Pharmaceutical compositions 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, a process for preparing the same, and its use as a medicine. 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 the pharmaceutically active compound, a process for preparing the same, and its use as a medicine. [Background technology]

[0002] Compound 1 is a TRPC4 / 5 cation channel inhibitor. TRPC5 inhibitors are known, for example, from WO2014 / 143799. TRPC5 inhibitors regulate the function of TRPC5 by inhibiting TRPC5-mediated ion flux, or by inhibiting TRPC5-mediated inward current, outward current, or both. Based on their TRPC5 inhibitory activity, TRPC5 inhibitors can be used to treat conditions such as neuropsychiatric disorders, neurodegenerative disorders, nephropathy, and seizure disorders. Compound 1 exhibits high lipophilicity (logP: 5.2) and low aqueous solubility under acidic to neutral conditions, and therefore, when compound 1 is incorporated into a conventional pharmaceutical dosage form for oral administration, its oral bioavailability tends to exhibit significant inter- and intra-individual variability depending on the patient's fasting state. Summary of the Invention

[0003] The object of the present invention is to provide suitable pharmaceutical compositions comprising Compound 1 as a pharmaceutically active compound, which allow oral administration of Compound 1 with high and reproducible bioavailability. It has been discovered that when Compound 1 is incorporated into a sugar alcohol-based solid composition, high oral bioavailability can be achieved with a fed / fasted ratio of about 2 or less.

[0004] According to the present invention, the following items are provided: Section 1 A solid oral pharmaceutical composition comprising Compound 1, a sugar alcohol, and at least one further pharmaceutically acceptable excipient. Section 2 2. The solid oral pharmaceutical composition of claim 1, wherein the sugar alcohol is selected from mannitol, sorbitol, and xylitol. Section 3 2. The solid oral pharmaceutical composition of claim 1, wherein the sugar alcohol is mannitol. Section 4 2. The solid oral pharmaceutical composition according to item 1, wherein the amount of the sugar alcohol is 40 to 80% [w / w]. Section 5 2. The solid oral pharmaceutical composition of paragraph 1, wherein the at least one additional pharmaceutically acceptable excipient comprises one or more selected from binders, fillers, disintegrants, glidants, lubricants, wetting agents, surfactants, and preservatives. Section 6 10. The solid oral pharmaceutical composition of claim 1, wherein the at least one additional pharmaceutically acceptable excipient comprises a binder. Section 7 7. The solid oral pharmaceutical composition of claim 6, wherein the binder is a cellulose derivative. Section 8 8. The solid oral pharmaceutical composition according to item 7, wherein the cellulose derivative is selected from methylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. Section 9 9. The solid oral pharmaceutical composition of claim 8, wherein the cellulose derivative is hydroxypropyl cellulose. Section 10 7. The solid oral pharmaceutical composition according to item 6, wherein the amount of the binder is 1-5% [w / w]. Section 11 7. The solid oral pharmaceutical composition of item 6, wherein the sugar alcohol is mannitol and the binder is hydroxypropyl cellulose. Section 12 Item 1. The solid oral pharmaceutical composition according to item 1, which is a granule, a hard capsule or a tablet. Section 13 13. The solid oral pharmaceutical composition according to item 12, which is a tablet, and which may be coated. Section 14 2. The solid oral pharmaceutical composition according to item 1, wherein Compound 1 is present in an amount of 5 to 50% [w / w]. Section 15 Item 1. A solid oral pharmaceutical composition according to item 1, wherein Compound 1 is present as the sole active ingredient. Section 16 Item 1. A solid oral pharmaceutical composition according to item 1, wherein compound 1 is incorporated in the form of particles having a particle size of D90<100 μm. Section 17 Item 1. A solid oral pharmaceutical composition according to item 1, wherein Compound 1 is incorporated in the form of particles having a particle size of D50<500 nm. Section 18 5 to 50% [w / w] Compound 1, 40-80% [w / w] sugar alcohol, and one or more additional pharmaceutically acceptable excipients wherein the total of Compound 1, the sugar alcohol, and the one or more additional pharmaceutically acceptable excipients together amounts to up to 100% [w / w]. Section 19 19. The solid oral pharmaceutical composition of item 18, wherein the sugar alcohol is mannitol. Section 20 a tablet, the tablet core comprising:

[0005] [Table 1] and 0-1% [w / w] each of wetting agent, surfactant and preservative wherein the total amount of Compound 1 and each excipient added together is up to 100% [w / w]; and 10. The solid oral pharmaceutical composition of claim 1, wherein the tablet is optionally coated. Section 21 a tablet, the tablet core comprising:

[0006] [Table 2] The total amount of Compound 1 and each excipient added together is up to 100% [w / w], and 10. The solid oral pharmaceutical composition of claim 1, wherein the tablet is optionally coated. Section 22 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. Section 23 23. The solid oral pharmaceutical composition according to any one of items 1 to 22, prepared by wet granulation, wherein Compound 1 is preferably suspended in a granulation liquid. Section 24 23. A method for preparing the solid oral pharmaceutical composition according to any one of items 1 to 22, which is a wet granulation method. Section 25 25. The method of claim 24, wherein the method is a fluidized bed granulation method and Compound 1 is suspended in the granulation liquid. Section 26 preparing a granulation liquid containing compound 1 in μm-sized or nanosized form, a first amount of the sugar alcohol, and the at least one further pharmaceutically acceptable excipient, preferably a binder, granulating a second quantity of the sugar alcohol with the granulation liquid in a suitable fluid bed granulator; drying the obtained wet granulation in the fluidized bed granulator to obtain a dry granulation; Optionally, sieving the dried granulation using a suitable sieve, combining the obtained granulation with one or more selected from a filler, a disintegrant, a glidant, and a lubricant to obtain a premix, optionally sieving the premix, and blending the optionally sieved premix to obtain a blend; compressing the blend into tablet cores using a suitable tablet press; and and optionally, coating the tablet cores with a pre-prepared film coating suspension by spray coating to produce film-coated tablets containing Compound 1. 25. The method of claim 24, comprising: Section 27 27. The method according to claim 26, wherein the at least one further pharmaceutically acceptable excipient contained in the granulation liquid comprises a binder and one or more of a wetting agent, a surfactant and a preservative, preferably a wetting agent and / or a surfactant. Section 28 A granulation liquid comprising Compound 1 in μm-sized or nano-sized form, a sugar alcohol, at least one further pharmaceutically acceptable excipient, preferably a binder and optionally one or more of a wetting agent, a surfactant, and a preservative, and water. Section 29 24. A solid oral pharmaceutical composition according to any one of items 1 to 23 for use as a medicament. Section 30 24. A solid oral pharmaceutical composition according to any one of clauses 1 to 23 for use in the treatment of conditions such as neuropsychiatric disorders, for example major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), neurodegenerative disorders, nephropathy and seizure disorders. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 is a schematic diagram illustrating a method for preparing a solid oral pharmaceutical composition of the present invention. [Figure 2] 1 is a flowchart showing a method for preparing Formulation Example A. [Figure 3] 1 is a flowchart showing the preparation methods of Formulation Examples B and C. [Figure 4] 1 is a flowchart showing a method for preparing Formulation Example D. [Figure 5] 1 is a graph showing the results of a comparative dissolution test of a 50 mg tablet core and a 50 mg final film-coated tablet for Formulation Example B. [Figure 6] 1 is an X-ray powder diffraction (XRPD) diagram of Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention is based on the finding that formulating Compound 1 in the form of a sugar alcohol-based solid composition can achieve high oral bioavailability of Compound 1 while significantly reducing the influence of the food effect. It is well known that drug bioavailability can be altered when administered with food. Essentially, the food effect on drug bioavailability is most pronounced when the drug is taken immediately after a meal. The food effect can be expressed by determining the fed / fasted ratio, i.e., by determining the bioavailability under fed and fasting conditions and comparing the results obtained by calculating the respective quotients. The postprandial / fasting ratio for the compositions of the present invention is less than 3, preferably less than 2.5, more preferably less than 2.1.

[0009] To achieve the aforementioned beneficial effects, according to the present invention, Compound 1 is formulated in the form of a sugar alcohol-based solid composition for oral use. 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 further pharmaceutically acceptable excipient. As used herein, the term "Compound 1" encompasses anhydrate as well as hydrates and solvates of Compound 1, in either amorphous or crystalline form, respectively. In one embodiment, Compound 1 used in the preparation of the solid oral pharmaceutical composition of the invention has a particle size of D<100 μm, preferably D≦15 μm. The corresponding Compound 1 particles are also referred to herein as "μm-sized."

[0010] In another embodiment, Compound 1 used in the preparation of the solid oral pharmaceutical composition of the present invention has a particle size of D50<500 nm, preferably D50<200 nm. The corresponding Compound 1 particles are also referred to herein as "nano-sized." In a preferred embodiment, compound 1 used in the preparation of the solid oral pharmaceutical composition of the present invention is of μm size. In another preferred embodiment, Compound 1 is present as the sole active ingredient in the solid oral pharmaceutical composition of the present invention. In a preferred embodiment, compound 1 is present in the solid oral pharmaceutical composition of the present invention in an amount of 5 to 50% [w / w], preferably in an amount of 5 to 30% [w / w], more preferably in an amount of 5 to 25% [w / w]. Here and hereinafter, when amounts are indicated as "% [w / w]", said amounts relate to the total amount of the solid oral pharmaceutical composition of the invention per se, i.e., the total amount not including any coating that may be applied.

[0011] In a preferred embodiment, the sugar alcohol for use in the present invention is selected from mannitol, sorbitol and xylitol. Preferably, the sugar alcohol is mannitol. In a preferred embodiment, the sugar alcohol is present in the solid oral pharmaceutical composition of the present invention in an amount of 40 to 80% [w / w], preferably in an amount of 50 to 70% [w / w]. In one embodiment, the at least one additional pharmaceutically acceptable excipient used in the solid oral pharmaceutical composition of the present invention comprises one or more selected from binders, fillers, disintegrants, glidants, lubricants, wetting agents, surfactants, and preservatives. In a preferred embodiment, the at least one additional pharmaceutically acceptable excipient used in the solid oral pharmaceutical composition of the present invention comprises a binder.

[0012] In another preferred embodiment, the at least one additional pharmaceutically acceptable excipient used in the pharmaceutical composition of the present invention comprises a binder, a wetting agent and / or a surfactant. Binders suitable for use in the solid oral pharmaceutical composition of the present invention can be selected from polyvinylpyrrolidone (PVP), copovidone, starch, cellulose derivatives, or polyethylene glycol. The binder is preferably a cellulose derivative, more preferably methylcellulose, hydroxyethylcellulose, or hydroxypropylcellulose. Most preferably, the binder is hydroxypropylcellulose. The binder used as the at least one further 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 in an amount of 1-5% [w / w], and most preferably in an amount of 2-3% [w / w]. Fillers suitable for use in the solid oral pharmaceutical composition of the present invention can be selected from inorganic phosphates, such as dibasic calcium phosphate, lactose, such as lactose monohydrate or water-free lactose, dextrose, sucrose, maltodextrin, isomalt, and microcrystalline cellulose. Preferably, the filler is microcrystalline cellulose.

[0013] The filler used as at least one further 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 in an amount of 5-25% [w / w], and most preferably in an amount of 10-20% [w / w]. Disintegrants suitable for use in the solid oral pharmaceutical composition of the present invention can be selected from crospovidone, sodium starch glycolate, alginate, pregelatinized starch, and croscarmellose sodium. Preferably, the disintegrant is croscarmellose sodium. The disintegrant used as the at least one further 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 in an amount of 1-5% [w / w], and most preferably in an amount of 2-3% [w / w].

[0014] Glidants suitable for use in the solid oral pharmaceutical compositions of the present invention can be selected from corn starch and colloidal silicon dioxide. Preferably, the glidant is colloidal silicon dioxide. The glidant used as the at least one further 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]. In a preferred embodiment, the solid oral pharmaceutical composition of the present invention does not contain a glidant. Lubricants suitable for use in the solid oral pharmaceutical composition of the present invention can be selected from talc, alkali or earth alkali salts of stearic acid, such as magnesium stearate and sodium stearyl fumarate. Preferably, the lubricant is magnesium stearate.

[0015] The lubricant used as the at least one further pharmaceutically acceptable excipient is preferably present in the solid oral pharmaceutical composition of the present invention in an amount of 0-5% [w / w], more preferably in an amount of 1-2% [w / w]. The at least one additional pharmaceutically acceptable excipient used in the solid oral pharmaceutical composition of the present invention may additionally comprise a wetting agent, a surfactant, or a combination thereof. Preferably, the wetting agent is sodium lauryl sulfate. The surfactant may be selected from polysorbate 80 and poloxamer 188. Preferably, the surfactant is polysorbate 80. In a preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises a wetting agent, preferably sodium lauryl sulfate. In another embodiment, sodium lauryl sulfate and polysorbate 80 are used in combination in the solid oral pharmaceutical composition of the present invention.

[0016] Additionally, the at least one additional pharmaceutically acceptable excipient used in the solid oral pharmaceutical composition of the present invention may comprise a preservative, preferably parahydroxybenzoate. When used in the solid oral pharmaceutical composition of the present invention, the wetting agent, surfactant, and preservative are preferably present in an amount of 1% [w / w] or less each, preferably 0.1% [w / w] or less each, and more preferably 0.01-1% [w / w] or 0.01-0.1% [w / w] each. In a preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises 5-50% [w / w] of compound 1 (incorporated in the form of μm-sized particles or nano-sized particles), 40-80% [w / w] sugar alcohol, and optionally one or more additional pharmaceutically acceptable excipients wherein the total of Compound 1, the sugar alcohol, and the one or more additional pharmaceutically acceptable excipients together is up to 100% [w / w].

[0017] In another preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises: [Table 3] and 0-1% [w / w] each of wetting agent, surfactant and preservative The total amount of Compound 1 and each excipient added together is up to 100% [w / w].

[0018] In a further preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises: [Table 4] and 0-1% [w / w] each of wetting agent, surfactant and preservative wherein the combined amounts of Compound 1 and each excipient total up to 100% [w / w]; or

[0019] [Table 5] and 0-1% [w / w] each of wetting agent, surfactant and preservative wherein the combined amounts of Compound 1 and each excipient total up to 100% [w / w]; or

[0020] [Table 6] and 0.01 to 1% [w / w] each of wetting agent, surfactant, and preservative wherein the combined amounts of Compound 1 and each excipient total up to 100% [w / w]; or

[0021] [Table 7] and 0.01 to 1% [w / w] each of wetting agent, surfactant, and preservative The total amount of Compound 1 and each excipient added together is up to 100% [w / w].

[0022] Preferably, the sugar alcohol in any of the foregoing compositions is mannitol. In yet another preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises: [Table 8] The total amount of Compound 1 and each excipient added together is up to 100% [w / w].

[0023] In a further preferred embodiment, the solid oral pharmaceutical composition of the present invention comprises: [Table 9] wherein the combined amounts of Compound 1 and each excipient total up to 100% [w / w]; or

[0024] [Table 10] wherein the combined amounts of Compound 1 and each excipient total up to 100% [w / w]; or

[0025] [Table 11] wherein the combined amounts of Compound 1 and each excipient total up to 100% [w / w]; or

[0026] [Table 12] The total amount of Compound 1 and each excipient added together is up to 100% [w / w].

[0027] The solid oral pharmaceutical composition of the present invention is preferably in the form of granules, hard capsules or tablets, most preferably tablets. In one embodiment, the solid oral pharmaceutical composition of the present invention is a tablet, which may be coated. The corresponding coating composition preferably comprises one or more film-forming polymers and one or more pharmaceutically acceptable excipients.

[0028] Suitable film-forming polymers for use in the coating composition include, for example, hydroxypropyl methylcellulose (hypromellose), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers such as Eudragit®, polyvinylpyrrolidone, polyvinyl alcohol, macrogol-poly(vinyl alcohol) graft copolymer, polyethylene glycol, or mixtures thereof. Other film-forming polymers known in the art can also be used.

[0029] 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. Pharmaceutically acceptable excipients suitable for use in the coating composition include, for example, softeners such as polyethylene glycol, GMCC (a mixture of mono- and diglycerides of caprylic and capric acid), medium chain triglycerides (MCT) and isomalt, anti-blocking agents such as talc, pigments such as titanium dioxide or calcium carbonate, and dyes such as iron oxide pigments.

[0030] An example of a film coating composition for use in the present invention comprises hydroxypropyl methylcellulose, propylene glycol, talc, titanium dioxide, and optionally iron oxide, such as yellow iron oxide and / or red iron oxide. In a preferred embodiment, the film coating composition for use in the present invention does not contain titanium dioxide. Titanium dioxide-free coatings suitable for use in the present invention include, for example: hydroxypropyl methylcellulose, hydroxypropyl cellulose, medium chain triglycerides, isomalt, calcium carbonate, and optionally iron oxides, such as yellow iron oxide and / or red iron oxide, Hydroxypropyl methylcellulose, hydroxypropyl cellulose, propylene glycol, talc, calcium carbonate, and optionally iron oxides, such as yellow iron oxide and / or red iron oxide, or Hydroxypropyl methylcellulose, propylene glycol, talc, calcium carbonate, and optionally iron oxides, such as yellow iron oxide and / or red iron oxide. may include:

[0031] In one embodiment, commercially available film coating compositions, such as Opadry® or Aquapolish® P, can be used to coat the solid oral pharmaceutical composition of the present invention. The coating can be applied by known film coating techniques, namely spray coating, fluidized bed coating or dip coating.

[0032] Examples of solvents that can be used to prepare the initial coating solution of the coating composition used in the film coating step are selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.

[0033] The coating compositions described herein generally do not contain Compound 1. In an alternative embodiment, the coating composition can contain at least a portion of Compound 1, with the remaining amount of Compound 1 being part of the tablet core. In a preferred embodiment, the solid oral pharmaceutical composition of the present invention is an immediate release film-coated tablet.

[0034] The following are preferred embodiments of solid oral pharmaceutical compositions of the present invention in the form of tablets, optionally coated: a) [Table 13] b) [Table 14] c)

[0035] [Table 15] d) [Table 16] e)

[0036] [Table 17]

[0037] In a second aspect, the present invention relates to a method 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. The preparation method of the present invention is a wet granulation method, preferably a fluidized bed granulation method. In a particularly preferred embodiment, the preparation method of the present invention is a fluidized bed granulation method, in which Compound 1 is suspended in a granulation fluid. Thus, the solid oral pharmaceutical compositions of the present invention are prepared by wet granulation, preferably by fluidized bed granulation. 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 a granulation fluid.

[0038] In one embodiment, the preparation method of the present invention comprises: preparing a granulation liquid containing compound 1 in μm-sized or nanosized form, a first amount of a sugar alcohol, and at least one further pharmaceutically acceptable excipient, preferably a binder; granulating a second quantity of the sugar alcohol with the granulation liquid in a suitable fluid bed granulator; drying the obtained wet granulation in the fluidized bed granulator to obtain a dry granulation; Optionally, sieving the dried granulation using a suitable sieve, combining the obtained granulation with one or more selected from a filler, a disintegrant, a glidant, and a lubricant to obtain a premix, optionally sieving the premix, and blending the optionally sieved premix to obtain a blend; compressing the blend into tablet cores using a suitable tablet press; and and optionally, coating the tablet cores with a pre-prepared film coating suspension by spray coating to produce film-coated tablets containing Compound 1. Includes:

[0039] In another embodiment, the preparation method of the present invention comprises: adding and mixing a first quantity of binder and one or more of a wetting agent, a surfactant and a preservative, preferably a wetting agent and / or a surfactant, to a solvent to form a vehicle; adding μm-sized compound 1 to the vehicle and stirring to obtain a suspension; grinding the suspension in a wet grinding process to obtain a nano-sized compound 1 suspension; mixing a second amount of binder with a solvent to obtain a binder liquid; adding a binder liquid to the nano-sized compound 1 suspension while stirring; thereafter, adding a first amount of sugar alcohol to obtain a granulation liquid; preheating a second amount of the sugar alcohol and then granulating it with the granulation liquid in a suitable fluid bed granulator; drying the resulting wet granulation in the fluidized bed granulator to obtain a dry granulation; and Optionally sieving the dried granulation using a suitable sieve. or alternatively, dissolving a binder and one or more of a wetting agent, a surfactant and a preservative, preferably a wetting agent and / or a surfactant, and a first amount of a sugar alcohol (optionally pre-screened) in a solvent, thereafter suspending the μm-sized compound 1 therein to obtain a granulation liquid, preheating a second amount of the sugar alcohol and then granulating it with the granulation liquid in a suitable fluid bed granulator; drying the resulting wet granulation in the fluidized bed granulator to obtain a dry granulation; and Optionally sieving the dried granulation using a suitable sieve. Includes:

[0040] The resulting granulation can be further processed into tablets by a direct compression process or as follows: blending the filler, disintegrant and, optionally, the pre-screened granulation to obtain a main blend; blending the main blend with a lubricant to form a final blend, preferably by blending a first amount of the main blend with the lubricant and then adding and blending the remaining main blend, or by blending the main blend with the lubricant all at once to form a final blend; compressing the final blend into tablet cores using a suitable tablet press; Or alternatively, blending the filler, the disintegrant and the optionally pre-screened granulation to obtain a blend; adding a lubricant to form a main blend, either by combining a first portion of the blend with the lubricant and then adding the remaining portion of the blend, or, preferably, by combining the blend with the lubricant all at once to form a main blend; Optionally sieving the primary blend; blending the optionally sieved primary blend to obtain a final blend; Compress the final blend into tablet cores using a suitable tablet press.

[0041] Without being bound by theory, it is speculated that the resulting tablets contain Compound 1 layered onto sugar alcohol particles, thereby forming a matrix in which Compound 1 is embedded. The tablets can be further film coated as follows: preparing a film coating suspension by dispersing the film coating composition in a solvent by agitation in a suitable mixing vessel; The tablet cores are coated with the film coating suspension by spraying to prepare film-coated tablets containing Compound 1.

[0042] Alternatively, the granules obtained by any of the above preparation methods can be processed into capsules, for example by blending the granules with a filler and then filling the same into capsules. In describing the present invention, when reference is made to blending respective materials, blending can include either mixing the materials as is or sieving the materials together. The solvent used to prepare the granulation liquid is selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof. Preferably, the solvent is water.

[0043] In a preferred embodiment, the granulation liquid contains Compound 1 in μm-sized or nano-sized form, a sugar alcohol, at least one further pharmaceutically acceptable excipient, preferably a binder and optionally one or more of a wetting agent, a surfactant, and a preservative, and water. μm-sized Compound 1 can be prepared by jet milling. Nano-sized Compound 1 can be prepared by wet milling a pre-prepared μm-sized Compound 1 suspension. In a third aspect, the present invention relates to the use as a medicament of a solid oral pharmaceutical composition of the present invention comprising Compound 1, a sugar alcohol, and at least one further pharmaceutically acceptable excipient. In a preferred embodiment, the solid oral pharmaceutical composition of the present invention is for use in the treatment of conditions such as neuropsychiatric disorders, including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), neurodegenerative disorders, nephropathy, and seizure disorders. [Example]

[0044] The following examples serve to further illustrate the present invention, but these examples should not be construed as limiting the scope of the invention disclosed herein. Example 1 Compound 1-containing immediate-release film-coated tablet formulations were prepared in dose strengths of 5 mg, 25 mg, 50 mg, 75 mg, 100 mg, and 125 mg. Tablets were prepared by wet granulation using mannitol, microcrystalline cellulose as a filler, magnesium stearate as a lubricant, hydroxypropyl cellulose as a binder, and croscarmellose sodium as a disintegrant, with Compound 1 suspended in the granulation liquid. The preparation method is shown schematically in Figure 1. The resulting granules had excellent flow properties, so the addition of a glidant, such as colloidal anhydrous silica, was not necessary.

[0045] Four tablet formulations, Formulation A, Formulation B, Formulation C and Formulation D, were prepared having the following compositions: [Table 18]

[0046] [Table 19]

[0047] [Table 20]

[0048] [Table 21] JPEG2026502517000022.jpg93144

[0049] The 5 mg tablets of Formulations A and B were dark red, round, biconvex, bevel-edged, film-coated tablets approximately 6 mm in diameter. The 25 mg tablets of Formulations A and B were dark red, oval, biconvex, film-coated tablets measuring approximately 14 mm in length and 6.8 mm in width. The 50 mg tablets of Formulations A and B were dark red, oval, biconvex, film-coated tablets measuring approximately 17.8 mm in length and 8.6 mm in width.

[0050] The 100 mg tablets of Formulation C were dark red, oval, biconvex, film-coated tablets measuring approximately 15 mm long and 7 mm wide. The tablets of Formulation D had the following size, shape and color: [Table 22]

[0051] The wet granulation process used to prepare tablets of Formulation A, Formulation B, Formulation C and Formulation D was a fluid bed granulation process using the following granulation conditions: Final blend for a 45kg batch size: [Table 23] Final blend for a batch size of 100 kg: [Table 24]

[0052] Each wet granulation process can be summarized as follows: Formulation A Preparation of Compound 1 suspension (Step 1) Step 1.1 Vehicle preparation Hydroxypropyl cellulose, sodium lauryl sulfate, polysorbate 80, and methyl parahydroxybenzoate are added to purified water and mixed to prepare a vehicle. Step 1.2 Preparation of suspension Jet-milled Compound 1, D90≦15 μm is added to this vehicle and stirred to obtain a suspension. Step 1.3 Crushing This suspension is milled in a wet milling process to obtain a suspension of nanosized Compound 1, target size D50<200 nm.

[0053] Preparation of Compound 1 Granulation Solution (Step 2) Step 2.1 Preparation of binder solution Hydroxypropyl cellulose and purified water are mixed in a suitable container to obtain a binder liquid. Step 2.2 Preparation of granulation liquid The binder liquid is added to the nano-sized compound 1 suspension obtained in step 1 while stirring, and then mannitol is added to obtain a granulation liquid. Preparation of Compound 1 Granules (Step 3) Step 3.1 and Step 3.2 Preheating and Granulation Mannitol is pre-screened, pre-heated and then granulated in a suitable fluid bed granulator using the granulation liquid from step 2. Step 3.3 Drying The resulting wet granulation is dried in a fluid bed granulator to obtain a dried granulation. Step 3.4 Dry sieving The dried granulation is sieved using a suitable sieve.

[0054] Preparation of Compound 1 Final Blend (Step 4) Step 4.1 Primary Blend Blend the microcrystalline cellulose, croscarmellose sodium and the pre-screened granulation from step 3 to obtain a master blend. Step 4.2 Pre-screening A portion of the main blend is pre-screened with magnesium stearate. Step 4.3 Final Blend The remainder of the main blend is blended with the pre-screened material to make the final blend.

[0055] Compound 1 Tablet Core Preparation (Step 5) Step 5.1 Tablet compression Compress the final blend from step 4 into tablet cores using a suitable tablet press. Preparation of Compound 1 film-coated tablets (Step 6) Step 6.1 Preparation of film coating suspension The film coating suspension is prepared by dispersing the film coating mixture (Opadry® Red) in purified water by stirring in a suitable mixing vessel. Step 6.2 Film Coating The tablet cores obtained in step 5 are coated with the film coating suspension by spraying in a drum coater to produce Compound 1 film coated tablets.

[0056] Formulation B and Formulation C Preparation of Compound 1 Granulation Solution (Step 1) Step 1.1 Preparation of granulation suspension Hydroxypropyl cellulose, sodium lauryl sulfate, and mannitol (optionally pre-screened) are dissolved in purified water, and then jet-milled Compound 1, D90≦15 μm, is suspended therein to obtain a granulation liquid. Preparation of Compound 1 Granules (Step 2) Step 2.1 and Step 2.2 Preheating and Granulation Mannitol is pre-screened, pre-heated and then granulated in a suitable fluid bed granulator using the granulation liquid from step 1. Step 2.3 Drying The resulting wet granulation is dried in a fluid bed granulator to obtain a dried granulation. Step 2.4 Dry sieving The dried granulation is sieved using a suitable sieve.

[0057] Preparation of Compound 1 Final Blend (Step 3) Step 3.1 Primary Blend Microcrystalline cellulose, croscarmellose sodium, and the pre-screened granulation from step 2 are blended to obtain a master blend. Step 3.2 Pre-screening A portion of the main blend is pre-screened with magnesium stearate. Step 3.3 Final Blend The remainder of the main blend is blended with the pre-screened material to make the final blend. Compound 1 Tablet Core Preparation (Step 4) Step 4.1 Tablet compression Compress the final blend from step 3 into tablet cores using a suitable tablet press.

[0058] Preparation of Compound 1 film-coated tablets (Step 5) Step 5.1 Preparation of film coating suspension The film coating suspension is prepared by dispersing the film coating mixture (Opadry® Red) in purified water by stirring in a suitable mixing vessel. Step 5.2 Film coating The tablet cores obtained in step 4 are coated with the film coating suspension by spraying in a drum coater to produce Compound 1 film coated tablets.

[0059] Formulation D Preparation of Compound 1 Granulation Solution (Step 1) Step 1.0 Preparation of the granulation suspension Hydroxypropyl cellulose, sodium lauryl sulfate, and mannitol are dissolved in purified water, and then jet-milled Compound 1 (D90≦15 μm) is suspended therein to obtain a granulation liquid. Preparation of Compound 1 Granules (Step 2) Step 2.1 and Step 2.2 Preheating and Granulation Mannitol is pre-screened, pre-heated and then granulated in a suitable fluid bed granulator using the granulation liquid from step 1. Step 2.3 Drying The resulting wet granulation is dried in a fluid bed granulator to obtain a dried granulation. Preparation of Compound 1 Final Blend (Step 3) Step 3.1 and Step 3.2 Primary Blend Microcrystalline cellulose, croscarmellose sodium, and the dried granulation from step 2 are blended together, and then magnesium stearate is added to obtain the master blend. Step 3.3 and Step 3.4 Sieving and final blending The primary blend is screened and finally blended to produce the final blend.

[0060] Compound 1 Tablet Core Preparation (Step 4) Step 4.1 Tablet compression Compress the final blend from step 3 into tablet cores using a suitable tablet press. Preparation of Compound 1 film-coated tablets (Step 5) Step 5.1 Preparation of film coating suspension The film coating suspension is prepared by dispersing the film coating mixture (Aquapolish® P) in purified water by stirring in a suitable mixing vessel. Step 5.2 Film coating The tablet cores obtained in step 4 are coated with the film coating suspension by spraying in a drum coater to produce Compound 1 film coated tablets. The corresponding preparation flow charts are shown in FIGS.

[0061] Example 2 Bioavailability Study Two bioavailability studies (Study 1 and Study 2) were conducted using tablets of Formulation A, Formulation B, and Formulation C. Healthy male subjects were used to examine differences in exposure (AUC) and food effect following oral administration under fed and fasted conditions.

[0062] The details of the study were as follows: [Table 25]

[0063] Bioavailability (AUC 0-∞ ) was determined based on the geometric mean (gMean) of the plasma concentration data obtained.

[0064] The results of the bioavailability test are shown in Tables 4a and 4b below. Sufficiently high AUC was obtained for all formulations in both fasted and fed states. [Table 26] [Table 27]

[0065] The results of Test 1 and Test 2 confirm that the solid oral pharmaceutical composition of the present invention has desirable pharmacokinetic properties, such as high oral bioavailability and a fed / fasted ratio of 2.03 or less.

[0066] Example 3 Dissolution test Dissolution testing was performed using 50 mg tablet cores and 50 mg final film-coated tablets of Formulation B under the following conditions: 0.1 M HCl pH 1 + 0.2% SLS, 900 mL, paddle, 100 rpm.

[0067] The results are shown in Figure 5. Both the tablet cores and the final film-coated tablets showed an immediate release profile with complete release of Compound 1 in less than 20 minutes.

[0068] Example 4 Preparation of Compound 1 List of abbreviations: APCI atmospheric pressure chemical ionization abs. Absolute value aq. aqueous solution BHT 3,5-di-tert-butyl-4-hydroxytoluene Concentrated DCM dichloromethane DIPEA N-ethyl-diisopropylamine DMAc Dimethylacetamide DMF Dimethylformamide DMSO dimethyl sulfoxide equiv. equivalent amount ESI electrospray ionization EtOAc ethyl acetate g grams h time HOAc acetic acid HPLC High-Performance Liquid Chromatography iPr Isopropyl kg kilogram NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance MeCN acetonitrile MeOH Methanol min mg milligram mL milliliter M mole (mol / L) TBABr Tetra-n-butylammonium bromide THF tetrahydrofuran

[0069] NMR method The NMR spectrum is divided into two parts: 1 600MHz for H-NMR experiments, 13 C-NMR experiments were recorded on a 150 MHz Bruker AVANCE III instrument and analyzed using TopSpin 3.2 pl6 software. Chemical shifts are given in parts per million (ppm) as δ units downfield from the internal trimethylsilane standard. Selected data are reported as follows: chemical shift (multiplicity, coupling constant (J), number of hydrogens). Abbreviations are as follows: s (singulet), d (doublet), t (triplet), q (quartet), spt (septet), m (multiplet), br (broad line). X-ray powder diffraction (XRPD) diagram X-ray powder diffraction measurements were performed using a Bruker D8 Advance diffractometer in reflector mode equipped with a LynxEye position-sensitive detector and a Cu anode as the X-ray source emitting CuKα radiation (λ = 1.54060 Å, 40 kV, 40 mA). The standard error of the 2θ values ​​is ±0.2°. Step 1: Preparation of 8-bromo-7-(4-chlorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (compound 2) 8-Bromo-3-methylxanthine (20.0 g, 81.6 mmol, 1.0 equiv.) and BHT (0.8 g, 3.6 mmol, 0.04 equiv.) are dissolved in dimethylacetamide (210 mL). The mixture is heated to 85° C. A solution of 4-chlorobenzyl chloride (15.8 g, 97.9 mmol, 1.2 equiv.) in dimethylacetamide (20 mL) is added, rinsing with dimethylacetamide (10 mL). Diisopropylethylamine (11.1 g, 85.7 mmol, 1.05 equiv.) is added, rinsing with dimethylacetamide (10 mL). The reaction is stirred at 85° C. until the starting material is consumed (8-bromo-3-methylxanthine <0.3%). An additional dosage of diisopropylethylamine (0.5 g, 4.1 mmol, 0.05 equiv.) may be added to drive the reaction to completion. After the conversion was complete, hydrochloric acid (4 M, 0.8 g, 8.2 mmol, 0.1 equiv.) was added. The reaction solvent was partially removed by vacuum distillation (until the remaining volume of the reaction mixture was approximately 150 mL). Acetonitrile (150 mL) was added, and the resulting suspension was slowly cooled to 20 °C. The product was isolated by filtration, and the filter cake was washed twice with acetonitrile (50 mL). The isolated material was dried under reduced pressure at 50 °C to give compound 2 (28.7 g, 78.0 mmol, 95% yield, 99.9% purity) as a colorless solid. Melting point: 270-271 °C. 1 H NMR (DMSO-d6) δ: 11.37 (s, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 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] + , experimental value 368.9763, calculated value 368.9748). Step 2: Preparation of 8-bromo-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (compound 3) Compound 2 (20.0 g, 54.1 mmol, 1.0 equiv.), sodium bicarbonate (6.8 g, 81.2 mmol, 1.5 equiv.), and tetrabutylammonium bromide (0.8 g, 2.7 mmol, 0.05 equiv.) were suspended in dimethylacetamide (170 mL). The mixture was heated to 110 °C. 3-Chloro-1-propanol (7.7 g, 81.5 mmol, 1.5 equiv.) was added and rinsed with dimethylacetamide (10 mL). Vacuum pressure (200-400 mbar) was then applied. The reaction was stirred at 110 °C until the starting material was consumed (compound 2 <0.5%). After complete conversion, the reaction mixture was cooled to 80 °C, filtered, and rinsed with dimethylacetamide (30 mL). Water (160 mL) is added to the filtrate at 90°C, followed by sodium bicarbonate (0.5 g, 5.4 mmol, 0.1 equiv). The mixture is cooled to 70°C, and seed crystals (47 mg) are added. The crystalline suspension is cooled to 40°C over 60 min, heated to 70°C, held at 70°C for at least 15 min, cooled to 20°C over 150 min, and stirred for 1 h. The product is isolated by filtration, and the filter cake is washed with water (160 mL). The isolated material is dried under reduced pressure at 60°C to give compound 3 (16.1 g, 37.7 mmol, 91% yield, 98.7% purity) as a colorless solid. Melting point: 148-149°C. 1 H NMR (DMSO-d6) δ: 7.43 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 5.52 (s, 2H), 4.48 (t, J=5.2 Hz, 1H), 3.89-3.96 (m, 2H), 3.43-3.48 (m, 2H), 3.38 (s, 2H), 1.65-1.74 (m, 2H); 13HRMS (ESI): m / z 427, ([M+H] + , experimental value 427.0188, calculated value 427.0167). 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]: 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 under reduced pressure (200-400 mbar) at 120 °C 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) is added over at least 30 min. The mixture is cooled to 58 °C and seed crystals (20 mg) are added. The crystalline suspension is successively cooled to 40 °C, heated to 60 °C, held at this temperature for at least 15 min, and cooled to 20 °C. The product is isolated by filtration, and the filter cake is washed with water (160 mL) and n-heptane (40 mL). The isolated material is dried under reduced pressure at 60 °C to give compound 1 [crude] (22.1 g, 42.1 mmol, 90% yield, 98.5% purity) as a colorless solid. Melting point: 124-125 °C. 1H 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=8.3 Hz, 1H), 5.44 (s, 2H), 4.47 (t, J=5.3 Hz, 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] + , experimental value 525.1151, calculated value 525.1147).

[0070] 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) Compound 1 [crude] (20.0 g, 38.1 mmol, 1.0 equiv.) 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 introduced. The crystalline suspension is stirred for at least 60 minutes, then n-heptane (100 mL) is added and stirred at 53° C. for an additional 60 minutes. The suspension is cooled to 5° C. over 90 minutes and stirred at 5° C. for 120 minutes. The product is isolated by filtration, and the filter cake is washed with n-heptane (100 mL). The isolated material is dried under reduced pressure at 50° C. to give compound 1 (18.9 g, 36.2 mmol, 95% yield, 99.8% purity) as a colorless solid. Melting point: 124° C. 1H 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=8.3 Hz, 1H), 5.44 (s, 2H), 4.47 (t, J=5.3 Hz, 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] + , experimental value 525.1150, calculated value 525.1147).

[0071] The recrystallized Compound 1 prepared according to Step 4 was analyzed by X-ray powder diffraction, and the results are shown in Figure 6 (XRPD diagram) and Table 5. [Table 28]

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

3. 2. The solid oral pharmaceutical composition of claim 1, wherein the sugar alcohol is mannitol.

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

5. 10. The solid oral pharmaceutical composition of claim 1, wherein the at least one additional pharmaceutically acceptable excipient comprises one or more selected from binders, fillers, disintegrants, glidants, lubricants, wetting agents, surfactants, and preservatives.

6. 10. The solid oral pharmaceutical composition of claim 1, wherein the at least one additional pharmaceutically acceptable excipient comprises a binder.

7. 7. The solid oral pharmaceutical composition of claim 6, wherein the binder is a cellulose derivative.

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

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

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

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

12. 10. The solid oral pharmaceutical composition of claim 1, which is a granule, a hard capsule, or a tablet.

13. 13. The solid oral pharmaceutical composition of claim 12, which is a tablet, said tablet optionally being coated.

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

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

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

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

18. 5 to 50% [w / w] Compound 1, 40 to 80% [w / w] sugar alcohol, and one or more additional pharmaceutically acceptable excipients wherein the total of Compound 1, said sugar alcohol, and said one or more additional pharmaceutically acceptable excipients together is up to 100% [w / w].

19. 19. The solid oral pharmaceutical composition of claim 18, wherein the sugar alcohol is mannitol.

20. a tablet, the tablet core comprising: Table 1 and 0-1% [w / w] each of a wetting agent, a surfactant, and a preservative. wherein the combined amounts of Compound 1 and each excipient total up to 100% [w / w]; and The solid oral pharmaceutical composition of claim 1 , wherein the tablet is optionally coated.

21. a tablet, the tablet core comprising: Table 2 wherein the combined amounts of Compound 1 and each excipient total up to 100% [w / w]; and The solid oral pharmaceutical composition of claim 1 , wherein the tablet is optionally coated.

22. 22. A 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, prepared by wet granulation, wherein Compound 1 is preferably suspended in a granulation liquid.

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

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

26. preparing a granulation liquid containing Compound 1 in μm-sized or nano-sized form, a first amount of said sugar alcohol, and said at least one further pharmaceutically acceptable excipient, preferably a binder; - granulating a second quantity of said sugar alcohol with said granulation liquid in a suitable fluid bed granulator; - drying the obtained wet granulation in the fluid bed granulator to obtain a dry granulation; Optionally, sieving the dried granulation using a suitable sieve; combining the obtained granulation with one or more selected from a filler, a disintegrant, a glidant and a lubricant to obtain a premix, optionally sieving said premix, and optionally blending said sieved premix to obtain a blend; compressing the blend into tablet cores using a suitable tablet press; and Optionally, coating the tablet cores with a pre-prepared film coating suspension by spray coating to produce film-coated tablets containing Compound 1.

25. The method of claim 24, comprising:

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

28. A granulation liquid comprising Compound 1 in μm-sized or nano-sized form, a sugar alcohol, at least one additional pharmaceutically acceptable excipient, preferably a binder and optionally one or more of 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. 24. A solid oral pharmaceutical composition according to any one of claims 1 to 23 for use in the treatment of conditions such as neuropsychiatric disorders, including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), neurodegenerative disorders, nephropathy and seizure disorders.

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