. The relevant substances in the solution were tested at 0h and 10h, respectively. The test results are shown in Table 3.

[0097] Table 3. Effects of different stabilizers on intermediate products of omalicycline tosylate lyophilized formulations

[0098]

[0099] As shown in Table 3, compared with the group without stabilizer (control group 2), all seven selected stabilizers effectively controlled the growth of impurities within 10 hours, with the growth values ​​of 4-β isomer impurities and total impurities remaining at low levels. To screen for superior stabilizers, a comprehensive evaluation of initial impurity levels (including 4-β isomers and total impurities) and impurity growth during storage was conducted. The sample groups containing sodium lactobionate, mannitol, and potassium chloride (sample groups 6-8) showed the best overall performance: these groups had low initial 4-β isomer levels (≤2.77%) and total impurity levels (≤4.02%), and the growth values ​​of impurities were significantly lower than those in the control group without stabilizers (4-β isomers ≤0.08%, total impurities ≤0.04%), laying a solid foundation for high-quality products and meeting the requirements for maintaining high-level quality control during pharmaceutical production.

[0100] In contrast, while the addition of sodium metabisulfite (sample group 11) effectively controlled the growth of 4-β isomers, its control of total impurities was poor, with a significant increase of 0.15%. The sodium citrate group (sample group 9) had relatively high initial levels of both 4-β isomers and total impurities, with relatively significant increases; 4-β isomers and total impurities increased by 0.06% and 0.11%, respectively. Although both sodium chloride group (sample group 10) and anhydrous sodium sulfate (sample group 12) effectively controlled the growth levels of 4-β isomers and total impurities, their initial 4-β isomer levels were relatively high (2.79% and 2.83%, respectively), making them unsuitable as preferred stabilizers. Therefore, sodium lactobionate, mannitol, and potassium chloride are the preferred stabilizers.

[0101] (3) Stability study of ometracycline tosylate lyophilized formulation for injection

[0102] The freeze-dried formulation samples were subjected to stability studies at 40℃ and 60℃, and the results are shown in Table 4.

[0103] Table 4. Results of experiments on the effects of high temperature on lyophilized toluenesulfonate formulations for injection.

[0104]

[0105]

[0106] As shown in Table 4, compared with the control group (3), the increase in impurities in the finished products after adding each of the seven stabilizers was significantly better than that in the control group (3). Furthermore, after adding stabilizers, the moisture content of the finished products did not exceed that of the control group (3), and the moisture content showed a decreasing trend after adding some stabilizers (sodium lactobionate, mannitol, potassium chloride, and sodium chloride).

[0107] To screen for superior stabilizers, it is necessary to comprehensively evaluate data such as initial impurity levels (including 4-β isomers and total impurities) and the growth trends of each impurity during the stabilization period. Analysis of the data in Table 4 shows that the sample groups containing sodium lactobionate, mannitol, potassium chloride, and sodium chloride (sample groups 13-15 and 17) performed best overall. These groups exhibited low impurity levels at both 40℃ and 60℃. At 40℃, the growth value of 4-β isomers was ≤0.15%, and the growth value of total impurities was ≤0.23%; at 60℃, the growth value of 4-β isomers was ≤1.44%, and the growth value of total impurities was ≤1.51%. In contrast, the group without stabilizer (control group 3) showed a growth value of 0.25% for 4-β isomers and 0.27% for total impurities at 40℃; and a growth value of 1.84% for 4-β isomers and 1.85% for total impurities at 60℃.

[0108] In contrast, although sodium citrate (sample group 16), sodium metabisulfite (sample group 18), and anhydrous sodium sulfate (sample group 19) could all effectively control the growth levels of 4-β isomers and total impurities, their initial total impurity levels were relatively high (≥4.10), and they were not preferred stabilizers.

[0109] Therefore, considering the time limit test of the intermediate product and the stability test of the formulation in Example 2, sodium lactobionate, mannitol and potassium chloride are preferred stabilizers.

[0110] Example 3: Effect of solution preparation temperature on omalicycline tosylate formulation

[0111] (1) Preparation of intermediate products of omalcycline tosylate for injection

[0112] The preparation of the intermediate product of lyophilized tomatine tosylate for injection includes the following steps: Add water for injection to a dry and clean container, control the water temperature (i.e., the solution preparation temperature) at 20℃, then add 1.31g of olmatine tosylate, 1g of sucrose, and stabilizer (0.12g of sodium lactobionate), and stir until completely dissolved. Adjust the pH to 4.6 with a pH adjuster, add water for injection to a final volume of 30mL, stir thoroughly to mix, filter, and obtain sample group 20.

[0113] Control group 4 did not include a stabilizer in its formulation, and the other formulations and process steps were the same as described above; control group 5 did not include a stabilizer in its formulation, and the solution preparation temperature was 8°C, and the other formulations and process steps were the same as described above.

[0114] (2) Detection of intermediate products of omalcycline tosylate for injection

[0115] The mixed drug solution (intermediate product) was stored at the corresponding solution preparation temperature for 0h and 10h, respectively, and the relevant substances were tested. The test results are shown in Table 5.

[0116] Table 5. Effect of solution preparation temperature on intermediate products of omalicycline tosylate lyophilized formulation

[0117]

[0118] As shown in Table 5, after the addition of the stabilizer, the growth of related substances in the drug solution prepared at 20°C was significantly better than that in control group 4, and the quality properties were comparable to those in control group 5. Therefore, the stability of the drug solution increased significantly after the addition of the stabilizer. This also shows that after the addition of the stabilizer, the production process of this preparation can be carried out in a wider temperature range without the need for low temperature conditions.

[0119] Example 4: Effect of pH range on omalicycline tosylate formulation

[0120] (1) Preparation of lyophilized omalicycline tosylate for injection

[0121] The preparation of lyophilized omalicycline tosylate for injection includes the following steps: Water for injection is added to a dry, clean container, and the water temperature is controlled at 20°C. Then, 1.31 g of omalicycline tosylate, 1 g of sucrose, and 0.12 g of sodium lactobionate are added and stirred until completely dissolved. The pH is adjusted to 4.0 and 4.6 using a pH adjuster. Water for injection is added to a final volume of 30 mL, and the mixture is thoroughly stirred and mixed. The mixture is then filtered, partially stoppered, and lyophilized to obtain the final product. Sample group 21 has a pH adjusted to 4.0, and sample group 22 has a pH adjusted to 4.6. The lyophilization process parameters are the same as in Example 2.

[0122] In control group 6, the pH was adjusted to 5.5, and the other formulations and process steps were the same as described above; in control group 7, no sodium lactobionate stabilizer was added, and the other formulations and process steps were the same as described above.

[0123] (2) Stability study of ometracycline tosylate lyophilized formulation for injection

[0124] The stability of the formulation samples was investigated at 40℃ and 60℃, and the results are shown in Table 6.

[0125] Table 6. Effects of different pH values ​​on lyophilized formulations of omalicycline tosylate for injection.

[0126]

[0127] Table 6 shows that after adding sodium lactobionate, there was no significant difference in the growth of related substances in the finished products with pH values ​​adjusted to 4.0–5.5. However, in the formulation without added sodium lactobionate, the related substances increased significantly at both 40°C and 60°C after adjusting the pH to 5.5. Therefore, it is preferable to add a stabilizer to the original formulation, which not only improves the stability of the formulation itself but also expands the pH control range and reduces production risks.

[0128] Example 5: Optimization of the lyophilization process for omalicycline tosylate for injection

[0129] The preparation of lyophilized omalicycline tosylate for injection includes the following steps: add water for injection to a dry and clean container, control the water temperature at 20℃, then add 1.31g of omalicycline tosylate, 1g of sucrose, and a stabilizer, and stir until completely dissolved. Adjust the pH to 4.6 with a pH adjuster, bring the volume to 30mL with water for injection, stir thoroughly to mix, filter, fill with half stopper, and lyophilize to obtain the final product.

[0130] To determine the optimal freeze-drying process parameters, a screening of freeze-drying process parameters was conducted, including three different freeze-drying processes, as shown in Tables 7 to 9.

[0131] In this embodiment, the samples are grouped as follows based on the different stabilizers and freeze-drying processes:

[0132] Sample group 23 was prepared using the first freeze-drying process with the addition of 0.12g sodium lactobionate stabilizer (Table 7).

[0133] Sample group 24 was prepared using the first freeze-drying process with the addition of 0.10g mannitol stabilizer (Table 7).

[0134] Sample group 25 was prepared using the second freeze-drying process with the addition of 0.12g sodium lactobionate stabilizer (Table 8).

[0135] Sample group 26 was prepared using the second freeze-drying process with the addition of 0.10g mannitol stabilizer (Table 8).

[0136] Sample group 27 was prepared using the second freeze-drying process with the addition of 0.12g sodium lactobionate stabilizer (Table 9).

[0137] Sample group 28 was prepared using the third freeze-drying process with the addition of 0.10g mannitol stabilizer (Table 9).

[0138] Control group 8, without stabilizer, uses the first freeze-drying process (Table 7).

[0139] Control group 9, without stabilizer, used the second freeze-drying process (Table 8).

[0140] The control group 10 did not contain stabilizers, and the third freeze-drying process was used (Table 9).

[0141] Table 7. Parameters for the first type of freeze-drying process

[0142]

[0143] Table 8. Parameters for the second type of freeze-drying process

[0144]

[0145] Table 9. Parameters for the third type of freeze-drying process

[0146]

[0147] The stability of the formulation samples was investigated at 40℃ and 60℃, and the results are shown in Table 10.

[0148] Table 10. Results of Experiments on High Temperature Influence Factors on Omacycline Tosylate Lyophilized Formulation for Injection

[0149]

[0150]

[0151] According to the results in the table above, under the three different freeze-drying conditions, the freeze-dried formulations obtained by adding a stabilizer (such as sodium lactobionate) to the omalicycline tosylate solution were all intact orange cake-like powder cakes. Figures 1-3 Furthermore, no significant collapse was observed in any of the three formulations. The moisture content of the three formulations showed no significant difference, and based on the results of related substance testing at 40℃ and 60℃ for different times, the impurity growth of the three formulations showed no significant difference. Therefore, the freeze-drying process parameters mentioned in this invention can yield formulations that meet the requirements. Compared with previously disclosed patents, this freeze-drying process does not require extremely high vacuum control precision and heating / cooling rates, reducing the requirements for high-performance equipment; this freeze-drying process only includes three procedures, effectively reducing potential operational risks and complexities in intermediate steps; this freeze-drying process consistently and stably guarantees the quality attributes of the product. Therefore, the freeze-drying process developed in this invention can meet the production requirements of conventional freeze dryers, reducing reliance on high-performance production equipment and improving production economics.

[0152] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. 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. An injectable omalicycline tosylate formulation, characterized in that, It comprises the following components by weight percentage (g / g): Omacycline toluenesulfonate 3%~6%; Stabilizer 0.1%~1.6%; Sucrose 3%~8%; Adjust the pH to 3.0-6.0 with a pH adjuster; and the remainder is water for injection; The stabilizer is selected from sodium lactobionate, potassium chloride, sodium chloride, sodium citrate, mannitol, sodium metabisulfite, and anhydrous sodium sulfate.

2. The omalicycline tosylate injection formulation as described in claim 1, characterized in that, The stabilizer is selected from sodium lactobionate, mannitol, potassium chloride, and sodium chloride; further, the stabilizer is selected from sodium lactobionate and mannitol.

3. The omalicycline tosylate injection formulation as described in claim 1 or 2, characterized in that, The stabilizer is sodium lactobionate; the amount of sodium lactobionate used is 0.2-1.6% by weight percentage (g / g), preferably 0.4-1.2%, and more preferably 0.4%.

4. The omalicycline tosylate injection formulation as described in claim 1, characterized in that, The pH adjuster adjusts the pH to 4.0~5.

5.

5. The omalicycline tosylate injection formulation according to any one of claims 1 to 4, characterized in that, It comprises the following components by weight percentage (g / g): Omacycline tosylate 4.4%; Sodium lactobionate 0.4%; Sucrose 3.3%; pH adjuster to pH 4.0-5.5; and the remainder is water for injection.

6. A method for preparing an injectable omalicycline tosylate formulation as described in any one of claims 1 to 5, characterized in that, The process includes the following steps: Under certain solution preparation temperature conditions, first mix omalicycline tosylate, stabilizer, sucrose, and water for injection, then adjust the pH, make up to volume, filter, and freeze dry to obtain the final product.

7. The preparation method according to claim 6, characterized in that, The solution preparation temperature is 5~25℃, preferably 8~20℃.

8. The preparation method according to claim 6, characterized in that, The freeze-drying process parameters used in the freeze-drying step are as follows: 。 9. The preparation method according to claim 6 or 8, characterized in that, The freeze-drying process parameters used in the freeze-drying step are as follows: 。

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