Pharmaceutical composition of imidazo[1,2-a]pyridine derivative and use thereof

Abstract

The present application relates to a stable pharmaceutical composition of an imidazo[1,2-a]pyridine derivative and use thereof. The pharmaceutical composition comprises an active pharmaceutical ingredient and an excipient, wherein the active pharmaceutical ingredient is (azetidin-1-yl)(8-((2,6-dimethylbenzyl)amino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone or a salt thereof, and the excipient comprises one or more selected from cyclodextrin or a salt thereof. The pharmaceutical composition further comprises a nitrite scavenger.

Description

Imidazolo[1,2-a]pyridine derivative pharmaceutical compositions and their uses

[0001] This application claims priority to Chinese Patent Application No. 2025104935868, filed on April 18, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application relates to the field of pharmaceutical formulations, specifically to imidazo[1,2-a]pyridine derivative pharmaceutical compositions and their uses. Background Technology

[0003] Gastrointestinal inflammatory diseases or acid-related disorders, such as peptic ulcers, gastric / duodenal ulcers, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD), are among the most common digestive system diseases. To overcome the shortcomings of traditional proton pump inhibitors (PPIs), the focus and clinical demand for potassium-competitive acid blockers (P-CABs, also known as acid pump antagonists) have been continuously increasing in recent years. These drugs work by reversibly binding H+ ions... + / K + - The potassium-binding site of ATPase exerts its acid-suppressing effect through competitive inhibition by potassium ions. In particular, unlike irreversible proton pump inhibitors, reversible proton pump inhibitors (PPIs) have the characteristics of rapid onset of action, and the timing of administration is not restricted by food intake, making them convenient to take before or after meals, and are expected to achieve better clinical efficacy.

[0004] Chinese patent CN109415362B discloses (azacyclobutane-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl) methyl ketone (Zastaprazan, compound shown in formula (I)). This is an innovative potassium-competitive acid blocker independently developed by Cheil Pharmaceutical Co., Ltd. of South Korea. It exhibits gastric acid secretion inhibition activity and can be effectively used to prevent or treat inflammatory gastroenteritis or acid-related diseases. Currently, a Phase III clinical trial for erosive esophagitis is underway in South Korea. Existing data indicates that Zastaprazan has the advantages of rapid onset of action, excellent and long-lasting acid suppression, and few adverse reactions. In the future, it can be expanded to treat duodenal ulcers, Helicobacter pylori infection, and non-erosive gastroesophageal reflux disease. Therefore, developing Zastaprazan formulations that meet clinical needs has significant clinical importance and broad market prospects. Summary of the Invention

[0005] This application provides a pharmaceutical preparation of (azacyclobutane-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl) methyl ketone or its salt that is stable, has low irritation and meets clinical needs.

[0006] In view of this,

[0007] On one hand, this application provides a pharmaceutical composition comprising a pharmaceutically active ingredient and excipients, wherein the pharmaceutically active ingredient is (azacyclobutane-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl) ketone or a salt thereof, the excipients comprising one or more selected from cyclodextrin or its salts, and the pharmaceutical composition optionally further comprises a nitrite scavenger.

[0008] In this application, the nitrite scavenger mainly functions to remove residual nitrite from raw materials and excipients, especially cyclodextrin, and prevent it from reacting with the secondary amine structure in the active ingredient to form nitrosamines. The nitrite scavenger is commonly used in the art and includes, but is not limited to, vitamin C or its derivatives, L-histidine, L-cysteine, L-lysine, glycine, arginine, ferulic acid, maltol, propyl gallate, para-aminobenzoic acid, caffeic acid, BHA, BHT or vitamin E and anhydrous sodium sulfite.

[0009] In some embodiments, the nitrite scavenger includes one or more of vitamin C or a derivative thereof, L-histidine, L-cysteine, L-lysine, glycine, arginine, anhydrous sodium sulfite, ferulic acid, maltol, propyl gallate, para-aminobenzoic acid, caffeic acid, BHA, BHT, or vitamin E.

[0010] In some embodiments, the nitrite scavenger is selected from one or more of vitamin C or its derivatives, L-histidine, L-cysteine, or anhydrous sodium sulfite.

[0011] In some embodiments, the nitrite scavenger is selected from one or more of vitamin C, L-cysteine, or anhydrous sodium sulfite.

[0012] In some embodiments, vitamin C or its derivatives are at least one of vitamin C or vitamin C esters, ester salts, glycosides or ethers; including but not limited to ascorbic acid, ascorbic acid tetraisopalmitate, magnesium ascorbic acid phosphate, L-ascorbic acid-2-glucosidate, ascorbic acid palmitate, 3-O-ethyl ascorbic acid ether, etc.

[0013] In some embodiments, the nitrite scavenger is vitamin C.

[0014] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:(0.0002-1.25), preferably 1:(0.0025-1.25), preferably 1:(0.0025-1), preferably 1:(0.0025-0.8), preferably 1:(0.0025-0.625), preferably 1:(0.0025-0.25), preferably 1:(0.0025-0.22), preferably 1:(0.01-0.5), optionally 1:(0.015-0.25), optionally 1:(0.02-0.22).

[0015] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:(0.025-1.25), optionally 1:(0.066-1.25), optionally 1:(0.11-1.25), or optionally 1:(0.176-1.25).

[0016] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:(0.025-1), optionally 1:(0.066-1), optionally 1:(0.11-1), or optionally 1:(0.176-1).

[0017] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:(0.025-0.8), optionally 1:(0.066-0.8), optionally 1:(0.11-0.8), or optionally 1:(0.176-0.8).

[0018] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:(0.025-0.625), optionally 1:(0.066-0.625), optionally 1:(0.11-0.625), or optionally 1:(0.176-0.625).

[0019] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:1.25.

[0020] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:0.22.

[0021] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:0.176.

[0022] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:0.125.

[0023] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:0.11.

[0024] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:0.066.

[0025] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:0.025.

[0026] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:0.0025.

[0027] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:0.000208.

[0028] In some embodiments, when the nitrite scavenger is L-cysteine, the mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:(0.0002-1), preferably 1:(0.0025-0.8), preferably 1:(0.0025-0.5), preferably 1:(0.0025-0.25), and preferably 1:(0.0025-0.22).

[0029] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:(5.5-446.94), more preferably 1:(5.5-63.60).

[0030] In some embodiments, the molar ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:(1.58-118.7), more preferably 1:(1.58-54.71); even more preferably 1:(1.58-16.89).

[0031] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:(5.5-446.94), more preferably 1:(5.5-63.60);

[0032] Alternatively, the molar ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:(1.58-118.7), more preferably 1:(1.58-54.71); even more preferably 1:(1.58-16.89.

[0033] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:42.

[0034] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:21.

[0035] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:7.5.

[0036] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:12.

[0037] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:17.00.

[0038] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:28.

[0039] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:33.01.

[0040] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:38.01.

[0041] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:45.

[0042] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:50.

[0043] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:200.

[0044] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:400.

[0045] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:62.5.

[0046] In some embodiments, the mass ratio of the active pharmaceutical ingredient to cyclodextrin or its salt is 1:20.625.

[0047] In some embodiments, the excipient is one or more selected from sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, or sodium sulfobutyl-β-cyclodextrin.

[0048] In some embodiments, the excipient is one or more selected from sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sodium sulfobutyl-β-cyclodextrin, which helps to improve the stability of the pharmaceutical composition and reduce its vascular irritation.

[0049] In some embodiments, the salt of the active pharmaceutical ingredient includes one or more of the following: phosphate, sulfate, citrate, hydrochloride, mesylate, nitrate, carbonate, acetate, and tartrate.

[0050] In some embodiments, the salt of the active pharmaceutical ingredient includes one or more of phosphate, sulfate, citrate, hydrochloride, and mesylate.

[0051] In some embodiments, the salt of the active pharmaceutical ingredient is a citrate.

[0052] In some embodiments, the cyclodextrin includes one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, or hydroxypropyl-γ-cyclodextrin.

[0053] In some embodiments, the cyclodextrin includes sulfobutyl-β-cyclodextrin.

[0054] In some embodiments, the salt of the cyclodextrin includes its sodium salt.

[0055] In some embodiments, the salt of the cyclodextrin includes sodium sulfobutyl-β-cyclodextrin.

[0056] In some embodiments, the pharmaceutical composition optionally includes a pH adjuster.

[0057] In some embodiments, the pH adjuster is selected from alkaline pH adjusters and / or acidic pH adjusters.

[0058] In some embodiments, the alkaline pH adjuster includes 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, and diethanolamine.

[0059] In some embodiments, the alkaline pH adjuster is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium citrate, sodium dihydrogen phosphate, arginine, lysine, histidine, glycine, tris(hydroxymethyl)aminomethane, meglumine, triethylamine, or diethanolamine.

[0060] In some embodiments, the alkaline pH adjuster is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium citrate, sodium dihydrogen phosphate, arginine, lysine, histidine, or glycine.

[0061] In some embodiments, the alkaline pH adjuster is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium citrate, and sodium dihydrogen phosphate.

[0062] In some embodiments, the acidic pH adjuster includes one or more of citric acid, ascorbic acid, lactic acid, malic acid, citric acid, fumaric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid, and acetic acid.

[0063] In some embodiments, the acidic pH adjuster 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.

[0064] In some embodiments, the acidic pH adjuster is selected from one or more of citric acid, ascorbic acid, lactic acid, malic acid, or citric acid.

[0065] In some embodiments, the acidic pH adjuster is selected from one or more of citric acid, ascorbic acid, or lactic acid.

[0066] In some embodiments, the acidic pH adjuster is citric acid.

[0067] In some embodiments, the pH adjuster is selected from one or more of citric acid, sodium hydroxide, and sodium citrate.

[0068] In this application, the pH adjuster is commonly used in the art, such as pharmaceutically usable acids or acidic reagents or acidic buffer solutions or acidic solutions, or bases or alkaline reagents or base solutions, such as strong bases or strong base solutions and alkaline buffers. Strong bases include, but are not limited to, sodium hydroxide and potassium hydroxide. Alkaline buffer solutions include, but are not limited to, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, etc. Acids include, but are not limited to, citric acid. The pH adjuster can not only adjust the pH to 1.5-5.5, preferably 2.0-5.3, more preferably 3.0-5.3, but also ensure that the pH of each batch of product remains consistent.

[0069] 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, and more preferably 3.5-4.5.

[0070] In some embodiments, the pH of the pharmaceutical composition may be 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 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, 5.4, or 5.5, or a range between any two of the foregoing.

[0071] In some embodiments, the pH of the pharmaceutical composition may be 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 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.

[0072] On the other hand, this application provides a lyophilized powder injection, wherein the raw materials for making the lyophilized powder injection comprise the pharmaceutical composition as described above; the pharmaceutical composition is lyophilized in a solvent-soluble form.

[0073] The solvent is a solvent commonly used in the art for preparing lyophilized powder injections, such as one or more selected from water, sodium chloride solution or glucose solution.

[0074] In some embodiments, the glucose is a 5%-10% (w / v) glucose solution, such as a 5% glucose solution or a 10% glucose solution.

[0075] In some embodiments, the solvent is a 0.9% w / v sodium chloride solution.

[0076] On the other hand, this application provides a method for preparing the pharmaceutical composition as described above or the lyophilized powder injection as described above, the method comprising the following steps:

[0077] (a) Dissolving the cyclodextrin or its salt in a solvent to form a solution;

[0078] (b) Add the active pharmaceutical ingredient to the solution formed in step (a);

[0079] (c) Freeze-drying.

[0080] On the other hand, this application provides a water-based injection, wherein the raw materials used to prepare the water-based injection comprise the pharmaceutical composition as described above.

[0081] On the other hand, this application provides a method for preparing the aqueous injection as described above, the method comprising the following steps:

[0082] (a) Dissolving the cyclodextrin or its salt in a solvent to form a solution;

[0083] (b) Add the active pharmaceutical ingredient to the solution formed in step (a).

[0084] On the other hand, this application provides a liquid formulation comprising the pharmaceutical composition as described above, the lyophilized powder injection as described above, or the aqueous injection as described above, and a solvent.

[0085] In some embodiments, the solvent is selected from water, sodium chloride solution, or glucose solution.

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

[0087] In some embodiments, the liquid formulation is an injectable formulation.

[0088] In some embodiments, the solvent, the pharmaceutical composition, or the liquid formulation formed after dissolving the lyophilized powder for injection is an isotonic solution, which is generally defined as a solution whose osmotic pressure is equal to that of plasma.

[0089] On the other hand, this application provides the use of the pharmaceutical compositions, lyophilized powder injections, aqueous injections, or liquid formulations as described above in the preparation of medicaments for the prevention or treatment of diseases caused by excessive gastric acid secretion.

[0090] On the other hand, this application provides a method for preventing and / or treating diseases caused by excessive gastric acid secretion, comprising the steps of administering to a patient in need the pharmaceutical composition as described above, the lyophilized powder injection as described above, the aqueous injection as described above, or the liquid preparation as described above.

[0091] On the other hand, this application provides the pharmaceutical compositions, lyophilized powder injections, aqueous injections, or liquid preparations as described above for prevention and / or treatment.

[0092] On the other hand, this application provides the pharmaceutical compositions, lyophilized powder injections, aqueous injections, or liquid preparations as described above for the prevention and / or treatment of diseases caused by excessive gastric acid secretion.

[0093] In some implementations, examples of diseases caused by excessive gastric acid secretion include inflammatory gastroenteritis or acid-related diseases. Inflammatory gastroenteritis or acid-related diseases include peptic ulcers, peptic ulcer bleeding, prevention of peptic ulcer bleeding, gastric and duodenal ulcers, non-steroidal anti-inflammatory drug (NSAID) induced ulcers, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease, laryngopharyngeal reflux disease, non-erosive reflux disease, visceral referred pain, cancer, heartburn, vomiting, esophagitis, dysphagia, excessive salivation, airway obstruction, or asthma.

[0094] In some implementations, the disease caused by excessive gastric acid secretion is a gastroenteritis or an acid-related disease.

[0095] In some implementations, the gastrointestinal inflammatory disease or gastric acid-related disease is selected from peptic ulcer, peptic ulcer bleeding, prevention of peptic ulcer bleeding, gastric and duodenal ulcers, nonsteroidal anti-inflammatory drug-induced ulcers, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease and nonerosive reflux disease.

[0096] The active pharmaceutical ingredient of this application has excellent activity in inhibiting gastric acid secretion, and therefore can be effectively used to prevent or treat inflammatory gastrointestinal diseases or gastric acid-related diseases, especially peptic ulcers, gastric and duodenal ulcers, gastroesophageal reflux disease and non-erosive reflux disease.

[0097] The dosage of the pharmaceutical composition according to this application can vary depending on the patient's condition and weight, the severity of the disease, the form of the drug and the route and duration of administration, and the dosage can be appropriately determined by those skilled in the art.

[0098] In some embodiments, the pharmaceutical composition of this application may further contain one or more active ingredients that exhibit the same or similar pharmacological effects as the compound of formula (I).

[0099] In some embodiments, the pharmaceutical composition of this application may further contain one or more selected from amoxicillin, clarithromycin, aceclofenac, meloxicam, and naproxen.

[0100] On the other hand, this application provides a method for preventing or treating diseases caused by excessive gastric acid secretion, the method comprising administering to a mammal (including a human) an effective amount of the pharmaceutical composition as described above, the lyophilized powder injection as described above, the aqueous injection as described above, or the liquid preparation as described above.

[0101] In some embodiments, the method includes administering therapeutically effective amounts of the pharmaceutical composition simultaneously, sequentially, or separately.

[0102] Unless they contradict each other, the details mentioned in the pharmaceutical compositions, flasks, methods of preparation of pharmaceutical compositions, uses, and treatment methods of this application shall be applied in the same manner. Attached Figure Description

[0103] Figure 1 shows the histopathological examination results in test example 2. Detailed Implementation

[0104] I. Terms and Definitions

[0105] In this application, unless otherwise stated, the scientific and technical terms used herein have meanings commonly understood by those skilled in the art. Furthermore, the relevant terms and laboratory procedures used herein are widely used terms and routine procedures in their respective fields. To better understand this application, definitions and explanations of relevant terms are provided below.

[0106] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0107] As used herein and unless otherwise stated, the terms “comprising,” “including,” “having,” and “containing” include their grammatical equivalents and should generally be understood as open-ended and non-restrictive, e.g., not excluding other unlisted elements or steps.

[0108] In this document, when pH is mentioned, it is understood that, due to measurement reasons, the range of pH should allow for fluctuations of 0.1 ± 0.1. For example, when pH is mentioned as 3.5 to 4.5, the range should include 3.5 ± 0.1 to 4.5 ± 0.1.

[0109] As used herein, the term "inclusion" refers to the technique of encapsulating one molecule within the cavity structure of another molecule to form an inclusion complex. An inclusion complex consists of two components: a host molecule and a guest molecule. The host molecule has a large cavity structure sufficient to encapsulate the guest molecule, forming a molecular capsule.

[0110] As used in this article, the term "treatment" includes reversing, reducing, or suppressing the symptoms, clinical signs, and underlying pathology of a condition, thereby improving or stabilizing the patient's condition.

[0111] As used herein, the terms “patient,” “individual,” and “subject” are used interchangeably to refer to any single animal, more preferably a mammal (including non-human animals such as cats, dogs, horses, rabbits, zoo animals, cattle, pigs, sheep, and non-human primates), which may be desired to be treated. In a particular embodiment, the patient herein is a human being.

[0112] As used herein, "pharmaceutical formulation" means a formulation in a form that allows the bioactivity of the active ingredient contained therein to be effective and does not contain any other components that would have unacceptable toxicity to a subject administering the formulation.

[0113] As used herein, “lyophilized powder for injection” refers to a solid powder preparation made by incorporating one or more active pharmaceutical ingredients (or active pharmaceutical ingredients, in this article referring to the citrate salt of compound (I)) into one or more excipients or dissolving them in one or more solvents (or media) and then processing them (e.g., freeze-drying) under certain conditions (preferably under sterile conditions).

[0114] Unless otherwise stated, "water for injection" refers to water that meets the relevant requirements for "water for injection" in the Chinese Pharmacopoeia.

[0115] Unless otherwise stated, “dissolve and clarify” (or its full name “dissolve and clarify”) means the operation or process of dissolving a sample in a solvent until it is clear or free of visible turbidity or precipitation, or the state in which the sample is dissolved in a solvent and there is no visible turbidity or precipitation.

[0116] Unless otherwise stated, "mass volume concentration" (or simply "mass concentration") refers to a concentration per unit volume (e.g., 1 cm³). 3 The mass of solute contained in a solution of 100 mL (e.g., 1 g or 1 mg) is usually expressed in mg / L or mg / mL. Unless otherwise stated, the term “% (w / v)” as used herein means the number of grams of solute contained in 100 mL of solution, i.e., “g / 100 mL”.

[0117] Unless otherwise stated, the term "freeze-drying" (or its full name "freeze-drying") as used in this application refers to a drying operation or process in which an aqueous material (e.g., an aqueous pharmaceutical solution, i.e., a solution of citrate and cyclodextrin containing the compound of formula (I) in this application) is first frozen below its freezing point, causing the water to turn into ice (freezing), and then the ice is removed by turning into water vapor (sublimation) under vacuum conditions. The material can be pre-frozen in a freezing device and then transferred to a drying device for drying, or it can be directly frozen in the drying device by rapid vacuuming and then dried. The water vapor generated during sublimation is removed by condensation in a condensing device, and the heat of vaporization required for the sublimation process is generally supplied by thermal radiation or thermal conduction.

[0118] As used herein, “administration” refers to the method of giving a subject (e.g., a patient) a dose of a pharmaceutical composition (e.g., Zastaprazan citrate injection). Administration can be made via any suitable route, such as by injection, like intravenous or subcutaneous injection, depending in part on whether the administration is short-term or long-term. Various administration regimens are considered herein, including but not limited to single or multiple administrations at different time points, bolus administration, and infusion administration.

[0119] As used herein, "pH adjuster" refers to a compound or mixture of compounds that can be used to ensure that the pH of a composition is within an acceptable range for administration to humans or mammals. Suitable pH adjusters include pharmaceutically acceptable buffers, pharmaceutically acceptable acids, and pharmaceutically acceptable bases. The pH adjuster may 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 process. In this document, 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.

[0120] As used herein, “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is harmless to the patient.

[0121] This application relates to methyl ketone of formula (I) (azacyclobutane-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl) The pharmaceutical compositions described herein were prepared using pharmaceutically acceptable citrate salts. The solubility, stability of the drug combination, and biocompatibility (e.g., vascular irritation) of different salts and the resulting compositions were investigated. Surprisingly, the excipients used in the compositions of this application were optimized (e.g., the formulation components were simplified as much as possible, production costs were reduced, and the solubilizing effect and excipient safety assessment were optimal). For example, among the excipients with solubilizing effects disclosed in the prior art: ① Tween 80 has moderate intravenous toxicity, moderate gastrointestinal toxicity, eye irritation, is an experimental carcinogen, has reproductive effects, and has been reported to be mutagenic. ② Polyoxyethylene castor oil has severe sensitization, peripheral neurotoxicity, and cytotoxicity when injected intravenously in humans and animals, and may cause hyperlipidemia and toxic kidney damage; moreover, polyoxyethylene castor oil can dissolve di(2-ethylhexyl)phthalate (DEHP) in polyvinyl chloride (PVC) infusion bottles, causing hepatotoxicity, testicular atrophy, and precocious puberty in children, increasing transportation costs. ③ Solutol HS-15 (polyethylene glycol-15-hydroxystearate) is a novel excipient, generally considered to have good safety, but dose-limiting toxicity has been reported in clinical use, such as injection site pain and redness, urticaria, etc. ④ N,N-Dimethylacetamide (DMA) is used as a solvent in parenteral preparations in pharmaceutical formulations. When used as an excipient, it is usually considered a non-toxic material. Repeated exposure to dimethylacetamide may be harmful and may cause liver damage. High intravenous doses (>400 mg / kg / day for 3 consecutive days) may produce hallucinations. ⑤ Ethanol is irritating to blood vessels; there are currently no cases of direct injection into the bloodstream. ⑥ Adverse reactions of glycerol mainly stem from its dehydrating properties, which may lead to hemolysis, hematuria, and kidney damage. No toxicity has been observed with slow administration. The maximum intravenous dose is 22.50%; the maximum intramuscular dose is 15.36%; and the maximum subcutaneous dose is 32.50%. Propylene glycol and PEG (e.g., PEG400) are generally considered to be non-toxic and low-irritant.

[0122] Based on our investigation, the pharmaceutical composition prepared by encapsulating the citrate of (azacyclobutane-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl) methyl ketone with cyclodextrin as an excipient exhibits the best performance in terms of solubility, stability and biocompatibility.

[0123] Furthermore, the pharmaceutical compositions of this application significantly improve the lyophilized reconstitution properties of the active ingredient, and are more stable for intravenous injection in clinical use, without precipitation, greatly improving the safety of clinical use. They also eliminate the need for specialized solvents, reducing the hassle of packaging, transportation, and clinical use. Moreover, these compositions exhibit superior physical properties (e.g., the appearance of the resulting lyophilized powder meets quality requirements through a simple process), greater stability of the product's physical properties during storage (e.g., minimal change in API content during storage), and relatively lower impurity content.

[0124] II. Examples

[0125] To make the objectives, technical solutions, and advantages of this application clearer, this application will be described in further detail below. The described embodiments should not be regarded as limitations on this application. All other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0126] Before providing a further detailed description of the embodiments of this application, the nouns and terms involved in the embodiments of this application will be explained, and the nouns and terms involved in the embodiments of this application shall be interpreted as follows.

[0127] The raw materials and equipment used in the specific embodiments of this application are all known products, obtained by purchasing commercially available products or by using the methods already applied for. For example, the citrate of compound (I) in the following examples is prepared by reacting compound (I) with citric acid. Compound (I) is obtained according to the preparation method of CN109415362B. The citrate of compound (I) can be obtained according to the preparation method of Korean Patent Application 10-2022-0095088.

[0128] The citrate preparation method of the following embodiments of this application is as follows: An appropriate amount of acetone, compound (I), and citric acid (the molar ratio of compound (I) to citric acid is 1:1) are added to a reaction flask, the temperature is raised to 57°C, and the mixture is stirred for 3 hours. Subsequently, the mixture is cooled to 10-20°C, and after the solid precipitates, it is filtered. The filter cake is dried to obtain the citrate of compound (I).

[0129] Example 1: Preparation of lyophilized powder injection of citrate of compound (I)

[0130] Preparation process:

[0131] 1) Weigh the prescribed amount of SBE-β-CD and add it to 2.1L of sterile water for injection to prepare a 30% (w / v) SBE-β-CD solution;

[0132] 2) Weigh the prescribed amount of API and add it to the prepared SBE-β-CD solution. Stir at 50°C until dissolved.

[0133] 3) Add water to bring the volume to 3L;

[0134] 4) Fill the prepared solution into vials, 4 mL / vial;

[0135] 5) Freeze-drying.

[0136] Example 2: Preparation of lyophilized powder injection of citrate of compound (I)

[0137] Preparation process:

[0138] 1) Add the prescribed amount of SBE-β-CD to 2.1L of purified water. After the SBE-β-CD has dissolved, add the prescribed amount of API and stir at 50°C until dissolved.

[0139] 2) Add water for injection to 2.7L, take a sample to measure the pH. If the pH is higher than 3.8, add 1mol / L citric acid solution to the solution to adjust the pH to 3.8.

[0140] 3) Add purified water to a final volume of 3L;

[0141] 4) Fill the prepared solution into vials, 2.5 mL / vial;

[0142] 5) Freeze-dry the canned samples.

[0143] Example 3: Preparation of lyophilized powder injection of citrate of compound (I)

[0144] Preparation process:

[0145] 1) Add the prescribed amount of SBE-β-CD to 2.1L of purified water. After the SBE-β-CD has dissolved, add the prescribed amount of API and stir at 50°C until dissolved.

[0146] 2) Add purified water to a final volume of 3L;

[0147] 3) Fill the prepared solution into vials, 2.5 mL / vial;

[0148] 4) Freeze-dry the canned samples.

[0149] Example 4: Preparation of lyophilized powder injection of citrate of compound (I)

[0150] The preparation process is the same as in Example 3.

[0151] Example 5: Preparation of lyophilized powder injection of citrate of compound (I)

[0152] The preparation process is the same as in Example 3.

[0153] Example 6: Preparation of lyophilized powder injection of citrate of compound (I)

[0154] The preparation process is the same as in Example 3.

[0155] Example 7: Preparation of lyophilized powder injection of citrate of compound (I)

[0156] The preparation process is the same as in Example 3.

[0157] Example 8: Preparation of lyophilized powder injection of citrate of compound (I)

[0158] The preparation process is the same as in Example 3.

[0159] Example 9: Preparation of lyophilized powder injection of citrate of compound (I)

[0160] The preparation process is the same as in Example 3.

[0161] Example 10: Preparation of lyophilized powder injection of citrate of compound (I)

[0162] The preparation process is the same as in Example 3.

[0163] Example 11: Preparation of lyophilized powder injection of citrate of compound (I)

[0164] The preparation process is the same as in Example 3.

[0165] Example 12: Preparation of an injectable liquid formulation of the citrate salt of compound (I)

[0166] Preparation process:

[0167] 1) Add the prescribed amount of SBE-β-CD to 2.1L of purified water. After the SBE-β-CD has dissolved, add the prescribed amount of API and stir at 50°C until dissolved.

[0168] 2) Add purified water to a final volume of 3L;

[0169] 3) Freeze-dry the prepared solution;

[0170] 4) The lyophilized sample was dispensed into 4.01g bottles;

[0171] 5) Reconstitute the sample to 38 mL before use.

[0172] Example 13: Preparation of an injectable liquid formulation of the citrate salt of compound (I)

[0173] Preparation process:

[0174] 1) Add the prescribed amount of SBE-β-CD to 2.1L of purified water. After the SBE-β-CD has dissolved, add the prescribed amount of API and stir at 50°C until dissolved.

[0175] 2) Add purified water to a final volume of 3L;

[0176] 3) Freeze-dry the prepared solution;

[0177] 4) The lyophilized sample was dispensed into 8.11g / bottles;

[0178] 5) Reconstitute the sample to 77 mL before use.

[0179] Example 14: Preparation of lyophilized powder injection of citrate of compound (I)

[0180] The preparation process is the same as in Example 3.

[0181] Example 15: Preparation of lyophilized powder injection of citrate of compound (I)

[0182] The preparation process is the same as in Example 3.

[0183] Example 16: Preparation of lyophilized powder injection of citrate of compound (I)

[0184] The preparation process is the same as in Example 3.

[0185] Example 17: Preparation of an aqueous injection of citrate of compound (I)

[0186] Preparation process:

[0187] 1) Add the prescribed amount of propylene glycol to 20 mL of purified water. After the two are mixed 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 until the solution is clear).

[0188] 2) Add purified water to a final volume of 50 mL;

[0189] 3) Fill the prepared solution into vials, 5 mL / vial.

[0190] Example 18: Preparation of an aqueous injection of citrate of compound (I)

[0191] The preparation process is the same as in Example 17.

[0192] Example 19: Preparation of lyophilized powder injection of citrate of compound (I)

[0193] Preparation process:

[0194] 1) Add the prescribed amount of HP-β-CD to 55 mL of purified water. After the HP-β-CD has dissolved, add the prescribed amount of API.

[0195] 2) Add an appropriate amount of 1 mol / L citric acid solution to the mixed solution in step 1), and stir at 50°C until dissolved;

[0196] 3) Add purified water to bring the volume to 100 mL;

[0197] 4) Fill the prepared solution into vials, 2.5 mL / vial;

[0198] 5) Freeze-dry the canned samples.

[0199] Example 20: Preparation of lyophilized powder injection of citrate of compound (I)

[0200] The preparation process is the same as in Example 19.

[0201] Example 21: Preparation of an aqueous injection of citrate of compound (I)

[0202] Preparation process:

[0203] 1) Add the prescribed amount of HP-r-CD to 55 mL of purified water. After the HP-r-CD has dissolved completely, add the prescribed amount of API.

[0204] 2) Add an appropriate amount of 1mol / L citric acid solution to the drug solution and stir at 50℃ until dissolved;

[0205] 3) Add purified water to bring the volume to 100 mL;

[0206] 4) Fill the prepared solution into vials, 5 mL / vial;

[0207] 5) Mix the bottled sample with 95 mL of sodium chloride injection solution.

[0208] Example 22: Preparation of an aqueous injection of citrate of compound (I)

[0209] The preparation process is the same as in Example 21.

[0210] Example 23: Preparation of an aqueous injection of citrate of compound (I)

[0211] The preparation process is the same as in Example 21.

[0212] Example 24: Preparation of lyophilized powder injection of citrate of compound (I)

[0213] Preparation process:

[0214] 1) Add the prescribed amount of SBE-β-CD to 2.1L of purified water. After the SBE-β-CD has dissolved, add the prescribed amount of vitamin C and stir at 50°C for 1 hour.

[0215] 2) Add the prescribed amount of API, stir at 50°C until dissolved, and continue stirring for 1 hour;

[0216] 2) Add water for injection to 2.7L, take a sample to determine the pH. If the pH is higher than 3.8, add 1mol / L citric acid solution to the solution to adjust the pH to 3.8. If the pH is lower than 3.8, you can choose not to add a pH adjuster, or add 0.1mol / L NaOH solution or 0.5mol / L sodium citrate solution to the solution to adjust the pH to 3.8.

[0217] 3) Add purified water to a final volume of 3L;

[0218] 4) Fill the prepared solution into vials, 2.5 mL / vial;

[0219] 5) Freeze-dry the canned samples.

[0220] Example 25: Preparation of lyophilized powder injection of citrate of compound (I)

[0221] The preparation process is the same as in Example 24.

[0222] Example 26: Preparation of lyophilized powder injection of citrate of compound (I)

[0223] The preparation process is the same as in Example 24.

[0224] Example 27: Preparation of lyophilized powder injection of citrate of compound (I)

[0225] The preparation process is the same as in Example 24.

[0226] Example 28: Preparation of lyophilized powder injection of citrate of compound (I)

[0227] The preparation process is the same as in Example 24.

[0228] Example 29: Preparation of lyophilized powder injection of citrate of compound (I)

[0229] The preparation process is the same as in Example 24.

[0230] Example 30: Preparation of lyophilized powder injection of citrate of compound (I)

[0231] The preparation process is the same as in Example 24.

[0232] Example 31: Preparation of lyophilized powder injection of citrate of compound (I)

[0233] The preparation process is the same as in Example 24.

[0234] Example 32: Preparation of lyophilized powder injection of citrate of compound (I)

[0235] The preparation process is the same as in Example 24.

[0236] Experimental Example 1: Solubility Test

[0237] The solubility of citrate of compound (I) was tested. The results showed that the solubility of compound (I) in water was 0.00044 mg / mL, and the solubility of citrate under neutral pH conditions was 0.0018 mg / mL. Although the solubility of citrate was improved, it was still far below the requirement of >0.4 mg / mL for injectable formulations. The inventors found that citrate of compound (I) of this application has good solubility in cyclodextrin solutions. For example, in a 10% w / v SBE-β-CD solution, the solubility can reach 6 mg / mL at pH 3.5 and 11 mg / mL at pH 4.0. In the embodiments of this application, the solutions containing API and cyclodextrin prepared before lyophilization, and the injectable liquid formulation obtained by reconstituted the prepared lyophilized powder in water, could all be completely dissolved and clarified, and the solubility was qualified, meeting the pharmaceutical requirements.

[0238] Experimental Example 2: Comparative Study of Stimulation Tests

[0239] Test sample and reference sample

[0240] Test samples 1, 6, and 7 were derived from the lyophilized powders prepared in Examples 2, 19, and 20. The lyophilized powders were reconstituted with 4 mL of sodium chloride injection solution and then mixed with 96 mL of sodium chloride injection solution. Test samples 8 to 10 were derived from the aqueous injections prepared in Examples 21 to 23. Reference standard 1 was a lyophilized powder prepared according to the formulation in the table below and the process in Example 3, which was then dissolved in sodium chloride solution. Reference standard 2 was a sodium chloride injection solution. The specific formulations of the test samples and reference standards are shown in Table 1 below.

[0241] Table 1: Formulations of test sample and reference standard (reconstituted concentration) Note: The API concentration of test samples 1, 6, and 7 after being mixed with sodium chloride injection is 0.2 mg / mL, and the excipient concentration is 0.42% (w / v).

[0242] Experimental methods

[0243] Experimental animals: 32 rabbits were used, divided into 8 groups of 4 rabbits each, and numbered according to the group number in Table 2. They were provided by Tianjin Yuda Experimental Animal Breeding Co., Ltd.

[0244] This experiment used intravenous injection (drip) via the ear margin. The injection solution listed in Table 2 was injected into the left ear margin vein of each rabbit using a sterile syringe, once daily for 7 consecutive days, for a total of 7 administrations. The irritant effect of the test product on blood vessels and surrounding tissues was observed.

[0245] Table 2: Group, Dosage, and Dosage Volume Note: All negative controls and test samples were isotonic solutions.

[0246] Inspection indicators

[0247] 1) Stimulus rating

[0248] Animals were observed at least once daily during all studies, and vascular irritation was assessed. Irritation responses were observed once daily before each administration and at 24, 48, and 72 hours after the last administration, as well as during the 14-day recovery period. Systemic reactions and vascular irritation symptoms at the injection site were visually observed, including the degree and extent of erythema, edema, and congestion, and scored according to Table 3. The average irritation response score for each administration group was calculated.

[0249] Table 3: Scoring Criteria for Vascular Irritation Response

[0250] Evaluation criteria: The average score of vascular stimulation response of each group of animals was calculated daily, and the scores of males and females were combined. The stimulation level was determined according to Table 4, and the irritation of the test product on rabbit blood vessels and surrounding tissues was comprehensively evaluated by combining the results of macroscopic observation and histopathological observation.

[0251] Table 4: Evaluation Criteria for Vascular Stimulation Intensity

[0252] 2) Histopathological examination

[0253] Two rabbits were selected for each of the following tests: 72 hours after the last administration of the negative control and the test sample, and 14 days after administration (or 21 days if the irritation had not subsided). The rabbits were anesthetized and euthanized, and the ear margin tissue 2 cm from the last injection site was removed (avoiding the mechanical stimulation site of the needle tip).

[0254] After fixation, dehydration, embedding, sectioning, and HE staining, the tissue was examined under a microscope for histomorphological analysis to describe the pathological changes at the drug administration site. Semi-quantitative analysis and judgment were performed when necessary.

[0255] The implementation and results of stimulation experiments

[0256] During the experiment, no struggling or abnormal vocalizations were observed in animals administering test samples 1 and 6. The main abnormalities observed in animals administering test samples 7 and 8 were: thickening, mild to moderate redness and swelling, and blackening of blood vessels at the injection site in the left ear after administration. The main abnormalities observed in animals administering test sample 9 were: thickening, mild redness and swelling, and congestion at the injection site in the left ear after administration. After administration of test sample 10, the blood vessels showed mild to moderate redness and swelling, the injection site thickened, and the left ear appeared purple or the blood vessels turned black. Among the rabbits administering test sample 10, rabbit M01 cried out, struggled, and then became paralyzed after the first administration; rabbit M02 died on the fifth day after administration; and rabbit F02 was found dead on the second day. During the observation period, no obvious irritation or systemic toxicity was observed at the intravenous injection site in the negative control group rabbits.

[0257] After administration and recovery period, the irritation response scores of the blood vessels at the rabbit ear vein injection sites for test products 1 and 6-8 were all 0; the irritation response scores of the blood vessels at the rabbit ear vein injection sites for test products 9 and 10 were both 1; detailed vascular irritation intensity scores are shown in Table 5 below.

[0258] Table 5: Vascular Irritation Intensity Score Note: The mean intensity of vascular irritation is calculated as: (∑(Vascular irritation response score of the animal on each day / number of evaluation days)) / number of animals.

[0259] Histopathological examination results

[0260] Microscopic examination 72 hours after the last administration showed that the vascular structure of animals in negative control 1, negative control 2, and test sample 1 was intact, the cell morphology was clear, and no obvious abnormalities were observed in the interstitium. Microscopic examination 14 days after the last administration showed that the vascular structure of animals in the negative control group and the test sample group was intact, the cell morphology was clear, and no obvious abnormalities were observed in the interstitium (see Figure 1). The liquid injection prepared by reconstitution of the lyophilized powder prepared in the embodiments of this application has no vascular irritation.

[0261] Experimental Example 3: Stability Study

[0262] (1) Stability study of multiple cyclodextrins

[0263] Citrate has poor solubility in water, but cyclodextrin has good solubility in citrate. At a 25% (w / v) concentration of cyclodextrin, all four cyclodextrins can completely dissolve the citrate of the compound shown in formula (I). The samples were filled into vials, capped, and stored at 60°C in the dark for 10 days for accelerated stability testing. The API content was measured, and the content change before and after storage was calculated. Test sample 2 was derived from Example 11, test sample 3 from Example 14, test sample 4 from Example 15, and test sample 5 from Example 16. The lyophilized powder was dissolved in water for injection. The test results shown in Table 6 below indicate that the lyophilized powder injections prepared by exemplary Examples 11 and 14 exhibited better stability after reconstitution.

[0264] Table 6: Results of stability study of citrates of different cyclodextrins and formula (I) Note: Content change = 0-day content - 60℃ / 10-day content.

[0265] Among them, 0d content is the API content on day 0 (calculated as the citrate content of compound (I)); 60℃ / 10d content is the API content after being placed at 60℃ for 10 days.

[0266] Detection Method: Take an appropriate amount of API reference standard and prepare a reference solution with acetonitrile aqueous solution; take an appropriate amount of test sample and prepare a solution with acetonitrile aqueous solution as the test sample solution, and determine the API content by HPLC. Instrument Method: Mobile Phase A: Mix 800 mL of sodium perchlorate aqueous solution with pH 2.0 and 100 mL of a tetrahydrofuran / acetonitrile mixed solution; Mobile Phase B: Tetrahydrofuran-acetonitrile (1:10); The chromatographic column is an octadecylsilane-bonded silica gel column; Detection wavelength: 254 nm; Flow rate: 1.0 mL / min; Column temperature: 25℃; Injection volume: 5 μL; Gradient elution is used for detection, and the specific elution program is as follows:

[0267] (2) Stability study of propylene glycol and PEG400

[0268] Besides cyclodextrin, propylene glycol and PEG400 can also improve the solubility of citrate. At a concentration of 25% (w / v), both can dissolve the citrate of the compound shown in formula (I). The samples were placed at 60°C for 10 days, and the API content was measured and the change in content before and after placement was calculated. Sample 11 was derived from Example 17, and sample 12 was derived from Example 18. The test results shown in Table 7 below indicate that the aqueous injections prepared by exemplary Examples 17 and 18 have relatively poor stability compared to the samples prepared with cyclodextrin.

[0269] Table 7: Stability Study Results of Citrate of Propylene Glycol, PEG400 and Formula (I) Note: Content change = 0-day content - 60℃ / 10-day content.

[0270] Among them, 0d content is the API content on day 0 (calculated as the citrate content of compound (I)); 60℃ / 10d content is the API content after being placed at 60℃ for 10 days.

[0271] As shown in Tables 6 and 7, the lyophilized powder injections prepared by SBE-β-CD and HP-β-CD both exhibit good stability; the stability of the lyophilized powder injections prepared by ME-β-CD and the aqueous injections prepared by propylene glycol is not significantly different; and the stability of the lyophilized powder injections prepared by HP-γ-CD and the aqueous injections prepared by PEG 400 is poor.

[0272] Experimental Example 4: Stability Study of Various Nitrite Scavengers

[0273] The following test samples 13 to 18 were prepared according to Examples 24 to 29, and their stability was investigated at 60°C. The nitrosamine content was determined after 30 days, and the results are shown in Table 8.

[0274] Table 8: Inhibition capacity of nitrite scavengers against nitrosamines

[0275] Among them, the total impurities are controlled to be ≤1.0% according to quality standards;

[0276] Detection methods for nitrosamines

[0277] Reference solution: Take an appropriate amount of nitrosamine impurity reference standard and prepare a reference solution with methanol-water solution; Test solution: Take the test sample and prepare a test solution with methanol-water solution.

[0278] LC-MS with a triple-quadrupole detector was used for detection. The mobile phase was formic acid-water formic acid-methanol (40:60), the flow rate was 0.2 mL / min, the column temperature was 30℃, the injection volume was 2 μL, the mass-to-charge ratio of the detected ion pair was 392 for the parent ion and 362 for the daughter ion, and the chromatographic column was an octadecylsilane-bonded silica column. Isocratic elution was performed, and detection was performed in positive ion mode using an ESI ion source.

[0279] Experimental results showed that the nitrosamine impurity content in sample 2 (without nitrite scavenger) exceeded the limit (200 ng / bottle); the nitrosamine impurities in samples 13 and 14 (with added vitamin C) were the least detected; no new impurities were generated in sample 13 (with low-dose vitamin C); and even at a high dose of vitamin C (sample 14), the quality control requirements were still met. Furthermore, vitamin C itself is acidic, which avoids pH increase after addition, facilitating pH control. In addition, when the amount of L-histidine added exceeds 0.1% w / v, it affects the physical stability of the product, causing the active pharmaceutical ingredient to precipitate.

[0280] Experimental Example 5: Investigation of Vitamin C Dosage

[0281] Lower limit of vitamin C dosage: Studies show that even at very low levels, the content of nitrosamines can be controlled to keep it within the limit. When the vitamin C content in test sample 14 of Example 4 was further reduced to 80% or even lower, the nitrosamine content after 30 days would not exceed the limit, meeting the quality control requirements. Calculations show that the highest nitrite content per unit preparation in test sample 13 or 14 is 1090 ng / bottle. Based on a 1:1 molar ratio of vitamin C to nitrite, the theoretical minimum dosage of vitamin C in the formulation is 4172.2 ng / bottle (equivalent to the amount of vitamin C added in Example 32).

[0282] Table 9: Calculation of Vitamin C Dosage Note: (1) The molecular weight of nitrite is 46.013; (2) The molecular weight of nitrosamine is 391.48; (3) The molecular weight of vitamin C is 176.124; (4) The theoretical concentration of nitrite in water for injection is determined with reference to the limit of nitrite in water for injection in the 2020 edition of the Chinese Pharmacopoeia.

[0283] Upper limit of vitamin C dosage: According to the data in Table 8 of Experimental Example 4, when the dosage of vitamin C is 1% w / v, new degradation impurities appear after 30 days of high temperature, and the total impurities reach the upper limit of the allowable value. Therefore, 1% w / v is set as the upper limit of vitamin C dosage.

[0284] The foregoing description of specific exemplary embodiments of this application is for illustrative and explanatory purposes. These descriptions are not intended to limit this application to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of this application and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of this application, as well as various different choices and variations. The scope of this application is intended to be defined by the claims and their equivalents.

Claims

1. A pharmaceutical composition comprising an active pharmaceutical ingredient and excipients, wherein, The active pharmaceutical ingredient is (azacyclobutane-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl) ketone or a salt thereof, the excipients include one or more selected from cyclodextrin or its salts, and the pharmaceutical composition optionally also includes a nitrite scavenger.

2. The pharmaceutical composition according to claim 1, wherein, The nitrite scavenger includes one or more of vitamin C or its derivatives, L-histidine, L-cysteine, L-lysine, glycine, arginine, anhydrous sodium sulfite, ferulic acid, maltol, propyl gallate, para-aminobenzoic acid, caffeic acid, BHA, BHT, or vitamin E.

3. The pharmaceutical composition according to claim 1 or 2, wherein, The mass ratio of the active pharmaceutical ingredient to the nitrite scavenger is 1:(0.0002-1.25).

4. The pharmaceutical composition according to any one of claims 1-3, wherein, The mass ratio of the active pharmaceutical ingredient to the cyclodextrin or its salt is 1:(5.5-446.94); Alternatively, the molar ratio of the active pharmaceutical ingredient to the cyclodextrin or its salt is 1:(1.58-118.7).

5. The pharmaceutical composition according to any one of claims 1-4, wherein, The salts of the active pharmaceutical ingredients include one or more of the following: phosphates, sulfates, citrates, hydrochlorides, mesylates, nitrates, carbonates, acetates, and tartrates.

6. The pharmaceutical composition according to any one of claims 1-5, wherein, The cyclodextrin includes one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, or hydroxypropyl-γ-cyclodextrin.

7. The pharmaceutical composition according to any one of claims 1-5, wherein, The salts of the cyclodextrin include its sodium salt.

8. The pharmaceutical composition according to any one of claims 1-7, wherein the pharmaceutical composition optionally comprises a pH adjuster; Preferably, the pH adjuster is selected from alkaline pH adjusters and / or acidic pH adjusters; Preferably, the alkaline pH adjuster includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate, arginine, lysine, histidine, glycine, tris(hydroxymethyl)aminomethane, meglumine, triethylamine, and diethanolamine. Preferably, the acidic pH adjuster includes one or more of citric acid, ascorbic acid, lactic acid, malic acid, citric acid, fumaric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid, and acetic acid.

9. The pharmaceutical composition according to claim 8, characterized in that, The pH of the pharmaceutical composition is 1.5-5.

5.

10. A lyophilized powder injection, wherein the raw material for preparing the lyophilized powder injection comprises the pharmaceutical composition according to any one of claims 1-9; Preferably, the pharmaceutical composition is lyophilized in a solvent-soluble form.

11. A method for preparing the pharmaceutical composition according to any one of claims 1-9 or the lyophilized powder injection according to claim 10, the method comprising the following steps: (a) Dissolving the cyclodextrin or its salt in a solvent to form a solution; (b) Add the active pharmaceutical ingredient to the solution formed in step (a); (c) Freeze-drying.

12. An aqueous injection, wherein the raw materials for making the aqueous injection comprise the pharmaceutical composition according to any one of claims 1-9.

13. A method for preparing the aqueous injection of claim 12, the method comprising the following steps: (a) Dissolving the cyclodextrin or its salt in a solvent to form a solution; (b) Add the active pharmaceutical ingredient to the solution formed in step (a).

14. A liquid formulation comprising the pharmaceutical composition of any one of claims 1-9, the lyophilized powder for injection of claim 10, or the aqueous injection of claim 12, and a solvent.

15. The use of the pharmaceutical composition according to any one of claims 1-9, the lyophilized powder for injection according to claim 10, the aqueous injection according to claim 12, or the liquid formulation according to claim 14 in the preparation of a medicament for the prevention or treatment of diseases caused by excessive gastric acid secretion; Preferably, the disease caused by excessive gastric acid secretion is an inflammatory gastroenteritis or a gastric acid-related disease.

16. A method for preventing and / or treating a disease caused by excessive gastric acid secretion, comprising administering to a patient in need the pharmaceutical composition of any one of claims 1-9, the lyophilized powder injection of claim 10, the aqueous injection of claim 12, or the liquid formulation of claim 14; Preferably, the disease caused by excessive gastric acid secretion is an inflammatory gastroenteritis or a gastric acid-related disease.

17. The pharmaceutical composition according to any one of claims 1-9, the lyophilized powder for injection according to claim 10, the aqueous injection according to claim 12, or the liquid formulation according to claim 14, for prevention and / or treatment; Preferably, the pharmaceutical composition according to any one of claims 1-9, the lyophilized powder injection according to claim 10, the aqueous injection according to claim 12, or the liquid preparation according to claim 14 is used for the prevention and / or treatment of diseases caused by excessive gastric acid secretion; Preferably, the disease caused by excessive gastric acid secretion is an inflammatory gastroenteritis or a gastric acid-related disease.

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