Pharmaceutical compositions of a2a receptor antagonists

Abstract

Disclosed are a pharmaceutical composition of A2a receptor having good stability and dissolution performance and a dosage form thereof, and a preparation method and use thereof.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical formulations, and more specifically to pharmaceutical compositions of A2a receptor antagonists, methods of their preparation, and uses thereof. Background Technology

[0002] Many immunosuppressive pathways are active in the tumor microenvironment, enabling tumor cells to evade elimination by cytotoxic T cells and reducing clinical response to immunotherapy using anti-checkpoint antibodies. However, only 20-30% of patients respond to checkpoint blockade, and the side effects of such treatments are significant (Sukari et al., 2016). Therefore, other approaches to enhance the cytotoxic potential of the tumor microenvironment are being actively investigated. This includes agents that can be used as monotherapy or, more likely, in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy.

[0003] One noteworthy approach is to interfere with the production and / or function of adenosine in the tumor microenvironment (Vijayan et al., 2017). Adenosine possesses immunosuppressive properties and is present in high concentrations in the tumor microenvironment. Adenosine regulates cellular function via specific GPCRs occupying the cell surface of P1 purine receptor subtypes. The P1 receptor family is further subdivided into A1, A2a, A2b, and A3. A2 receptors are subdivided into A2a and A2b based on their high and low affinity for adenosine, respectively. A2a is expressed by lymphocytes, and activation of A2a leads to the inhibition of cytokine production and other effector functions. Recent research has facilitated the development of selective A2a receptor antagonists for cancer immunotherapy.

[0004] International patent application publication WO2021 / 224636 discloses a series of compounds that act as A2a receptor antagonists. One of the described compounds is 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4-yl)-N-[(2S)-3-hydroxy-3-methylbut-2-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide (hereinafter referred to as "the compound of formula I"):

[0005] .

[0006] The compound of Formula I is an orally bioavailable small-molecule selective A2a receptor antagonist. In vitro, it enhances T cell activation and cytokine secretion in primary CD4+ and CD8+ T cells. In vivo, in combination with anti-PD-1 in three different mouse tumor models (CT-26, B16F10, and EG7-OVA), it enhances the antitumor response to radiotherapy, resulting in enhanced tumor growth inhibition, tumor regression, and increased survival compared to monotherapy or combination therapy with either agent.

[0007] Therefore, there is a need to research and develop pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts that are suitable for medical use. Summary of the Invention

[0008] This application describes pharmaceutical compositions of A2a receptor antagonists, their preparation methods, and their uses.

[0009] In one general aspect, this document provides a pharmaceutical composition comprising a compound of formula (I).

[0010]

[0011] Or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0012] Preferably, the compound of formula (I) or its pharmaceutically acceptable salt is present in an amount of about 0.5%-15%, preferably about 1%-10%, and more preferably about 1%-7.5% by weight relative to the weight of the pharmaceutical composition.

[0013] Preferably, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a carrier, wherein the carrier is one or more selected from the group consisting of: disintegrants, fillers, binders, surfactants, and lubricants, and preferably, the weight percentage of each component in the pharmaceutical composition is as follows:

[0014] Compounds of formula (I) or pharmaceutically acceptable salts thereof 0.5-15% filler 70-95% lubricant 0.5-5% Disintegrant 1-10% Flow aid 0.5-5%。

[0015] Optionally, the pharmaceutical composition may further comprise a flavoring agent, a coloring agent, or a coating material; most preferably, the sum of the weight percentages of the above components is 100%.

[0016] More preferably, in the pharmaceutical composition, the weight percentage of each component is as follows:

[0017] Compounds of formula (I) or pharmaceutically acceptable salts thereof 1-10% filler 75-95% lubricant 0.5-3% Disintegrant 2-8% Flow aid 0.5-3%。

[0018] More preferably, in the pharmaceutical composition, the weight percentage of each component is as follows:

[0019] Compounds of formula (I) or pharmaceutically acceptable salts thereof 1-7.5% filler 80-92% lubricant 0.5-2% Disintegrant 3-7% Flow aid 0.5-2%。

[0020] Preferably, the filler is at least one selected from the group consisting of: starch, powdered sugar, dextrin, lactose, pregelatinized starch, dicalcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, microcrystalline cellulose, and silicified microcrystalline cellulose. More preferably, the filler is at least one selected from the group consisting of: lactose, microcrystalline cellulose, starch, mannitol, and silicified microcrystalline cellulose. Most preferably, the filler is silicified microcrystalline cellulose.

[0021] Preferably, the lubricant is at least one selected from the group consisting of: magnesium stearate, stearic acid, sodium stearoyl fumarate, glyceryl behenate, colloidal silica, talc, and silica. More preferably, the lubricant is at least one selected from the group consisting of: stearic acid, glyceryl behenate, colloidal silica, and magnesium stearate. Most preferably, the lubricant is magnesium stearate.

[0022] Preferably, the disintegrant is at least one selected from the group consisting of: croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, dry starch, and low-substituted hydroxypropyl cellulose. More preferably, the disintegrant is at least one selected from the group consisting of: croscarmellose, carboxymethyl starch sodium, and croscarmellose sodium. Most preferably, the disintegrant is croscarmellose sodium.

[0023] Preferably, the flow aid is at least one selected from the group consisting of silica, talc, and micronized silica. More preferably, the flow aid is silica. Most preferably, the flow aid is anhydrous colloidal silica.

[0024] In another general aspect, the present invention provides a method for preparing a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt.

[0025] In some implementations, the method includes:

[0026] 1) The compound of formula (I) or its pharmaceutically acceptable salt, filler, disintegrant and gliding agent are screened, and then the above components are blended to form a first mixture;

[0027] 2) The lubricant is screened and added to the first mixture, and then blended to form a second mixture; and

[0028] 3) Compress the second mixture to obtain tablets.

[0029] In another general aspect, the present invention provides the use of pharmaceutical compositions of compounds of formula (I) or pharmaceutically acceptable salts.

[0030] Details of one or more embodiments of the present invention are shown in the following description. Other features and advantages will become apparent from the following detailed description and the appended claims. Attached Figure Description

[0031] The foregoing and other objects, aspects, features and advantages of the exemplary embodiments will become more apparent and better understood by referring to the following description in conjunction with the accompanying drawings.

[0032] Figure 1 A flowchart of the process for preparing tablets of compound (I) is shown. Detailed Implementation

[0033] The disclosed pharmaceutical compositions and methods can be readily understood by referring to the following specific embodiments, which form a part of this disclosure. It should be understood that the methods disclosed herein are not limited to the specific methods described and / or shown herein, and the terminology used herein is for illustrative purposes only and is not intended to limit the methods protected by the claims.

[0034] The background and description throughout this specification reference or describe various publications, articles, and patents; the full text of each of these references is incorporated herein by reference. Discussions of documents, actions, materials, devices, articles, etc., included in this specification are intended to provide context for the invention. Such discussions are not an admission that any or all of these matters constitute prior art with respect to any invention disclosed or protected by the claims.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings set forth in this specification. All patents, published patent applications, and publications cited herein are incorporated herein by reference as if fully set forth herein.

[0036] definition

[0037] It should be noted that, unless the context clearly indicates otherwise, the singular forms “a” and “the” as used herein and in the appended claims include plural references.

[0038] When a list is provided, unless otherwise indicated, it should be understood that each individual element in the list and each combination of the list is a separate implementation. For example, a list of implementations presented as “A, B or C” will be understood to include implementations “A”, “B”, “C”, “A or B”, “A or C”, “B or C”, or “A, B or C”.

[0039] As used herein, unless otherwise stated, the term “about” preceding a numerical value or series of numerical values ​​means ±10% of the value. For example, “about 100 mg” means 90 mg to 110 mg.

[0040] Unless otherwise stated, the term "at least" preceding a series of elements should be understood to refer to each element in the series. Those skilled in the art will recognize, or can determine, various equivalents of the specific embodiments of the invention described herein using only conventional experiments. Such equivalents are intended to be covered by this invention.

[0041] Throughout this specification and the following claims, unless the context otherwise requires, the word “comprising” and variations such as “including” and “containing” shall be understood to imply inclusion of the stated integers or steps or groups of integers or steps, but not to exclude any other integers or steps or groups of integers or steps. When used herein, the term “comprising” may be replaced by the terms “containing” or “including”, or sometimes by the term “having”.

[0042] When used herein, "composed of" excludes any element, step, or component not specified in the elements of the claims. When used herein, "substantially composed of" does not exclude materials or steps that do not substantially affect the essential and novel features of the claims. Whenever used herein in the context of an aspect or embodiment of the invention, any of the foregoing terms "comprising," "containing," "including," and "having" may be replaced by the terms "composed of" or "substantially composed of" to change the scope of this disclosure.

[0043] As used herein, the connecting term "and / or" between multiple listed elements is understood to include both individual options and combined options. For example, in the case where two elements are connected by "and / or", the first option means that the first element applies even without the second element. The second option means that the second element applies even without the first element. The third option means that both the first and second elements apply together. Any of these options is understood to fall within the meaning and therefore satisfies the requirement of the term "and / or" as used herein. The concurrent applicability of more than one option is also understood to fall within the meaning and therefore satisfies the requirement of the term "and / or".

[0044] As used herein, “treatment” refers to the treatment of a patient’s disease, disorder, or medical condition (such as an inflammatory gastrointestinal disease) (such as a mammal, particularly a human) that includes one or more of the following:

[0045] (a) Prevention of disease, disorder or medical condition, i.e., prevention of recurrence of disease or medical condition or preventive treatment of patients susceptible to disease or medical condition.

[0046] (b) Improvement of disease, disorder or medical condition, that is, elimination or remission of the patient’s disease, disorder or medical condition, including counteracting the effects of other therapeutic agents;

[0047] (c) Suppressing disease, disorder, or medical condition, that is, slowing or preventing the progression of the patient's disease, disorder, or medical condition; or

[0048] (d) To alleviate the symptoms of a patient’s disease, disorder or medical condition.

[0049] As used herein, in the context of dosage, dosage regimen, treatment, or method, the terms "efficacy" and "effectiveness" refer to the effectiveness of a particular dosage, dosage regimen, or treatment regimen. Effectiveness can be measured based on changes in the disease course response to the pharmaceutical agent of the invention. For example, a compound of formula (I) is administered to a subject at an amount and for a duration sufficient to induce improvement in at least one indicator reflecting the severity of the treated disorder, preferably with sustained improvement. Whether the amount and duration of treatment are adequate can be determined by assessing various indicators reflecting the severity of the subject's disease, illness, or symptom. Such indicators include, for example, indicators of clinically recognized disease severity, symptoms, or manifestations of the disorder under consideration. The degree of improvement is typically determined by a physician, who may make this determination based on signs, symptoms, biopsy, or other test results, and may also use questionnaires administered to the subject, such as quality of life questionnaires developed for a given disease.

[0050] The term "effective dose" refers to the amount that is sufficient to achieve therapeutic effect when administered to a patient in need of treatment.

[0051] A "pharmaceuticalally acceptable carrier" or "excipient" refers to a component in a pharmaceutical composition other than the active ingredient that is non-toxic to the subject. Exemplary pharmaceutically acceptable carriers are buffers, stabilizers, or preservatives.

[0052] "Subject" includes any human or non-human animal. "Non-human animal" includes all vertebrates, such as mammals and non-mammals, including non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, etc. The terms "subject" and "patient" are used interchangeably in this document.

[0053] Pharmaceutical Composition

[0054] In one general aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I).

[0055]

[0056] Or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0057] According to embodiments of the present invention, the compound of formula (I) or its pharmaceutically acceptable salt may be in any solid form, including amorphous and crystalline forms.

[0058] As used herein, a pharmaceutically acceptable salt of a compound of formula (I) means a salt that is acceptable for administration to human subjects, such as a salt that has acceptable mammalian safety for a given dosage regimen. Representative pharmaceutically acceptable salts include salts of acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, ethanedisulfonic acid, fumaric acid, gentian acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, mesylate, mucoic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, nicotinic acid, nitric acid, orotic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and hydroxynaphthoic acid, etc.

[0059] The pharmaceutical compositions of the present invention typically contain a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. However, those skilled in the art will recognize that pharmaceutical compositions may contain more than a therapeutically effective amount, for example, in bulk compositions, or less than a therapeutically effective amount, for example, in single unit doses designed for multiple administrations to achieve a therapeutically effective amount.

[0060] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt is present in an amount of about 0.5% to 15% by weight relative to the weight of the pharmaceutical composition, such as 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%, or any amount between thereof.

[0061] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt is present in an amount of about 1% to 10%, preferably about 1% to 7.5%, by weight relative to the weight of the pharmaceutical composition.

[0062] As used herein, the amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof refers to the amount of a compound based on formula (I) (i.e., in its free base form). For example, 100 mg of a pharmaceutically acceptable salt means an amount equivalent to 100 mg of a compound of formula (I).

[0063] The pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable carrier. As used herein, the term "carrier" means any excipient, diluent, buffer, stabilizer, or other material well known in the art for use in pharmaceutical formulations. A pharmaceutically acceptable carrier is non-toxic and should not interfere with the efficacy of the active ingredient. Pharmaceutically acceptable carriers include excipients and / or additives suitable for use in pharmaceutical compositions known in the art, for example, as listed in the following literature: "Remington: The Science & Practice of Pharmacy," 19th edition, Williams & Williams, (1995) and "Physician's Desk Reference," 52nd edition, Medical Economics, Montvale, NJ (1998), the entire disclosure of which is incorporated herein by reference. Any conventional carrier or excipient may be used in the pharmaceutical compositions of the present invention.

[0064] The choice of a specific carrier or excipient, or a combination of carriers or excipients, will depend on the administration modality or the type of medical condition or disease state intended to treat a particular patient. In this regard, the preparation of a suitable pharmaceutical composition for a specific administration modality is entirely within the capabilities of a person skilled in the pharmaceutical art. Furthermore, the carriers or excipients used in the pharmaceutical compositions of this invention are commercially available. As further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th edition, Lippincott Williams & White, Baltimore, Maryland (2000); and H.C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition, Lippincott Williams & White, Baltimore, Maryland (1999).

[0065] Representative examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, the following substances: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose, such as microcrystalline cellulose; and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragali gum; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic compatible substances for use in pharmaceutical compositions.

[0066] Preferably, the carrier is one or more selected from the group consisting of: disintegrants, fillers, binders, surfactants, and lubricants.

[0067] Preferably, the filler is at least one selected from the group consisting of: starch, powdered sugar, dextrin, lactose, pregelatinized starch, dicalcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, microcrystalline cellulose, and silicified microcrystalline cellulose. More preferably, the filler is at least one selected from the group consisting of: lactose, microcrystalline cellulose, starch, mannitol, and silicified microcrystalline cellulose. Most preferably, the filler is silicified microcrystalline cellulose.

[0068] In some embodiments, the filler is present in an amount of about 70% to 95% by weight relative to the weight of the pharmaceutical composition, such as 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%, or any amount between therewith.

[0069] In some embodiments, the filler is present in an amount of about 75%-95%, preferably about 80%-92%, by weight relative to the weight of the pharmaceutical composition.

[0070] Preferably, the lubricant is at least one selected from the group consisting of: magnesium stearate, stearic acid, sodium stearoyl fumarate, glyceryl behenate, colloidal silica, talc, and silica. More preferably, the lubricant is at least one selected from the group consisting of: stearic acid, glyceryl behenate, colloidal silica, and magnesium stearate. Most preferably, the lubricant is magnesium stearate.

[0071] In some embodiments, the lubricant is present in an amount of about 0.5% to 5% by weight relative to the weight of the pharmaceutical composition, such as 0.5%, 1%, 2%, 3%, 4% or 5%, or any amount between therewith.

[0072] In some embodiments, the lubricant is present in an amount of about 0.5%-3%, preferably about 0.5%-2%, by weight relative to the weight of the pharmaceutical composition.

[0073] Preferably, the disintegrant is at least one selected from the group consisting of: croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, dry starch, and low-substituted hydroxypropyl cellulose. More preferably, the disintegrant is at least one selected from the group consisting of: croscarmellose, carboxymethyl starch sodium, and croscarmellose sodium. Most preferably, the disintegrant is croscarmellose sodium.

[0074] In some embodiments, the disintegrant is present in an amount of about 1% to 10% by weight relative to the weight of the pharmaceutical composition, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%, or any amount between therewith.

[0075] In some embodiments, the disintegrant is present in an amount of about 2%-8%, preferably about 3%-7%, by weight relative to the weight of the pharmaceutical composition.

[0076] Preferably, the flow aid is at least one selected from the group consisting of silica, talc, and micronized silica. More preferably, the flow aid is silica. Most preferably, the flow aid is anhydrous colloidal silica.

[0077] In some embodiments, the descent agent is present in an amount of about 0.5% to 5% by weight relative to the weight of the pharmaceutical composition, such as 0.5%, 1%, 2%, 3%, 4% or 5%, or any amount between therewith.

[0078] In some embodiments, the gliding agent is present in an amount of about 0.5%-3%, preferably about 0.5%-2%, by weight relative to the weight of the pharmaceutical composition.

[0079] Optionally, the pharmaceutical composition further comprises flavoring agents, coloring agents, coating materials and / or stabilizers, and most preferably, the sum of the weight percentages of the above components is 100%.

[0080] Preferably, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a carrier, wherein the carrier is one or more selected from the group consisting of: disintegrants, fillers, binders, surfactants, and lubricants, and preferably, the weight percentage of each component in the pharmaceutical composition is as follows:

[0081] Compounds of formula (I) or pharmaceutically acceptable salts thereof 0.5-15% filler 70-95% lubricant 0.5-5% Disintegrant 1-10% Flow aid 0.5-5%。

[0082] More preferably, in the pharmaceutical composition, the weight percentage of each component is as follows:

[0083] Compounds of formula (I) or pharmaceutically acceptable salts thereof 1-10% filler 75-95% lubricant 0.5-3% Disintegrant 2-8% Flow aid 0.5-3%。

[0084] More preferably, in the pharmaceutical composition, the weight percentage of each component is as follows:

[0085] Compounds of formula (I) or pharmaceutically acceptable salts thereof 1-7.5% filler 80-92% lubricant 0.5-2% Disintegrant 3-7% Flow aid 0.5-2%。

[0086] The pharmaceutical compositions of the present invention are preferably packaged in unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable for administration to a patient, i.e., each unit contains a predetermined amount of active agent that is calculated to produce the desired therapeutic effect whether used alone or in combination with one or more other units. For example, such unit dosage forms may be capsules, tablets, pills, etc., or unit packages suitable for parenteral administration.

[0087] In some implementations, the unit dosage form of the pharmaceutical composition is a tablet.

[0088] In another general aspect, the present invention provides a method for preparing a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt.

[0089] In some implementations, the method includes:

[0090] 1) The compound of formula (I) or its pharmaceutically acceptable salt, filler, disintegrant and gliding agent are screened, and then the above components are blended to form a first mixture;

[0091] 2) The lubricant is screened and added to the first mixture, and then blended to form a second mixture; and

[0092] 3) Compress the second mixture to obtain tablets.

[0093] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt is present in an amount of about 0.5% to 15% by weight relative to the weight of the tablet, such as 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%, or any amount between thereof.

[0094] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt is present in an amount of about 1% to 10%, preferably about 1% to 7.5%, by weight relative to the weight of the tablet.

[0095] Preferably, the filler is at least one selected from the group consisting of: starch, powdered sugar, dextrin, lactose, pregelatinized starch, dicalcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, microcrystalline cellulose, and silicified microcrystalline cellulose. More preferably, the filler is at least one selected from the group consisting of: lactose, microcrystalline cellulose, starch, mannitol, and silicified microcrystalline cellulose. Most preferably, the filler is silicified microcrystalline cellulose.

[0096] Preferably, the lubricant is at least one selected from the group consisting of: magnesium stearate, stearic acid, sodium stearoyl fumarate, glyceryl behenate, colloidal silica, talc, and silica. More preferably, the lubricant is at least one selected from the group consisting of: stearic acid, glyceryl behenate, colloidal silica, and magnesium stearate. Most preferably, the lubricant is magnesium stearate.

[0097] Preferably, the disintegrant is at least one selected from the group consisting of: croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, dry starch, and low-substituted hydroxypropyl cellulose. More preferably, the disintegrant is at least one selected from the group consisting of: croscarmellose, carboxymethyl starch sodium, and croscarmellose sodium. Most preferably, the disintegrant is croscarmellose sodium.

[0098] Preferably, the flow aid is at least one selected from the group consisting of silica, talc, and micronized silica. More preferably, the flow aid is silica. Most preferably, the flow aid is anhydrous colloidal silica.

[0099] In some implementations, the method includes:

[0100] 1) The compound of formula (I), silicified microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and anhydrous colloidal silica are screened, and then the above components are blended to form a first mixture;

[0101] 2) Magnesium stearate is sieved and added to the first mixture, and then blended to form a second mixture; and

[0102] 3) Compress the second mixture to obtain tablets.

[0103] In some embodiments, the filler is present in an amount of about 70%-95%, preferably about 75%-95%, and more preferably about 80%-92% by weight relative to the weight of the tablet.

[0104] In some embodiments, the lubricant is present in an amount of about 0.5%-5%, preferably about 0.5%-3%, more preferably about 0.5%-2% by weight relative to the tablet.

[0105] In some embodiments, the disintegrant is present in an amount of about 1%-10%, preferably about 2%-8%, and more preferably about 3%-7% by weight relative to the weight of the tablet.

[0106] In some embodiments, the gliding agent is present in an amount of about 0.5%-5%, preferably about 0.5%-3%, and more preferably about 0.5%-2% by weight relative to the weight of the tablet.

[0107] Optionally, the tablets also contain flavoring agents, coloring agents, coating materials and / or stabilizers, and most preferably, the sum of the weight percentages of the above components is 100%.

[0108] In some embodiments, the pharmaceutical composition exhibits good stability and dissolution properties.

[0109] In some implementations, the pharmaceutical composition is suitable for medical use, particularly for clinical trials.

[0110] How to use

[0111] In another general aspect, the present invention provides the use of the pharmaceutical compositions of the invention, particularly as A2a receptor antagonists.

[0112] In one embodiment, the present invention provides a method for treating a disease or disorder associated with A2a, the method comprising administering an effective amount of the pharmaceutical composition described herein to a subject in need.

[0113] In some implementations, the disease or disorder is one that is associated with A2a receptor activity.

[0114] In some implementations, the disease or obstacle is cancer, particularly a solid tumor such as lung cancer.

[0115] In some implementations, the lung cancer is non-small cell lung cancer.

[0116] Example

[0117] Example 1: Limited excipient compatibility

[0118] Limited excipient compatibility (LimExcC) studies were conducted on the compounds of formula (I), in which the API-excipient chemical compatibility of a limited number of excipients was evaluated. The API-excipient blends were exposed to stress conditions in an open-plate manner, and the chemical stability of the API in each blend was subsequently evaluated.

[0119] Sample preparation:

[0120] A 1:1 dilution of water / acetonitrile was used. The final sample concentration was 0.5 mg DS / mL. All samples were analyzed using a general-purpose UPLC method. The area percentage of compound (I) in each sample was determined by LC at 266 nm using a PDA detector.

[0121] LC method description :

[0122] column: Waters Acquity UPLC BEH C18 Column length: 150mm Column diameter: 2.1mm Column temperature: 45℃ Particle size: 1.7μm flow: 0.3 mL / min Injection volume: 0.8μL Solvent A: <![CDATA[10 mM NH₄OAc in H₂O]]> Solvent B: Acetonitrile

[0123]

[0124] result :

[0125] The results are summarized in Tables 1 and 2 below.

[0126]

[0127]

[0128] in conclusion :

[0129] The LimExcC study revealed that the active pharmaceutical ingredient (API) is stable in combination with the evaluated fillers (microcrystalline cellulose, lactose, mannitol), disintegrants (crosslinked sodium carboxymethyl cellulose, crosslinked povidone), lubricant (magnesium stearate), and in combination with PEG.

[0130] Example 2: Formulation of compound (I)

[0131] Dosage form :

[0132] Quantitative and qualitative compositions of 1 mg oral tablets, 5 mg oral tablets, 15 mg oral tablets and 50 mg oral tablets are provided in Table 3.

[0133] Table 3. Dosage Form Compositions

[0134]

[0135] Preparation process :

[0136] The preparation process of the above dosage forms and the control during the process are as follows: Figure 1As shown. The compound of formula (I), silicified microcrystalline cellulose, croscarmellose sodium, and anhydrous colloidal silica were screened and then blended using a suitable blender to form a first mixture. Magnesium stearate was screened and then added to the first mixture, and then blended together using a suitable blender to form a second mixture. The second mixture was compressed into tablets using a suitable tableting machine. After compression, the appearance, weight, hardness, and thickness of the tablets were controlled.

[0137] Dissolution test :

[0138] The dissolution of the above oral tablets was tested under the conditions listed in Table 4.

[0139] Table 4. Dissolution Operating Conditions

[0140]

[0141] Average and individual dissolution data at 45 minutes are listed in Table 5.

[0142] Table 5. Dissolution test results

[0143] 1mg (G001) 5mg (G002) 15mg (G003) 50mg (G004) 45 minutes 97（95-100） 99（99-101） l 00（98-102） 100（99-102）

[0144] Example 3: Stability of the formulation

[0145] Stability data are provided for 1 mg (G001) and 15 mg (G003) oral tablets. These data are considered representative and support the stability of all four tablet strengths (1 mg, 5 mg, 15 mg, and 50 mg). The 5 mg (G002) oral tablet (drug loading = 3.3% w / w) is represented by parentheses for the 1 mg (G001) oral tablet (drug loading = 1.0% w / w) and 15 mg (G003) oral tablet (drug loading = 7.5% w / w). The 15 mg (G003) and 50 mg (G004) oral tablets are derived from a common formulation blend, differing only in tablet weight, and are prepared using the same method as described above. Therefore, the 15 mg (G003) oral tablet is considered dose-proportional to the 50 mg (G004) oral tablet. Therefore, the stability behavior of the 15 mg (G003) oral tablet is considered representative of the 50 mg (G004) oral tablet.

[0146] Stability solution:

[0147] The chemical stability of the above dosage forms was evaluated over a 28-day period using a risk-based predictive stability (RiBPS) study. More specifically, this study was conducted on the pharmaceutical products stored in open petri dishes under a range of humidity conditions at elevated temperatures, with the goal of achieving the specification limits of the defined shelf-life limitation property under each condition. The stability protocols provided in Table 6 describe the RiBPS study.

[0148] Table 6: Storage Conditions and Testing Frequency

[0149]

[0150] Results and Conclusions

[0151] During the RiBPS study at G00l, two trend degradation products were generated during storage, with RRT 0.77 being the major and only shelf-life-limiting degradation product. The results indicate that, for a specification limit of 0.70%, the probability of a pharmaceutical product stored in a 40cc HDPE bottle (containing 24 tablets, excluding desiccant) lasting 36 months is 95% when stored at 25°C / 60% RH and 30°C / 75% RH.

[0152] The RiBPS study results for G003 indicate that degradation is not a stability limiting parameter. During the 28-day stability test of the drug product at elevated temperature and humidity, no significant degradation products were generated, and no reduction in the measured values ​​was observed.

[0153] When stored in 40cc HDPE bottles (containing 24 tablets, excluding desiccant), the initial shelf life of G00l, G002, G003 and G004 at 25°C / 60% RH and 30°C / 75% RH can be determined to be 12 months.

[0154] The above dosage forms, 1 mg oral tablets, 5 mg oral tablets, 15 mg oral tablets and 50 mg oral tablets, are suitable formulations of compounds of formula I.

[0155] Those skilled in the art will understand that modifications can be made to the above embodiments without departing from the broad inventive concept of the present invention. Therefore, it should be understood that the present invention is not limited to the specific embodiments disclosed, but is intended to cover modifications within the spirit and scope of the invention, as defined in the specific description.

Claims

1. A pharmaceutical composition comprising a compound of formula (I). Or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5%-15%, preferably about 1%-10%, and more preferably about 1%-7.5% by weight relative to the weight of the pharmaceutical composition.

3. The pharmaceutical composition according to claim 1, wherein the carrier is at least one selected from the group consisting of: fillers, lubricants, disintegrants, and flow aids; preferably, the weight percentage of each component in the pharmaceutical composition is as follows:

4. The pharmaceutical composition according to claim 3, wherein the weight percentage of each component in the pharmaceutical composition is as follows:

5. The pharmaceutical composition according to claim 4, wherein the weight percentage of each component in the pharmaceutical composition is as follows:

6. The pharmaceutical composition according to any one of claims 3 to 5, wherein the filler is at least one selected from the group consisting of: starch, powdered sugar, dextrin, lactose, pregelatinized starch, dicalcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, microcrystalline cellulose and silicified microcrystalline cellulose, preferably at least one selected from the group consisting of: lactose, microcrystalline cellulose, starch, mannitol and silicified microcrystalline cellulose, more preferably silicified microcrystalline cellulose.

7. The pharmaceutical composition according to any one of claims 3 to 5, wherein the lubricant is at least one selected from the group consisting of: magnesium stearate, stearic acid, glyceryl stearate, colloidal silica, silica, talc, and glyceryl behenate, preferably at least one selected from the group consisting of: magnesium stearate, stearic acid, glyceryl behenate, and colloidal silica, more preferably magnesium stearate.

8. The pharmaceutical composition according to any one of claims 3 to 5, wherein the disintegrant is at least one selected from the group consisting of: croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, dry starch and low-substituted hydroxypropyl cellulose, preferably at least one selected from the group consisting of: croscarmellose, carboxymethyl starch sodium and croscarmellose sodium, more preferably croscarmellose sodium.

9. The pharmaceutical composition according to any one of claims 3 to 5, wherein the gliding agent is at least one selected from the group consisting of: silica, talc and micronized silica, preferably silica, more preferably anhydrous colloidal silica.

10. A method for preparing a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, The method includes: 1) The compound of formula (I) or its pharmaceutically acceptable salt, filler, disintegrant and gliding agent are screened, and then the above components are blended to form a first mixture; 2) The lubricant is screened and added to the first mixture, and then blended to form a second mixture; as well as 3) Compress the second mixture to obtain tablets.

11. The method according to claim 10, wherein the filler is at least one selected from the group consisting of: starch, powdered sugar, dextrin, lactose, pregelatinized starch, dicalcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, microcrystalline cellulose, and silicified microcrystalline cellulose, preferably at least one selected from the group consisting of: lactose, microcrystalline cellulose, starch, mannitol, and silicified microcrystalline cellulose, more preferably silicified microcrystalline cellulose.

12. The method according to claim 10 or 11, wherein the lubricant is at least one selected from the group consisting of: magnesium stearate, stearic acid, glyceryl stearate, colloidal silica, silica, talc, and glyceryl behenate, preferably at least one selected from the group consisting of: magnesium stearate, stearic acid, glyceryl behenate, and colloidal silica, more preferably magnesium stearate.

13. The method according to any one of claims 10 to 12, wherein the disintegrant is at least one selected from the group consisting of: croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, dry starch and low-substituted hydroxypropyl cellulose, preferably at least one selected from the group consisting of: croscarmellose, carboxymethyl starch sodium and croscarmellose sodium, more preferably croscarmellose sodium.

14. The method according to any one of claims 10 to 13, wherein the flow aid is at least one selected from the group consisting of silica, talc and micronized silica, preferably silica, more preferably anhydrous colloidal silica.

15. The method according to any one of claims 10 to 14, wherein the pharmaceutical composition comprises a compound of formula (I).

16. A pharmaceutical composition of a compound of formula (I), The pharmaceutical composition comprises:

17. A method for preparing the pharmaceutical composition according to claim 16, The method includes: 1) The compound of formula (I), silicified microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and anhydrous colloidal silica are screened, and then the above components are blended to form a first mixture; 2) Magnesium stearate is screened and added to the first mixture, and then blended to form a second mixture; as well as 3) Compress the second mixture to obtain tablets.

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