Drug composition containing pyrrole-type gastric acid secretion inhibitors and method for preparing the same

Abstract

A pharmaceutical composition containing a pyrrole-type gastric acid secretion inhibitor, which comprises a pharmaceutically acceptable salt of the compound represented by formula I and a stabilizer, and a method for preparing the same. At the same time, a method for preparing the composition, which is simple, economical and suitable for industrial mass production, is further provided. Currently, there is still no injectable composition of the compound in clinical practice.

Description

Technical Field

[0001] The present invention relates to an injectable composition and a method for preparing the same, and more particularly, to an injectable composition containing a pyrrole gastric acid secretion inhibitor and a method for preparing the same.

Background Art

[0002] Proton pump inhibitors treat peptic ulcers, reflux esophagitis, Zollinger-Ellison syndrome, etc. by suppressing gastric acid secretion and are widely used clinically. Potassium-competitive acid blockers (P-CABs) are novel acid suppressants that reversibly and competitively inhibit the potassium ion binding site in the proton pump in gastric parietal cells. P-CABs are immediately ionized in an acidic environment and inhibit by binding to H

[0004] , , , , ,

[0003] -K​​​​​​​​​The chemical name of the compound shown in formula I is 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrole-3-yl]-N-methylmethaneamine, and it is a potassium-competitive acid blocker (P-CAB). It is used for the treatment and prevention of gastric acid-related diseases, including (but not limited to) gastrointestinal diseases such as peptic ulcers, Zollinger-Ellison syndrome, gastritis, gastric ulcers, duodenal ulcers, ulcers caused by nonsteroidal anti-inflammatory drugs, Helicobacter pylori infection, gastroesophageal reflux disease, and reflux esophagitis.

[0005] [ka]

[0006] Chinese patent CN108969520A discloses a composition of a crystalline compound of N-methylformamide hydrochloride, which is a hydrochloride salt formed by the combination of a compound of formula I and hydrochloric acid, with the specific structure shown in formula II. Furthermore, an oral administration composition comprising the compound shown in formula II is specifically disclosed. However, compliance is poor in patients with gastrointestinal bleeding, acute peptic ulcers, and those who cannot take oral medication, and it fails to meet the clinical requirement for a rapid effect. Injectable drugs have advantages over tablets, such as higher bioavailability and a rapid onset of action.

[0007] [ka]

[0008] The hydrochloride salt shown in Formula II is prone to generating corresponding decomposition impurities during preparation and storage. The main known decomposition impurities are impurity 1 and impurity 2, whose structures are as follows.

[0009] [ka]

[0010] The hydrochloride salt shown in Formula II, a novel potassium-competitive acid blocker (P-CAB), is currently not available as a proton pump inhibitor in injectable form for clinical use. Developing it as an injectable solution requires not only resolving solubility issues but also minimizing the types and amounts of auxiliary materials used to reduce side effects on the human body and improve safety. Furthermore, it is necessary to control the content of relevant impurities during production and storage to improve the formulation stability of the composition. [Overview of the project]

[0011] In a first aspect of the present invention, an injectable composition is provided comprising a pharmaceutically acceptable salt of a compound shown in formula I and a stabilizer which is an edetate. [Modes for carrying out the invention]

[0012] In some embodiments, the edetate is one or more of disodium edetate, calcium sodium edetate, tetrasodium edetate, and dicalcium edetate. In some more specific embodiments, the stabilizer is disodium edetate. In some more specific embodiments, the stabilizer is calcium sodium edetate.

[0013] [ka]

[0014] In some embodiments, pharmaceutically acceptable salts of the compound shown in formula I are fumarate, oxalate, succinate, lactate, methanesulfonate, L-malate, citrate, nitrate, hydrobromide, hydrochloride, phosphate, and sulfate. In some specific examples, the salt of the compound shown in formula I may be the hydrochloride shown in formula II below.

[0015] [ka]

[0016] In some embodiments, the injectable composition of the present invention comprises a pharmaceutically acceptable salt of the compound shown in formula I and a stabilizer, wherein the weight ratio of the pharmaceutically acceptable salt of the compound shown in formula I to the stabilizer is 1:1 to 20:1. In some embodiments, the weight ratio of the pharmaceutically acceptable salt of the compound shown in formula I to the stabilizer may be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1 or 20:1, or any range formed by both, for example, 5:1 to 20:1, 5:1 to 15:1 or 5:1 to 10:1 are preferred. The weight ratio here is calculated using the hydrochloride salt shown in formula II, and for salts other than the compound shown in formula I or its hydrochloride salt, the corresponding weight ratio range can be calculated by conversion.

[0017] In some embodiments, the pH of the injectable composition of the present invention is a pharmaceutically acceptable pH, and in some embodiments, the pH of the composition is 3.0 to 4.5. In some embodiments, the pH of the composition is 3.0 to 4.0. In some examples, the pH of the composition is 3.5. In some examples, the pH of the composition is 4.0. In some examples, the pH of the composition is 4.5. The compositions described in the present invention may be prepared by methods common in the art.

[0018] In some embodiments, the present invention may include pH adjusters or the like to adjust the pH of the composition. Here, when preparing the injection composition, a general pH adjuster for adjusting the pH of the composition may be added, and the pH adjuster is, for example, one or more of hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, fumaric acid, tartaric acid, and sodium bicarbonate. In some specific embodiments, the pH adjuster is hydrochloric acid.

[0019] The amount of the active ingredient contained in the injection composition of the present disclosure varies according to the usage conditions of the target patient and the degree of target treatment. In some embodiments, the injection composition contains the hydrochloride shown in Formula II at a concentration of 1 mg / mL to 20 mg / mL. In some embodiments, the composition contains 1 mg to 10 mg of the hydrochloride shown in Formula II per 1 mL. In some embodiments, the composition contains 1 mg to 5 mg of the hydrochloride shown in Formula II per 1 mL. In some embodiments, the composition contains 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg of the hydrochloride shown in Formula II per 1 mL. For example, the composition contains 2.5 mg of the compound shown in Formula II (or any specific numerical value within the scope of the present invention) per 1 mL, and contains 0.125 to 0.5 mg, or preferably 0.25 to 0.5 mg of a stabilizer.

[0020] The injection composition of the pharmaceutically acceptable salt of the compound according to Formula I disclosed in the present invention may not contain additives other than a stabilizer and a pH adjuster. For example, the injection composition consists of a pharmaceutically acceptable salt of the compound shown in Formula I, a stabilizer, a pH adjuster, and water for injection. Here, the pharmaceutically acceptable salt of the compound shown in Formula I has an active ingredient concentration of 1 to 20 mg / mL, and the weight ratio of the pharmaceutically acceptable salt of the compound shown in Formula I to edetate is 1:1 to 20:1, preferably 5:1 to 10:1, and the pH is 3.0 to 4.5. The amount of the pH adjuster only needs to be able to maintain the pH of the composition.

[0021] The injection composition of the pharmaceutically acceptable salt of the compound according to Formula I disclosed in the present invention may selectively contain auxiliary materials commonly used in this field, such as an osmotic pressure regulator and a buffer solution, but is not limited thereto. The osmotic pressure regulator may be one of sodium chloride and glucose. The ratio of the osmotic pressure regulator to the total volume of the injection is 0.6% to 1.0% (W / V, g / 100 mL). In some embodiments, the osmotic pressure regulator is sodium chloride. In some embodiments, the usage amount of the sodium chloride is 0.6%, 0.7%, 0.8%, 0.9% or 1.0%.

[0022] The injectable composition of the present invention may be prepared as a solution-type injection. In some embodiments, the injection is a large-volume injection solution. In some embodiments, the injection is a small-volume injection.

[0023] The present invention further provides a combination comprising the above injection solution and infusion solution. The infusion solution may be an electrolyte solution (such as saline, Ringer's solution, etc.), a nutrient infusion solution (such as a carbohydrate solution (e.g., glucose solution, such as 5% (w / v) glucose solution, etc.)). The composition of the present invention has simple components, a safe process, prepares a pharmaceutically acceptable salt of the compound shown in Formula I as an injectable composition, adds a certain amount of stabilizer, and controls the pH of the composition, thereby ensuring good physicochemical stability of the composition, being easy to control the content of impurities, having few increments, meeting the requirements of the quality and solubility of the injection, and not requiring the addition of auxiliary materials such as solubilizers or dissolution aids, and improving the safety of the composition preparation.

[0024] The composition of the present invention has higher safety for the human body after injection as the type and amount of auxiliary materials used are less. The injection solution composition of the present invention can endow the composition with high stability with only a small amount of stabilizer used, and effectively reduce the contents of impurity 1 and impurity 2.

[0025] The injection solution composition has higher safety, higher storage stability, provides a new drug choice for special people who are not suitable for oral administration, and meets the clinical requirements for patients with gastrointestinal bleeding and acute peptic ulcers who need rapid effects.

[0026] In the second aspect of the present invention, there is provided a method for preparing the above composition, which is simple, easy to implement, can be sterilized by the final sterilization method, has excellent stability, high safety, and is suitable for industrial production.

[0027] To achieve a second objective of the present invention, the present invention provides a method for preparing a composition of a pharmaceutically acceptable salt of a compound represented by formula I, comprising the steps of adding a pharmaceutically acceptable salt of a compound represented by formula I and a stabilizer to a certain volume of water for injection, dissolving them, filling and sealing a container, and sterilizing the container, using the following technical solutions.

[0028] Furthermore, a pharmaceutically acceptable salt of the compound shown in Formula I and a stabilizer are added to a certain volume of sterile water for injection, dissolved, the pH is adjusted to 3.0-4.5 with a pH adjuster, the mixture is filled into a container, sealed, and sterilized by moist heat for 15-30 minutes.

[0029] The stabilizer is an edetate, and is, for example, one or more of disodium edetate, calcium sodium edetate, tetrasodium edetate, and dicalcium edetate. In some embodiments, the stabilizer is disodium edetate. In some embodiments, the stabilizer is calcium sodium edetate.

[0030] In some embodiments, the pharmaceutically acceptable salts of the compounds shown in formula I are hydrochloride salts, and specific compounds are shown in formula II.

[0031] In some embodiments, the hydrochloride salt shown in Formula II and calcium sodium edetate or disodium edetate are added to a certain volume of water for injection, dissolved, the pH is adjusted to 3.0-4.5 with a pH adjuster, the volume is adjusted to a fixed level, and the mixture is moist-heat sterilized at 121°C for 15-30 minutes.

[0032] In some embodiments, depending on the amount used in a production batch, 80-90% sterile water for injection is taken, the hydrochloride salt shown in Formula II and calcium sodium edetate or disodium edetate are added, the mixture is stirred to dissolve, the pH is adjusted to a range of 3.0-4.5 with 1 mol / L hydrochloric acid, the sterile water for injection is added to the final volume, the mixture is filtered, nitrogen gas is injected, the mixture is filled into containers and sealed, and moist heat sterilization is performed at 121°C for 15 minutes.

[0033] The preparation of the injectable solution according to the present invention is simple in process, uses few types and amounts of auxiliary materials, is sterilized by a final sterilization method, does not require activated carbon, reduces preparation costs, and is clinically safe.

[0034] A third aspect of the present invention provides specific uses of the composition. When the composition is composed of a pharmaceutically acceptable salt of the compound shown in formula I or the compound shown in formula (II) as the pharmaceutically active ingredient, it can be used to treat or prevent peptic ulcers (e.g., gastric ulcers, duodenal ulcers or anastomotic ulcers), Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (e.g., non-erosive reflux disease or gastroesophageal reflux disease without esophagitis), Barrett's esophagitis, functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by nonsteroidal anti-inflammatory drugs, or hyperacidity or ulcers due to postoperative stress, or it can be used to suppress peptic ulcers, acute stress ulcers, hemorrhagic gastritis, or upper gastrointestinal bleeding due to invasive stress.

[0035] The injectable composition of the present invention, or an injectable preparation prepared using the injectable composition, has a rapid hemostatic effect against upper gastrointestinal bleeding and is suitable for patients with upper gastrointestinal bleeding who have difficulty receiving oral administration. [Examples]

[0036] The following examples are provided to better understand the present invention and do not limit it. Unless otherwise specified, the experimental methods in the following examples are all general methods. Unless otherwise specified, the test materials used in the following examples were purchased from a regular biochemical reagent supplier.

[0037] Examples 1 to 6 The compound and stabilizer shown in Formula II were weighed and dissolved in 90% of the prescribed volume of sterile water for injection. The pH of the solution was adjusted with hydrochloric acid, and then sterile water for injection was added to the final volume. The solution was filled into 2 mL ampoules, and nitrogen gas was injected before and after filling and sealing. The composition was sterilized under conditions of 121°C / 15 minutes. The properties and changes in impurities of samples from various examples were examined. Changes in impurities were detected by HPLC. The analytical method for detecting the impurity content is as follows.

[0038] A column packed with octadecylsilane-bound silica gel and a UV detector were used. The detection wavelength was 230 nm, and the mobile phase was 0.01 mol / L dipotassium hydrogen phosphate buffer-acetonitrile.

[0039] The impurity detection results are shown as the peak area (%) of each impurity calculated by the principal component self-control method. Specific examples and study results are shown in Table 1.

[0040] [Table 1]

[0041] As shown in Table 1, after 0 days and 10 days under high temperature conditions of 60°C, the compositions with different stabilizers showed no change in properties and only small changes in impurities. After irradiating the compositions with light at 5000 Lx for 10 days, the properties of the composition without stabilizer changed from a colorless, transparent liquid to a pale yellow suspension, and the amount of related substances increased significantly. When a stabilizer was added to the composition, the stability of the composition improved to some extent. The injectable compositions in which disodium edetate and calcium sodium edetate were selected as stabilizers as described in the present invention showed significantly improved stability and good properties, and in particular, the increase in impurities 1 and 2 was significantly reduced.

[0042] Examples 7 to 16 The compound shown in Formula II, disodium edetate, or calcium sodium edetate was weighed and dissolved in 90% of the prescribed volume of sterile water for injection. The pH of the solution was adjusted with hydrochloric acid, and then sterile water for injection was added to the final volume. The solution was filled into 2 mL ampoules, nitrogen gas was injected before and after filling and sealing, and the samples were sterilized under conditions of 121°C / 15 minutes. The stability of the compositions was examined by placing them under high temperature conditions of 60°C and light irradiation of 5000 Lx, and changes in the properties of the injection solution and impurities were confirmed. The results are shown in Tables 2 and 3.

[0043] [Table 2]

[0044] [Table 3]

[0045] As shown in Tables 2 and 3, when the mass ratio of the stabilizer to the compound shown in Formula II was 0.02, the stability of the composition decreased slightly. Furthermore, under high temperature and light irradiation conditions, the sample showed a significant increase in impurities, and the color of the composition changed from colorless to pale yellow under light irradiation conditions. When the mass ratio of the stabilizer to the compound shown in Formula II is within the range of 0.05 to 1.0 as described in the present invention, the injectable solution composition is stable under high temperature and light irradiation conditions and does not undergo any significant change in properties.

[0046] Examples 17-21 The compound shown in Formula II, disodium edetate, or calcium sodium edetate was weighed and dissolved in 90% of the prescribed volume of sterile water for injection. The pH of the solution was adjusted with hydrochloric acid, and then sterile water for injection was added to the final volume. The solution was filled into 2 mL ampoules, nitrogen gas was injected before and after filling and sealing, and the samples were sterilized under conditions of 121°C / 15 minutes. The compositions were subjected to stability tests under high temperature conditions of 60°C and light irradiation of 5000 Lx to confirm changes in the properties of the injection solution and impurities. The results are shown in Table 4.

[0047] [Table 4]

[0048] The results in the table above confirm the effect of pH on the stability of the injection solution composition. Referring to Examples 17 to 21, when the pH of the injection solution composition was 2.0, the solubility of the compound shown in Formula II decreased due to the low pH, and crystals precipitated in the composition. When the pH of the injection solution composition was 5.0, the stability of the composition decreased, and after being left under high temperature and light irradiation conditions, the amount of impurities increased significantly, and under light irradiation conditions, the color of the solution changed from colorless to pale yellow. When the pH of the injection solution composition is within the range of 3.0 to 4.5 as described in the present invention, the composition is highly stable and there is no significant change in its properties.

[0049] Examples 22-27 The compound shown in Formula II, disodium edetate, or calcium sodium edetate was weighed and dissolved in 90% of the prescribed volume of sterile water for injection. The pH of the solution was adjusted with hydrochloric acid or phosphoric acid, and then the volume was replenished with sterile water for injection to the final volume. The solution was filled into 2 mL brown ampoule bottles, and nitrogen gas was injected before and after filling and sealing. The composition was sterilized under conditions of 121°C / 15 minutes. The results are shown in Table 5.

[0050] [Table 5]

[0051] As shown in Table 5, when the concentration of the compound shown in formula II in the injectable solution composition is 25 mg / mL, the sample precipitates crystals during preparation, making it difficult to satisfy the solubility requirements of the composition, and precipitation and impurities may occur during preparation and storage. When the concentration of the compound shown in formula II in the injectable solution composition is 1 mg / mL or less, a large amount of injectable liquid is required to achieve a sufficient therapeutic effect, increasing the difficulty of use. When the concentration of the compound shown in formula II as described in the present invention is in the range of 1 mg / mL to 20 mg / mL, the above problems are effectively overcome.

[0052] Although some aspects of the present patent have been described in detail above, it will be obvious to those skilled in the art that such detailed descriptions are merely for illustrative purposes and should not be understood as limiting the scope of the present patent. Accordingly, the substantial scope of this disclosure is limited by the appended claims and their equivalents.

Claims

1. An injectable composition comprising a pharmaceutically acceptable salt of a compound and a stabilizer which is an edetate, wherein the pharmaceutically acceptable salt of the compound is a hydrochloride salt shown in the following formula II, the concentration of the pharmaceutically acceptable salt of the compound shown in formula II as an active ingredient is 1 to 20 mg / mL, the weight ratio of the pharmaceutically acceptable salt of the compound shown in formula II to the edetate is 1:1 to 20:1, and the pH of the injectable composition is 3.0 to 4.

5. 【Chemistry 1】

2. The injectable composition according to claim 1, characterized in that the edetate is one or more of disodium edetate, calcium sodium edetate, tetrasodium edetate, and dicalcium edetate.

3. The injectable composition according to claim 2, characterized in that the edetate is one or more of disodium edetate or calcium sodium edetate.

4. The injectable composition according to any one of claims 1 to 3, characterized in that the weight ratio of the pharmaceutically acceptable salt of the compound shown in formula II to the edetate is 5:1 to 10:

1.

5. The injectable composition according to claim 1, further comprising one or more pH adjusters selected from hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, fumaric acid, tartaric acid, and sodium bicarbonate.

6. The injectable composition according to claim 5, characterized by containing hydrochloric acid.

7. The injectable composition according to claim 1, characterized by comprising a pharmaceutically acceptable salt of a compound shown in formula II, a stabilizer, a pH adjuster, and water for injection.

8. The injectable composition according to claim 7, characterized in that the weight ratio of the pharmaceutically acceptable salt of the compound shown in formula II to the edetate is 5:1 to 10:

1.

9. The injectable composition according to claim 1, characterized in that each 1 mL of the composition contains 2.5 mg of the compound shown in formula II and 0.125 to 0.5 mg of a stabilizer.

10. The injectable composition according to claim 9, characterized by containing 0.25 to 0.5 mg of a stabilizer.

11. The injectable composition according to claim 1 or 2, characterized in that it is prepared as a solution-type injectable preparation.

12. The injectable composition according to claim 11, characterized in that the aforementioned solution-type injectable preparation is a small-volume or large-volume infusion solution.

13. The injectable composition according to claim 1 or 2, further comprising an osmotic pressure adjusting agent.

14. The injectable composition according to claim 13, characterized in that the osmotic pressure adjusting agent is one of sodium chloride and glucose.

15. The injectable composition according to claim 13, characterized in that the osmotic pressure regulator is sodium chloride, and the weight ratio of the osmotic pressure regulator to the total volume of the injection solution is 0.6% to 1.0%.

16. The injectable composition according to claim 15, characterized in that the weight ratio of the osmotic pressure adjusting agent to the total volume of the injection solution is 0.6%, 0.7%, 0.8%, or 0.9%.

17. A method for preparing an injectable composition according to claim 1, characterized by adding a pharmaceutically acceptable salt and an EDTA salt of a compound shown in formula II to a certain volume of water for injection, dissolving them, and sterilizing the mixture.

18. A method for preparing an injectable composition according to claim 17, characterized by adding a pharmaceutically acceptable salt and EDTA of a compound shown in formula II to a certain volume of sterile water for injection, dissolving them, adjusting the pH to 3.0 to 4.5 with a pH adjusting agent, adding sterile water for injection to a fixed volume, and sterilizing with moist heat for 15 to 30 minutes.

19. A method for preparing an injectable composition according to claim 17 or 18, characterized by taking 80% to 90% of the prescribed amount of sterile water for injection, adding a pharmaceutically acceptable salt and EDTA of the compound shown in formula II, stirring to dissolve, adjusting the pH to 3.0 to 4.0 with 1 mol / L hydrochloric acid, replenishing with sterile water for injection to the full volume, filtering, injecting nitrogen gas, filling into a container and sealing, and moist heat sterilizing at 121°C for 15 to 30 minutes.

20. Use of the injectable composition according to claim 1 in the preparation of drugs for the treatment or prevention of peptic ulcers, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by nonsteroidal anti-inflammatory drugs, or hyperacidity or ulcers caused by postoperative stress.

21. Use of the injectable composition according to claim 1 in the preparation of a drug for suppressing peptic ulcers, acute stress ulcers, hemorrhagic gastritis, or upper gastrointestinal bleeding caused by invasive stress.

22. The use according to claim 20, characterized in that the peptic ulcer includes a gastric ulcer, a duodenal ulcer, or an anastomotic ulcer, and the symptomatic gastroesophageal reflux disease includes a non-erosive reflux disease or a gastroesophageal reflux disease without esophagitis.

23. The use according to claim 21, characterized in that the peptic ulcer includes a gastric ulcer, a duodenal ulcer, or an anastomotic ulcer.

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