Pharmaceutical composition comprising a phthalazinone derivative

Abstract

The present invention relates to a stable pharmaceutical composition comprising a phthalazinone derivative having excellent activity as a poly(ADP-ribose) polymerase inhibitor.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. nonprovisional patent application No. 17 / 072,233, filed October 16, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a stability-improved pharmaceutical composition comprising a phthalazinone derivative that inhibits the activity of poly(ADP-ribose) polymerase. Background Technology

[0004] Due to the physical and chemical properties of the active pharmaceutical ingredient (API), it can interact with excipients commonly used in pharmaceutical active ingredients, making certain pharmaceutical compositions difficult to prepare and maintain stability. Furthermore, it is important to maintain the stability and efficacy of the pharmaceutical composition throughout its intended shelf life, such as the total expected time of preparation, distribution, storage, and administration to patients.

[0005] U.S. Patent 9,682,973 discloses an inhibitor of poly(ADP-ribose) polymerase ("PARP") with antitumor activity, wherein the PARP inhibitor is characterized by Formula I or a pharmaceutically acceptable salt thereof. Formula I is characterized according to the International Union of Pure and Applied Chemistry (IUPAC) nomenclature as 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorophenyl]phthalazine-1(2H)-one. In particular, the hydrochloride salt of the compound of Formula I is one of the promising candidates for antitumor agents.

[0006] [Formula I]

[0007]

[0008] However, in the development of pharmaceutical compositions comprising a pharmaceutical active ingredient of Formula I or a salt thereof, it has been found that certain compositions using common excipients have lower stability. Summary of the Invention

[0009] The present invention provides a stable pharmaceutical composition comprising the pharmaceutically active ingredient of Formula I or a pharmaceutically acceptable salt thereof.

[0010] In one specific embodiment, the present invention provides a pharmaceutical composition comprising: a pharmaceutically active ingredient of formula I or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient, and having a pH of about 2.6 to about 6.74 when measured in a 1% (w / v) aqueous suspension.

[0011] [Formula I]

[0012]

[0013] The active pharmaceutical ingredient may be a hydrochloride salt of Formula I.

[0014] In another specific embodiment, the pharmaceutically acceptable excipient may be a diluent, binder, disintegrant, lubricant, or any combination thereof.

[0015] In some specific embodiments, the composition includes, by weight of about 40% to about 90% of a diluent; by weight of about 0.1% to about 30% of a binder; by weight of about 1% to about 40% of the disintegrant; and by weight of about 0.5% to about 40% of a lubricant.

[0016] In some specific embodiments, the diluent is selected from the group consisting of lactose hydrate, anhydrous lactose, mannitol, sorbitol, microcrystalline cellulose, dibasic calcium phosphate hydrate, or any combination thereof; the binder is selected from the group consisting of hydroxypropyl cellulose (HPC) and povidone, or any combination thereof; the disintegrant is selected from the group consisting of carmellose, crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethyl cellulose (CMC), CMC-Ca, low-substituted hydroxypropyl cellulose, corn starch, and polacrilin potassium, or any combination thereof; and the lubricant is selected from the group consisting of colloidal silica, magnesium stearate, sodium stearyl fumarate, talc, stearic acid, or any combination thereof.

[0017] The present invention further provides a solid oral administration form comprising: a compound of formula I.

[0018] Or a pharmaceutically acceptable salt thereof; and at least one excipient selected from the group consisting of diluents, binders, disintegrants, lubricants, and any combination thereof.

[0019] Additionally, a stable solid oral administration formulation is provided, comprising: a pharmaceutically acceptable excipient; and a compound of formula I.

[0020]

[0021] Or a pharmaceutically acceptable salt thereof, and when stored at 20°C and 75% relative humidity for at least one month, retaining at least 99% by weight of the compound of formula I.

[0022] In one specific embodiment, the solid oral administration form is a tablet.

[0023] In some specific embodiments, the solid oral administration form comprises, by weight of the total composition, about 40% to about 90% of a diluent; by weight of the total composition, about 0.1% to about 30% of a binder; by weight of the total composition, about 1% to about 40% of the disintegrant; and by weight of the total composition, about 0.5% to about 40% of a lubricant.

[0024] In one specific embodiment, the present invention provides a method for preparing a pharmaceutical composition having a pH of about 2.6 to about 6.74 when measured in a 1% w / v aqueous suspension, comprising: (a) mixing a compound of formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient to obtain a blend.

[0025] [Formula I]

[0026] and (b) direct compression of the mixture.

[0027] In one specific embodiment, the present invention provides a product obtained by the method described in this specification. Detailed Implementation

[0028] The present invention provides a pharmaceutical composition comprising: a pharmaceutically active ingredient of formula I or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient, and having a pH of about 2.6 to about 6.74 when measured in a 1% w / v aqueous suspension.

[0029] [Formula I]

[0030]

[0031] As provided in more detail in the examples, experimental results show that when the pH of a composition comprising a pharmaceutically active ingredient of Formula I or a pharmaceutically acceptable salt thereof is adjusted to a predetermined range, the amount of decomposition of the active ingredient of Formula I is significantly lower during long-term storage. The resulting pharmaceutical composition exhibits improved stability during the intended normal storage period of the composition.

[0032] The pH of the pharmaceutical composition was measured by preparing an aqueous suspension of the composition in a 1% w / v (weight / volume) aqueous suspension prepared at room temperature according to Experimental Example 1. Methods for measuring pH are known to those skilled in the art of pharmaceutical compositions. For example, the pH of the test substance can be measured by dissolving the substance in water at a concentration of 1% w / v to obtain an aqueous suspension prepared according to Experimental Example 1, and then measuring the suspension. Standard techniques can be used to determine the pH value.

[0033] The pharmaceutical compositions of the present invention may have a pH of about 2.6 to about 6.74, preferably about 2.9 to about 6.5, and more preferably about 2.95 to about 4.95. In some specific embodiments, when an aqueous suspension of the composition is prepared and measured in a 1% w / v (weight / volume) aqueous suspension, the pH of the pharmaceutical composition is about 2 to about 8 (e.g., about 2 to about 7.5, about 2 to about 7, about 2 to about 6.5, about 2 to 6, about 2 to about 5.5, about 2 to about 5, about 2 to about 4.5, about 2.5 to about 7.5, about 2.5 to about 7, about 2.5 to about 6.5, about 2.5 to about 6, about 2.5 to about 5.5, about 2.5 to about 5, about 2.5 to about 4.5), or any specific value within the range. In some specific embodiments, when an aqueous suspension of the composition is prepared and measured in a 1% w / v (weight / volume) aqueous suspension, the pH of the pharmaceutical composition is preferably from about 3 to about 8 (e.g., from about 3 to about 7.5, between about 3 and about 7, about 3 to about 6.5, about 3 to about 6, about 3 to about 5.5, or about 3 to about 5). The pharmaceutical compositions of the present invention can have any pH within the aforementioned specific range, i.e., pH values ​​without the prefix "about".

[0034] I. Definition

[0035] The term "the active pharmaceutical ingredient of Formula I" may also be referred to as "compound 1" or "this compound". Similarly, "a salt of the active pharmaceutical ingredient of Formula I" may also be referred to as "a salt of compound 1" or "a salt of this compound". For example, an active pharmaceutical ingredient of Formula I in hydrochloride form may be referred to as "the hydrochloride salt of compound 1" or "the hydrochloride salt of this compound".

[0036] In this specification, a "pharmaceutically acceptable salt" may be prepared by any suitable method available in the art, for example, by treating the pharmaceutically active ingredient of Formula I in its free base form with an inorganic acid. Examples of effective inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc., or include organic acids such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, glucuronic acid or galacturonic acid and other pyranoside acids, α-hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, etc. Most preferably is the hydrochloride salt of the pharmaceutically active ingredient of Formula I.

[0037] In this specification, "pharmaceuticalally acceptable carrier" refers to a non-toxic carrier, excipient, or loading agent that does not impair the pharmacological activity of the formulated compound. Pharmaceutically acceptable carriers, excipients, or loading agents that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, buffers (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0038] In this specification, the terms "stable" and "stable" mean that the pharmaceutical composition is stable to, for example, heat, light, temperature, and / or humidity. For example, a pharmaceutical composition is stable when the amount of total impurities included in the pharmaceutical composition of the present invention or the amount of M1 impurities of the active ingredient ("M1 impurities") is a specific percentage or lower after the pharmaceutical composition has been stored under specific conditions. M1 impurities are any inactive form of the active ingredient, such as synthetic intermediates, metabolic intermediates, byproducts, or degradation products of the active ingredient.

[0039] Total impurities, as measured by HPLC, can be defined as having a relative retention time (RRT) of about 0.11 to 2.10 relative to the peak of compound 1, more specifically, about 0.90, about 1.12, about 1.35, or about 1.38. Impurity M1 can be defined as having an RRT of about 0.90 relative to the peak of compound 1. As is known in the art, HPLC RRT values ​​can have an experimental error of ±10% of the displayed value. In conclusion, the values ​​described above should be interpreted in light of experimental error.

[0040] In this specification, the term "subject" intended for application includes, but is not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)). In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. In this specification, the terms "person," "patient," and "subject" are used interchangeably.

[0041] In this specification, the terms “cured,” “therapeutic,” and “treatment” refer to actions that reduce symptoms, severity of impairment, or progression of a condition, disorder, or state that occur in a subject, or delay the progression of the condition, disorder, or state (“therapeutic treatment”), or actions that occur before a subject suffers from a particular disease, disorder, or state (“preventive treatment”), unless otherwise stated.

[0042] In this specification, a "therapeuticly effective amount" of a compound means an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize at least one symptom of the disease, disorder, or condition, unless otherwise stated. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall therapy, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic efficacy of other therapeutic agents.

[0043] In this specification, the term "about" will be understood by those skilled in the art and varies depending on the context in which it is used. When a term is unclear to those skilled in the art, "about" means a maximum of ±10% of the specific term, taking into account the context in which it is used. For pH values, the term "about" means a maximum of ±0.5% of the pH value.

[0044] In this specification, "analysis" refers to a specific stability representation procedure for determining the content of a pharmaceutical substance. For example, an analysis may include chromatographic methods (e.g., HPLC) using reference standards.

[0045] In this specification, "crystal" refers to a solid with a highly regular chemical structure, that is, a solid with a long-range structural order in a crystal lattice. Molecules are arranged in a regular, periodic manner in the three-dimensional space of the crystal lattice. In particular, crystalline forms can be generated in one or more single-crystal forms.

[0046] In this specification, "excipient" means a pharmaceutically acceptable inactive ingredient commonly used in the preparation of pharmaceutical formulations. Examples of suitable excipients can be found in Sheskey et al., Handbook of Pharmaceutical Excipients, 8th Edition, written (Pharmaceutical Press 2017), which is incorporated herein by reference in its entirety. Excipients can be classified according to their functional properties as, for example, diluents, binders, disintegrants, superdisintegrants, lubricants, pH controllers, glidants, fillers, stabilizers, antioxidants, and film-coating agents. However, as is known in the art, a particular excipient can be classified into at least one of the functional groups listed above, depending on the time and manner of use. For example, an excipient may be classified as a disintegrant in one formulation and as a binder in another. In some cases, a particular excipient may be multifunctional, i.e., classified into one or more functional groups in the same formulation. The considerations that are typically required when formulating and / or preparing pharmaceutical compositions are described, for example, in Remington's Pharmaceutical Sciences, 16th edition, EW Martin (Mack Publishing Co., Easton, PA, 1980) and Remington: The Science and Practice of Pharmacy, 21st edition (Lippincott Williams & Wilkins, 2005), which are incorporated herein by reference in their entirety.

[0047] In this specification, "binder" refers to an excipient that imparts enhanced cohesiveness or tensile strength (e.g., hardness) to a pharmaceutical composition. Examples of binders include dicalcium phosphate, sucrose, corn starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose).

[0048] In this specification, "diluent" refers to an excipient that increases the volume of a pharmaceutical composition. Examples of diluents include lactose, sorbitol, cellulose, calcium phosphate, starch, sugars (e.g., mannitol, sucrose, etc.) or any combination thereof.

[0049] In this specification, "disintegrant" refers to an excipient that hydrates the pharmaceutical composition and facilitates tablet dispersion. Examples of disintegrants include croscarmellose sodium and / or starch glycolate sodium.

[0050] In this specification, "lubricant" refers to an excipient added to a pharmaceutical composition compressed into tablets. The lubricant facilitates the expulsion of the tablet composition from the molding machine after the granules are compressed into tablets. Examples of lubricants include magnesium stearate, stearic acid (stear), hydrogenated oil, sodium stearate fumarate, or any combination thereof.

[0051] II. Compounds

[0052] This specification describes pharmaceutical compositions comprising compounds that help with diseases, disorders, or conditions, such as those that can be used to prevent and / or treat cancer-related diseases, disorders, or conditions.

[0053] On one hand, the present invention relates to a pharmaceutical composition comprising: formula I

[0054]

[0055] Or a pharmaceutically acceptable salt.

[0056] Formula I or a pharmaceutically acceptable salt thereof is described in U.S. Patent No. 9,682,973, which is incorporated herein by reference.

[0057] The crystalline form of the phthalazinone compound is also disclosed in U.S. Patent Application 16 / 858,158, filed April 2, 2020, which is incorporated herein by reference in its entirety.

[0058] In some specific embodiments, the hydrochloride of Formula I is in a crystalline form (hereinafter referred to as "crystalline form A"), and its X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles of 2θ ± 0.2° at 13.7°, 15.9°, and 24.1°. In some specific embodiments, crystalline form A may exhibit an XRPD pattern including three or more, preferably four or more, peaks at 2θ ± 0.2° values ​​selected from the group consisting of 9.1°, 11.9°, 13.2°, 13.7°, 15.9°, 16.8°, 18.1°, 23.2°, 24.1°, 25.5°, and 26.6°. In particular, crystalline form A may exhibit an XRPD pattern including peaks at 2θ ± 0.2° values ​​at 9.1°, 13.2°, 13.7°, 15.9°, 16.8°, 24.1°, and 26.6°. More specifically, crystalline morphology A can exhibit an XRPD pattern comprising peaks selected at 2θ ± 0.2° values ​​of 9.1°, 11.9°, 13.2°, 13.7°, 15.9°, 16.8°, 18.1°, 23.2°, 24.1°, 25.5°, and 26.6°. The XRPD pattern can be obtained by any method known to those skilled in the art, including irradiation with a Cu-Kα light source, for example, with a D8 Advance (Bruker ASX, Germany) analyzer. The Cu-Kα light source can have… The wavelength.

[0059] III. Application Form and Composition

[0060] On the one hand, this disclosure is characterized by its ability to be used in the form or composition of an application for the prevention and / or treatment of diseases, disorders or conditions, such as cancer, as described in this invention.

[0061] This invention provides a pharmaceutical composition comprising a compound described herein (e.g., compound 1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, said excipient including but not limited to carriers, diluents, binders, disintegrants, and lubricants. The pharmaceutical composition may be administered alone or in combination with other therapeutic agents.

[0062] Based on the total weight of the composition, the pharmaceutical composition of the present invention may comprise from about 0.1% to about 70% by weight, preferably from about 1% to 40% by weight, of compound 1 or a pharmaceutically acceptable salt thereof. In total, the pharmaceutical composition of the present invention comprises from about 1 mg to about 400 mg, preferably from about 10 mg to about 240 mg, per unit dose, of compound 1 or a pharmaceutically acceptable salt thereof. Other specific embodiments of the pharmaceutical composition include 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, or 240 mg of compound 1 or a pharmaceutically acceptable salt thereof. The above amounts are based on the free base of compound 1.

[0063] In one specific embodiment, the composition of the present invention, after stability testing, has a preferred threshold of total impurities in the pharmaceutical composition. After storing the pharmaceutical composition of the present invention at a temperature of 25°C to 70°C (e.g., 25°C, 40°C, 50°C, 60°C, or 70°C) and a relative humidity (RH) of 60% to 75% (e.g., 60% or 75%) for about 1 week to 12 months (e.g., 1 week, 2 weeks, 4 weeks, 1 month, 3 months, 6 months, or 12 months), the total impurity content of the pharmaceutical composition, measured by HPLC, is less than or equal to 1.50% by weight of the pharmaceutical composition, preferably less than or equal to 1.0%, more preferably less than or equal to 0.80%, and more preferably less than or equal to 0.40%. For example, after storing the composition of the present invention at 50°C and 75% relative humidity for 1 month, the total impurity content of the active ingredient may be less than or equal to 1.0%.

[0064] In another specific embodiment, the compositions of the present invention, after stability testing, have a preferred threshold level of M1 impurity in the pharmaceutical composition. After storing the pharmaceutical compositions of the present invention at a temperature of 25°C to 70°C (e.g., 25°C, 40°C, 50°C, 60°C, or 70°C) and a relative humidity (RH) of 60% to 75% (e.g., 60% or 75%) for about 1 week to 12 months (e.g., 1 week, 2 weeks, 4 weeks, 1 month, 3 months, 6 months, or 12 months), the M1 impurity content of the active ingredient, as measured by HPLC, is less than or equal to 0.50%, preferably less than or equal to 0.4%, and more preferably less than or equal to 0.20% by weight of the pharmaceutical composition. For example, after storing the compositions of the present invention at 50°C and 75% relative humidity for 1 month, the M1 impurity content of the active ingredient may be less than or equal to 0.50%.

[0065] The pharmaceutical compositions of this invention contain at least one pharmaceutically acceptable excipient. The type and amount of excipient can be suitably selected such that the pharmaceutical compositions of this invention satisfy a pH of about 2.6 to about 6.74 as measured in a 1% w / v aqueous suspension prepared according to Experimental Example 1. Furthermore, the excipient can improve the processing characteristics of the formulation, such as flowability and / or aggregation, to allow for better compression of the pharmaceutical composition. Moreover, it is preferable to select the excipient by taking into account the elution rate of the pharmaceutical composition.

[0066] In one specific embodiment, the pharmaceutical composition of the present invention includes a diluent, a binder, a disintegrant, a lubricant, or any combination thereof.

[0067] The diluent may include, but is not limited to, the following substances: lactose, such as anhydrous lactose or lactose hydrate (e.g., Flowlac 100); microcrystalline cellulose (e.g., Avicel pH-101 or Pharmacel 101); dicalcium phosphate hydrate (e.g., carboxymethyl cellulose, EMCOMPRESS); mannitol such as D-mannitol (e.g., Mannogem EZ); sorbitol such as D-sorbitol (e.g., XTAB 200S); refined sugars such as compressible sugars, glucose dextrin, or dextrin; pulverized cellulose; or any combination thereof. Preferably, the diluent of the present invention may be lactose hydrate, anhydrous lactose, mannitol, sorbitol, microcrystalline cellulose, dicalcium phosphate hydrate, or any combination thereof; more preferably, lactose hydrate, mannitol, sorbitol, microcrystalline cellulose, or any combination thereof; and most preferably, lactose hydrate, microcrystalline cellulose, or any combination thereof.

[0068] In some embodiments, the diluent is lactose hydrate. In some embodiments, the diluent is anhydrous lactose. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is calcium hydrogen phosphate hydrate. In some embodiments, the diluent is mannitol. In some embodiments, the diluent is sorbitol. In some embodiments, the diluent is refined sugar. In some embodiments, the diluent is pulverized cellulose.

[0069] Based on the total weight of the composition, the content of the diluent can be from about 40% to about 90% by weight, preferably from about 70% to about 90% by weight.

[0070] The adhesive may include, but is not limited to, the following substances: hydroxypropyl cellulose (e.g., HPC-L or HPC-EXF), povidone (e.g., K-30); hydroxyethyl cellulose; hydroxypropyl methylcellulose (e.g., METHOCEL); sucrose; glucose; corn syrup; polysaccharides; or any combination thereof. Preferably, the adhesive of the present invention may be hydroxypropyl cellulose, povidone, or any combination thereof, and more preferably, it may be hydroxypropyl cellulose.

[0071] In some embodiments, the binder is hydroxypropyl cellulose. In some embodiments, the binder is povidone. In some embodiments, the binder is hydroxyethyl cellulose. In some embodiments, the binder is sucrose. In some embodiments, the binder is dextrose. In some embodiments, the binder is corn syrup. In some embodiments, the binder is a polysaccharide.

[0072] Based on the total weight of the composition, the content of the adhesive can be from about 0.1% by weight to about 30% by weight, preferably from about 0.5% by weight to about 20% by weight.

[0073] The disintegrant may include, but is not limited to, the following substances: carboxymethyl cellulose (CMC; also known as carboxymethyl cellulose, e.g., NS-300); calcium carboxymethyl cellulose (CMC-Ca); sodium carboxymethyl cellulose (CMC-Na); low-substituted hydroxypropyl cellulose (e.g., LH-11, LH-21, LH-31 grades with 11% hydroxypropyl ester content); corn starch; potassium polycrylamide; pregelatinized starch; clay; sodium alginate; gum or any combination thereof. Preferably, the disintegrant of the present invention may be CMC, CMC-Ca, CMC-Na, low-substituted hydroxypropyl cellulose, corn starch, potassium polycrylamide, or any combination thereof; more preferably, it may be CMC.

[0074] In some embodiments, the disintegrant is carboxymethyl cellulose. In some embodiments, the disintegrant is calcium carboxymethyl cellulose. In some embodiments, the disintegrant is sodium carboxymethyl cellulose. In some embodiments, the disintegrant is low-substituted hydroxypropyl cellulose. In some embodiments, the disintegrant is corn starch. In some embodiments, the disintegrant is potassium polycrylene. In some embodiments, the disintegrant is pregelatinized starch. In some embodiments, the disintegrant is clay. In some embodiments, the disintegrant is sodium alginate. In some embodiments, the disintegrant is gum.

[0075] Based on the total weight of the composition, the content of the disintegrant can be from about 1% to about 40% by weight, preferably from about 3% to about 20% by weight.

[0076] The lubricant may include, but is not limited to, the following substances: colloidal silica; talc; stearic acid; magnesium stearate; calcium stearate; sodium stearate fumarate (e.g., Pruv); or any combination thereof. Preferably, the lubricant of the present invention may be colloidal silica, magnesium stearate, sodium stearate fumarate, talc, stearic acid, or any combination thereof; more preferably, it may be colloidal silica, magnesium stearate, or any combination thereof.

[0077] In some embodiments, the lubricant is colloidal silica. In some embodiments, the lubricant is talc. In some embodiments, the lubricant is stearic acid, magnesium stearate, or calcium stearate. In some embodiments, the lubricant is sodium stearate fumarate.

[0078] Based on the total weight of the composition, the content of the lubricant can be from about 0.5% by weight to about 40% by weight, preferably from about 1% by weight to about 20% by weight.

[0079] In another specific embodiment, the pharmaceutical composition of the present invention may further include a pH control agent. When the pH of the pharmaceutical composition in the 1% w / v aqueous suspension prepared according to Experimental Example 1 is in the range of about 2.6 to 6.74 without a pH control agent, no additional pH control agent is required. When the pH of the pharmaceutical composition is outside the range without a pH control agent, a pH control agent may be appropriately added to adjust the pH of the pharmaceutical composition to the pH range. In an exemplary specific embodiment, when the pharmaceutical composition includes CMC as a disintegrant (sample 2), the pH of the 1% w / v aqueous suspension prepared according to Experimental Example 1 is about 4.3, indicating that no additional pH control agent is required. On the other hand, when the pharmaceutical composition includes potassium polycrylene as a disintegrant, the pH is about 7.97 and becomes unstable due to increased impurity content (sample 9). In this case, an additional pH control agent is required to bring it into the desired pH range. When CMC-Na is used (sample 11), the impurity content also increases, and an additional pH control agent may be used to improve the stability of the pharmaceutical composition.

[0080] As long as the desired pH range is achieved, any combination of pH control agents or pH agonists known in the field can be used.

[0081] In a preferred embodiment, the pH control agent used in this invention may be a pH control agent having a pH of about 1 to about 5, preferably about 1.5 to about 3, and more preferably about 2 to about 2.5. The pH of the pH control agent is defined as the pH of the solution or suspension obtained when the pH control agent is dissolved or suspended in water at a concentration of 1% w / v.

[0082] The pH control agent may include, but is not limited to, the following substances: tartaric acid, citric acid, lactic acid, fumaric acid, maleic acid, ascorbic acid, acetic acid, or acidic amino acids (e.g., glutamic acid or aspartic acid); inorganic salts of acidic substances (e.g., alkali metal salts, alkaline earth metal salts, ammonium, etc.); salts of acidic substances with organic bases (e.g., basic amino acids such as lysine, arginine, and meglumine); and their hydrates, solvates, or any combination thereof. Preferably, the pH control agent may be citric acid, fumaric acid, maleic acid, or any combination thereof.

[0083] Based on the total weight of the composition, the content of the pH control agent can be from about 0.01% by weight to about 20% by weight, preferably from about 0.05% by weight to about 10% by weight.

[0084] In another specific embodiment, the pharmaceutical composition of the present invention may further include a superdisintegrant. The superdisintegrant may include, but is not limited to, the following substances: crospovidone; crospovidone sodium carboxymethyl cellulose; sodium starch glycolate; natural, modified, or pregelatinized starch; effervescent disintegration systems; or any combination thereof. Preferably, the superdisintegrant may be crospovidone, crospovidone sodium carboxymethyl cellulose, sodium starch glycolate, or any combination thereof.

[0085] In some embodiments, the superdisintegrant is crospovidone. In some embodiments, the superdisintegrant is crospovidone sodium carboxymethyl cellulose. In some embodiments, the superdisintegrant is sodium starch glycolate. In some embodiments, the superdisintegrant is natural, modified, or pregelatinized starch. In some embodiments, the superdisintegrant is an effervescent disintegration system.

[0086] Based on the total weight of the composition, the content of the superdisintegrant can be from about 0.01% by weight to about 20% by weight, preferably from about 1% by weight to about 10% by weight, and more preferably from about 1% by weight to about 5% by weight.

[0087] The functions or roles of the exemplary excipients described above are not absolute, but in some cases an excipient may have at least two functions. For example, a partially disintegrant can also act as a binder and a filler. The various functions or roles of excipients can be determined as is known in the art.

[0088] Oral administration is the route of administration for the compounds according to the present invention. Administration can be by means of capsules or tablets, etc. In preparing the pharmaceutical composition comprising at least one compound of this specification, the active ingredient is typically diluted with an excipient and / or encapsulated in a carrier, which may be in the form of capsules, sachets, paper, or other containers. When the excipient acts as a diluent, it may be in the form of a solid, semi-solid, or liquid material (as described above) acting as a carrier, transporter, or medium for the active ingredient. Therefore, the composition may be in the form of tablets, pills, powders, lozenges, sachets, tablets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), for example, ointments containing up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions, and sterile encapsulated powders.

[0089] The pharmaceutical composition of the present invention can be in the form of solid oral administration, such as tablets, granules, microparticles, capsules, or pills, or in the form of solid dosage forms. Solid dosage forms are preferably tablets, for example, tablets coated with a film-coating agent. In some specific embodiments, the pharmaceutical composition can be formulated into tablets. In some specific embodiments, tablets comprising the pharmaceutical composition as described in this specification can be coated with a film-coating agent. In some specific embodiments, tablets comprising the pharmaceutical composition as described in this specification can be coated with an enteric coating agent.

[0090] Tablets containing the pharmaceutical compositions described in this invention can also be film-coated. For example, the film can be used for enteric coating. In some specific embodiments, the film comprises a cellulose polymer (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, or any combination thereof). An exemplary film-coating agent may be an opadry comprising hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), for example... White 03B28796.

[0091] IV. Preparation Method

[0092] The pharmaceutical composition of the present invention can be prepared by any known method or process, such as grinding, mixing or blending, granulation, drying, molding (tableting), film coating, crystallization, etc.

[0093] As described above, the present invention provides a method for preparing a pharmaceutical composition having a pH of about 2.6 to about 6.74 when measured in a 1% w / v aqueous suspension, comprising:

[0094] (a) A mixture is obtained by mixing a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient and at least one pharmaceutically acceptable excipient;

[0095] [Formula I]

[0096]

[0097] (b) Directly compress the mixture.

[0098] In one embodiment, the present invention provides a direct compression method for preparing a pharmaceutical composition, comprising:

[0099] (a) Pre-blending the active ingredient with some or most of the excipients in a mixer to obtain a premix;

[0100] (b) Optionally, the premixture may be dry-sieved to separate aggregated particles and improve content consistency;

[0101] (c) The premix from step (a) or (b) and the remaining excipients are mixed in a mixer to obtain the final mixture;

[0102] (d) Compressing and tableting the final mixture from step (c) in a tablet press to prepare a tablet core; and

[0103] (e) Optionally, the core from step (d) is coated with a film.

[0104] According to one specific embodiment, the active ingredient, diluent, binder, disintegrant, and lubricant are premixed in a diffusion mixer, sieved in a hand sieve or sieve mill, and then premixed again in a diffusion mixer to prepare a mixed intermediate composition. An additional lubricant is sieved separately in a hand sieve or sieve mill and then mixed with the mixed intermediate in the diffusion mixer to prepare a mixture. The mixture is directly compressed using a rotary tablet press to obtain tablets (plain tablets), and then a film-coating agent is added to prepare film-coated tablets.

[0105] The particles of the pharmaceutical composition according to the present invention can be prepared by any method known to those skilled in the art. Preferred methods for granulating the active ingredient together with the excipient include wet granulation such as high-shear wet granulation or fluidized bed wet granulation, as well as dry granulation, also known as rolling.

[0106] In the wet granulation process, the granulation liquid is a formulation of one or more binders in a solvent, solvent, or solvent mixture. Suitable binders are as described above. Examples include hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and copovidone. Suitable solvents include, for example, purified water, ethanol, methanol, isopropanol, acetone, preferably purified water, including mixtures thereof. The solvent is a volatile component that will not remain in the final product. One or more active ingredients and other excipients, particularly one or more diluents and one or more disintegrants, typically excluding lubricants, are premixed with the granulation liquid and granulated, for example using a high-shear granulator. The wet granulation step is typically followed by at least one drying and sieving step. For example, a drying oven or fluidized bed dryer may be used for drying.

[0107] The dried particles are sieved through a suitable sieve. After selectively adding other excipients, particularly disintegrants, binders, fillers and / or lubricants, the mixture is blended through a suitable mixer (e.g., a free-fall mixer), and a final mixing is carried out in the mixer after adding one or more lubricants (e.g., magnesium stearate).

[0108] In a specific embodiment, the present invention provides a wet granulation method for preparing a pharmaceutical composition, comprising:

[0109] (a) Premixing an excipient comprising part or most of the active ingredient and binder in a mixer to obtain a premix;

[0110] (b) The premixture of step (a) is granulated by adding a granulation liquid (preferably purified water);

[0111] (c) Dry the particles from step (b) in a fluidized bed dryer or drying oven;

[0112] (d) Optionally, the dried particles from step (c) are dry-sieved;

[0113] (e) The dried particles, lubricant, flow aid and other excipients from step (d) are mixed in a mixer to obtain the final mixture;

[0114] (f) The final mixture from step (e) is compressed in a suitable tablet press to produce a tablet core; and

[0115] (g) Optionally, the core from step (f) may be coated with a film.

[0116] In another specific embodiment, the present invention provides a dry granulation method for preparing a pharmaceutical composition, comprising:

[0117] (a) Mixing the active ingredient with all or part of the excipients in a mixer;

[0118] (b) Compressing the mixture from step (a) in a suitable roller press;

[0119] (c) The strip obtained in step (b) is converted into granules, preferably small granules, by appropriate grinding or sieving steps;

[0120] (d) Optionally, the particles from step (c) are mixed with the remaining excipients in a mixer to obtain a final mixture;

[0121] (e) Compressing the particles of step (c) or the final mixture of step (d) using a suitable tablet press to produce a tablet core; and

[0122] (f) Optionally, the core from step (e) may be coated with a film.

[0123] In addition, the present invention provides a pharmaceutical composition such as a tablet, which can be obtained by the following method.

[0124] Granules and microgranules can be prepared by granulation using the same methods as those used for tablets (e.g., wet or dry granulation). Alternatively, they can be prepared by spraying a coating solution comprising the active ingredient and excipients, particularly binders such as sucrose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, onto sugar spheres to form coated spheres. As described above, the granules can be wet or dry granules.

[0125] Capsules are prepared by filling capsules made of gelatin such as hydroxypropyl methylcellulose with granules or microparticles, or by filling capsules made of gelatin such as hydroxypropyl methylcellulose with active ingredients and excipients (e.g., lactose, sucrose, glucose, starch, sugars, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate, etc.).

[0126] V. Use and Treatment Methods

[0127] A feature of this invention relates to a pharmaceutical composition that is effective as a therapeutic agent for diseases improved by PARP inhibition or for cancers caused by genetic defects in BRCA1, BRCA2, and ERG fusion genes. In some specific embodiments, the pharmaceutical compositions comprising Formula I, as provided in this disclosure, are effective against cancers such as gastric cancer, ovarian cancer, and breast cancer. Other specific embodiments of methods using the compositions described in this invention are disclosed in U.S. Patent No. 9,682,973, which is incorporated herein by reference in its entirety.

[0128] The present invention will be further described in detail below through embodiments. However, the embodiments are used to illustrate the present invention and are not intended to limit the present invention.

[0129] Example

[0130] The following embodiments are provided to enable a more complete understanding of the invention described in this specification. The embodiments described in this application are used to illustrate the features of the invention and the implementation methods provided in this specification, and should not be construed as limiting its scope in any way.

[0131] Abbreviations

[0132] BRT is below the reporting threshold.

[0133] CMC (carboxymethyl cellulose)

[0134] CMC-Ca Carboxymethyl Cellulose Calcium

[0135] HDPE (high density polyethylene)

[0136] HPLC (High Performance Liquid Chromatography)

[0137] HPC Hydroxypropyl Cellulose

[0138] ND is not determined.

[0139] RH (Relative Humidity)

[0140] UV ultraviolet rays

[0141] Experimental Example 1: Stability of tablets from samples 1 to 9 relative to different pH values

[0142] The hydrochloride salt and excipients of this compound were mixed according to the formulation in Table 1 below and then compressed to prepare uncoated tablets. Each tablet was placed in triple-distilled water to achieve a tablet concentration of 1% w / v (weight / volume) and stirred at 1200 rpm for 5 minutes at room temperature using a magnetic stir bar to form an aqueous suspension (referred to as the "1% w / v aqueous suspension"). After the suspension was allowed to stand for 5 minutes, the pH of the suspension was measured at room temperature using a Mettler Toledo S20 SevenEasy pH meter. The pH of each tablet prepared from samples 1 to 9 was measured, and the results are shown in Table 1 below.

[0143] In addition, the stability of the tablets prepared in Examples 1 to 9 was evaluated. Each tablet was stored for 2 and 4 weeks in HDPE bottles sealed with a desiccant (silica gel) at 50°C and 75% RH (relative humidity). The M1 impurity content (%) and total impurity content (%) of each tablet were then determined by HPLC.

[0144] HPLC analysis was performed using a C18 column (4.6 mm × 15 cm; 5 μm) on a detector with UVmax set to or close to 280 nm. The mobile phase was a mixture of purified water and formic acid or a mixture of methanol and formic acid. The M1 impurity content (%) and total impurity content (%) were analyzed at the initial date (0 days), 2 weeks, and 4 weeks. The impurity content (%) was calculated as follows.

[0145] M1 impurity content (%) = (peak area of ​​M1 impurity in the sample / total peak area of ​​the sample) × 100

[0146] Total impurity content (%) = (sum of peak areas of all impurities in the sample / total peak area of ​​the sample) × 100

[0147] The results are shown in Table 1 below.

[0148] [Table 1]

[0149]

[0150]

[0151] ※ND: Not confirmed

[0152] The pharmaceutical compositions (samples 1 to 8) containing the hydrochloride salt of this compound at pH values ​​from about pH 2.6 to pH 6.48 have demonstrated significant stability with low impurity content after prolonged storage. They are particularly stable near pH 3.0 (samples 3 and 7). Conversely, when the pH is greater than 7.0, impurities increase sharply, and stability decreases (sample 9).

[0153] Therefore, the compounds of the present invention are confirmed to be stable in the pH range of 2.6 to 6.48.

[0154] Experimental Example 2: Stability of tablets of samples 2, 10 to 21 relative to different excipients

[0155] Based on the preparation method described in samples 1 to 9, the hydrochloride salt of this compound and each additive were mixed according to the formulations in Tables 2 and 3 below and then compressed into tablets to prepare unprocessed tablets.

[0156] The pH of each tablet prepared in samples 2, 10 to 21 was measured in the same manner as in Experimental Example 1, and the results are shown in Tables 2 and 3 below.

[0157] Stability evaluations were performed on tablets prepared from samples 2, 10 to 21 containing other excipients. After storage at 50°C and 75% RH for one week in the unsealed state, the impurity (M1) content (%) in each tablet was measured by HPLC according to the method described in Experimental Example 1. The results are shown in Tables 2 and 3.

[0158] Samples 2, 10 to 17

[0159] [Table 2]

[0160]

[0161]

[0162] ※BRT (below reporting threshold)

[0163] The above results confirm that tablets of samples 2, 10, 12 to 17 exhibited excellent stability, while tablet of sample 11 showed low stability. In sample 11, CMC-Na was used as a disintegrant, which was determined to increase the overall pH of the tablet, thereby reducing the stability of the active ingredient.

[0164] Samples 18 to 21

[0165] [Table 3]

[0166]

[0167]

[0168] ※ND: Not confirmed

[0169] Sample 21 provided the best stability results. The stability of samples 18 to 20 was lower than that of sample 21 due to the increased M1 impurity; however, samples 18 to 19 (and 21) still showed less than 0.50% of M1 impurity, which was below the desired level. Sample 20 was an exception.

[0170] Experimental Example 3: Stability of tablets of samples 22 to 33 relative to various excipients

[0171] Based on the preparation methods described in samples 1 to 9, the hydrochloride salt of this compound and each additive were mixed according to the formulation in Table 4 below and then compressed into tablets to prepare unprocessed tablets.

[0172] The pH of each tablet prepared in samples 22 and 33 was measured in the same manner as in Experimental Example 1, and the results are shown in Table 4 below.

[0173] Stability evaluations were performed on tablets prepared from samples 22 to 33 containing different excipients. After storage in a closed state at 50°C for 2 and 4 weeks without adjusting the RH of each tablet, the M1 impurity content (%) and total impurity content (%) of each tablet were determined according to the HP LC method described in Experimental Example 1. The results are shown in Table 4 below.

[0174] [Table 4]

[0175]

[0176]

[0177] ※ND: Not confirmed

[0178] The above results confirm the improved stability of the compositions of the present invention at pH values ​​ranging from 2.8 to 6.55. In fact, all samples except sample 28 were stable. In particular, samples 23, 25, 27, 29, 31, and 33, whose pH was adjusted to approximately 3 using a pH control agent, exhibited significantly improved stability.

[0179] Experimental Example 4: Stability of film-coated sheets based on excipients, samples 34 to 36

[0180] Based on the preparation methods described in samples 1 to 9, the hydrochloride salt of this compound and each additive were mixed according to the formulations in Table 5 below and then compressed to prepare tablets (ordinary). Membrane coating was performed to prepare membrane-coated sheets of samples 34 to 36.

[0181] The stability of the tablets prepared in samples 34 to 36 was evaluated. Each tablet was encapsulated in Alu-Alu at 40°C and 75% RH and stored in a sealed state for 3 and 6 months. The M1 impurity content (%) and total impurity content (%) were measured by HPLC as described in Example 1. The results are shown in Table 5.

[0182] [Table 5]

[0183]

[0184]

[0185] The stability of the pharmaceutical composition comprising the active pharmaceutical ingredient of Formula I or a pharmaceutically acceptable salt thereof and a coating film of at least one pharmaceutically acceptable excipient was demonstrated when the pH of the composition was measured to be from about 2.6 to about 6.74 in a 1% w / v aqueous suspension prepared according to Experimental Example 1.

[0186] Equivalents and scope

[0187] In the claims, articles such as “a,” “an,” and “the” may indicate one or more, unless indicated to the contrary or clearly apparent from the context. The presence, use, or association with one, one, or all members of a product or method not explicitly shown is considered to satisfy a claim or description including “or” among one or more members of the group. This invention includes the presence, use, or other association with exactly one member of the group in a given product or method. This invention includes the presence, use, or other association with one or more or all members of the group in a given product or method.

[0188] Furthermore, this invention includes all variations, combinations, and arrangements of one or more of the listed claims that introduce one or more limitations, elements, clauses, and descriptive terms different from other claims. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where elements are presented in list form (e.g., in Markush group format), each subgroup of elements is also disclosed, and any element may be removed from the group. It should be understood that where a particular embodiment or aspect of the invention is generally described as including a specific element and / or feature, that particular embodiment or aspect of the invention is constituted by, or erroneously constituted by, such element and / or feature. For simplicity, such embodiments are not specifically described in this specification. Furthermore, it should be noted that the terms “comprising” and “containing” are intended to be open-ended and allow for the inclusion of additional elements or steps. The given scope includes endpoints. Furthermore, values ​​expressed as scopes may take any specific value or lower limit range up to one-tenth of the lower unit in other embodiments of the invention (scopes not explicitly indicated by the context), unless otherwise stated or clearly understood by one of the art from the context.

[0189] This application relates to various granted patents, published patent applications, journal articles, and other publications, which are incorporated herein by reference in their entirety. In the event of any conflict between any incorporated reference and this specification, this specification shall prevail. Furthermore, any particular embodiment of the invention falling within the scope of the prior art may be expressly excluded from any one or more claims. Because such embodiments are considered known to those skilled in the art, they may be excluded even if not expressly excluded in this specification. Any particular embodiment of the invention may be excluded from the claims for any reason, regardless of the presence or absence of prior art. [000110] Those skilled in the art can identify and confirm various equivalents of the particular embodiments described in this specification through conventional experiments. The scope of the particular embodiments described in this specification is not intended to be limited to the foregoing description, but rather depends on the appended claims. Those skilled in the art will understand that various changes and modifications may be made to this description without departing from the spirit or scope of the invention as defined by the appended claims.

Claims

1. A pharmaceutical composition comprising, as an active ingredient, a compound of the following Formula I or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient, wherein the composition has a pH of 2.8 to 6.55 when measured in a 1% w / v aqueous suspension, wherein the pharmaceutically acceptable excipient is a diluent, a binder, a disintegrant, a lubricant, a pH controlling agent, or any combination thereof, wherein the diluent is present in an amount of 40% to 90% by weight based on the total weight of the pharmaceutical composition; wherein the binder is present in an amount of 0.1% to 30% by weight based on the total weight of the pharmaceutical composition; wherein the disintegrant is present in an amount of 1% to 40% by weight based on the total weight of the pharmaceutical composition; wherein the lubricant is present in an amount of 0.5% to 40% by weight based on the total weight of the pharmaceutical composition; wherein the pH controlling agent is present in an amount of 0.01% to 20% by weight based on the total weight of the pharmaceutical composition; wherein the diluent is selected from the group consisting of lactose hydrate, lactose anhydrous, mannitol, sorbitol, microcrystalline cellulose, calcium hydrogen phosphate hydrate, or any combination thereof; wherein the binder is selected from the group consisting of hydroxypropyl cellulose and povidone, or any combination thereof; wherein the disintegrant is selected from the group consisting of carboxymethyl cellulose, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, corn starch, and potassium polyplasdone, or any combination thereof; wherein the lubricant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, stearic acid, or any combination thereof, and wherein the pH controlling agent is selected from the group consisting of citric acid, fumaric acid, maleic acid, or any combination thereof; [Formula I] 。 2. The pharmaceutical composition of claim 1, wherein the active ingredient is a hydrochloride salt of the compound of Formula I.

3. The pharmaceutical composition of claim 1, wherein the diluent is selected from the group consisting of lactose hydrate, lactose anhydrous, and microcrystalline cellulose.

4. The pharmaceutical composition of claim 1, wherein the diluent is lactose hydrate.

5. The pharmaceutical composition of claim 1, wherein the diluent is microcrystalline cellulose.

6. The pharmaceutical composition of claim 1, wherein the binder is hydroxypropyl cellulose.

7. The pharmaceutical composition of claim 1, wherein the binder is povidone.

8. The pharmaceutical composition of claim 1, wherein the disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, corn starch, potassium polyplasdone, and carboxymethyl cellulose.

9. The pharmaceutical composition of claim 1, wherein the disintegrant is carboxymethyl cellulose.

10. The pharmaceutical composition of claim 1, wherein the lubricant is selected from the group consisting of colloidal silicon dioxide and magnesium stearate.

11. The pharmaceutical composition of claim 1, wherein the lubricant is magnesium stearate.

12. The pharmaceutical composition of claim 1, wherein the pH controlling agent has a pH of 1 to 5.

13. The pharmaceutical composition of claim 1, wherein the pH controlling agent is fumaric acid.

14. The pharmaceutical composition of claim 1, further comprising a super disintegrant.

15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition comprises 0.01% to 20% by weight of the super disintegrant based on the total weight of the composition.

16. The pharmaceutical composition of claim 14, wherein the super disintegrant is selected from the group consisting of cross-linked povidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, or any combination thereof.

17. The pharmaceutical composition of claim 1, comprising 10 mg to 240 mg of the active ingredient per unit dose.

18. The pharmaceutical composition of claim 1, which is in a solid form.

19. The pharmaceutical composition of claim 18, wherein the solid form is selected from the group consisting of a tablet, a wet granule, a dry granule, a microparticle, or a capsule.

20. The pharmaceutical composition of claim 19, wherein the solid form is a tablet.

21. The pharmaceutical composition of claim 20, wherein the solid form is a film-coated tablet.

22. The pharmaceutical composition of claim 20, wherein the solid form is an enteric-coated tablet.

23. The pharmaceutical composition of claim 1, wherein the impurity content of the active ingredient is less than or equal to 0.50% by weight after storage at 20°C, 75% relative humidity for 1 month.

24. A solid oral dosage form comprising a compound of Formula I or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, a pH controlling agent, and any combination thereof; wherein the diluent is present in an amount of 40% to 90% by weight based on the total weight of the solid oral dosage form; wherein the binder is present in an amount of 0.1% to 30% by weight based on the total weight of the solid oral dosage form; wherein the disintegrant is present in an amount of 1% to 40% by weight based on the total weight of the solid oral dosage form; wherein the lubricant is present in an amount of 0.5% to 40% by weight based on the total weight of the solid oral dosage form; wherein the pH controlling agent is present in an amount of 0.01% to 20% by weight based on the total weight of the solid oral dosage form; wherein the diluent is selected from the group consisting of lactose hydrate, lactose anhydrous, mannitol, sorbitol, microcrystalline cellulose, calcium hydrogen phosphate hydrate, or any combination thereof; wherein the binder is selected from the group consisting of hydroxypropyl cellulose and povidone, or any combination thereof; wherein the disintegrant is selected from the group consisting of carboxymethyl cellulose, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, corn starch, and potassium polyplasdone, or any combination thereof; and wherein the lubricant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, stearic acid, or any combination thereof. （I）， ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ wherein the pH controlling agent is selected from the group consisting of citric acid, fumaric acid, maleic acid or any combination thereof; wherein the solid oral dosage form has a pH of 2.8 to 6.55 when measured in a 1% w / v aqueous suspension.

25. A stable solid oral dosage form comprising a pharmaceutically acceptable excipient and a compound of Formula I, or a pharmaceutically acceptable salt thereof, （I）， wherein, the solid oral dosage form retains at least 99% by weight of the compound of Formula I after storage at 20 °C, 75% relative humidity for at least one month, wherein the pharmaceutically acceptable excipient is a diluent, a binder, a disintegrant, a lubricant, a pH controlling agent or any combination thereof; wherein the diluent is present in an amount of 40% to 90% by weight based on the total weight of the solid oral dosage form; wherein the binder is present in an amount of 0.1% to 30% by weight based on the total weight of the solid oral dosage form; wherein the disintegrant is present in an amount of 1% to 40% by weight based on the total weight of the solid oral dosage form; wherein the lubricant is present in an amount of 0.5% to 40% by weight based on the total weight of the solid oral dosage form; wherein the pH controlling agent is present in an amount of 0.01% to 20% by weight based on the total weight of the solid oral dosage form; wherein the diluent is selected from the group consisting of lactose hydrate, lactose anhydrous, mannitol, sorbitol, microcrystalline cellulose, calcium hydrogen phosphate hydrate or any combination thereof; wherein the binder is selected from the group consisting of hydroxypropyl cellulose and povidone or any combination thereof; wherein the disintegrant is selected from the group consisting of carboxymethyl cellulose, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, corn starch and potassium croscarmellose or any combination thereof; wherein the lubricant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, stearic acid or any combination thereof, and wherein the pH controlling agent is selected from the group consisting of citric acid, fumaric acid, maleic acid or any combination thereof; wherein the stable solid oral dosage form has a pH of 2.8 to 6.55 when measured in a 1% w / v aqueous suspension.

26. The solid oral dosage form of claim 24 or 25, wherein the solid oral dosage form is a tablet.

27. The solid oral dosage form of claim 24 or 25, wherein the compound is present in the solid oral dosage form 3 months after the solid oral dosage form is configured.

28. A method of preparing a pharmaceutical composition having a pH of 2.8 to 6.55 when measured in a 1% w / v aqueous suspension, the method comprising: (a) mixing a compound of the following Formula I, or a pharmaceutically acceptable salt thereof, as an active ingredient and at least one pharmaceutically acceptable excipient to obtain a mixture; [Formula I] ； and (b) directly compressing the mixture, wherein the pharmaceutically acceptable excipient is a diluent, a binder, a disintegrant, a lubricant, a pH controlling agent or any combination thereof; wherein the diluent is present in an amount of 40% to 90% by weight based on the total weight of the pharmaceutical composition; wherein the diluent is present in an amount of 40% to 90% by weight based on the total weight of the pharmaceutical composition; wherein the content of the binder is 0.1 to 30% by weight based on the total weight of the pharmaceutical composition; wherein the content of the disintegrant is 1 to 40% by weight based on the total weight of the pharmaceutical composition; wherein the content of the lubricant is 0.5 to 40% by weight based on the total weight of the pharmaceutical composition; wherein the content of the pH controlling agent is 0.01 to 20% by weight based on the total weight of the pharmaceutical composition; wherein the diluent is selected from the group consisting of lactose hydrate, lactose anhydrous, mannitol, sorbitol, microcrystalline cellulose, calcium hydrogen phosphate hydrate, or any combination thereof; wherein the binder is selected from the group consisting of hydroxypropyl cellulose and povidone, or any combination thereof; wherein the disintegrant is selected from the group consisting of carboxymethyl cellulose, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, corn starch, and potassium polyplasdone, or any combination thereof; wherein the lubricant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, stearic acid, or any combination thereof, and wherein the pH controlling agent is selected from the group consisting of citric acid, fumaric acid, maleic acid, or any combination thereof.

29. A product obtained by the method of claim 28.

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