9-aminomethyl cycline antibiotic freeze-dried powder injection and preparation method thereof

Abstract

The invention relates to a 9-aminomethyl cycline antibiotic freeze-dried powder injection and a preparation method thereof, in particular to an omasycine tosylate freeze-dried powder injection for injection. The omagazines tosylate freeze-dried powder injection for injection contains omagazines tosylate, excipients and a sodium-free pH regulator, and a special preparation process is adopted, so that the following improvements are obtained: 1) the redissolution speed of the freeze-dried powder injection is increased, and meanwhile, the clarity of the redissolved solution is not influenced; 2) the long-term dependence of a traditional freeze-drying process on a sucrose excipient is broken through, and by virtue of the unique cavity inclusion effect of cyclodextrin molecules, the moisture content and the growth rate of related substances are effectively reduced, and the stability is improved; and 3) the applicable crowd of the medicine is expanded.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and relates to a freeze-dried powder injection of 9-aminomethylcycline antibiotics and a preparation method thereof, specifically to a freeze-dried powder injection of omadacycline tosylate for injection and a preparation method thereof. Background Art

[0002] Omadacycline is a novel 9-aminomethylcycline drug, with the chemical name of (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, and the molecular formula of C 29 H 40 N4O7, and the structural formula is as follows:

[0003]

[0004] Omadacycline is a semi-synthetic compound obtained by chemically modifying minocycline and belongs to the tetracycline family. Omadacycline specifically binds to the A site of the 30S subunit of the bacterial ribosome, inhibits the normal binding of aminoacyl-tRNA to this site, causes the termination of peptide chain elongation, and blocks protein synthesis, thereby producing an antibacterial effect.

[0005] Omadacycline tosylate is a salt-type compound formed by the combination of omadacycline and p-toluenesulfonic acid, and the structural formula is as follows:

[0006]

[0007] The original research enterprise of omadacycline tosylate is Paratek Pharm. The US FDA approved the listing of two dosage forms, freeze-dried powder injection and tablets, in October 2018, with the trade name of The China Food and Drug Administration approved its listing in December 2021, with the trade name of As a broad-spectrum antibiotic, this drug has important clinical value in the treatment of community-acquired pneumonia, acute bacterial skin and skin structure infections, etc.

[0008] However, There are still some defects in the clinical application and production process of the freeze-dried powder injection dosage form of

[0009] 1) Limited clinical application

[0010] The current original preparation uses sodium hydroxide as a pH regulator, and the introduced sodium ions pose potential clinical risks to special patient groups. For example, for patients who need to strictly limit sodium intake (such as those with chronic kidney disease and cirrhosis with ascites), the additional intake of sodium ions may exacerbate water and sodium retention, leading to electrolyte disorders and increased circulatory load; for high-risk groups who are sensitive to abnormal sodium metabolism (such as the elderly and obese), long-term use of sodium-containing preparations may induce hypernatremia; for patients with congestive heart failure or end-stage renal disease, even a trace amount of sodium intake may lead to deterioration of the condition.

[0011] 2) Freeze-drying process defects

[0012] Traditional preparations use sucrose as the main excipient, which has inherent defects in the freeze-drying process. For example, it reduces the eutectic point and glass transition temperature of the solution, requiring a lower freezing temperature and more precise process control; it increases the solution viscosity, hinders ice crystal growth, resulting in a tortuous sublimation path and increased resistance; it forms hydrogen bonds with water molecules, increasing the proportion of bound water and prolonging the drying time; it forms a dense dry layer structure, hindering the escape of water vapor. The above factors result in a freeze-drying cycle usually exceeding 19 hours, which becomes a key factor restricting the improvement of production capacity. At the same time, the excessive freeze-drying time significantly increases the energy consumption cost and reduces the utilization rate of the production line.

[0013] Therefore, there is an urgent need in the art for an omadacycline tosylate injection preparation with a wider clinical application and a better freeze-drying process. Summary of the Invention

[0014] Based on the above technical problems, the present invention provides an omadacycline tosylate freeze-dried powder injection and a preparation method thereof, which adopt a sodium-free buffer-cyclodextrin synergistic stabilization system and a gradient annealing process, significantly improving the reconstitution speed, enhancing the product stability, and making the clinical application more extensive.

[0015] In the first aspect of the present invention, there is provided an omadacycline tosylate freeze-dried powder injection, which comprises omadacycline tosylate, an excipient, and a pH regulator;

[0016] The excipient is selected from the group consisting of mannitol, trehalose, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, or a combination thereof.

[0017] In another preferred embodiment, the freeze-dried powder injection contains no or only a residual amount of solvent, and the no or only a residual amount of solvent means that the solvent content is <0.8 wt%, preferably <0.6 wt%, more preferably <0.4 wt%, and most preferably <0.3 wt%.

[0018] In a preferred embodiment, the pH regulator does not contain sodium element.

[0019] In a preferred embodiment, the pH regulator is selected from the group consisting of citric acid, histidine, tromethamine, arginine, or a combination thereof.

[0020] In a preferred embodiment, the lyophilized powder for injection comprises:

[0021] omadacycline tosylate 125 to 135 parts by weight;

[0022] excipient 100 to 700 parts by weight;

[0023] an amount of pH regulator such that the pH of the reconstituted solution is 3.0 to 8.0.

[0024] In another preferred embodiment, the lyophilized powder for injection comprises 310 to 700 parts by weight of excipient, preferably 310 to 600 parts by weight, more preferably 310 to 500 parts by weight.

[0025] In another preferred embodiment, the lyophilized powder for injection comprises 350 to 500 parts by weight of excipient, preferably 350 to 450 parts by weight.

[0026] In another preferred embodiment, the amount that makes the pH of the reconstituted solution 3.0 to 8.0 includes 5 to 15 mg of arginine and 10 to 20 mg of citric acid.

[0027] In a preferred embodiment, the lyophilized powder for injection is prepared from an omadacycline tosylate solution;

[0028] The solution comprises omadacycline tosylate, excipient, pH regulator and an optional solvent.

[0029] In a preferred embodiment, the solvent is water for injection.

[0030] In another preferred embodiment, the solution comprises:

[0031]

[0032] In another preferred embodiment, the solution comprises:

[0033]

[0034] In another preferred embodiment, the solution comprises 310 to 700 parts by weight of excipient, preferably 310 to 600 parts by weight, more preferably 310 to 500 parts by weight.

[0035] In another preferred embodiment, the solution comprises 350 to 500 parts by weight of excipient, preferably 350 to 450 parts by weight.

[0036] In another preferred example, the pH of the liquid medicine is 3.5 to 7.5, preferably 3.5 to 7.0, and more preferably 3.5 to 6.5.

[0037] In another preferred example, the pH of the liquid medicine is 3.5 to 6.0, preferably 3.5 to 5.5, more preferably 3.5 to 5.0, and most preferably 4.0 to 5.0.

[0038] In another preferred example, the amount for making the pH of the liquid medicine be 3.0 to 8.0 includes 5 to 15 mg of arginine and 10 to 20 mg of citric acid.

[0039] In another preferred example, the liquid medicine includes 2500 to 3400 parts by weight of a solvent, preferably 2500 to 3300 parts by weight, and more preferably 2600 to 3200 parts by weight.

[0040] In another preferred example, the liquid medicine includes 2600 to 3100 parts by weight of a solvent, preferably 2600 to 3000 parts by weight, and more preferably 2700 to 3000 parts by weight.

[0041] In another preferred example, the liquid medicine includes 2800 to 3100 parts by weight of a solvent, preferably 2900 to 3000 parts by weight.

[0042] In another preferred example, the pH of the liquid medicine is 3.0 to 8.0;

[0043] In another preferred example, the liquid medicine includes: omadacycline tosylate at 40 to 50 g / L, excipient at 30 to 250 g / L, and the rest is a pH regulator and water.

[0044] In another preferred example, the liquid medicine includes omadacycline tosylate at 40 to 45 g / L.

[0045] In another preferred example, the liquid medicine includes excipient at 105 to 235 g / L, preferably excipient at 105 to 200 g / L, and more preferably excipient at 105 to 170 g / L.

[0046] In another preferred example, the liquid medicine includes excipient at 115 to 170 g / L, preferably excipient at 115 to 150 g / L, and more preferably excipient at 120 to 150 g / L.

[0047] In another preferred example, the reconstitution time of the freeze-dried powder injection at day 0 is 10 to 70 seconds, preferably 10 to 50 seconds, and more preferably 10 to 41 seconds.

[0048] In another preferred example, the reconstitution time of the freeze-dried powder injection at day 0 is 10 to 40 seconds, preferably 10 to 35 seconds.

[0049] In a preferred embodiment, the water content in the freeze-dried powder injection is 0.01 - 0.4 wt%, preferably 0.1 - 0.4 wt%, more preferably 0.1 - 0.35 wt%, and most preferably 0.2 - 0.3 wt%.

[0050] In a second aspect of the present invention, there is provided a method for preparing a freeze-dried powder injection as described in the first aspect of the present invention, the preparation method comprising the following steps:

[0051] S1. Mix omadacycline tosylate, excipient, pH regulator and solvent to obtain an omadacycline tosylate medicinal solution;

[0052] S2. Freeze-dry the omadacycline tosylate medicinal solution obtained in step S1 to obtain omadacycline tosylate freeze-dried powder.

[0053] In a preferred embodiment, step S1 comprises the following steps: Dissolve the excipient in a part of the solvent, add omadacycline tosylate at 20 - 30 °C to dissolve it, add a pH regulator to make the pH 3.0 - 8.0, supplement the remaining solvent, and filter to obtain an omadacycline tosylate medicinal solution.

[0054] In a preferred embodiment, the freeze-drying in step S2 comprises the following steps:

[0055] Pre-freezing: Cool the omadacycline tosylate medicinal solution obtained in step S1 at a cooling rate of 1 - 10 °C / min to -50 - -40 °C, and keep warm for 1 - 5 h;

[0056] Warming and freezing: Warm up at a warming rate of 1 - 10 °C / min to -30 - -10 °C, and keep warm for 0.5 - 4 h;

[0057] Cooling and freezing: Cool at a cooling rate of 0.5 - 5 °C / min to -50 - -40 °C, and keep warm for 0.5 - 4 h;

[0058] Primary drying: Under the condition of -15 - -2 °C, vacuum dry for 5 - 15 h;

[0059] Secondary drying: Under the condition of 35 - 45 °C, vacuum dry for 1 - 8 h.

[0060] In another preferred embodiment, the pre-freezing further comprises the following steps: Place the omadacycline tosylate medicinal solution obtained in step S1 in a container at a temperature of 0 - 5 °C, and cool at a cooling rate of 2 - 7 °C / min to -47 - -42 °C, and keep warm for 1 - 3 h.

[0061] In another preferred embodiment, the warming and freezing further comprises the following steps: Warm up at a warming rate of 2 - 7 °C / min to -25 - -10 °C, and keep warm for 0.5 - 3 h.

[0062] In another preferred example, the cooling and freezing further includes the following steps: cooling to -47 to -42 °C at a cooling rate of 0.5 to 2 °C / min, and holding for 0.5 to 3 h.

[0063] In another preferred example, the primary drying includes the following steps: under the condition of -12 to -5 °C, vacuum drying for 5 to 12 h.

[0064] In another preferred example, the primary drying further includes the following steps: heating to -15 to -2 °C within 0.5 to 5 h.

[0065] In another preferred example, the primary drying further includes the following steps: heating to -12 to -5 °C within 0.5 to 2 h.

[0066] In another preferred example, the primary drying further includes the following steps: heating to -15 to -2 °C within 0.5 to 5 h, and drying for 5 to 15 h under the above temperature condition.

[0067] In another preferred example, the primary drying further includes the following steps: heating to -12 to -5 °C within 0.5 to 2 h, and drying for 5 to 12 h under the above temperature condition.

[0068] In another preferred example, the vacuum degree during vacuum drying in the primary drying is 0.01 to 0.5 mbar, preferably 0.1 to 0.5 mbar, and more preferably 0.1 to 0.3 mbar.

[0069] In another preferred example, the secondary drying includes the following steps: under the condition of 38 to 42 °C, vacuum drying for 2 to 6 h.

[0070] In another preferred example, the secondary drying further includes the following steps: heating to 35 to 45 °C within 0.5 to 5 h.

[0071] In another preferred example, the secondary drying further includes the following steps: heating to 38 to 42 °C within 0.5 to 2 h.

[0072] In another preferred example, the vacuum degree during vacuum drying in the secondary drying is 0.01 to 0.1 mbar, preferably 0.01 to 0.06 mbar, and preferably 0.01 to 0.04 mbar.

[0073] In the third aspect of the present invention, there is provided a drug combination, which includes the freeze-dried powder injection as described in the first aspect of the present invention and a solvent for reconstitution.

[0074] In another preferred example, the solvent for reconstitution is water for injection.

[0075] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Detailed implementation mode

[0076] Through long-term and in-depth research and extensive screening, the inventors have for the first time developed a omadacycline tosylate lyophilized powder for injection and its preparation method, which adopts a sodium-free buffer-cyclodextrin synergistic stabilization system and a gradient annealing process, significantly improving the reconstitution speed, enhancing the product stability, and at the same time making the clinical application more extensive. Based on this, the inventors have completed the present invention.

[0077] Omadacycline tosylate lyophilized powder for injection

[0078] The present invention provides a omadacycline tosylate lyophilized powder for injection, which is obtained by freeze-drying omadacycline tosylate liquid medicine;

[0079] Wherein the omadacycline tosylate liquid medicine contains omadacycline tosylate, excipients, pH regulators and solvents;

[0080] The pH regulator does not contain sodium element.

[0081] In another preferred example, the excipient is selected from any one or a combination mixture of mannitol, trehalose, hydroxypropyl-β-cyclodextrin and hydroxypropyl-γ-cyclodextrin.

[0082] In another preferred example, the excipient is mannitol and trehalose, and the mass ratio is (1-2):3, preferably 1:3, preferably 2:3.

[0083] In another preferred example, the omadacycline tosylate lyophilized powder for injection contains 200-700 parts by weight of hydroxypropyl-β-cyclodextrin, preferably 200-500 parts by weight, more preferably 400-500 parts by weight.

[0084] In another preferred example, the omadacycline tosylate lyophilized powder for injection contains 200-700 parts by weight of hydroxypropyl-γ-cyclodextrin, preferably 200-500 parts by weight.

[0085] In another preferred example, the pH regulator is selected from any one or a combination mixture of citric acid, histidine, tromethamine and arginine.

[0086] In another preferred example, the pH of the liquid medicine is adjusted to 4.0-8.0 with a pH regulator, preferably 4.0.

[0087] In another preferred example, the solvent is water for injection.

[0088] Preparation Method of Omadacycline Tosylate Freeze-Dried Powder for Injection

[0089] The present invention provides a preparation method of omadacycline tosylate freeze-dried powder for injection, comprising the following steps:

[0090] 1) Solution preparation: Weigh each component according to the prescription amount; Add 80% of the total volume of injection water to the solution preparation and filling, add excipients, and stir to dissolve them fully; Then add omadacycline tosylate and continue stirring until completely dissolved; Make up the remaining injection water, and the obtained solution is filtered to obtain omadacycline tosylate medicinal solution;

[0091] 2) Freeze-drying: Fill the omadacycline tosylate medicinal solution and obtain omadacycline tosylate freeze-dried powder for injection by freeze-drying.

[0092] In another preferred example, the freeze-drying comprises the following steps:

[0093] Pre-freezing: Fill the omadacycline tosylate medicinal solution and place it on the partition board of a freeze-dryer pre-cooled to maintain a temperature of 5°C. After all samples are put into the box, cool it at a cooling rate of 1-5°C / min to -45°C and pre-freeze for 2h;

[0094] Heating and freezing: Heat it at a heating rate of 1-5°C / min to -25 to -10°C and continue freezing for 0.5-2h;

[0095] Cooling and freezing: Cool it again at a cooling rate of 1-5°C / min to -50 to -40°C and continue freezing for 1h;

[0096] Primary drying: Under the condition of -10 to 0°C, conduct vacuum drying for 8h;

[0097] Secondary drying: Under the condition of 35 to 50°C, conduct vacuum drying for 4h.

[0098] In another preferred example, the secondary drying process is to heat up to 35°C within 1h and dry at 35°C for 3h; heat up to 45°C within 10min and dry at 45°C for 1h.

[0099] In another preferred example, the vacuum degree during the primary drying process is 0.25mbar; the vacuum degree during the secondary drying process is 0.02-0.1mbar.

[0100] Advantages of the present invention:

[0101] 1. The present invention precisely regulates the ice crystal morphology and product microstructure by using a gradient annealing process, significantly improving the reconstitution speed of the freeze-dried powder for injection, and at the same time, the clarity and color of the solution after reconstitution are not affected.

[0102] 2. Break through the long-term dependence on sucrose excipients in the traditional freeze-drying process. With the unique cavity inclusion effect of cyclodextrin molecules, the water content is effectively reduced, the growth rate of related substances slows down, and the product stability is improved.

[0103] 3. By screening a sodium-free pH regulator, it can be used for patients who need to strictly limit sodium intake (such as those with chronic kidney disease, liver cirrhosis with ascites), successfully expanding the applicable population of the drug.

[0104] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer, but are not limited to these specifically described embodiments. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0105] To more clearly illustrate the advantages of the present invention, the original omadacycline tosylate for injection (trade name: ) is used as a reference preparation for comparative study with the samples prepared by the present invention.

[0106] The sources of the materials used in the experiments are as follows:

[0107] Omadacycline tosylate for injection (trade name: ) has a prescription composition of 131 mg of omadacycline tosylate (equivalent to 100 mg of omadacycline), 100 mg of sucrose, hydrochloric acid, and sodium hydroxide; purchased from: Shenzhen Zhuoyue Biomedical Technology Co., Ltd.; Holder: Zai Ding Pharmaceutical (Shanghai) Co., Ltd., batch number: 6230208.

[0108] Omadacycline tosylate raw material: purchased from Shanghai Desano Chemical Pharmaceutical Co., Ltd., batch number: JJ-240723-1-16; mannitol purchased from: Qingdao Mingyue Seaweed Group Co., Ltd.; trehalose purchased from: Hubei Gedian Humanwell Pharmaceutical Excipients Co., Ltd.; hydroxypropyl-β-cyclodextrin purchased from: Shijiazhuang Pharmaceutical Group Ouyi Pharmaceutical Co., Ltd.; hydroxypropyl-γ-cyclodextrin purchased from: Zibo Qianhui Biotechnology Co., Ltd.; citric acid purchased from: Nanjing Chemical Reagent Co., Ltd.; histidine and arginine are both purchased from: Shanghai Union Amino Acid Co., Ltd.; tromethamine purchased from: Chengdu Huayi Pharmaceutical Excipients Manufacturing Co., Ltd.

[0109] Example 1

[0110] A freeze-dried powder injection of omadacycline tosylate for injection, and the prescription content per single vial is shown in the following table:

[0111]

[0112] The preparation method comprises the following steps:

[0113] 1) Solution preparation

[0114] Weigh each component according to the prescription amount.

[0115] Add 80% of the total volume of injection water to the liquid preparation filling, add excipients, and stir to dissolve them fully. The stirring speed is 200 rpm; adjust the system temperature to 25 °C (hydrolysis is likely to occur at too high a temperature, and the dissolution rate is slow at too low a temperature). Then add omadacycline tosylate and continue stirring until completely dissolved. Add a pH regulator to adjust the pH of the liquid medicine to 4.0. Make up the remaining injection water. The obtained solution is filtered through a 0.45 μm bacteria-reducing filter (made of PVDF material), and then filtered again through a secondary 0.22 μm bacteria-sterilizing filter (made of PVDF material) to finally obtain the omadacycline tosylate liquid medicine.

[0116] 2) Freeze-drying

[0117] Pre-freezing: Fill the omadacycline tosylate liquid medicine and place it on the partition of the freeze-dryer that has been pre-cooled to a temperature of 5 °C. After all the samples are put into the chamber, cool it at a cooling rate of 1 °C / min to -45 °C and pre-freeze for 2 h;

[0118] Warming and freezing (annealing): Warm it up to -10 °C at a warming rate of 5 °C / min and continue freezing for 1 h;

[0119] Cooling and freezing: Cool it down to -45 °C again at a cooling rate of 1 °C / min and continue freezing for 1 h;

[0120] Primary drying: Warm it up to -8 °C within 1 h and dry it at -8 °C for 8 h with a vacuum degree of 0.25 mbar;

[0121] Secondary drying: Warm it up to 35 °C within 1 h and dry it at 35 °C for 3 h; warm it up to 45 °C within 10 min and dry it at 45 °C for 1 h with a vacuum degree of 0.02 mbar;

[0122] Conduct a pressure increase experiment to detect the end point of freeze-drying. If it is qualified, complete the freeze-drying cycle, and perform recompression with sterile nitrogen. The recompression pressure is 800 mbar, and release the air after plugging to obtain the freeze-dried powder injection of omadacycline tosylate for injection.

[0123] Example 2

[0124] A freeze-dried powder injection of omadacycline tosylate for injection. The prescription content per single vial is shown in the following table:

[0125]

[0126] The difference from the prescription of Example 1 is that the dosage of mannitol in the excipient is 60 mg

[0127] The preparation method comprises the following steps:

[0128] 1) The solution preparation is the same as that in Example 1.

[0129] 2) Freeze-drying

[0130] Pre-freezing: Fill the omadacycline tosylate liquid medicine, place it on the partition plate of the freeze-dryer pre-cooled to maintain a temperature of 5°C. After all the samples are put into the chamber, cool it at a cooling rate of 1°C / min to -45°C and pre-freeze for 2 h;

[0131] Warming and freezing (annealing): Warm it at a warming rate of 1°C / min to -10°C and continue to freeze for 1 h;

[0132] Cooling and freezing: Cool it again at a cooling rate of 1°C / min to -45°C and continue to freeze for 1 h;

[0133] Primary drying: Warm it to -8°C within 1 h and dry it at -8°C for 8 h with a vacuum degree of 0.25 mbar;

[0134] Secondary drying: Warm it to 35°C within 1 h and dry it at 35°C for 3 h with a vacuum degree of 0.1 mbar;

[0135] Detect the end point of freeze-drying by a pressure boosting experiment. If it is qualified, complete the freeze-drying cycle, perform re-pressurization with sterile nitrogen gas, the re-pressurization pressure is 800 mbar, and release the air after plugging to obtain the freeze-dried powder injection of omadacycline tosylate for injection.

[0136] Example 3

[0137] A freeze-dried powder injection of omadacycline tosylate for injection, the content of a single vial prescription is shown in the following table:

[0138]

[0139] The difference from the prescription in Example 1 is that the excipient is selected as hydroxypropyl-γ-cyclodextrin, and the pH regulator is selected as citric acid / tromethamine.

[0140] The preparation method comprises the following steps:

[0141] 1) The solution preparation is the same as that in Example 1.

[0142] 2) Freeze-drying:

[0143] Pre-freezing: Fill the omadacycline tosylate liquid medicine, place it on the partition plate of the freeze-dryer pre-cooled to maintain a temperature of 5°C. After all the samples are put into the chamber, cool it at a cooling rate of 1°C / min to -45°C and pre-freeze for 2 h;

[0144] Heating and freezing (annealing): Heat up to -10°C at a heating rate of 5°C / min and continue to freeze for 1 h;

[0145] Cooling and freezing: Cool down to -45°C again at a cooling rate of 1°C / min and continue to freeze for 1 h;

[0146] Primary drying: Heat up to -8°C within 1 h, dry at -8°C for 8 h, and the vacuum degree is 0.25 mbar;

[0147] Secondary drying: Heat up to 40°C within 1 h, dry at 40°C for 3 h, and the vacuum degree is 0.1 mbar;

[0148] Conduct a pressure boost experiment to detect the end point of freeze-drying. If qualified, complete the freeze-drying cycle, repressurize with sterile nitrogen, the repressurization pressure is 800 mbar, and release the gas after pressing the stopper to obtain the lyophilized powder for injection of omadacycline tosylate.

[0149] Example 4

[0150] A lyophilized powder for injection of omadacycline tosylate, and the content of a single vial prescription is shown in the following table:

[0151]

[0152]

[0153] The difference from the prescription of Example 1 is that in this example, the dosage of the excipient hydroxypropyl-γ-cyclodextrin is 408 mg. The preparation method is the same as that of Example 3.

[0154] Example 5

[0155] A lyophilized powder for injection of omadacycline tosylate, and the single vial prescription content is shown in the following table:

[0156]

[0157] The difference from the prescription of Example 1 is that in this example, the dosage of the excipient hydroxypropyl-γ-cyclodextrin is 510 mg. The preparation method is the same as that of Example 3.

[0158] Example 6

[0159] A lyophilized powder for injection of omadacycline tosylate, and the single vial prescription content is shown in the following table:

[0160]

[0161] The difference from the prescription of Example 3 is that in this example, the dosage of the excipient hydroxypropyl-γ-cyclodextrin is 612 mg. The preparation method is the same as that of Example 3.

[0162] Example 7

[0163] An omadacycline tosylate lyophilized powder for injection, the single-vial prescription content is shown in the following table:

[0164]

[0165]

[0166] The difference from the prescription of Example 1 is that in this example, the excipient is selected as hydroxypropyl-γ-cyclodextrin, and the pH regulator is selected as citric acid / arginine.

[0167] The preparation method includes the following steps:

[0168] 1) Solution preparation is the same as in Example 1.

[0169] 2) Freeze-drying:

[0170] Pre-freezing: Fill the omadacycline tosylate solution into vials, place them on the shelf of a freeze-dryer pre-cooled to a temperature of 5°C. After all the samples are put into the chamber, cool them at a rate of 5°C / min to -45°C and pre-freeze for 2 h;

[0171] Warming and freezing (annealing): Warm up at a rate of 5°C / min to -10°C and continue to freeze for 1.5 h;

[0172] Cooling and freezing: Cool down again at a rate of 1°C / min to -45°C and continue to freeze for 1 h;

[0173] Primary drying: Warm up to -8°C within 1 h, dry at -8°C for 8 h, and the vacuum degree is 0.25 mbar;

[0174] Secondary drying: Warm up to 40°C within 1 h, dry at 40°C for 3 h, and the vacuum degree is 0.02 mbar;

[0175] Conduct a pressure-rise experiment to detect the end point of freeze-drying. If it is qualified, complete the freeze-drying cycle, perform recompression with sterile nitrogen, the recompression pressure is 800 mbar, and release the pressure after plugging to obtain the omadacycline tosylate lyophilized powder for injection.

[0176] Example 8

[0177] An omadacycline tosylate lyophilized powder for injection, the single-vial prescription content is shown in the following table:

[0178]

[0179] The difference from the prescription of Example 7 is that in this example, the dosage of hydroxypropyl-β-cyclodextrin as the excipient is 306 mg, the pH regulator is arginine, and the pH of the solution is adjusted to about 8.0.

[0180] The preparation method comprises the following steps:

[0181] 1) The solution preparation is the same as that in Example 1.

[0182] 2) The lyophilization process is the same as that in Example 7.

[0183] Example 9

[0184] A lyophilized powder injection of omadacycline tosylate for injection, the single-vial prescription content is shown in the following table:

[0185] Function Raw and auxiliary materials Unit dosage Active ingredient Omadacycline tosylate 131 mg Excipient Hydroxypropyl-β-cyclodextrin 204 mg Solvent Add water for injection to 3ml

[0186] The difference from the prescription of Example 7 is that in this example, the content of the excipient hydroxypropyl-β-cyclodextrin is 204 mg, no pH regulator is added, and the pH of the solution is adjusted to about 6.0.

[0187] The preparation method comprises the following steps:

[0188] 1) The solution preparation is the same as that in Example 1.

[0189] 2) The lyophilization process is the same as that in Example 7.

[0190] Example 10

[0191] A lyophilized powder injection of omadacycline tosylate for injection, the single-vial prescription content is shown in the following table:

[0192]

[0193] The difference from the prescription of Example 7 is that in this example, the content of the excipient hydroxypropyl-β-cyclodextrin is 204 mg.

[0194] The preparation method comprises the following steps:

[0195] 1) The solution preparation is the same as that in Example 1.

[0196] 2) The lyophilization process is the same as that in Example 7.

[0197] Example 11 (Adjusting annealing temperature and time)

[0198] A lyophilized powder injection of omadacycline tosylate for injection, the single-vial prescription content is the same as that in Example 7.

[0199] The difference in the preparation method from Example 7 lies in the annealing temperature and time in the lyophilization process, which are specifically as follows:

[0200] Heating and freezing (annealing): Heating at a rate of 5 °C / min to -15 °C and continuing to freeze for 1 h.

[0201] Example 12 (Adjusting annealing temperature and time)

[0202] An omadacycline tosylate lyophilized powder for injection, with the same single vial prescription content as in Example 7.

[0203] The preparation method is different from that of Example 7 in the annealing temperature and time in the freeze-drying process, specifically as follows:

[0204] Heating and freezing (annealing): Heating at a rate of 5°C / min to -10°C and continuing to freeze for 30 min;

[0205] Example 13 (adjusting annealing temperature and time)

[0206] An omadacycline tosylate lyophilized powder for injection, with the same single vial prescription content as in Example 7.

[0207] The preparation method is different from that of Example 7 in the annealing temperature and time in the freeze-drying process, specifically as follows:

[0208] Heating and freezing (annealing): Heating at a rate of 5°C / min to -25°C and continuing to freeze for 2 h;

[0209] Comparative Example 1

[0210] A sample prepared according to the prescription and preparation method of Example 3 of Chinese Patent CN118845678A.

[0211] Test Example 1

[0212] Appearance: Visual inspection.

[0213] Clarity and color of the solution: Take 1 vial of the sample, dissolve it in 5 ml of water, and check the clarity according to the first method of General Chapter 0902 in Part IV of the Chinese Pharmacopoeia 2020 Edition. Color: Precisely measure 1 ml of the above solution, add water according to the labeled amount to make a solution containing about 10 μg of omadacycline per 1 ml, and check according to the third method of General Chapter 0901 in Part IV of the Chinese Pharmacopoeia 2020 Edition.

[0214] The Chinese Pharmacopoeia divides the color standard color comparison solution of the solution into 6 hues, including greenish yellow (GY), yellow (Y), yellowish green (YG), etc. Each hue contains 11 color numbers from 0.5 to 10, and the larger the value, the deeper the color.

[0215] Water content: Take 1 vial of the sample, dissolve the content in the vial with anhydrous methanol, and determine it according to the water content determination method (the first method 1 of General Chapter 0832 in Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0216] The test results are as follows:

[0217]

[0218]

[0219] In Examples 1-7, 10-13, during the 6-month accelerated inspection period, the appearance, clarity and color of the solution could remain relatively stable, comparable to those of Comparative Example 1 and the reference preparation.

[0220] As for the water content, the water content of Examples 1-13 of this application was less than 0.4 wt%, that is, they were all superior to the reference preparation (water content 0.6 wt%), and were superior to or comparable to Comparative Example 1 (water content 0.4 wt%). In particular, Examples 7, 11 (both with a water content of 0.2 wt%) and 12 (water content 0.3 wt%) were significantly superior to Comparative Example 1 and the reference preparation.

[0221] During the preparation process of Examples 8 and 9, the pH of the liquid medicine was on the high side, and the shape and color of the obtained samples were relatively dark.

[0222] Test Example 2

[0223] Acidity: Take 1 bottle of the sample, dissolve it with 5 ml of water, and determine the pH value of the solution according to the law (General Chapter 0631, Four Parts of Chinese Pharmacopoeia 2020 Edition).

[0224] Redissolution time: Take 1 bottle of this product, inject 5 ml of water for injection respectively, shake gently, and record the time when the content is completely dissolved.

[0225] Insoluble particles: Take this product and check it according to the law (the first method of General Chapter 0903, Four Parts of Chinese Pharmacopoeia 2020 Edition).

[0226] Related substances: Determined by high performance liquid chromatography (General Chapter 0512, Four Parts of Chinese Pharmacopoeia 2020 Edition), operating under light protection. Chromatographic conditions: Using octadecylsilane chemically bonded silica gel as the filler (Phenomenex Gemini C18, 4.6 mm × 250 mm, 5 μm); using potassium dihydrogen phosphate buffer solution as mobile phase A and acetonitrile as mobile phase B, and performing gradient elution according to the following table; the flow rate is 1.2 ml per minute; the column temperature is 35 °C; the detection wavelength is 280 nm; the injection chamber temperature is 5 °C; the injection volume is 10 μl.

[0227] Preparation of potassium dihydrogen phosphate buffer solution: Take 13.6 g of potassium dihydrogen phosphate, dissolve it in 900 ml of water, adjust the pH value to 6.45 - 6.50 with 10 mol / L sodium hydroxide solution, dilute it with water to 1000 ml, and then add 0.5 g of tetrabutylammonium hydrogen sulfate and 0.4 g of disodium ethylenediaminetetraacetate, dissolve and mix well.

[0228]

[0229] The test results are as follows:

[0230]

[0231]

[0232] The conclusions are as follows:

[0233] 1. The pH stability of the preparation of the present invention is outstanding: In terms of pH stability, except for Examples 8 and 9, the pH value fluctuations of the remaining examples (Examples 1-7, 10-13) after the accelerated test are all ≤0.1, and the stability performance is significantly better than that of Comparative Example 1 (the fluctuation is 0.12) and the reference preparation (the fluctuation is 0.17).

[0234] 2. The reconstitution time of the preparation of the present invention is greatly shortened: The reconstitution time of the reference preparation is 42-50 seconds, and the reconstitution time of Comparative Example 1 is as high as 1 minute and 20 seconds. Except for Examples 1, 8-10, the reconstitution times of the remaining examples of the present application are all less than 42 seconds. In particular, for Example 7, the reconstitution time is 10 seconds, and the reconstitution efficiency is improved by 4-8 times compared with Comparative Example 1 and the reference preparation, greatly optimizing the convenience of clinical use.

[0235] 3. The insoluble particles of the preparation of the present invention are significantly reduced: The reference preparation has ≥34 particles / bottle of ≥10μm and 1 particle / bottle of ≥25μm at 0 day, and Comparative Example 1 has ≥112 particles / bottle of ≥10μm and 1 particle / bottle of ≥25μm. The insoluble particle conditions of Examples 3, 7, 11-13 of the present application at 0 day are all better than those of the reference preparation and Comparative Example 1. In particular, for Example 7 at 0 day, the insoluble particle condition is ≥8 particles / bottle of ≥10μm and 0 particles / bottle of ≥25μm, and the number of insoluble particles is significantly reduced compared with the reference preparation and Comparative Example 1, greatly improving the safety of clinical medication.

[0236] 4. The total impurity amount of the preparation of the present application is strongly controllable: After the accelerated test, the total impurity of the reference preparation increased from 3.80% to 6.81% (the increase rate is 3.01%), and the total impurity of Comparative Example 1 increased from 2.76% to 4.96% (the increase rate is 2.20%). However, the total impurity number and increase rate of Examples 7, 11-13 of the present application are better than those of the reference preparation and Comparative Example 1. In particular, for Example 7, the total impurity only increased from 2.26% to 2.98% (the increase rate is 0.07%), and the impurity degradation rate is significantly reduced, indicating that the present application preparation has obvious advantages in the control of the total impurity amount during storage.

[0237] In summary, the omadacycline tosylate lyophilized powder for injection of the present invention contains omadacycline tosylate, excipients and a sodium-free pH regulator, and uses a special preparation process (preferably the prescription composition and preparation method of Examples 7, 11-13 of the present invention), and the following improvements are achieved:

[0238] 1) The reconstitution speed of the lyophilized powder for injection is increased, and at the same time, the clarity of the solution after reconstitution is not affected;

[0239] 2) Break through the long-term dependence on sucrose excipients in traditional freeze-drying processes. By means of the unique cavity inclusion effect of cyclodextrin molecules, effectively reduce the moisture content and the growth rate of related substances, and improve the stability;

[0240] 3) Expand the applicable population of the drug.

[0241] All documents mentioned in the present invention are cited herein for reference as if each document was individually cited for reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. Omadacycline tosylate lyophilized powder for injection, characterized in that, The lyophilized powder injection comprises omadacycline tosylate, an excipient and a pH regulator; The excipient is selected from the group consisting of mannitol, trehalose, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, or a combination thereof.

2. The freeze-dried powder injection according to claim 1, wherein The pH regulator does not contain sodium element.

3. The freeze-dried powder injection according to claim 1, wherein The pH regulator is selected from the group consisting of citric acid, histidine, tromethamine, arginine, or a combination thereof.

4. The freeze-dried powder injection according to claim 1, characterized in that, The lyophilized powder injection comprises: 125-135 parts by weight of omadacycline tosylate; 100-700 parts by weight of excipient; The pH regulator in an amount such that the pH of the reconstituted solution is 3.0-8.

0.

5. The freeze-dried powder injection according to claim 1, wherein The said lyophilized powder injection is prepared from an omadacycline tosylate solution; The said solution comprises omadacycline tosylate, an excipient, a pH regulator and an optional solvent.

6. The freeze-dried powder injection according to claim 1, wherein The said solvent is water for injection.

7. The freeze-dried powder injection according to claim 1, wherein, The water content in the lyophilized powder injection is 0.01-0.4 wt%, preferably 0.1-0.4 wt%, more preferably 0.1-0.35 wt%, and most preferably 0.2-0.3 wt%.

8. A method for preparing a freeze-dried powder injection according to any one of claims 1-7, characterized in that, The said preparation method comprises the following steps: S1. Mix omadacycline tosylate, an excipient, a pH regulator and a solvent to obtain an omadacycline tosylate solution; S2. Lyophilize the omadacycline tosylate solution obtained in step S1 to obtain omadacycline tosylate lyophilized powder.

9. The preparation method according to claim 1, wherein The said step S1 comprises the following steps: Dissolve the excipient in a part of the solvent, add omadacycline tosylate to dissolve it at 20-30 °C, add the pH regulator to make the pH 3.0-8.0, supplement the remaining solvent, and filter to obtain the omadacycline tosylate solution.

10. The preparation method according to claim 1, characterized in that, The lyophilization in the said step S2 comprises the following steps: Pre-freezing: Cool the omadacycline tosylate solution obtained in step S1 at a cooling rate of 1-10 °C / min to -50--40 °C and keep it warm for 1-5 h; Heating and freezing: Heat it at a heating rate of 1-10 °C / min to -30--10 °C and keep it warm for 0.5-4 h; Cooling and freezing: Cool it at a cooling rate of 0.5-5 °C / min to -50--40 °C and keep it warm for 0.5-4 h; Primary drying: Under the condition of -15--2 °C, vacuum dry for 5-15 h; Secondary drying: Under the condition of 35-45 °C, vacuum dry for 1-8 h.

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