Tgorazan injection and preparation method thereof

Abstract

The invention provides a tigorazan injection and a preparation method thereof. The injection comprises tigorazan, pyroglutamic acid, a cosolvent and water for injection. The preparation method comprises the following steps: preparing pyroglutamic acid into a pyroglutamic acid solution with a certain concentration by using water for injection; the preparation method comprises the following steps: adding tigorazan into a cosolvent, adding a pyroglutamic acid solution for dissolving, filtering, filling, filling nitrogen, sealing and sterilizing. The obtained product is excellent in clarity and stability, and the preparation method is low in production cost, simple in technological process, high in operability and suitable for industrial mass production.

Description

[0001] This application claims priority to Chinese Patent Application No. 2024113698918, filed on September 29, 2024. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical preparations, specifically to a ticoraxen injection and its preparation method. Background Technology

[0003] Tigorafenib is a potassium-competitive acid blocker (P-CAB) that inhibits acid secretion by competitively blocking the activity of potassium ions in HK-ATPase.

[0004] The main ingredient of this product is ticoraxan, chemical name: (S)-4-[(5,7-difluorobenzodihydropyran-4-yl)oxy]-N,N,2-trimethyl-1H-benzo[d]imidazol-6-carboxamide.

[0005] Chemical structural formula:

[0006]

[0007] Molecular weight: 387.5.

[0008] Tigrasen has the use of prevention and treatment for diseases mediated by acid pump antagonistic activity, including various diseases of duodenal ulcers, gastric ulcers, and reflux esophagitis.

[0009] Tigorafenib itself is a poorly soluble drug, making it difficult to formulate into an injection by dissolving it in an aqueous solvent. Therefore, there is an urgent need to research new formulations and preparation methods to solve the technical challenges faced by existing technologies. Summary of the Invention

[0010] To address the problems existing in the prior art, this invention provides a ticoraxen injection and its preparation method. This invention solves the product solubility problem, and the preparation method has fewer process steps, reduces production costs, is highly operable, and is suitable for large-scale industrial production.

[0011] One object of the present invention is to provide a ticoraxen injection comprising ticoraxen, pyroglutamic acid, a solubilizer and water for injection.

[0012] Preferably, the ticoraxen injection contains 2.5% ticoraxen by weight.

[0013] Preferably, the tegoprasen injection contains 0.8% pyroglutamic acid by weight.

[0014] Preferably, the cosolvent content in the ticoraxone injection is 70-90% by weight, more preferably 80-90%.

[0015] Preferably, the water for injection in the injection contains 6.7% to 26.7% by weight, more preferably 6.7% to 16.7%.

[0016] Preferably, the weight ratio of ticoraxan, pyroglutamic acid, solubilizer, and water for injection is 2.5%:0.8%:70-90%:6.7%-26.7%; more preferably, the weight ratio of ticoraxan, pyroglutamic acid, solubilizer, and water for injection is 2.5%:0.8%:80-90%:6.7%-16.7%.

[0017] Preferably, the co-solvent is one or a combination of two of propylene glycol, polyethylene glycol and anhydrous ethanol; more preferably, the co-solvent is propylene glycol.

[0018] Another object of the present invention is to provide a method for preparing the above-mentioned ticoraxen injection, comprising the following steps:

[0019] 1) Prepare a pyroglutamic acid solution with a mass percentage concentration of 3% to 20% using water for injection;

[0020] 2) Add ticoraxan to the solubilizer, add pyroglutamic acid solution until ticoraxan is completely dissolved, filter, fill, fill with nitrogen, seal, and sterilize.

[0021] Preferably, the sterilization conditions are: sterilization temperature 115-121℃, sterilization time 15-30 minutes.

[0022] The beneficial effects achieved by this invention are as follows:

[0023] 1) The tigorasen injection formulation provided by this invention solves the technical problem of product solubility and has good drug stability, meeting all quality requirements for injections;

[0024] 2) This invention involves the formation of a salt from water-insoluble ticoraxan and pyroglutamic acid in a solvent, and the simultaneous preparation of an injection solution. This method has a simple process flow, strong operability, low production cost, and is suitable for large-scale industrial production. Detailed Implementation

[0025] The present invention will now be described in detail with reference to specific embodiments.

[0026] Example 1

[0027] A ticoraxen injection is prepared from the following raw materials by weight:

[0028]

[0029] The preparation method of ticoraxen injection includes the following steps:

[0030] 1) Prepare a pyroglutamic acid solution with a mass percentage concentration of 5% using water for injection;

[0031] 2) Add ticoraxan to propylene glycol and continue adding pyroglutamic acid solution until ticoraxan is completely dissolved. Filter, fill, fill with nitrogen, seal, and finally sterilize at 115°C for 30 minutes.

[0032] Example 2

[0033] A ticoraxen injection is prepared from the following raw materials by weight:

[0034]

[0035] The preparation method of ticoraxen injection includes the following steps:

[0036] 1) Prepare a pyroglutamic acid solution with a mass percentage concentration of 12% using water for injection;

[0037] 2) Add ticoraxan to propylene glycol and continue adding pyroglutamic acid solution until ticoraxan is completely dissolved. Filter, fill, fill with nitrogen, seal, and finally sterilize at 121°C for 15 minutes.

[0038] Example 3

[0039] A ticoraxen injection is prepared from the following raw materials by weight:

[0040]

[0041] The preparation method of ticoraxen injection includes the following steps:

[0042] 1) Prepare a pyroglutamic acid solution with a mass percentage concentration of 3% using water for injection;

[0043] 2) Add ticoraxan to propylene glycol and continue adding pyroglutamic acid solution until ticoraxan is completely dissolved. Filter, fill, fill with nitrogen, seal, and finally sterilize at 117°C for 18 minutes.

[0044] Example 4

[0045] A ticoraxen injection is prepared from the following raw materials by weight:

[0046]

[0047] The preparation method of ticoraxen injection includes the following steps:

[0048] 1) Prepare a 7% (w / w) pyroglutamic acid solution using water for injection;

[0049] 2) Add ticoraxan to anhydrous ethanol, and continuously add pyroglutamic acid solution until ticoraxan is completely dissolved. Filter, fill, fill with nitrogen, seal, and finally sterilize at 121°C for 15 minutes.

[0050] Example 5

[0051] A ticoraxen injection is prepared from the following raw materials by weight:

[0052]

[0053]

[0054] The preparation method of ticoraxen injection includes the following steps:

[0055] 1) Prepare a 7% (w / w) pyroglutamic acid solution using water for injection;

[0056] 2) Add ticoraxan to polyethylene glycol and continue adding pyroglutamic acid solution until ticoraxan is completely dissolved. Filter, fill, fill with nitrogen, seal, and finally sterilize at 121°C for 15 minutes.

[0057] Verification Example 1: Investigation of Solution Clarity

[0058] The solutions of the present invention prepared according to the methods of Examples 1-5 were examined for clarity before and after filtration, and for clarity when the filtered solution was mixed with 0.9% sodium chloride injection (1:5) and 5% glucose injection (1:5). The experimental results are shown in Table 1.

[0059] Table 1: Clarity results of the solution before and after filtration and after mixing with glucose and sodium chloride.

[0060]

[0061] As can be seen from Table 1, the pyroglutamic acid ticoraxan solution prepared with anhydrous ethanol as the co-solvent had solid precipitation before filtration. The pyroglutamic acid ticoraxan solution prepared with polyethylene glycol showed significantly improved clarity after mixing. Therefore, the product prepared in this invention containing propylene glycol as the co-solvent is significantly superior to other co-solvents in terms of clarity.

[0062] Verification Example 2: Sterilization Examination

[0063] The injection solutions prepared according to the methods of Examples 1-3 and Example 5 were examined for their clarity after sterilization, as well as their clarity when mixed with 0.9% sodium chloride injection (1:5) and 5% glucose injection (1:5). The experimental results are shown in Table 2.

[0064] Table 2: Results of Clarity Evaluation After Sterilization and Mixing with Glucose and Sodium Chloride

[0065]

[0066]

[0067] As can be seen from Table 2, after sterilization, the salt-forming agent and co-solvent propylene glycol selected for the ticoraxan injection of the present invention have no significant effect on the clarity of the formulation. However, the clarity and color of the formulation are deepened after preparation with polyethylene glycol.

[0068] Verification Example 3: Results of the investigation on the stability of the relevant substances

[0069] The injection solution of the present invention was prepared according to the methods of Examples 1-3 and Example 5. The results of the stability study of the relevant substances are shown in Table 3.

[0070] Table 3: Results of Sterilization Stability Study

[0071]

[0072] As can be seen from Table 3, the related substances in the ticoraxane injection prepared by this invention are significantly reduced with the increase of the proportion of propylene glycol as a cosolvent. The preferred weight ratio of propylene glycol is 80-90%.

Claims

1. A tegoprazan injection, characterized by, The tegoprazan injection contains tegoprazan, pyroglutamic acid, a cosolvent and water for injection.

2. Tigobarine injection as claimed in claim 1, wherein, The tegoprazan injection meets one or more of the following conditions: The tegoprazan injection contains 2.5% tegoprazan by weight; The tegoprazan injection contains 0.8% pyroglutamic acid by weight; The tegoprazan injection contains 70-90% cosolvent by weight, preferably 80-90% by weight; The injection contains 6.7-26.7% water for injection by weight, preferably 6.7-16.7% by weight.

3. Tigobarine injection as claimed in claim 1, wherein, The tegoprazan, pyroglutamic acid, cosolvent and water for injection are in a weight ratio of 2.5%:0.8%:70-90%:6.7%-26.7%.

4. Tigobarine injection as claimed in claim 3, wherein, The tegoprazan, pyroglutamic acid, cosolvent and water for injection are in a weight ratio of 2.5%:0.8%:80-90%:6.7%-16.7%.

5. Tigobarine injection as claimed in claim 1, wherein, The cosolvent is one or a combination of propylene glycol, polyethylene glycol or anhydrous ethanol.

6. Tigobarine injection as claimed in claim 5, wherein, The cosolvent is propylene glycol.

7. Tigobarine injection as claimed in claim 1, wherein, The preparation method of the tegoprazan injection includes the following steps: 1) Prepare a pyroglutamic acid solution by dissolving pyroglutamic acid in water for injection; 2) Add tegoprazan to the cosolvent, add the pyroglutamic acid solution until the tegoprazan is completely dissolved, filter, fill, fill with nitrogen, seal, sterilize.

8. Tigobarine injection as claimed in claim 7, wherein, The sterilization conditions are a sterilization temperature of 115-121°C and a sterilization time of 15-30 minutes.

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