Stable pharmaceutical composition of CYP11A1 inhibitor

Abstract

The present invention relates to a pharmaceutical composition for oral administration, for example in the form of a tablet or in the form of a powder suitable for filling into a capsule shell, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl) piperidin-4-yl) methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof. Compound (I) or a pharmaceutically acceptable salt thereof is a selective inhibitor of the CYP11A1 enzyme and is useful in the treatment of hormone-regulated diseases, such as cancers including prostate cancer and breast cancer.

Description

Applications related to stable pharmaceutical compositions of CYP11A1 inhibitors

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 514,501, filed July 19, 2023, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] The present invention relates to stable pharmaceutical compositions for oral administration, such as pharmaceutical compositions in the form of tablets, pills or powders suitable for filling into capsule shells, comprising 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Background Technology

[0003] Compound 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) and its derivatives have been disclosed in WO 2018 / 115591. Compound (I) is a selective inhibitor of the CYP11A1 enzyme and may be used to treat hormone-regulated diseases, such as cancers including prostate and breast cancer.

[0004]

[0005] Compounds of formula (I) and their pharmaceutically acceptable salts have been found to be suitable for oral administration. However, when formulated with carriers and excipients for the development of solid oral compositions (e.g., tablets and capsules), stability issues have been found with the active ingredient. Therefore, there is a need for pharmaceutical compositions of 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or its pharmaceutically acceptable salts that exhibit improved stability. Summary of the Invention

[0006] Studies have found that the chemical stability of a pharmaceutical composition (e.g., in the form of tablets, pills, or powder suitable for filling into capsule shells) of 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof can be significantly improved by providing a stability-enhancing amount of a pharmaceutically acceptable organic acid. This improved chemical stability makes the composition particularly suitable as a dosage form for treating patients with hormone-regulated diseases requiring CYP11A1 inhibition (e.g., prostate cancer and breast cancer).

[0007] Therefore, according to one aspect, this disclosure provides a pharmaceutical composition comprising, as an active ingredient, 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable amount of a stability-enhancing organic acid. Detailed Implementation

[0008] This disclosure relates to pharmaceutical compositions for oral administration, such as those in the form of tablets, pills, or powders suitable for filling into capsule shells, comprising 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof as an active ingredient. According to a particular embodiment, the pharmaceutical composition is in the form of tablets, such as directly compressed tablets, wet-granulated tablets, or dry-granulated tablets. The compound of formula (I) or a pharmaceutically acceptable salt thereof may be in an amorphous or crystalline state. According to one embodiment, compound (I) is in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of compound (I) include toluenesulfonate, naphthalenesulfonate, hydrobromide, and benzyl salt. A specific embodiment of the pharmaceutically acceptable salt of this disclosure is a toluenesulfonate.

[0009] Studies have found that the chemical stability of a pharmaceutical composition can be significantly improved by providing a stability-enhancing amount of a pharmaceutically acceptable organic acid to the pharmaceutical composition containing 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0010] Therefore, according to one embodiment, this disclosure provides a pharmaceutical composition comprising 2-(isoindoline-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable organic acid.

[0011] According to another embodiment, this disclosure provides a composition comprising about 0.1% to about 15% (e.g., about 0.2% to about 10% or about 0.5% to about 8%) of a pharmaceutically acceptable organic acid by weight of the composition.

[0012] According to one embodiment, the pKa value of a pharmaceutically acceptable organic acid is about 5 or lower. According to another embodiment, the pKa value of a pharmaceutically acceptable organic acid is in the range of about -3 to about 5.

[0013] According to another implementation scheme, the pharmaceutically acceptable organic acid is selected from citric acid, maleic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, lactic acid, oxalic acid, malonic acid, glutaric acid, malic acid, adipic acid, gluconic acid, glutamic acid, glucuronic acid, fumaric acid, glycolic acid, ascorbic acid, aspartic acid, benzoic acid, and hyaluronic acid.

[0014] According to another implementation plan, the pharmaceutically acceptable organic acid is citric acid or maleic acid.

[0015] In any of the above embodiments, there is a pharmaceutical composition comprising about 0.5% to about 20% (e.g., about 1% to about 15%, about 2% to about 10%) of 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof, by weight of the composition.

[0016] In any of the above embodiments, there is a pharmaceutical composition comprising a pharmaceutically acceptable salt of 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) as an active ingredient.

[0017] In the subclass of the above embodiments is a pharmaceutical composition comprising a toluenesulfonate of 2-(isoindoline-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) as an active ingredient.

[0018] In any of the above embodiments, there is a pharmaceutical composition comprising about 50% to about 90% (e.g., about 60% to about 88% or about 70% to about 85%) of a filler by weight of the composition.

[0019] In any of the above embodiments, there is a pharmaceutical composition comprising about 0.5% to about 10% (e.g., about 1% to about 8% or about 2% to about 6%) of a disintegrant by weight of the composition.

[0020] In any of the above embodiments, there is a pharmaceutical composition comprising about 0.5% to about 15% (e.g., about 1% to about 10% or about 2% to about 8%) of binder by weight of the composition.

[0021] In any of the above embodiments, there is a pharmaceutical composition comprising about 0.5% to about 10% (e.g., about 0.8% to about 8% or about 1% to about 5%) of a lubricant by weight of the composition.

[0022] The compositions disclosed herein may be in the form of tablets, pills, or powders suitable for filling into capsule shells.

[0023] As used herein, the term "powder" refers to powdered materials, such as granules or ground powder.

[0024] According to one embodiment, the pharmaceutical composition is in the form of tablets. The tablets can be manufactured by direct compression, wet granulation, or dry granulation (blocking or rolling) processes.

[0025] Direct compression is considered a relatively fast process in which powdered materials contained in a solid dosage form are directly compressed without altering their physical properties. Typically, the active ingredient and other excipients (such as lubricants to prevent tablet material from adhering to the surface of the tableting machine punch) are mixed in a mixer or similar low-shear device before being compressed into tablets using a tableting machine.

[0026] Therefore, according to one embodiment of the present disclosure, a pharmaceutical composition comprising 2-(isoindoline-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amount of a stability-enhancing organic acid, and optionally one or more other excipients, is provided for direct compression into tablets.

[0027] According to another embodiment, this disclosure provides a pharmaceutical composition comprising: a) about 0.5% to about 20% by weight of 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof; b) about 0.1% to about 15% by weight of the composition of a pharmaceutically acceptable organic acid; c) about 50% to about 90% by weight of the composition of a filler; d) about 0.5% to about 10% by weight of the composition of a disintegrant; e) about 0.5% to about 15% by weight of the composition of a binder; and f) about 0.5% to about 10% by weight of the composition of a lubricant.

[0028] The subclass of the above embodiments is a pharmaceutical composition comprising a) about 2% to about 10% by weight of 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof; b) about 0.5% to about 8% by weight of the composition of a pharmaceutically acceptable organic acid; c) about 70% to about 85% by weight of the composition of a filler; d) about 2% to about 6% by weight of the composition of a disintegrant; e) about 2% to about 8% by weight of the composition of a binder; and f) about 1% to about 5% by weight of the composition of a lubricant.

[0029] Wet granulation typically involves mixing the active ingredient and other intragranular components in a suitable mixer, spraying a granulation solution (e.g., water) into the mixture to granulate it, and then drying the wet granules. If the composition also contains extragranular components, these are appropriately mixed with the dried granules. If the composition is a tablet, the resulting mixture is compressed into tablets. If the composition is in capsule form, the resulting mixture can be directly filled into capsule shells. Pharmaceutically acceptable organic acids that improve stability can be mixed with intragranular components in solid form or dissolved in the granulation solution.

[0030] Therefore, according to one embodiment of the invention, a wet-granulated pharmaceutical composition comprising 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amount of a stability-enhancing organic acid, and optionally one or more other excipients is provided.

[0031] According to another embodiment, wet granulation tablets include an inner portion and an outer portion.

[0032] According to one embodiment, the pharmaceutical composition comprises: (a) an inner portion comprising 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable organic acid in an amount that enhances stability; and (b) an outer portion comprising at least one excipient.

[0033] A subclass of the above embodiments is a wet-granulated pharmaceutical composition wherein a pharmaceutically acceptable organic acid is dissolved or dispersed in the granulation solution.

[0034] According to one embodiment, this disclosure provides a pharmaceutical composition comprising: (a) an inner portion comprising, by weight of said inner portion, (i) about 0.5% to about 20% of 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof; (ii) about 0.1% to about 15% of a pharmaceutically acceptable organic acid; (iii) about 50% to about 90% of a filler; (iv) about 0.5% to about 10% of a disintegrant; (v) about 0.5% to about 15% of a binder; (b) an outer portion comprising, by weight of said outer portion, (i) about 50% to about 100% of a filler; (ii) 0% to about 25% of a disintegrant; and (iii) 0% to about 25% of a lubricant.

[0035] In any of the above embodiments, the composition is a pharmaceutical composition wherein the particulate portion constitutes about 30% to about 95% of the composition by weight (e.g., about 50% to about 90% or about 70% to about 85%).

[0036] It should be understood that when the composition is in the form of powder (including granules), the above component percentages refer to powdered pharmaceutical compositions without capsule shells.

[0037] If desired, a water-soluble film coating can be provided for the tablet core to facilitate tablet swallowing, prevent direct contact with the drug substance, and improve aesthetics. Suitable film coating agents can be selected from plasticizers, film-forming agents, surfactants, colorants, and flavoring agents. Anti-sticking agents, flow aids, or opacifiers can optionally be used. Plasticizers (e.g., polyethylene glycol (PEG) or glycerin), film-forming agents (e.g., hydroxypropyl methylcellulose (HPMC)), colorants (e.g., iron oxides or titanium dioxide), flow aids (e.g., talc or magnesium stearate), and flavoring agents (e.g., polydextrose or sucrose) can be combined with a film coating liquid (preferably water) to produce a homogeneous coating suspension that is carried (preferably sprayed) onto the tablet in a suitable coating device (e.g., a perforated roller coater). The film coating typically constitutes about 2% to about 5% by weight of the tablet composition, for example, about 2.5% to about 4%.

[0038] In any of the above embodiments, there is a pharmaceutical composition comprising about 0.1 mg to about 30 mg (e.g., about 0.5 mg to about 25 mg, about 1 mg to about 20 mg, about 2 mg to about 10 mg, about 2.5 mg, about 3.5 mg, about 5 mg or about 7.1 mg) of 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof (e.g., toluenesulfonate).

[0039] As used herein, the term "pKa" is the commonly used symbol for expressing acid strength, which relates to the dissociation constant of the acid in aqueous solution. For polybasic acids, the term pKa refers to the first pKa (pKa1).

[0040] As used herein, "filler" refers to one or more pharmaceutically acceptable excipients that increase the volume of a pharmaceutical composition. Examples of fillers include sugars (e.g., mannitol or sucrose), starch, pregelatinized starch, microcrystalline cellulose, lactose, dicalcium phosphate, and sorbitol. According to one embodiment, the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, lactose, dicalcium phosphate, and combinations thereof. According to another embodiment, the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, and combinations thereof.

[0041] As used herein, a "disintegrant" refers to one or more pharmaceutically acceptable excipients added to a pharmaceutical composition to disintegrate it, thereby supporting the release of the active ingredient from the pharmaceutical composition. Examples of disintegrants include polyvinylpyrrolidone and sodium starch glycolate. According to one embodiment, the disintegrant is selected from croscarmellose, sodium starch glycolate, and combinations thereof. According to another embodiment, the disintegrant is croscarmellose sodium.

[0042] As used herein, "binder" refers to one or more pharmaceutically acceptable excipients that impart enhanced cohesiveness by binding the active ingredient and the excipient together in a mixture. Examples of binders include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl acetate, and polyvinyl alcohol. According to one embodiment, the binder is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and combinations thereof. According to another preferred embodiment, the binder is hydroxypropyl methylcellulose (HPMC). According to yet another embodiment, the binder is hydroxypropyl methylcellulose (HPMC), and the disintegrant is croscarmellose sodium. For wet-granulated tablets, the binder may be added to the granule portion in the form of a dry powder or dissolved or dispersed in the granulation solution.

[0043] As used herein, "lubricant" refers to one or more pharmaceutically acceptable excipients added to a pharmaceutical composition to reduce friction, heat, and abrasion when introduced between solid surfaces. Examples of lubricants include sodium stearoyl fumarate, magnesium stearate, talc, silica, calcium stearate, and carnauba wax. According to one embodiment, the lubricant is sodium stearoyl fumarate.

[0044] To manufacture a pharmaceutical composition, a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., toluenesulfonate) is appropriately ground to the desired particle size. The ground compound may have a particle size with a median diameter (Dv50) not exceeding 50 μm, 30 μm, or 25 μm. For example, Dv50 may be in the range of 1–25 µm, 2–20 µm, or 5–15 µm. The particle size distribution can be analyzed by laser diffraction, for example using a Beckman Coulter LS13320 laser diffractometer equipped with a Tornado dry powder system, using air as the dispersion medium, a measurement pressure of 24”H2O±2”H2O, a sample volume of 10 ml, 5% system control target for masking, and applying a Fraunhofer optical model.

[0045] The grinding of active ingredients can be performed using suitable feeders and grinding equipment, such as single-screw or twin-screw / spiral feeders, hammer mills, pin mills, jet mills, or screen mills, using appropriate rotor speeds, such as 3000–10000 rpm. Grinding can be carried out at suitable temperatures, such as room temperature or lower.

[0046] A compound of formula (I) or a pharmaceutically acceptable salt thereof may be appropriately administered to a patient in an amount ranging from about 0.5 mg to about 30 mg or about 1 mg to about 25 mg daily (e.g., about 2 mg to about 15 mg, such as about 5 mg or about 7 mg), for example, to treat hormone-dependent cancers (e.g., prostate cancer). This dose may be administered once daily or divided into several daily doses, such as twice daily.

[0047] The present invention is further illustrated by the following embodiments.

[0048] Example 1. Tablet Composition (Directly Compressed into Tablets)

[0049] Example 2. Tablet composition (directly compressed into tablets)

[0050] Example 3. Tablet Composition (Directly Compressed into Tablets)

[0051] Example 4. Tablet Composition (Directly Compressed into Tablets)

[0052] Example 5. Tablet composition (directly compressed into tablets)

[0053] Example 6. Tablet Composition (Directly Compressed into Tablets)

[0054] Example 7. Tablet Composition (Directly Compressed into Tablets)

[0055] Example 8. Tablet Composition (Directly Compressed into Tablets)

[0056] The tablet compositions of Examples 1 to 8 were prepared by blending the components together and compressing the mixture into tablets using a tableting machine.

[0057] Example 9. Tablet composition (wet granulation)

[0058] Example 10. Tablet composition (wet granulation)

[0059] The tablet compositions of Examples 9 and 10 were prepared by mixing the intragranular components in a high-shear mixer. The mixture was granulated by spraying water into it. The granules were dried in a fluidized bed dryer and sieved using a conical mill. The extragranular components were added, and the blend was then compressed into tablets using a tableting machine.

[0060] Example 11. Tablet composition (wet granulation, acid in granulation solution)

[0061] Example 12. Tablet composition (wet granulation, acid in granulation solution)

[0062] Example 13 Tablet composition (wet granulation, acid in granulation solution)

[0063] Example 14. Tablet composition (wet granulation, acid in granulation solution)

[0064] The tablet compositions of Examples 11 to 14 were prepared by mixing intragranular components (including acid) in a high-shear mixer. A granulation solution was prepared by dissolving the acid in water. The mixture was granulated by spraying the granulation solution into the mixture. The granules were dried in a fluidized bed dryer and sieved using a conical mill. Extragranular components were added, and the blend was then compressed into tablets using a tableting machine.

[0065] Example 15. Relative Stability Study I. Various direct-compressed tablet compositions DC1 to DC10 were prepared by blending the components together and compressing the mixture into tablets using a tableting machine. The stability of the compositions was tested by storing the tablets in open containers at 60°C / 75% RH for 4 weeks. Table 1 gives the formulation description and the total amount of degradation impurities formed after 4 weeks. Tables 2 and 3 show the quantitative composition of the formulation. It can be seen that acids appear to improve the chemical stability of the direct-compressed tablet compositions.

[0066] Table 1. Results of Relative Stability Study I

[0067] Table 2. Quantitative direct compression tablet formulations DC1-DC5. Total tablet mass 425 mg.

[0068]

[0069] API = Active pharmaceutical ingredient (compound (I), toluenesulfonate) HPMC = hydroxypropyl methylcellulose CCS = croscarmellose sodium cellulose MCC = microcrystalline cellulose SSF = sodium stearoyl fumarate Table 3. Quantitative direct compression tablet formulations DC6-DC10. Total tablet weight 75 mg.

[0070]

[0071] API = Active pharmaceutical ingredient (compound (I), toluenesulfonate) HPMC = hydroxypropyl methylcellulose CCS = croscarmellose sodium cellulose MCC = microcrystalline cellulose SSF = sodium stearoyl fumarate Example 16. Relative Stability Study II Various wet granulation (WG) tablets were prepared by mixing the intragranular components in a high-shear mixer. The mixture was granulated by spraying water into it. The granules were dried in a fluidized bed dryer and sieved using a conical mill. Extragranular components were added, and the blend was then compressed into tablets using a tableting machine. The stability of the composition was tested by storing the tablets in a closed container at 40°C / 75% RH for 6 months. Table 4 gives the formulation description and the total amount of degradation impurities formed after 6 months. Table 5 shows the actual composition of wet granulation (WG) formulations WG1 to WG3. It can be seen that the acid added to the intragranular portion in solid form appears to improve the chemical stability of the wet granulation (WG) composition.

[0072] Table 4. Results of Relative Stability Study II

[0073] Table 5. Quantitative wet granulation (WG) tablet formulations WG1-WG3. Total tablet mass 75 mg. Acid is added to the granule portion in solid form.

[0074]

[0075] API = Active pharmaceutical ingredient (compound (I), toluenesulfonate) HPMC = hydroxypropyl methylcellulose CCS = croscarmellose sodium cellulose MCC = microcrystalline cellulose SSF = sodium stearoyl fumarate Example 17. Relative Stability Study III Various wet granulation (WG) tablets were prepared by mixing intragranular components in a high-shear mixer. The mixture was granulated by spraying water or an acid dissolved in water into the mixture. The granules were dried in a fluidized bed dryer and sieved using a conical mill. Extragranular components were added, and the blend was then compressed into tablets using a tableting machine. The stability of the composition was tested by storing the tablets in a closed container at 40°C / 75% RH for 6 months. Table 6 gives the formulation description and the total amount of degradation impurities formed after 6 months. Table 7 shows the actual composition of wet granulation (WG) formulations WG4 to WG8. It can be seen that the acid dissolved in the granulation solution appears to improve the chemical stability of the wet granulation (WG) compositions.

[0076] Table 6. Results of Relative Stability Study III

[0077] Table 7. Quantitative wet granulation (WG) tablet formulations WG4-WG8. Total tablet mass 75 mg. Acid dissolved in the granulation solution.

[0078]

[0079] API = Active pharmaceutical ingredient (compound (I), toluenesulfonate) HPMC = Hydroxypropyl methylcellulose CCS = Cross-linked carboxymethyl cellulose sodium MCC = Microcrystalline cellulose SSF = Sodium stearoyl fumarate

Claims

1. A pharmaceutical composition comprising, as an active ingredient, 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable amount of a stability-enhancing organic acid.

2. The pharmaceutical composition according to claim 1, comprising about 0.1% to about 15% by weight of the pharmaceutical composition a pharmaceutically acceptable organic acid.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pKa value of the pharmaceutically acceptable organic acid is about 5 or lower.

4. The pharmaceutical composition of claim 3, wherein the pKa value of the pharmaceutically acceptable organic acid is in the range of about -3 to about 5.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutically acceptable organic acid is selected from citric acid, maleic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, lactic acid, oxalic acid, malonic acid, glutaric acid, malic acid, adipic acid, gluconic acid, glutamic acid, glucuronic acid, fumaric acid, glycolic acid, ascorbic acid, aspartic acid, benzoic acid, and hyaluronic acid.

6. The pharmaceutical composition according to any one of the preceding claims, comprising about 0.5% to about 20% by weight of the pharmaceutical composition 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to any one of the preceding claims, comprising a pharmaceutically acceptable salt of 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) as an active ingredient.

8. The pharmaceutical composition according to any one of the preceding claims, comprising toluenesulfonate of 2-(isoindoline-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) as an active ingredient.

9. The pharmaceutical composition according to any one of the preceding claims, comprising about 50% to about 90% of a filler based on the weight of the pharmaceutical composition.

10. The pharmaceutical composition according to any one of the preceding claims, comprising about 0.5% to about 10% of a disintegrant based on the weight of the pharmaceutical composition.

11. The pharmaceutical composition according to any one of the preceding claims, comprising about 0.5% to about 15% of a binder based on the weight of the pharmaceutical composition.

12. The pharmaceutical composition according to any one of the preceding claims, comprising about 0.5% to about 10% of a lubricant by weight of the pharmaceutical composition.

13. The pharmaceutical composition according to any one of claims 1-12, wherein the pharmaceutical composition is in tablet form.

14. The pharmaceutical composition according to claim 13, wherein it is a tablet directly compressed into a tablet.

15. The pharmaceutical composition according to claim 13, wherein it is a wet-granulated tablet.

16. The pharmaceutical composition of claim 1, comprising a) from about 0.5% to about 20% by weight of 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof; b) from about 0.1% to about 15% by weight of the pharmaceutical composition, a pharmaceutically acceptable organic acid; c) from about 50% to about 90% by weight of the pharmaceutical composition, a filler; d) from about 0.5% to about 10% by weight of the pharmaceutical composition, a disintegrant; e) from about 0.5% to about 15% by weight of the pharmaceutical composition, a binder; and f) from about 0.5% to about 10% by weight of the pharmaceutical composition, a lubricant.

17. The pharmaceutical composition of claim 1, comprising (a) an inner part comprising, by weight of the inner part, (i) about 0.5% to about 20% of 2-(isoindoline-2-ylmethyl)-5-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof; (ii) about 0.1% to about 15% of a pharmaceutically acceptable organic acid; (iii) about 50% to about 90% of a filler; (iv) about 0.5% to about 10% of a disintegrant; (v) about 0.5% to about 15% of a binder; and (b) an outer part comprising, by weight of the outer part, (i) about 50% to about 100% of a filler; (ii) 0% to about 25% of a disintegrant; and (iii) 0% to about 25% of a lubricant.

18. The pharmaceutical composition according to claim 16 or 17, wherein the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, lactose, and dicalcium phosphate.

19. The pharmaceutical composition according to any one of claims 16 to 18, wherein the disintegrant comprises croscarmellose sodium or starch glycolate sodium.

20. The pharmaceutical composition according to any one of claims 16 to 19, wherein the binder comprises HPMC or HPC.

21. The pharmaceutical composition according to any one of claims 16 to 20, wherein the lubricant comprises sodium stearoyl fumarate.

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