Imidazo[1,2-a]pyridine derivative pharmaceutical composition, preparation method therefor, and use thereof

Abstract

The present disclosure relates to the technical field of pharmaceutical formulations and particularly provides, in the specification, a stable imidazo[1,2-a]pyridine derivative pharmaceutical composition, a preparation method therefor, and use thereof. The pharmaceutical composition comprises an active pharmaceutical ingredient and auxiliary materials, wherein the active pharmaceutical ingredient is (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone citrate; the auxiliary materials include one or more selected from cyclodextrin, a salt of cyclodextrin, propylene glycol, and PEG400.

Description

Imidazo[1,2-a]pyridine derivative pharmaceutical composition, and preparation method and use thereof

[0001] Cross-reference to Related Applications

[0002] This application claims the benefit of Chinese Patent Application No. CN202410478619.7, filed April 19, 2024; the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present disclosure belongs to the field of pharmaceutical preparations, in particular to a citrate formulation of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone and a preparation method and use thereof. BACKGROUND

[0004] Gastrointestinal inflammatory diseases or gastric acid-related diseases such as peptic ulcer, gastric / dueodenal ulcer, gastritis, gastro-esophageal reflux disease (GERD), non-erosive reflux disease (NERD), etc. are the most common digestive system diseases. In order to solve the problems of traditional proton pump inhibitors (PPIs), in recent proton pump inhibitors (PPIs), the interest and demand for H+ / K+-ATPase+potassium ion competitive acid blocker (P-CAB, acid pump antagonist) drugs, which have a mechanism of inhibiting acid secretion by reversibly binding to the binding site to inhibit potassium competition, are growing. In particular, unlike irreversible proton pump inhibitors (PPIs), reversible proton pump inhibitors (P-CAB) are fast-acting in mechanism, and are very convenient to take before or after meals, and are expected to achieve better efficacy.

[0005] Chinese patent CN109415362B discloses (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone (Zastaprazan, a compound represented by formula (I)), which is an innovative potassium ion competitive acid blocker (P-CAB) independently developed by the first pharmaceutical company of Korea, has gastric acid secretion inhibitory activity, and can be effectively used for preventing or treating gastrointestinal inflammatory diseases or gastric acid related diseases. At present, a phase III clinical trial for erosive esophagitis is being carried out in Korea, and existing data show that Zastaprazan has the advantages of fast onset, good acid inhibition effect, long-acting, and few adverse reactions, and can be expanded to the treatment of duodenal ulcer, Helicobacter pylori infection and non-erosive gastroesophageal reflux disease in the future, therefore, the development of Zastaprazan preparations suitable for clinical needs has important clinical significance and broad market prospects. SUMMARY

[0006] The present disclosure provides a pharmaceutical preparation of a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone which is stable in properties, has little irritation and can meet clinical needs.

[0007] Therefore,

[0008] In one aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutical active ingredient and an excipient, wherein the pharmaceutical active ingredient is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and the excipient comprises one or more selected from cyclodextrin, a salt of cyclodextrin, propylene glycol, PEG400.

[0009] In some embodiments, the pharmaceutical composition comprises a pharmaceutical active ingredient and an excipient, wherein the pharmaceutical active ingredient is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and the excipient comprises one or more selected from cyclodextrin or a salt thereof.

[0010] In some embodiments, the pharmaceutical composition comprises a pharmaceutical active ingredient and an excipient, wherein the pharmaceutical active ingredient is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and the excipient comprises cyclodextrin.

[0011] In some embodiments, the pharmaceutical composition comprises a pharmaceutically active ingredient and an excipient, wherein the pharmaceutically active ingredient is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2- a]pyridin-6-yl)methanone, and the excipient comprises a salt of cyclodextrin.

[0012] In some embodiments, the pharmaceutical composition comprises a pharmaceutically active ingredient and an excipient, wherein the pharmaceutically active ingredient is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2- a]pyridin-6-yl)methanone, and the excipient comprises propylene glycol.

[0013] In some embodiments, the pharmaceutical composition comprises a pharmaceutically active ingredient and an excipient, wherein the pharmaceutically active ingredient is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2- a]pyridin-6-yl)methanone, and the excipient comprises PEG400.

[0014] In some embodiments, the cyclodextrin comprises one or more of sulfobutyl- -cyclodextrin, hydroxypropyl- -cyclodextrin, methyl- -cyclodextrin, or hydroxypropyl- -cyclodextrin.

[0015] In some embodiments, the salt of cyclodextrin comprises a sodium salt.

[0016] In some embodiments, the salt of cyclodextrin comprises sulfobutyl- -cyclodextrin sodium.

[0017] In some embodiments, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1:(5.5-446.94), more preferably 1:(5.5-63.60), based on the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2- a]pyridin-6-yl)methanone.

[0018] In some embodiments, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1:(5.95-446.94), more preferably 1:(5.95-63.60), based on the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2- a]pyridin-6-yl)methanone.

[0019] In some embodiments, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (5.5-9), 1 : (11-13), 1 : (15-19), 1 : (21-29), 1 : (31-39), 1 : (41-49), 1 : (51-59), or 1 : (61-462.96); preferably 1 : (21-29), 1 : (41-49), or 1 : (15-19), for example it can be 1 : 7-8, 1 : 12, 1 : 17, 1 : 21, 1 : 28, 1 : 33, 1 : 38, 1 : 42, 1 : 45, 1 : 62.5, 1 : 200, or 1 : 400.

[0020] In some embodiments, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (5.5-9), 1 : (11-13), 1 : (15-19), 1 : (21-29), 1 : (31-39), 1 : (41-59), or 1 : (61-462.96); preferably 1 : (21-29), 1 : (41-49), or 1 : (15-19), for example it can be 1 : 21 or 1 : 42.

[0021] In some embodiments, the molar ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (1.58-118.7), more preferably 1 : (1.58-54.71), more preferably 1 : (1.58-16.89) in terms of the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone.

[0022] In some embodiments, the mass ratio of the pharmaceutically active ingredient to propylene glycol is 1 : (5-100), preferably 1 : (10-90), preferably 1 : (15-80), preferably 1 : (18-70), more preferably 1 : (20-65) in terms of the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone.

[0023] In some embodiments, the molar ratio of the pharmaceutically active ingredient to propylene glycol is 1 : (100-500), more preferably 1 : (120-480), more preferably 1 : (140-460) in terms of the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone.

[0024] In some embodiments, the mass ratio of the pharmaceutically active ingredient to PEG400 is 1 : (5-100), preferably 1 : (10-90), preferably 1 : (15-80), preferably 1 : (18-70), more preferably 1 : (20-65), calculated as the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2- a]pyridin-6-yl)methanone.

[0025] In some embodiments, the molar ratio of the pharmaceutically active ingredient to PEG400 is 1 : (1.5-150), more preferably 1 : (2-100); more preferably 1 : (2.5-90), calculated as the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2- a]pyridin-6-yl)methanone.

[0026] In some embodiments, the pharmaceutical composition optionally comprises a pH adjusting agent.

[0027] In some embodiments, the pH adjusting agent is selected from a basic pH adjusting agent and / or an acidic pH adjusting agent.

[0028] In some embodiments, the basic pH adjusting agent is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, arginine, lysine, histidine, glycine, tris-hydroxymethyl aminomethane, meglumine, triethylamine, or diethanolamine.

[0029] In some embodiments, the basic pH adjusting agent is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, arginine, lysine, histidine, or glycine.

[0030] In some embodiments, the basic pH adjusting agent is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate.

[0031] In some embodiments, the acidic pH adjusting agent is selected from one or more of citric acid, ascorbic acid, lactic acid, malic acid, citric acid, fumaric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid, or acetic acid.

[0032] In some embodiments, the acidic pH adjusting agent is selected from one or more of citric acid, ascorbic acid, lactic acid, malic acid, or citric acid.

[0033] In some embodiments, the acidic pH adjusting agent is selected from one or more of citric acid, ascorbic acid, or lactic acid.

[0034] In some embodiments, the acidic pH adjusting agent is citric acid.

[0035] In some embodiments, the pH adjusting agent is citric acid.

[0036] In some embodiments, the pH of the pharmaceutical composition is 1.5-5.5, preferably 2.0-5.3, preferably 3.0-5.3, preferably 3.0-4.5, more preferably 3.5-4.5.

[0037] In a preferred embodiment, the excipient does not comprise albumin.

[0038] In some embodiments, the excipient is one or more selected from sulfobutyl-β- cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, or sulfobutyl-β- cyclodextrin sodium.

[0039] In some embodiments, the excipient is one or more selected from sulfobutyl-β- cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin sodium, which helps to improve the stability of the pharmaceutical composition, reduce its vascular irritation.

[0040] In some embodiments, the pH of the pharmaceutical composition is 1.5-5.5, preferably 2.0-5.3, preferably 3.0-5.3; for example, it can be 3.0-4.5 or 3.5-4.5. It can further be 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, or 5.3, or a range between any two of the foregoing.

[0041] In a preferred embodiment, the pharmaceutical composition is a lyophilized powder for injection.

[0042] In some embodiments, during the preparation of the pharmaceutical composition, the pH of the lyophilized pre-lyophilized pharmaceutical solution is controlled to be 1.5-5.5, preferably 2.0-5.3, preferably 3.0-5.3; or, the pH of the pharmaceutical composition after being dissolved is 1.5-5.5, preferably 2.0-5.3, preferably 3.0-5.3.

[0043] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically active ingredient which is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and an excipient, wherein the excipient comprises one or more selected from a cyclodextrin or a salt thereof, and a pH adjusting agent, and the pH of the pharmaceutical composition is 1.5-5.5, preferably 2.0-5.3, preferably 3.0-5.3, further can be 3.0-4.5 or 3.5-4.5; preferably the mass ratio of the pharmaceutically active ingredient to the cyclodextrin or a salt thereof is 1:(5.5-446.94), more preferably 1:(5.5-63.60). Preferably the cyclodextrin comprises one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin or hydroxypropyl-γ-cyclodextrin, and the salt of the cyclodextrin comprises a sodium salt, preferably comprises sulfobutyl-β-cyclodextrin sodium.

[0044] In the present disclosure, the pH adjusting agent is commonly used in the art, for example, a pharmaceutically acceptable acid or acidic agent or acidic buffer or solution of acid, or a base or basic agent or solution of base, for example, a strong base or solution of strong base and a basic buffer. The strong base includes but is not limited to sodium hydroxide, potassium hydroxide. The basic buffer includes but is not limited to disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, etc. The acid includes but is not limited to citric acid. The pH adjusting agent not only can adjust the pH to 1.5-5.5, preferably 2.0-5.3, preferably 3.0-5.3, but also can ensure that the pH of each batch of product is consistent.

[0045] In another aspect, the present disclosure provides a lyophilized powder injection, and the raw material for preparing the lyophilized powder injection comprises the pharmaceutical composition as described above.

[0046] In some embodiments, a lyophilized powder injection, and the raw material for preparing the lyophilized powder injection comprises the pharmaceutical composition as described above; the pharmaceutical composition is lyophilized in the form of being dissolved in a solvent.

[0047] In some embodiments, a lyophilized powder injection, and the raw material for preparing the lyophilized powder injection comprises a pharmaceutically active ingredient which is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and an excipient, wherein the excipient comprises one or more selected from a cyclodextrin, a salt of cyclodextrin, propylene glycol, PEG400.

[0048] In some embodiments, a lyophilized powder for injection, the raw material for producing the lyophilized powder for injection comprises a pharmaceutical active ingredient which is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and a bulking agent which comprises one or more selected from a cyclodextrin or a salt thereof.

[0049] In some embodiments, a lyophilized powder for injection, the raw material for producing the lyophilized powder for injection comprises a pharmaceutical active ingredient which is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and a bulking agent which comprises a cyclodextrin.

[0050] In some embodiments, a lyophilized powder for injection, the raw material for producing the lyophilized powder for injection comprises a pharmaceutical active ingredient which is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and a bulking agent which comprises a salt of a cyclodextrin.

[0051] In some embodiments, a lyophilized powder for injection, the raw material for producing the lyophilized powder for injection comprises a pharmaceutical active ingredient which is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and a bulking agent which comprises propylene glycol.

[0052] In some embodiments, a lyophilized powder for injection, the raw material for producing the lyophilized powder for injection comprises a pharmaceutical active ingredient which is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and a bulking agent which comprises PEG400.

[0053] In some embodiments, optionally, the raw material for producing the lyophilized powder for injection comprises a pH adjusting agent.

[0054] In some embodiments, the lyophilized powder for injection according to the present disclosure, the pH adjusting agent is citric acid.

[0055] In some embodiments, the cyclodextrin comprises one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, or hydroxypropyl-γ-cyclodextrin.

[0056] In some embodiments, the salt of a cyclodextrin comprises a sodium salt.

[0057] In some embodiments, the salt of the cyclodextrin comprises sulfobutyl-β- cyclodextrin sodium.

[0058] The pharmaceutically active ingredient and the excipient are lyophilized in a form of being dissolved in a solvent. The solvent is a solvent commonly used in the art for preparing a lyophilized powder injection, for example, including one or more of water, a sodium chloride solution, or a glucose solution.

[0059] In some embodiments, the glucose is a 5%-10% (w / v) glucose solution, for example, a 5% glucose solution or a 10% glucose solution.

[0060] In some embodiments, the solvent is a 0.9% w / v sodium chloride solution.

[0061] In some embodiments, the liquid formulation formed after the solvent, the pharmaceutical composition, or the lyophilized powder injection is dissolved is an isotonic solution, which generally refers to a solution having an osmotic pressure equal to that of blood plasma.

[0062] Optionally, the raw material further comprises a pH adjusting agent, which is used in an amount to adjust the pH to 1.5-5.5, preferably to 2.0-5.3, preferably to 3.0-5.3.

[0063] In another aspect, the present disclosure provides a method for preparing a pharmaceutical composition or a lyophilized powder injection as previously described, the method comprising the following steps:

[0064] (a) dissolving the excipient in a solvent to form a solution;

[0065] (b) adding a pharmaceutically active ingredient to the solution formed in step (a);

[0066] (c) lyophilizing.

[0067] In some embodiments, the step (b) and the step (c) further comprise a step of adjusting the pH.

[0068] In some embodiments, the adjusting the pH is adjusting the pH to 1.5-5.5, preferably to 2.0-5.3, preferably to 3.0-5.3, for example, it can be 3.0-4.5 or 3.5-4.5. It can further be 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, or 5.3, or a range between any two of the foregoing.

[0069] In another aspect, the present disclosure provides an aqueous injection, the raw material for preparing the aqueous injection comprising a pharmaceutical composition as previously described.

[0070] In some embodiments, a water injection, the raw materials for making the water injection comprise a pharmaceutically active ingredient and an excipient, wherein the pharmaceutically active ingredient is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and the excipient comprises one or more selected from a cyclodextrin, a salt of a cyclodextrin, propylene glycol, PEG400.

[0071] In some embodiments, a water injection, the raw materials for making the water injection comprise a pharmaceutically active ingredient and an excipient, wherein the pharmaceutically active ingredient is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and the excipient comprises a cyclodextrin.

[0072] In some embodiments, a water injection, the raw materials for making the water injection comprise a pharmaceutically active ingredient and an excipient, wherein the pharmaceutically active ingredient is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and the excipient comprises a salt of a cyclodextrin.

[0073] In some embodiments, a water injection, the raw materials for making the water injection comprise a pharmaceutically active ingredient and an excipient, wherein the pharmaceutically active ingredient is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and the excipient comprises propylene glycol.

[0074] In some embodiments, a water injection, the raw materials for making the water injection comprise a pharmaceutically active ingredient and an excipient, wherein the pharmaceutically active ingredient is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and the excipient comprises PEG400.

[0075] In some embodiments, optionally, the raw materials for making the water injection comprise a pH adjusting agent.

[0076] In some embodiments, the water injection according to the present disclosure, the pH adjusting agent is citric acid.

[0077] In some embodiments, the water injection according to the present disclosure, the cyclodextrin comprises one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, or hydroxypropyl-γ-cyclodextrin; and the salt of a cyclodextrin comprises a sodium salt.

[0078] In some embodiments, the salt of the cyclodextrin in the aqueous injection according to the present disclosure comprises sulfobutyl-β-cyclodextrin sodium.

[0079] In another aspect, the present disclosure provides a method of preparing the aqueous injection as previously described, the method comprising the steps of:

[0080] (a) dissolving the excipient in a solvent to form a solution;

[0081] (b) adding a pharmaceutically active ingredient to the solution formed in step (a).

[0082] In another aspect, the present disclosure provides a liquid formulation comprising the pharmaceutical composition as previously described, the lyophilized powder injection as previously described, or the aqueous injection as previously described, and a solvent.

[0083] In some embodiments, the pH of the liquid formulation is 1.5-5.5, preferably 2.0-5.3, preferably 3.0-5.3, for example, it can be 3.0-4.5 or 3.5-4.5, further it can be 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, or a range between any two of the foregoing.

[0084] In some embodiments, the solvent comprises water, sodium chloride solution, or glucose solution.

[0085] In a preferred embodiment, the water is water for injection.

[0086] In some embodiments, the water is sterile water for injection.

[0087] In a preferred embodiment, the liquid formulation is an injection.

[0088] In another aspect, the present disclosure provides use of the pharmaceutical composition as previously described, or the lyophilized powder injection as previously described, or the aqueous injection as previously described, or the liquid formulation as previously described, in the manufacture of a medicament for preventing and / or treating a disease caused by excessive secretion of gastric acid.

[0089] In another aspect, the present disclosure provides a method of preventing and / or treating a disease caused by excessive secretion of gastric acid, comprising the step of administering to a patient in need thereof the pharmaceutical composition as previously described, or the lyophilized powder injection as previously described, or the aqueous injection as previously described, or the liquid formulation as previously described.

[0090] In another aspect, the present disclosure provides the pharmaceutical composition as previously described, or the lyophilized powder injection as previously described, or the aqueous injection as previously described, or the liquid formulation as previously described, for use in prevention and / or treatment.

[0091] In another aspect, the present disclosure provides a pharmaceutical composition as described previously or a lyophilized powder injection as described previously or an aqueous injection as described previously or a liquid preparation as described previously for use in the prevention and / or treatment of a disease caused by excessive gastric acid secretion.

[0092] In some embodiments, examples of the disease caused by excessive gastric acid secretion include a gastrointestinal inflammatory disease or a gastric acid-related disease. The gastrointestinal inflammatory disease or the gastric acid-related disease includes a peptic ulcer, a peptic ulcer bleeding, a prevention of peptic ulcer bleeding, a gastric and duodenal ulcer, a non-steroidal anti-inflammatory drug (NSAID)-induced ulcer, a Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), laryngopharyngeal reflux disease, non-erosive reflux disease (NERD), visceral involvement pain, cancer, heartburn, vomiting, esophagitis, dysphagia, hypersalivation, airway obstruction, or asthma.

[0093] The pharmaceutical active ingredient according to the present disclosure has excellent activity in inhibiting gastric acid secretion, and thus can be effectively used for the prevention or treatment of a gastrointestinal inflammatory disease or a gastric acid-related disease, particularly a peptic ulcer, a gastric and duodenal ulcer, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD).

[0094] The dose of the pharmaceutical composition according to the present disclosure can vary depending on the condition and body weight of a patient, the severity of a disease, the form and administration route and period of a drug, and the dose can be appropriately determined by one skilled in the art.

[0095] In some embodiments, the pharmaceutical composition of the present disclosure can further contain one or more active ingredients showing the same or similar efficacy as the compound of formula (I).

[0096] In some embodiments, the pharmaceutical composition of the present disclosure can further contain one or more selected from amoxicillin, clarithromycin, aceclofenac, meloxicam, and naproxen.

[0097] In another aspect, the present disclosure provides a method for preventing or treating a disease caused by excessive gastric acid secretion, the method including administering to a mammal (including a human) an effective amount of a pharmaceutical composition as described previously or a lyophilized powder injection, an aqueous injection as described previously or a liquid preparation as described previously.

[0098] In one aspect, the method includes simultaneously, sequentially, or separately administering a therapeutically effective amount of the pharmaceutical composition.

[0099] The details mentioned in the pharmaceutical composition, the kit, the method of preparing the pharmaceutical composition, the use, the treatment method of the present disclosure are applied in the same way unless they contradict each other. BRIEF DESCRIPTION OF DRAWINGS

[0100] In order to more clearly illustrate the technical solutions in the specific embodiments of the present disclosure or the prior art, the drawings required to be used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present disclosure, and those skilled in the art can also obtain other drawings according to these drawings without creative labor. The drawings herein are incorporated into the specification and form part of the specification, show embodiments consistent with the present disclosure, and together with the specification serve to explain the principles of the present disclosure.

[0101] Figure 1 is the histopathological examination result of the negative control group and the test product group after the last administration. DETAILED DESCRIPTION

[0102] I. Terms and definitions

[0103] In the present disclosure, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by a person skilled in the art. And the relevant terms and laboratory operation steps used herein are the terms and conventional steps widely used in the corresponding field. At the same time, in order to better understand the present disclosure, the definitions and explanations of the relevant terms are provided below.

[0104] In the description herein, the description of "some embodiments", "some implementations" or "some implementations" describes a subset of all possible embodiments, but it can be understood that "some embodiments" can be the same subset or different subset of all possible embodiments, and can be combined with each other without conflict.

[0105] As used herein and unless otherwise indicated, the terms "comprise", "include", "have", "contain", including their grammatical equivalents, should generally be understood to be open-ended and non-limiting, for example, not excluding other unlisted elements or steps.

[0106] In this document, when referring to pH, it can be understood that due to measurement reasons, the range of the pH should allow fluctuations of up to and down 0.1, for example, when referring to pH of 3.5 to 4.5, the range should include 3.5±0.1 to 4.5±0.1.

[0107] As used herein, the term "clathration" refers to a technique in which one molecule is embedded in the cavity structure of another molecule to form a clathrate. A clathrate is composed of two components, a host molecule and a guest molecule, the host molecule having a large cavity structure sufficient to accommodate the guest molecule within it to form a molecular capsule.

[0108] As used herein, the term "treatment" includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition, in such a way as to improve or stabilize a patient's condition.

[0109] As used herein, the terms "patient," "individual," and "subject" are used interchangeably and refer to any individual animal, more preferably a mammal (including, e.g., non-human animals such as cats, dogs, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates) for which treatment is desired. In particular embodiments, the patient herein is a human.

[0110] As used herein, "pharmaceutical formulation" refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to the subject to which the formulation would be administered.

[0111] As used herein, "lyophilized powder for injection" refers to a solid powder-like preparation of one or more pharmaceutically active ingredients (or drug substances, herein referring to the citrate salt of the compound of Formula (I)) incorporated in one or more excipients or dissolved in one or more solvents (or vehicles) processed (e.g., freeze-dried) in a (preferably sterile) environment.

[0112] Unless otherwise specified, "water for injection" refers to water complying with the relevant provisions under the item "water for injection" in the Chinese Pharmacopoeia.

[0113] Unless otherwise specified, "dissolution" (or its full name "dissolution clarification") refers to an operation or process in which a sample to be dissolved is dissolved in a solvent to be clear or free of visible turbidity or precipitation, or a state in which the sample is dissolved in the solvent and free of visible turbidity or precipitation.

[0114] Unless otherwise specified, "mass concentration" (or its abbreviation "mass concentration") refers to the mass number (e.g., 1 g or 1 mg) of a solute contained in a unit volume (e.g., 1 cm 3 , 1 mL) of a solution, usually expressed in mg / L, mg / mL. Unless otherwise specified, the term "% (w / v)" used in the present disclosure means the number of grams of solute contained in each 100 mL of solution, i.e., "g / 100 mL".

[0115] As used in the present disclosure, the term "lyophilization" (or its full name "lyophilization") means a drying operation or process in which a water-containing material (e.g., an aqueous pharmaceutical solution, i.e., a solution containing a citrate salt of a compound of Formula (I) and a cyclodextrin in the present disclosure) is first frozen to below the freezing point of water, causing the water to change to ice (freezing), and then the ice is removed by sublimation to water vapor under vacuum conditions. The material can be frozen in advance in a freezing device and then transferred to a drying device for drying, or the material can be frozen directly in the drying device by rapid vacuuming and then dried. The water vapor produced in the sublimation process is removed by condensation in a condensing device, and the heat of vaporization required for sublimation is generally supplied by heat radiation or heat conduction.

[0116] As used herein, "administering" means the method of giving a subject (e.g., a patient) a dose of a pharmaceutical composition (e.g., Zastaprazan citrate injection). The administration can be by any suitable route, for example, by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is acute or chronic. Various administration regimens are contemplated herein, including but not limited to single or multiple administrations at different points in time, bolus administration, and drip administration.

[0117] As used herein, "pH adjusting agent" means a compound or mixture of compounds that can be used to ensure that the pH of a composition is within an acceptable range for human or mammalian administration. Suitable pH adjusting agents include pharmaceutically acceptable buffers, pharmaceutically acceptable acids, and pharmaceutically acceptable bases. The pH adjusting agent can optionally be mixed with the pharmaceutically active ingredient, or provided in a separate vial or container, so that the user can adjust the pH as part of a multi-step procedure. Herein, the pH is preferably 3.0-5.3, for example, it can be 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, or 5.3, or a range between any two of the foregoing.

[0118] As used herein, "pharmaceutically acceptable carrier" means a pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0119] The present application is directed to (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3- dimethylimidazo[1,2-a]pyridin-6-yl)methanone of Formula (I) pharmaceutically acceptable citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)- 2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone. The solubility, stability and biological safety (e.g. vascular irritation) of different salts and the prepared compositions were investigated. At the same time, it was surprisingly found that the excipients of the composition of the present disclosure were optimized (e.g. the prescription ingredients were as simple as possible, the production cost was reduced, the solubilization effect was optimal, and the safety of the excipients was evaluated). For example, among the excipients disclosed in the prior art which have a solubilization effect, ① Tween 80 has moderate toxicity for intravenous injection, moderate toxicity for gastrointestinal uptake, eye irritation, is an experimental carcinogen, has an impact on reproduction, and has been reported to be mutagenic. ② Polyoxyethylene castor oil has relatively serious sensitization, peripheral nerve toxicity, cytotoxicity, and can cause hyperlipidemia and toxic kidney damage when injected intravenously in humans and animals; and polyoxyethylene castor oil can dissolve dioctyl phthalate (DEHP) in polyvinyl chloride (PVC) infusion bottles, causing liver toxicity, testicular atrophy and precocious puberty in children, increasing transportation costs. ③ Solutol HS-15 (polyethylene glycol-15 hydroxystearate) is a new excipient, which is generally considered to be safe, but there have been reports of dose-limiting toxicities when used clinically, such as injection site pain and redness, urticaria, etc. ④ N,N-dimethylacetyl (DMA) dimethylacetamide is used as a solvent in parenteral formulations in pharmaceutical preparations, and when used as an excipient, it is generally considered to be a non-toxic material. Repeated exposure to dimethylacetamide can be harmful and can cause liver damage, and high intravenous doses (400 mg / kg / day for 3 consecutive days) can produce hallucinations. ⑤ Ethanol has a stimulating effect on blood vessels, and there have been no cases of direct bolus injection into blood vessels. ⑥ The adverse reactions of glycerol are mainly derived from the dehydrating property of glycerol, which can cause hemolysis, hematuria and kidney damage. Slow administration has not been found to be toxic. The maximum dose for intravenous injection is 22.50%; the maximum dose for intramuscular injection is 15.36%; and the maximum dose for subcutaneous injection is 32.50%. Propylene glycol and PEG (e.g. PEG400) are generally considered to be non-toxic and low-irritating.

[0120] The present disclosure investigated that the pharmaceutical composition prepared by inclusion of the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone with cyclodextrin as an excipient performed best in terms of solubility, stability and biological safety.

[0121] In addition, the pharmaceutical composition of the present disclosure significantly improves the freeze-drying re-dissolution performance of the active ingredient of the present disclosure, and is more stable for clinical use of intravenous injection without precipitation, greatly improving the safety of clinical use, and also eliminating the need for special solvents, reducing the trouble of packaging, transportation and clinical use. And the physical properties of these compositions are better (for example, the appearance of the prepared freeze-dried powder can meet the quality requirements through a simple process), the physical properties of the product are more stable during storage (for example, the API content changes little during storage), and the impurity content in the composition is relatively low.

[0122] As used herein, the term "SBE-β-CD" refers to sulfobutyl betadex sodium.

[0123] As used herein, the term "HP-β-CD" refers to hydroxypropyl betadex.

[0124] As used herein, the term "ME-β-CD" refers to methyl betadex.

[0125] As used herein, the term "HP-γ-CD" refers to hydroxypropyl gammatex.

[0126] As used herein, the term "PEG400" refers to polyethylene glycol 400.

[0127] II. Examples

[0128] In order to make the purposes, technical solutions and advantages of the present disclosure clearer, the present disclosure will be further described in detail below. The described examples should not be considered as limiting the present disclosure, and all other examples obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present disclosure.

[0129] Before further detailing the examples of the present disclosure, the terms and phrases involved in the examples of the present disclosure are explained, and the terms and phrases involved in the examples of the present disclosure are applicable to the following explanations.

[0130] The raw materials and equipment used in the specific embodiments of the present disclosure are known products, which can be obtained by purchasing commercially available products or using publicly disclosed methods. For example, the citrate salt of the compound of formula (I) in the following examples is prepared by reacting the compound of formula (I) with citric acid. The compound of formula (I) is obtained according to the preparation method of CN109415362B. The citrate salt of the compound of formula (I) is obtained according to the conventional preparation method of citrate salt in the art.

[0131] The preparation method of the citrate salt of the following examples of the present disclosure is as follows: acetone, the compound of formula (I), and citric acid are added to a reaction bottle, and the temperature is raised to 57°C, and stirred for 3h. Then, after cooling to 10-20°C, the solid is precipitated, and then filtered. The filter cake is dried to obtain the citrate salt of the compound of formula (I).

[0132] Preparation of lyophilized powder injection of citrate salt of compound of formula (I) of Example 1

[0133] Preparation process:

[0134] 1) Take the prescribed amount of cyclodextrin, add 2.1 L of sterilized water for injection to prepare a 30% (w / v) cyclodextrin solution;

[0135] 2) Take the prescribed amount of API and add it to the prepared cyclodextrin solution, stir at 50°C until dissolved;

[0136] 3) Add water to make up to 3 L;

[0137] 4) Fill the prepared solution into a Westlin bottle, 4 ml per bottle;

[0138] 5) Lyophilize.

[0139] Preparation of lyophilized powder injection of citrate salt of compound of formula (I) of Example 2

[0140] Preparation process:

[0141] 1) Add 2.1 L of purified water, add the prescribed amount of SBE-β-CD, and after the SBE-β-CD is dissolved, add the prescribed amount of API, stir at 50°C until dissolved;

[0142] 2) Add purified water to make up to 2.7 L, take a sample to measure the pH, if the pH is higher than 3.8, add 1 mol / L citric acid solution to the drug solution, and adjust the pH of the drug solution to 3.8;

[0143] 3) Add purified water to make up to 3 L;

[0144] 4) Fill the prepared solution into a Westlin bottle, the filling amount is 2.5 ml per bottle;

[0145] 5) Lyophilize the filled sample.

[0146] Preparation of lyophilized powder injection of citrate salt of compound of formula (I) of Example 3

[0147] Preparation process:

[0148] 1) Add 2.1 L of purified water, add the prescribed amount of SBE-β-CD, and after the SBE-β-CD is dissolved, add the prescribed amount of API, stir at 50°C until dissolved;

[0149] 2) Add purified water to make up to 3 L;

[0150] 3) The formulated solution was filled into vials, the filling volume was 2.5ml / vial;

[0151] 4) The filled samples were lyophilized.

[0152] Example 4 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0153] The preparation process referred to Example 3.

[0154] Example 5 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0155] The preparation process referred to Example 3.

[0156] Example 6 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0157] The preparation process referred to Example 3.

[0158] Example 7 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0159] The preparation process referred to Example 3.

[0160] Example 8 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0161] The preparation process referred to Example 3.

[0162] Example 9 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0163] The preparation process referred to Example 3.

[0164] Example 10 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0165] The preparation process referred to Example 3.

[0166] Example 11 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0167] The preparation process referred to Example 3.

[0168] Example 12 Preparation of liquid injection of citrate salt of compound of formula (I)

[0169] Preparation process:

[0170] 1) Add 2.1 L of purified water, add the prescription amount of SBE-β-CD, and after the SBE-β-CD is dissolved, add the prescription amount of API, and stir at 50°C until dissolved;

[0171] 2) Add purified water to 3 L;

[0172] 3) The prepared solution is freeze-dried;

[0173] 4) The freeze-dried sample is subpackaged, 4.01 g / bottle;

[0174] 5) The sample is reconstituted to 38 ml for use.

[0175] Example 13 Preparation of an injection liquid preparation of a citrate salt of the compound of formula (I)

[0176] Preparation process:

[0177] 1) Add 2.1 L of purified water, add the prescription amount of SBE-β-CD, and after the SBE-β-CD is dissolved, add the prescription amount of API, and stir at 50°C until dissolved;

[0178] 2) Add purified water to 3 L;

[0179] 3) The prepared solution is freeze-dried;

[0180] 4) The freeze-dried sample is subpackaged, 8.11 g / bottle;

[0181] 5) The sample is reconstituted to 77 ml for use.

[0182] Example 14 Preparation of a freeze-dried powder injection of a citrate salt of the compound of formula (I)

[0183] The preparation process refers to Example 3.

[0184] Example 15 Preparation of a freeze-dried powder injection of a citrate salt of the compound of formula (I)

[0185] The preparation process refers to Example 3.

[0186] Example 16 Preparation of a freeze-dried powder injection of a citrate salt of the compound of formula (I)

[0187] The preparation process refers to Example 3.

[0188] Example 17 Preparation of an aqueous injection of a citrate salt of the compound of formula (I)

[0189] Preparation process:

[0190] 1) Add 20 ml of purified water, add the prescribed amount of propylene glycol, and after mixing evenly, add the prescribed amount of API, and stir at 50°C until the solution is clear (if the solution is not clear, add an appropriate amount of citric acid to make the solution clear);

[0191] 2) Add purified water to 50 ml;

[0192] 3) The prepared solution is filled into a vial, and the filling amount is 5 ml / vial.

[0193] Preparation of the water injection of the citric acid salt of the compound of formula (I)

[0194] The preparation process is referred to in Example 17.

[0195] Preparation of the lyophilized powder injection of the citric acid salt of the compound of formula (I)

[0196] Preparation process:

[0197] 1) Add 55 ml of purified water, add the prescribed amount of HP-β-CD, and after the HP-β-CD is clear, add the prescribed amount of API;

[0198] 2) Add an appropriate amount of 1 mol / L citric acid solution to the drug solution, and stir at 50°C until the solution is clear (pH is 3);

[0199] 3) Add purified water to 100 ml;

[0200] 4) The prepared solution is filled into a vial, and the filling amount is 2.5 ml / vial;

[0201] 5) Freeze-dry the filled sample.

[0202] Preparation of the lyophilized powder injection of the citric acid salt of the compound of formula (I)

[0203] The preparation process is referred to in Example 19.

[0204] Preparation of the water injection of the citric acid salt of the compound of formula (I)

[0205] Preparation process:

[0206] 1) Add 55 ml of purified water, add the prescribed amount of HP-r-CD, and after the HP-r-CD is clear, add the prescribed amount of API;

[0207] 2) Add an appropriate amount of 1 mol / L citric acid solution to the drug solution, and stir at 50°C until the solution is clear;

[0208] 3) Add purified water to make up to 100 ml;

[0209] 4) The prepared solution is filled into a vial, and the filling amount is 5 ml / vial;

[0210] 5) The filled sample is mixed with 95 ml of sodium chloride injection.

[0211] Preparation of an aqueous injection of the citrate salt of the compound of formula (I) according to Example 22

[0212] The preparation process refers to Example 21.

[0213] Preparation of an aqueous injection of the citrate salt of the compound of formula (I) according to Example 23

[0214] The preparation process refers to Example 21.

[0215] Test Example 1: Solubility test

[0216] The solubility of the citrate salt of the compound of formula (I) (prepared according to the method described in Chinese Patent Application CN201780039504.6 and Korean Patent Application 10-2022-0095088) was tested, and the results showed that the solubility of the free base in water was 0.00044 mg / mL, the solubility of the citrate salt under neutral pH conditions was 0.0018 mg / mL, and although the solubility of the citrate salt was improved, it still did not meet the requirements of injection preparation. The inventors found that the citrate salt of the compound of formula (I) according to the present disclosure has good solubility in a cyclodextrin solution. In the examples of the present disclosure, the solution containing API and cyclodextrin prepared before lyophilization, and the injection liquid preparation obtained after reconstituting the lyophilized powder in water, can all be completely dissolved and clear, and the solubility is qualified and meets the requirements for pharmaceutical use.

[0217] Test Example 2: Comparison of irritation experiments

[0218] Test sample and control sample

[0219] Test samples 1, 6, and 7 were derived from the lyophilized powder prepared in Examples 2, 19, and 20, respectively. The lyophilized powder was reconstituted with 4 mL of sodium chloride injection and mixed with 96 mL of sodium chloride injection to obtain the test sample. Test samples 8 to 10 were derived from the aqueous injection prepared in Examples 21 to 23. Control sample 1 was a lyophilized powder prepared according to the formula in the table below and the process in Example 3, and was dissolved in a sodium chloride solution to obtain the control sample. Control sample 2 was a sodium chloride injection. The specific formula of the test sample and the control sample is shown in Table 1 below.

[0220] Table 1 (reconstitution concentration)

[0221] Note: The API concentration of test products 1, 6, and 7 after being mixed with sodium chloride injection is 0.2 mg / ml, and the concentration of excipients is 0.42% (w / v).

[0222] Experimental method

[0223] Experimental animals: 32 rabbits were taken, divided into 8 groups, 4 rabbits in each group, numbered according to Table 2, provided by Tianjin Yuda Experimental Animal Breeding Co., Ltd.

[0224] In this test, the administration method of ear margin intravenous injection (infusion) was selected. Each rabbit was injected with the injection solution in Table 2 through the left ear margin vein with a sterile syringe, once a day for 7 consecutive days, a total of 7 times. The irritability of the test product to blood vessels and their surrounding tissues was observed.

[0225] Table 2 Group, dose, and administration volume

[0226] Examination index

[0227] 1) Irritability score

[0228] All animals were observed at least once a day during the experiment, and the vascular irritability score was recorded. Before each administration and 24, 48, 72 hours after the last administration, and during the 14-day recovery period, the irritation reaction was observed once a day. The general reaction of the animals and the irritation symptoms of the injection site blood vessels, including the degree and range of erythema, edema, and hyperemia, were observed macroscopically, and scored according to Table 3. The average score of each administration group was calculated.

[0229] Table 3 Vascular irritation reaction scoring criteria

[0230] Result evaluation criteria: Calculate the average score of the vascular irritation reaction of each group of animals each day, and combine the results of male and female animals. According to Table 4, the irritation level is determined, and the macroscopic observation results and histopathological observation results are comprehensively evaluated to evaluate the irritability of the test product to rabbit blood vessels and surrounding tissues.

[0231] Table 4 Vascular irritation intensity evaluation criteria

[0232] 2) Histopathological examination

[0233] At 72 hours after the last administration and 14 days after administration (if the irritation does not recover, it will be extended to 21 days after administration), 2 rabbits were selected from the negative control group and test product 1 group, respectively, after anesthesia, euthanasia, and dissection of the ear margin tissue 2 cm from the last injection site (avoiding the needle tip mechanical stimulation site) near the heart end.

[0234] After fixation, dehydration, embedding, sectioning, HE staining, the tissue morphology is examined under a microscope, and the pathological changes at the administration site are described, and if necessary, semi-quantitative analysis and judgment are performed.

[0235] Implementation and results of the irritation experiment

[0236] During the experiment, no animal struggled and made abnormal sounds during the administration of Test Product 1 and 6. The main abnormal performance of animals in Test Product Groups 7 and 8 was that the left ear needle insertion site was thickened, slightly to moderately red and swollen, and the blood vessels were black. The main abnormal performance of animals in Test Product Group 9 was that the left ear needle insertion site was thickened, slightly red and congested. After administration of Test Product Group 10, the blood vessels were slightly to moderately red and swollen, the needle insertion site was thickened, and the left ear was purple or the blood vessels were black. Among them, the rabbit numbered M01 in Test Product 10 screamed at the first administration, and was paralyzed after struggling; the rabbit numbered M02 died after the fifth administration; the rabbit numbered F02 was found dead on the second day. During the observation period, no obvious irritation reaction was observed at the injection site of the rabbits in the negative control group, and no systemic toxicity reaction was observed.

[0237] After the end of the administration and recovery period, the irritation reaction score of the rabbit auricular vein injection site blood vessels in Test Product 1, Test Product 6 to 8 groups was 0; the irritation reaction score of the rabbit auricular vein injection site blood vessels in Test Product 9 and 10 groups was 1; the detailed blood vessel irritation intensity score is shown in Table 5 below.

[0238] Table 5 Blood vessel irritation intensity score

[0239] Note: The mean value of blood vessel irritation intensity is calculated as (∑(animal daily blood vessel irritation reaction score / evaluation days)) / number of animals

[0240] Histopathological examination results

[0241] After 72 hours of the last administration, the blood vessel structure of the animals in the negative control group and Test Product 1 group was complete, the cell morphology was clear, and no obvious abnormality was observed in the interstitium. After 14 days of the last administration, the blood vessel structure of the animals in the negative control group and Test Product group was complete, the cell morphology was clear, and no obvious abnormality was observed in the interstitium (see Figure 1), and the liquid injection prepared by reconstituting the freeze-dried powder injection prepared by the method of the present disclosure had no blood vessel irritation.

[0242] Test Example 3 Stability investigation

[0243] (1) Stability investigation of various cyclodextrins

[0244] Citrate is less soluble in water, but cyclodextrins have good solubility for citrate. At a concentration of 25% (w / v), all four cyclodextrins can make the citrate salt of the compound of formula (I) soluble. The samples were placed at 60°C for 10 days, and the content was detected and the content change before and after placement was calculated. Among them, test sample 2 is derived from Example 11, test sample 3 is derived from Example 14, test sample 4 is derived from Example 15, and test sample 5 is derived from Example 16, which is dissolved in water for injection to obtain a freeze-dried powder. The test results shown in Table 5 below show that the freeze-dried powder injections prepared from the exemplary Examples 11 and 14 exhibit better stability after reconstitution.

[0245] Table 6 Compatibility results of different cyclodextrins with citrate salt of the compound of formula (I)

[0246] Note: Content change = 0d content - 60°C / 10d content.

[0247] Among them, 0d content is the API content on day 0 (calculated as the content of citrate salt of the compound of formula (I)); 60°C / 10d content is the API content after being placed at 60°C for 10 days.

[0248] (2) Stability investigation of propylene glycol and PEG400

[0249] In addition to cyclodextrins, propylene glycol and PEG400 can also improve the solubility of citrate. At a concentration of 25% (w / v), both can make the citrate salt of the compound of formula (I) soluble. The samples were placed at 60°C for 10 days, and the content was detected and the content change before and after placement was calculated. Among them, test sample 11 is derived from Example 17, and test sample 12 is derived from Example 18. The test results shown in Table 7 below show that the water injections prepared from the exemplary Examples 17 and 18 have poorer stability than the samples prepared from cyclodextrins.

[0250] Table 7 Compatibility results of propylene glycol, PEG400 with citrate salt of the compound of formula (I)

[0251] Note: Content change = 0d content - 60°C / 10d content.

[0252] Among them, 0d content is the API content on day 0 (calculated as the content of citrate salt of the compound of formula (I)); 60°C / 10d content is the API content after being placed at 60°C for 10 days.

[0253] Through the stability investigation of cyclodextrin and the stability investigation of propylene glycol and PEG400, it is found that the stability of the lyophilized powder injection prepared by SBE-β-CD is better than that of the lyophilized powder injection prepared by HP-β-CD; the stability of the lyophilized powder injection prepared by ME-β-CD is not much different from that of the water injection prepared by propylene glycol; the stability of the lyophilized powder injection prepared by HP-γ-CD is poorer than that of the water injection prepared by PEG400.

[0254] The foregoing description of specific exemplary embodiments of the disclosure has been presented for the purposes of illustration and explanation. It is not intended to be exhaustive or to limit the disclosure to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching. The examples were chosen and described in order to explain the principles of the disclosure and its practical application and to thereby enable others skilled in the art to best utilize the disclosure and various embodiments with various modifications as are suited to the particular use contemplated. It is intended that the scope of the disclosure be defined by the claims and their equivalents.

Claims

1. A pharmaceutical composition comprising a pharmaceutically active ingredient which is a citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and an excipient comprising one or more selected from cyclodextrin, a salt of cyclodextrin, propylene glycol, PEG400.

2. The pharmaceutical composition according to claim 1, wherein, the cyclodextrin comprises one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, or hydroxypropyl-γ-cyclodextrin; the salt of cyclodextrin comprises a sodium salt; preferably, the salt of cyclodextrin comprises sulfobutyl-β-cyclodextrin sodium.

3. The pharmaceutical composition of claim 1, wherein, the excipient comprises one or more selected from sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin sodium, propylene glycol, PEG400.

4. The pharmaceutical composition according to any one of claims 1-3, wherein, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1:(5.5-446.94), more preferably 1:(5.5-63.60), in terms of the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone; or, the molar ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1:(1.58-118.7), more preferably 1:(1.58-54.71), more preferably 1:(1.58-16.89), in terms of the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone; preferably, the mass ratio of the pharmaceutically active ingredient to propylene glycol is 1:(5-100), preferably 1:(10-90), preferably 1:(15-80), preferably 1:(18-70), more preferably 1:(20-65), in terms of the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone; or, the molar ratio of the pharmaceutically active ingredient to propylene glycol is 1:(100-500), more preferably 1:(120-480), more preferably 1:(140-460), in terms of the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone; preferably, the mass ratio of the pharmaceutically active ingredient to PEG400 is 1:(5-100), preferably 1:(10-90), preferably 1:(15-80), preferably 1:(18-70), more preferably 1:(20-65), in terms of the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone; or, the molar ratio of the pharmaceutically active ingredient to PEG 400 is 1 : (1.5-150), more preferably 1 : (2-100); more preferably 1 : (2.5-90), in terms of the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone.

5. The pharmaceutical composition of claim 4, wherein, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (5.5-9); or, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (11-13); or, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (15-19); or, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (21-29); or, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (31-39); or, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (41-49); or, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (51-59); or, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (61-462.96).

6. The pharmaceutical composition of claim 5, wherein, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (21-29); or, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (41-49); or, the mass ratio of the pharmaceutically active ingredient to cyclodextrin or a salt thereof is 1 : (15-19).

7. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition optionally comprises a pH adjusting agent; Preferably, the pH adjusting agent is selected from the group consisting of a basic pH adjusting agent and / or an acidic pH adjusting agent; Preferably, the pH adjusting agent is citric acid; Preferably, the pH of the pharmaceutical composition is 1.5-5.5, preferably 2.0-5.3, preferably 3.0-5.3, preferably 3.0-4.5, more preferably 3.5-4.

5.

8. A lyophilized powder injection, the raw material for making the lyophilized powder injection comprising the pharmaceutical composition of any one of claims 1-7; the pharmaceutical composition being lyophilized in a form dissolved in a solvent.

9. A method for preparing the pharmaceutical composition of any one of claims 1-7 or the lyophilized powder injection of claim 8, the method comprising the following steps: (a) dissolving the excipient in a solvent to form a solution; (b) adding the pharmaceutically active ingredient to the solution formed in step (a); (c) lyophilizing.

10. An aqueous injection, the raw material for making the aqueous injection comprising the pharmaceutical composition of any one of claims 1-7.

11. A method for preparing the aqueous injection of claim 10, the method comprising the following steps: (a) dissolving the excipient in a solvent to form a solution; (b) adding the pharmaceutically active ingredient to the solution formed in step (a).

12. A liquid preparation comprising the pharmaceutical composition of any one of claims 1-7, the lyophilized powder injection of claim 8 or the aqueous injection of claim 10, and a solvent. Preferably, the solvent comprises water, a sodium chloride solution or a glucose solution; preferably, the water is sterile water for injection; Preferably, the liquid preparation is an injection.

13. Use of the pharmaceutical composition of any one of claims 1-7, the lyophilized powder injection of claim 8, the aqueous injection of claim 10 or the liquid preparation of claim 12 in the preparation of a medicament for preventing and / or treating a disease caused by excessive gastric acid secretion; Preferably, the disease caused by excessive gastric acid secretion is a gastrointestinal inflammatory disease or a gastric acid-related disease; Preferably, the gastrointestinal inflammatory disease or the gastric acid-related disease is selected from peptic ulcer, peptic ulcer bleeding, prevention of peptic ulcer bleeding, gastric and duodenal ulcer, non-steroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD) and non-erosive reflux disease (NERD).

14. A method of preventing and / or treating a disease caused by excessive gastric acid secretion, comprising the step of administering to a patient in need thereof the pharmaceutical composition of any one of claims 1-7, the lyophilized powder injection of claim 8, the aqueous injection of claim 10 or the liquid preparation of claim 12; Preferably, the disease caused by excessive gastric acid secretion is a gastrointestinal inflammatory disease or a gastric acid-related disease; Preferably, the gastrointestinal inflammatory disease or the gastric acid-related disease is selected from peptic ulcer, peptic ulcer bleeding, prevention of peptic ulcer bleeding, gastric and duodenal ulcer, non-steroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD) and non-erosive reflux disease (NERD).

15. The pharmaceutical composition of any one of claims 1-7, the lyophilized powder injection of claim 8, the aqueous injection of claim 10 or the liquid preparation of claim 12 for use in prevention and / or treatment; Preferably, the pharmaceutical composition of any one of claims 1-7, the lyophilized powder injection of claim 8, the aqueous injection of claim 10 or the liquid preparation of claim 12 for use in prevention and / or treatment of a disease caused by excessive gastric acid secretion; Preferably, the disease caused by excessive gastric acid secretion is a gastrointestinal inflammatory disease or a gastric acid-related disease; Preferably, the gastrointestinal inflammatory disease or the gastric acid-related disease is selected from peptic ulcer, peptic ulcer bleeding, prevention of peptic ulcer bleeding, gastric and duodenal ulcer, non-steroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD) and non-erosive reflux disease (NERD).

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