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

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly provides a stable imidazo [1, 2-a] pyridine derivative pharmaceutical composition as well as a preparation method and application thereof.The pharmaceutical composition comprises an active pharmaceutical ingredient and auxiliary materials, the active pharmaceutical ingredient is (azetidine-1-yl) (8-(2, 6-dimethyl benzylamino)-2, 3, 4-triazolo [1, 2-a] pyridine)-2, 3, 4-triazolo [1, 2-a] pyridine derivative, and the auxiliary materials are selected from the group consisting of 2, 3, 4-triazolo [1, 2-a] pyridine derivative, 2, 3-triazolo [ the auxiliary material comprises citrate of 2, 3-dimethylimidazo [1, 2-a] pyridine-6-yl) ketone, and the auxiliary material comprises one or more selected from cyclodextrin or salts thereof.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates 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

[0002] Gastrointestinal tract ulcer, gastric / duodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD) and other gastrointestinal inflammatory diseases or gastric acid-related diseases 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-competitive acid blocker (P-CAB, acid pump antagonist) drugs are growing, which has a mechanism of inhibiting acid secretion by reversibly binding to the binding site to inhibit potassium competition. In particular, unlike irreversible proton pump inhibitors (PPIs), reversible proton pump inhibitors (P-CAB) have a fast onset of action in mechanism, and are very convenient to take before or after meals, and are expected to achieve better efficacy.

[0003] 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, and has gastric acid secretion inhibitory activity, and can be effectively used for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases. A phase III clinical trial for the treatment of erosive esophagitis is currently being carried out in Korea, and existing data show that Zastaprazan has the advantages of fast onset, good acid inhibition effect, long-lasting action 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, and therefore, the development of Zastaprazan formulations suitable for clinical needs has important clinical significance and broad market prospects.

[0004] SUMMARY

[0005] The present application provides a pharmaceutical preparation of a citrate 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.

[0006] Therefore,

[0007] In a first aspect of the present disclosure, there is provided a pharmaceutical composition comprising 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 or a salt thereof.

[0008] In an embodiment, the cyclodextrin is selected from one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, or hydroxypropyl-γ-cyclodextrin.

[0009] In an embodiment, the salt of the cyclodextrin is sulfobutyl-β-cyclodextrin sodium.

[0010] In an embodiment, the mass ratio of the pharmaceutically active ingredient to the cyclodextrin or a salt thereof is 1:(5.95-446.94), more preferably 1:(5.59-63.60), in terms of the citrate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone.

[0011] In some embodiments, the mass ratio of the pharmaceutically active ingredient to the 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.

[0012] In some embodiments, the mass ratio of the pharmaceutically active ingredient to the 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.

[0013] In one embodiment, the molar ratio of the pharmaceutically active ingredient to cyclodextrin or its salt 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.

[0014] In a preferred embodiment, the excipient does not comprise albumin.

[0015] 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.

[0016] 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.

[0017] In some embodiments, the pH of the pharmaceutical composition is 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.

[0018] In a preferred embodiment, the pharmaceutical composition is a lyophilized powder for injection.

[0019] In one embodiment, during the preparation of the pre-lyophilized drug solution, the pH of the pre-lyophilized drug solution is controlled to be between 3.0 and 5.3 before the lyophilized powder for injection is lyophilized; or, the pH of the pharmaceutical composition after being dissolved is 3.0-5.3.

[0020] In a second aspect of the present application, a pharmaceutical composition is provided, which comprises a pharmaceutically active ingredient and excipients, 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 excipients comprise one or more selected from cyclodextrin or a salt thereof, and a pH adjusting agent, the pH of the pharmaceutical composition is 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 cyclodextrin or a salt thereof is 1:(5.95-446.94), more preferably 1:(5.59-63.60). Preferably the cyclodextrin is selected from one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin or hydroxypropyl-γ-cyclodextrin, preferably the salt of the cyclodextrin is sulfobutyl-β-cyclodextrin sodium.

[0021] 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 3.0-5.3, but also can ensure the pH of each batch of product to be consistent.

[0022] In a third aspect of the present application, a lyophilized powder injection is also provided, the raw material for preparing the lyophilized powder injection comprises a pharmaceutically active ingredient and excipients, 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 excipients comprise one or more selected from cyclodextrin or a salt thereof.

[0023] In an embodiment, the cyclodextrin is selected from one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin or hydroxypropyl-γ-cyclodextrin; the salt of the cyclodextrin is sulfobutyl-β-cyclodextrin sodium.

[0024] The pharmaceutically active ingredient and excipients are lyophilized in the form of being dissolved in a solvent. The solvent is commonly used in the art for preparing lyophilized powder injection, for example, one or more selected from water, sodium chloride solution or glucose solution.

[0025] In an embodiment, the glucose is a 5%-10%(w / v) glucose solution, for example, a 5% glucose solution or a 10% glucose solution.

[0026] In one embodiment, the solvent is a 0.9% w / v sodium chloride solution.

[0027] In one embodiment, the liquid formulation formed after the solvent dissolving the pharmaceutical composition or the lyophilized powder is an isotonic solution. An isotonic solution generally refers to a solution having an osmotic pressure equal to that of blood plasma.

[0028] Optionally, the raw material further comprises a pH adjusting agent, and the pH adjusting agent is in an amount to adjust the pH to 3.0-5.3.

[0029] In a fourth aspect of the present disclosure, there is provided a method for preparing the pharmaceutical composition or the lyophilized powder according to the first aspect, the method comprising the steps of:

[0030] (a) dissolving the cyclodextrin in a solvent to form a solution;

[0031] (b) adding the pharmaceutically active ingredient to the solution formed in step (a);

[0032] (c) lyophilizing.

[0033] In one embodiment, the method further comprises a step of adjusting the pH between step (b) and step (c).

[0034] In one embodiment, the pH adjusting is adjusting the pH to 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, or 5.3, or a range between any two of the foregoing.

[0035] In a fifth aspect of the present disclosure, there is provided a liquid formulation comprising the pharmaceutical composition or the lyophilized powder according to the first aspect, and a solvent.

[0036] In one embodiment, the pH of the liquid formulation is 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.

[0037] In one embodiment, the solvent is selected from water, a sodium chloride solution, or a glucose solution.

[0038] In a preferred embodiment, the water is water for injection.

[0039] In a preferred embodiment, the liquid formulation is an injection.

[0040] In a sixth aspect of the present disclosure, there is provided use of the pharmaceutical composition according to the first or second aspect, or the lyophilized powder according to the third aspect, or the liquid formulation according to the fifth aspect, in the manufacture of a medicament for preventing or treating a disease caused by excessive gastric acid secretion.

[0041] In an embodiment, 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 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, 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.

[0042] The pharmaceutical active ingredient according to the present disclosure has excellent activity in inhibiting gastric acid secretion, and thus can be effectively used for preventing or treating a gastrointestinal inflammatory disease or a gastric acid-related disease, particularly, peptic ulcer, gastric and duodenal ulcer, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD).

[0043] 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.

[0044] In an embodiment, 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).

[0045] In an embodiment, the pharmaceutical composition of the present disclosure can further contain one or more selected from amoxicillin, clarithromycin, aceclofenac, meloxicam, and naproxen.

[0046] In a fifth aspect of the present disclosure, there is provided 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 the pharmaceutical composition according to the first aspect, or the lyophilized powder according to the third aspect, or the liquid formulation according to the fifth aspect.

[0047] In an aspect, the method includes administering a therapeutically effective amount of the pharmaceutical composition simultaneously, sequentially, or separately.

[0048] The details mentioned in the pharmaceutical composition, the kit, the method of preparing the pharmaceutical composition, the use, the method of treatment of the present disclosure are applied in the same way, unless contradictory to each other. BRIEF DESCRIPTION OF DRAWINGS

[0049] Figure 1 Histopathological examination results in Experimental Example 2 are shown. DETAILED DESCRIPTION

[0050] I. Terms and Definitions

[0051] In the present application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by a person skilled in the art. Also, 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 application, the definitions and explanations of the relevant terms are provided as follows.

[0052] 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 subsets of all possible embodiments, and can be combined with each other without conflict.

[0053] As used herein and unless otherwise indicated, the terms "comprising", "including", "having", "containing", including grammatical variations thereof, shall be understood to be open-ended and non-limiting, e.g., not excluding additional unlisted elements or steps.

[0054] In the present application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by a person skilled in the art. Also, 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 application, the definitions and explanations of the relevant terms are provided as follows.

[0055] As used herein, the term "inclusion" refers to a technique in which one molecule is embedded in the cavity structure of another molecule to form an inclusion compound. The inclusion compound 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 inside to form a molecular capsule.

[0056] As used herein, the term "treatment" includes reversing, reducing, or inhibiting the symptoms, clinical signs, and underlying pathology of a condition, in such a way as to improve or stabilize the condition in a patient.

[0057] 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.

[0058] 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.

[0059] As used herein, "lyophilized powder for injection" refers to a solid powder-like preparation which is made by incorporating (preferably in a sterile environment) one or more pharmaceutically active ingredients (or drug substances, herein referring to the citrate salt of the compound of Formula (I)) into one or more excipients or dissolving in one or more solvents (or vehicles), followed by certain processing (e.g., freeze-drying).

[0060] Unless otherwise specified, "water for injection" refers to water that meets the relevant requirements under the item of "water for injection" in the Chinese Pharmacopoeia.

[0061] Unless otherwise specified, "dissolution" (or its full name "dissolution clarification") refers to an operation or process by 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.

[0062] 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 solution per unit volume (e.g., 1 cm 3 , 1 mL), usually expressed in mg / L, mg / mL. Unless otherwise specified, the term "% (w / v)" used in the present application means the number of grams of solute contained in each 100 mL of solution, i.e., "g / 100 mL".

[0063] Unless otherwise specified, the term "lyophilization" (or its full name "freeze-drying") used in the present application refers to a drying operation or process in which a water-containing material (e.g., an aqueous drug solution, i.e., a solution containing the citrate salt of the compound of Formula (I) and cyclodextrin in the present application) is first frozen below the freezing point so that water is converted into ice (solidification), and then the ice is converted into water vapor (sublimation) under vacuum conditions to remove. Not only can the material be pre-frozen in a freezing device and then transferred to a drying device for drying, but the material can also be frozen directly in a drying device by rapid vacuumization and then dried. The water vapor produced during sublimation is removed by condensation in a condensation device, and the heat of vaporization required for sublimation is generally supplied by heat radiation or heat conduction.

[0064] 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 short term or long term. Various dosing regimens are contemplated herein, including but not limited to single or multiple administrations at different points in time, bolus administration, and drip administration.

[0065] As used herein, "pH adjusting agent" means a compound or mixture of compounds that can be used to ensure that the pH of the 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, such 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.

[0066] 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.

[0067] 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 of different salts and the prepared compositions, the stability of the pharmaceutical composition, and the product biosafety (e.g., vascular irritation) were investigated. At the same time, it was surprisingly found that the excipient of the composition of the present application was 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 excipient was evaluated). For example, among the excipients disclosed in the prior art that 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, and cytotoxicity in humans and animals for intravenous injection, and can cause hyperlipidemia and toxic kidney damage; and polyoxyethylene castor oil can dissolve dioctyl phthalate (DEHP) in a polyvinyl chloride (PVC) material infusion bottle, 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 toxicity 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 cause 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 amount for intravenous injection is 22.50%; the maximum amount for intramuscular injection is 15.36%; and the maximum amount for subcutaneous injection is 32.50%. Propylene glycol and PEG (e.g., PEG400) are generally considered to be non-toxic and low-stimulating.

[0068] The present application was investigated, and it was found 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 biosafety.

[0069] In addition, the pharmaceutical composition of the present application significantly improves the freeze-drying re-dissolution performance of the active ingredient of the present application, and is more stable for clinical use of intravenous injection without precipitation, greatly improving the safety of clinical use, and without the need to equip with 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.

[0070] II. Examples

[0071] 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 regarded as limitations of 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.

[0072] Before the embodiments of the present disclosure are further described in detail, the terms and phrases involved in the embodiments of the present disclosure are explained, and the terms and phrases involved in the embodiments of the present disclosure are applicable to the following explanations.

[0073] 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.

[0074] Example 1 Preparation of a freeze-dried powder injection of a citrate salt of a compound of formula (I)

[0075]

[0076] Preparation process:

[0077] 1) Take the prescribed amount of cyclodextrin and add it to 2.1 L of sterilized water for injection to prepare a cyclodextrin solution with a concentration of 30% (w / v);

[0078] 2) Take the prescribed amount of API and add it to the prepared cyclodextrin solution, and stir at 50°C until the solution is clear;

[0079] 3) Add water to make up to 3 L;

[0080] 4) Fill the prepared solution into a Westlin bottle, 4 ml per bottle;

[0081] 5) Freeze-drying.

[0082] Example 2 Preparation of a freeze-dried powder injection of a citrate salt of a compound of formula (I)

[0083] Raw and auxiliary materials Dosage Citrate salt of compound of formula (I) 24g SBE-β-CD 504g Citric acid (optional) Suitable amount Add water to constant volume 3L

[0084] Preparation process:

[0085] 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, and stir at 50°C until dissolved;

[0086] 2) Add purified water to 2.7 L, and measure the pH of the sample. If the pH is higher than 3.8, then add 1 mol / L citric acid solution to the solution, and adjust the pH of the solution to 3.8;

[0087] 3) Add purified water to make up to 3 L;

[0088] 4) Fill the prepared solution into a vial, and the filling amount is 2.5 ml / vial;

[0089] 5) Freeze-dry the sample after filling.

[0090] Preparation of a freeze-dried powder injection of a citrate salt of the compound of formula (I) according to Example 3

[0091] Raw and auxiliary materials Dosage Citrate salt of compound of formula (I) 24g SBE-β-CD 504g Add water to constant volume 3L

[0092] Preparation process:

[0093] 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, and stir at 50°C until dissolved;

[0094] 2) Add purified water to make up to 3 L;

[0095] 3) Fill the prepared solution into a vial, and the filling amount is 2.5 ml / vial;

[0096] 4) Freeze-dry the sample after filling.

[0097] Preparation of a freeze-dried powder injection of a citrate salt of the compound of formula (I) according to Example 4

[0098] Raw and auxiliary materials Dosage Citrate salt of compound of formula (I) 42g SBE-β-CD 315g Add water to constant volume 3L Filling amount 1.43ml

[0099] The preparation process refers to Example 3.

[0100] Preparation of a freeze-dried powder injection of a citrate salt of the compound of formula (I) according to Example 5

[0101] Raw and auxiliary materials Dosage Citrate salt of compound of formula (I) 26.25g SBE-β-CD 315g Add water to constant volume 3L Filling amount 2.29ml

[0102] The preparation process refers to Example 3.

[0103] Preparation of a freeze-dried powder injection of a citrate salt of the compound of formula (I) according to Example 6

[0104] Raw and auxiliary materials Dosage Citrate salt of compound of formula (I) 18.53g SBE-β-CD 315g Add water to constant volume 3L Filling amount 3.24ml

[0105] Preparation process Refer to Example 3.

[0106] Example 7 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0107] Raw and auxiliary materials Dosage Citrate salt of compound of formula (I) 11.25g SBE-β-CD 315g Add water to constant volume 3L Filling amount 5.33ml

[0108] Preparation process Refer to Example 3.

[0109] Example 8 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0110] Raw and auxiliary materials Dosage Citrate salt of compound of formula (I) 15.27g SBE-β-CD 504g Add water to constant volume 3L Filling amount 3.93ml

[0111] Preparation process Refer to Example 3.

[0112] Example 9 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0113]

[0114]

[0115] Preparation process Refer to Example 3.

[0116] Example 10 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0117] Raw and auxiliary materials Dosage Citrate salt of compound of formula (I) 11.20g SBE-β-CD 504g Add water to constant volume 3L Filling amount 5.36ml

[0118] Preparation process Refer to Example 3.

[0119] Example 11 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0120] Raw and auxiliary materials Dosage Citrate salt of compound of formula (I) 12g SBE-β-CD 750g Add water to constant volume 3L Filling amount 5ml

[0121] Preparation process Refer to Example 3.

[0122] Example 12 Preparation of injection liquid preparation of citrate salt of compound of formula (I)

[0123] Raw and auxiliary materials Dosage Citrate salt of compound of formula (I) 1.575g SBE-β-CD 315g Add water to constant volume 3L

[0124] Preparation process:

[0125] 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;

[0126] 2) Add purified water to 3 L;

[0127] 3) Freeze-dry the prepared solution;

[0128] 4) The sample after lyophilization is divided, 4.01 g / bottle;

[0129] 5) The sample is reconstituted to 38 ml when used.

[0130] Example 13 Preparation of injection liquid preparation of citrate salt of compound of formula (I)

[0131]

[0132]

[0133] Preparation process:

[0134] 1) 2.1 L of purified water is added, and the prescribed amount of SBE-β-CD is added. After the SBE-β-CD is dissolved, the prescribed amount of API is added, and stirring is carried out at 50°C until dissolution;

[0135] 2) Purified water is added to make up to 3 L;

[0136] 3) The prepared solution is lyophilized;

[0137] 4) The sample after lyophilization is divided, 8.11 g / bottle;

[0138] 5) The sample is reconstituted to 77 ml when used.

[0139] Example 14 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0140] Filling amount Raw and auxiliary materials Dosage 0.4g Citrate salt of compound of formula (I) 25g HP-β-CD 100ml Add water to constant volume 5ml

[0141] The preparation process refers to Example 3.

[0142] Example 15 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0143] Filling amount Raw and auxiliary materials Dosage 0.4g Citrate salt of compound of formula (I) 25g ME-β-CD 100ml Add water to constant volume 5ml

[0144] The preparation process refers to Example 3.

[0145] Example 16 Preparation of lyophilized powder injection of citrate salt of compound of formula (I)

[0146] Filling amount Raw and auxiliary materials Dosage 0.4g Citrate salt of compound of formula (I) 25g HP-γ-CD 100ml Add water to constant volume 5ml

[0147] The preparation process refers to Example 3.

[0148] Test Example 1 Solubility test

[0149] 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 drug. The inventors found that the citrate salt of the compound of formula (I) has good solubility in a cyclodextrin solution. In the examples of the present application, the solution containing API and cyclodextrin prepared before lyophilization, and the injection liquid preparation obtained by reconstituting the lyophilized powder in water, can all be completely dissolved and clear, and the solubility is qualified and meets the pharmaceutical requirements.

[0150] Test Example 2 Comparison of Irritation Test

[0151] Filling amount

[0152] Test sample 1 was derived from the lyophilized powder prepared in Example 2, which was dissolved in water for injection. Reference sample 1 was a lyophilized powder prepared according to the following table and the process of Example 3, which was dissolved in a sodium chloride solution. Reference sample 2 was a sodium chloride injection. The specific formulations of the test samples and reference samples are shown in Table 1 below.

[0153] Table 1

[0154]

[0155] Test sample and control sample

[0156] In this test, the ear marginal vein injection (bolus) administration method was selected to observe the irritation of the test sample to the blood vessels and the surrounding tissues.

[0157] Table 2 Group, Dose, Volume of Administration

[0158]

[0159] Experimental method

[0160] 1) Irritation Score

[0161] All animals were observed at least once a day during the test period, and the vascular irritation 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 the irritation reaction of each administration group was calculated.

[0162] Table 3 Vascular irritation reaction score criteria

[0163]

[0164] Result evaluation criteria: the average score of the vascular irritation reaction of each group of animals per day was calculated, and the male and female were combined for statistics. According to Table 4, the irritation level was judged, and the results of visual observation and histopathological observation were comprehensively evaluated to comprehensively evaluate the irritation of the test product to the rabbit blood vessels and surrounding tissues.

[0165] Table 4 Vascular irritation intensity evaluation criteria

[0166] Checking index Score 0.0-0.4 Evaluation 0.5-1.4 None 1.5-2.4 Mild 2.5-3.4 Light 3.5-4.4 Moderate Severe 4.5 and above

[0167] 2) Histopathological examination

[0168] At 72 hours after the last administration and 14 days after administration (if the irritation does not recover, it is extended to 21 days after administration), 2 rabbits were selected, anesthetized and euthanized, and the auricle tissue 2 cm from the last injection site was dissected (avoiding the needle tip mechanical stimulation site).

[0169] After the tissue is fixed, dehydrated, embedded, sectioned, and HE stained, the histomorphological examination is carried out under a microscope, the pathological changes at the administration site are described, and if necessary, semi-quantitative analysis and judgment are carried out.

[0170] Serious

[0171] During the experiment, no animal struggle and abnormal sound were observed during the administration of the test product 1. During the observation period, no obvious irritation reaction was observed in the vein injection site of the negative control group rabbits, and no any systemic toxicity reaction was observed.

[0172] The average score of the irritation reaction of the auricle vein injection site of each group after administration and recovery was 0.

[0173] Implementation and results of irritation experiment

[0174] At 72 hours after the last administration, the animals in the negative control group and the test product 1 group were observed under a microscope, and the vascular structure was complete, the cell morphology was clear, and the interstitium was not obviously abnormal. At 14 days after the last administration, the animals in the negative control group and the test product group were observed under a microscope, and the vascular structure was complete, the cell morphology was clear, and the interstitium was not obviously abnormal (see Histopathological examination results ), and the liquid injection prepared by reconstituting the freeze-dried powder injection prepared by the embodiment of the application has no vascular irritation.

[0175] Test Example 3 Stability investigation of various cyclodextrins

[0176] Citrate is poorly soluble in water, but cyclodextrins are good solubilizers for citrate. At 25% (w / v) concentration, all four cyclodextrins can solubilize the citrate salt of the compound of Formula (I). The samples were placed at 60 °C for 10 days, and the content was measured and the content change was calculated. Test article 2 was derived from Example 11, test article 3 was derived from Example 14, test article 4 was derived from Example 15, and test article 5 was derived from Example 16, which was reconstituted from the lyophilized powder in water for injection. The results shown in Table 5 below indicate that the lyophilized powder injections prepared from the exemplary Examples 11 and 14 exhibit better stability performance after reconstitution.

[0177] Table 5 Compatibility results of different cyclodextrins with citrate salt of the compound of Formula (I)

[0178] Figure 1 0d 60℃ / 10d Auxiliary materials Content change Test sample 2 96.58％ 86.87％ 9.71％ SBE-β-CD Test sample 3 95.34％ 90.33％ 5.01％ HP-β-CD Test sample 4 95.41％ 75.53％ 19.88％ ME-β-CD Test sample 5 HP-γ-CD 89.62％ 54.30％ 35.32％

[0179] Note: Content change = 0 d content - 60 °C / 10 d content.

[0180] Wherein, 0 d content is the API content on day 0 (as the content of citrate salt of the compound of Formula (I)); 60 °C / 10 d content is the API content after 10 days at 60 °C.

[0181] The foregoing description of specific exemplary embodiments of the application has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the application to the precise form disclosed, and various modifications and variations are possible in light of the above teachings. It is intended that the application encompass all such modifications and variations as fall within the scope of the claims and their equivalents. The claims are intended to cover all changes and modifications of the application which fall within the scope of the claims, along with all equivalent arrangements.

Claims

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

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

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

4. The pharmaceutical composition according to any one of claims 1-3, wherein, the mass ratio of the pharmaceutically active ingredient to the cyclodextrin or a salt thereof is 1:(5.95- 446.94), more preferably 1:(5.59-63.60), in terms of the citrate salt of (azetidin-l-yl)(8-(2,6- dimethylbenzylamino)-2,3-dimethylimidazo[l,2-a]pyridin-6-yl)methanone; or, the molar ratio of the pharmaceutically active ingredient to the 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-l-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[l,2-a]pyridin-6- yl)methanone.

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

6. The pharmaceutical composition according to claim 3, wherein, the mass ratio of the pharmaceutically active ingredient to the cyclodextrin or a salt thereof is 1:(21-29); the mass ratio of the pharmaceutically active ingredient to the cyclodextrin or a salt thereof is 1:(41-49); or, the mass ratio of the pharmaceutically active ingredient to the cyclodextrin or a salt thereof is 1:(15-19).

7. A lyophilized powder for injection, the raw material for making the lyophilized powder for injection comprising a pharmaceutically active ingredient which is a citrate salt of (azetidin-l-yl)(8-(2,6- dimethylbenzylamino)-2,3-dimethylimidazo[l,2-a]pyridin-6-yl)methanone, and an excipient comprising one or more selected from a cyclodextrin or a salt thereof. Preferably, the cyclodextrin is selected from one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin or hydroxypropyl-γ-cyclodextrin; and the salt of the cyclodextrin is sulfobutyl-β-cyclodextrin sodium. The pharmaceutically active ingredient and the excipient are lyophilized in the form of being dissolved in a solvent.

8. A method for preparing the pharmaceutical composition of any one of claims 1 to 6 or the lyophilized powder injection of claim 7, the method comprising the steps of: (a) dissolving the cyclodextrin or the salt thereof in a solvent to form a solution; (b) adding a pharmaceutically active ingredient to the solution formed in step (a); (c) lyophilizing.

9. A liquid preparation comprising the pharmaceutical composition of any one of claims 1 to 6 or the lyophilized powder injection of claim 7, and a solvent. Preferably, the solvent is selected from water, sodium chloride solution or glucose solution; preferably, the water is sterile water for injection. Preferably, the liquid preparation is an injection.

10. Use of the pharmaceutical composition of any one of claims 1 to 6, the lyophilized powder injection of claim 7 or the liquid preparation of claim 9 in the preparation of a medicament for preventing or treating a disease caused by excessive secretion of gastric acid. Preferably, the disease caused by excessive secretion of gastric acid 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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