Pharmaceutical composition containing pyrrole gastric acid secretion inhibitor and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition containing a pyrrole gastric acid secretion inhibitor and a preparation method thereof. The pharmaceutical composition comprises pharmaceutically acceptable salts of a compound represented by a formula I and a stabilizer. Meanwhile, the invention further provides a preparation method of the composition, and the method is simple, economical and suitable for industrial mass production. At present, an injection composition of the compound does not exist clinically.

Description

A pharmaceutical composition containing a pyrrole gastric acid secretion inhibitor and a preparation method thereof Technical Field

[0001] The present invention relates to an injection composition and a preparation method thereof, and in particular to an injection composition containing a pyrrole gastric acid secretion inhibitor and a preparation method thereof. Background Art

[0002] Proton pump inhibitors are widely used in clinical practice to treat peptic ulcers, reflux esophagitis, and Zollinger-Ellison syndrome by inhibiting gastric acid secretion. Potassium-competitive acid blockers (P-CABs) are a new type of acid-suppressing drug that reversibly competitively inhibits the potassium ion binding sites in the proton pump on gastric parietal cells. In an acidic environment, P-CABs immediately ionize and inhibit H + -K + -ATPase does not need to be concentrated in the microcapsules and microtubules of the gastric wall cells and is not activated by acid. It can quickly increase the pH value in the stomach. After dissociation, the enzyme activity is restored. It has a strong inhibitory effect on mucosal damage in the upper digestive tract and is used for gastric ulcers, duodenal ulcers, reflux esophagitis, etc.

[0003] Currently, there are no proton pump inhibitors in the form of injectable solutions available clinically, primarily in the form of oral solid preparations or lyophilized powder injections. Oral solid preparations of proton pump inhibitors, such as tablets, have poor compliance for patients with gastrointestinal bleeding, acute peptic ulcers, and those who are unable to take oral medication, thus failing to meet the clinical need for rapid onset of action. While injectable lyophilized powder injections can address these issues, they involve a greater number of excipients and higher packaging costs. Due to raw material stability issues, terminal sterilization processes with the highest level of sterility assurance cannot be used, resulting in higher preparation processes and production costs. Furthermore, their storage conditions are more demanding, requiring low-temperature storage.

[0004] The compound represented by Formula I, whose chemical name is 1-[5-(2-fluoro-phenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine, is a potassium ion competitive acid blocker (P-CAB). It is useful for preventing and treating gastric acid-related diseases, including (but not limited to) gastrointestinal diseases such as peptic ulcer, Zollinger-Ellison syndrome, gastritis, gastric ulcer, duodenal ulcer, ulcer caused by nonsteroidal anti-inflammatory drugs, Helicobacter pylori infection, gastroesophageal reflux disease, reflux esophagitis, and the like.

[0005] Chinese patent CN 108969520A discloses a composition of a crystalline form A of N-methylformamide hydrochloride, a hydrochloride formed by combining a compound of Formula I with hydrochloric acid, with a specific structure shown in Formula II. The invention also specifically discloses an oral composition comprising the compound of Formula II. For patients requiring rapid onset of action for gastrointestinal bleeding, acute peptic ulcers, and those unable to take the drug orally, the drug has poor compliance and fails to meet the clinical need for rapid onset of action. Compared to tablets, injections offer advantages such as high bioavailability and rapid onset of action.

[0006] The hydrochloride represented by Formula II is prone to produce corresponding degradation impurities during preparation and storage. The main known degradation impurities are impurity 1 and impurity 2, whose structures are as follows:

[0007] The hydrochloride salt represented by Formula II is a new type of potassium ion competitive acid blocker (P-CAB). Currently, there is no proton pump inhibitor in the form of an injectable solution in clinical practice. To develop it into an injectable solution, it is necessary to solve the solubility problem and minimize the type and amount of excipients to reduce the adverse reactions of the preparation to the human body caused by the excipients and improve its safety. At the same time, it is necessary to control the content of related impurities during the production and storage process to improve the preparation stability of the composition.

[0008] Summary of the Invention

[0009] The first aspect of the present invention provides an injectable composition comprising a pharmaceutically acceptable salt of a compound represented by Formula I and a stabilizer, wherein the stabilizer is edetate.

[0010] In some embodiments, the edetate salt is one or more of edetate disodium, edetate calcium sodium, edetate tetrasodium, and edetate dicalcium. In some more specific embodiments, the stabilizer is edetate disodium. In some more specific embodiments, the stabilizer is edetate calcium sodium.

[0011] In some embodiments, the pharmaceutically acceptable salt of the compound represented by Formula I is fumarate, oxalate, succinate, lactate, methanesulfonate, L-malate, citrate, nitrate, hydrobromide, hydrochloride, phosphate, or sulfate. In some specific embodiments, the salt of the compound represented by Formula I can be the hydrochloride salt represented by the following Formula II.

[0012] In some embodiments, the injection composition of the present invention comprises a pharmaceutically acceptable salt of a compound represented by Formula I and a stabilizer, and the weight ratio of the pharmaceutically acceptable salt of the compound represented by 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 represented by Formula I to the stabilizer can 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 therefrom, such as preferably 5:1 to 20:1, 5:1 to 15:1 or 5:1 to 10:1. The weight ratio described herein is based on the hydrochloride represented by Formula II. The compound represented by Formula I, or its other salts other than the hydrochloride, can be converted to calculate the corresponding weight ratio range.

[0013] In some embodiments, the pH of the injectable composition of the present invention is a physiologically acceptable pH value, and in some embodiments, the pH of the composition is between 3.0 and 4.5. In some embodiments, the pH of the composition is between 3.0 and 4.0. In some embodiments, the pH of the composition is 3.5; in some embodiments, the pH of the composition is 4.0; and in some embodiments, the pH of the composition is 4.5. The composition of the present invention can be adjusted according to conventional methods in the art.

[0014] In some embodiments, the present invention may add a pH adjuster to adjust the pH of the composition. When preparing the injection composition, a conventional pH adjuster for adjusting the pH of the composition may be added thereto. For example, the pH adjuster may be 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.

[0015] The amount of active ingredient contained in the injection composition of the present disclosure varies according to the conditions of use of the target patient, the degree of targeted treatment, etc. In some embodiments, the injection composition contains a hydrochloride salt represented by Formula II at a concentration of 1 mg / ml to 20 mg / ml. In some embodiments, each 1 ml of the composition contains 1 mg to 10 mg of the hydrochloride salt represented by Formula II. In some embodiments, each 1 ml of the composition contains 1 mg to 5 mg of the hydrochloride salt represented by Formula II. In some embodiments, each 1 ml of 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 salt represented by Formula II. For example, each 1 mL of the composition contains 2.5 mg of the compound represented by Formula II (or any specific numerical value within the scope of the present invention), 0.125 to 0.5 mg of stabilizer; or the stabilizer is preferably 0.25 to 0.5 mg.

[0016] The injectable composition of the pharmaceutically acceptable salt of the compound of Formula I disclosed herein may not contain additives other than stabilizers and pH adjusters. For example, the injectable composition comprises a pharmaceutically acceptable salt of the compound of Formula I, a stabilizer, a pH adjuster, and water for injection; wherein the active ingredient concentration of the pharmaceutically acceptable salt of the compound of Formula I is 1 to 20 mg / ml; the weight ratio of the pharmaceutically acceptable salt of the compound of 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 pH adjuster is sufficient to maintain the pH of the composition.

[0017] The composition for injection of the pharmaceutically acceptable salt of the compound of Formula I disclosed in the present invention may also optionally include, but not be limited to, excipients conventionally used in the art, such as osmotic pressure regulators, buffer solutions, etc. The osmotic pressure regulator can 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 / 100mL). In some embodiments, the osmotic pressure regulator is sodium chloride. In some embodiments, the amount of sodium chloride is 0.6%, 0.7%, 0.8%, 0.9% or 1.0%.

[0018] The composition for injection of the present invention can be prepared as a solution-type injection. In some embodiments, the injection is a large-volume injection. In some embodiments, the injection is a small-volume injection.

[0019] The present invention also provides a combination comprising the above-mentioned injection solution and an infusion solution. The infusion solution may be an electrolyte solution (saline, Ringer's solution, etc.), a nutrient infusion solution (carbohydrate solution (e.g., glucose solution, such as 5% (w / v) glucose solution, etc.)), etc. The composition of the present invention has simple components and a safe process. By preparing a pharmaceutically acceptable salt of the compound of Formula I into an injectable composition, and by adding a certain amount of stabilizer and controlling the pH value of the composition, the composition can ensure good physical and chemical stability, and the impurity content is easily controlled and increases less, meeting the quality and solubility requirements of the injection. No additional auxiliary materials such as cosolvents or solubilizers are required, thereby improving the safety of the composition preparation.

[0020] The fewer the types and amounts of excipients in the composition of the present invention, the higher the safety to the human body after injection. The injection composition of the present invention can achieve better stability of the composition by using a smaller amount of stabilizer, thereby effectively reducing the content of impurity 1 and impurity 2.

[0021] The injection composition has higher safety and good storage stability, providing a new medication option for special groups of people who are not suitable for oral administration, and meeting the clinical needs of patients with gastrointestinal bleeding and acute peptic ulcers who need rapid onset of action.

[0022] The second aspect of the present invention provides a method for preparing the above-mentioned composition. The method is simple and easy to implement, can be sterilized by terminal sterilization, has good stability and high safety, and is suitable for industrial production.

[0023] To achieve the second object of the present invention, the present invention adopts the following technical solution: providing a method for preparing the aforementioned pharmaceutically acceptable salt composition containing the compound represented by Formula I, comprising the following steps:

[0024] The pharmaceutically acceptable salt of the compound of formula I and a stabilizer are added to a certain volume of water for injection, dissolved, filled, sealed, and sterilized to obtain the product.

[0025] Furthermore, a pharmaceutically acceptable salt of the compound represented by Formula I and a stabilizer are added to a certain volume of water for injection, dissolved, and the pH is adjusted to 3.0-4.5 with a pH regulator, filled and sealed, and sterilized with moist heat for 15-30 minutes.

[0026] The stabilizer is an edetate salt, for example, one or more of edetate disodium, edetate calcium sodium, edetate tetrasodium, and edetate dicalcium. In some embodiments, the stabilizer is edetate disodium. In some embodiments, the stabilizer is edetate calcium sodium.

[0027] In some embodiments, the pharmaceutically acceptable salt of the compound represented by Formula I is a hydrochloride salt, and the specific compound is represented by Formula II.

[0028] In some embodiments, the hydrochloride represented by Formula II and edetate sodium calcium or edetate disodium are added to a certain volume of water for injection, dissolved, adjusted to pH 3.0-4.5 with a pH regulator, and constant to volume; and sterilized by moist heat at 121° C. for 15-30 minutes.

[0029] In some embodiments, 80-90% of the water for injection is taken according to the production batch amount, the hydrochloride represented by Formula II and calcium sodium edetate or disodium edetate are added, and the mixture is stirred to dissolve; the pH is adjusted to a range of 3.0-4.5 with 1 mol / L hydrochloric acid, and water for injection is added to the full amount; the mixture is filtered, filled with nitrogen, filled and sealed, and sterilized by moist heat at 121°C for 15 minutes.

[0030] The injection is prepared by the present invention, has a simple process, requires fewer types and amounts of auxiliary materials, adopts terminal sterilization method for sterilization, does not need to use activated carbon, reduces production costs, and has higher clinical safety.

[0031] The third aspect of the present invention provides a specific use of the composition. When a pharmaceutically acceptable salt of the compound shown in Formula I or a compound of Formula (II) is used as a pharmaceutically active ingredient to form a composition, it can be used to treat or prevent peptic ulcers (for example, gastric ulcers, duodenal ulcers, or anastomotic ulcers, etc.), Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (for example, 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 non-steroidal anti-inflammatory drugs, or hyperacidity or ulcers caused by postoperative stress; or in the preparation of a medicament for inhibiting upper gastrointestinal bleeding caused by peptic ulcers, acute stress ulcers, hemorrhagic gastritis, or invasive stress.

[0032] The injection composition of the present invention or the injection prepared according to the injection composition has a rapid hemostatic effect on upper gastrointestinal bleeding, and is useful for patients with upper gastrointestinal bleeding who are difficult to administer the drug orally. DETAILED DESCRIPTION

[0033] The following examples are provided to facilitate a better understanding of the present invention, but are not intended to limit the present invention. The experimental methods in the following examples, unless otherwise specified, are conventional methods. The test materials used in the following examples, unless otherwise specified, were purchased from conventional biochemical reagent stores.

[0034] Example 1 to Example 6

[0035] Weigh the compound represented by Formula II and the stabilizer and dissolve them in 90% of the prescribed volume of water for injection. Adjust the pH of the solution with hydrochloric acid and then make up the volume with water for injection. Fill the solution to 2 ml, purging with nitrogen before and after filling. Sterilize the composition at 121°C for 15 minutes to obtain the product. The properties and impurity changes of samples from different examples were examined. Impurity changes were detected by HPLC. The analytical method for detecting impurity content is as follows:

[0036] The chromatographic column was filled with octadecylsilane bonded silica gel, the detector was UV, and the detection wavelength was 230 nm; the mobile phase was 0.01 mol / L potassium dihydrogen phosphate buffer-acetonitrile.

[0037] The impurity detection results are expressed as the peak area (%) of each impurity calculated by the main component self-comparison method. Specific examples and investigation results are shown in Table 1.

[0038] Table 1

[0039] As shown in Table 1, the properties of the compositions containing different stabilizers remained unchanged after exposure to light at 5000 Lx for 10 days, with minimal changes in impurities. After exposure to 5000 Lx light for 10 days, the composition without stabilizers changed from a colorless, clear liquid to a pale yellow suspension, with a significant increase in related substances. The addition of stabilizers improved the composition's stability to varying degrees. The injection compositions using edetate disodium and edetate calcium sodium as stabilizers showed significantly increased stability and better properties, particularly a significant reduction in the growth of impurities 1 and 2.

[0040] Example 7 to Example 16

[0041] Weigh the compound represented by Formula II, edetate disodium, or edetate calcium sodium, and dissolve them in 90% of the prescribed volume of water for injection. Adjust the pH of the solution with hydrochloric acid and make up to the final volume with water for injection. Fill the solution into 2ml ampoules, flushing with nitrogen before and after filling. Sterilize the sample at 121°C / 15 min. Stability testing of the composition was performed at 60°C and 5000 Lx of light to determine the properties and impurities of the injection. The results are shown in Tables 2 and 3.

[0042] Table 2

[0043] Table 3

[0044] As shown in Tables 2 and 3, when the mass ratio of the stabilizer to the compound represented by Formula II is 0.02, the stability of the composition is slightly poor, and the impurities of the sample increase significantly under high temperature and light conditions, and the color of the composition changes from colorless to light yellow under light conditions; when the mass ratio of the stabilizer to the compound represented by Formula II is within the range of 0.05 to 1.0 as described in the present invention, the injection composition has good stability under high temperature and light conditions, and the properties do not change significantly.

[0045] Example 17 to Example 21

[0046] Weigh the compound represented by Formula II, edetate disodium, or edetate calcium sodium, and dissolve them in 90% of the prescribed volume of water for injection. Adjust the pH of the solution with hydrochloric acid and make up to the final volume with water for injection. Fill the solution into 2 ml ampoules, flushing with nitrogen before and after filling. Sterilize the sample at 121°C / 15 min. Stability testing was performed under conditions of 60°C and 5000 Lx of light to determine the properties and impurities of the injection. The results are shown in Table 4.

[0047] Table 4

[0048] The results in the above table demonstrate the effect of pH on the stability of the injection composition. In combination with Examples 17 to 21, when the pH of the injection composition was 2.0, the lower pH reduced the solubility of the compound represented by Formula II, resulting in crystal precipitation in the composition. When the pH of the injection composition was 5.0, the stability of the composition deteriorated, and after exposure to high temperatures and light, impurities increased significantly, with the solution color changing from colorless to pale yellow under light conditions. When the pH of the injection composition was within the range of 3.0 to 4.5 as described herein, the composition exhibited excellent stability, with no significant changes in properties.

[0049] Example 22 to Example 27

[0050] Weigh the compound represented by Formula II and edetate disodium or edetate calcium sodium and dissolve them in 90% of the prescribed volume of water for injection. Adjust the pH of the solution with hydrochloric acid or phosphoric acid, and then make up the pH with water for injection. Fill the solution into 2 ml brown ampoules, flushing with nitrogen before and after filling. Sterilize the composition at 121°C for 15 minutes. The results are shown in Table 5.

[0051] Table 5

[0052] As shown in Table 5, when the concentration of the compound of Formula II in the injectable composition was 25 mg / ml, crystals precipitated during sample preparation, making it difficult to dissolve the composition. Furthermore, precipitation and impurities may occur during preparation and storage. When the concentration of the compound of Formula II in the injectable composition was 1 mg / ml or lower, a large dose of the injectable solution was required to achieve a sufficient therapeutic effect, increasing the difficulty of use. However, when the concentration of the compound of Formula II in the present invention was in the range of 1 mg / ml to 20 mg / ml, these issues were effectively overcome.

[0053] Although some components of this patent have been described in detail above, it is obvious to those skilled in the art that such detailed description is only for the purpose of illustrating exemplary embodiments and should not be construed as limiting the scope of this patent. Therefore, the actual scope of this disclosure is defined by the appended claims and their equivalents.

Claims

1. A composition for injection, comprising a pharmaceutically acceptable salt of a compound represented by Formula I and a stabilizer, wherein the stabilizer is edetate, 2. The composition for injection according to claim 1, characterized in that The pharmaceutically acceptable salt is selected from the group consisting of fumarate, oxalate, succinate, lactate, methanesulfonate, L-malate, citrate, nitrate, hydrobromide, hydrochloride, phosphate, and sulfate.

3. The composition for injection according to claim 1, characterized in that The pharmaceutically acceptable salt of the compound of formula I is hydrochloride, and the specific compound is shown in the following formula II:

4. The composition for injection according to claim 1, characterized in that The edetate salt is one or more of edetate disodium, edetate calcium sodium, edetate tetrasodium, and edetate dicalcium; preferably one or more of edetate disodium or edetate calcium sodium.

5. The composition for injection according to any one of claims 1 to 4, characterized in that The active ingredient concentration of the pharmaceutically acceptable salt of the compound of Formula I is 1-20 mg / mL.

6. The composition for injection according to any one of claims 1 to 4, characterized in that The weight ratio of the pharmaceutically acceptable salt of the compound of Formula I to edetate is 1:1 to 20:1, preferably 5:1 to 10:

1.

7. The composition for injection according to any one of claims 1 to 4, characterized in that The pH value of the injection composition is 3.0-4.

5.

8. The composition for injection according to claim 1, characterized in that The injection composition further comprises a pH adjuster, which is one or more of hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, fumaric acid, tartaric acid, and sodium bicarbonate, preferably hydrochloric acid.

9. The composition for injection according to claim 1, characterized in that The injection composition is composed of a pharmaceutically acceptable salt of a compound represented by Formula I, a stabilizer, a pH adjuster, and water for injection; wherein the concentration of the active ingredient of the pharmaceutically acceptable salt of the compound represented by Formula I is 1-20 mg / ml; the weight ratio of the pharmaceutically acceptable salt of the compound represented by Formula I to edetate is 1:1 to 20:1, preferably 5:1 to 10:1; and the pH value is 3.0 to 4.

5.

10. The composition for injection according to claim 3, characterized in that The composition for injection contains 2.5 mg of the compound represented by Formula II and 0.125 to 0.5 mg of a stabilizer per 1 mL of the composition; the stabilizer is preferably 0.25 to 0.5 mg.

11. The composition for injection according to any one of claims 1 to 4, characterized in that: The injection composition is prepared as a solution-type injection.

12. The composition for injection according to claim 11, characterized in that The solution-type injection is a small-volume infusion or a large-volume infusion.

13. The composition for injection according to any one of claims 1 to 4, characterized in that The composition for injection further comprises an osmotic pressure regulator.

14. The composition for injection according to claim 13, characterized in that The osmotic pressure regulator is one of sodium chloride and glucose.

15. The composition for injection according to claim 13, characterized in that The osmotic pressure regulator is sodium chloride. The weight ratio of the osmotic pressure regulator to the total volume of the injection is 0.6% to 1.0%, preferably 0.6%, 0.7%, 0.8% or 0.9%.

16. A method for preparing the composition for injection according to any one of claims 1 to 15, characterized in that: The pharmaceutically acceptable salt and edetate of the compound of formula I are added to a certain volume of water for injection, dissolved, and sterilized to obtain the product.

17. The method for preparing the composition for injection according to claim 16, characterized in that: The pharmaceutically acceptable salt and edetate of the compound of formula I are added to a certain volume of water for injection and dissolved; the pH is adjusted to 3.0-4.5 with a pH regulator; water for injection is added to the volume; and moist heat sterilization is performed for 15-30 minutes.

18. The method for preparing the composition for injection according to claim 16 or 17, characterized in that: Take 80% to 90% of the prescribed amount of water for injection, add the pharmaceutically acceptable salt and edetate of the compound described in I, and stir to dissolve; Adjust the pH to 3.0-4.0 with 1 mol / L hydrochloric acid, add water for injection to the full volume; filter, fill with nitrogen, fill and seal, and sterilize with moist heat at 121°C for 15-30 min.

19. Use of the injectable composition according to any one of claims 1 to 15 in the preparation of a medicament for treating or preventing peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagus, 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; or use of the injectable composition according to any one of claims 1 to 15 in the preparation of a medicament for inhibiting upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer, hemorrhagic gastritis, or invasive stress.

20. The use according to claim 19, characterized in that The peptic ulcer includes gastric ulcer, duodenal ulcer or anastomotic ulcer; the symptomatic gastroesophageal reflux disease includes non-erosive reflux disease or gastroesophageal reflux disease without esophagitis.