Pharmaceutical composition containing phthalazinone derivatives

Abstract

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

Description

Technical Field

[0001] The present invention relates to a pharmaceutically composition with improved stability, comprising a phthalazinone derivative capable of suppressing poly(ADP-ribose) polymerase activity.

Background Art

[0002] Due to the physical and chemical properties of pharmaceutically active ingredients, certain pharmaceutically compositions are difficult to manufacture and maintain stability because the pharmaceutically active ingredients can interact with commonly used pharmaceutical excipients. Also, it is important to maintain the safety and efficacy of the pharmaceutically composition during the expected shelf life, for example, the total expected time involved in manufacture, distribution, storage, and administration to patients.

[0003] US Patent 9,682,973 discloses inhibitors of poly(ADP-ribose) polymerase (「PARP」) having anti-neoplastic activity, where the PARP inhibitor is characterized by the following formula 1, or a pharmaceutically acceptable salt thereof. Formula 1 is also characterized as 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one by the IUPAC (International Union of Pure and Applied Chemistry) nomenclature. In particular, the hydrochloride salt of the compound of formula 1 is one of the promising candidates as an anti-neoplastic agent:

[0004]

Chemical Formula

[0005] However, in the process of research and development of a pharmaceutically composition containing the pharmaceutically active ingredient of formula 1 or a salt thereof, it has been revealed that a specific composition using commonly used excipients lacks stability.

Prior Art Documents

Patent Documents

[0006] [Patent Document 1] U.S. Patent 9,682,973 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] The present invention provides a stable pharmaceutical composition comprising the pharmaceutically active ingredient of Formula 1, or a pharmaceutically acceptable salt thereof. [Means for solving the problem]

[0008] In one specific example, the present invention provides a pharmaceutical composition comprising a pharmaceutically active ingredient of formula 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH of about 2.6 to about 6.74 when measured in a 1% (w / v) aqueous suspension: [ka]

[0009] The aforementioned pharmaceutically active ingredient is also the hydrochloride salt of formula 1.

[0010] In other specific examples, the pharmaceutically acceptable excipients may also be diluents, binders, disintegrants, lubricants, or any combination thereof.

[0011] In some specific examples, the composition includes, based on the total weight of the composition, a diluent in an amount of about 40 to about 90% by weight, a binder in an amount of about 0.1 to about 30% by weight, a disintegrant in an amount of about 1 to about 40% by weight, and a lubricant in an amount of about 0.5 to about 40% by weight.

[0012] In some specific examples, the diluent is selected from the group consisting of lactose monohydrate, 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, carboxymethylcellulose (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 silicon dioxide, magnesium stearate, sodium stearyl fumarate. Selected from the group consisting of stearyl fumarate, talc, stearic acid, or any combination thereof.

[0013] The present invention also relates to compounds of the following formula I: [ka] The present invention provides a solid oral administration form comprising a pharmaceutically acceptable salt thereof and one or more excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, and any combination thereof.

[0014] Also, pharmaceutically acceptable excipients and compounds of formula I: [ka] A stable solid oral dosage form comprising the compound of formula I or a pharmaceutically acceptable salt thereof, which maintains at least 99% by weight of the compound of formula I when stored at 20 °C at 75% relative humidity for at least 1 month is provided.

[0015] In one specific example, the solid oral dosage form is a tablet.

[0016] In some specific examples, the solid oral dosage form comprises about 40 to about 90% by weight of a diluent, about 0.1 to about 30% by weight of a binder, about 1 to about 40% by weight of a disintegrant, and about 0.5 to about 40% by weight of a lubricant, based on the total weight of the composition.

[0017] In one specific example, the present invention is a method for producing a pharmaceutical composition having a pH of about 2.6 to about 6.74 measured in a 1% w / v aqueous suspension, comprising: (a) mixing a compound of formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient with one or more pharmaceutically acceptable excipients to obtain a blend

Chemical formula

[0018] In one specific example, the present invention provides a product obtained from the method described herein.

Mode for Carrying Out the Invention

[0019] The present invention provides a pharmaceutical composition comprising an active ingredient of formula 1 below or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, and having a pH of about 2.6 to about 6.74 when measured in a 1% w / v aqueous suspension:

Chemical formula

[0020] As will be provided in more detail in the examples, experimental results show that when the pH of a composition containing the pharmaceutically active ingredient of Formula 1, or a pharmaceutically acceptable salt thereof, is adjusted to a predetermined range, a significantly smaller amount of degradation of the active ingredient of Formula 1 is observed during long-term storage. The resulting pharmaceutically active composition exhibits improved stability throughout the expected normal shelf life of the composition.

[0021] The pH of the pharmaceutical composition is measured by preparing an aqueous suspension of the composition in a 1% w / v (weight by volume) aqueous suspension at room temperature, as prepared by Experimental Example 1. Methods for measuring pH are well known to those skilled in the art of pharmaceutical composition. For example, the pH of a substance can be measured by dissolving the substance in water at a 1% w / v concentration, obtaining an aqueous suspension as prepared by Experimental Example 1, and then measuring the pH of the suspension. The pH value can be determined using standard techniques.

[0022] 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 examples, 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 about 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 above range. In some specific examples, when measured by preparing an aqueous suspension of the composition in a 1% w / v (weight per volume) aqueous suspension, the pH of the pharmaceutical composition is preferably about 3 to about 8 (e.g., about 3 to about 7.5, about 3 to about 7, about 3 to about 6.5, about 3 to about 6, about 3 to about 5.5, about 3 to about 5). The pharmaceutical compositions of the present invention may have any of the above specific ranges of pH, that is, they may have pH values ​​without the word "about" preceding the pH value.

[0023] I. Definition The term “pharmaceutical active ingredient of Formula 1” is also referred to as “Compound 1” or “the Compound.” Similarly, “salt of the pharmaceutical active ingredient of Formula 1” as described in the claims is also referred to as “salt of Compound 1” or “salt of the Compound.” For example, the pharmaceutical active ingredient of Formula 1 in hydrochloride form is also referred to as “hydrochloride of Compound 1” or “hydrochloride of the Compound.”

[0024] In this specification, “pharmaceutically acceptable salt” can be prepared by any suitable method available in the industry, for example, by treating the pharmaceutically active ingredient of Formula 1 in its free base form with an inorganic acid. Examples of useful inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc., or 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, pyranosidylic acids such as glucuronic acid or galacturonic acid, 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, and sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid. Hydrochloride salts of the pharmaceutically active ingredient of Formula 1 are most preferred.

[0025] As used herein, “pharmaceutically acceptable carrier” refers to a non-toxic carrier, auxiliary, or vehicle that does not impair the pharmacological activity of the compound being formulated. Pharmaceutically acceptable carriers, auxiliary, or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, buffering materials such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat.

[0026] In this specification, the terms “stable” and “stability” mean that a pharmaceutical composition is stable against, for example, heat, light, temperature and / or humidity. For example, the pharmaceutical composition of the present invention is stable if the total amount of impurities contained in the pharmaceutical composition, or the amount of M1 impurities of the active ingredient (the “M1 impurities”), is less than or equal to a specific percentage after storage of the pharmaceutical composition under specific conditions. The M1 impurities are any inactive forms of the active ingredient, such as synthetic intermediates, metabolic intermediates, by-products or degradation products of the active ingredient.

[0027] The total impurities measured by HPLC are also defined as having a relative retention time (RRT) of approximately 0.11 to 2.10, more specifically, approximately 0.90, 1.12, 1.35, or 1.38, for the peak associated with compound 1. The M1 impurity is also defined as having an RRT of approximately 0.90 compared to the peak associated with compound 1. As is well known in the art, HPLC RRT values ​​may have an experimental error of ±10% of the stated value. Consequently, the aforementioned values ​​must be interpreted taking experimental error into account.

[0028] As used herein, the “subject” under consideration for administration includes, but is not limited to, human beings (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly)). In specific examples, the subject is human. In specific examples, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0029] As used herein, unless otherwise expressly stated, the terms “to treat,” “to treat,” and “treatment” consider actions that reduce the severity of a particular disease, disorder, or condition that occurs while an object is suffering from such disease, disorder, or condition, or that slow or delay the progression of such disease, disorder, or condition ("therapeutic treatment"), or actions that occur before an object begins to suffer from such disease, disorder, or condition ("preventive treatment").

[0030] As used herein and unless otherwise expressly stated, the “therapeutic effective dose” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. The therapeutic effective dose of a compound means the amount of the therapeutic agent alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutic effective dose” may also include amounts that improve overall therapy, reduce or avoid symptoms or causes of a disease or condition, or enhance the therapeutic efficacy of other therapeutic agents.

[0031] As used herein, "approximately" will be understood by those skilled in the art, but to some extent, depending on the context in which it is used. Where there is a use of terminology that is not clear to those skilled in the art, in the context in which it is used, "approximately" means up to ±10% of the given term. In the case of pH values, the term "approximately" means up to ±0.5% of the pH value.

[0032] As used in this application, "assay" refers to a specific stability labeling procedure for determining the content of a drug substance. For example, such an assay may also be a chromatographic method (e.g., HPLC) that includes the use of a reference standard.

[0033] As used herein, "crystalline" refers to a solid having a highly regular chemical structure, that is, a long-range structural order in its crystal lattice. Molecules are arranged in a regular and periodic manner in the three-dimensional space of the lattice. In particular, crystalline forms can also be produced in the form of one or more single crystals.

[0034] As used herein, “excipients” are pharmaceutically acceptable inert components commonly used to manufacture pharmaceutically acceptable dosage forms. Examples of suitable excipients can be found in Sheskey et al., Handbook of Pharmaceutical Excipients, Eighth Ed., Pharmaceutical Press 2017, which is included herein by reference in its entirety. Excipients can also be classified by their functional properties, for example, as diluents, binders, disintegrants, super-disintegrants, lubricants, pH adjusters, glidants, fillers, stabilizers, antioxidants, and film coatings. However, as is well known in the art, certain excipients can also be classified as belonging to more than one of the functional groups listed above, depending on when and how they are used. For example, a certain excipient may be classified as a disintegrant in one dosage form and as a binder in another. In some cases, specific excipients are also multifunctional, meaning they may belong to more than one functional group within the same dosage form. General considerations for the dosage form and / or manufacture of pharmaceutical composition formulations are described, for example, in the literature [Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005)], both of which are included herein by reference in their entirety.

[0035] As used herein, “binders” are excipients that impart improved cohesiveness or tensile strength (e.g., hardness) to a pharmaceutical composition. Examples of binders include dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethylcellulose).

[0036] As used herein, “diluent” refers to an excipient that adds volume to a pharmaceutical composition. Examples of diluents include lactose, sorbitol, cellulose, calcium phosphate, starch, sugars (e.g., mannitol, sucrose, etc.), or any combination thereof.

[0037] As used herein, “disintegrant” is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion. Examples of such disintegrants include sodium croscarmellose and / or sodium starch glycolate.

[0038] As used herein, “lubricant” is an excipient added to a pharmaceutical composition to be compressed into a tablet. The lubricant helps to compress the granules into a tablet and to facilitate the ejection of the tablet of the pharmaceutical composition from the die press. Examples of the lubricant include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.

[0039] II. Compounds The present application describes pharmaceutical compositions comprising compounds useful for preventing and / or treating diseases, disorders, or conditions, such as those related to cancer.

[0040] In one embodiment, the contents of this disclosure are as follows: Formula I: [ka] This relates to pharmaceutical compositions containing a pharmaceutically acceptable salt thereof.

[0041] Formula I, or a pharmaceutically acceptable salt thereof, is described in U.S. Patent No. 9,682,973, which is included herein by reference in its entirety.

[0042] The crystalline form of the phthalazinon compound is also disclosed in U.S. Patent Application No. 16 / 858,158, filed on 24 April 2020, which is included herein by reference in its entirety.

[0043] In some specific examples, the hydrochloride salt of formula I exhibits a crystalline form (hereinafter referred to as "crystalline form A") that shows an X-ray powder diffraction (XRPD) pattern with peaks at diffraction angles of 13.7°, 15.9°, and 24.1° at a diffraction angle of 2θ±0.2°. In some specific examples, crystalline form A may exhibit an XRPD pattern with peaks at three or more, preferably four or more, 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 with peaks at 9.1°, 13.2°, 13.7°, 15.9°, 16.8°, 24.1°, and 26.6° at a diffraction angle of 2θ±0.2°. More specifically, crystalline morphology A may exhibit an XRPD pattern containing peaks 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°. This XRPD pattern can be obtained using any method known to those skilled in the art, including irradiation with a Cu-Kα light source, such as a D8 Advance (Bruker ASX, Germany) analyzer. The Cu-Kα light source may have a wavelength of 1.54056 Å.

[0044] III. Dosage Forms and Compositions In one embodiment, the present disclosure features a dosage form or composition useful for preventing and / or treating a disease, disorder, or condition described herein, such as cancer.

[0045] The present invention provides a pharmaceutical composition comprising, as an active ingredient, any one or more compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, including but not limited to, any one of carriers, diluents, binders, disintegrants, and lubricants. The pharmaceutical composition may be administered alone or in combination with other therapeutic agents.

[0046] The pharmaceutical composition of the present invention also contains, based on the total weight of the composition, about 0.1 to about 70% by weight, preferably about 1 to 40% by weight of compound 1 or a pharmaceutically acceptable salt thereof. In terms of total amount, the pharmaceutical composition of the present invention contains about 1 to about 400 mg, preferably about 10 to about 240 mg of compound 1 or a pharmaceutically acceptable salt thereof per unit dose. Other specific examples of the pharmaceutical composition contain 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, or 240 mg of compound 1 or a pharmaceutically acceptable salt thereof. The aforementioned amounts are based on the free base of compound 1.

[0047] In one specific example, the composition of the present invention has a desirable threshold for total impurities in the pharmaceutical composition after stability testing. After storing the pharmaceutical composition of the present invention for approximately 1 week to 12 months (e.g., 1 week, 2 weeks, 4 weeks, 1 month, 3 months, 6 months, or 12 months) 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%), the total impurity content of the pharmaceutical composition measured by HPLC is 1.50% or less, preferably 1.0% or less, more preferably 0.80% or less, and still more preferably 0.40% or less, based on the total weight of the pharmaceutical composition. 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 is also 1.0% or less.

[0048] In further specific examples, the compositions of the present invention have a desirable threshold for M1 impurities in the pharmaceutical composition after stability testing. After storing the pharmaceutical composition of the present invention for approximately 1 week to 12 months (e.g., 1 week, 2 weeks, 4 weeks, 1 month, 3 months, 6 months, or 12 months) 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%), the M1 impurity content of the active ingredient measured by HPLC is 0.50% or less, preferably 0.4% or less, and more preferably 0.20% or less, based on the total weight of the pharmaceutical composition. For example, after storing the aforementioned composition of the present invention at 50°C and 75% relative humidity for 1 month, the M1 impurity content of the active ingredient is also 0.50% or less.

[0049] The pharmaceutical composition of the present invention comprises one or more pharmaceutically acceptable excipients. The type and amount of the excipient can be appropriately selected such that the pharmaceutical composition of the present invention satisfies a pH of approximately 2.6 to approximately 6.74, as measured in a 1% w / v aqueous suspension prepared according to Experimental Example 1. The excipient can also improve the processing characteristics of the dosage form, such as fluidity and / or aggregation, and allow for better compression of the pharmaceutical composition. It is also desirable to select the excipient with consideration to the elution rate of the pharmaceutical composition.

[0050] In one specific example, the pharmaceutical composition of the present invention comprises a diluent, a binder, a disintegrant, a lubricant, or any combination thereof.

[0051] The diluents include, but are not limited to, the following: lactose, e.g., anhydrous lactose or lactose monohydrate (e.g., Flowlac 100); microcrystalline cellulose (e.g., Avicel pH-101 or Pharmacel 101); dibasic calcium phosphate monohydrate (e.g., Carmellose, EMCOMPRESS); mannitol such as D-mannitol (e.g., Mannogem EZ); sorbitol such as D-sorbitol (e.g., XTAB 200S); refined sugars such as compressible sugar, dextrose, dextrin or dextrose; ground cellulose; or any combination thereof. Preferably, the diluent of the present invention may be lactose monohydrate, anhydrous lactose, mannitol, sorbitol, microcrystalline cellulose, dibasic calcium phosphate hydrate, or any combination thereof; more preferably, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, or any combination thereof; and most preferably, lactose monohydrate, microcrystalline cellulose, or any combination thereof.

[0052] In some specific examples, the diluent is lactose monohydrate. In some specific examples, the diluent is anhydrous lactose. In some specific examples, the diluent is microcrystalline cellulose. In some specific examples, the diluent is dibasic calcium phosphate monohydrate. In some specific examples, the diluent is mannitol. In some specific examples, the diluent is sorbitol. In some specific examples, the diluent is refined sugar. In some specific examples, the diluent is pulverized cellulose.

[0053] The diluent is also included in an amount of about 40 to about 90% by weight, preferably about 70 to about 90% by weight, based on the total weight of the composition.

[0054] The binder may include, but is not limited to, the following: 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 binder of the present invention may be hydroxypropyl cellulose, povidone, or any combination thereof, and more preferably hydroxypropyl cellulose.

[0055] In some specific examples, the binder is hydroxypropylcellulose. In some specific examples, the binder is povidone. In some specific examples, the binder is hydroxyethylcellulose. In some specific examples, the binder is sucrose. In some specific examples, the binder is dextrose. In some specific examples, the binder is corn syrup. In some specific examples, the binder is a polysaccharide.

[0056] The binder is also included in an amount of about 0.1 to about 30% by weight, preferably about 0.5 to about 20% by weight, based on the total weight of the composition.

[0057] The disintegrant may include, but is not limited to, the following: carboxymethylcellulose (CMC) (also known as carmellose, e.g., NS-300); calcium carboxymethylcellulose (CMC-Ca); sodium carboxymethylcellulose (CMC-Na); low-substituted hydroxypropylcellulose (e.g., grades LH-11, LH-21, LH-31, etc., with a hydroxypropoxy content of 11%); corn starch; potassium polaritrin; pre-gelatinized starch; clay; alginate; gum; or any combination thereof. Preferably, the disintegrant of the present invention may be CMC, CMC-Ca, CMC-Na, low-substituted hydroxypropylcellulose, corn starch, potassium polaritrin, or any combination thereof, and more preferably, CMC.

[0058] In some specific examples, the disintegrant is carboxymethylcellulose. In some specific examples, the disintegrant is calcium carboxymethylcellulose. In some specific examples, the disintegrant is sodium carboxymethylcellulose. In some specific examples, the disintegrant is low-substituted hydroxypropylcellulose. In some specific examples, the disintegrant is corn starch. In some specific examples, the disintegrant is potassium polaritrin. In some specific examples, the disintegrant is pre-gelatinized starch. In some specific examples, the disintegrant is clay. In some specific examples, the disintegrant is alginate. In some specific examples, the disintegrant is gum.

[0059] The disintegrant is also included in an amount of about 1 to about 40% by weight, preferably about 3 to about 20% by weight, based on the total weight of the composition.

[0060] The lubricant may include, but is not limited to, the following: colloidal silicon dioxide; talc; stearic acid, magnesium stearate, calcium stearate; sodium stearyl fumarate (e.g., Pruv); or any combination thereof. Preferably, the lubricant of the present invention may be colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, stearic acid, or any combination thereof, and more preferably, colloidal silicon dioxide, magnesium stearate, or any combination thereof.

[0061] In some specific examples, the lubricant is colloidal silicon dioxide. In some specific examples, the lubricant is talc. In some specific examples, the lubricant is stearic acid, magnesium stearate, or calcium stearate. In some specific examples, the lubricant is sodium stearyl fumarate.

[0062] The lubricant is also included in an amount of about 0.5 to about 40% by weight, preferably about 1 to about 20% by weight, based on the total weight of the composition.

[0063] In other embodiments, the pharmaceutical composition of the present invention also contains an additional pH adjuster. If the pH of the pharmaceutical composition in the 1% w / v aqueous suspension prepared by Experimental Example 1 is within the range of about 2.6 to 6.74 without a pH adjuster, then no further pH adjuster is needed. If the pH of the pharmaceutical composition falls outside this range without a pH adjuster, then a pH adjuster can be appropriately added to adjust the pH of the pharmaceutical composition within the pH range. In an exemplary embodiment, if the pharmaceutical composition contains CMC as a disintegrant (Test Sample 2), the pH of the 1% w / v aqueous suspension prepared by Experimental Example 1 is about 4.3, meaning that no additional pH adjuster is needed. On the other hand, if the pharmaceutical composition contains potassium polaritrin as a disintegrant, the pH is about 7.97, and the impurity content increases, making it unstable (Test Sample 9). In this case, the additional use of a pH adjuster is required to bring it within the desired pH range. Even when CMC-Na (test sample 11) is used, the impurity content increases, and by adding a pH adjuster, the stability of the pharmaceutical composition can be improved.

[0064] Any combination of pH adjusters or pH activators known in the industry may be used, provided that the desired pH range is achieved.

[0065] In a preferred example, the pH adjusting agent used in the present invention is also a pH adjusting 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. Here, the pH of the pH adjusting agent is defined as the pH of the solution or suspension obtained when the pH adjusting agent is dissolved or suspended in water at a concentration of 1% w / v at room temperature.

[0066] The pH adjusting agent may include, but is not limited to, the following: 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 having an organic base (e.g., basic amino acids such as lysine, arginine, and meglumine); and hydrates thereof, solvates thereof, or any combination thereof. Preferably, the pH adjusting agent may also be citric acid, fumaric acid, maleic acid, or any combination thereof.

[0067] The pH adjusting agent is also included in an amount of about 0.01 to about 20% by weight, preferably about 0.05 to about 10% by weight, based on the total weight of the composition.

[0068] In other embodiments, the pharmaceutical composition of the present invention also includes, but is not limited to, a superdisintegrant. The superdisintegrant may include, but is not limited to, crospovidone; croscarmellose sodium; sodium starch glycolate; natural, modified, or pre-gelatinized starch; effervescent disintegrants; or any combination thereof. Preferably, the superdisintegrant may be crospovidone, croscarmellose sodium, sodium starch glycolate, or any combination thereof.

[0069] In some specific examples, the super-disintegrant is crospovidone. In some specific examples, the super-disintegrant is croscarmellose sodium. In some specific examples, the super-disintegrant is sodium starch glycolate. In some specific examples, the super-disintegrant is natural, modified, or pre-gelatinized starch. In some specific examples, the super-disintegrant is a foaming disintegrant.

[0070] The super-disintegrant is also included in an amount of about 0.01 to about 20% by weight, preferably about 1 to about 10% by weight, and more preferably about 1 to about 5% by weight, based on the total weight of the composition.

[0071] The functions or effects of excipients exemplified above are not absolute, but one excipient may, in some cases, have at least two functions. For example, some disintegrants can also function as binders and fillers. The diverse functions or effects of such excipients can be determined as is already known in the art.

[0072] Oral administration is a route of administration of the compounds according to the present invention. Such administration may also be carried out via capsules or tablets, etc. In the preparation of the pharmaceutical composition comprising at least one compound described herein, the active ingredient is generally diluted with an excipient and / or encapsulated in such a carrier, which may also be in the form of a capsule, sachet, paper, or other container. When the excipient acts with a diluent, it may also be in the form of a solid, semi-solid, or liquid substance (as described above) acting as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may also be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid media), ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions, and sterile packaging powders.

[0073] The pharmaceutical composition of the present invention may also be in the form of a solid oral administration form or solid preparation, such as a tablet, granules, fine granules, capsule, or pill. The solid preparation may preferably be a tablet, for example, a tablet coated with a film coating agent. In some specific examples, the pharmaceutical composition may also be manufactured as a tablet. In some specific examples, a tablet containing the pharmaceutical composition as described herein may also be coated by a film coating. In some specific examples, a tablet containing the pharmaceutical composition as described herein may also be coated by an enteric coating.

[0074] Tablets containing the pharmaceutical composition of the present invention may also be coated with a film. For example, the film may be for enteric coating. In some specific examples, the film may contain a cellulose polymer (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, or any combination thereof). One exemplary film coating agent is Opadry® White 03B28796, which contains hydroxypropylmethylcellulose (hypromellose).

[0075] IV. Manufacturing method The pharmaceutical compositions of the present invention may also be produced by any known method or process, such as grinding, mixing or blending, granulation, drying, molding (tableting), film coating, crystallization, etc.

[0076] Thus, the present invention also relates to a method for producing a pharmaceutical composition having a pH of about 2.6 to about 6.74 as measured in a 1% w / v aqueous suspension. (a) A step of obtaining a blend by mixing a compound of the following formula 1, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients as an active ingredient, [ka] (b) A method is provided which includes the step of directly compressing the blend.

[0077] In one embodiment, the present invention is a direct compression method for producing a pharmaceutical composition. (a) The step of pre-blending the active ingredient with some or most of the excipients in a mixer to obtain a pre-blended blender, (b) Selectively, the preliminary blender is dry-screened through a screen to separate agglomerating particles and improve content uniformity, (c) The step of mixing the preliminary blender from step (a) or step (b) with the remaining excipient in a mixer to obtain the final blender, (d) The final blender from step (c) above is compressed and tableted in a tablet press to produce a tablet core, (e) optionally, a method comprising the step of film-coating the tablet core of step (d).

[0078] In one specific example, the active ingredient, diluent, binder, disintegrant, and lubricant are pre-blended in a diffusion mixer, sieved in a hand screen or screen mill, and then pre-blended again in a diffusion mixer to produce a blended intermediate composition. The additional lubricant is separately sieved in a hand screen or screen mill and then blended with the blended intermediate in a diffusion mixer to produce a blend. The blend is directly compressed in a rotary tablet press to obtain tablets (plain tablets), after which a film coating agent is added to produce film-coated tablets.

[0079] The granules of the pharmaceutical composition according to the present invention may also be produced by any method well known to those skilled in the art. Preferred methods for granulating the active ingredient together with the excipients include wet granulation, such as high-shear wet granulation or fluidized bed wet granulation, and dry granulation, also known as roller compression.

[0080] The granulation liquid in the wet granulation step is a formulation of one or more binders in a solvent alone, or in a solvent mixture. Suitable binders are described above. Examples include hypromellose, hydroxypropylcellulose, povidone, and copovidone. Suitable solvents include, for example, purified water, ethanol, methanol, isopropanol, and acetone, preferably purified water, but including mixtures thereof. The solvent is a volatile component that does not remain in the final product. One or more active ingredients, and other excipients, particularly one or more diluents, and one or more disintegrants, generally except for lubricants, are pre-mixed with the granulation liquid and granulated, for example, using a high-shear granulator. The wet granulation step is generally followed by one or more drying and sieving steps. For example, a drying oven or a fluidized bed dryer may be used for drying.

[0081] The dried granules are sieved with a suitable sieve. After the selective addition of other excipients, particularly disintegrants, binders, fillers and / or lubricants, the mixture is blended in a suitable blender, such as a free-fall blender, then one or more lubricants, such as magnesium stearate, are added and the mixture is final-blended in the blender.

[0082] In one specific example, the present invention provides a wet granulation method for producing a pharmaceutical composition comprising the following steps: (a) A step of pre-blending some or most of the excipients, including the active ingredient and binder, in a mixer to obtain a pre-blended product; (b) Adding a granular liquid, preferably purified water, to granulate the pre-blender from step (a); (c) A step of drying the granules from step (b) in a fluidized bed dryer or drying oven; (d) Selectively, a step of dry sieving the dried granules of step (c); (e)(d) The dried granules from step (e)(d) are mixed in a mixer with the remaining excipients such as lubricants and fluidizers to obtain the final mixture; (f) The final mixture from step (e) is compressed in a suitable tablet press to form a tablet core; and (g) Selectively, the step of film-coating the tablet core of step (f).

[0083] In other specific examples, the present invention provides a dry granulation method for producing a pharmaceutical composition comprising the following steps: (a) The step of mixing the active ingredient with all or part of the excipients in a mixer; (b) A step of pressing the mixture from step (a) with a suitable roller press; (c) A step of converting the ribbon obtained between steps (b) into granules, preferably small granules, by an appropriate milling or sieving step; (d) Selectively, the granules from step (c) are mixed with the remaining excipients in a mixer to obtain the final mixture; (e) The step of compressing the granules of step (c) or the final mixture of step (d) on a suitable tablet press to produce a tablet core; and (f) Selectively, the step of film-coating the tablet core of step (e).

[0084] Furthermore, the present invention provides the aforementioned pharmaceutical composition, such as a tablet, which can be obtained by the following method.

[0085] Granules and fine granules can be produced by granulation (e.g., wet granulation or dry granulation) using the same method as that used for tablets. Alternatively, they can be produced by spraying a coating solution containing the active ingredient and excipients, particularly binders such as sucrose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, onto sugar spheres to coat them. Thus, the granules can be either wet granules or dry granules.

[0086] The capsules are manufactured by filling capsules made of gelatin such as hydroxypropyl methylcellulose with granules or microgranules, or by filling capsules made of gelatin such as hydroxypropyl methylcellulose with the active ingredient together with excipients (e.g., lactose, sucrose, glucose, starch, sugars, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate, etc.).

[0087] V. Methods of Use and Treatment One feature of the present invention relates to a pharmaceutical composition that may be useful as a therapeutic agent for the treatment of diseases improved by PARP suppression, or cancers caused by genetic defects of BRCA1, BRCA2, and ERG fusion genes. In some specific examples, the pharmaceutical composition comprising formula I, as provided herein, is effective in treating cancers such as gastric cancer, ovarian cancer, and breast cancer. Other specific examples of methods of using the compositions of the present invention are described in U.S. Patent No. 9,682,973, which is included herein by reference in its entirety.

[0088] The present invention will be described in more detail below through the examples provided. However, the examples are for illustrative purposes only and are not intended to limit the present invention. [Examples]

[0089] Examples are provided below to allow for a more complete understanding of the invention described herein. The examples described herein are provided to illustrate aspects of the invention and the examples provided therein, but are not to be construed as limiting their scope in any way.

[0090] Abbreviation BRT below reporting threshold CMC (Carboxymethylcellulose) CMC-Ca Calcium Carboxymethylcellulose HDPE (High-Density Polyethylene) HPLC (High-Performance Liquid Chromatography) HPC (Hydroxypropylcellulose) ND: Not decided (undetermined) RH (Relative Humidity) UV ultraviolet light

[0091] Experimental Example 1: pH-dependent stability of tablets of test samples 1 to 9. The hydrochloride salt of this compound and an excipient were mixed according to the composition shown in Table 1 below, and compressed to produce plain uncoated tablets. Each tablet was placed in triple distilled water to a concentration of 1% w / v (weight by volume), and stirred at room temperature at 1,200 rpm for 5 minutes using a magnetic stirring bar to form an aqueous suspension (referred to as "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 an S20 SevenEasy pH meter manufactured by Mettler Toledo. The pH of each tablet produced in test samples 1 to 9 was measured, and the results are shown in Table 1 below.

[0092] Furthermore, the stability of each tablet produced in Examples 1 to 9 was evaluated. Each tablet was sealed in an HDPE bottle with a desiccant (silica gel) at 50°C and 75% RH (relative humidity) and stored for 2 weeks and 4 weeks, respectively. The M1 impurity content (%) and total impurity content (%) of each tablet were then determined by HPLC.

[0093] HPLC analysis was performed using a C18 column (4.6 mm x 15 cm; 5 μm) and UV light set to 280 nm or nearby. maxThe analysis was performed using a detector with [specified detector type], and the mobile phase was a mixture of purified water and formic acid, or a mixture of methanol and formic acid. Analysis of M1 impurity content (%) and total impurity content (%) was performed on the start date (initial) (day 0), at week 2, and at week 4. The impurity content (%) was calculated as follows: M1 impurity content (%) = (peak area of ​​M1 impurities in the sample / total peak area of ​​the sample) x 100 Total impurity content (%) = (Sum of peak areas of each impurity in the sample / Total peak area of ​​the sample) x 100

[0094] The results are shown in Table 1 below.

[0095] [Table 1]

[0096] The pharmaceutical compositions containing the hydrochloride salt of this compound, with a pH of approximately 2.6 to 6.48 (test samples 1 to 8), showed remarkable stability after long-term storage, as evidenced by the low levels of impurities. In particular, they were shown to be most stable around pH 3.0 (test samples 3 and 7). On the other hand, when the pH was higher than 7.0, the amount of impurities increased rapidly, and stability decreased (test sample 9).

[0097] Therefore, it was confirmed that the compound of the present invention is stable in a pH range of approximately 2.6 to 6.48.

[0098] Experimental Example 2: Stability of tablets of test sample 2 and test samples 10 to 21 with different excipients.

[0099] Using the manufacturing methods described for test samples 1 to 9, the hydrochloride salt of the compound and each additive were mixed in the compositions shown in Tables 2 and 3 below, and then compressed to produce uncoated tablets.

[0100] The pH of each tablet produced using test sample 2 and test samples 10 to 21 was measured as in Experimental Example 1, and the results are shown in Tables 2 and 3 below.

[0101] The stability of each tablet produced using test sample 2, which contained different excipients, and test samples 10 through 21 was evaluated. Each tablet was stored at 50°C and 75% RH for one week after opening, and the impurity (M1) content (%) in each tablet was measured using the HPLC method described in Experimental Example 1. The results are shown in Tables 2 and 3.

[0102] Test sample 2, and test samples 10 to 17

[0103] [Table 2]

[0104] From the above results, it was confirmed that the tablets of test samples 2, 10, and 12 through 17 showed excellent stability, while the tablet of test sample 11 had low stability. In test sample 11, CMC-Na was used as a disintegrant, and it was determined that this component increased the overall pH of the tablet and reduced the stability of the active ingredient.

[0105] Test samples 18 to 21

[0106] [Table 3]

[0107] Test sample 21 provided the best stability results. Test samples 18 through 20 were less stable than test sample 21 due to increased M1 impurities, but test samples 18 and 19 (and 21) still showed M1 impurities below the desired level of less than 0.50%. Test sample 20 was an exception.

[0108] Experimental Example 3: Stability of Test Samples 22 to 33 Tablets with Various Excipients

[0109] Using the manufacturing methods described in Test Samples 1 to 9, the hydrochloride salt of the compound and each additive were mixed in the compositions shown in Table 4 below, and then compressed to produce uncoated tablets.

[0110] The pH of each tablet produced using test samples 22 and 33 was measured as in Experimental Example 1, and the results are shown in Table 4 below.

[0111] The stability of each tablet produced using test samples 22 to 33, each containing different excipients, was evaluated. Each tablet was stored at 50°C for 2 and 4 weeks in a sealed container without adjusting the RH, and then the M1 impurity content (%) and total impurity content (%) of each tablet were measured by the HPLC method described in Experimental Example 1. The results are shown in Table 4 below.

[0112] [Table 4-1] [Table 4-2]

[0113] The results described above demonstrate improved stability for the compositions of the present invention with a pH of 2.8 to 6.55. In fact, with the exception of test sample 28, the remaining test samples were stable. In particular, the stability was greatly improved in the test samples whose pH was adjusted to approximately 3 using a pH adjusting agent, i.e., test samples 23, 25, 27, 29, 31 and 33.

[0114] Experimental Example 4: Stability of film-coated tablets with excipients of test samples 34 to 36

[0115] Using the manufacturing methods described for test samples 1 to 9, the hydrochloride salt of the compound and each additive were mixed in the compositions shown in Table 5 below, compressed into tablets, and manufactured general tablets. These tablets were then film-coated with Opadry® to produce film-coated tablets for test samples 34 to 36.

[0116] The stability of each tablet produced using test samples 34 to 36 was evaluated. Each tablet was stored at 40°C and 75% RH in sealed Alu-Alu packaging for 3 months and 6 months, respectively. The M1 impurity content (%) and total impurity content (%) of each tablet were then measured by HPLC according to Experimental Example 1. Table 5 shows the results.

[0117] [Table 5]

[0118] The stability of film-coated pharmaceutical compositions containing the pharmaceutically active ingredient of Formula 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients was confirmed when measured in a 1% w / v aqueous suspension prepared according to Experimental Example 1, and the pH of the composition was in the range of approximately 2.6 to approximately 6.74.

[0119] Equivalents and Scope In the claims, articles such as “a,” “an,” and “the” may mean one or more unless they are shown to be contradictory or are not particularly obvious in the context. A claim or description containing “or” among one or more members of a group is considered satisfied if, in a given product or method not explicitly stated, one, more than one, or any of the members of the group are present, adopted, or involved. The present invention includes specific examples that are present, adopted, or particularly relevant to the given product or method, even if only one member of the group is precisely involved. The present invention includes specific examples that are present, adopted, or particularly relevant to the given product or method, even if one or more, of the members of the group are involved.

[0120] Furthermore, the present invention includes all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into other claims. For example, all claims belonging to other claims are also modified to include one or more limitations found in other claims belonging to the same basic claim. Where such elements are indicated by a list, for example, in Markush group format, each subgroup of the element is also disclosed, and any element is removed from the group as well. In general, where the present invention or an aspect of the present invention is referred to as including certain elements and / or features, it should be interpreted that a particular example of the present invention or an aspect of the present invention is composed of, or is essentially composed of, such elements and / or features. For the sake of brevity, such examples are not described literally in this specification. Also note that the terms “including” and “contain” are intended to be open and allow for the inclusion of additional elements or stages. Where a scope is given, an endpoint is included. Furthermore, unless otherwise explicitly stated or evident from the context and understanding of those skilled in the art, values ​​expressed as a range may take any specific value or sub-range up to one-tenth of the lower limit unit of the range, within the ranges mentioned in other specific examples of the present invention, unless otherwise explicitly stated in the context.

[0121] This application refers to a variety of issued patents, published patent applications, journal articles, and other publications, all of which are included herein by reference. In the event of any conflict between the combined references and this specification, this specification shall prevail. Furthermore, any specific example of the present invention belonging to the prior art may be expressly excluded from one or more claims. Such examples are considered to be known to those skilled in the art and may be excluded even if the exclusion is not expressly stated herein. Any specific example of the present invention may be excluded from any claim for any reason, whether or not it is related to the existence of the prior art.

[0122] Those skilled in the art will be able to recognize and verify many equivalents relating to the specific examples described herein simply by using routine experiments. The scope of these specific examples described herein is not intended to be limited as stated above, but rather as described in the appended claims. Those skilled in the art will understand that various changes and modifications relating to this description will be made without deviating from the spirit or scope of the invention as defined in the following claims.

Claims

1. A pharmaceutical composition comprising, as an active ingredient, a compound of the following formula 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, having a pH of 2.8 to 6.55 as measured in a 1% w / v aqueous suspension. The pharmaceutically acceptable excipients include diluents, binders, disintegrants, lubricants, pH adjusters, or any combination thereof. The aforementioned composition, Based on the total weight of the composition, 40 to 90% by weight of the diluent, Based on the total weight of the composition, 0.1 to 30% by weight of the binder, Based on the total weight of the composition, 1 to 40% by weight of the disintegrant, Based on the total weight of the composition, 0.5 to 40% by weight of lubricant and The composition contains 0.01 to 20% by weight of a pH adjusting agent, based on the total weight of the composition. The diluent is selected from the group consisting of lactose monohydrate, 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, calcium carboxymethylcellulose (CMC-Ca), sodium carboxymethylcellulose (CMC-Na), low-substituted hydroxypropylcellulose, corn starch, and potassium polaritrin, or any combination thereof. The lubricant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, stearic acid, or any combination thereof. The pH adjusting agent is a pharmaceutical composition selected from the group consisting of citric acid, fumaric acid, maleic acid, or any combination thereof: 【Chemistry 1】

2. The pharmaceutical composition according to claim 1, wherein the active ingredient is the hydrochloride salt of the compound of formula 1.

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

4. The pharmaceutical composition according to claim 1, wherein the diluent is lactose monohydrate.

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

6. The pharmaceutical composition according to claim 1, wherein the binder is hydroxypropylcellulose.

7. The pharmaceutically acceptable composition according to claim 1, wherein the binder is povidone.

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

9. The pharmaceutical composition according to claim 1, wherein the disintegrant is carmellose.

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

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

12. The pharmaceutical composition according to claim 1, wherein the pH adjusting agent has a pH of 2.8 to 5.

13. The pharmaceutical composition according to claim 1, wherein the pH adjusting agent is fumaric acid.

14. The pharmaceutical composition according to claim 1, further comprising a superdisintegrant selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, or any combination thereof.

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

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

17. The pharmaceutical composition according to claim 1, which is in solid form.

18. The pharmaceutical composition according to claim 17, wherein the solid form is selected from the group consisting of tablets, wet granules, dry granules, fine granules, or capsules.

19. The pharmaceutical composition according to claim 17, wherein the solid form is a tablet.

20. The pharmaceutical composition according to claim 19, wherein the solid form is a film-coated tablet.

21. The pharmaceutical composition according to claim 19, wherein the solid form is an enteric-coated tablet.

22. The pharmaceutical composition according to claim 1, wherein, after storage for one month at 20°C and 75% relative humidity, the active ingredient impurities are present in an amount of 0.50% by weight or less.

23. A stable solid oral administration agent comprising a pharmaceutically acceptable excipient and a compound of formula I, or a pharmaceutically acceptable salt thereof, which retains at least 99% by weight of the compound of formula I when stored for at least one month under conditions of 75% relative humidity and 20°C. The pharmaceutically acceptable excipients include diluents, binders, disintegrants, lubricants, pH adjusters, or any combination thereof. The aforementioned composition, Based on the total weight of the composition, 40 to 90% by weight of the diluent, Based on the total weight of the composition, 0.1 to 30% by weight of the binder, Based on the total weight of the composition, 1 to 40% by weight of the disintegrant, Based on the total weight of the composition, 0.5 to 40% by weight of lubricant and The composition contains 0.01 to 20% by weight of a pH adjusting agent, based on the total weight of the composition. The diluent is selected from the group consisting of lactose monohydrate, 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, calcium carboxymethylcellulose (CMC-Ca), sodium carboxymethylcellulose (CMC-Na), low-substituted hydroxypropylcellulose, corn starch, and potassium polaritrin, or any combination thereof. The lubricant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, stearic acid, or any combination thereof. The pH adjusting agent is selected from the group consisting of citric acid, fumaric acid, maleic acid, or any combination thereof. A 1% w / v aqueous suspension having a pH of 2.8 to 6.55, 【Chemistry 2】 A solid oral medication.

24. The solid oral administration agent according to claim 23, wherein the solid oral administration agent is a tablet.

25. The solid oral administration agent according to claim 23 or 24, wherein the compound is present in the solid oral administration agent three months after the solid oral administration agent has been formed into a dosage form.

26. The solid oral administration agent according to claim 25, wherein the solid oral administration agent comprises a diluent, a binder, a disintegrant, and a lubricant.

27. A method for producing a pharmaceutical composition having a pH of 2.8 to 6.55 as measured in a 1% w / v aqueous suspension, (a) A step of obtaining a blend by mixing a compound of formula 1 below, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients as an active ingredient: 【Transformation 3】 and (b) including a step of directly compressing the blend, The pharmaceutically acceptable excipients include diluents, binders, disintegrants, lubricants, pH adjusters, or any combination thereof. The aforementioned composition, Based on the total weight of the composition, 40 to 90% by weight of the diluent, Based on the total weight of the composition, 0.1 to 30% by weight of the binder, Based on the total weight of the composition, 1 to 40% by weight of the disintegrant, Based on the total weight of the composition, 0.5 to 40% by weight of lubricant and The composition contains 0.01 to 20% by weight of a pH adjusting agent, based on the total weight of the composition. The diluent is selected from the group consisting of lactose monohydrate, 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, calcium carboxymethylcellulose (CMC-Ca), sodium carboxymethylcellulose (CMC-Na), low-substituted hydroxypropylcellulose, corn starch, and potassium polaritrin, or any combination thereof. The lubricant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, stearic acid, or any combination thereof. The pH adjusting agent is selected from the group consisting of citric acid, fumaric acid, maleic acid, or any combination thereof. method.

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