Drug composition containing a pyrrole-type gastric acid secretion inhibitor 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 specifically, to an injectable composition containing a pyrrole-type gastric acid secretion inhibitor and a method for preparing the same.

Background Art

[0002] Proton pump inhibitors treat peptic ulcers, gastroesophageal reflux disease, 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 bind to H + -K + -ATPase to inhibit it. Therefore, it does not require concentration in the microvesicles or microtubules of gastric parietal cells or acid activation, and can rapidly increase the gastric pH. After dissociation, the enzyme activity is restored, and it has a strong inhibitory effect on mucosal damage in the upper digestive tract and is used for gastric ulcers, duodenal ulcers, gastroesophageal reflux disease, etc.

[0003] Currently, there is still no proton pump inhibitor in the form of an injection solution clinically, and it is mainly an oral solid preparation or a lyophilized powder for injection. Proton pump inhibitors in oral solid preparations such as tablets have poor compliance for patients with gastrointestinal bleeding, acute peptic ulcers, and those who cannot take oral medications who require rapid effects, and cannot meet the clinical requirements of rapidly exerting effects. Lyophilized powder for injection can solve the above-mentioned problems, but there are many auxiliary materials related to its preparation, the cost of the packaging material is higher, and due to the stability problems of its raw materials, the final sterilization process that provides the highest sterility assurance level cannot be adopted. Both its preparation process and production cost are high, and its storage conditions are also more stringent, requiring low-temperature storage.

[0004] The chemical name of the compound shown in Formula I is 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine, which is a potassium ion-competitive acid blocker (P-CABs). It is used for the treatment and prevention of 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 non-steroidal anti-inflammatory drugs, Helicobacter pylori infection, gastroesophageal reflux disease, and reflux esophagitis.

[0005]

Chemical formula

[0006] Chinese Patent CN108969520A discloses a hydrochloride salt in which the compound of Formula I is combined with hydrochloric acid, and specifically, a composition of A crystalline form compound of N-methylformamide hydrochloride salt whose specific structure is shown in Formula II. Furthermore, an oral administration composition composed of the compound shown in Formula II is specifically disclosed. However, for patients with gastrointestinal bleeding, acute peptic ulcer, and those who cannot take oral administration and require a rapid effect, the compliance is poor, and it cannot meet the clinical requirements of quickly exerting effects. Compared with tablets, injections have advantages such as high bioavailability and rapid onset of effects.

[0007]

Chemical formula

[0008] The hydrochloride salt shown in Formula II is likely to generate corresponding decomposition impurities during preparation and storage. Here, the known main decomposition impurities are Impurity 1 and Impurity 2, and their structures are as follows.

[0009]

Chemical formula

[0010] The hydrochloride shown in Formula II, which is a novel potassium ion-competitive acid blocker (P-CABs), currently has no proton pump inhibitor in the form of an injection solution in clinical practice. To develop it as an injection solution, it is necessary not only to solve the solubility problem, but also to reduce the side effects of the preparation on the human body caused by auxiliary materials and to reduce the types and amounts of auxiliary materials used as much as possible to improve its safety. In addition, it is necessary to control the content of related impurities in the production and storage processes and improve the preparation stability of the composition.

Summary of the Invention

[0011] In a first aspect of the present invention, there is provided an injection composition comprising a pharmaceutically acceptable salt of a compound shown in Formula I and a stabilizer which is an edetate.

Embodiments 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 examples, the stabilizer is disodium edetate. In some more specific examples, the stabilizer is calcium sodium edetate.

[0013]

Chemical formula

[0014] In some embodiments, the pharmaceutically acceptable salt of the compound shown in Formula I is a fumarate, oxalate, succinate, lactate, methanesulfonate, L-malate, citrate, nitrate, hydrobromide, hydrochloride, phosphate, or sulfate. In some specific examples, the salt of the compound shown in Formula I may be the hydrochloride shown in the following Formula II.

[0015]

Chemical formula

[0016] In some embodiments, the injection composition of the present invention comprises a pharmaceutically acceptable salt of the 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 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 may be any range formed by both of them. For example, 5:1 to 20:1, 5:1 to 15:1 or 5:1 to 10:1, etc. are preferred. The weight ratio here is calculated based on the hydrochloride represented by formula II, and salts other than the compound or hydrochloride represented by formula I can calculate the corresponding weight ratio range by conversion.

[0017] In some embodiments, the pH of the injection composition of the present invention is a pharmaceutically acceptable pH. 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 composition described in the present invention may be adjusted by a general method in this field.

[0018] In some embodiments, the present invention may add a pH adjuster 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. The pH adjuster is, for example, one or more of hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, fumaric acid, tartaric acid, sodium bicarbonate. In some specific examples, the pH adjuster is hydrochloric acid.

[0019] The amount of the active ingredient contained in the injection composition of the present disclosure varies depending on the usage conditions of the target patient and the degree of the 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 (or any specific numerical value within the scope of the present invention) of the compound shown in Formula II per 1 mL, and contains 0.125 mg to 0.5 mg, or preferably 0.25 mg to 0.5 mg of the 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 the stabilizer and the pH adjuster. For example, the injection composition consists of the 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 the 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 generally used in this field such as an osmotic pressure adjuster and a buffer solution, but is not limited thereto. The osmotic pressure adjuster may be one of sodium chloride and glucose. The ratio of the osmotic pressure adjuster to the total volume of the injection is 0.6% to 1.0% (W / V, g / 100 mL). In some embodiments, the osmotic pressure adjuster 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 nutritional 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. By preparing a pharmaceutically acceptable salt of the compound shown in Formula I as an injectable composition, adding a certain amount of stabilizer, and controlling the pH of the composition, good physicochemical stability of the composition can be ensured, the content of impurities can be easily controlled, and the increase is small, meeting the requirements of the quality and solubility of the injection, without the need to add auxiliary materials such as solubilizers or dissolution aids, and improving the safety of the composition formulation.

[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 option 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 the second object of the present invention, the present invention uses the following technical solution, adding a pharmaceutically acceptable salt and a stabilizer of the compound represented by formula I to a certain volume of water for injection, dissolving, filling into a container, sealing, and sterilizing, to provide a method for preparing a composition of a pharmaceutically acceptable salt of the compound represented by formula I described above.

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

[0029] The stabilizer is an edetate, 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 salt of the compound represented by formula I is a hydrochloride salt, and the specific compound is represented by formula II.

[0031] In some embodiments, the hydrochloride salt represented by 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 fixed, and sterilized by moist heat at 121°C for 15 minutes to 30 minutes.

[0032] In some embodiments, according to the usage amount of the production batch, 80 - 90% of the water for injection is taken, the hydrochloride salt represented by formula II and calcium sodium edetate or disodium edetate are added, stirred and dissolved, the pH is adjusted to the range of 3.0 - 4.5 with 1 mol / L hydrochloric acid, the water for injection is supplemented to the full volume, filtered, nitrogen gas is injected, filled into a container, sealed, and sterilized by moist heat at 121°C for 15 minutes.

[0033] The preparation of the injection according to the present invention has a simple process, requires fewer types and amounts of auxiliary materials, is sterilized by the final sterilization method, does not require activated carbon, reduces the preparation cost, and has high clinical safety.

[0034] In a third aspect of the present invention, a specific use of the composition is provided. When a pharmaceutically acceptable salt of the compound represented by Formula I or the compound represented by Formula (II) is used as a pharmaceutically active ingredient to form a composition, it can be used for treating or preventing peptic ulcers (such as gastric ulcer, duodenal ulcer or anastomotic ulcer, etc.), Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (such as non-erosive reflux disease or gastroesophageal reflux disease without esophagitis), Barrett 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 can be used to inhibit peptic ulcers, acute stress ulcers, hemorrhagic gastritis, or upper gastrointestinal bleeding caused by invasive stress.

[0035] The injectable composition of the present invention or an injection prepared from the injectable composition has a rapid hemostatic effect on upper gastrointestinal bleeding and is suitable for patients with upper gastrointestinal bleeding who have difficulty taking oral medications.

Examples

[0036] The following examples are for better understanding of the present invention and do not limit the present invention. The experimental methods in the following examples are all common methods unless otherwise specified. The test materials used in the following examples are all purchased from ordinary biochemical reagent sales companies unless otherwise specified.

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

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

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

[0040]

Table 1

[0041] As shown in Table 1, after the compositions related to different stabilizers had passed for 0 days and 10 days under the condition of high temperature at 60 °C, the properties of all the samples did not change and the change in impurities was small. After the composition was irradiated with light under the condition of 5000 Lx for 10 days, the property of the composition without the addition of the stabilizer changed from a colorless and transparent liquid to a pale yellow suspension, and the related substances increased significantly. When the stabilizer was added to the composition, the stability of the composition was improved to a certain extent. The injection composition selected the disodium edetate and calcium sodium edetate described in the present invention as the stabilizer, and had significantly improved stability and good properties. In particular, the increase in Impurities 1 and 2 was significantly reduced.

[0042] Examples 7 to 16 Weighed the compound shown in Formula II, disodium edetate or calcium sodium edetate, dissolved it in 90% of the prescription volume of water for injection, adjusted the pH of the solution with hydrochloric acid, and then supplemented the water for injection to the full volume. Filled the solution into 2-mL ampoules, injected nitrogen gas before and after filling and sealing, and sterilized the samples under the conditions of 121 °C for 15 minutes. The composition was placed under the conditions of high temperature of 60 °C and light irradiation of 5000 Lx to study the stability, and the changes in the properties and impurities of the injection solution were confirmed. The results are shown in Tables 2 to 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, the samples significantly increased the impurities under the conditions of high temperature and light irradiation, and the color of the composition changed from colorless to light yellow under the conditions of light irradiation. When the mass ratio of the stabilizer to the compound shown in Formula II was within the range of 0.05 to 1.0 described in the present invention, the injection solution composition had good stability and no significant change in properties under the conditions of high temperature and light irradiation.

[0046] Examples 17 to 21 Weighed the compound shown in Formula II, disodium edetate or calcium sodium edetate, dissolved it in 90% of the prescription volume of water for injection, adjusted the pH of the solution with hydrochloric acid, and then supplemented the water for injection to the full volume. Filled the solution into 2-mL ampoules, injected nitrogen gas before and after filling and sealing, and sterilized the samples under the conditions of 121 °C for 15 minutes. The composition was placed under the conditions of high temperature of 60 °C and light irradiation of 5000 Lx to conduct a stability study, and the changes in the properties and impurities of the injection solution were confirmed. The results are shown in Table 4.

[0047]

Table 4

[0048] From the results in the above table, the influence of pH on the stability of the injection composition was confirmed. Referring to Examples 17 to 21, when the pH of the injection composition was 2.0, the low pH decreased the solubility of the compound shown in Formula II, and crystals precipitated in the composition. When the pH of the injection composition was 5.0, the stability of the composition was low, and after standing under conditions of high temperature and light irradiation, the impurities increased significantly, and the color of the solution changed from colorless to light yellow under light irradiation conditions. When the pH of the injection composition is within the range of 3.0 to 4.5 described in the present invention, the composition has high stability and no significant change in properties.

[0049] Examples 22 to 27 The compound shown in Formula II, disodium edetate or calcium sodium edetate was weighed and dissolved in 90% of the prescription volume of water for injection. After adjusting the pH of the solution with hydrochloric acid or phosphoric acid, the water for injection was supplemented to the total volume. The solution was filled into 2 mL amber ampoules, nitrogen gas was injected before and after filling and sealing, and the composition was sterilized under the 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 injection composition is 25 mg / mL, crystals precipitate during the preparation of the sample, it is difficult to meet the solubility of the composition, and there is a possibility of precipitation and impurities during preparation and storage. When the concentration of the compound shown in Formula II in the injection composition is 1 mg / mL or less, a large amount of injectable liquid is required to achieve a sufficient therapeutic effect, and the difficulty during use is increased. When the concentration of the compound shown in Formula II 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 components of the present patent have been described in detail above, it is obvious to those skilled in the art that such detailed description is only for explaining exemplary embodiments and should not be construed as limiting the scope of the present patent. Therefore, the substantial scope of the present disclosure is defined by the appended claims and their equivalents.

Claims

1. An injectable composition comprising a pharmaceutically acceptable salt of the compound represented by formula I and a stabilizer which is an edetate. 【Chemical 1】

2. The pharmaceutically acceptable salt according to claim 1, wherein the pharmaceutically acceptable salt is one selected from fumarate, oxalate, succinate, lactate, methanesulfonate, L-malate, citrate, nitrate, hydrobromide, hydrochloride, phosphate, sulfate. Injectable composition described.

3. The pharmaceutically acceptable salt of the compound represented by formula I according to claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, and the specific compound is the compound represented by formula II below. Injectable composition described. 【Chemical 2】

4. The edetate is one or more of disodium edetate, calcium sodium edetate, tetrasodium edetate, dicalcium edetate, and preferably one or more of disodium edetate or calcium sodium edetate. Injectable composition described.

5. The injectable composition according to any one of claims 1 to 4, wherein the concentration of the pharmaceutically acceptable salt of the compound represented by formula I as an active ingredient is 1 to 20 mg / mL.

6. The weight ratio of the pharmaceutically acceptable salt of the compound represented by formula I to the edetate is 1:1 to 20:1, preferably 5:1 to 10:

1. Injectable composition described.

7. The injectable composition according to any one of claims 1 to 4, wherein the pH is 3.0 to 4.

5.

8. The injectable composition according to claim 1, further comprising a pH adjuster which is one or more of hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, fumaric acid, tartaric acid, sodium bicarbonate, and preferably hydrochloric acid.

9. It consists of a pharmaceutically acceptable salt of the compound represented by formula I, a stabilizer, a pH adjuster and water for injection, and the concentration of the pharmaceutically acceptable salt of the compound represented by formula I as an active ingredient is 1 to 20 mg / mL, and the weight ratio of the pharmaceutically acceptable salt of the compound represented by formula I to the edetate is 1:1 to 20:1, preferably 5:1 to 10:1, and the pH is 3.0 to 4.

5. Injectable composition described.

10. The injectable composition according to claim 3, characterized in that it contains 2.5 mg of the compound represented by formula II per 1 mL of the composition, and 0.125 to 0.5 mg, preferably 0.25 to 0.5 mg of a stabilizer.

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

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

13. The injectable composition according to any one of claims 1 to 4, further comprising an osmotic pressure regulator.

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

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

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

17. A pharmaceutically acceptable salt and edetate of the compound represented by formula I are added to a certain volume of water for injection, dissolved, the pH is adjusted to 3.0 to 4.5 with a pH adjuster, water for injection is added to make up the volume, and it is sterilized by moist heat for 15 to 30 minutes. A method for preparing the injectable composition according to claim 16, characterized in that.

18. Take 80% to 90% of the prescription amount of water for injection, add a pharmaceutically acceptable salt and edetate of the compound represented by formula I, stir to dissolve, adjust the pH to 3.0 to 4.0 with 1 mol / L hydrochloric acid, and supplement the total amount with water for injection. Filter, inject nitrogen gas, fill and seal the container, and sterilize by moist heat at 121 °C for 15 to 30 minutes. A method for preparing the injectable composition according to claim 16 or 17, characterized in that.

19. Use of the injectable composition according to any one of claims 1 to 15 in the preparation of a medicament for the treatment or prevention of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett esophagitis, functional dyspepsia, Helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcer due to non-steroidal anti-inflammatory drugs, or hyperacidity or ulcer due to postoperative stress, or use in the preparation of a medicament for suppressing upper gastrointestinal bleeding due to peptic ulcer, acute stress ulcer, hemorrhagic gastritis, or invasive stress.

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

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