Tgorasone fumarate injection and preparation method thereof

Abstract

The invention provides a tigorasone fumarate injection and a preparation method thereof, and belongs to the technical field of medicines. The injection provided by the invention is prepared from tigorasone fumarate, a pH (Potential of Hydrogen) regulator and water for injection. The tegorasone fumarate injection has various medicine applications of inhibiting gastric acid secretion, promoting gastric ulcer healing and preventing reflux esophagitis. The injection can tolerate terminal sterilization, and is high in safety and good in stability.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a tegolan fumarate injection and a preparation method thereof. Background Art

[0002] Tegoprazan, chemically known as (S)-4-[(5,7-difluorobenzodihydropyran-4-yl)oxy]-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, is a new potassium ion competitive acid inhibitor developed by Pfizer Pharmaceuticals Co., Ltd. It was approved in South Korea in 2018 for the treatment of erosive esophagitis and gastroesophageal reflux disease. It is developed, produced and commercialized in China by Luoxin Pharmaceuticals, and was approved for marketing in China in April 2022, with the indication of reflux esophagitis.

[0003] The structural formula of tegrasen is as follows:

[0004]

[0005] Tigorazine is a novel potassium ion competitive acid inhibitor that can be highly concentrated in the H cells of the oxyntic tubule wall. + / K + -The lumenal surface of the ATPase (proton pump) is rapidly protonated and non-covalently binds to the K of the proton pump in the gastric parietal cells in the form of ions. + It competitively binds to the site, competitively blocking the binding of potassium ions with hydrogen ions and potassium ion-ATPase in the final stage of gastric acid secretion by gastric parietal cells, thus exerting a powerful and lasting inhibitory effect on gastric acid secretion.

[0006] Due to China's diet and lifestyle, the incidence of esophagitis and gastroesophageal reflux disease is high in China, but there are few first-line drugs available, and most of them are oral solid preparations, which makes it very difficult for children, the elderly and patients with dysphagia to take medicine, and it is difficult to ensure patient compliance. Therefore, the public is looking for injectable dosage forms that can significantly improve patient compliance, take effect quickly, have higher bioavailability, and are safe and stable.

[0007] However, there are huge challenges in developing an injectable dosage form of tigolasen due to the following reasons: 1) tigolasen has low solubility in aqueous media over a wide pH range; 2) tigolasen aqueous solutions have poor stability, especially in acidic aqueous solutions below pH 3.0, where they are prone to degradation.

[0008] Patent KR20240109898 reports a method for preparing solid dispersions using a solvent method to improve drug solubility. Tigorapen and polymer carriers, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and polyvidone (PVP), are dissolved in organic reagents such as ethanol and methanol, and then dried by rotary evaporation to obtain a solid dispersion of Tigorapen, thereby improving the solubility of the drug. However, this method requires the use of a large amount of organic reagents, which seriously affects the safety of the drug.

[0009] Patent CN110876259A reports a freeze-dried preparation composed of a pharmaceutically acceptable salt of tigorafenib and a stabilizer, which solves the solubility problem of tigorafenib in water and the stability problem of the aqueous solution. However, the salt-forming step may introduce other organic and inorganic impurities that have an irreversible effect on the product quality; and the preparation process is complex and energy-intensive.

[0010] Patent WO2004012738 reports the preparation of desloratadine into desloratadine fumarate with higher stability and solubility.

[0011] Therefore, those skilled in the art still expect to find a tegrasin injection that can be directly administered intravenously. Compared with lyophilized preparations, injections are not only more convenient and quicker in clinical use, but also have simpler production processes, shorter production cycles, and lower production costs. Compared with oral solid preparations, injections take effect more quickly and are suitable for patients with oral dysphagia. Of course, any such intravenous preparation must show chemical and physical stability within the shelf life of the product. Summary of the invention

[0012] The object of the present invention is to provide a tigolasan fumarate injection and a preparation method thereof, so as to solve the technical problems that tigolasan has low solubility in the body and is not easily accepted by people with dysphagia, and there is no pharmaceutical preparation of tigolasan for direct intravenous injection.

[0013] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0014] The present invention provides a teigolan fumarate injection, comprising teigolan fumarate, a pH regulator and water for injection;

[0015] The chemical structural formula of the fumarate teigolan is as follows:

[0016]

[0017] Furthermore, the pH adjuster comprises one or more of hydrochloric acid, citric acid, fumaric acid, acetic acid and lactic acid.

[0018] Furthermore, the adjustment range of the pH adjuster is 3.0 to 5.1.

[0019] Furthermore, the content of tigolasan fumarate in the tigolasan fumarate injection is 2.5 to 10.0 mg / mL.

[0020] The present invention provides a method for preparing tegolan fumarate injection, comprising the following steps:

[0021] 1) Weighing a prescribed amount of tegoraxan fumarate and dissolving it in 80% water for injection to prepare a liquid to obtain a drug solution;

[0022] 2) Using a pH adjuster to adjust the pH of the drug solution to 3.0-5.1, adding water for injection to the full amount, to obtain an injection solution;

[0023] 3) Filter the injection solution through 0.45 μm and 0.22 μm filter membranes in sequence;

[0024] 4) The filtered injection solution is filled, sealed and sterilized in sequence.

[0025] Furthermore, the temperature of the prepared solution is 25-75°C.

[0026] Furthermore, the sterilization temperature is 116-121° C., and the sterilization time is 8-40 minutes.

[0027] Beneficial effects of the present invention:

[0028] The injection of the invention can withstand terminal sterilization and has high safety and good stability. DETAILED DESCRIPTION

[0029] The present invention provides a teigolan fumarate injection, comprising teigolan fumarate, a pH regulator and water for injection;

[0030] The chemical structural formula of the fumarate teigolan is as follows:

[0031]

[0032] In the present invention, the pH adjuster comprises one or more of hydrochloric acid, citric acid, fumaric acid, acetic acid and lactic acid, preferably a 1M hydrochloric acid solution.

[0033] In the present invention, the pH adjusting agent has an adjustment range of 3.0 to 5.1, preferably 3.1 to 5.0, and more preferably 3.5 to 3.99.

[0034] In the present invention, the content of tegolasen fumarate in the tegolasen fumarate injection is 2.5 to 10.0 mg / mL, preferably 3.0 to 8.0 mg / mL, and more preferably 3.25 to 6 mg / mL.

[0035] The present invention provides a method for preparing tegolan fumarate injection, comprising the following steps:

[0036] 1) Weighing a prescribed amount of tegoraxan fumarate and dissolving it in 80% water for injection to prepare a liquid to obtain a drug solution;

[0037] 2) Using a pH adjuster to adjust the pH of the drug solution to 3.0-5.1, adding water for injection to the full amount, to obtain an injection solution;

[0038] 3) Filter the injection solution through 0.45 μm and 0.22 μm filter membranes in sequence;

[0039] 4) The filtered injection solution is filled, sealed and sterilized in sequence.

[0040] In the present invention, the temperature of the prepared solution is 25 to 75°C, preferably 35 to 65°C, and more preferably 45 to 55°C.

[0041] In the present invention, the sterilization temperature is 116-121° C., preferably 121° C.; the sterilization time is 8-40 min, preferably 10-30 min, and more preferably 15-20 min.

[0042] In the present invention, the prepared tegolan fumarate injection is administered in the form of intravenous drip.

[0043] In the present invention, the prepared tegolan fumarate injection has multiple pharmaceutical uses of inhibiting gastric acid secretion, promoting gastric ulcer healing and preventing reflux esophagitis.

[0044] In the present invention, the inventors prepared tigolasen into fumarate, and the solubility of the drug was significantly increased compared with tigolasen. Table 1 shows the solubility data of tigolasen and tigolasen fumarate under various pH conditions.

[0045] Table 1 Raw material solubility data

[0046]

[0047] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0048] The compositions of the injection solutions of Examples 1 to 6 are shown in Table 2 below.

[0049] Table 2 Injection composition of Examples 1 to 6

[0050]

[0051] Preparation method:

[0052] (1) Take 80% of the prescribed amount of water for injection, add tegolanine fumarate under different preparation temperatures, and stir to dissolve.

[0053] (2) Use 1M hydrochloric acid solution to adjust the pH of the solution to 3.0-5.0 and add water for injection to the full amount.

[0054] (3) Place each sample at different temperatures and take samples at 0 h, 10 h, and 24 h to detect related substances and pH values.

[0055] The compositions of the injection solutions of Examples 7 to 11 are shown in Table 3 below.

[0056] Table 3 Composition of injection solutions of Examples 7 to 11

[0057] Components Example 7 Example 8 Example 9 Example 10 Embodiment 11 Tegolaxan Fumarate 3.25g 3.25g 3.25g 3.25g 3.25g 1M hydrochloric acid solution Moderate Moderate Moderate Moderate Moderate Made in total 500mL 500mL 500mL 500mL 500mL pH 1.99 3.01 3.99 5.03 6.02

[0058] Preparation method:

[0059] (1) Weigh the prescribed amount of API and dissolve it in 80% water for injection at a temperature of 25-75°C.

[0060] (2) Use 1M hydrochloric acid solution to adjust the pH of the solution and add water for injection to the full volume.

[0061] (4) The drug solution was filtered through 0.45 μm and 0.22 μm filter membranes respectively.

[0062] (5) Fill each sample in a glass ampoule and seal it with a melt.

[0063] (6) Sterilize at 121°C for 15 min.

[0064] The compositions of the injection solutions of Examples 12 to 14 are shown in Table 4 below.

[0065] Table 4 Composition of injection solutions of Examples 12 to 14

[0066]

[0067] Preparation method:

[0068] (1) Weigh the prescribed amount of API and dissolve it in 80% water for injection at a temperature of 25-75°C.

[0069] (2) Use 1M hydrochloric acid solution to adjust the pH of the solution to 3.0-5.0. Add water for injection to the full amount.

[0070] (3) The drug solution was filtered through 0.45 μm and 0.22 μm filter membranes respectively.

[0071] (4) Fill each sample in a glass ampoule and seal it with a melt.

[0072] (5) Different sterilization conditions were used to sterilize each example.

[0073] Test Example 1

[0074] According to the guiding principles for drug stability research in the 2020 edition of the Chinese Pharmacopoeia, the influencing factors of the teigolasen fumarate injection prepared in representative examples 7-14 were investigated, and the specific conditions were: strong light (4500±500LX) and high temperature (60°C). The teigolasen fumarate injection prepared in representative example 9 was subjected to long-term and accelerated stability tests, and the specific conditions were: long-term test temperature 25±2°C, relative humidity 60±5%; accelerated test conditions were temperature 40±2°C, relative humidity 75±5%.

[0075] The content of tigolasan in tigolasan fumarate injection can be determined according to the following HPLC conditions: chromatographic column: octadecylsilane bonded silica gel column (waters XBridge RP184.6×250mm, 5μm); column temperature: 35°C; mobile phase A: 0.1% trifluoroacetic acid aqueous solution (adjusting the pH value to 6.0 with triethylamine)-acetonitrile (95:5); mobile phase B: 0.1% trifluoroacetic acid aqueous solution (adjusting the pH value to 6.0 with triethylamine)-acetonitrile (5:95); flow rate: 1.0mL / min; injection volume: 20μl; detector: UV detector (wavelength 254nm);

[0076] Table 5 Gradient elution program

[0077] Time / min Mobile phase A / % Mobile phase B / % 0 90 10 10 90 10 20 50 50 40 50 50 50 90 10 65 90 10

[0078] The determination of related substances in tigelophan fumarate injection can be carried out by referring to the same HPLC conditions as the above content determination, and the impurities in the composition or raw material drug are quantitatively calculated according to the main component self-dilution control method.

[0079] Other evaluation indicators of tigolasen fumarate injection, such as properties and pH value, can be measured by referring to the pharmacopoeia methods recognized by ICH member countries, or validated methods, using appropriate instruments and equipment.

[0080] Table 6, related substances and pH test results of representative examples 1-6.

[0081] Table 6 Representative Examples 1-6 Related substances and pH test results

[0082]

[0083] Example 1-6 investigates the effects of different preparation temperatures on the related substances and pH of tigolasan fumarate injection. The test data show that when the preparation temperature is between 25 and 75°C, the related substances and pH value of tigolasan fumarate injection do not change significantly.

[0084] Table 7, representative examples 7 to 11 influencing factor detection data.

[0085] Table 7 Influencing factors test data

[0086]

[0087]

[0088] According to the influencing factor detection data, the pH value of Example 7 is 2.0, and the related substances have obvious growth on the 0th day after the sample is sterilized. After the influencing factors are placed, the related substances have an obvious growth trend. The pH value of Example 11 is 6.0, and the test data of the sample on the 0th day after sterilization are good. After the influencing factors are placed, the properties change under the light conditions, and drugs are precipitated. It may be due to the fact that under the pH 6.0 condition, the solubility of the drug is close to the injection specification, resulting in obvious changes in properties. The pH values ​​of Examples 8, 9, and 10 are 3.0, 4.0, and 5.0, respectively. After the sample is sterilized, the pH value, properties and related substances have no obvious changes, indicating that the quality of tegrassen fumarate injection is good in the pH range of 3.0 to 5.0.

[0089] Table 8, representative test data of influencing factors of Example 9 and Examples 12 to 14.

[0090] Table 8 Influencing factors test data

[0091]

[0092] According to the influencing factor detection data, the pH value, properties and related substances of the samples of the embodiments under different sterilization conditions did not change significantly under the conditions of various influencing factors, indicating that the tigelophan fumarate injection can withstand terminal sterilization conditions.

[0093] Table 9, stability test data of representative embodiment 9.

[0094] Table 9 Stability test data

[0095]

[0096] Example 9 Under the conditions of accelerated tests and long-term tests, the quality attributes of the tegrashen fumarate injection provided by the present invention did not change significantly, and the stability was good, which can fully meet the requirements of drug production, transportation and storage.

[0097] Test Example 2

[0098] The recommended injection administration procedure for tigoraxan fumarate injection in clinical practice is: dilute the injection with normal saline or 5% glucose injection and then perform intravenous drip. Since the solubility of tigoraxan fumarate is significantly pH-dependent, precipitation may occur during the dilution process. Therefore, we studied the compatibility (clinical use) stability of the injection of Example 9 with normal saline and 5% glucose injection.

[0099] The teigolan fumarate injection was diluted to 0.5 mg / mL with normal saline or 5% glucose injection. The prepared drug solution was placed at room temperature for 6 h and 12 h, and the properties, pH, content and 5-hydroxymethylfurfural (compatibility with glucose) of the prepared solution before and after placement were tested. The test results are shown in Table 10 below.

[0100] Table 10 Compatibility stability test results

[0101]

[0102]

[0103] The properties, pH, content, related substances, and 5-hydroxymethylfurfural (compatible with glucose) of the tegolan fumarate injection prepared in Example 9 did not change significantly within 12 hours of compatibility, and the requirements for clinical use were met.

[0104] It can be seen from the above examples that the present invention provides a tegolan fumarate injection and a preparation method thereof. The injection of the present invention can withstand terminal sterilization, has high safety and good stability.

[0105] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A teigolan fumarate injection, characterized in that: Contains teigolan fumarate, a pH adjuster, and water for injection; The chemical structural formula of the fumarate teigolan is as follows:

2. The tegolan fumarate injection according to claim 1, characterized in that: The pH adjuster comprises one or more of hydrochloric acid, citric acid, fumaric acid, acetic acid and lactic acid.

3. The tegolan fumarate injection according to claim 1 or 2, characterized in that: The adjustment range of the pH adjuster is 3.0 to 5.

1.

4. The tegolan fumarate injection according to claim 3, characterized in that: The content of tigolaxan fumarate in the tigolaxan fumarate injection is 2.5-10.0 mg / mL.

5. The method for preparing the tegolan fumarate injection according to any one of claims 1 to 4, characterized in that: The following steps are involved: 1) Weighing a prescribed amount of tegoraxan fumarate and dissolving it in 80% water for injection to prepare a liquid to obtain a drug solution; 2) Using a pH adjuster to adjust the pH of the drug solution to 3.0-5.1, adding water for injection to the full amount, to obtain an injection solution; 3) Filter the injection solution through 0.45 μm and 0.22 μm filter membranes in sequence; 4) The filtered injection solution is filled, sealed and sterilized in sequence.

6. The preparation method according to claim 5, characterized in that: The temperature of the prepared solution is 25-75°C.

7. The preparation method according to claim 5 or 6, characterized in that: The sterilization temperature is 116-121° C., and the sterilization time is 8-40 minutes.

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