Tegoprazan pyroglutamate injection and preparation method therefor

Abstract

A tegoprazan pyroglutamate injection consisting of an active ingredient tegoprazan pyroglutamate and an alcohol solvent, and a preparation method therefor. The injection has relatively high stability.

Description

Pyroglutamic acid tegoprazan injection and preparation method thereof

[0001] The present application claims priority to Chinese patent application 2024112325120 with the filing date of 2024 / 9 / 4. The present application incorporates the entire text of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to the field of pharmaceutical preparations, in particular, to a pyroglutamic acid tegoprazan injection and a preparation method thereof. BACKGROUND

[0003] The pyroglutamic acid tegoprazan injection is a potassium ion competitive acid blocker (P-CAB), which inhibits acid secretion by competitively blocking the activity of potassium ions in H-K-ATPase.

[0004] The main component of the product is pyroglutamic acid tegoprazan, and the chemical name is (S)-4-[(5,7-difluorobenzodihydropyran-4-yl)oxy]-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide pyroglutamate.

[0005] Chemical structural formula:

[0006] In the application of clinical treatment of various diseases such as duodenal ulcer, gastric ulcer and reflux esophagitis, the pharmaceutical preparation needs to have rapid release and quickly reach the therapeutic effect to reduce the pain of the clinical patients, and intravenous infusion is the most commonly used method for the disease in clinical practice. Since pyroglutamic acid tegoprazan is easily dissociated into tegoprazan in water, the solubility of tegoprazan compound is very low, although the solubility of pyroglutamic acid tegoprazan is increased, but it is not enough to produce a significant effect, it is difficult to prepare a stable preparation in aqueous solution, therefore, a solubilizing agent, such as a surfactant and a non-aqueous solvent, is needed to improve the solubility and avoid the risk of dissociation into tegoprazan precipitation, which affects the clinical compatibility. SUMMARY

[0007] The present application provides a pyroglutamic acid tegoprazan injection and a preparation method thereof to solve the problems in the prior art. The prepared product has good drug stability and does not have crystallization phenomenon after long-term storage, meeting the quality requirements of injections.

[0008] The purpose of the present application is to provide a pyroglutamic acid tegoprazan injection.

[0009] Preferably, the pyroglutamic acid tegoprazan injection is composed of the active ingredient pyroglutamic acid tegoprazan and an alcohol solvent.

[0010] Preferably, the alcohol solvent is one or more of propylene glycol, absolute ethanol and polyethylene glycol; further preferably, the alcohol solvent is one of propylene glycol, polyethylene glycol or a combination of propylene glycol and polyethylene glycol.

[0011] Preferably, the polyethylene glycol is polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 800 or a mixture thereof, further preferably, the polyethylene glycol is polyethylene glycol 400.

[0012] Preferably, the weight ratio of pyroglutamic acid tegoprazin (calculated as tegoprazin) to alcohol solvent is 1:10-100; further preferably, the weight ratio of pyroglutamic acid tegoprazin (calculated as tegoprazin) to alcohol solvent is 1:20-50.

[0013] Another object of the present application is to provide a preparation method of the pyroglutamic acid tegoprazin injection as described above, which comprises the following steps:

[0014] The pyroglutamic acid tegoprazin is added to the alcohol solvent under stirring, stirred uniformly, filtered, and the resulting medicinal liquid is filled into ampoules, fusion sealed, and then sterilized by over-sterilization, to obtain the pyroglutamic acid tegoprazin injection.

[0015] Preferably, the temperature of the sterilization method is 121℃, and the sterilization time is 12min-15min.

[0016] Preferably, the temperature of the sterilization method is 121℃, and the sterilization time is 12min-15min.

[0017] The present application achieves the following beneficial technical effects:

[0018] (1) The prescription of the present application contains an alcohol solvent, which avoids the dissociation of pyroglutamic acid tegoprazin into tegoprazin, improves the product stability and compatibility stability, and ensures the product quality and medication safety;

[0019] (2) The auxiliary materials used in the present application are all conventional auxiliary materials for injections, and the preparation method has simple operation procedures and easy-to-control processes. DETAILED DESCRIPTION

[0020] The pyroglutamic acid tegoprazin raw material is prepared according to the method of Example 1 of patent CN109769392B.

[0021] Example 1

[0022] Prescription:

[0023] The component content of the pyroglutamic acid tegoprazin injection is:

[0024] Pyroglutamic acid tegoprazin (calculated as tegoprazin) 1g

[0025] Propylene glycol 20 g

[0026] Preparation method: pyroglutamic acid tegoprazin is added into the prescribed amount of alcohol solvent under stirring, stirred uniformly, filtered, and the obtained medicinal liquid is filled into ampoule bottles, sealed, and then sterilized by over-sterilization method.

[0027] Example 2

[0028] Prescription:

[0029] The component content of pyroglutamic acid tegoprazin injection is:

[0030] Pyroglutamic acid tegoprazin (calculated as tegoprazin) 1 g

[0031] Anhydrous ethanol 20 g

[0032] Preparation method: pyroglutamic acid tegoprazin is added into the prescribed amount of alcohol solvent under stirring, stirred uniformly, filtered, and the obtained medicinal liquid is filled into ampoule bottles, sealed, and then sterilized by over-sterilization method.

[0033] Example 3

[0034] Prescription:

[0035] The component content of pyroglutamic acid tegoprazin injection is:

[0036] Pyroglutamic acid tegoprazin (calculated as tegoprazin) 1 g

[0037] Polyethylene glycol 400 50 g

[0038] Preparation method: pyroglutamic acid tegoprazin is added into the prescribed amount of alcohol solvent under stirring, stirred uniformly, filtered, and the obtained medicinal liquid is filled into ampoule bottles, sealed, and then sterilized by over-sterilization method.

[0039] Example 4

[0040] Prescription:

[0041] The component content of pyroglutamic acid tegoprazin injection is:

[0042] Pyroglutamic acid tegoprazin (calculated as tegoprazin) 1 g

[0043] Polyethylene glycol 400 10 g

[0044] Preparation method: pyroglutamic acid tegoprazin is added into the prescribed amount of alcohol solvent under stirring, stirred uniformly, filtered, and the obtained solution is filled into ampoule bottles, sealed, and then sterilized by over-sterilization method.

[0045] Example 5

[0046] Prescription:

[0047] The component content of pyroglutamic acid tegoprazin injection is:

[0048] Pyroglutamic acid tegoprazin (calculated as tegoprazin) 1 g

[0049] Propylene glycol 50 g

[0050] Polyethylene glycol 400 50 g

[0051] Preparation method: pyroglutamic acid tegoprazin is added into the prescribed amount of alcohol solvent under stirring, stirred uniformly, filtered, and the obtained solution is filled into ampoule bottles, sealed, and then sterilized by over-sterilization method.

[0052] Comparative example 1

[0053] Prescription with injection water:

[0054] Pyroglutamic acid tegoprazin (calculated as tegoprazin) 1 g

[0055] Injection water 20 g

[0056] Preparation method: pyroglutamic acid tegoprazin is added into the prescribed amount of injection water under stirring, stirred uniformly, filtered, and the obtained solution is filled into ampoule bottles, sealed, and then sterilized by over-sterilization method. The obtained product is turbid.

[0057] Experimental example 1: solution stability investigation

[0058] The solutions before sterilization prepared according to the methods of examples 1-5 and comparative example 1 are respectively placed at room temperature for 12 h and 24 h, and the stability of the solution before sterilization is investigated, and the experimental results are shown in Table 1.

[0059] Table 1: solution stability results

[0060] As shown in Table 1, the pyroglutamic acid tegoprazin product component prepared by the present application contains an alcoholic solvent, and is stable when left at room temperature for 24 hours, meeting the requirements of injection preparations. In the control example 1, water for injection is used as the solvent, and the prepared solution does not meet the pharmaceutical requirements in terms of clarity.

[0061] Experimental Example 2: Sterilization results

[0062] The injection solutions prepared according to the methods of Examples 1-5 and the control example 1 are sterilized, and the product clarity and total impurity results are shown in Table 2.

[0063] Table 2: Comparison of sterilization results

[0064] As shown in Table 2, the pyroglutamic acid tegoprazin injection prepared by the present application contains an alcoholic solvent, and after sterilization, the clarity and total impurities meet the requirements of the preparation; in the control example 1, water for injection is used as the solvent, and the prepared solution has a clarity of >2 and a high total impurity content, which does not meet the pharmaceutical requirements.

[0065] Experimental Example 3: Compatibility stability investigation results

[0066] The injection solutions of the present application prepared according to the methods of Examples 1-5 and the control example 1 are diluted 25-fold and 125-fold with 0.9% sodium chloride injection and 5% glucose injection, respectively, and left at room temperature for 24 hours, and the clarity is observed, and the results are shown in Table 3.

[0067] Table 3: Compatibility stability investigation results

[0068] As shown in Table 3, the pyroglutamic acid tegoprazin injection prepared by the present application has a clarity that meets the requirements of the preparation after being diluted.

Claims

1. Pyritinol tegolapant injection, characterized by, The pyroglutamic acid tegoprazin injection is composed of pyroglutamic acid tegoprazin and an alcohol solvent.

2. Pyritinol injection according to claim 1, characterized in that, The alcohol solvent is one or more of propylene glycol, anhydrous ethanol and polyethylene glycol.

3. Pyritinol injection according to claim 1, characterized in that, The pyroglutamic acid tegoprazin is tegoprazin, and the weight ratio of tegoprazin to the alcohol solvent is 1:10-100.

4. Pyritinol injection according to claim 3, characterized in that, The pyroglutamic acid tegoprazin is tegoprazin, and the weight ratio of tegoprazin to the alcohol solvent is 1:20-50.

5. The pyritinyl tegoprazan injection of claim 2, wherein the pyritinyl tegoprazan injection is a solution of pyritinyl tegoprazan in a pharmaceutically acceptable solvent. The alcohol solvent is propylene glycol.

6. The pyritinyl tegoprazan injection of claim 2, wherein the pyritinyl tegoprazan injection is a solution of pyritinyl tegoprazan in a pharmaceutically acceptable solvent. The alcohol solvent is polyethylene glycol.

7. Pyritinol injection according to claim 6, characterized in that, The polyethylene glycol is polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 800 or a mixture thereof.

8. Pyritinol injection according to claim 7, characterized in that, The polyethylene glycol is polyethylene glycol 400.

9. The pyroglutamic acid tegoprazin injection of claim 2, wherein the alcohol solvent is a combination of propylene glycol and polyethylene glycol.

10. A method for preparing pyritinyl tegoprazan injection according to any one of claims 1 to 9, characterized by, The preparation method comprises the following steps: The pyroglutamic acid tegoprazin is added into the alcohol solvent under stirring, stirred uniformly, filtered, and then the obtained medicine solution is filled into ampoules, sealed, sterilized by over-sterilization, and then the pyroglutamic acid tegoprazin injection is obtained; wherein the sterilization temperature is 121℃, and the sterilization time is 12min-15min.

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