Pharmaceutical composition comprising 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)-phenoxy)-3, 7-dihydro-1h-purine-2, 6-dione

Abstract

The present invention relates to a novel solid oral pharmaceutical composition comprising 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)-phenoxy)-3, 7-dihydro-1H-purine-2, 6-dione (Compound 1) as a pharmaceutically active compound, to a process for the preparation thereof and to the use thereof as a medicament. The novel solid oral pharmaceutical composition comprises Compound 1, a sugar alcohol and at least one additional pharmaceutically acceptable excipient.

Description

Technical Field

[0001] The present invention relates to a novel solid oral pharmaceutical composition comprising 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)-phenoxy)-3,7-dihydro-1H-purine-2,6-dione (Compound 1) as a pharmaceutically active compound, a process for preparing the same and its use as a medicament. Background Art

[0002] Compound 1 is a TRPC4 / 5 cation channel inhibitor. For example, TRPC5 inhibitors are known from WO2014 / 143799. TRPC5 inhibitors modulate TRPC5 function by inhibiting TRPC5-mediated ion flux or by inhibiting inward current, outward current, or both currents mediated by TRPC5. Based on their TRPC5 inhibitory activity, they can be used to treat conditions such as neuropsychiatric disorders, neurodegenerative disorders, kidney disease, and epilepsy.

[0003] Compound 1 exhibits high lipophilicity (logP: 5.2) and low water solubility under acidic to neutral conditions. Therefore, when incorporated into conventional pharmaceutical dosage forms for oral administration, the oral bioavailability of Compound 1 is likely to exhibit considerable inter- and intra-individual fluctuations depending on the patient's fasting state.

[0004] The object of the present invention is to provide a suitable pharmaceutical composition comprising Compound 1 as pharmaceutically active compound, which allows oral administration of Compound 1 with high and reproducible bioavailability. Summary of the Invention

[0005] It was found that when Compound 1 was incorporated into a sugar alcohol-based solid composition, high oral bioavailability with a fed / fasted ratio of about 2 or less could be achieved.

[0006] According to the present invention, the following items are provided:

[0007] 1. A solid oral pharmaceutical composition comprising Compound 1, a sugar alcohol and at least one additional pharmaceutically acceptable excipient.

[0008] 2. The solid oral pharmaceutical composition according to claim 1, wherein the sugar alcohol is selected from mannitol, sorbitol and xylitol.

[0009] 3. The solid oral pharmaceutical composition according to claim 1, wherein the sugar alcohol is mannitol.

[0010] 4. The solid oral pharmaceutical composition according to item 1, wherein the amount of the sugar alcohol is 40-80% [w / w].

[0011] 5. A solid oral pharmaceutical composition according to claim 1, wherein the at least one additional pharmaceutically acceptable excipient comprises one or more selected from the group consisting of binders, fillers, disintegrants, glidants, lubricants, wetting agents, surfactants and preservatives.

[0012] 6. A solid oral pharmaceutical composition according to claim 1, wherein the at least one additional pharmaceutically acceptable excipient comprises a binder.

[0013] 7. The solid oral pharmaceutical composition according to item 6, wherein the binder is a cellulose derivative.

[0014] 8. The solid oral pharmaceutical composition according to claim 7, wherein the cellulose derivative is selected from methyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.

[0015] 9. The solid oral pharmaceutical composition according to claim 8, wherein the cellulose derivative is hydroxypropyl cellulose.

[0016] 10. The solid oral pharmaceutical composition according to item 6, wherein the amount of the binder is 1-5% [w / w].

[0017] 11. The solid oral pharmaceutical composition according to item 6, wherein the sugar alcohol is mannitol and the binder is hydroxypropyl cellulose.

[0018] 12. The solid oral pharmaceutical composition according to claim 1, wherein the composition is in the form of granules, hard capsules or tablets.

[0019] 13. A solid oral pharmaceutical composition according to claim 12, wherein the composition is a tablet, which is optionally coated.

[0020] 14. The solid oral pharmaceutical composition according to item 1, wherein Compound 1 is present in an amount of 5-50% [w / w].

[0021] 15. The solid oral pharmaceutical composition according to claim 1, wherein Compound 1 is present as the sole active ingredient.

[0022] 16. The solid oral pharmaceutical composition according to claim 1, wherein Compound 1 is incorporated in the form of particles having a particle size of D90 < 100 μm.

[0023] 17. The solid oral pharmaceutical composition according to claim 1, wherein Compound 1 is incorporated in the form of particles having a particle size of D50 < 500 nm.

[0024] 18. A solid oral pharmaceutical composition according to claim 1, wherein the composition comprises:

[0025] 5-50% [w / w] of compound 1,

[0026] 40-80% [w / w] sugar alcohols, and

[0027] one or more additional pharmaceutically acceptable excipients, wherein Compound 1, the sugar alcohol, and the one or more additional pharmaceutically acceptable excipients total 100% [w / w].

[0028] 19. The solid oral pharmaceutical composition according to item 18, wherein the sugar alcohol is mannitol.

[0029] 20. The solid oral pharmaceutical composition according to claim 1, wherein the composition is a tablet, and the tablet core comprises:

[0030] 5-50% [w / w] Compound 1 (incorporated in the form of micronized particles or nanosized particles),

[0031] 40-80% [w / w] sugar alcohols,

[0032] 0-10% [w / w] binder,

[0033] 0-30% [w / w] filler,

[0034] 0-10% [w / w] disintegrant,

[0035] 0-5% [w / w] glidant,

[0036] 0-5% [w / w] lubricant,

[0037] and 0-1% [w / w] each of a wetting agent, a surfactant and a preservative, wherein the amount of compound 1 and the corresponding excipients totals 100% [w / w] and,

[0038] The tablet is optionally coated.

[0039] 21. The solid oral pharmaceutical composition of claim 1, wherein the composition is a tablet, and the tablet core comprises:

[0040] 5-50% [w / w] Compound 1 (incorporated in the form of micronized particles or nanosized particles),

[0041] 40-80% [w / w] mannitol,

[0042] 0-10% [w / w] hydroxypropyl cellulose,

[0043] 0-30% [w / w] microcrystalline cellulose,

[0044] 0-10% [w / w] croscarmellose sodium,

[0045] 0-5% [w / w] colloidal silicon dioxide,

[0046] 0-5% [w / w] magnesium stearate,

[0047] 0-1% [w / w] sodium lauryl sulfate,

[0048] 0-1% [w / w] polysorbate 80, and

[0049] 0-1% [w / w] parahydroxybenzoic acid,

[0050] wherein the amounts of Compound 1 and corresponding excipients total 100% [w / w] and,

[0051] The tablet is optionally coated.

[0052] 22. A solid oral pharmaceutical composition according to any one of items 13, 20 and 21, wherein the tablet is coated and the coating does not contain titanium dioxide.

[0053] 23. The solid oral pharmaceutical composition according to any one of items 1 to 22, which is prepared by a wet granulation method, wherein Compound 1 is preferably suspended in the granulation liquid.

[0054] 24. A method for preparing a solid oral pharmaceutical composition according to any one of items 1 to 22, wherein the method is a wet granulation method.

[0055] 25. The method of item 24, wherein the method is a fluidized bed granulation method and Compound 1 is suspended in the granulation liquid.

[0056] 26. The method according to claim 24, wherein the method comprises the following steps:

[0057] preparing a granulation liquid containing Compound 1 in micronized or nanosized form, a first portion of the sugar alcohol, and at least one additional pharmaceutically acceptable excipient, preferably a binder;

[0058] granulating the second portion of sugar alcohol with a granulating liquid in a suitable fluid bed granulator;

[0059] Drying the wet granules in a fluidized bed granulator to obtain dry granules;

[0060] Optionally, sieve the dried granules through a suitable sieve;

[0061] combining the granules with one or more selected from the group consisting of a filler, a disintegrant, a glidant, and a lubricant to obtain a premix, optionally sieving the premix, and mixing the optionally sifted premix to obtain a mixture;

[0062] Compressing the mixture into tablet cores using a suitable tablet press; and

[0063] • Further optionally, coating the cores with the previously prepared film coating suspension by spraying to produce film-coated tablets containing Compound 1.

[0064] 27. A method according to item 26, wherein the at least one additional pharmaceutically acceptable excipient contained in the granulation liquid comprises a binder and one or more of the following: a wetting agent, a surfactant and a preservative, preferably a wetting agent and / or a surfactant.

[0065] 28. A granulation liquid comprising Compound 1 in micronized or nanosized form, a sugar alcohol, at least one additional pharmaceutically acceptable excipient, preferably a binder, and optionally one or more of the following: a wetting agent, a surfactant and a preservative, and water.

[0066] 29. A solid oral pharmaceutical composition according to any one of items 1 to 23 for use as a medicament.

[0067] 30. A solid oral pharmaceutical composition according to any one of items 1 to 23 for use in treating conditions such as neuropsychiatric disorders, e.g., major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), neurodegenerative disorders, renal diseases and epileptic disorders. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 The preparation method of the solid oral pharmaceutical composition of the present invention is schematically shown.

[0069] Figure 2 A flow chart showing the preparation method of Example Formulation A is shown.

[0070] Figure 3 A flow chart showing the preparation of Example Formulations B and C is shown.

[0071] Figure 4 A flow chart showing the preparation method of Example Formulation D is shown.

[0072] Figure 5 Comparative dissolution testing results for 50 mg core tablets and 50 mg final film-coated tablets of Example Formulation B are shown.

[0073] Figure 6 The X-ray powder diffraction (XRPD) pattern of Compound 1 is shown. DETAILED DESCRIPTION

[0074] The present invention is based on the discovery that when Compound 1 is formulated in a solid composition based on a sugar alcohol, high oral bioavailability of Compound 1 can be achieved while significantly reducing the impact of the food effect. It is well known that administering a drug with food can alter its bioavailability. Essentially, the food effect on drug bioavailability is most pronounced when the drug is taken shortly after a meal. The food effect can be represented by determining the fed / fasted ratio, i.e., by determining the bioavailability under fed and fasted conditions and comparing the results by forming the corresponding quotients.

[0075] The fed / fasted ratio of the composition used in the present invention is less than 3, preferably less than 2.5 and more preferably less than 2.1.

[0076] In order to achieve the above-described beneficial effects, Compound 1 is formulated into a sugar alcohol-based solid composition for oral use according to the present invention.

[0077] Thus, in a first aspect, the present invention relates to a solid oral pharmaceutical composition comprising Compound 1, a sugar alcohol and at least one additional pharmaceutically acceptable excipient.

[0078] As used herein, the term "Compound 1" includes anhydrates as well as hydrates and solvates of Compound 1 in amorphous or crystalline form, respectively.

[0079] In one embodiment, the compound 1 used to prepare the solid oral pharmaceutical composition of the present invention has a particle size of D90 < 100 μm, preferably D90 ≤ 15 μm. The corresponding particles of compound 1 are also referred to herein as "micronized".

[0080] In another embodiment, the compound 1 used to prepare the solid oral pharmaceutical composition of the present invention has a particle size of D50 < 500 nm, preferably D50 < 200 nm. The corresponding particles of compound 1 are also referred to herein as "nanosized".

[0081] In a preferred embodiment, Compound 1 used to prepare the solid oral pharmaceutical composition of the present invention is micronized.

[0082] In another preferred embodiment, Compound 1 is present as the sole active ingredient in the solid oral pharmaceutical composition of the present invention.

[0083] In a preferred embodiment, Compound 1 is present in the solid oral pharmaceutical composition of the present invention in an amount of 5-50% [w / w], preferably 5-30% [w / w] and more preferably 5-25% [w / w].

[0084] When an amount is indicated as "% [w / w]", this refers here and hereinafter to the total amount of the solid oral pharmaceutical composition according to the invention (ie without any potential coating).

[0085] In a preferred embodiment, the sugar alcohol used in the present invention is selected from mannitol, sorbitol and xylitol. Preferably, the sugar alcohol is mannitol.

[0086] In a preferred embodiment, the sugar alcohol is present in the solid oral pharmaceutical composition of the present invention in an amount of 40-80% [w / w] and preferably 50-70% [w / w].

[0087] In one embodiment, the at least one additional pharmaceutically acceptable excipient of the solid oral pharmaceutical composition of the present invention comprises one or more selected from the group consisting of binders, fillers, disintegrants, glidants, lubricants, wetting agents, surfactants and preservatives.

[0088] In a preferred embodiment, the at least one additional pharmaceutically acceptable excipient of the solid oral pharmaceutical composition of the present invention comprises a binder.

[0089] In another preferred embodiment, the at least one additional pharmaceutically acceptable excipient of the solid oral pharmaceutical composition of the present invention comprises a binder, a wetting agent and / or a surfactant.

[0090] The binder suitable for solid oral pharmaceutical composition of the present invention can be selected from polyvinylpyrrolidone (PVP), copolyvidone, starch, cellulose derivative or polyethylene glycol. The binder is preferably a cellulose derivative, and more preferably methylcellulose, hydroxyethylcellulose or hydroxypropylcellulose. Most preferably, the binder is hydroxypropylcellulose.

[0091] The binder used as at least one additional pharmaceutically acceptable excipient is preferably present in the solid oral pharmaceutical composition of the present invention in an amount of 0-10% [w / w], more preferably 1-5% [w / w] and most preferably 2-3% [w / w].

[0092] The filler suitable for the solid oral pharmaceutical composition of the present invention can be selected from inorganic phosphates, for example, dibasic calcium phosphate, lactose, such as lactose monohydrate or anhydrous lactose, glucose, sucrose, maltodextrin, isomalt and microcrystalline cellulose. Preferably, the filler is microcrystalline cellulose.

[0093] The filler serving as at least one additional pharmaceutically acceptable excipient is preferably present in the solid oral pharmaceutical composition of the present invention in an amount of 0-30% [w / w], more preferably 5-25% [w / w] and most preferably 10-20% [w / w].

[0094] The disintegrant suitable for the solid oral pharmaceutical composition of the present invention can be selected from cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, alginate, pregelatinized starch and cross-linked sodium carboxymethyl cellulose. Preferably, the disintegrant is cross-linked sodium carboxymethyl cellulose.

[0095] The disintegrant used as at least one additional pharmaceutically acceptable excipient is preferably present in the solid oral pharmaceutical composition of the present invention in an amount of 0-10% [w / w], more preferably 1-5% [w / w] and most preferably 2-3% [w / w].

[0096] The glidant suitable for the solid oral pharmaceutical composition of the present invention can be selected from corn starch and colloidal silicon dioxide. Preferably, the glidant is colloidal silicon dioxide.

[0097] The glidant used as at least one additional pharmaceutically acceptable excipient is preferably present in the solid oral pharmaceutical composition of the present invention in an amount of 0-5% [w / w] or 1-2% [w / w].

[0098] In a preferred embodiment, the solid oral pharmaceutical composition of the present invention does not contain a glidant.

[0099] The lubricant suitable for the solid oral pharmaceutical composition of the present invention can be selected from talc, alkali salts or alkaline earth salts of stearic acid, for example, magnesium stearate and sodium stearyl fumarate. Preferably, the lubricant is magnesium stearate.

[0100] The lubricant used as at least one additional pharmaceutically acceptable excipient is preferably present in the solid oral pharmaceutical composition of the present invention in an amount of 0-5% [w / w] and more preferably 1-2% [w / w].

[0101] The at least one additional pharmaceutically acceptable excipient of the solid oral pharmaceutical composition of the present invention may further comprise a wetting agent, a surfactant, or a combination thereof. Preferably, the wetting agent is sodium lauryl sulfate. The surfactant may be selected from any one of polysorbate 80 and poloxamer 188. Preferably, the surfactant is polysorbate 80.

[0102] In a preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises a wetting agent, preferably sodium lauryl sulfate.

[0103] In another embodiment, sodium lauryl sulfate and polysorbate 80 are used in combination in the solid oral pharmaceutical composition of the present invention.

[0104] Furthermore, the at least one additional pharmaceutically acceptable excipient of the solid oral pharmaceutical composition of the present invention may optionally comprise a preservative, preferably a paraben.

[0105] When used in the solid oral pharmaceutical composition of the present invention, the wetting agent, the surfactant and the preservative are preferably present in an amount of not more than 1% [w / w] each, preferably not more than 0.1% [w / w] each, and further preferably 0.01-1% [w / w] or 0.01-0.1% [w / w] each.

[0106] In a preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises

[0107] 5-50% [w / w] Compound 1 (incorporated in the form of micronized or nanosized particles),

[0108] 40-80% [w / w] sugar alcohols, and

[0109] Optionally one or more additional pharmaceutically acceptable excipients, wherein Compound 1, the sugar alcohol and the one or more additional pharmaceutically acceptable excipients total 100% [w / w].

[0110] In another preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises

[0111]

[0112] and wetting agents, surfactants and preservatives each 0-1% [w / w], wherein Compound 1 and corresponding excipients total 100% [w / w].

[0113] In another preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises

[0114]

[0115] and 0-1% [w / w] each of a wetting agent, a surfactant, and a preservative, wherein the total of Compound 1 and the corresponding excipients is 100% [w / w]; or

[0116]

[0117] and 0-1% [w / w] each of a wetting agent, a surfactant, and a preservative, wherein the amount of Compound 1 and the corresponding excipients totals 100% [w / w]; or

[0118]

[0119] and 0.01-1% [w / w] each of a wetting agent, a surfactant, and a preservative, wherein the amount of Compound 1 and the corresponding excipients totals 100% [w / w]; or

[0120]

[0121] and a wetting agent, a surfactant and a preservative each at 0.01-1% [w / w], wherein the amount of Compound 1 and the corresponding excipients totals 100% [w / w].

[0122] Preferably, the sugar alcohol in any of the above compositions is mannitol.

[0123] In another preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises

[0124]

[0125]

[0126] The amounts of Compound 1 and corresponding excipients total 100% [w / w].

[0127] In a further preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises

[0128] wherein the amount of Compound 1 and the corresponding excipients totals 100% [w / w]; or

[0129] wherein the amount of Compound 1 and the corresponding excipients totals 100% [w / w]; or

[0130]

[0131] wherein the amount of Compound 1 and the corresponding excipients totals 100% [w / w]; or

[0132]

[0133] The amounts of Compound 1 and corresponding excipients are 100% [w / w].

[0134] The solid oral pharmaceutical composition of the present invention is preferably a granule, a hard capsule or a tablet, and most preferably a tablet.

[0135] In one embodiment, the solid oral pharmaceutical composition of the present invention is a tablet, which is optionally coated.

[0136] The corresponding coating composition preferably comprises one or more film-forming polymers and one or more pharmaceutically acceptable excipients.

[0137] Suitable film-forming polymers for use in the coating composition include, for example, hydroxypropyl methylcellulose (Hypromellose), ethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers, e.g. Polyvinyl pyrrolidone, polyvinyl alcohol, macrogol-poly(vinyl alcohol) graft copolymer, polyethylene glycol, or mixtures thereof. Other film-forming polymers known in the art may also be used.

[0138] In a preferred embodiment, the film-forming polymer is hydroxypropyl methylcellulose.In another preferred embodiment, hydroxypropyl methylcellulose is used as the film-forming polymer in combination with hydroxypropyl cellulose.

[0139] Suitable pharmaceutically acceptable excipients for use in the coating composition include, for example, emollients such as polyethylene glycol, GMCC (a mixture of mono- and diglycerides of caprylic and capric acid), medium chain triglycerides (MCT) and isomalt, anti-adhesives such as talc, pigments such as titanium dioxide or calcium carbonate, and dyes such as iron oxide pigments.

[0140] Examples of film coating compositions for use in the present invention include hydroxypropyl methylcellulose, propylene glycol, talc, titanium dioxide, and optionally iron oxide, such as yellow iron oxide and / or red iron oxide.

[0141] In a preferred embodiment, the film coating composition used in the present invention does not contain titanium dioxide. Titanium dioxide-free coatings suitable for use in the present invention may, for example, comprise

[0142] Hydroxypropyl methylcellulose, hydroxypropyl cellulose, medium chain triglycerides, isomalt, calcium carbonate and optionally iron oxide, for example, yellow iron oxide and / or red iron oxide;

[0143] Hydroxypropyl methylcellulose, hydroxypropyl cellulose, propylene glycol, talc, calcium carbonate and optionally iron oxide, for example, yellow iron oxide and / or red iron oxide; or

[0144] Hydroxypropyl methylcellulose, propylene glycol, talc, calcium carbonate and optionally iron oxide,

[0145] For example, yellow iron oxide and / or red iron oxide.

[0146] In one embodiment, commercially available film coating compositions such as or P can be used to coat the solid oral pharmaceutical composition of the present invention.

[0147] The coating can be applied by known film coating equipment, ie, spray coating, fluidized bed coating or dip coating.

[0148] Examples of solvents that can be used to prepare the initial coating solution of the coating composition applied to the film coating step are selected from methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, chloroform, methyl chloride, water, or mixtures thereof.

[0149] The coating compositions described herein generally do not contain Compound 1.

[0150] In alternative embodiments, the coating composition may contain at least a portion of Compound 1, with the remainder of Compound 1 being part of the tablet core.

[0151] In a preferred embodiment, the solid oral pharmaceutical composition of the present invention is an immediate-release film-coated tablet.

[0152] The following are preferred embodiments of the solid oral pharmaceutical compositions of the present invention in the form of optionally coated tablets:

[0153] a)

[0154]

[0155] b)

[0156]

[0157] c)

[0158]

[0159] d)

[0160]

[0161]

[0162] e)

[0163]

[0164] In a second aspect, the present invention relates to a process for preparing a solid oral pharmaceutical composition of the present invention comprising Compound 1, a sugar alcohol and at least one additional pharmaceutically acceptable excipient.

[0165] The preparation method of the present invention is a wet granulation method, preferably a fluidized bed granulation method.

[0166] In a particularly preferred embodiment, the preparation method of the present invention is a fluidized bed granulation method, wherein Compound 1 is suspended in a granulation liquid.

[0167] Therefore, the solid oral pharmaceutical composition of the present invention is prepared by a wet granulation method, preferably a fluidized bed granulation method.

[0168] In a preferred embodiment, the solid oral pharmaceutical composition of the present invention is prepared by fluidized bed granulation, wherein Compound 1 is suspended in the granulation liquid.

[0169] In one embodiment, the preparation method of the present invention comprises the following steps:

[0170] preparing a granulation liquid containing Compound 1 in micronized or nanosized form, a first portion of the sugar alcohol, and at least one additional pharmaceutically acceptable excipient, preferably a binder;

[0171] granulating the second portion of sugar alcohol with a granulating liquid in a suitable fluid bed granulator;

[0172] Drying the wet granules in a fluidized bed granulator to obtain dry granules;

[0173] Optionally, sieve the dried granules through a suitable sieve;

[0174] combining the granules with one or more selected from the group consisting of a filler, a disintegrant, a glidant, and a lubricant to obtain a premix, optionally sieving the premix, and mixing the optionally sifted premix to obtain a mixture;

[0175] Compressing the mixture into tablet cores using a suitable tablet press; and

[0176] • Further optionally, the cores are coated with the previously prepared film coating suspension by spray coating to produce film-coated tablets containing Compound 1.

[0177] In another embodiment, the preparation method of the present invention comprises the following steps:

[0178] adding the first part of the binder, one or more of a wetting agent, a surfactant, and a preservative, preferably a wetting agent and / or a surfactant, to a solvent and mixing to produce a vehicle;

[0179] Add micronized Compound 1 to the vehicle and stir to obtain a suspension;

[0180] Grinding the suspension by a wet grinding process to obtain a suspension of nanosized compound 1;

[0181] mixing the second part of the adhesive with the solvent to obtain an adhesive liquid;

[0182] While stirring the suspension of nanocompound 1, adding a binder liquid;

[0183] Then, the first portion of the sugar alcohol is added to obtain a granulation liquid;

[0184] Preheating the second portion of the sugar alcohol and subsequently granulating it with the granulation liquid in a suitable fluid bed granulator;

[0185] drying the wet granules in the fluid bed granulator to obtain dry granules; and

[0186] Optionally sieving the dried granules through a suitable sieve;

[0187] or alternatively:

[0188] dissolving a binder; one or more of a wetting agent, a surfactant, and a preservative, preferably a wetting agent and / or a surfactant; and a first portion of the sugar alcohol (optionally pre-sieved) in a solvent;

[0189] Then, micronized compound 1 is suspended therein to obtain a granulation liquid;

[0190] Preheating the second portion of the sugar alcohol and subsequently granulating it with the granulation liquid in a suitable fluid bed granulator;

[0191] drying the wet granules in the fluid bed granulator to obtain dry granules; and

[0192] - Optionally sieve the dried granules through a suitable sieve.

[0193] The obtained granules can be further processed into tablets by direct compression process or as follows:

[0194] • mixing the filler, disintegrant and optionally pre-sieved granules to obtain a main mix;

[0195] mixing the main mixture and lubricant to produce a final mixture, wherein, preferably, a first portion of the main mixture is mixed with the lubricant and then the remaining portion of the main mixture is added and mixed, or the main mixture and lubricant are mixed all at once; and

[0196] Compress the final mixture into tablet cores using a suitable tablet press;

[0197] or alternatively:

[0198] • mixing the filler, disintegrant and optionally pre-sieved granules to obtain a mixture;

[0199] adding a lubricant to create a main mixture, wherein a first portion of the mixture is combined with the lubricant and then the remainder of the mixture is added, or preferably, the mixture and the lubricant are mixed all at once;

[0200] Optionally sieving the main mixture; and

[0201] · mixing the optionally sieved main mixture to obtain the final mixture; and

[0202] • Compress the final blend into tablet cores using a suitable tablet press.

[0203] Without being bound by theory, it is believed that the resulting tablet comprises Compound 1 layered on sugar alcohol particles, thereby forming a matrix in which Compound 1 is embedded.

[0204] Tablets can be further film-coated as follows:

[0205] Dispersing the film coating composition in the solvent by stirring in a suitable mixing vessel to prepare a film coating suspension; and

[0206] • Coat the tablet cores with the film coating suspension by spray coating to produce film-coated tablets containing Compound 1.

[0207] Alternatively, the granules obtained by any of the above-mentioned preparation methods can be processed into capsules by optionally mixing the granules with, for example, a filler, and then filling them into capsules.

[0208] When reference is made in this specification to mixing the respective materials, this may include mixing them as such or sieving them together.

[0209] The solvent used to prepare the granulation liquid is selected from methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, chloroform, methyl chloride, water or a mixture thereof. Preferably, the solvent is water.

[0210] In a preferred embodiment, the granulation liquid contains Compound 1 in micronized or nanosized form, a sugar alcohol, at least one other pharmaceutically acceptable excipient, preferably a binder and optionally one or more of a wetting agent, a surfactant and a preservative, and water.

[0211] Micronized Compound 1 can be prepared by jet milling. Nanosized Compound 1 can be prepared by wet milling a previously prepared suspension of micronized Compound 1.

[0212] In a third aspect, the present invention relates to the use of a solid oral pharmaceutical composition of the present invention comprising Compound 1, a sugar alcohol and at least one additional pharmaceutically acceptable excipient as a medicament.

[0213] In a preferred embodiment, the solid oral pharmaceutical composition of the present invention is used to treat conditions such as neuropsychiatric disorders, eg, major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), neurodegenerative disorders, renal diseases, and epileptic disorders.

[0214] Example

[0215] The following examples are provided to further illustrate the present invention; however, they should not be construed as limiting the scope of the invention disclosed herein.

[0216] Example 1

[0217] Immediate release film-coated tablet formulations containing Compound 1 were prepared in dosage strengths of 5 mg, 25 mg, 50 mg, 75 mg, 100 mg, and 125 mg.

[0218] Tablets were prepared by wet granulation using mannitol and microcrystalline cellulose as fillers, magnesium stearate as a lubricant, hydroxypropyl cellulose as a binder, and croscarmellose sodium as a disintegrant, while Compound 1 was suspended in a granulation liquid. The preparation method is schematically shown as follows: Figure 1 Due to the excellent flowability of the resulting granules, there is no need to add glidants such as colloidal anhydrous silicon dioxide.

[0219] Four tablet formulations were prepared, Formulation A, Formulation B, Formulation C, and Formulation D, having the following compositions:

[0220] Table 1 Composition of Preparation A

[0221]

[0222]

[0223] *Film coating composition: Hydroxypropyl methylcellulose 2910, Macrogol 6000, titanium dioxide, talc, iron oxide red

[0224] Table 2 Composition of Preparation B

[0225]

[0226] *Film coating composition: Hydroxypropyl methylcellulose 2910, Macrogol 6000, titanium dioxide, talc, red iron oxide

[0227] Table 3 Composition of Formulation C

[0228]

[0229]

[0230] *Film coating composition: Hydroxypropyl methylcellulose 2910, Macrogol 6000, titanium dioxide, talc, red iron oxide

[0231] Table 4 Composition of Formulation D

[0232]

[0233]

[0234]

[0235] # Film coating composition: Hydroxypropyl methylcellulose 2910, hydroxypropyl cellulose, calcium carbonate, isomalt, medium chain triglycerides, iron oxide yellow

[0236] The 5 mg tablets of Formulations A and B are dark red, round, biconvex, film-coated tablets with beveled edges approximately 6 mm in diameter.

[0237] The 25 mg tablets of Formulations A and B are dark red, oval, biconvex, film-coated tablets, approximately 14 x 6.8 mm in length and width.

[0238] The 50 mg tablets of Formulations A and B are dark red, oval, biconvex, film-coated tablets, approximately 17.8 x 8.6 mm in length and width.

[0239] The 100 mg tablets of Formulation C are dark red, oval, biconvex, film-coated tablets approximately 15 x 7 mm in length and width.

[0240] The tablets of Formulation D have the following sizes, shapes, and colors:

[0241]

[0242] The wet granulation process used to prepare the tablets of Formulations A, B, C and D was a fluidized bed granulation process using the following granulation conditions:

[0243] Final blend batch size 45 kg:

[0244] Inlet air temperature 80-100℃

[0245] Intake volume 800-1400m 3 / h

[0246] Spraying rate 300-400g / min

[0247] Final mixture batch size 100 kg:

[0248] Inlet air temperature 90℃

[0249] Intake volume 1400-2300m 3 / h

[0250] Spraying rate 650-680g / min

[0251] The corresponding wet granulation process can be summarized as follows.

[0252] Preparation A

[0253] Preparation of Compound 1 Suspension (Step 1)

[0254] Step 1.1 Preparation of medium

[0255] Hydroxypropylcellulose, sodium lauryl sulfate, polysorbate 80, and methylparaben were added to purified water and mixed to create a vehicle.

[0256] Step 1.2 Preparation of suspension

[0257] Jet-milled Compound 1 with D90 ≤ 15 μm was added to the vehicle and stirred to obtain a suspension.

[0258] Step 1.3 Grinding

[0259] The suspension was milled in a wet milling process to obtain a nanosized suspension of Compound 1 with a target size of D50 < 200 nm.

[0260] Preparation of Compound 1 Granulation Liquid (Step 2)

[0261] Step 2.1 Preparation of adhesive liquid

[0262] Combine hydroxypropyl cellulose and purified water in a suitable container to produce an adhesive liquid.

[0263] Step 2.2 Preparation of granulation liquid

[0264] The binder liquid is added while stirring the suspension of nanosized compound 1 obtained in step 1. Mannitol is then added to obtain a granulation liquid.

[0265] Preparation of Compound 1 Particles (Step 3)

[0266] Preheating and granulation in steps 3.1 and 3.2

[0267] Mannitol is pre-sieved and pre-heated and then granulated with the granulation liquid obtained in step 2 in a suitable fluid bed granulator.

[0268] Step 3.3 Drying

[0269] The obtained wet granules were dried in a fluidized bed granulator to obtain dry granules.

[0270] Step 3.4 Drying and sieving

[0271] The dried granules are sieved through a suitable sieve.

[0272] Preparation of Compound 1 Final Mixture (Step 4)

[0273] Step 4.1 Main Mixing

[0274] The microcrystalline cellulose, croscarmellose sodium and the pre-sieved granules obtained in step 3 are mixed to obtain a main blend.

[0275] Step 4.2 Pre-screening

[0276] A portion of the main blend was pre-screened with magnesium stearate.

[0277] Step 4.3 Final Mixing

[0278] The remainder of the main mix is ​​mixed with the pre-screened material to produce the final mix.

[0279] Preparation of Compound 1 Tablet Cores (Step 5)

[0280] Step 5.1 Tablet Compression

[0281] The final blend obtained in step 4 is compressed into tablet cores using a suitable tablet press.

[0282] Preparation of Compound 1 Film-Coated Tablets (Step 6)

[0283] Step 6.1 Preparation of film coating suspension

[0284] The film coating mixture ( red) was dispersed in purified water to prepare a film coating suspension.

[0285] Step 6.2 Film coating

[0286] The tablet cores obtained in step 5 were coated with the film coating suspension by spraying in a drum coater to produce Compound 1 film-coated tablets.

[0287] Formulations B and C

[0288] Preparation of Compound 1 Granulation Liquid (Step 1)

[0289] Step 1.1 Preparation of granulation suspension

[0290] Hydroxypropylcellulose, sodium lauryl sulfate and mannitol (optionally pre-sieved) were dissolved in purified water, and jet-milled Compound 1 with D90 ≤ 15 μm was then suspended therein to obtain a granulation liquid.

[0291] Preparation of Compound 1 Particles (Step 2)

[0292] Preheating and granulation in steps 2.1 and 2.2

[0293] Mannitol is pre-sieved and pre-heated and then granulated with the granulation liquid obtained in step 1 in a suitable fluid bed granulator.

[0294] Step 2.3 Drying

[0295] The obtained wet granules were dried in a fluidized bed granulator to obtain dry granules.

[0296] Step 2.4 Drying and sieving

[0297] Sieve the dried granules through a suitable sieve.

[0298] Preparation of Compound 1 Final Mixture (Step 3)

[0299] Step 3.1 Main Mixing

[0300] The microcrystalline cellulose, croscarmellose sodium and the pre-sieved granules obtained in step 2 are mixed to obtain a main blend.

[0301] Step 3.2 Pre-screening

[0302] A portion of the main blend was pre-screened with magnesium stearate.

[0303] Step 3.3 Final mixing

[0304] The remainder of the main mix and the pre-screened material are combined to produce the final mix.

[0305] Preparation of Compound 1 Tablet Cores (Step 4)

[0306] Step 4.1 Tablet Compression

[0307] The final blend obtained in step 3 is compressed into tablet cores using a suitable tablet press.

[0308] Preparation of Compound 1 Film-Coated Tablets (Step 5)

[0309] Step 5.1 Preparation of film coating suspension

[0310] The film coating mixture ( red) was dispersed in purified water to prepare a film coating suspension.

[0311] Step 5.2 Film coating

[0312] The tablet cores obtained in step 4 were coated with the film coating suspension by spray coating in a drum coater to produce Compound 1 film-coated tablets.

[0313] Preparation D

[0314] Preparation of Compound 1 Granulation Liquid (Step 1)

[0315] Step 1.0 Preparation of granulation suspension

[0316] Hydroxypropylcellulose, sodium lauryl sulfate and mannitol were dissolved in purified water, and then jet-milled Compound 1 with a D90 of ≤ 15 μm was suspended therein to obtain a granulation liquid.

[0317] Preparation of Compound 1 Particles (Step 2)

[0318] Preheating and granulation in steps 2.1 and 2.2

[0319] Mannitol is pre-sieved and pre-heated and then granulated with the granulation liquid obtained in step 1 in a suitable fluid bed granulator.

[0320] Step 2.3 Drying

[0321] The obtained wet granules were dried in a fluidized bed granulator to obtain dry granules.

[0322] Preparation of Compound 1 Final Mixture (Step 3)

[0323] Step 3.1 and step 3.2 main mixing

[0324] Microcrystalline cellulose, croscarmellose sodium and the dried granules obtained in step 2 are mixed, and then magnesium stearate is added to obtain a main mixture.

[0325] Sieving and final mixing in steps 3.3 and 3.4

[0326] The main mixture was sieved and finally mixed to produce the final mixture.

[0327] Preparation of Compound 1 Tablet Cores (Step 4)

[0328] Step 4.1 Tablet Compression

[0329] The final blend obtained in step 3 is compressed into tablet cores using a suitable tablet press.

[0330] Preparation of Compound 1 Film-Coated Tablets (Step 5)

[0331] Step 5.1 Preparation of film coating suspension

[0332] The film coating mixture ( P) was dispersed in purified water to prepare a film coating suspension.

[0333] Step 5.2 Film coating

[0334] The tablet cores obtained in step 4 were coated with the film coating suspension by spray coating in a drum coater to produce Compound 1 film-coated tablets.

[0335] The flow chart of the corresponding preparation method is as follows Figure 2 、 3 and 4.

[0336] Example 2 Bioavailability Test

[0337] Two bioavailability studies (Study 1 and Study 2) were conducted using tablets of Formulations A, B, and C. Exposure differences (AUC) following oral administration in healthy male subjects under fed and fasted conditions, as well as food effect differences, were investigated.

[0338] The details of the study are as follows:

[0339] Study Design: Open-label, single-dose, randomized crossover study Number of patients: 24

[0340] Inclusion criteria: healthy male subjects,

[0341] Study 1: Age 18 to 50 years (inclusive),

[0342] Study 2: Age 18 to 55 years (inclusive),

[0343] Body mass index (BMI) 18.5 to 29.9 kg / m 2 (Inclusive)

[0344] Study Drug: Study 1: Formulation A and Formulation B tablets each containing 50 mg of Compound 1

[0345] Study 2: Tablets of Formulation B, each containing 50 mg

[0346] Tablets of compound 1 and preparation C, each containing 100

[0347] mg compound 1

[0348] Dosage: 100mg (2 x 50mg or 1 x 100mg)

[0349] Mode of administration: After a high-fat, high-calorie breakfast (meal) with 240

[0350] Take two 50mg tablets or one tablet orally with mL of water

[0351] 100 mg tablet, or

[0352] Take two 50 mg tablets orally at once or after fasting for at least 24 hours

[0353] One 100 mg tablet taken orally after 10 hours (fasting)

[0354] Duration of treatment: One day per treatment (single dose), with at least

[0355] 17-day washout period

[0356] Bioavailability (AUC 0-∞ ) were determined based on the geometric mean (gMean) of the obtained plasma concentration data.

[0357] Tables 4a and 4b below show the results of the bioavailability studies. All formulations gave sufficiently high AUCs in both fasted and fed states.

[0358] Table 4a Results of Study 1 on Oral Bioavailability and Food Effect

[0359]

[0360] Table 4b Results of Study 2 on oral bioavailability and food effect

[0361]

[0362]

[0363] The results of Study 1 and Study 2 demonstrated that the solid oral pharmaceutical composition of the present invention has good pharmacokinetic properties, with high oral bioavailability and a fed / fasted ratio of 2.03 or less.

[0364] Example 3 Dissolution Test

[0365] Dissolution testing was performed on 50 mg core tablets and final 50 mg film-coated tablets of Formulation B under the following conditions:

[0366] 0.1M hydrochloric acid pH 1 + 0.2% SLS, 900 mL, paddle method, 100 rpm.

[0367] The results are as follows Figure 5 Both the core tablet and the final film-coated tablet exhibited an immediate release profile, wherein Compound 1 was completely released in less than 20 min.

[0368] Example 4 Preparation of Compound 1

[0369] Abbreviations:

[0370] APCI Atmospheric Pressure Chemical Ionization

[0371] abs. Absolute

[0372] aq. BHT 3,5-di-tert-butyl-4-hydroxytoluene in water

[0373] conc concentrated

[0374] DCM dichloromethane

[0375] DIPEA N-ethyl-diisopropylamine

[0376] DMAc dimethylacetamide

[0377] DMF dimethylformamide

[0378] DMSO dimethyl sulfoxide

[0379] equiv. equivalent

[0380] ESI electrospray ionization

[0381] EtOAc

[0382] g grams

[0383] h hour

[0384] HOAc acetic acid

[0385] HPLC high-performance liquid chromatography

[0386] iPr Isopropyl

[0387] kg kilogram

[0388] NMP N-Methyl-2-pyrrolidone

[0389] NMR Nuclear Magnetic Resonance

[0390] MeCN Acetonitrile

[0391] MeOH methanol

[0392] min

[0393] mg milligrams

[0394] mL milliliters

[0395] M mole (mol / L)

[0396] TBABr Tetra-n-butylammonium bromide

[0397] THF Tetrahydrofuran

[0398] NMR methods

[0399] With a frequency of 600MHz (for 1 H-NMR experiments) and a frequency of 150 MHz (for 13 NMR spectra were recorded on a Bruker AVANCE III instrument equipped with a C-NMR experiment and analyzed using TopSpin 3.2p16 software. Chemical shifts are reported in parts per million (ppm) downfield from the internal reference tetramethylsilane. Selected data are reported as follows: chemical shift (multiplicity, coupling constant (J), hydrogen number). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), spt (septet), m (multiplet), br (broad).

[0400] X-ray powder diffraction (XRPD) pattern

[0401] X-ray powder diffraction measurements were performed using a Bruker D8 advanced diffractometer equipped with a LynxEye position sensitive detector and CuKα1 radiation in reflection mode. A Cu-anode (40 kV, 40 mA) was used as the X-ray source. The standard error of the 2θ values ​​was ±0.2°.

[0402] Step 1: Preparation of 8-bromo-7-(4-chlorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (Compound 2)

[0403] 8-Bromo-3-methylxanthine (20.0 g, 81.6 mmol, 1.0 equiv) and BHT (0.8 g, 3.6 mmol, 0.04 equiv) were dissolved in dimethylacetamide (210 mL). The mixture was heated to 85°C. A solution of 4-chlorobenzyl chloride (15.8 g, 97.9 mmol, 1.2 equiv) in dimethylacetamide (20 mL) was added and rinsed with dimethylacetamide (10 mL). Diisopropylethylamine (11.1 g, 85.7 mmol, 1.05 equiv) was added and rinsed with dimethylacetamide (10 mL). The reaction was stirred at 85°C until the starting material was consumed (8-bromo-3-methylxanthine <0.3%). Optionally, a further dose of diisopropylethylamine (0.5 g, 4.1 mmol, 0.05 equiv) could be added to complete the reaction. After complete conversion, hydrochloric acid (4M, 0.8 g, 8.2 mmol, 0.1 equivalent) was added. The reaction solvent was partially removed via vacuum distillation (until the residual volume of the reaction mixture was approximately 150 mL). Acetonitrile (150 mL) was added and the product suspension was slowly cooled to 20 ° C. The product was separated by filtration and the filter cake was washed twice with acetonitrile (50 mL). The isolated material was dried at 50 ° C under reduced pressure to give compound 2 (28.7 g, 78.0 mmol, 95% yield, 99.9% purity) as a colorless solid. Melting point: 270-271 ° C.

[0404] 1 H NMR(DMSO-d6)δ:11.37(s,1H),7.44(d,J=8.5Hz,2H),7.29(d,J=8.5Hz,2H),5.48(s,2H),3.34(s,3H); 13 C NMR(DMSO-d6)δ:154.0,150.5,149.3,134.5,132.6,129.0,128.7,127.9,108.6,48.6,28.5; HRMS(ESI):m / z 369,([M+H] + , predicted value 368.9763, calculated value 368.9748).

[0405] Step 2: Preparation of 8-bromo-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (Compound 3)

[0406] Compound 2 (20.0 g, 54.1 mmol, 1.0 equiv) was suspended in dimethylacetamide (170 mL) along with sodium bicarbonate (6.8 g, 81.2 mmol, 1.5 equiv) and tetrabutylammonium bromide (0.8 g, 2.7 mmol, 0.05 equiv). The mixture was heated to 110°C, 3-chloro-1-propanol (7.7 g, 81.5 mmol, 1.5 equiv) was added, and the mixture was rinsed with dimethylacetamide (10 mL). A vacuum (200-400 mbar) was then applied. The reaction was stirred at 110°C until the starting material was consumed (compound 2 <0.5%). Upon complete conversion, the reaction mixture was cooled to 80°C, filtered, and rinsed with dimethylacetamide (30 mL). Water (160 mL) was added to the filtrate at 90°C, followed by sodium bicarbonate (0.5 g, 5.4 mmol, 0.1 equiv). The mixture was cooled to 70°C and seed crystals (47 mg) were added. The crystal suspension was cooled to 40°C over 60 min, heated to 70°C, kept at 70°C for at least 15 min and cooled to 20°C over 150 min and stirred for 1 h. The product was separated by filtration and the filter cake was washed with water (160 mL). The isolated material was dried at 60°C under reduced pressure to obtain compound 3 (16.1 g, 37.7 mmol, 91% yield, 98.7% purity) as a colorless solid. Melting point: 148-149°C.

[0407] 1 H NMR(DMSO-d6)δ:7.43(d,J=8.5Hz,2H),7.30(d,J=8.5Hz,2H),5.52(s,2H),4.48(t, J=5.2Hz,1H),3.89-3.96(m,2H),3.43-3.48(m,2H),3.38(s,2H),1.65-1.74(m,2H); 13 C NMR(DMSO-d6)δ:153.5,150.3,147.9,134.5,132.6,129.0,128.7,128.2,108.2,58.7,48.7,38.5,30.8,29.5; HRMS(ESI):m / z 427,([M+H] + , predicted value 427.0188, calculated value 427.0167).

[0408] Step 3: Preparation of 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-3,7-dihydro-1H-purine-2,6-dione (Compound 1) [crude]

[0409] Compound 3 (20.0 g, 46.8 mmol, 1.0 equiv), tetrabutylammonium bromide (0.8 g, 2.4 mmol, 0.05 equiv), and sodium carbonate (3.5 g, 32.7 mmol, 0.7 equiv) were suspended in N-methyl-2-pyrrolidone (135 mL). The mixture was heated to 50°C. 3-(Trifluoromethoxy)phenol (9.2 g, 51.7 mmol, 1.1 equiv) was added and rinsed with N-methyl-2-pyrrolidone (10 mL). The mixture was heated to 120°C and stirred at 120°C under reduced pressure (200-400 mbar) until the starting material was consumed (compound 3 <1.0%). After complete conversion, the reaction mixture was cooled to 80°C, filtered, and rinsed with N-methyl-2-pyrrolidone (15 mL). Acetonitrile (40 mL) was added. Water (110 mL) was added over at least 30 minutes. The mixture was cooled to 58 ° C and seed crystals (20 mg) were added. The crystal suspension was continuously cooled to 40 ° C, heated to 60 ° C, kept at the same temperature for at least 15 min and cooled to 20 ° C. The product was separated by filtration and the filter cake was washed with water (160 mL) and n-heptane (40 mL). The separated material was dried under reduced pressure at 60 ° C to obtain compound 1 [crude material] (22.1 g, 42.1 mmol, 90% yield, 98.5% purity) as a colorless solid. Melting point: 124-125 ° C.

[0410] 1 H NMR(DMSO-d6)δ:7.56-7.63(m,1H),7.49(s,1H),7.40-7.45(m,5H),7.32(br d,J=8.3Hz,1H),5.44(s,2H),4.47(t,J=5.3Hz,1H),3.87-3.96(m,2H),3.39-3.48(m,2H),3.29(s,3H),1.63-1.75(m,2H); 13 C NMR(DMSO-d6)δ:153.8,153.7,152.1,150.5,148.6,145.4,135.1,132.5,131.3,129.5, 128.7,118.8,118.2,119.9,113.1,102.5,58.7,45.8,38.3,30.9,29.5; HRMS(ESI):m / z 525([M+H] + , predicted value 525.1151, calculated value 525.1147).

[0411] Step 4: Recrystallization of 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-3,7-dihydro-1H-purine-2,6-dione (Compound 1)

[0412] Compound 1 [crude material] (20.0 g, 38.1 mmol, 1.0 equivalent) is suspended in ethyl acetate (90 mL). The mixture is heated to 65 ° C, filtered and n-heptane (100 mL) is added to the solution. The mixture is cooled to 53 ° C and seed crystals (40 mg) are added. The crystal suspension is stirred for at least 60 min, then n-heptane (100 mL) is added and stirred at 53 ° C for another 60 min. The suspension is cooled to 5 ° C over 90 min and stirred at 5 ° C for 120 min. The product is separated via filtration and the filter cake is washed with n-heptane (100 mL). The separated material is dried at 50 ° C under reduced pressure to obtain compound 1 (18.9 g, 36.2 mmol, 95% yield, 99.8% purity) as a colorless solid. Melting point: 124 ° C.

[0413] 1 H NMR(DMSO-d6)δ:7.56-7.63(m,1H),7.49(s,1H),7.40-7.45(m,5H),7.32(br d,J=8.3Hz,1H),5.44(s,2H),4.47(t,J=5.3Hz,1H),3.87-3.96(m,2H),3.39-3.48(m,2H),3.29(s,3H),1.63-1.75(m,2H); 13 C NMR(DMSO-d6)δ:153.8,153.7,152.1,150.5,148.6,145.4,135.1,132.5,131.3,129.5, 128.7,118.8,118.2,119.9,113.1,102.5,58.7,45.8,38.3,30.9,29.5; HRMS(ESI):m / z 525([M+H] + , predicted value 525.1150, calculated value 525.1147).

[0414] The recrystallized compound 1 prepared according to step 4 was analyzed by X-ray powder diffraction. Figure 6 (XRPD-pattern) and shown in Table 5.

[0415] Table 5 XRPD data of compound 1

[0416]

Claims

1. A solid oral pharmaceutical composition comprising 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)-phenoxy)-3,7-dihydro-1H-purine-2,6-dione (Compound 1), a sugar alcohol, and at least one additional pharmaceutically acceptable excipient.

2. The solid oral pharmaceutical composition according to claim 1, wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol and xylitol. The solid oral pharmaceutical composition according to claim 1 , wherein the sugar alcohol is mannitol.

4. The solid oral pharmaceutical composition according to claim 1, wherein the amount of the sugar alcohol is 40-80% [w / w].

5. The solid oral pharmaceutical composition according to claim 1, wherein the at least one additional pharmaceutically acceptable excipient comprises one or more selected from the group consisting of a binder, a filler, a disintegrant, a glidant, a lubricant, a wetting agent, a surfactant, and a preservative.

6. The solid oral pharmaceutical composition of claim 1, wherein the at least one additional pharmaceutically acceptable excipient comprises a binder. The solid oral pharmaceutical composition according to claim 6 , wherein the binder is a cellulose derivative.

8. The solid oral pharmaceutical composition according to claim 7, wherein the cellulose derivative is selected from methylcellulose, hydroxyethylcellulose and hydroxypropylcellulose.

9. The solid oral pharmaceutical composition according to claim 8, wherein the cellulose derivative is hydroxypropyl cellulose.

10. The solid oral pharmaceutical composition according to claim 6, wherein the amount of the binder is 1-5% [w / w].

11. The solid oral pharmaceutical composition according to claim 6, wherein the sugar alcohol is mannitol and the binder is hydroxypropyl cellulose.

12. The solid oral pharmaceutical composition according to claim 1, wherein the composition is in the form of granules, hard capsules or tablets.

13. The solid oral pharmaceutical composition according to claim 12, wherein the composition is a tablet, which is optionally coated.

14. The solid oral pharmaceutical composition according to claim 1, wherein Compound 1 is present in an amount of 5-50% [w / w].

15. The solid oral pharmaceutical composition according to claim 1, wherein Compound 1 is present as the sole active ingredient.

16. The solid oral pharmaceutical composition according to claim 1, wherein Compound 1 is incorporated in the form of particles having a particle size of D90 < 100 μm.

17. The solid oral pharmaceutical composition according to claim 1, wherein Compound 1 is incorporated in the form of particles having a particle size of D50 < 500 nm.

18. The solid oral pharmaceutical composition according to claim 1, wherein the composition comprises: 5-50% [w / w] Compound 1, 40-80% [w / w] sugar alcohols, and one or more additional pharmaceutically acceptable excipients, wherein Compound 1, the sugar alcohol, and the one or more additional pharmaceutically acceptable excipients total 100% [w / w]. The solid oral pharmaceutical composition according to claim 18 , wherein the sugar alcohol is mannitol.

20. The solid oral pharmaceutical composition according to claim 1, wherein the composition is a tablet and the core comprises: and 0-1% [w / w] each of a wetting agent, a surfactant and a preservative, wherein the amount of compound 1 and the corresponding excipients totals 100% [w / w] and, The tablet is optionally coated.

21. The solid oral pharmaceutical composition of claim 1, wherein the composition is a tablet and the core comprises: wherein the amounts of Compound 1 and corresponding excipients total 100% [w / w] and wherein the tablet is optionally coated.

22. The solid oral pharmaceutical composition according to any one of claims 13, 20 and 21, wherein the tablet is coated and the coating does not contain titanium dioxide.

23. The solid oral pharmaceutical composition according to any one of claims 1 to 22, which is prepared by a wet granulation method, wherein Compound 1 is preferably suspended in the granulation liquid.

24. A method for preparing a solid oral pharmaceutical composition according to any one of claims 1 to 22, wherein the method is a wet granulation method.

25. The method of claim 24, wherein the method is a fluidized bed granulation method and Compound 1 is suspended in the granulation liquid.

26. The method according to claim 24, wherein the method comprises the following steps: preparing a granulation liquid containing Compound 1 in micronized or nanosized form, a first portion of the sugar alcohol, and at least one additional pharmaceutically acceptable excipient, preferably a binder; granulating the second portion of the sugar alcohol with the granulation liquid in a suitable fluid bed granulator; Drying the wet granules in a fluidized bed granulator to obtain dry granules; Optionally, sieve the dried granules through a suitable sieve; combining the granules with one or more selected from the group consisting of a filler, a disintegrant, a glidant, and a lubricant to obtain a premix, optionally sieving the premix, and mixing the optionally sifted premix to obtain a mixture; Compress the mixture into tablet cores using a suitable tablet press; as well as • Further optionally, coating the cores with the previously prepared film coating suspension by spraying to produce film-coated tablets containing Compound 1.

27. The method according to claim 26, wherein the at least one additional pharmaceutically acceptable excipient contained in the granulation liquid comprises a binder and one or more of the following: a wetting agent, a surfactant and a preservative, preferably a wetting agent and / or a surfactant.

28. A granulation liquid comprising Compound 1 in micronized or nanosized form, a sugar alcohol, at least one additional pharmaceutically acceptable excipient, preferably a binder, and optionally one or more of the following: a wetting agent, a surfactant and a preservative, and water.

29. A solid oral pharmaceutical composition according to any one of claims 1 to 23 for use as a medicament.

30. A solid oral pharmaceutical composition according to any one of claims 1 to 23 for use in treating conditions such as neuropsychiatric disorders, e.g., major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), neurodegenerative disorders, renal diseases and epileptic disorders.

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