Pharmaceutical Compositions of CYP11A1 Inhibitors

Abstract

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

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for oral administration, in particular in the form of a powder suitable for filling tablets or capsule shells, comprising as active ingredient 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof. [Background technology]

[0002] The compound 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) and its derivatives are disclosed in WO 2018 / 115591. The compounds of formula (I) are selective inhibitors of the CYP11A1 enzyme and are useful in the treatment of hormone-regulated disorders such as cancer, including prostate and breast cancer. [ka]

[0003] Compound (I) and its pharma- ceutically acceptable salts have been found to be suitable for oral administration. However, it has been found that the active ingredient tends to cause stability problems when formulated with carriers and excipients in the development of solid oral compositions such as tablets and capsules. It has also been found that the suitable amount of active ingredient in solid oral compositions for the treatment of human patients is very small, generally about 0.5 mg to about 10 mg, typically about 1 mg to about 8 mg. Therefore, the percentage of active ingredient in the tablet composition remains small while the tablet should not be too small so that it is difficult for the patient to handle it. Summary of the Invention

[0004] The present invention provides a pharmaceutical composition for oral administration, in particular in the form of a powder suitable for filling into tablets or capsule shells, comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof as an active ingredient. It has been found that the stability of the active ingredient is improved by wet granulation, high intragranular drug loading, the use of neutral or weakly acidic pharmaceutical ingredients, and / or the inclusion of an oxygen scavenger. Furthermore, it has been found that the amount of active ingredient sufficient in the composition for the treatment of human patients is extremely small. The composition provides good dose content uniformity and efficient release of the active ingredient as well as constant dissolution characteristics, resulting in effective and reproducible in vivo plasma concentrations. Thus, the composition according to the present invention is particularly suitable as a dosage form for the treatment of patients suffering from hormone-regulated diseases, such as prostate and breast cancer, where CYP11A1 inhibition is desired.

[0005] Thus, according to one embodiment, the present invention discloses a wet granulation pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof and at least one excipient.

[0006] According to another embodiment, the present invention comprises: (a) an intragranular portion comprising at least 5% by weight of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof, and at least one excipient; (b) an extraparticulate portion comprising at least one excipient.

[0007] According to yet another embodiment, the present invention provides a package containing a pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof and at least one excipient, the package also comprising an oxygen scavenger. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present invention relates to a pharmaceutical composition for oral administration, in particular in the form of a powder suitable for filling into tablets or capsules, comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof as active ingredient. The compound of formula (I) or a pharma- ceutically acceptable salt thereof may be in an amorphous or crystalline state. Suitable pharma- ceutically acceptable salts of compound (I) are salts with organic or inorganic acids, including salts with p-toluenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, hydrobromic acid, nitric acid, benzenesulfonic acid, hydrochloric acid, maleic acid, 1,2-ethanedisulfonic acid, oxalic acid, ethanesulfonic acid, sulfuric acid and methanesulfonic acid. A particular embodiment of the invention is the salt with p-toluenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid and hydrobromic acid. Another particular embodiment of the invention is the salt with p-toluenesulfonic acid.

[0009] According to one embodiment of the present invention, there is provided a wet granulated pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof and at least one excipient. The wet granulation process has been found to prevent degradation of compound (I) or a pharma- ceutically acceptable salt thereof during manufacture and / or storage of dosage forms such as tablets and powders, and especially tablets.

[0010] According to another embodiment, the present invention comprises: (a) an intragranular portion comprising at least 5% by weight of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof, and at least one excipient; (b) an extraparticulate portion comprising at least one excipient.

[0011] According to another embodiment, the present invention provides a package containing a pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof and at least one excipient, the package also containing an oxygen scavenger. The oxygen scavenger has been found to improve the stability of the dosage form by preventing or inhibiting degradation of the active ingredient during storage of the dosage form.

[0012] A subclass of any of the above embodiments includes compositions comprising an intra-particle portion comprising at least about 5%, e.g., about 5% to about 20%, about 5% to about 15%, or about 5% to about 12%, by weight of the intra-particle portion, of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof, and at least one excipient.

[0013] A subclass of the above embodiment includes a pharmaceutical composition comprising: (a) an inner particle portion, the inner particle portion comprising at least 5% by weight, for example, about 5% to about 20%, about 5% to about 15%, or about 5% to about 12% of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof, and at least one excipient; (b) an extraparticulate portion comprising at least one excipient.

[0014] A subclass of any of the above embodiments includes a pharmaceutical composition comprising about 0.5 mg to about 10 mg, e.g., about 1 mg to about 8 mg, e.g., about 2.5 mg, about 3.5 mg, about 5 mg, or about 7.1 mg of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I), or a pharma- ceutically acceptable salt thereof.

[0015] It has been found that a high drug loading in the intraparticular portion improves the stability of the compound of formula (I) or its pharma- ceutically acceptable salt.Thus, even if the suitable amount of the compound of formula (I) or its pharma- ceutically acceptable salt in the dosage form is low, it is preferable to maintain a high drug loading in the intraparticular portion in order to improve the stability of the dosage form during manufacture and / or storage.

[0016] Subclasses of any of the above embodiments include: (a) an intragranular portion, per weight of the intragranular portion; (i) at least about 5%, e.g., from about 5% to about 20%, from about 5% to about 15%, or from about 5% to about 12% of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof; (ii) about 55% to about 95%, e.g., about 70% to about 90%, of a filler; (iii) about 0.5% to about 10%, e.g., about 1% to about 5%, of a disintegrant, and (iv) an intragranular portion comprising about 1% to about 15%, e.g., about 2% to about 10%, of a binder; (b) an extra-particle portion, per weight of the extra-particle portion: (i) about 50% to 100%, e.g., about 70% to about 100%, of a filler; (ii) from about 0% to about 25%, e.g., from about 0% to about 20%, or from about 2% to about 15%, of a disintegrant; and (iii) an extraparticulate portion comprising about 0% to about 25%, for example, about 0% to about 20%, or about 2% to about 15% of a lubricant.

[0017] As used herein, "filler" refers to one or more pharma- ceutically acceptable excipient(s) that provide bulk 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 combinations thereof. According to one embodiment, the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, and combinations thereof.

[0018] The term "calcium hydrogen phosphate" or "dicalcium phosphate" as used herein includes anhydrous calcium hydrogen phosphate and hydrates such as calcium hydrogen phosphate dihydrate.

[0019] As used herein, "disintegrant" refers to one or more pharma- ceutically acceptable excipient(s) added to a pharmaceutical composition to cause its disintegration to aid in 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 combinations thereof. According to another embodiment, the disintegrant is croscarmellose sodium.

[0020] As used herein, "binder" refers to one or more pharma- ceutically acceptable excipient(s) that enhance adhesion by binding active ingredients and excipients together in a mixture. Examples of binders include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl acetate, and polyvinyl alcohol. According to one embodiment, the binder is selected from hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), and combinations thereof. According to another preferred embodiment, the binder is hydroxypropylmethylcellulose (HPMC). According to yet another embodiment, the binder is hydroxypropylmethylcellulose (HPMC) and the disintegrant is croscarmellose sodium.

[0021] As used herein, "lubricant" refers to one or more pharma- ceutically acceptable excipient(s) added to a pharmaceutical composition to reduce friction, heat, and wear when introduced between solid surfaces. Examples of lubricants include sodium stearyl fumarate, magnesium stearate, stearic acid, talc, silica, calcium stearate, and carnauba wax. According to one embodiment, the lubricant is sodium stearyl fumarate.

[0022] Subclasses of any of the above embodiments include: (a) an intragranular portion, per weight of the intragranular portion; (i) at least about 5%, e.g., from about 5% to about 20%, from about 5% to about 15%, or from about 5% to about 12% of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof; (ii) about 55% to about 95%, e.g., about 70% to about 90%, of a filler selected from mannitol, pregelatinized starch, microcrystalline cellulose, lactose, calcium hydrogen phosphate, and combinations thereof; (iii) about 0.5% to about 10%, e.g., about 1% to about 5%, of a disintegrant selected from croscarmellose sodium, sodium starch glycolate, and combinations thereof; and (iv) an intra-particle portion comprising about 1% to about 15%, e.g., about 2% to about 10%, of a binder selected from HPMC, HPC, and combinations thereof; (b) an extra-particle portion, per weight of the extra-particle portion: (i) about 50% to 100%, for example, about 70% to about 100%, of a filler selected from microcrystalline cellulose, mannitol, lactose, calcium hydrogen phosphate, and combinations thereof; (ii) 0% to about 25%, e.g., about 0% to about 20%, or about 2 to about 15%, of a disintegrant selected from croscarmellose sodium, sodium starch glycolate, and combinations thereof; and (iii) an extraparticulate portion comprising 0% to about 25%, for example, about 0% to about 20%, or about 2 to about 15%, of a lubricant, wherein the lubricant is sodium stearyl fumarate.

[0023] Subclasses of any of the above embodiments include: (a) an intragranular portion, per weight of the intragranular portion; (i) at least about 5%, e.g., from about 5% to about 20%, from about 5% to about 15%, or from about 5% to about 12% of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof; (ii) about 55% to about 95%, e.g., about 70% to about 90%, of a combination of mannitol and pregelatinized starch; (iii) about 0.5% to about 10%, for example, about 1% to about 5%, of croscarmellose sodium; (iv) an intra-particle portion comprising about 1% to about 15%, e.g., about 2% to about 10% HPMC; (b) an extra-particle portion, per weight of the extra-particle portion: (i) about 50% to 100%, for example, about 70% to about 90%, microcrystalline cellulose; (ii) 0% to about 25%, e.g., about 2% to about 20%, or about 5% to about 15%, of croscarmellose sodium, and (iii) an extra-particle portion comprising 0% to about 25%, for example, about 2% to about 20%, or about 5% to about 15% sodium stearyl fumarate.

[0024] Subclasses of any of the above embodiments include pharmaceutical compositions wherein the intraparticulate portion comprises from about 30% to about 95%, e.g., from about 50% to about 90%, or from about 70% to about 85%, by weight of the composition.

[0025] It has been found that fine particles of a compound of formula (I) or a pharma- ceutically acceptable salt thereof provide better dissolution rate and content uniformity than coarse particles.

[0026] Thus, in the preparation of a pharmaceutical composition, the compound of formula (I) or a pharma- ceutically acceptable salt thereof, such as the p-toluenesulfonate salt, is suitably milled. In various embodiments, the milled compound has a particle size with a volume median diameter (Dv50) of 50 μm or less, 30 μm or less, or 25 μm or less. For example, the Dv50 may range from 1 to 25 μm, 2 to 20 μm, or 5 to 15 μm. The particle size distribution can be analyzed by laser diffraction, for example, using a Beckman Coulter LS13320 laser diffraction particle size analyzer equipped with a Tornado Dry Powder System, with air as the carrier medium, a measurement pressure of 24"H2O±2"H2O, a sample volume of 10 ml, and a system control target for opacity of 5%, applying the Fraunhofer optical model.

[0027] Milling of the active ingredient can be carried out using suitable feeder and milling equipment, such as single or twin screw / auger feeders, hammer mills, pin mills, jet mills, or sieve mills, with suitable rotor speeds, such as, for example, 3000-10000 rpm. Milling can be carried out at a suitable temperature, such as, for example, room temperature or below.

[0028] Thus, a further subclass of any of the above embodiments includes a pharmaceutical composition that provides dissolution of at least 80% by weight of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof in 0.05M phosphate buffer at pH 6.8 within 60 minutes, preferably within 45 minutes, using a paddle apparatus (USP Apparatus 2) with a vessel volume of 500 ml at a paddle speed of 75 rpm at 37°C. In one embodiment, the active ingredient is the p-toluenesulfonate salt of compound (I), wherein the pharmaceutical composition provides dissolution of at least 80% by weight of the p-toluenesulfonate salt of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) within 60 minutes, or within 45 minutes, in 0.05 M phosphate buffer at pH 6.8 using a paddle apparatus (USP Apparatus 2) with a vessel volume of 500 ml at a paddle speed of 75 rpm at 37°C.

[0029] A further subclass of any of the above embodiments includes the pharmaceutical composition in the form of a coated or uncoated tablet. According to another subclass of any of the above embodiments, the pharmaceutical composition is in the form of a powder comprising granules, which may be suitable for filling a capsule shell.

[0030] Thus, the term "powder" as used herein refers to a powdered substance such as a pulverized powder or granules.

[0031] A further subclass of any of the above embodiments includes pharmaceutical compositions prepared by a process comprising wet granulation.

[0032] Where the composition is in the form of a powder containing granules, it should be understood that the percentages of ingredients above refer to the powder pharmaceutical composition without the capsule shell.

[0033] The composition is suitably prepared by wet granulation, as this has been found to prevent degradation of the compound of formula (I) or a pharma- ceutically acceptable salt thereof during manufacture and / or storage of the dosage form.

[0034] Thus, according to one embodiment of the present invention, the process for producing a pharmaceutical composition according to any of the above embodiments is characterized by the steps of: (a) mixing the compound of formula (I) or a pharma- ceutically acceptable salt thereof with other intragranular ingredients in a suitable mixer; (b) granulating the mixture by spraying a granulating liquid, e.g. water, onto the mixture; (c) drying the wet granules; (d) mixing the extragranular ingredients with the dried granules; and (e) compressing the resulting mixture into a tablet, if the composition is a tablet. If the composition is a powder, the mixture of step (d) can be directly filled into capsule shells.

[0035] According to another embodiment of the present invention, the process for producing a pharmaceutical composition according to any of the above embodiments is characterized by the steps of: (a) mixing the compound of formula (I) or a pharma- ceutically acceptable salt thereof with other intragranular ingredients other than at least a portion of the binder in a suitable mixer; (b) granulating the mixture by spraying a granulation liquid, e.g., a combination of water and at least a portion of the binder, onto the mixture; (c) drying the wet granules; (d) mixing the extragranular ingredients with the dried granules; and (e) compressing the resulting mixture into a tablet, if the composition is a tablet. If the composition is a powder, the mixture of step (d) can be directly filled into a capsule shell.

[0036] According to another embodiment, all the ingredients are blended together and filled into the capsule shells without a granulation step.

[0037] According to one embodiment, the composition of the present invention is suitably prepared, for example, by first mixing at least a portion (typically about 30% to about 70%, e.g., about 50% by weight of the total) of the compound of formula (I) or its pharma- ceutically acceptable salt, the filler, the binder, and the disintegrant in a suitable granulator vessel, for example, a wet high shear granulator. The mixture is then suitably granulated in the granulator using purified water as the granulation liquid. Alternatively, the binder can be mixed with the granulation liquid instead of mixing the binder with the other intragranular ingredients in the first step. The wet granules can then be sieved, for example, using a sieving mill device (rotating impeller), and then dried, for example, in a fluidized bed dryer.

[0038] The dried granules may then be sieved using a sieving device, such as a sieving mill. If the composition is a powder to be filled into a capsule shell, the extragranular filler and any other ingredients are mixed with the granules. The resulting powder can then be filled into a capsule shell, such as a gelatin capsule shell or an HPMC capsule shell. If the composition is a tablet, the extragranular filler and possible remaining disintegrants can be added to the granules, followed by blending the mixture, for example, in a diffusion mixer. A lubricant is added to the compact from the previous step, followed by blending. The tablet compact is then compressed into a tablet core, for example, in an electrically assisted rotary tablet press.

[0039] The tablet core can be provided with a water-soluble film coating, if desired, to facilitate tablet swallowing, prevent direct contact with the drug substance, and improve aesthetics. Suitable film coating agents may be selected from the group consisting of plasticizers, film formers, surfactants, colorants, and flavorants. Optionally, anti-adherents, glidants, or opacifiers may be used. Plasticizers such as polyethylene glycol (PEG) or glycerol, film formers such as hydroxypropylmethylcellulose (HPMC), colorants such as ferric oxide or titanium dioxide, glidants such as talc or magnesium stearate, and flavorants such as polydextrose or sucrose can be mixed with a film-forming liquid, preferably water, to result in a homogenous coating suspension. This homogenous coating suspension is introduced onto the tablet in a suitable coating apparatus, such as a perforated drum coater, preferably sprayed. The film coating typically amounts to about 2% to about 5%, for example about 2.5% to about 4%, by weight of the tablet composition.

[0040] The unit dose tablet or unit dose powder filled into the capsule shell typically contains about 0.5 mg to about 10 mg, such as about 1 mg to about 8 mg, such as about 2.5 mg, about 3.5 mg, about 5.0 mg, or about 7.1 mg of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof, such as a salt of p-toluenesulfonic acid. The unit dose tablet or unit dose powder typically has a weight of about 50 mg to about 100 mg, such as about 70 mg to about 90 mg. The tablet may, for example, have an oval or circular shape and typically have a diameter of about 4 mm to about 8 mm, such as about 5 mm to about 7 mm, such as 6 mm.

[0041] The tablets or capsules can be packaged in conventional pharmaceutical containers such as bottles or blisters, e.g., HDPE bottles or PET blister packs covered with aluminum foil. Oxygen scavengers have been found to improve the stability of the dosage form by preventing or inhibiting the degradation of the active ingredient during storage of the dosage form. Thus, the container may contain an oxygen scavenger. The term "oxygen scavenger" refers to a substance that consumes, reduces, or reduces the amount of oxygen from a given environment. Examples of oxygen scavenger substances include transition metals or their salts, including but not limited to manganese II or III, iron II or III, cobalt II or III, nickel II or III, copper II or III, rhodium II, III or IV, and ruthenium, as well as non-metallic substances or their salts, such as ascorbic acid, ethylene glycol, propylene glycol, glyceric acid, gallic acid, catechol, unsaturated hydrocarbons, and hydrogenated rubber. Small canisters containing oxygen scavenger material are commercially available, such as the PharmaKeep® CD canisters from Airnov Healthcare Packaging and the StabilOx® canisters from Multisorb Filtration Group. Such canisters can be included within a pharmaceutical container, such as a plastic bottle, along with tablets or capsules.

[0042] The compound of formula (I) or a pharma- ceutical acceptable salt thereof is suitably administered to a patient 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, for example, about 5 mg or about 7 mg per day, for example, for the treatment of hormone-dependent cancer, such as prostate cancer. The dose can be administered once a day, or in divided doses several times a day, for example, twice a day.

[0043] The present invention is further illustrated by the following examples.

[0044] Example 1. Tablet composition [Table 1]

[0045] Example 2. Tablet Composition [Table 2]

[0046] Example 3. Tablet Composition [Table 3]

[0047] The tablet compositions of Examples 1-3 are prepared by mixing the intragranular ingredients in a high shear mixer. The mixture is granulated by spraying water onto the mixture. The granules are dried in a fluid bed dryer and sieved using a conical mill. The extragranular ingredients are added and the blend is compressed into tablets using a tablet press. Finally, the tablets are coated by spraying the coating suspension onto the tablet cores in a heated pan coater until the theoretical weight gain of the tablet is reached.

[0048] Example 4. Tablet Composition [Table 4]

[0049] Example 5. Tablet Composition [Table 5]

[0050] Example 6. Tablet Composition [Table 6]

[0051] Example 7. Tablet Composition [Table 7]

[0052] Example 8. Tablet Composition [Table 8]

[0053] Example 9. Tablet Composition [Table 9]

[0054] Example 10. Tablet Composition [Table 10]

[0055] Example 11. Tablet Composition [Table 11]

[0056] Example 12. Tablet Composition [Table 12]

[0057] The tablet compositions of Examples 4-12 are prepared by mixing the intragranular ingredients in a high shear mixer. The mixture is granulated by spraying water onto the mixture. The granules are dried in a fluid bed dryer and sieved using a conical mill. The extragranular ingredients are added and the blend is compressed into tablets using a tablet press.

[0058] Example 13. Powder composition filled into capsule shells [Table 13]

[0059] Example 14. Powder composition filled into capsule shells [Table 14]

[0060] The powder compositions of Examples 13 and 14 are prepared by mixing the intragranular components in a high shear mixer. The mixture is granulated by spraying water into the mixture. The granules are dried in a fluidized bed dryer and sieved using a conical mill. The extragranular components are added, followed by blending. The blend is filled into capsule shells.

[0061] Example 15. Comparative Stability Study I Various wet granulated (WG) tablet compositions WG1-WG9 were prepared using the methods described in Examples 4-12. The stability of the compositions was tested by storing the tablets at 60°C / 75% RH conditions for 4 weeks. The formulation description and total amount of impurities formed after 4 weeks are shown in Table 1. The quantitative composition of the formulations is shown in Table 2. Formulations WG6-WG8 did not contain any extragranular components and had poor tablet quality. Croscarmellose sodium is seen to improve the stability of HPMC-containing compositions.

[0062] Table 1. Results of comparative stability studies [Table 15]

[0063] Table 2. Quantitative formulation of compositions WG1-WG9 (WG3 is similar to WG1 except that mannitol is replaced by lactose) [Table 16-1] [Table 16-2]

[0064] Example 16. Comparative Stability Study II Wet granulation (WG) tablets according to Example 3 (without film coating) and corresponding direct compression (DC) tablets with equivalent quantitative composition were studied for stability. Other direct compression tablets were also prepared for this study. The stability of the compositions was tested by storing the tablets at 60°C / 75%RH conditions for 4 weeks. The formulation description and total amount of impurities formed after 4 weeks are shown in Table 3. The actual composition of direct compression formulations DC1-DC4 is shown in Table 4. It is seen that the wet granulation compositions have better stability than the corresponding direct compression compositions.

[0065] Table 3. Results of comparative stability studies [Table 17]

[0066] Table 4. Quantitative formulation of direct compression (DC) compositions [Table 18]

[0067] Direct compression tablets were prepared by blending the ingredients together and compressing the mixture into tablets using a tablet press.

[0068] Example 17. Comparative Stability Study III The stability of wet granulated (WG) tablets WG11-WG15 was studied. The tablets were prepared using the method described in Examples 4-12. The stability of the tablets was tested by storing 65 tablets in sealed 60ml or 100ml HDPE bottles with 2g of silica desiccant at 40°C / 75%RH conditions for 6 months. The formulation description is shown in Table 5, and the total amount of impurities formed and intragranular drug loading after 6 months are shown in Table 6. The results show that high intragranular drug loading improves the stability of the wet granulated compositions.

[0069] Table 5. Quantitative formulation of wet granulation (WG) compositions [Table 19]

[0070] Table 6. Results of comparative stability studies [Table 20]

[0071] Example 18. Comparative Stability Study IV The effect of oxygen scavengers on the stability of tablets WG14 and WG15 (see Example 17) was studied. The stability of the tablets was tested by storing 65 tablets with 2 g of silica desiccant in a sealed 60 ml HDPE bottle at 40° C. / 75% RH conditions for 6 months. The stability was tested inside the bottle with or without an oxygen scavengers canister (PharmaKeep® Capsule CD-2.15G, Airnov Healthcare Packaging for WG14 and StabilOx®, Multisorb Filtration Group for WG15). The results are shown in Table 7. The results show that the inclusion of oxygen scavengers improved the stability of the compositions.

[0072] Table 7. Results of comparative stability studies [Table 21]

Claims

1. A wet granulation pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof and at least one excipient.

2. 2. The composition of claim 1, comprising an intra-particle portion comprising at least about 5% by weight of said intra-particle portion of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof, and at least one excipient.

3. 3. The composition of claim 2, wherein the intra-particle portion comprises about 5% to about 20% of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof, by weight of the intra-particle portion.

4. (a) an intra-particle portion comprising at least 5% by weight of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof, and at least one excipient; (b) an extra-particulate portion comprising at least one excipient.

5. 13. The composition of any of the preceding claims, comprising about 0.5 mg to about 10 mg of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I), or a pharma- ceutically acceptable salt thereof.

6. (a) an intragranular portion, per weight of said intragranular portion: (i) from about 5% to about 20% of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof; (ii) about 55% to about 95% filler; (iii) about 0.5% to about 10% of a disintegrant, and (iv) said intragranular portion comprising about 1% to about 15% binder; (b) an extra-particle portion, per weight of said extra-particle portion: (i) about 50% to 100% filler; (ii) 0% to about 25% of a disintegrant, and (iii) the extraparticulate portion comprising from 0% to about 25% of a lubricant.

7. 7. The pharmaceutical composition of claim 6, wherein the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, lactose, and calcium hydrogen phosphate.

8. 8. The pharmaceutical composition of claim 6 or 7, wherein the disintegrant comprises croscarmellose sodium or sodium starch glycolate.

9. The pharmaceutical composition of any one of claims 6 to 8, wherein the binder comprises HPMC or HPC.

10. The pharmaceutical composition according to any one of claims 6 to 9, wherein the lubricant comprises sodium stearyl fumarate.

11. The pharmaceutical composition according to any one of claims 6 to 10, wherein the binder comprises HPMC and the disintegrant comprises croscarmellose sodium.

12. (a) an intragranular portion, per weight of said intragranular portion: (i) from about 5% to about 20% of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof; (ii) about 55% to about 95% of a filler selected from mannitol, pregelatinized starch, microcrystalline cellulose, lactose, calcium hydrogen phosphate, and combinations thereof; (iii) about 0.5% to about 10% of a disintegrant selected from croscarmellose sodium, sodium starch glycolate, and combinations thereof; and (iv) the intragranular portion comprising about 1% to about 15% of a binder comprising HPMC, HPC, or a combination thereof; (b) an extra-particle portion, per weight of said extra-particle portion: (i) about 50% to 100% of a filler selected from microcrystalline cellulose, mannitol, lactose, calcium hydrogen phosphate, and combinations thereof; (ii) 0% to about 25% of a disintegrant selected from croscarmellose sodium, sodium starch glycolate, and combinations thereof; and (iii) the extraparticulate portion comprising 0% to about 25% of a lubricant comprising sodium stearyl fumarate.

13. (a) an intragranular portion, per weight of said intragranular portion: (i) from about 5% to about 20% of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof; (ii) about 55% to about 95% of a combination of mannitol and pregelatinized starch; (iii) about 0.5% to about 10% croscarmellose sodium; (iv) an intragranular portion comprising about 1% to about 15% HPMC; (b) an extra-particle portion, per weight of said extra-particle portion: (i) about 50% to 100% microcrystalline cellulose; (ii) 0% to about 25% croscarmellose sodium, and and (iii) the extraparticulate portion comprising 0% to about 25% sodium stearyl fumarate.

14. 14. The pharmaceutical composition of any one of claims 2 to 13, wherein the intra-particle portion comprises about 30% to 95%, about 50% to about 90%, or about 70% to about 85% by weight of the composition.

15. 10. A pharmaceutical composition according to any preceding claim in the form of a powder suitable for filling into tablets or capsule shells.

16. 10. A pharmaceutical composition according to any one of the preceding claims, comprising the p-toluenesulfonic acid salt of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I).

17. 10. The pharmaceutical composition according to any of the preceding claims, wherein the composition results in dissolution of at least 80% by weight of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof within 60 minutes, or within 45 minutes, in 0.05M phosphate buffer, pH 6.8, using a paddle apparatus (USP apparatus 2) with a vessel volume of 500 ml, at a paddle speed of 75 rpm at 37°C.

18. 18. The pharmaceutical composition of claim 17, which results in dissolution of at least 80% by weight of the p-toluenesulfonic acid salt of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I).

19. 2. The pharmaceutical composition of any of the preceding claims, wherein the particles of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof have a volume median diameter (Dv50) of 50 μm or less, 30 μm or less, or 25 μm or less.

20. 13. A package comprising a pharmaceutical composition according to any of the preceding claims together with an oxygen scavenger.

21. (a) an intra-particle portion comprising at least 5% by weight of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof, and at least one excipient; (b) an extraparticulate portion comprising at least one excipient.

22. A package containing a pharmaceutical composition comprising 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (I) or a pharma- ceutically acceptable salt thereof and at least one excipient, the package also containing an oxygen scavenger.

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