Imidazo [1, 2-a] pyridine derivative preparation 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 preparation and a preparation method and application thereof.The preparation comprises a pharmaceutical active ingredient and one or more of cyclodextrin, cyclodextrin derivatives or cyclodextrin salts, the pharmaceutical active ingredient is phosphate of a compound shown in the formula (I), and the compound shown in the formula (I) is a compound shown in the description. The phosphate has better solubility in water;

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Chinese patent application CN202410445505.2 filed on April 12, 2024; the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a phosphate preparation of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, a preparation method thereof, and uses thereof. Background Art

[0004] Gastrointestinal inflammatory diseases or gastric acid-related diseases such as peptic ulcer, gastric / duodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD) 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), H + / K + Interest in and demand for potassium-competitive acid blockers (P-CABs) is increasing. These drugs inhibit acid secretion by reversibly binding to the binding site, thereby inhibiting potassium competition. Unlike irreversible proton pump inhibitors (PPIs), reversible proton pump inhibitors (P-CABs) have a rapid onset of action and are convenient to take with or without meals, potentially leading to improved efficacy.

[0005] Chinese patent CN109415362B discloses (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone (Zastaprazan, a compound represented by formula (I)). This is an innovative potassium ion competitive acid blocker (P-CAB) independently developed by Korea First Pharmaceutical Co., Ltd. It has gastric acid secretion inhibitory activity and can be effectively used to prevent or treat gastrointestinal inflammatory diseases or gastric acid-related diseases. Phase III clinical trials for erosive esophagitis are currently underway in South Korea. Existing data show that Zastaprazan has the advantages of rapid onset of action, excellent and long-lasting acid suppression, and few adverse reactions. In the future, it may be expanded to the treatment of duodenal ulcers, Helicobacter pylori infection, and non-erosive gastroesophageal reflux disease.

[0006]

[0007] However, the solubility of the free base of Zastaprazan is low, which is not conducive to subsequent drug development. Therefore, it is urgent to develop new pharmaceutical salts of Zastaprazan or their preparations to solve the problem of low solubility. Summary of the Invention

[0008] Different salts of active pharmaceutical ingredients may exhibit distinct properties. These salts can significantly vary in appearance, solubility, melting point, dissolution rate, and bioavailability, and can also have varying effects on drug stability, safety, bioavailability, and efficacy. Therefore, comprehensive consideration of the salt form of a drug is crucial during drug development.

[0009] During the research process, the inventors found that the free base of the compound represented by formula (I) and its citrate salt have extremely low solubility, which is not conducive to subsequent drug development, and the citrate salt of the compound represented by formula (I) will change color under light conditions.

[0010] In view of this, the object of the present disclosure is to provide a pharmaceutical preparation of the phosphate salt of the compound represented by formula (I) (Zastaprazan) with good solubility and capable of meeting clinical needs.

[0011] Another object of the present disclosure is to provide a stable pharmaceutical composition comprising Zastaprazan phosphate.

[0012] Another object of the present disclosure is to provide a pharmaceutical composition comprising Zastaprazan phosphate that causes little or no irritation to blood vessels of a subject.

[0013] Another object of the present disclosure is to provide a method for preparing a stable, ready-to-dilute pharmaceutical composition comprising Zastaprazan phosphate.

[0014] Another object of the present disclosure is to provide a use of a stable pharmaceutical composition comprising zastaprazan phosphate in the preparation of a medicament for preventing or treating a disease caused by excessive gastric acid secretion, or a method for preventing or treating a disease caused by excessive gastric acid secretion.

[0015] In a first aspect of the present disclosure, a pharmaceutical composition is provided, comprising a pharmaceutically active ingredient and an excipient, wherein the excipient comprises one or more selected from cyclodextrin, its derivatives or salts thereof;

[0016] wherein the active pharmaceutical ingredient is a phosphate salt of a compound of formula (I);

[0017]

[0018] In one embodiment, the mass ratio of the pharmaceutical active ingredient to cyclodextrin is 1:(6.15-462.96) in parts by mass, for example, it can be 1:6.15, 1:6.3, 1:10, 1:12, 1:12.49, 1:21, 1:40, 1:42, 1:45.87, 1:50, 1:65, 1:65.17, 1:65.86, 1:100, 1:145.38, 1:201, 1:213.36, 1:459, 1:462.96 or a range between any two of the foregoing, more preferably 1:(5-215), 1:(5-220) or 1:(6.15-213.36), more preferably 1:(5-66), 1:(5-70), 1:(6.15-65.86).

[0019] In one embodiment, the molar ratio of the pharmaceutical active ingredient to cyclodextrin, calculated as the phosphate of the compound of formula (I), is 1:(1.58-118.7), for example, it can be 1:1.58, 1:1.63, 1:2.5, 1:5.4, 1:16.9, 1:25.7, 1:37.5, 1:51.9, 118.7 or a range between any two of the foregoing, preferably 1:(1.58-54.71); more preferably 1:(1.58-16.89).

[0020] In one embodiment, the pharmaceutical composition is prepared by freeze-drying raw materials comprising the following components: a phosphate salt of a compound of formula (I), a cyclodextrin or a derivative or salt thereof; optionally, the raw materials further comprise a pH adjuster, and the pH adjuster is used in an amount to adjust the pH to 3.0-5.3.

[0021] The phosphate salt of the compound of formula (I), cyclodextrin or its derivative or salt and the auxiliary materials are lyophilized in the form of being dissolved in a solvent;

[0022] In one embodiment, the solvent is selected from water, sodium chloride solution or glucose solution.

[0023] In one embodiment, the glucose is a glucose solution with a mass concentration of 5%-10% (w / v), preferably a 5% glucose solution or a 10% glucose solution.

[0024] In one embodiment, the solvent is a 0.9% w / v sodium chloride solution.

[0025] In one embodiment, the solvent is an isotonic solution, which generally refers to a solution whose osmotic pressure is equal to that of plasma, such as 0.9% w / v sodium chloride solution and 5% w / v glucose solution.

[0026] In the present disclosure, the pH adjusting agent is commonly used in the art, such as a pharmaceutically acceptable base or alkaline agent or alkaline solution, such as a strong base or a strong base solution and an alkaline buffer. Strong bases include but are not limited to sodium hydroxide and potassium hydroxide. Alkaline buffers include but are not limited to disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, etc.

[0027] In one embodiment, the cyclodextrin is β-cyclodextrin and / or γ-cyclodextrin.

[0028] In one embodiment, the cyclodextrin is one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin or hydroxypropyl-γ-cyclodextrin; preferably sulfobutyl-β-cyclodextrin and / or hydroxypropyl-β-cyclodextrin; more preferably sulfobutyl-β-cyclodextrin.

[0029] In one embodiment, the pH of the pharmaceutical composition is 3.0-5.3, for example, 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.

[0030] In one embodiment, the pH of the pharmaceutical composition is 3.0-4.5.

[0031] In one embodiment, the pH of the pharmaceutical composition is 3.5-4.5.

[0032] In one embodiment, the pharmaceutical composition is a lyophilized powder injection, and during the preparation of the pre-lyophilized drug solution of the lyophilized powder injection, the pH is controlled between 3.0 and 5.3, further between 3.0 and 4.5 or between 3.5 and 4.5.

[0033] In one embodiment, the pH of the pharmaceutical composition after dissolution is 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, and further can be 3.0-4.5 or 3.5-4.5.

[0034] In one embodiment, the phosphate salt of the compound of formula (I) is prepared by a method comprising the following steps:

[0035] S1: adding the compound of formula (I) into organic solvent 1;

[0036] S2: adding a mixed solution of phosphoric acid and organic solvent 2 to the solution prepared in S1;

[0037] S3: solid-liquid separation to obtain the phosphate of the compound of formula (I).

[0038] In one embodiment, the organic solvent 1 is an alcohol solvent, preferably methanol, ethanol or propanol, more preferably n-propanol.

[0039] In one embodiment, the organic solvent 2 is an alcohol solvent, preferably methanol, ethanol or propanol, more preferably ethanol.

[0040] In one embodiment, before solid-liquid separation, mixing is performed for a period of time, which is 12-36 hours, more preferably 20-28 hours, and more preferably 24 hours.

[0041] The pharmaceutical composition disclosed herein may further contain pharmaceutically acceptable carriers such as buffers, viscosity enhancers, and preservatives as needed.

[0042] In a first aspect of the present disclosure, a lyophilized powder injection is further provided, wherein the raw materials for preparing the lyophilized powder injection include a pharmaceutical active ingredient and an excipient, wherein the excipient includes one or more selected from cyclodextrin, its derivatives or salts thereof;

[0043]

[0044] The active pharmaceutical ingredient and excipients are freeze-dried in a form dissolved in a solvent;

[0045] Optionally, the raw materials further comprise a pH regulator, and the pH regulator is used in an amount to adjust the pH value to 3.0-5.3.

[0046] Preferably, the molar ratio of the active pharmaceutical ingredient to cyclodextrin, calculated as the phosphate of the compound of formula (I), is 1:(1.58-118.7), more preferably 1:(1.58-54.71); more preferably 1:(1.58-16.89); or,

[0047] Calculated on the basis of the phosphate salt of the compound of formula (I), the mass ratio of the pharmaceutical active ingredient to cyclodextrin is 1:(6.15-462.96), more preferably 1:(6.15-213.36), and even more preferably 1:(6.15-65.86);

[0048] Preferably, the cyclodextrin, cyclodextrin derivative or cyclodextrin salt is as described above.

[0049] Preferably, the solvent is selected from water, sodium chloride solution or glucose solution; preferably, the water is water for injection.

[0050] A second aspect of the present disclosure provides a method for preparing the pharmaceutical composition or lyophilized powder injection according to the first aspect, the preparation method comprising the following steps:

[0051] (a) dissolving the cyclodextrin in a solvent to form a solution;

[0052] (b) adding a pharmaceutically active ingredient to the solution formed in step (a);

[0053] (c) freeze-drying;

[0054] Optionally, a step of adjusting pH is further included between step (b) and step (c);

[0055] Preferably, the pH is adjusted to 3.0-5.3, for example, 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, and further 3.0-4.5 or 3.5-4.5.

[0056] In one embodiment, the pH of the pharmaceutical composition to be prepared is 3.0-5.3, for example, it can be 3.0-4.5 or 3.5-4.5, and 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.

[0057] In one embodiment, in step (b), the concentration of the active pharmaceutical ingredient is 0.5-10 mg / mL based on mass volume concentration (ratio of the mass of the phosphate salt of the active pharmaceutical ingredient, the compound of formula (I), to the total volume of the solution).

[0058] In one embodiment, in step (b), the concentration of the pharmaceutically active ingredient is 0.5 mg / mL, 1 mg / mL, 3 mg / mL, 5 mg / mL, 7 mg / mL, 10 mg / mL, 12 mg / mL or 15 mg / mL or a range between any two of the foregoing.

[0059] In one embodiment, the preparation method comprises:

[0060] (1) Dissolve cyclodextrin in water for injection;

[0061] (2) adding the phosphate of the compound of formula (I) to the obtained solution;

[0062] (3) Freeze-drying.

[0063] In one embodiment, the preparation method comprises:

[0064] (1') dissolving cyclodextrin in water for injection;

[0065] (2') adding the phosphate salt of the compound of formula (I) to the obtained solution;

[0066] (3') adjusting the pH to 3.0-5.3 with a pH adjuster;

[0067] (4') adding solvent to make up the volume;

[0068] (5') Lyophilized.

[0069] The third aspect of the present disclosure provides a liquid preparation comprising the pharmaceutical composition according to the first aspect, and a solvent;

[0070] In one embodiment, the pH of the liquid preparation is 3.0-5.3, for example, 3.0-4.5 or 3.5-4.5, and further 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.

[0071] In one embodiment, the solvent is selected from water, sodium chloride solution or glucose solution.

[0072] In a preferred embodiment, the water is water for injection.

[0073] Preferably, the liquid preparation is an injection.

[0074] The fourth aspect of the present disclosure provides use of the pharmaceutical composition or lyophilized powder injection described in the first aspect or the liquid preparation described in the third aspect in the preparation of a medicament for preventing or treating diseases caused by excessive gastric acid secretion.

[0075] In one embodiment, examples of diseases caused by excessive gastric acid secretion include gastrointestinal inflammatory diseases or gastric acid-related diseases. Gastrointestinal inflammatory diseases or gastric acid-related diseases include peptic ulcer, peptic ulcer bleeding, prevention of peptic ulcer bleeding, gastric and duodenal ulcers, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), laryngopharyngeal reflux disease, non-erosive reflux disease (NERD), visceral referred pain, cancer, heartburn, vomiting, esophagitis, dysphagia, excessive salivation, airway obstruction or asthma.

[0076] The pharmaceutical active ingredient according to the present disclosure has excellent activity in inhibiting gastric acid secretion and can therefore be effectively used to prevent or treat gastrointestinal inflammatory diseases or gastric acid-related diseases, particularly peptic ulcer, gastric and duodenal ulcer, gastroesophageal reflux disease (GERD) and non-erosive reflux disease (NERD).

[0077] The dosage of the pharmaceutical composition according to the present disclosure may vary according to the patient's condition and weight, severity of the disease, the form of the drug, and the administration route and cycle, and the dosage may be appropriately determined by those skilled in the art.

[0078] In one embodiment, the pharmaceutical composition of the present disclosure may further contain one or more active ingredients that exhibit the same or similar pharmaceutical effects as the compound of formula (I).

[0079] In one embodiment, the pharmaceutical composition of the present disclosure may further contain one or more selected from amoxicillin, clarithromycin, aceclofenac, meloxicam, and naproxen.

[0080] The fifth aspect of the present disclosure also provides a method for preventing or treating diseases caused by excessive gastric acid secretion, which comprises administering to a mammal (including a human) an effective amount of the pharmaceutical composition or lyophilized powder injection described in the first aspect or the liquid preparation described in the third aspect.

[0081] In one embodiment, the method comprises the simultaneous, sequential or separate administration of therapeutically effective amounts of the pharmaceutical composition.

[0082] Unless otherwise contradictory, the details mentioned in the pharmaceutical composition, pharmaceutical kit, preparation method, use, and treatment method of the present disclosure apply in the same manner. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 The results of the vascular irritation test of the test sample group in Experimental Example 2 are shown. DETAILED DESCRIPTION

[0084] I. Terms and Definitions

[0085] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the relevant terms and laboratory procedures used herein are those widely used in the relevant fields and routine procedures. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0086] In the description herein, references to “some embodiments,” “some implementation schemes,” or “some implementation plans” describe a subset of all possible embodiments, but it will be 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.

[0087] As used herein and unless otherwise specified, the terms "comprises", "includes", "has", "contains", including their grammatical equivalents, should generally be understood as open and non-limiting, for example, not excluding other unlisted elements or steps.

[0088] Herein, when referring to pH, it is understood that the pH range should allow for fluctuations of 0.1 up and down due to measurement reasons. For example, when referring to pH as 3.5 to 4.5, the range should include 3.5±0.1 to 4.5±0.1.

[0089] As used herein, the term "inclusion" refers to the process by which one molecule is embedded within the cavity of another molecule, forming an inclusion complex. An inclusion complex consists of two components, a host molecule and a guest molecule, with the host molecule possessing a cavity large enough to accommodate the guest molecule, forming a molecular capsule.

[0090] As used herein, the term "treating" includes reversing, reducing, or inhibiting the symptoms, clinical signs, and underlying pathology of a disorder, thereby improving or stabilizing the patient's condition.

[0091] As used herein, the terms "patient," "individual," and "subject" are used interchangeably to refer to any single animal, more preferably a mammal (including, for example, non-human animals such as cats, dogs, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates) for which treatment is desired. In certain embodiments, the patient herein is a human.

[0092] As used herein, a "pharmaceutical formulation" refers to a preparation that is in a form that permits the biological activity of the active ingredient contained therein to be effective and that contains no other components that are unacceptably toxic to a subject to which the formulation is administered.

[0093] As used herein, "lyophilized powder injection" refers to a solid powder preparation prepared by incorporating (preferably under a sterile environment) one or more pharmaceutically active ingredients (or raw materials, herein referring to the phosphate salt of the compound of formula (I)) into one or more excipients or dissolving in one or more solvents (or vehicles) and undergoing certain processing (e.g., freeze-drying).

[0094] Unless otherwise specified, "water for injection" refers to water that complies with the relevant provisions under "water for injection" in the Chinese Pharmacopoeia.

[0095] Unless otherwise specified, "dissolving and clarifying" (or its full name "dissolving and clarifying") refers to the operation or process of dissolving the sample to be dissolved in the solvent until it is clear or has no visible turbidity or precipitation, or the state in which the sample is dissolved in the solvent and has no visible turbidity or precipitation.

[0096] Unless otherwise specified, “mass volume concentration” (or simply “mass concentration”) refers to the concentration per unit volume (e.g., 1 cm 3 The mass of a solute (e.g., 1 g or 1 mg) contained in a solution (e.g., 1 mL) is typically expressed in mg / L or mg / mL. Unless otherwise specified, the term "% (w / v)" as used herein means grams of solute per 100 mL of solution, i.e., "g / 100 mL."

[0097] Unless otherwise specified, the term "lyophilization" (or its full name "freeze drying") used in the present invention refers to a drying operation or process in which a water-containing material (e.g., an aqueous liquid, i.e., a solution of phosphate and cyclodextrin containing the compound of formula (I) in the present invention) is first frozen to below the freezing point to convert the water into ice (solidification), and then, under vacuum conditions, the ice is converted into water vapor (sublimation) and removed. The material can be frozen in a freezing device in advance and then transferred to a drying device for drying, or the material can be directly frozen in the drying device by rapid vacuumization and then dried. The water vapor generated during the sublimation process is removed by the condensation action of a condensing device, and the heat of vaporization required for the sublimation process is generally supplied by thermal radiation or heat conduction.

[0098] As used herein, "administering" refers to a method of administering a dose of a pharmaceutical composition (e.g., Zastaprazan phosphate injection) to a subject (e.g., a patient). Administration can be performed by any suitable route, such as 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 time points, bolus administration, and infusion administration.

[0099] As used herein, "pH adjusting agent" refers to a compound or mixture of compounds that can be used to ensure that the pH of the composition is within an acceptable range for administration to humans or mammals. Suitable pH adjusting agents include pharmaceutically acceptable buffers, pharmaceutically acceptable acids, and pharmaceutically acceptable bases. The pH adjusting agent can optionally be mixed with the pharmaceutically active ingredient, or provided in a separate vial or container so that the user can adjust the pH as part of a multi-step procedure. Herein, the pH is preferably 3.0-5.3, for example, it can be 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2 or 5.3 or a range between any two of the foregoing.

[0100] 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. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch, potato starch and substituted or unsubstituted β-cyclodextrins; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions provided herein are pyrogen-free, i.e., they do not induce a significant temperature increase when administered to a patient.

[0101] The present application prepares the pharmaceutical compositions described herein for the pharmaceutically acceptable phosphate salt of (azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone, and examines the solubility, stability, and product biosafety (e.g., vascular irritation) of different pharmaceutical compositions. It was surprisingly found that the use of excipients in the compositions of the present invention is optimized (e.g., the prescription ingredients are simplified as much as possible, reducing production costs), significantly improving the freeze-dried resolubility of the active ingredient, the reversible proton pump inhibitor, of the present invention. Furthermore, the intravenous injection is more stable during clinical use and does not precipitate, greatly improving the safety of clinical use. There is no need for special solvents, reducing the trouble of packaging, transportation, and clinical use. Furthermore, these compositions have better physical properties (e.g., the appearance of the prepared lyophilized powder can meet quality requirements through a simple process), the physical properties of the product are more stable during storage (e.g., the API content changes little during storage), and the impurity content in the composition is relatively low.

[0102] II. Examples

[0103] In order to make the purpose, technical solutions and advantages of the present disclosure clearer, the present disclosure will be further described in detail below. The described embodiments should not be regarded as limiting the present disclosure. All other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present disclosure.

[0104] Before further describing the embodiments of the present disclosure in detail, the nouns and terms involved in the embodiments of the present disclosure are explained. The nouns and terms involved in the embodiments of the present disclosure are subject to the following interpretations.

[0105] The raw materials and equipment used in the specific embodiments of the present disclosure are all known products, which are obtained by purchasing commercial products or preparing them using disclosed methods.

[0106] Example 1 Preparation of the Phosphate of the Compound of Formula (I)

[0107] 50 g of the compound represented by formula (I) was weighed and added to 2.27 L of n-propanol, followed by the addition of 204 mL of ethanolic phosphoric acid solution (concentration of 1 mol / L). After stirring for 1 day, the suspension was filtered and separated, and the filter cake was vacuum-dried at room temperature overnight to obtain a solid, which was the phosphate.

[0108] Example 2 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0109] Raw materials Dosage Phosphate of the compound of formula (I) 24g SBE-B-CD 504g Add water to volume 3L

[0110] Specific steps:

[0111] (1) Weigh the prescribed amount of cyclodextrin and add sterile water for injection to prepare a 16.8% (w / v) SBE-B-CD solution;

[0112] (2) Weigh the prescribed amount of the phosphate salt of the compound represented by formula (I) (API), add it to the prepared cyclodextrin solution, and stir at room temperature until the solution becomes clear.

[0113] (3) Add water to make up to the prescribed volume (pH is less than 3);

[0114] (4) Fill the prepared solution into vials, 2.5 mL / vial;

[0115] (5) Freeze-dry the sample.

[0116] Example 3 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0117] Raw materials Dosage Phosphate of the compound of formula (I) 24g SBE-B-CD 504g NaOH appropriate amount Add water to volume 3L

[0118] Specific steps:

[0119] (1) Weigh the prescribed amount of cyclodextrin and add 1.68 L of sterile water for injection to prepare a 30% (w / v) cyclodextrin solution;

[0120] (2) Weigh the prescribed amount of the phosphate salt of the compound represented by formula (I) and add it to the prepared cyclodextrin solution.

[0121] (3) The solution prepared in step (2) was adjusted to pH 3.5 using 0.1 mol / L NaOH;

[0122] (4) Add water to make up to the prescribed volume;

[0123] (5) Fill the prepared solution into vials, 2.5 mL / vial;

[0124] (6) Freeze-drying.

[0125] Example 4 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0126]

[0127]

[0128] Please refer to Example 3 for the specific steps.

[0129] Example 5 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0130] Raw materials Dosage Phosphate of the compound of formula (I) 4.64g SBE-β-CD 46.41g NaOH appropriate amount Add water to volume 580ml

[0131] Please refer to Example 3 for the specific steps.

[0132] Example 6 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0133] Raw materials Dosage Phosphate of the compound of formula (I) 4.64g HP-β-CD 57.99g NaOH appropriate amount 5% glucose solution 270.69ml Add water to volume 580ml

[0134] Specific steps:

[0135] (1) Weigh the prescribed amount of cyclodextrin and add 154.7 ml of sterile water for injection to prepare a 30% (w / v) cyclodextrin solution;

[0136] (2) Weigh the prescribed amount of the phosphate salt of the compound represented by formula (I) and add it to the prepared cyclodextrin solution.

[0137] (3) The solution prepared in step (2) was adjusted to pH 3.5 using 0.1 mol / L NaOH;

[0138] (4) Add the prescribed amount of 5% glucose solution and dilute to 580 ml with water;

[0139] (5) Fill the prepared solution into vials, 2.5 mL / vial;

[0140] (6) Freeze-drying.

[0141] Example 7 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0142] Raw materials Dosage Phosphate of the compound of formula (I) 5g HP-β-CD 210g NaOH appropriate amount

[0143] Specific steps:

[0144] (1) Weigh the prescribed amount of cyclodextrin and add 700 mL of sterile water for injection to prepare a 30% (w / v) cyclodextrin solution;

[0145] (2) Weigh the prescribed amount of the phosphate salt of the compound represented by formula (I) and add it to the prepared cyclodextrin solution.

[0146] (3) The solution prepared in step (2) was adjusted to pH 3.5 using 0.1 mol / L NaOH;

[0147] (4) Add water to make up to 1 L;

[0148] (5) Fill the prepared solution into vials, 4 mL / vial;

[0149] (6) Freeze-drying: the freeze-drying process is the same as that in Example 3.

[0150] Example 8 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0151] Raw materials Dosage Phosphate of the compound of formula (I) 5g HP-β-CD 210g

[0152] Specific steps:

[0153] (1) Weigh the prescribed amount of cyclodextrin and add 1 L of sterile water for injection to prepare a 21% (w / v) cyclodextrin solution;

[0154] (2) Weigh the prescribed amount of the phosphate salt of the compound represented by formula (I) and add it to the prepared cyclodextrin solution (pH is measured to be less than 3);

[0155] (3) Fill the prepared solution into vials, 4 mL / vial;

[0156] (4) Freeze-drying: the freeze-drying process is the same as that in Example 3.

[0157] Example 9 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0158] Raw materials Dosage Phosphate of the compound of formula (I) 5g ME-β-CD 250g NaOH appropriate amount

[0159] Specific steps:

[0160] (1) Weigh the prescribed amount of cyclodextrin and add 833.3 mL of sterile water for injection to prepare a 30% (w / v) cyclodextrin solution;

[0161] (2) Weigh the prescribed amount of the phosphate compound of formula (I) and add it to the prepared cyclodextrin solution.

[0162] (3) The solution prepared in step (2) was adjusted to pH 3.5 using 0.1 mol / L NaOH;

[0163] (4) Add water to make up to 1 L;

[0164] (5) Fill the prepared solution into vials, 4 mL / vial;

[0165] (6) Freeze-drying: the freeze-drying process is the same as that in Example 3.

[0166] Example 10 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0167]

[0168]

[0169] Specific steps:

[0170] (1) Weigh the prescribed amount of cyclodextrin and add 833.3 mL of sterile water for injection to prepare a 30% (w / v) cyclodextrin solution;

[0171] (2) Weigh the prescribed amount of the phosphate compound of formula (I) and add it to the prepared cyclodextrin solution.

[0172] (3) The solution prepared in step (2) was adjusted to pH 3.5 using 0.1 mol / L NaOH;

[0173] (4) Add water to make up to 1 L;

[0174] (5) Fill the prepared solution into vials, 4 mL / vial;

[0175] (6) Freeze-drying: the freeze-drying process is the same as that in Example 3.

[0176] Example 11 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0177] Raw materials Dosage Phosphate of the compound of formula (I) 3g SBE-β-CD 18.9g NaOH appropriate amount Rehydrate to 180ml

[0178] Please refer to Example 3 for the specific steps.

[0179] Example 12 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0180] Raw materials Dosage Phosphate of the compound of formula (I) 290mg SBE-β-CD 18.9g NaOH appropriate amount Rehydrate to 180ml

[0181] Please refer to Example 3 for the specific steps.

[0182] Example 13 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0183] Raw materials Dosage Phosphate of the compound of formula (I) 130mg SBE-β-CD 18.9g NaOH appropriate amount Rehydrate to 180ml

[0184] Please refer to Example 3 for the specific steps.

[0185] Example 14 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0186] Raw materials Dosage Phosphate of the compound of formula (I) 94mg SBE-β-CD 18.9g NaOH appropriate amount Rehydrate to 180ml

[0187] Please refer to Example 3 for the specific steps.

[0188] Example 15 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0189] Raw materials Dosage Phosphate of the compound of formula (I) 189mg SBE-β-CD 18.9g NaOH appropriate amount Rehydrate to 180ml

[0190] Please refer to Example 3 for the specific steps.

[0191] Example 16 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0192] Raw materials Dosage Phosphate of the compound of formula (I) 41.2mg SBE-β-CD 18.9g NaOH appropriate amount Rehydrate to 180ml

[0193] Please refer to Example 3 for the specific steps.

[0194] Example 17 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0195] Raw materials Dosage Phosphate of the compound of formula (I) 5g HP-β-CD 250g NaOH appropriate amount

[0196] Please refer to Example 10 for the specific steps.

[0197] Example 18 Preparation of Lyophilized Powder Injection of Phosphate Salt of Compound of Formula (I)

[0198] Raw materials Dosage Phosphate of the compound of formula (I) 5g SBE-β-CD 250g NaOH appropriate amount

[0199] Please refer to Example 10 for the specific steps.

[0200] Experimental Example 1 Solubility Test of Phosphate of Compound of Formula (I)

[0201] The phosphate salt of the compound of formula (I) has good solubility, significantly improved compared to the free base and citrate salt. Testing of the solubility of the phosphate salt of the compound of formula (I) in water showed that the solubility of the phosphate salt of the compound of formula (I) in water was not less than 27.5 mg / mL, while the solubility of the free base was only 0.0044 mg / mL and the solubility of the citrate salt was only 0.0018 mg / mL.

[0202] Table 1 Dissolution of phosphate salts of the compound of formula (I) at different concentrations

[0203] Preparation concentration Initial state Room temperature overnight -57.5mg / mL clarify Crystal precipitation -37.5 mg / m clarify Crystal precipitation, relatively small amount -27.5mg / mL clarify clarify

[0204] Experimental Example 2 Irritation Test of Phosphate Preparation of Compound of Formula (I)

[0205] The vascular irritation response scoring standard and vascular irritation intensity evaluation standard used in this experimental example are shown in Tables 2 and 3 below, respectively.

[0206] Table 2 Vascular irritation response scoring criteria

[0207] Reaction level stimulus response 0 No obvious reaction 1 Mild congestion 2 Moderate congestion 3 Severe congestion, redness and swelling 4 Venous vascular degeneration and necrosis 5 Extensive necrosis of venous vessels

[0208] Vascular irritation evaluation criteria: Calculate the average vascular irritation response score for each group of animals daily, expressed as the mean x, with males and females combined. Determine the irritation level according to Table 3. Combine visual and histopathological observations to comprehensively evaluate the irritation of the test article to the rabbit's blood vessels and surrounding tissues.

[0209] Table 3 Vascular irritation evaluation standards

[0210]

[0211]

[0212] 2.1. Irritation of phosphate salts of compounds of formula (I) containing cyclodextrin

[0213] The inventors have found through experimental studies that direct injection of the phosphate salt of the compound of formula (I) causes mild to severe irritation, and the inventors intend to improve the irritation by means of a formulation.

[0214] Experimental design

[0215] The settings of test samples 1-3 are shown in Table 4 below. Among them, test sample 1 was prepared using the phosphate salt of the compound of formula (I) with glucose injection, test sample 2 was derived from the lyophilized powder prepared in Example 8, and test sample 3 was derived from the lyophilized powder prepared in Example 7, which was obtained by dissolving the lyophilized powder in water for injection.

[0216] Table 4

[0217]

[0218] Experimental methods

[0219] This study consisted of three groups, designated Test Article Groups 1-3. This study used a bolus injection into the auricular vein for 7 days (1 mL / ear), followed by a 14-day recovery period. During this period, the irritation of the test article on blood vessels and surrounding tissues was observed. Daily irritation scores were recorded according to the Vascular Irritation Response Scoring Criteria in Table 2, and the intensity of irritation was determined according to Table 3.

[0220] Table 5 Dosage regimen

[0221]

[0222]

[0223] Experimental results

[0224] Daily rating results can be found at Figure 1 Unexpectedly, based on the daily average score results, test sample 1 scored an average of 1.6, indicating irritation. Test samples 2 (average score 0.3) and 3 (average score 0) were non-irritating. The results showed that the irritation of test sample group 2, which contained the phosphate salt of the compound of formula (I) encapsulated in cyclodextrin, was significantly lower than that of test sample group 1, which contained the phosphate salt of the compound of formula (I) alone. This shows that the irritation of the preparation prepared from the phosphate salt of the compound of formula (I) and cyclodextrin to blood vessels was significantly reduced. If the pH of the injection was adjusted to 3.5 (test sample group 3), the irritation was further reduced.

[0225] Experimental Example 3 Solubility of the Phosphate-containing Cyclodextrin Formulation of the Compound of Formula (I)

[0226] The inventors also found in experimental studies that the solubility of the phosphate salt of the compound of formula (I) decreases when the pH is increased to above 3.5 (by adding a pH adjuster). Based on this, the solubility of the phosphate salt after inclusion in cyclodextrin was further measured at pH 3.5-4.

[0227] Referring to the method in Example 3, formulations containing different types of cyclodextrins were prepared at a phosphate concentration of 5 mg / mL of the compound of formula (I) and a pH of 3.5 and 4.0, respectively. The solutions were observed for different periods of time to observe whether solid precipitation occurred. The solubility of the API in the formulations at pH 3.5 and 4.0 was tested. The experimental results are shown in Table 6.

[0228] It can be seen from the experimental results in Table 6 that the exemplary freeze-dried powders prepared in the present invention have good solubility in water.

[0229] Table 6

[0230]

[0231] Experimental Example 4 Stability of the Phosphate-containing Cyclodextrin Injection of the Compound of Formula (I)

[0232] At a cyclodextrin concentration of 25% (w / v), lyophilized powders prepared from SBE-β-CD (from Example 18), HP-β-CD (from Example 17), ME-β-CD (from Example 9), and HP-γ-CD cyclodextrin (from Example 10) were all soluble in water. Samples of these dissolved samples were stored at 60°C for 10 days, and the content was measured, and the change in content before and after storage was calculated.

[0233] From the experimental results in Table 7, it can be seen that the injection (lyophilized powder injection) prepared by SBE-β-CD and the injection (lyophilized powder injection) prepared by HP-β-CD have good stability; the injection (lyophilized powder injection) prepared by ME-β-CD and the injection (lyophilized powder injection) prepared by HP-γ-CD have poor stability.

[0234] Table 7 Changes in API content in preparations containing different cyclodextrins during the observation period

[0235]

[0236] Note: Content change = 0d content - 60℃ / 10d content.

[0237] The 0d content is the API content on day 0 (calculated as the content of the pharmaceutically acceptable salt of the compound of formula (I)); the 60°C / 10d content is the API content after being placed at 60°C for 10 days.

[0238] The foregoing descriptions of specific exemplary embodiments of the present invention are for purposes of illustration and description. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many variations and modifications are possible in light of the foregoing teachings. The exemplary embodiments have been selected and described for the purpose of explaining the specific principles of the invention and their practical application, thereby enabling those skilled in the art to realize and utilize a variety of exemplary embodiments of the invention and various options and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A pharmaceutical composition comprising a pharmaceutically active ingredient and an excipient, wherein the excipient comprises one or more selected from cyclodextrin, its derivatives or salts thereof; wherein the active pharmaceutical ingredient is a phosphate salt of a compound of formula (I); 2. The pharmaceutical composition according to claim 1, wherein Calculated on the basis of the phosphate salt of the compound of formula (I), the molar ratio of the pharmaceutical active ingredient to cyclodextrin is 1:(1.58-118.7), more preferably 1:(1.58-54.71); and even more preferably 1:(1.58-16.89).

3. The pharmaceutical composition according to claim 1, wherein Calculated on the basis of the phosphate of the compound of formula (I), the mass ratio of the pharmaceutical active ingredient to cyclodextrin is 1:(6.15-462.96), more preferably 1:(6.15-213.36), and even more preferably 1:(6.15-65.86).

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein The cyclodextrin is β-cyclodextrin and / or γ-cyclodextrin; Preferably, the cyclodextrin is one or more of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin or hydroxypropyl-γ-cyclodextrin; more preferably, sulfobutyl-β-cyclodextrin and / or hydroxypropyl-β-cyclodextrin; more preferably, sulfobutyl-β-cyclodextrin; Preferably, the salt of cyclodextrin is sodium sulfobutyl-β-cyclodextrin and / or sodium hydroxypropyl-β-cyclodextrin.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein The pH of the pharmaceutical composition is 3.0-5.3; more preferably 3.0-4.5; more preferably 3.5-4.

5.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein The pharmaceutical composition is a lyophilized powder injection, and during the preparation of the lyophilized pre-drug solution of the lyophilized powder injection, the pH of the pre-lyophilized pre-drug solution is controlled between 3.0 and 5.3; Alternatively, the pH of the pharmaceutical composition after dissolution is 3.0-5.3; more preferably 3.0-4.5; more preferably 3.5-4.

5.

7. A lyophilized powder injection, wherein the raw materials for preparing the lyophilized powder injection include a pharmaceutically active ingredient and excipients, wherein the excipients include one or more selected from cyclodextrin, its derivatives, or salts thereof; The active pharmaceutical ingredient and excipients are freeze-dried in a form dissolved in a solvent; Optionally, the raw material further comprises a pH regulator, and the pH regulator is used in an amount to adjust the pH value to 3.0-5.3; Preferably, wherein The molar ratio of the active pharmaceutical ingredient to cyclodextrin, calculated as the phosphate of the compound of formula (I), is 1:(1.58-118.7), more preferably 1:(1.58-54.71); more preferably 1:(1.58-16.89); or, Calculated on the basis of the phosphate salt of the compound of formula (I), the mass ratio of the pharmaceutical active ingredient to cyclodextrin is 1:(6.15-462.96), more preferably 1:(6.15-213.36), and even more preferably 1:(6.15-65.86); Preferably, the cyclodextrin, cyclodextrin derivative or cyclodextrin salt is as described in claim 4.

8. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6 or the lyophilized powder injection according to claim 7, comprising the following steps: (a) dissolving the cyclodextrin in a solvent to form a solution; (b) adding a pharmaceutically active ingredient to the solution formed in step (a); (c) freeze-drying; Optionally, a step of adjusting pH is further included between step (b) and step (c); Preferably, the pH is adjusted to 3.0-5.

3.

9. A liquid preparation comprising the pharmaceutical composition according to any one of claims 1 to 6 or the lyophilized powder injection according to claim 7, and a solvent; Preferably, the pH of the liquid preparation is 3.0-5.3; more preferably 3.0-4.5; more preferably 3.5-4.5; Preferably, the solvent is selected from water, sodium chloride solution or glucose solution; preferably, the water is water for injection; Preferably, the liquid preparation is an injection.

10. Use of the pharmaceutical composition according to any one of claims 1 to 6, the lyophilized powder injection according to claim 7, or the liquid preparation according to claim 9 in the preparation of a medicament for preventing or treating diseases caused by excessive gastric acid secretion; Preferably, the disease caused by excessive gastric acid secretion is a gastrointestinal inflammatory disease or a gastric acid-related disease; Preferably, the gastrointestinal inflammatory disease or gastric acid-related disease is selected from peptic ulcer, peptic ulcer bleeding, prevention of peptic ulcer bleeding, gastric and duodenal ulcer, nonsteroidal 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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