Stable pharmaceutical compositions of a CYP11a1 inhibitor

Abstract

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

Description

STABLE PHARMACEUTICAL COMPOSITIONS OF A CYP11A1 INHIBITORRelated Applications

[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, for example in the form of a tablet, pellets or powder suitable to be filled into a capsule shell, comprising 2-(isoindolin-2-ylmethyl)-5-((l-(methyl- sulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof as an active ingredient.Background of the invention

[0003] The compound 2-(isoindolin-2-ylmethyl)-5-((l- (methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) and derivatives thereof have been disclosed in WO 2018 / 115591. Compound of formula (I) is a selective inhibitor of CYP11 Al enzyme and is useful in the treatment of hormonally regulated diseases such as cancer including prostate cancer and breast cancer.

[0004] Compound of formula (I) and pharmaceutically acceptable salts thereof have been found to be suitable for oral administration. However, when formulated together with carriers and excipients for the development of solid oral compositions, for example tablets and capsules, the active ingredient was found to be prone to stability issues. Thus, there is a need for pharmaceutical compositions of 2-(iso- indolin-2-ylmethyl)-5-((l-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or pharmaceutically acceptable salts thereof which exhibit improved stability.Summary of the invention

[0005] .It has been found that the chemical stability of pharmaceutical compositions of 2-(isoindolin-2-ylmethyl)-5-((l-(methylsulfonyl)piperidin-4- yl)methoxy)-4H-pyran-4-one (I) or pharmaceutically acceptable salts thereof, for example in the form of a tablet, pellets or powder suitable to be filled into a capsuleshell, can be significantly improved by providing the composition with a stability enhancing amount of a pharmaceutically acceptable organic acid. The present composition having improved chemical stability is particularly suitable as a dosage

[0006] form for the treatment of patients suffering from hormonally regulated diseases where CYP11 Al inhibition is desired, such as prostate cancer and breast cancer.

[0007] Thus, according to one aspect, the present disclosure provides a pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((l-(methyl- sulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof as an active ingredient and a stability enhancing amount of a pharmaceutically acceptable organic acid.Detailed description of the invention

[0008] The present disclosure relates to a pharmaceutical composition for oral administration, for example in the form of a tablet, pellets, or powder suitable to be filled into a capsule shell, comprising 2-(isoindolin-2-ylmethyl)-5-((l-(methyl- sulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof as an active ingredient. According to one particular embodiment, the pharmaceutical composition is in the form of a tablet, such as direct compressed tablet, wet granulated tablet or dry granulated tablet. Compound (I) or a pharmaceutically acceptable salt thereof may be in 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) are tosylate, napsylate, hydrobromic and benzylate salts. One particular embodiment of a pharmaceutically acceptable salt of the present disclosure is a tosylate salt.

[0009] It has been found that the chemical stability of pharmaceutical compositions comprising 2-(isoindolin-2-ylmethyl)-5-((l-(methylsulfonyl)piperidin- 4-yl)methoxy)-4H-pyran-4-one (I) or pharmaceutically acceptable salts thereof as an active ingredient can be significantly improved by providing the composition with a stability enhancing amount of a pharmaceutically acceptable organic acid.

[0010] Thus, according to one embodiment, the present disclosure provides a pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((l-(methyl- sulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable organic acid.

[0011] According to another embodiment, the present disclosure provides a composition comprising from about 0.1 % to about 15 %, for example from about 0.2% to about 10 %, or from about 0.5 % to about 8 %, per weight of the composition, of a pharmaceutically acceptable organic acid.

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

[0013] According to another embodiment, the pharmaceutically acceptable organic acid is selected from the group consisting of 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 embodiment, the pharmaceutically acceptable organic acid is citric acid or maleic acid.

[0015] In a subclass of any of the above embodiments is a pharmaceutical composition which comprises from about 0.5 % to about 20 %, for example from about 1 % to about 15 %, or from about 2 % to about 10 %, per weight of the composition, of 2-(isoindolin-2-ylmethyl)-5-((l-(methylsulfonyl)piperidin-4- yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof.

[0016] In a subclass of any of the above embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable salt of 2-(isoindolin-2-yl- methyl)-5-((l-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) as an active ingredient.

[0017] In a subclass of the above embodiment is a pharmaceutical composition comprising a tosylate salt of 2-(isoindolin-2-ylmethyl)-5-((l-(methylsulfonyl)- piperidin-4-yl)methoxy)-4H-pyran-4-one (I) as an active ingredient.

[0018] In a subclass of any of the above embodiments is a pharmaceutical composition comprising from about 50 % to about 90 %, for example from about 60 % to about 88 %, or from about 70 % to about 85 %, per weight of the composition, of a filler.

[0019] In a subclass of any of the above embodiments is a pharmaceutical composition comprising from about 0.5 % to about 10 %, for example from about 1 % to about 8 %, or from about 2 % to about 6 %, per weight of the composition, of a disintegrant.

[0020] In a subclass of any of the above embodiments is a pharmaceutical composition comprising from about 0.5 % to about 15 %, for example from about 1 % to about 10 %, or from about 2 % to about 8 %, per weight of the composition, of a binder.

[0021] In a subclass of any of the above embodiments is a pharmaceutical composition comprising from about 0.5 % to about 10 %, for example from about 0.8 % to about 8 %, or from about 1 % to about 5 %, per weight of the composition, of a lubricant.

[0022] The compositions of the present disclosure can be, for example, in the form of a tablet, pellets, or powder suitable to be filled into a capsule shell.

[0023] As used herein, the term “powder” refers to powdery material such as granules or milled powder.

[0024] According to one embodiment, the pharmaceutical composition is in the form of a tablet. Tablets can be manufactured by the process of direct compression, wet granulation, or dry granulation (slugging or roller compaction).

[0025] Direct compression is regarded as a relatively quick process wherein the powdered materials included in the solid dosage form are compressed directly without modifying their physical nature. Usually, the active ingredient, and other excipients, such as lubricant to prevent adhesion of the tablet material to the surface of the punches of the tablet press, are blended in a blender or similar low shear apparatus before being compressed into tablets using a tablet press vehicle.

[0026] Thus, in accordance with one embodiment of the present disclosure, there is provided a direct compressed pharmaceutical composition comprising 2- (isoindolin-2-ylmethyl)-5-((l-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4- one (I) or a pharmaceutically acceptable salt thereof, a stability enhancing amount of a pharmaceutically acceptable organic acid, and optionally one or more other excipients.

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

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

[0029] Wet granulation typically comprises mixing the active ingredient and other intragranular components in a suitable mixer, granulating the mixture by spraying granulating liquid, for example water, into the mixture and drying the wet granules. If the composition also comprises extragranular components, they are suitably mixed with the dried granules, and, in case the composition is a tablet, the obtained mixture is compressed into tablets. In case the composition is in the form of capsule, the obtained mixture can be filled directly into a capsule shell. The stability enhancing pharmaceutically acceptable organic acid can be mixed as solid with intragranular components or dissolved in the granulating liquid.

[0030] Thus, in accordance with one embodiment of the present invention, there is provided a wet granulated pharmaceutical composition comprising 2-(isoindolin-2- ylmethyl)-5-((l-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof, a stability enhancing amount of a pharmaceutically acceptable organic acid, and optionally one or more other excipients.

[0031] According to another embodiment, the wet granulated tablet comprises an intragranular part and an extragranular part.

[0032] According to one embodiment, the pharmaceutical composition comprises(a) an intragranular part comprising 2-(isoindolin-2-ylmethyl)-5-((l-(methyl- sulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof, and a stability enhancing amount of a pharmaceutically acceptable organic acid, and(b) an extragranular part comprising at least one excipient.

[0033] In a subclass of the above embodiment is a wet granulated pharmaceutical composition wherein the pharmaceutically acceptable organic acid is dissolved or dispersed in the granulating liquid.

[0034] According to one embodiment, the present disclosure provides a pharmaceutical composition comprising(a) an intragranular part comprising, per weight of the intragranular part,(i) from about 0.5 % to about 20 % of 2-(isoindolin-2-ylmethyl)-5-((l- (methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof;(ii) from about 0.1 % to about 15 % of a pharmaceutically acceptable organic acid;(iii) from about 50 % to about 90 % of a filler;(iv) from about 0.5 % to about 10 % of a disintegrant;(v) from about 0.5 % to about 15 % of a binder;(b) an extragranular part comprising, per weight of the extragranular part,(i) from about 50 % to 100 % of a filler;(ii) from 0 % to about 25 % of a disintegrant; and(iii) from 0 % to about 25 % of a lubricant.

[0035] In a subclass of any of the above embodiments are pharmaceutical compositions, wherein the intragranular part comprises, from about 30 % to about 95 %, for example from about 50 % to about 90 % or from about 70 % to about 85 %, per weight of the composition.

[0036] It is to be understood that when the composition is in the form of a powder, including granules, the component percentages above refer to the powder pharmaceutical composition without the capsule shell.

[0037] The tablet cores can be provided with a water-soluble film coating, if desired, to facilitate tablet swallowing, to protect from direct contact with the drug substance and to improve aesthetics. A suitable film coating agent may be selected from the group consisting of plasticizers, film-forming agents, surfactants, colorants, and flavouring agents. Optionally an anti-tacking agent, glidant or opacifier may be used. A plasticizer, such as polyethylene glycol (PEG) or glycerol, a film-forming agent such as hydroxypropylmethyl cellulose (HPMC), a colorant, such as ferric oxide or titanium dioxide, a glidant such as talc or magnesium stearate, and a flavouring agent such as polydextrose or sucrose, may be combined with a filmcoating liquid, preferably water, to result in a homogeneous coating suspension which is brought up, preferably sprayed, on the tablets in a suitable coating device, such as for example a perforated drum coater. The film coating typically amounts to from about 2 % to about 5 %, for example from about 2.5 % to about 4 %, per weight of the tablet composition.

[0038] In a subclass of any of the above embodiments are pharmaceutical compositions comprising from about 0.1 mg to about 30 mg, for example from about 0.5 mg to about 25 mg, for example from about 1 mg to about 20 mg, for example from about 2 mg to about 10 mg, for example about 2.5 mg, about 3.5 mg, about 5 mg or about 7.1 mg, of 2-(isoindolin-2-ylmethyl)-5-((l-(methylsulfonyl)piperidin-4- yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof, for example tosylate salt.

[0039] As used herein, the term “pKa” refers to the common symbol used to express the strength of an acid and is related to the dissociation constant for the acid in aqueous solution. In the case of polyprotic acid, the term pKa refers to the first pKa (pKal).

[0040] As used herein, a “filler” refers to one or more pharmaceutically acceptable excipient(s) that adds bulkiness to a pharmaceutical composition. Examples of fillers include sugars (e.g., mannitol or sucrose), starch, pregelatinized starch, microcrystalline cellulose, lactose, calcium hydrogen phosphate and sorbitol. According to one embodiment, the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, lactose, calcium hydrogen phosphate and a combination thereof. According to another embodiment, the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, and combinations thereof.

[0041] As used herein, a “disintegranf ’ refers to one or more pharmaceutically acceptable excipient(s) which is added to the pharmaceutical composition to cause itsdisintegration to support the release of the active ingredient from the pharmaceutical composition. Examples of disintegrants include croscarmellose sodium, cross-linked polyvinylpyrrolidone and sodium starch glycolate. According to one embodiment, the disintegrant is selected from croscarmellose sodium, sodium starch glycolate and a combination thereof. According to another embodiment, the disintegrant is croscarmellose sodium.

[0042] As used herein, a “binder” refers to one or more pharmaceutically acceptable excipient(s) that imparts enhanced cohesion by binding the active ingredient and the excipients together in a mixture. Examples of binders include hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl acetate and polyvinyl alcohol. According to one embodiment, the binder is selected from hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and a combination thereof. According to another preferred embodiment, the binder is hydroxypropylmethyl cellulose (HPMC). According to still another embodiment, the binder is hydroxypropylmethyl cellulose (HPMC) and the disintegrant is croscarmellose sodium. In case of wet granulated tablets, the binder can be incorporated into the intragranular part as dry powder or dissolved or dispersed in the granulation liquid.

[0043] As used herein, a “lubricant” refers to one or more pharmaceutically acceptable excipient(s), which is added to the pharmaceutical composition to reduce friction, heat, and wear when introduced between solid surfaces. Examples of lubricants include sodium stearyl fumarate, magnesium stearate, talc, silica, calcium stearate and carnauba wax. According to one embodiment, the lubricant is sodium stearyl fumarate.

[0044] For the manufacture of the pharmaceutical composition, compound of formula (I) or a pharmaceutically acceptable salt thereof, for example tosylate salt, is suitably milled into the desired particle size. The milled compound can have a particle size having the volume median diameter (Dv50) of not more than 50 pm, not more than 30 pm, or not more than 25 pm. For example, Dv50 may be in the range of 1 - 25 pm, between 2 - 20 pm, or between 5 - 15 pm. The particle size distribution can be analyzed by laser light diffraction, for example using Beckman Coulter LS13320 laser diffraction particle size analyzer equipped with Tornado Dry Powder System using air as dispersion medium with measurement pressure 24”H2O ± 2”H2O, sample amount 10 ml, system-controlled target 5 % for obscuration and applying Fraunhofer optical model.

[0045] Milling of the active ingredient can be carried out using suitable feeder and milling equipment, for example, single or twin screw / auger feeders, hammer mills, pin mills, jet mills or sieve mills, using suitable rotor speeds such as, for example 3000 - 10000 rpm. The milling can be conducted in a suitable temperature, for example, in room temperature or lower.

[0046] Compound of formula (I) or a pharmaceutically acceptable salt thereof is suitably administered, for example for the treatment of hormone dependent cancers, for example prostate cancer, in an amount ranging from about 0.5 mg to about 30 mg, or from about 1 mg to about 25 mg, for example from about 2 mg to about 15 mg, such as about 5 mg or about 7 mg per day to the patient. The dose can be administered once daily or divided to several times a day, for example twice daily.

[0047] The invention is further illustrated by the following examples.EXAMPLES

[0048] Example 1. Tablet composition (direct compressed)Composition Amount (mg)Compound (I), tosylate salt 35.32Mannitol 226.79Pregelatinized starch 50.40Hydroxypropyl methylcellulose (HPMC) 16.02Croscarmellose sodium 15.98Citric acid 8.50Microcrystalline cellulose 64.00Sodium stearyl fumarate 7.99Weight 425.00

[0049] Example 2. Tablet composition (direct compressed)Composition Amount (mg)Compound (I), tosylate salt 35.32Mannitol 216.36Pregelatinized starch 48.08Hydroxypropyl methylcellulose (HPMC) 16.02Croscarmellose sodium 15.98Citric acid 21.25Microcrystalline cellulose 64.00Sodium stearyl fumarate 7.99Composition Amount (mg)Weight 425.00

[0050] Example 3. Tablet composition (direct compressed)Composition Amount (mg)Compound (I), tosylate salt 35.32Mannitol 226.79Pregelatinized starch 50.40Hydroxypropyl methylcellulose (HPMC) 16.02Croscarmellose sodium 15.98Maleic acid 8.50Microcrystalline cellulose 64.00Sodium stearyl fumarate 7.99Weight 425.00

[0051] Example 4. Tablet composition (direct compressed)Composition Amount (mg)Compound (I), tosylate salt 35.32Mannitol 216.36Pregelatinized starch 48.08Hydroxypropyl methylcellulose (HPMC) 16.02Croscarmellose sodium 15.98Maleic acid 21.25Microcrystalline cellulose 64.00Sodium stearyl fumarate 7.99Weight 425.00

[0052] Example 5. Tablet composition (direct compressed)Composition Amount (mg)Compound (I), tosylate salt 3.53Mannitol 42.23Pregelatinized starch 9.39Hydroxypropyl methylcellulose (HPMC) 2.83Croscarmellose sodium 2.82Citric acid 1.50Microcrystalline cellulose 11.29Composition Amount (mg)Sodium stearyl fumarate 1.41Weight 75.00

[0053] Example 6. Tablet composition (direct compressed)Composition Amount (mg)Compound (I), tosylate salt 3.53Mannitol 40.39Pregelatinized starch 8.98Hydroxypropyl methylcellulose (HPMC) 2.83Croscarmellose sodium 2.82Citric acid 3.75Microcrystalline cellulose 11.29Sodium stearyl fumarate 1.41Weight 75.00

[0054] Example 7. Tablet composition (direct compressed)Composition Amount (mg)Compound (I), tosylate salt 3.53Mannitol 42.23Pregelatinized starch 9.39Hydroxypropyl methylcellulose (HPMC) 2.83Croscarmellose sodium 2.82Maleic acid 1.50Microcrystalline cellulose 11.29Sodium stearyl fumarate 1.41Weight 75.00

[0055] Example 8. Tablet composition (direct compressed)Composition Amount (mg)Compound (I), tosylate salt 3.53Mannitol 40.39Pregelatinized starch 8.98Hydroxypropyl methylcellulose (HPMC) 2.83Croscarmellose sodium 2.82Composition Amount (mg)Maleic acid 3.75Microcrystalline cellulose 11.29Sodium stearyl fumarate 1.41Weight 75.0

[0056] Tablet compositions of Examples 1 to 8 were prepared by blending the components together and compressing the mixture into tablets with a tablet press.

[0057] Example 9. Tablet composition (wet granulated)Composition Amount (mg)Intr agranularCompound (I), tosylate salt 3.53Mannitol 42.45Pregelatinized starch 9.44Hydroxypropyl methylcellulose (HPMC) 2.83Croscarmellose sodium 1.41Citric acid 1.22Extr agranularMicrocrystalline cellulose 11.30Croscarmellose sodium 1.41Sodium stearyl fumarate 1.41Total weight 75.00

[0058] Example 10. Tablet composition (wet granulated)Composition Amount (mg)Intr agranularCompound (I), tosylate salt 3.53Mannitol 40.97Pregelatinized starch 9.10Hydroxypropyl methylcellulose (HPMC) 2.83Croscarmellose sodium 1.41Citric acid 3.04Extr agranularMicrocrystalline cellulose 11.30Croscarmellose sodium 1.41Sodium stearyl fumarate 1.41 Total weight 75.00

[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 the mixture. The granules were dried in a fluid-bed dryer and screened with a conical mill. Extragranular components were added, and the blend was compressed into tablets with a tablet press.

[0060] Example 11. Tablet composition (wet granulated, acid in granulation liquid)Composition Amount (mg)IntragranularCompound (I), tosylate salt 3.53Mannitol 42.43Pregelatinized starch 9.43Hydroxypropyl methylcellulose (HPMC) 2.83Croscarmellose sodium 1.41Citric acid 1.25ExtragranularMicrocrystalline cellulose 11.30Croscarmellose sodium 1.41Sodium stearyl fumarate 1.41Total weight 75.00

[0061] Example 12. Tablet composition (wet granulated, acid in granulation liquid)Composition Amount (mg)IntragranularCompound (I), tosylate salt 3.53Mannitol 42.84Pregelatinized starch 9.52Hydroxypropyl methylcellulose (HPMC) 2.83Croscarmellose sodium 1.41Maleic acid 0.75Extr agranularMicrocrystalline cellulose 11.30Croscarmellose sodium 1.41Sodium stearyl fumarate 1.41Total weight 75.00

[0062] Example 13. Tablet composition (wet granulated, acid in granulation liquid)Composition Amount (mg)Intr agranularCompound (I), tosylate salt 3.53Mannitol 42.82Pregelatinized starch 9.52Hydroxypropyl methylcellulose (HPMC) 2.83Croscarmellose sodium 1.41Succinic acid 0.77Extr agranularMicrocrystalline cellulose 11.30Croscarmellose sodium 1.41Sodium stearyl fumarate 1.41Total weight 75.00

[0063] Example 14. Tablet composition (wet granulated, acid in granulation liquid)Composition Amount (mg)Intr agranularCompound (I), tosylate salt 3.53Mannitol 43.22Pregelatinized starch 9.61Hydroxypropyl methylcellulose (HPMC) 2.83Croscarmellose sodium 1.41 p-Toluenesulfonic acid 0.28Extr agranularMicrocrystalline cellulose 11.30Croscarmellose sodium 1.41Sodium stearyl fumarate 1.41Total weight 75.00

[0064] The tablet compositions of Examples 11 to 14 were prepared by mixing the intragranular components (excluding the acid) in a high-shear mixer. The granulating liquid was prepared by dissolving the acid into water. The mixture was granulated by spraying the granulating liquid into the mixture. The granules were dried in a fluid-bed dryer and screened with a conical mill. Extragranular components were added, and the blend was compressed into tablets with a tablet press.

[0065] Example 15. Comparative stability study I

[0066] Various direct compressed (DC) tablet compositions DC1 to DC 10 were prepared by blending the components together and compressing the mixture into tablets with a tablet press. The stability of the compositions was tested by storing the tablets in an open container in 60 °C / 75 % RH conditions for 4 weeks. The formulation descriptions and total amount of formed degradation impurities after 4 weeks are given in the Table 1. The quantitative compositions of the formulations are presented in Table 2 and Table 3. It can be seen that acid appeared to improve chemical stability of the direct compressed compositions.

[0067] Table 1. Results of the comparative stability study IComposition Description Total impuritiesDC1 Composition of DC 1 (without acid) 1.30 %DC2 DC1 like composition with 2 % citric acid 0.80 %DC3 DC1 like composition with 5 % citric acid 0.40 %DC4 DC1 like composition with 2 % maleic acid 0.10 %DC5 DC1 like composition with 5 % maleic acid 0.10 %DC6 Composition of DC6 (without acid) 3.00 %DC7 DC6 like composition with 2 % citric acid 0.80 %DC8 DC6 like composition with 5 % citric acid 0.70 %DC9 DC6 like composition with 2 % maleic acid 0.14 %DC10 DC6 like composition with 5 % maleic acid 0.06 %

[0068] Table 2. Quantitative direct compressed (DC) tablet formulations DC1- DC5. Total tablet mass 425 mg.API = Active pharmaceutical ingredient (Compound (I), tosylate salt)HPMC = Hydroxypropylmethyl celluloseCCS = Croscarmellose sodiumMCC = Microcrystalline celluloseSSF = Sodium stearyl fumarate

[0069] Table 3. Quantitative direct compressed (DC) tablet formulations DC6- DC10. Total tablet mass 75 mg.API = Active pharmaceutical ingredient (Compound (I) tosylate salt)HPMC = Hydroxypropylmethyl celluloseCCS = Croscarmellose sodiumMCC = Microcrystalline cellulose SSF = Sodium stearyl fumarate

[0070] Example 16. Comparative stability study IIVarious wet granulated (WG) tablets were prepared by mixing the intragranular components in a high-shear mixer. The mixture was granulated by spraying water into the mixture. The granules were dried in a fluid-bed dryer and screened with a conical mill. Extragranular components were added, and the blend was compressed into tablets with a tablet press. The stability of the compositions was tested by storing the tablets in a closed container in 40 °C / 75 % RH conditions for 6 months. The formulation descriptions and total amount of formed degradation impurities after 6 months are given in the Table 4. The actual compositions of the wet granulated (WG) formulations WG1 to WG3 are presented in Table 5. It can be seen that acid added as solid to the intragranular part appeared to improve chemical stability of the wet granulated (WG) compositions.

[0071] Table 4. Results of the comparative stability study IIComposition Description Total impuritiesWG1 Composition of WG1 (without acid) 0.7 %WG2 WG1 like composition with 2 % citric acid (dry) in o 3 ° / granuleWG1 like composition with 5 % citric acid (dry) in _ _n / W(J . 0.2 / o granule

[0072] Table 5. Quantitative wet granulated (WG) tablet formulations WG1- WG3. Total tablet mass 75 mg. Acid added as a solid into the intragranular part.API = Active pharmaceutical ingredient (Compound (I), tosylate salt) HPMC = Hydroxypropylmethyl cellulose CCS = Croscarmellose sodium MCC = Microcrystalline cellulose SSF = Sodium stearyl fumarate

[0073] Example 17. Comparative stability study III

[0074] Various wet granulated (WG) tablets were prepared by mixing the intragranular components in a high-shear mixer. The mixture was granulated by spraying into the mixture water or an acid dissolved in water. The granules were dried in a fluid-bed dryer and screened with a conical mill. Extragranular components were added, and the blend was compressed into tablets with a tablet press. The stability of the compositions was tested by storing the tablets in a closed container in 40 °C / 75 % RH conditions for 6 months. The formulation descriptions and total amount of formed degradation impurities after 6 months are given in the Table 6. The actual compositions of the wet granulated (WG) formulations WG4 to WG8 are presented in Table 7. It can be seen that acid dissolved into the granulation liquid appeared to improve chemical stability of the wet granulated (WG) compositions.

[0075] Table 6. Results of the comparative stability study IIIComposition Description Total impuritiesWG4 Composition of WG4 (without acid) 0.7 %WG5 WG4 like composition with 1.66 % citric acid 0.3 %WG6 WG4 like composition with 1.01 % maleic acid 0.3 %WG7 WG4 like composition with 1.02 % succinic acid 0.5 % xx / z-o WG4 like composition with 0.37 % p-toluenesulfonic „ .Vv ro . , U.40 / / o acid

[0076] Table 7. Quantitative wet granulated (WG) tablet formulations WG4- WG8. Total tablet mass 75 mg. Acid dissolved into the granulation liquid.API = Active pharmaceutical ingredient (Compound (I) tosylate salt)HPMC = Hydroxypropylmethyl celluloseCCS = Croscarmellose sodiumMCC = Microcrystalline celluloseSSF = Sodium stearyl fumarate

Claims

Claims1. A pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((l- (methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof as an active ingredient and a stability enhancing amount of a pharmaceutically acceptable organic acid.

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

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

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

5. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutically acceptable organic acid is selected from the group consisting of 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 of the preceding claims, comprising from about 0.5 % to about 20 %, per weight of the pharmaceutical composition, of 2-(isoindolin-2-ylmethyl)-5-((l-(methylsulfonyl)piperidin-4- yl)methoxy)-4H-pyran-4-one (I) or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

14. The pharmaceutical composition according to claim 13, which is a direct compressed tablet.

15. The pharmaceutical composition according to claim 13, which is a wet granulated tablet.

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

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

18. The pharmaceutical composition according to claims 16 or 17, wherein the filler is selected from the group consisting of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, and calcium hydrogen phosphate.

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

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 stearyl fumarate.

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