Ombalecycline tosylate preparation for injection and preparation method thereof

Abstract

The invention discloses an omagazines tosylate preparation for injection and a preparation method of the omagazines tosylate preparation, and relates to the technical field of pharmaceutical preparations. The invention relates to an omagazines tosylate preparation for injection, which is prepared from the following raw materials in parts by weight: 128 to 134 parts of omagazines tosylate, 20 to 40 parts of inclusion agent, 95 to 108 parts of filling agent, 0.5 to 1.2 parts of stabilizing agent, pH (Potential of Hydrogen) regulator for regulating the pH value to 4.8 to 4.9, 0.05 to 0.12 part of wetting agent and 390 to 715 parts of solvent. The problems of freeze-drying process, freeze-drying stability, redissolving performance and the like are solved.

Description

Technical Field

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

[0002] Omadacycline tosylate, with the chemical name of (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-((2,2-dimethylpropyl)aminomethyl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide 4-methylbenzenesulfonate, is a novel broad-spectrum tetracycline derivative - an aminomethylcycline drug, belonging to class IV drugs, and is prepared by domino chemical modification. It inhibits the synthesis of bacterial proteins by binding to ribosomes, can resist the specific acquired resistance mechanism of tetracycline, and has broad-spectrum antibacterial activity, including many Gram-positive, Gram-negative, anaerobic, and atypical pathogenic bacteria. By binding to the 30S ribosomal subunit of microorganisms, it inhibits protein synthesis. As an important antibacterial drug, omadacycline tosylate for injection has been widely used in the treatment of various infectious diseases, such as community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI), etc. However, the existing omadacycline tosylate preparations for injection still have many problems in terms of ingredient ratio, lyophilization process, and reconstitution performance, etc.

[0003] Firstly, the research on the ingredient ratio of omadacycline tosylate preparations for injection is relatively less. The omadacycline tosylate solution usually consists of omadacycline, diluent, water for injection, etc., but the optimal ratio between the components has not been widely and deeply studied. An inappropriate ingredient ratio may lead to a decrease in drug stability, thereby affecting its efficacy and safety.

[0004] Secondly, the mechanical structure performance of the drug during the lyophilization process is poor, increasing the difficulty of lyophilization. Lyophilization is a process of freezing the solution at a low temperature and sublimating the water in a vacuum environment to obtain a dry product. However, the existing omadacycline tosylate preparations for injection often have problems such as loose structure and fragility during the lyophilization process, which not only affects the appearance quality of the product but also may reduce its dissolution rate and bioavailability.

[0005] In addition, poor lyophilization stability is also a major challenge currently faced. The lyophilized product needs to maintain its physical and chemical stability during long-term storage to ensure its efficacy and safety. However, the existing omadacycline tosylate preparations for injection may have problems such as crystallization and discoloration during storage, resulting in a decrease in their stability.

[0006] Furthermore, the reconstitution time needs to be shortened, and the stability and reconstitution effect of the reconstituted liquid medicine also need to be improved. Reconstitution is the process of redissolving freeze-dried products into liquid medicine, which is crucial for injectable drugs. However, existing omadacycline tosylate for injection preparations often have problems such as slow dissolution rate and incomplete dissolution during the reconstitution process, which not only prolongs the operation time but also may affect the efficacy and safety of the drug. At the same time, the stability of the reconstituted liquid medicine is poor, and phenomena such as precipitation and discoloration are likely to occur, further limiting its clinical application.

[0007] In summary, there are still many problems with existing omadacycline tosylate for injection preparations in terms of ingredient ratio, freeze-drying process, freeze-drying stability, and reconstitution performance. There is an urgent need to develop a new type of omadacycline tosylate for injection preparation and its preparation method to solve the above problems and improve the efficacy and safety of the drug. Summary of the Invention

[0008] The technical problem to be solved by the present invention is that there are still many problems with existing omadacycline tosylate for injection preparations in terms of freeze-drying process, freeze-drying stability, and reconstitution performance. The purpose is to provide an omadacycline tosylate for injection preparation and its preparation method, which solve the problems of freeze-drying process, freeze-drying stability, and reconstitution performance.

[0009] The present invention is achieved through the following technical solutions:

[0010] In the first aspect, the present invention provides an omadacycline tosylate for injection preparation, comprising the following raw materials in parts by weight:

[0011] Omadacycline tosylate 128 - 134 parts,

[0012] Inclusion agent 20 - 40 parts,

[0013] Filler 95 - 108 parts,

[0014] Stabilizer 0.5 - 1.2 parts,

[0015] pH regulator to adjust the pH value to 4.8 - 4.9,

[0016] Wetting agent 0.05 - 0.12 parts,

[0017] Solvent 390 - 715 parts.

[0018] As a possible design, the above inclusion agent includes sulfobutyl ether-β-cyclodextrin;

[0019] The filler includes mannitol, trehalose, and poloxamer 188;

[0020] The stabilizer includes L-methionine;

[0021] The pH regulator includes citric acid, citric acid, sodium citrate or disodium hydrogen phosphate;

[0022] The wetting agent includes polysorbate 80;

[0023] The solvent includes water for injection.

[0024] As a possible design, the weight ratio of the above-mentioned mannitol, trehalose and poloxamer 188 is (15-18):(6-9):1

[0025] As a possible design, the D50 particle size of the above-mentioned omadacycline tosylate for injection preparation is 185-250 nm.

[0026] In a second aspect, the present invention provides a preparation method of an omadacycline tosylate for injection preparation, including the following steps:

[0027] Dissolve the complexing agent in purified water, dissolve omadacycline tosylate in absolute ethanol, dissolve it by ultrasonic wave, drop the omadacycline tosylate ethanol solution into the complexing agent, stir and dissolve to obtain a mixed solution, take the continuous filtrate after filtration, and freeze-dry the continuous filtrate to obtain omadacycline tosylate clathrate;

[0028] Add a filler, a stabilizer and a wetting agent to 70%-90% by weight of the solvent and mix evenly, then add omadacycline tosylate clathrate, adjust the pH value to 4.8-4.9 with a pH regulator, supplement the remaining solvent, and filter to obtain an omadacycline tosylate solution;

[0029] After the omadacycline tosylate solution is freeze-dried by gradient, an omadacycline tosylate for injection preparation is obtained. The gradient freeze-drying process ensures that the preparation exists in an amorphous state and avoids phase separation.

[0030] As a possible design, the above-mentioned stirring is specifically to drop the omadacycline tosylate ethanol solution into the complexing agent, stir magnetically for 20-40 min and then stand for 2-3 h to obtain a mixed solution.

[0031] As a possible design, the above-mentioned mixed solution is centrifuged at 6000-7000 r / min for 5-10 min before filtration.

[0032] As a possible design, the above-mentioned continuous filtrate is first refrigerated, then pre-frozen, and finally obtained omadacycline tosylate clathrate with a particle size of 185-250 nm after freeze-drying and pulverization.

[0033] As a possible design, the above-mentioned filtrate is refrigerated at 3-5°C for 3-4 hours, then pre-frozen at -75 to -85°C for 4-5 hours, and then freeze-dried and pulverized to obtain omadacycline tosylate inclusion complexes with a particle size of 185-250 nm.

[0034] As a possible design, the above-mentioned gradient freeze-drying includes the following steps:

[0035] First temperature reduction: The omadacycline tosylate solution is cooled to -5 to -10°C at a temperature reduction rate of 1-1.5°C / min and maintained for 0.5-1 hour;

[0036] Second temperature reduction: It is cooled to -40 to -50°C at a temperature reduction rate of 0.3-0.6°C / min and pre-frozen for 1.5-2.5 hours;

[0037] First temperature increase: It is heated to -30 to -20°C at a temperature increase rate of 0.3-0.6°C / min and continuously frozen for 2-3 hours;

[0038] First drying: Vacuum drying is carried out at 45-50 Pa and -25 to -15°C for 8-10 hours;

[0039] Second drying: First, it is heated to -10 to 0°C at a temperature increase rate of 0.3-0.6°C / min and dried at 25-35 Pa for 8.5-12.5 hours; then it is heated to 20-30°C at a temperature increase rate of 0.1-0.4°C / min and dried at 8-15 Pa for 2.5-3.5 hours.

[0040] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0041] In the present invention, by complexing omadacycline with a complexing agent, its solubility and stability are improved, crystallization and discoloration of the drug during storage are prevented, and aggregation in the injection solution can also be prevented; then, with the help of a filler, a rigid gradient pore structure is provided for it to ensure the stability of its structure during the freeze-drying process and easy reconstitution later. In addition, during reconstitution, poloxamer 188 in the filler forms a complex micelle with the complexing agent, and the drug re-aggregation is inhibited through steric hindrance, thereby improving the stability of the preparation; and the wettability agent is used to improve the solubility during reconstitution and accelerate the dissolution rate. The combined effect makes the freeze-dried structure of the preparation have high stability, fast reconstitution speed, high bioavailability and high drug stability. Specific embodiments

[0042] To make the objectives, technical solutions and advantages of the present invention more clear and understandable, the present invention will be further described in detail below in conjunction with embodiments. The illustrative embodiments and descriptions of the present invention are only used to explain the present invention and are not intended to limit the present invention. For those conditions not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. For those reagents or instruments without indicating the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0043] Based on the existing omadacycline tosylate for injection, there are problems such as poor drug stability; its structure is loose and fragile during the freeze-drying process, resulting in reduced dissolution rate and bioavailability; the reconstitution time needs to be shortened, and the stability and reconstitution effect of the reconstituted liquid also need to be improved. The present invention particularly provides a new omadacycline tosylate for injection, which has the advantages of good freeze-drying structural stability, fast reconstitution speed, high bioavailability and high drug stability.

[0044] An omadacycline tosylate for injection, comprising the following raw materials in parts by weight:

[0045] 128-134 parts of omadacycline tosylate,

[0046] 20-40 parts of complexing agent,

[0047] 95-108 parts of filler,

[0048] 0.5-1.2 parts of stabilizer,

[0049] pH regulator to adjust the pH value to 4.8-4.9,

[0050] 0.05-0.12 parts of wetting agent,

[0051] 390-715 parts of solvent.

[0052] In some embodiments of the present invention, the above complexing agent includes sulfobutyl ether-β-cyclodextrin (SBE-β-CD). The complexing agent reduces the contact between omadacycline tosylate and moisture through supramolecular inclusion, inhibiting hydrolysis and oxidation side reactions.

[0053] In some embodiments of the present invention, the above filler includes mannitol, trehalose and poloxamer 188. The three are compounded to form a rigid gradient pore structure, which can improve the structural framework of the freeze-dried preparation and ensure the subsequent reconstitution effect; in addition, the addition of poloxamer 188 will form a thermosensitive colloid after reconstitution, delaying drug sedimentation and improving infusion stability.

[0054] In some embodiments of the present invention, the weight ratio of the above mannitol, trehalose and poloxamer 188 is (15-18):(6-9):1. Under a specific ratio, the stability is the best.

[0055] Preferably, the weight ratio of mannitol, trehalose and poloxamer 188 is 16:7:1.

[0056] In some embodiments of the present invention, the stabilizer includes L-methionine. L-methionine improves the stability of the formulation by scavenging free radicals.

[0057] In some embodiments of the present invention, the pH adjuster includes citric acid, citric acid, sodium citrate or disodium hydrogen phosphate.

[0058] In some embodiments of the present invention, the wetting agent includes polysorbate 80.

[0059] In some embodiments of the present invention, the solvent includes water for injection.

[0060] In some embodiments of the present invention, the D50 particle size of the above-mentioned omadacycline tosylate injection preparation is 185-250 nm. By controlling the particle size of the preparation to 200-400 nm, the specific surface area can be increased, and the dissolution rate and stability can be improved.

[0061] Preferably, the D90 particle size of the above-mentioned omadacycline tosylate injection preparation is less than 270 nm.

[0062] The present invention also provides a method for preparing an omadacycline tosylate preparation for injection, comprising the following steps:

[0063] S1. Dissolve the inclusion agent in purified water, dissolve omadacycline tosylate in anhydrous ethanol, dissolve by ultrasonication, dropwise add the omadacycline tosylate ethanol solution into the inclusion agent, stir and dissolve to obtain a mixed solution, filter and collect the filtrate, and freeze-dry the filtrate to obtain the omadacycline tosylate inclusion complex.

[0064] By inclusion complexation, the solubility and stability of omadacycline tosylate are improved, and the drug is prevented from crystallizing and discoloring during storage. The inclusion agent carries a negative charge (Zeta potential -35mV), which synergizes with the surface charge of the nanocrystals to prevent aggregation. In addition, the inclusion agent can reduce the irritation of the injection to the administration site, allowing the drug to quickly reach the required blood concentration and prolong the drug's duration of action.

[0065] In some embodiments of the present invention, the stirring in S1 is specifically to drop the ethanol solution of omadacycline tosylate into the inclusion agent, stir magnetically for 20 to 40 minutes, and then let it stand for 2 to 3 hours to obtain a mixed solution.

[0066] Stir thoroughly to improve the uniformity of the solution.

[0067] In some embodiments of the present invention, the above-mentioned mixture in S1 is centrifuged at a rotational speed of 6000 - 7000 r / min for 5 - 10 min before filtration, and then the filtrate is taken after filtration. The filtrate is refrigerated at 3 - 5°C for 3 - 4 h, then pre-frozen at -75 - 85°C for 4 - 5 h, and then freeze-dried and pulverized to obtain omadacycline tosylate inclusion complex with a particle size of 185 - 250 nm.

[0068] Preferably, the refrigeration temperature is 4°C and the pre-freezing temperature is -80°C.

[0069] Through refrigeration, the inclusion reaction is promoted, and refrigeration helps the stable formation of the inclusion complex and improves the inclusion rate; at the same time, the un-included drugs and impurities will gradually precipitate, and then through filtration and separation, the purity of the inclusion complex is improved. Pre-freezing at -80°C can quickly freeze the solution to form small and uniform ice crystals, which helps the ice crystals to sublimate uniformly during the subsequent freeze-drying process, avoiding local overheating or overcooling, thereby improving the quality and stability of the freeze-dried product; in addition, rapid freezing at this temperature can reduce the mechanical damage of the ice crystals to the drug molecules and protect the activity and structural integrity of the drug. During the freeze-drying process, the ice crystals directly change from a solid state to a gaseous state, avoiding the destruction of the drug molecules by liquid water, thereby maintaining the activity and stability of the drug; in addition, the inclusion complex obtained by freeze-drying has a porous structure, and when redissolved, water can quickly penetrate into the sample interior, improving the redissolution speed and the activity of the drug after redissolution.

[0070] S2. Add a filler, a stabilizer, and a wetting agent to 70% - 90% by weight of a solvent and mix evenly, then add omadacycline tosylate inclusion complex, adjust the pH value to 4.8 - 4.9 with a pH regulator, add the remaining solvent, and filter to obtain an omadacycline tosylate solution.

[0071] S3. After the omadacycline tosylate solution is subjected to gradient freeze-drying, an injectable omadacycline tosylate preparation is obtained. The gradient freeze-drying process ensures that the preparation exists in an amorphous state and avoids phase separation.

[0072] In some embodiments of the present invention, the gradient freeze-drying in S3 includes the following steps:

[0073] S31. First temperature reduction: Cool the omadacycline tosylate solution at a temperature reduction rate of 1 - 1.5°C / min to -5 - 10°C and hold for 0.5 - 1 h;

[0074] S32. Second temperature reduction: Cool at a temperature reduction rate of 0.3 - 0.6°C / min to -40 - 50°C and pre-freeze for 1.5 - 2.5 h;

[0075] S33. First temperature increase: Increase the temperature at a temperature increase rate of 0.3 - 0.6°C / min to -30 - 20°C and continue to freeze for 2 - 3 h;

[0076] S34, Primary drying: Vacuum drying at 45 - 50 Pa and -25 - -15 °C for 8 - 10 h;

[0077] S35, Secondary drying: First, increase the temperature at a rate of 0.3 - 0.6 °C / min to -10 - 0 °C and dry at 25 - 35 Pa for 8.5 - 12.5 h; then increase the temperature at a rate of 0.1 - 0.4 °C / min to 20 - 30 °C and dry at 8 - 15 Pa for 2.5 - 3.5 h.

[0078] Through slow cooling in one - step cooling, fine ice crystals are formed in the solution, which helps to reduce the damage of ice crystals to drug molecules and protect the activity and structural integrity of the drug. Secondary cooling further reduces the temperature to completely freeze the solution, forming a stable ice crystal structure, and the extension of the pre - freezing time helps to ensure the uniformity and stability of the ice crystals, providing a good basis for the subsequent drying process. Then, microcrystal nuclei are eliminated under one - step heating treatment to ensure that the proportion of the amorphous state is ≥95%. Under low temperature and vacuum conditions, ice crystals directly sublimate from the solid state to the gaseous state to remove the moisture in the sample. The main purpose of primary drying is to remove most of the moisture and preliminarily dry the product. Secondary drying further removes the residual moisture in the sample by gradually increasing the temperature, forming nano - level pores, and ensuring the stability and effectiveness of the product during storage and use.

[0079] Example 1

[0080] A preparation method of omadacycline tosylate for injection:

[0081] Raw materials:

[0082] 128 g of omadacycline tosylate,

[0083] 22 g of complexing agent (sulfobutyl ether - β - cyclodextrin),

[0084] 95 g of filler (mannitol, trehalose and poloxamer 188 with a weight ratio of 15:9:1),

[0085] 0.5 g of stabilizer (L - methionine),

[0086] pH regulator (citric acid and disodium hydrogen phosphate) to adjust the pH value to 4.8,

[0087] 0.05 g of wetting agent (polysorbate 80),

[0088] 405 g of solvent.

[0089] Steps:

[0090] Dissolve the complexing agent in purified water, dissolve omadacycline tosylate in absolute ethanol, and dissolve it by ultrasonic treatment. Drop the omadacycline tosylate ethanol solution into the complexing agent, stir magnetically for 20 min, and then let it stand for 2 h to obtain a mixed solution. Centrifuge the mixed solution at 6000 r / min for 8 min, take the continuous filtrate after filtration, refrigerate the continuous filtrate at 4 °C for 4 h, pre-freeze it at -80 °C for 5 h, and then freeze-dry and pulverize it to obtain an omadacycline tosylate inclusion complex with a D50 particle size of 185 - 250 nm;

[0091] Add a filler, a stabilizer, and a wetting agent to 70% by weight of the solvent and mix evenly. Then add the omadacycline tosylate inclusion complex, adjust the pH value to 4.8 with a pH regulator, and make up the remaining solvent. Filter to obtain an omadacycline tosylate solution;

[0092] Gradient freeze-dry the omadacycline tosylate solution according to the following steps

[0093] First cooling: Cool the omadacycline tosylate solution to -5 °C at a cooling rate of 1 °C / min and hold for 0.5 h;

[0094] Second cooling: Cool to -40 °C at a cooling rate of 0.3 °C / min and pre-freeze for 1.5 h;

[0095] First heating: Heat to -30 °C at a heating rate of 0.3 °C / min and continue to freeze for 2 h;

[0096] First drying: Vacuum dry at 45 Pa and -25 °C for 8 h;

[0097] Second drying: Heat to -10 °C at a heating rate of 0.3 °C / min and dry at 25 Pa for 8.5 h; then heat to 20 °C at a heating rate of 0.1 °C / min and dry at 8 Pa for 2.5 h to obtain an omadacycline tosylate injection preparation.

[0098] Example 2

[0099] A preparation method of an omadacycline tosylate injection preparation:

[0100] Raw materials:

[0101] 130 g of omadacycline tosylate,

[0102] 30 g of complexing agent (sulfobutylether-β-cyclodextrin),

[0103] 105 g of filler (mannitol, trehalose, and poloxamer 188 with a weight ratio of 18:6:1),

[0104] 0.9 g of stabilizer (L-methionine),

[0105] pH regulator (citric acid, sodium citrate), adjust the pH value to 4.85,

[0106] Wetting agent (polysorbate 80) 0.09 g,

[0107] Solvent 600 g.

[0108] Steps:

[0109] Dissolve the complexing agent in purified water, dissolve omadacycline tosylate in absolute ethanol, dissolve it by ultrasonic treatment, drop the omadacycline tosylate ethanol solution into the complexing agent, stir magnetically for 30 min and then let it stand for 2 h to obtain a mixed solution. Centrifuge the mixed solution at 6500 r / min for 8 min, take the continuous filtrate after filtration, refrigerate the continuous filtrate at 4 °C for 3.5 h, then pre-freeze it at -80 °C for 0.5 h, and then freeze-dry it. After pulverization, an omadacycline tosylate inclusion complex with a D50 particle size of 185 - 250 nm is obtained;

[0110] Add the filler, stabilizer and wetting agent to 80% by weight of the solvent and mix evenly, then add the omadacycline tosylate inclusion complex, adjust the pH value to 4.85 with the pH regulator, supplement the remaining solvent, and filter to obtain the omadacycline tosylate solution;

[0111] Gradient freeze-dry the omadacycline tosylate solution according to the following steps

[0112] First temperature reduction: Cool the omadacycline tosylate solution to -8 °C at a temperature reduction rate of 1.5 °C / min and hold for 1 h;

[0113] Second temperature reduction: Cool to -45 °C at a temperature reduction rate of 0.4 °C / min and pre-freeze for 2 h;

[0114] First temperature increase: Heat to -25 °C at a temperature increase rate of 0.4 °C / min and continue to freeze for 2.5 h;

[0115] First drying: Vacuum dry at 48 Pa and -20 °C for 9 h;

[0116] Second drying: Heat to -5 °C at a temperature increase rate of 0.4 °C / min and dry at 30 Pa for 10 h; then heat to 25 °C at a temperature increase rate of 0.3 °C / min and dry at 12 Pa for 3 h to obtain the injectable omadacycline tosylate preparation.

[0117] Example 3

[0118] A preparation method of an injectable omadacycline tosylate preparation:

[0119] Raw materials:

[0120] Omadacycline tosylate 134 g,

[0121] Complexing agent (sulfobutyl ether-β-cyclodextrin) 40 g,

[0122] Filler (mannitol, trehalose and poloxamer 188 with a weight ratio of 16:7:1) 108 g,

[0123] Stabilizer (L-methionine) 1.2 g,

[0124] pH regulator (citric acid, disodium hydrogen phosphate), adjusting the pH value to 4.9,

[0125] Wetting agent (polysorbate 80) 0.12 g,

[0126] Solvent 715 g.

[0127] Steps:

[0128] Dissolve the complexing agent in purified water, dissolve omadacycline tosylate in absolute ethanol, dissolve it by ultrasonic treatment, drop the omadacycline tosylate ethanol solution into the complexing agent, stir magnetically for 40 min and then let it stand for 3 h to obtain a mixed solution. Centrifuge the mixed solution at 7000 r / min for 10 min, take the subsequent filtrate after filtration, refrigerate the subsequent filtrate at 4 °C for 4 h, pre-freeze it at -80 °C for 5 h, and then freeze-dry and pulverize it to obtain an omadacycline tosylate inclusion complex with a D50 particle size of 185 - 250 nm;

[0129] Add the filler, stabilizer and wetting agent to 90% by weight of the solvent and mix evenly, then add the omadacycline tosylate inclusion complex, adjust the pH value to 4.9 with the pH regulator, make up the balance of the solvent, and filter to obtain an omadacycline tosylate solution;

[0130] Gradient freeze-dry the omadacycline tosylate solution according to the following steps

[0131] First temperature reduction: Cool the omadacycline tosylate solution to -10 °C at a temperature reduction rate of 1.5 °C / min and hold for 1 h;

[0132] Second temperature reduction: Cool to -50 °C at a temperature reduction rate of 0.6 °C / min and pre-freeze for 2.5 h;

[0133] First temperature increase: Increase the temperature to -20 °C at a temperature increase rate of 0.6 °C / min and continue to freeze for 3 h;

[0134] First drying: Vacuum dry at 50 Pa and -15 °C for 10 h;

[0135] Second drying: Increase the temperature to -10 °C at a temperature increase rate of 0.3 °C / min and dry at 25 Pa for 8.5 h; then increase the temperature to 20 °C at a temperature increase rate of 0.1 °C / min and dry at 8 Pa for 2.5 h to obtain an injectable omadacycline tosylate preparation.

[0136] Comparative Example 1

[0137] This comparative example is basically the same as Example 2, except that: no complexing agent is used.

[0138] Comparative Example 2

[0139] This comparative example is basically the same as Example 2, except that: no complexing agent is used, and the filler includes mannitol and trehalose with a weight ratio of 18:7.

[0140] Comparative Example 3

[0141] This comparative example is basically the same as Example 2, except that: the filler is all mannitol.

[0142] Comparative Example 4

[0143] This comparative example is basically the same as Example 2, except that: the D50 particle size of the omadacycline tosylate for injection preparation is 300 nm.

[0144] Comparative Example 5

[0145] This comparative example is basically the same as Example 2, except that: the continuous filtrate is not only refrigerated and pre-frozen, but directly freeze-dried, pulverized, and then the omadacycline tosylate clathrate is obtained.

[0146] Comparative Example 6

[0147] This comparative example is basically the same as Example 2, except that: the gradient freeze-drying step directly performs primary drying after the secondary temperature drop, without performing primary warming.

[0148] Comparative Example 7

[0149] This comparative example is basically the same as Example 2, except that: the pH value is 5.2.

[0150] Experimental Example

[0151] (1). Dissolve the preparations of Examples 1-3 and Comparative Examples 1-7 in injection water, and observe the reconstitution time, color and clarity of the reconstituted solution by visual method. The results are shown in Table 1.

[0152] Reconstituted solution ratio: 100 mg of the preparation is dissolved in 5 mL of injection water.

[0153] Table 1

[0154]

[0155] It can be observed from the table that the reconstitution rate of Example 2 is the best.

[0156] (2) Accelerated stability tests were conducted on the preparations of Example 2 and Comparative Examples 1-7. This experiment followed the ICH Q1A guidelines.

[0157] Experimental conditions: 40°C / 75% RH (relative humidity), light (1.2×106 Lux·hr). Sampling times: 1 month, 3 months, and 6 months.

[0158] Reconstitution solution ratio: 100 mg of the preparation was dissolved in 5 mL of water for injection.

[0159] By detecting the reconstitution time, color, clarity, and single impurity content of the preparation, the results are shown in Table 2.

[0160] Table 2

[0161]

[0162]

[0163] Observing Table 2, it can be seen that the stability of Example 2 is the best.

[0164] The specific embodiments described above further elaborate on the purpose, technical solutions, and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not used to limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. An omadacycline tosylate preparation for injection, characterized in that: The composition comprises the following raw materials in parts by weight: 128-134 parts of omadacycline tosylate, 20 to 40 parts of inclusion compound, 95-108 parts of filler, 0.5-1.2 parts of stabilizer, pH adjuster, adjust pH value to 4.8-4.9, Wetting agent 0.05-0.12 parts, 390 to 715 parts of solvent.

2. An omadacycline tosylate preparation for injection according to claim 1, characterized in that: The inclusion agent includes sulfobutyl ether-β-cyclodextrin; The filler includes mannitol, trehalose and poloxamer 188; The stabilizer includes L-methionine; The pH adjuster includes citric acid, citric acid, sodium citrate or disodium hydrogen phosphate; The wetting agent includes polysorbate 80; The solvent includes water for injection.

3. An omadacycline tosylate preparation for injection according to claim 2, characterized in that: The weight ratio of mannitol, trehalose and poloxamer 188 is (15-18):(6-9):

1.

4. The omadacycline tosylate preparation for injection according to claim 1, characterized in that: The D50 particle size of the omadacycline tosylate preparation for injection is 185 to 250 nm.

5. The method for preparing an omadacycline tosylate preparation for injection according to any one of claims 1 to 4, characterized in that: The steps include: The inclusion agent is dissolved in purified water, omadacycline tosylate is dissolved in anhydrous ethanol, and the mixture is dissolved by ultrasonication, and the omadacycline tosylate ethanol solution is added dropwise to the inclusion agent, and the mixture is stirred and dissolved to obtain a mixed solution, and the filtrate is filtered and then collected, and the filtrate is freeze-dried to obtain the omadacycline tosylate inclusion compound; Adding a filler, a stabilizer and a wetting agent to 70% to 90% by weight of a solvent and mixing them evenly, then adding the omadacycline tosylate inclusion compound, adjusting the pH value to 4.8 to 4.9 with a pH adjuster, adding the remaining solvent, and filtering to obtain an omadacycline tosylate solution; The omadacycline tosylate solution is subjected to gradient freeze-drying to obtain an omadacycline tosylate preparation for injection. The gradient freeze-drying process ensures that the preparation exists in an amorphous state to avoid phase separation.

6. The method for preparing an omadacycline tosylate preparation for injection according to claim 5, characterized in that: The stirring is specifically to drop the ethanol solution of omadacycline tosylate into the inclusion agent, stir magnetically for 20 to 40 minutes, and then stand for 2 to 3 hours to obtain a mixed solution.

7. The method for preparing an omadacycline tosylate preparation for injection according to claim 5, characterized in that: The mixed solution is centrifuged at a speed of 6000-7000 r / min for 5-10 min before filtering.

8. The method for preparing an omadacycline tosylate preparation for injection according to claim 5, characterized in that: The subsequent filtrate is first refrigerated, then pre-frozen, and finally freeze-dried and pulverized to obtain an omadacycline tosylate inclusion compound with a particle size of 185 to 250 nm.

9. The method for preparing an omadacycline tosylate preparation for injection according to claim 8, characterized in that: The subsequent filtrate is refrigerated at 3-5°C for 3-4 hours, and then pre-frozen at -75-85°C for 4-5 hours, and then freeze-dried and pulverized to obtain an omadacycline tosylate inclusion complex with a particle size of 185-250 nm.

10. The method for preparing an omadacycline tosylate preparation for injection according to claim 5, characterized in that: The gradient freeze-drying comprises the following steps: Primary cooling: cool the omadacycline tosylate solution to -5--10°C at a cooling rate of 1-1.5°C / min and maintain for 0.5-1h; Second cooling: cool down to -40~-50℃ at a cooling rate of 0.3~0.6℃ / min, pre-freeze for 1.5~2.5h; Primary heating: heating to -30~-20℃ at a heating rate of 0.3~0.6℃ / min, and continue freezing for 2~3h; Primary drying: vacuum drying at 45-50 Pa, -25--15°C for 8-10 hours; Secondary drying: first increase the temperature to -10-0°C at a rate of 0.3-0.6°C / min, and dry at 25-35Pa for 8.5-12.5h; then increase the temperature to 20-30°C at a rate of 0.1-0.4°C / min, and dry at 8-15Pa for 2.5-3.5h.

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