Pharmaceutical compositions of an a2a receptor antagonist

Abstract

Disclosed is pharmaceutical compositions of an A2a receptor, and the dosage form thereof with good stability and dissolution performance, as well as preparation methods thereof and uses thereof.

Description

[0001] PHARMACEUTICAL COMPOSITIONS OF AN A2A RECEPTOR ANTAGONIST

[0002] TECHINICAL FIELD

[0003] The application relates to the field of pharmaceutical preparation, and specifically relates to pharmaceutical compositions of an A2a receptor antagonist, preparation methods thereof, and uses thereof.

[0004] BACKGROUND

[0005] A number of immunosuppressive pathways are active in the tumour microenvironment which enable tumour cells to evade elimination by cytotoxic T cells and can diminish the clinical response of patients to immunotherapy with 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). Consequently, other approaches to enhance the cytotoxic potential of the tumour microenvironment are actively being investigated. This includes agents that could be used as monotherapies or, more likely, used in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy.

[0006] One approach that has attracted attention is to interfere with the production and / or action of adenosine in the tumour microenvironment (Vijayan et al, 2017). Adenosine has immunosuppressive properties and is present in the tumour microenvironment at high concentrations. Adenosine regulates cell function via occupancy of specific GPCRs on the cell surface of the Pl purinoceptor subtypes. The Pl receptor family is further subdivided into Al, A2a, A2b and A3. A2 receptors are subdivided into A2a and A2b, based on high and low affinity for adenosine, respectively. A2a is expressed by lymphocytes and activation of A2a leads to suppression of cytokine production and other effector functions. Recent studies have prompted the development of selective A2a receptor antagonists for use in cancer immunotherapy.

[0007] International patent application publication WO2021 / 224636 disclosed a series of compounds as A2a receptor antagonists. One of the compounds described is 2-(3-cyanophenyl)- 3-(2,6-dimethylpyridin-4-yl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl] pyrazolo[l,5- a]pyrimidine-5-carboxamide (hereinafter referred to as "compound of formula I"):

[0008]

[0009] The compound of formula I is an orally bioavailable small molecule selective A2a receptor antagonist. In vitro, it enhanced T cell activation and cytokine secretion in primary CD4+ and CD8+ T cells. In vivo, it potentiated anti-tumor response to radiation therapy in combination with anti-PD-1 in 3 different mouse tumor models (CT-26, B16F10, and EG7- OVA) resulting in enhanced tumor growth inhibition, tumor regression, and increased survival compared to monotherapy with either agent or the combination.

[0010] Therefore, there is a need to research and develop pharmaceutical compositions comprising the compound of formula (I) or the pharmaceutically acceptable salt, which can be suitable for medical use.

[0011] BRIEF SUMMARY

[0012] The application describes pharmaceutical compositions of an A2a receptor antagonist, preparation methods thereof, and uses thereof.

[0013] In one general aspect, provided here is a pharmaceutical composition, comprising a or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0014] Preferably, the compound of formula (I) or the pharmaceutically acceptable salt thereof is present in an amount of about 0.5%- 15%, preferably about 1 %- 10%, further preferably about l%-7.5% by weight, relative to the weight of the pharmaceutical composition.

[0015] Preferably, the pharmaceutical composition comprises the compound of formula (I) or the pharmaceutically acceptable salt thereof and the carrier, wherein the carrier is one or more selected from the group consisting of a disintegrant, filler, binder, surfactant, and lubricant, preferably, the weight percentage of each component in the pharmaceutical composition is as follows: the compound of formula (I) or the

[0016] 0.5-15% pharmaceutically acceptable salt thereof the filler 70-95% the lubricant 0.5-5% the disintegrant 1-10% the glidant 0.5-5%.

[0017] Optionally, the pharmaceutical composition further comprises a flavoring agent, a colorant or a coating material, most preferably, the sum of the weight percentages of the aforementioned components is 100%.

[0018] Further preferably, in the pharmaceutical composition, the weight percentage of each component is as follows: the compound of formula (I) or the

[0019] 1-10% pharmaceutically acceptable salt thereof the filler 75-95% the lubricant 0.5-3% the disintegrant 2-8% the glidant 0.5-3%.

[0020] More preferably, in the pharmaceutical composition, the weight percentage of each component is as follows: the compound of formula (I) or the

[0021] 1-7.5% pharmaceutically acceptable salt thereof the filler 80-92% the lubricant 0.5-2% the disintegrant 3-7% the glidant 0.5-2%.

[0022] Preferably, the filler is at least one selected from the group consisting of starch, powdered sugar, dextrin, lactose, pregelatinized starch, calcium hydrogen 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.

[0023] Preferably, the lubricant is at least one selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl 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.

[0024] Preferably, the disintegrant is at least one selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, dry starch, and low- substituted hydroxypropyl cellulose. More preferably, the disintegrant is at least one selected from the group consisting of crospovidone, sodium carboxymethyl starch, and croscarmellose sodium. Most preferably, the disintegrant is croscarmellose sodium.

[0025] Preferably, the glidant is at least one selected from the group consisting of silica, talc, and micro powder silica gel. More preferably, the glidant is silica. Most preferably, the glidant is colloidal anhydrous silica.

[0026] In another general aspect, the invention presents a method of preparing a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt.

[0027] In some embodiments, the method comprises: 1) screening the compound of formula (I) or the pharmaceutically acceptable salt thereof, a filler, a disintegrant, and a glidant, and then blending the aforementioned components to form a first mixture;

[0028] 2) screening a lubricant and adding it to the first mixture, and then blending to form a second mixture; and

[0029] 3) compressing the second mixture to obtain a tablet.

[0030] In one another general aspect, the invention presents the uses of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt.

[0031] The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages will be apparent from the following detailed description, and the appended claims.

[0032] BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The foregoing and other objects, aspects, features, and advantages of exemplary embodiments will become more apparent and may be better understood by referring to the following description taken in conjunction with the accompanying drawings.

[0034] FIG. 1 illustrates a flow chart of the process for preparing tablets of the compound of formula (I).

[0035] DETAILED DESCRIPTION

[0036] The disclosed pharmaceutical compositions and methods may be understood more readily by reference to the following detailed description, which form a part of this disclosure. It is to be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods.

[0037] Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed.

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein.

[0039] Definitions

[0040] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0041] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C ,” “A or B,” “A or C,” “B or C ,” or “A, B, or C.”

[0042] As used herein, the term “about” preceding a numerical value or a series of numerical values means ±10% of the numerical value unless otherwise indicated. For example, “about 100 mg” means 90 to 110 mg.

[0043] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the invention.

[0044] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having”. When used herein “consisting of’ excludes any element, step, or ingredient not specified in the claim element. When used herein, “consisting essentially of’ does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any of the aforementioned terms of “comprising”, “containing”, “including”, and “having”, whenever used herein in the context of an aspect or embodiment of the invention can be replaced with the term “consisting of’ or “consisting essentially of’ to vary scopes of the disclosure.

[0045] As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or”, a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0046] As used herein, “treatment” or “treat” refers to the treatment of a disease, disorder, or medical condition (such as a gastrointestinal inflammatory disease), in a patient, such as a mammal (particularly a human) which includes one or more of the following:

[0047] (a) preventing the disease, disorder, or medical condition from occurring, i.e., preventing the reoccurrence of the disease or medical condition or prophylactic treatment of a patient that is pre-disposed to the disease or medical condition;

[0048] (b) ameliorating the disease, disorder, or medical condition, i.e., eliminating or causing regression of the disease, disorder, or medical condition in a patient, including counteracting the effects of other therapeutic agents;

[0049] (c) suppressing the disease, disorder, or medical condition, i.e., slowing or arresting the development of the disease, disorder, or medical condition in a patient; or

[0050] (d) alleviating the symptoms of the disease, disorder, or medical condition in a patient.

[0051] The terms “efficacy” and “effective” as used herein in the context of a dose, dosage regimen, treatment or method refer to the effectiveness of a particular dose, dosage or treatment regimen. Efficacy can be measured based on change in the course of the disease in response to an agent of the present invention. For example, the compound of formula (I) can be administered to a subject in an amount and for a time sufficient to induce an improvement, preferably a sustained improvement, in at least one indicator that reflects the severity of the disorder that is being treated. Various indicators that reflect the extent of the subject's illness, disease or condition can be assessed for determining whether the amount and time of the treatment is sufficient. Such indicators include, for example, clinically recognized indicators of disease severity, symptoms, or manifestations of the disorder in question. The degree of improvement generally is determined by a physician, who can make this determination based on signs, symptoms, biopsies, or other test results, and who can also employ questionnaires that are administered to the subject, such as quality-of-life questionnaires developed for a given disease.

[0052] The term “an effective amount” means an amount sufficient to affect treatment when administered to a patient in need of treatment.

[0053] “Pharmaceutically acceptable carrier” or “excipient” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject. Exemplary pharmaceutically acceptable carriers are a buffer, stabilizer or preservative.

[0054] “Subject” includes any human or nonhuman animal. “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms “subject” and “patient” can be used interchangeably herein.

[0055] Pharmaceutical Compositions

[0056] In one general aspect, the invention relates to a pharmaceutical composition, comprising a compound of formula (I)

[0057] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0058] According to the embodiments of the invention, the compound of formula (I) or the pharmaceutically acceptable salt thereof can be any solid forms, including amorphous and crystalline forms.

[0059] As used herein, the pharmaceutically acceptable salt of the compound of formula (I) means a salt that is acceptable for administration to a human subject, e.g., salts having acceptable mammalian safety for a given dosage regime. Representative pharmaceutically acceptable salts include salts of acetic, ascorbic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, edisylic, fumaric, gentisic, gluconic, glucoronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, naphthalene- 1,5 -disulfonic, naphthalene-2,6- disulfonic, nicotinic, nitric, orotic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic and xinafoic acid, and the like.

[0060] The pharmaceutical compositions of the invention typically contain a therapeutically effective amount of the compound of formula (I) or the pharmaceutically acceptable salt thereof. Those skilled in the art will recognize, however, that a pharmaceutical composition can contain more than a therapeutically effective amount, e.g., bulk compositions, or less than a therapeutically effective amount, e. g., individual unit doses designed for multiple administration to achieve a therapeutically effective amount.

[0061] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt is present in an amount of about 0.5%- 15% by weight, such as 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%, or any amount in between thereof, relative to the weight of the pharmaceutical composition.

[0062] In certain embodiments, the compound of formula (I) or the pharmaceutically acceptable salt is present in an amount of about 1 %- 10%, preferably about 1 %-7.5% by weight, relative to the weight of the pharmaceutical composition.

[0063] As used herein, the amount of the compound of formula (I) or the pharmaceutically acceptable salt thereof refers to an amount based on the compound of formula (I), i.e., the free base form. For example, the amount of 100 mg of a pharmaceutically acceptable salt means an amount equivalent to 100 mg of the compound of formula (I).

[0064] The pharmaceutical compositions of the invention comprise a pharmaceutically acceptable carrier. As used herein, the term “carrier” refers to any excipient, diluent, buffer, stabilizer, or other material well known in the art for pharmaceutical formulations. Pharmaceutically acceptable carriers in particular are non-toxic and should not interfere with the efficacy of the active ingredient. The pharmaceutically acceptable carriers include excipients and / or additives suitable for use in the pharmaceutical compositions known in the art, e.g., as listed in “Remington: The Science & Practice of Pharmacy”, 19th ed., Williams & Williams, (1995), and in the “Physician's Desk Reference”, 52nd ed., Medical Economics, Montvale, N.J. (1998), the disclosures of which are entirely incorporated herein by reference. Any conventional carrier or excipient may be used in the pharmaceutical compositions of the invention.

[0065] The choice of a particular carrier or excipient, or combinations of carriers or excipients, will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state. In this regard, the preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts. Additionally, the carriers or excipients used in the pharmaceutical compositions of this invention are commercially-available. By way of 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). Representative examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; 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 glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical compositions.

[0066] Preferably, the carrier is one or more selected from the group consisting of a disintegrant, filler, binder, surfactant, and lubricant.

[0067] Preferably, the filler is at least one selected from the group consisting of starch, powdered sugar, dextrin, lactose, pregelatinized starch, calcium hydrogen 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%-95% by weight, 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 in between thereof, relative to the weight of the pharmaceutical composition.

[0069] In certain 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 stearyl 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%-5% by weight, such as 0.5%, 1%, 2%, 3%, 4%, or 5%, or any amount in between thereof, relative to the weight of the pharmaceutical composition.

[0072] In certain 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, sodium carboxymethyl starch, crospovidone, dry starch, and low- substituted hydroxypropyl cellulose. More preferably, the disintegrant is at least one selected from the group consisting of crospovidone, sodium carboxymethyl starch, and croscarmellose sodium. Most preferably, the disintegrant is croscarmellose sodium.

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

[0075] In certain 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 glidant is at least one selected from the group consisting of silica, talc, and micro powder silica gel. More preferably, the glidant is silica. Most preferably, the glidant is colloidal anhydrous silica.

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

[0078] In certain embodiments, the glidant 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 a flavoring agent, a colorant, a coating material, and / or a stabilizer, most preferably, the sum of the weight percentages of the aforementioned components is 100%. Preferably, the pharmaceutical composition comprises the compound of formula (I) or the pharmaceutically acceptable salt thereof and the carrier, wherein the carrier is one or more selected from the group consisting of a disintegrant, filler, binder, surfactant, and lubricant, preferably, the weight percentage of each component in the pharmaceutical composition is as follows: the compound of formula (I) or the

[0080] 0.5-15% pharmaceutically acceptable salt thereof the filler 70-95% the lubricant 0.5-5% the disintegrant 1-10% the glidant 0.5-5%.

[0081] Further preferably, in the pharmaceutical composition, the weight percentage of each component is as follows: the compound of formula (I) or the

[0082] 1-10% pharmaceutically acceptable salt thereof the filler 75-95% the lubricant 0.5-3% the disintegrant 2-8% the glidant 0.5-3%.

[0083] More preferably, in the pharmaceutical composition, the weight percentage of each component is as follows: the compound of formula (I) or the

[0084] 1-7.5% pharmaceutically acceptable salt thereof the filler 80-92% the lubricant 0.5-2% the disintegrant 3-7% the glidant 0.5-2%. The pharmaceutical compositions of the invention are preferably packaged in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for dosing a patient, i.e., each unit containing a predetermined quantity of active agent calculated to produce the desired therapeutic effect either alone or in combination with one or more additional units. For example, such unit dosage forms may be capsules, tablets, pills, and the like, or unit packages suitable for parenteral administration.

[0085] In some embodiment, the unit dosage form of the pharmaceutical composition is a tablet.

[0086] In another general aspect, the invention presents a method of preparing a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt.

[0087] In some embodiments, the method comprises:

[0088] 1) screening the compound of formula (I) or the pharmaceutically acceptable salt thereof, a filler, a disintegrant, and a glidant, and then blending the aforementioned components to form a first mixture;

[0089] 2) screening a lubricant and adding it to the first mixture, and then blending to form a second mixture; and

[0090] 3) compressing the second mixture to obtain a tablet.

[0091] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt is present in an amount of about 0.5%- 15% by weight, such as 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%, or any amount in between thereof, relative to the weight of the tablet.

[0092] In certain embodiments, the compound of formula (I) or the pharmaceutically acceptable salt is present in an amount of about 1 %- 10%, preferably about 1 %-7.5% by weight, relative to the weight of the tablet.

[0093] Preferably, the filler is at least one selected from the group consisting of starch, powdered sugar, dextrin, lactose, pregelatinized starch, calcium hydrogen 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. Preferably, the lubricant is at least one selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl 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.

[0094] Preferably, the disintegrant is at least one selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, dry starch, and low- substituted hydroxypropyl cellulose. More preferably, the disintegrant is at least one selected from the group consisting of crospovidone, sodium carboxymethyl starch, and croscarmellose sodium. Most preferably, the disintegrant is croscarmellose sodium.

[0095] Preferably, the glidant is at least one selected from the group consisting of silica, talc, and micro powder silica gel. More preferably, the glidant is silica. Most preferably, the glidant is colloidal anhydrous silica.

[0096] In certain embodiments, the method comprises:

[0097] 1) screening the compound of formula (I), silicified microcrystalline cellulose, croscarmellose sodium, and colloidal anhydrous silica, and then blending the aforementioned components to form a first mixture;

[0098] 2) screening and adding magnesium stearate to the first mixture, and then blending to form a second mixture; and

[0099] 3) compressing the second mixture to obtain a tablet.

[0100] In some embodiments, the filler is present in an amount of about 70%-95%, preferably about 75%-95%, more preferably about 80%-92%, by weight, relative to the weight of the tablet.

[0101] 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 weight of the tablet.

[0102] In some embodiments, the disintegrant is present in an amount of about 1 %- 10%, preferably about 2%-8%, more preferably about 3%-7%, by weight, relative to the weight of the tablet. In some embodiments, the glidant 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 weight of the tablet.

[0103] Optionally, the tablet further comprises a flavoring agent, a colorant, a coating material, and / or a stabilizer, most preferably, the sum of the weight percentages of the aforementioned components is 100%.

[0104] In some embodiments, the pharmaceutical composition has good stability and dissolution performance.

[0105] In some embodiments, the pharmaceutical composition is suitable for medical uses, in particular for clinical trials.

[0106] Methods of Use

[0107] In one another general aspect, the invention presents the uses of the pharmaceutical compositions of the invention, particularly the uses as A2a receptor antagonists.

[0108] In one embodiment, the invention presents a method of treating a disease or disorder in which A2a is implicated, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition described herein.

[0109] In certain embodiments, the disease or disorder is one in which A2a receptor activity is implicated.

[0110] In certain embodiments, the disease or disorder is cancer, particularly solid tumors such as lung cancer.

[0111] In certain embodiments, the lung cancer is non-small cell lung cancer.

[0112] EXAMPLES

[0113] Example 1 : Limited Excipient Compatibility

[0114] A limited excipient compatibility (LimExcC) study was performed on the compound of formula (I), in which API-excipient chemical compatibility was assessed for a limited number of excipients. API-excipient blends were exposed open dish to stress conditions, followed by evaluation of the chemical stability of the API in each blend.

[0115] Sample preparation: Water / acetonitrile 1: 1 was used as dilution solvent. The final sample concentration was 0.5 mg DS per mL. All samples were analyzed with a generic UPLC method. The area% of the compound of formula (I) was determined for each sample by LC at 266 nm using a PDA detector.

[0116] LC method Description:

[0117] Column: Waters Acquity UPLC BEH C18

[0118] Column Length: 150 mm

[0119] Column Diameter: 2.1 mm

[0120] Column Temperature: 45 °C

[0121] Particle Size: 1.7 |im

[0122] Flow: 0.3 mL / min

[0123] Injection Volume: 0.8 |1L

[0124] Solvent A: 10 mM NH4OAC in H2O

[0125] Solvent B: Acetonitrile

[0126] Gradient Time 0 22 25 26 30

[0127] (min)

[0128] QDa Parameters

[0129] Gain: 1

[0130] Probe Temperature: 600 °C

[0131] Capillary Pos Voltage: 1.5 kV

[0132] Start Mass: 50.00 Da

[0133] End Mass: 800.00 Da

[0134] Data: Centroid

[0135] Cone Voltage: 15 V

[0136] Sampling Rate: 2 points / sec

[0137] Results:

[0138] The results are summarized in Table 1 and Table 2 below. Table 1 : Results of the Limited Excipient Compatibility Study (Fillers, Lubricant)

[0139] RRT Area% of Degradants by Daysa(%)

[0140] MCC = microcrystalline cellulose; MgSt = magnesium stearate; Reporting threshold = 0.05%aOnly peaks >0.10% and / or peaks observed in the forced degradation study are shown.bPeaks <0.05% were included to calculate the sum of degradation products.

[0141] Table 2: Results of the Limited Excipient Compatibility Study (Disintegrants, PEG)

[0142] RRT Area% of Degradants by Daysa(%)

[0143] CCS= croscarmellose sodium; CPV= crospovidone; Reporting threshold = 0.05%aOnly peaks >0.10% and / or peaks observed in the forced degradation study are shown.bPeaks <0.05% were included to calculate the sum of degradation products.

[0144] Conclusion:

[0145] The LimExcC study revealed that the drug substance is stable in combination with the evaluated fillers (microcrystalline cellulose, lactose, mannitol), disintegrants (croscarmellose sodium, crospovidone), lubricant (magnesium stearate), and with PEG.

[0146] Example 2: Formulations of the Compound (I)

[0147] Dosage Forms:

[0148] The quantitative and qualitative compositions of 1 mg oral tablet, 5 mg oral tablet, 15 mg oral tablet and 50 mg oral tablet are provided in Table 3.

[0149] Table 3. Compositions of Dosage Forms

[0150] Quantity per Unit (mg / tablet)

[0151] Component Function 1 mg (G001) 5 mg (G002) 15 mg (G003) 50 mg (G004)

[0152] Compound of formula (I) Active 1.0 5.0 15.0 50.0

[0153] Silicified Filler 92.0 134.5 171.0 570.0

[0154] Microcrystalline

[0155] Cellulose

[0156] Magnesium Stearate Lubricant 1.0 1.5 2.0 6.7

[0157] Croscarmellose Disintegrant 5.0 7.5 10.0 33.3

[0158] Sodium

[0159] Silica, Colloidal Glidant 1.0 1.5 2.0 6.7

[0160] Anhydrous

[0161] Total tablet weight 100.0 150.0 200.0 666.7

[0162] Preparation Process:

[0163] The preparation process together with the in-process controls for the above dosage forms are shown in FIG. 1. The compound of formula (I), silicified microcl ystalline cellulose, croscarmellose sodium and colloidal anhydrous 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 tablet press. After compression, the tablets were controlled for appearance, weight, hardness, and thickness. Dissolution Testing:

[0164] The above oral tablets were tested for dissolution under the conditions listed in Table 4.

[0165] Table 4. Dissolution Operating Conditions

[0166] Parameter Conditions

[0167] Dissolution Apparatus Paddle (USP, Ph.Eur, JP.)

[0168] Dissolution Medium Temperature: 37.0 ± 0.5 °C

[0169] Dissolution Medium Volume: 900mL

[0170] Dissolution Medium: 0.1 N HC1

[0171] Paddle Rotation Speed: 75 rpm

[0172] Sample Filter: Whatman®Spartan®0.2 pm RC (regenerated cellulose) membrane 30-mm diameter filter, or equivalent (first choice)

[0173] Analytical Finish: UHPLC with U V detection at 266 nm

[0174] The mean and individual dissolution data at 45 minutes are listed in Table 5.

[0175] Table 5. Dissolution Test Results

[0176] Example 3: Stability of the Formulations

[0177] Stability data were provided for the 1 mg (G001) and 15 mg (G003) oral tablets. These data are considered to represent and support the stability for all 4 tablet strengths (1 mg, 5 mg, 15mg, and 50 mg). The 5 mg (G002) oral tablet (drug loading= 3.3% w / w) is represented by the 1 mg (G001) oral tablet (drug loading= 1.0 % w / w) and 15 mg (G003) oral tablet (drug loading= 7.5% w / w) by bracketing approach. The 15 mg (G003) and 50 mg (G004) oral tablets are derived from a common formulation blend differing only by weight of the tablets and are manufactured by the same process as described above. The 15 mg (G003) oral tablet is therefore considered dose proportional to the 50 mg (G004) oral tablet. Hence, the stability behavior of the 15 mg (G003) oral tablet is considered representative for the 50 mg (G004) oral tablet.

[0178] Stability Protocol: The chemical stability of the above dosage forms has been evaluated over a 28-day period using a Risk Based Predictive Stability (RiBPS) study. More specifically, this study was conducted on the drug product when stored open-dish at elevated temperatures over a range of humidity conditions with the goal of reaching the specification limit for the identified shelf life period limiting attribute at each condition. The stability protocol presented in Table 6 describes the RiBPS study.

[0179] Table 6: Storage Conditions and Testing Frequency

[0180] Storage Conditions a Obtained data is being used as TO reference. Samples are stored in closed vials. b Duplicate samples (two samples are placed in condition and tested at this time point / storage condition) c Triplicate samples (three samples are placed in condition and tested at this time point / storage condition) Tests performed: A= Appearance, assay, and chromatographic purity

[0181] NT= Not tested

[0182] Results and Conclusions

[0183] During the RiBPS study of G001, two trending degradation products are generated during storage with RRT 0.77 as main and only shelf life limiting degradation product. The results demonstrated that for the drug product stored in a 40 cc HDPE bottle with 24 tablets without desiccant, and the probability to pass 36 months is 95% for the specification limit of 0.70% when stored at 25 °C / 60% RH and at 30 °C / 75% RH.

[0184] The results of the RiBPS study for G003 showed that degradation is not a stability limiting parameter. No significant degradation products are generated, and no decrease in assay was observed during stability testing of the drug product at elevated temperature and humidity for 28 days.

[0185] An initial shelf life for G001, G002, G003, and G004 of 12 months at 25 °C / 60% RH and 30 °C / 75% RH can be established when stored in a 40cc HDPE bottle with 24 tablets without desiccant. The above dosage forms, 1 mg oral tablet, 5 mg oral tablet, 15 mg oral tablet and 50 mg oral tablet, are suitable formulations of the compound of Formula I.

[0186] It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present inventions as defined by the specific description.

Claims

CLAIMS1. A pharmaceutical composition comprising a compound of formula (I)or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1 , wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is present in an amount of about 0.5 %- 15%, preferably about 1 %- 10%, further 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 a filler, lubricant, disintegrant, and glidant; preferably, the weight percentage of each component in the pharmaceutical composition is as follows: the compound of formula (I) or the0.5-15% pharmaceutically acceptable salt thereof the filler 70-95% the lubricant 0.5-5% the disintegrant 1-10% the glidant 0.5-5%.

4. The pharmaceutical composition according to claim 3, wherein the weight percentage of each component in the pharmaceutical composition is as follows: the compound of formula (I) or the1-10% pharmaceutically acceptable salt thereof the filler 75-95% the lubricant 0.5-3% the disintegrant 2-8% the glidant 0.5-3%.

5. The pharmaceutical composition according to claim 4, wherein the weight percentage of each component in the pharmaceutical composition is as follows: the compound of formula (I) or the1-7.5% pharmaceutically acceptable salt thereof the filler 80-92% the lubricant 0.5-2% the disintegrant 3-7% the glidant 0.5-2%.

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, calcium hydrogen 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 oneselected 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, sodium carboxymethyl starch, crospovidone, dry starch and low- substituted hydroxypropyl cellulose, preferably, at least one selected from the group consisting of crospovidone, sodium carboxymethyl starch, and croscarmellose sodium, more preferably, croscarmellose sodium.

9. The pharmaceutical composition according to any one of claims 3 to 5, wherein the glidant is at least one selected from the group consisting of silica, talc, and micro powder silica gel, preferably, silica, more preferably, colloidal anhydrous silica.

10. A method of preparing a pharmaceutical composition of a compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein the method comprises:1) screening the compound of formula (I) or the pharmaceutically acceptable salt thereof, a filler, a disintegrant, and a glidant, and then blending the aforementioned components to form a first mixture;2) screening a lubricant and adding it to the first mixture, and then blending to form a second mixture; and3) compressing the second mixture to obtain a tablet.

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, calcium hydrogen 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 10-12, wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, dry starch and low-substituted hydroxypropyl cellulose, preferably, at least one selected from the group consisting of crospovidone, sodium carboxymethyl starch, and croscarmellose sodium, more preferably, croscarmellose sodium.

14. The method according to any one of claims 10-13, wherein the glidant is at least one selected from the group consisting of silica, talc, and micro powder silica gel, preferably, silica, more preferably, colloidal anhydrous silica.

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

16. A pharmaceutical composition of a compound of formula (I)comprising: the compound of formula (I) 1-7.5% silicified microcrystalline cellulose 80-92% magnesium stearate 0.5-2% croscarmellose sodium 3-7% colloidal anhydrous silica 0.5-2%.

17. A method of preparing the pharmaceutical composition according to claim 16, wherein the method comprises:1) screening the compound of formula (I), silicified microcrystalline cellulose, croscarmellose sodium, and colloidal anhydrous silica, and then blending the aforementioned components to form a first mixture;2) screening and adding magnesium stearate to the first mixture, and then blending to form a second mixture; and3) compressing the second mixture to obtain a tablet.

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