Ombalecycline tosylate preparation and preparation method thereof

Abstract

The invention relates to an omagazines tosylate preparation and a preparation method thereof. The preparation method comprises the following steps: mixing and dissolving ombracin tosylate, a pH regulator and an excipient to obtain an ombracin tosylate dissolved solution; and freeze-drying the omagazines tosylate dissolving solution to obtain the omagazines tosylate preparation. By controlling the temperature, the pH and the freeze-drying process of the prepared solution, the high-quality omagazines tosylate preparation is obtained, the impurity content is low, the adverse effects of illumination and high temperature on the preparation can be improved, the stability of the preparation in the transportation, storage and use processes is greatly improved, the safety of the omagazines tosylate preparation is improved, and the application prospect is wide. The medicine has obvious clinical advantages.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, in particular to an omadacycline tosylate preparation and a preparation method thereof. Background Art

[0002] Omadacycline tosylate (API), with the chemical name (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-(2,2-dimethylpropylaminomethyl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide p-toluenesulfonate, is a new tetracycline drug specifically designed to overcome tetracycline resistance and improve broad-spectrum antibacterial activity, such as bacterial infections caused by Gram-positive, Gram-negative, atypical and many other pathogens. It can be clinically used to treat community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults. Omadacycline is a 9-aminomethylcycline antibiotic, a yellow solid, which is particularly unstable when exposed to air, light and moisture. Therefore, under solid conditions, omadacycline must be stored below 0°C, or even below -18°C, and light, air and moisture must be controlled, which makes transportation, storage and preparation difficult.

[0003] The prior art prepares omadacycline into omadacycline tosylate, i.e., omadacycline tosylate, to improve its stability for storage, transportation and preparation. However, since omadacycline tosylate decomposes into toluenesulfonic acid and omadacycline with poor stability in the aqueous solution state, degradation products such as isomeric impurities represented by 4Beta isomer impurities and 4-keto impurities and oxidative impurities are easily generated. In particular, 4Beta isomer impurities will affect the content of API, making it impossible to maintain the dosage or drug concentration required for treatment, affecting the efficacy, and may even aggravate toxic side effects such as nausea and vomiting.

[0004] The currently marketed solid oral preparations and lyophilized preparations for injection of omadacycline tosylate both have certain disadvantages. The dosage of oral preparations is huge, and the gastrointestinal side effects such as nausea and vomiting are extremely large, which may even affect the patient's medication, and the compliance of medication is poor; lyophilized preparations for injection can reduce gastrointestinal side effects, but the current industrial preparations have a high water content, high impurities, and poor stability, which limits their application in medical treatment. Summary of the invention

[0005] Therefore, the technical problem to be solved by the present invention is to overcome the problem that omadacycline tosylate in the prior art omadacycline tosylate preparation is easily degraded and has poor stability.

[0006] In order to solve the above technical problems, the present invention provides an omadacycline tosylate preparation and a preparation method thereof. The present invention controls the temperature during liquid preparation, the pH of the liquid and combines a specific freeze-drying process to suppress the formation of 4Beta isomer impurities and 4-keto impurities to the greatest extent, reduces the degradation of omadacycline tosylate during storage and transportation, and improves the stability of the drug.

[0007] The first object of the present invention is to provide a method for preparing an omadacycline tosylate preparation, comprising the following steps:

[0008] S1, mixing and dissolving omadacycline tosylate, a pH adjuster and an excipient to obtain an omadacycline tosylate solution;

[0009] S2, freeze-drying the omadacycline tosylate solution to obtain the omadacycline tosylate preparation;

[0010] Wherein, the temperature during dissolution in step S1 is 2-8°C.

[0011] Furthermore, the pH during the dissolution in step S1 is 3.6-4.6.

[0012] Furthermore, the excipient in step S1 is selected from one or more of lactose, mannitol, dextran, glucose, sucrose, povidone, and citric acid.

[0013] Furthermore, in step S2, the freeze-drying includes pre-freezing, primary drying and secondary drying.

[0014] Further, the pre-freezing is divided into three stages, wherein:

[0015] The temperature of the first stage is -40℃~-50℃, and the time is 110-130 minutes;

[0016] The temperature of the second stage is -10℃~0℃, and the time is 20-80 minutes;

[0017] The temperature of the third stage is -40°C to -50°C, and the time is 200-280 minutes.

[0018] Furthermore, an annealing process is used in the pre-freezing stage, and the crystals inside the product will be rearranged to form a more stable crystal structure, making the molecular structure of the sample more uniform, thereby eliminating the original stress and defects, and making the freeze-dried sample more stable.

[0019] Further, the primary drying includes nine stages, wherein:

[0020] The temperature of the first stage is -40℃~-50℃, the time is 50-70 minutes, and the vacuum degree is 150-250mTorr;

[0021] The temperature of the second stage is -15℃~-25℃, the time is 50-70 minutes, and the vacuum degree is 150-250mTorr;

[0022] The temperature of the third stage is -5℃~-15℃, the time is 500-700 minutes, and the vacuum degree is 150-250mTorr;

[0023] The temperature of the fourth stage is 0℃~-10℃, the time is 100-140 minutes, and the vacuum degree is 150-250mTorr;

[0024] The temperature of the fifth stage is 5°C to -5°C, the time is 50-70 minutes, and the vacuum degree is 150-250mTorr;

[0025] The temperature of the sixth stage is 0°C to 10°C, the time is 40-80 minutes, and the vacuum degree is 150-250mTorr;

[0026] The temperature of the seventh stage is 10°C to 20°C, the time is 40-80 minutes, and the vacuum degree is 150-250mTorr;

[0027] The temperature of the eighth stage is 20°C to 30°C, the time is 40-80 minutes, and the vacuum degree is 150-250mTorr;

[0028] The temperature of the ninth stage is 20° C. to 50° C., the time is 20-40 minutes, and the vacuum degree is 40-60 mTorr.

[0029] Furthermore, in the first drying, the temperature must be slowly raised to a temperature slightly below the eutectic point (about -7°C) for long-term freeze-drying to prevent the product from "collapsing", and then the temperature is slowly raised and the vacuum degree is adjusted to the temperature and vacuum degree of the second freeze-drying to prevent the product from cracking, too dark color, and uneven color.

[0030] Furthermore, the secondary drying is carried out at a temperature of 20-50° C. and for a time of 360-480 minutes.

[0031] Furthermore, the vacuum degree of the secondary drying is 40-60 mTorr.

[0032] The second object of the present invention is to provide an omadacycline tosylate preparation obtained by the above preparation method.

[0033] Beneficial effects of the present invention:

[0034] The present invention controls the preparation process of the omadacycline tosylate preparation, so that the obtained omadacycline tosylate preparation has low moisture content and less impurity content, and can improve the adverse effects of light and high temperature on the preparation, thereby greatly improving the stability of the preparation during transportation, storage and use, and improving the safety of the omadacycline tosylate preparation, thereby having obvious clinical advantages. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below according to specific embodiments of the present invention in conjunction with the accompanying drawings, wherein

[0036] Figure 1 is the molecular structural formula of omadacycline;

[0037] Figure 2 is the molecular structural formula of omadacycline tosylate;

[0038] Figure 3 It is the molecular formula of the 4Beta isomer impurity;

[0039] Figure 4 It is the molecular structure formula of 4-keto impurity. DETAILED DESCRIPTION

[0040] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0041] Example 1: Effect of Preparation Temperature on Omadacycline Tosylate Preparations

[0042] (1) Liquid preparation

[0043] Control 180 mL of water for injection in a specific temperature range (2-8°C / room temperature (25°C)), dissolve 10.0 g of sucrose in water, add hydrochloric acid and / or sodium hydroxide solution, adjust the pH of the solution to 4.2, then add 13.1 g of omadacycline tosylate, stir to dissolve, add water for injection to 300 mL, and maintain the specific temperature (2-8°C / room temperature (25°C)) for 2 hours.

[0044] (2) Filling

[0045] Dispense the drug solution into vials at 3 mL / vial and half-stopper them.

[0046] (3) Freeze-drying

[0047] Transfer the half-stoppered sample to a lyophilizer; lyophilize according to the following parameters.

[0048] Table 1 Parameters related to the freeze-drying stage of Example 1

[0049]

[0050] (4) Unpacking and capping

[0051] After the freeze-drying is completed, the vacuum stopper is pressed and the sample is taken out of the box, and the freeze-dried preparation for injection is ready. The different samples obtained after freeze-drying are analyzed by HPLC, and the results are shown in the table below.

[0052] Table 2 HPLC analysis results of samples obtained in Example 1

[0053]

[0054]

[0055] The results in Table 2 show that the degradation products of the freeze-dried solution prepared at a preparation temperature of 2-8°C are significantly lower than those prepared at room temperature (25°C). Therefore, a preparation temperature of 2-8°C is preferred.

[0056] Example 2: Effect of pH of the preparation on omadacycline tosylate preparations

[0057] (1) Liquid preparation

[0058] Prepare 180 mL of water for injection at a temperature range of 2-8°C, dissolve 10.0 g of sucrose in water, add hydrochloric acid and / or sodium hydroxide solution, adjust the pH of the solution to a specific value (3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8), then add 13.1 g of omadacycline tosylate, stir to dissolve, and add water for injection to 300 mL.

[0059] (2) Filling

[0060] Dispense the drug solution into vials at 3 mL / vial and half-stopper them.

[0061] (3) Freeze-drying

[0062] Transfer the half-stoppered sample to a lyophilizer; lyophilize according to the following parameters.

[0063] Table 3 Parameters related to the freeze-drying stage of Example 2

[0064]

[0065] (4) Unpacking and capping

[0066] After freeze-drying, the freeze-dried preparation for injection is completed.

[0067] Samples with different pH values ​​were prepared according to the above method, and their acidity and HPLC-related substance analyses were performed. The results are shown in the table below.

[0068] Table 4 Acidity of samples obtained in Example 2 and HPLC related substance analysis results

[0069]

[0070] The results in Table 4 show that the 4Beta isomer impurities and total impurities of the freeze-dried finished products with the solution pH adjusted to 4.0 and 4.2 are at a low level, and after high temperature and light exposure, they are also lower than other samples. Therefore, it is preferred that the pH of the drug solution be adjusted to 4.0-4.2.

[0071] Example 3: Effect of lyophilization on omadacycline tosylate formulations

[0072] (1) Liquid preparation:

[0073] Prepare 180 mL of water for injection at a temperature range of 2-8°C, dissolve 10.0 g of sucrose in water, add hydrochloric acid and / or sodium hydroxide solution to adjust the pH of the solution to 4.1, then add 13.1 g of omadacycline tosylate, stir to dissolve, and add water for injection to 300 mL.

[0074] (2) Filling

[0075] Dispense the drug solution into vials at 3 mL / vial and half-stopper them.

[0076] (3) Freeze-drying

[0077] Transfer the half-stoppered sample to the freeze dryer; perform freeze drying according to the parameters corresponding to the corresponding batch number below.

[0078] Table 5 Freeze-drying related parameters of Example 3

[0079]

[0080] (4) Unpacking and capping

[0081] After freeze-drying, the freeze-dried preparation for injection is completed.

[0082] Different samples prepared according to the above method were subjected to HPLC related substance analysis and water content detection. The results are shown in the table below.

[0083] Table 6 HPLC related substance analysis and moisture detection results of the samples obtained in Example 3

[0084]

[0085] The results in Table 6 show that the moisture content of samples 3-1 to 3-3 is basically the same, and the level of related substances in sample 3-1 is slightly better than that in samples 3-2 and 3-3. Therefore, the freeze-drying process corresponding to sample 3-1 is preferred.

[0086] Comparative Example 1

[0087] The marketed omadacycline tosylate injection preparation with batch number 6230106 was selected as comparative example 1.

[0088] Comparative Example 2

[0089] The marketed omadacycline tosylate injection preparation with batch number 6230402 was selected as comparative example 2.

[0090] Three batches of samples, namely, sample 4, sample 5 and sample 6, were prepared by continuously adopting the conditions of liquid preparation temperature of 2-8°C, adjusting the pH of the liquid to 4.0-4.2 and freeze-drying of sample 3-1 in Table 5. The samples of comparative examples 1 and 2 and sample 4, sample 5 and sample 6 were subjected to HPLC related substance analysis and water content detection.

[0091] Table 7 HPLC analysis of related substances and water content of commercially available preparations and preparations of the present invention

[0092]

[0093]

[0094]

[0095] The results in Table 7 show that compared with Comparative Examples 1 and 2, the omadacycline tosylate preparation of the present invention obtained by controlling the temperature, pH of the solution and the freeze-drying process has low moisture content, fewer impurities, and can improve the adverse effects of light and high temperature on the preparation.

[0096] Obviously, the above embodiments are merely examples for clear explanation and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A method for preparing an omadacycline tosylate preparation, characterized in that: The following steps are involved: S1, mixing and dissolving omadacycline tosylate, a pH adjuster, an excipient and a solvent to obtain an omadacycline tosylate solution; S2, freeze-drying the omadacycline tosylate solution to obtain the omadacycline tosylate preparation; Wherein, the temperature during dissolution in step S1 is 2-8°C.

2. The preparation method according to claim 1, characterized in that: The pH during the dissolution in step S1 is 3.6-4.

6.

3. The preparation method according to claim 1, characterized in that: The pH adjuster in step S1 includes one or more of hydrochloric acid, acetic acid, citric acid, sodium hydroxide, sodium citrate, sodium phosphate, and sodium acetate.

4. The preparation method according to claim 1, characterized in that: The excipient in step S1 is selected from one or more of lactose, mannitol, dextran, glucose, sucrose, povidone, and citric acid.

5. The preparation method according to claim 1, characterized in that: The freeze-drying in step S2 includes pre-freezing, primary drying and secondary drying.

6. The preparation method according to claim 5, characterized in that: The pre-freezing is divided into three stages, wherein: The temperature of the first stage is -40℃~-50℃, and the time is 110-130 minutes; The temperature of the second stage is -10℃~0℃, and the time is 20-80 minutes; The temperature of the third stage is -40°C to -50°C, and the time is 200-280 minutes.

7. The preparation method according to claim 5, characterized in that: The primary drying includes nine stages, wherein The temperature of the first stage is -40℃~-50℃, the time is 50-70 minutes, and the vacuum degree is 150-250mTorr; The temperature of the second stage is -15℃~-25℃, the time is 50-70 minutes, and the vacuum degree is 150-250mTorr; The temperature of the third stage is -5℃~-15℃, the time is 500-700 minutes, and the vacuum degree is 150-250mTorr; The temperature of the fourth stage is 0℃~-10℃, the time is 100-140 minutes, and the vacuum degree is 150-250mTorr; The temperature of the fifth stage is 5°C to -5°C, the time is 50-70 minutes, and the vacuum degree is 150-250mTorr; The temperature of the sixth stage is 0°C to 10°C, the time is 40-80 minutes, and the vacuum degree is 150-250mTorr; The temperature of the seventh stage is 10°C to 20°C, the time is 40-80 minutes, and the vacuum degree is 150-250mTorr; The temperature of the eighth stage is 20°C to 30°C, the time is 40-80 minutes, and the vacuum degree is 150-250mTorr; The temperature of the ninth stage is 20° C. to 50° C., the time is 20-40 minutes, and the vacuum degree is 40-60 mTorr.

8. The preparation method according to claim 5, characterized in that: The temperature of the secondary drying is 20-50° C., and the time is 200-300 minutes; the vacuum degree of the secondary drying is 40-60 mTorr.

9. The preparation method according to claim 1, characterized in that: The solvent in step S1 includes water.

10. The omadacycline tosylate preparation obtained by the preparation method according to any one of claims 1 to 9.

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