Solid dosage formulations of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

Abstract

Solid pharmaceutical formulations containing AZD4635 are described. The solid formulations may include a polymeric stabilizer (e.g., polyvinylpyrrolidone), an ionic surfactant (e.g., docusate sodium), and a non-ionic surfactant (e.g., poloxamer).

Description

[Technical Field]

[0001] Adenosine regulates many physiological functions. Within cells, adenosine is involved in energy metabolism, nucleic acid metabolism, and the methionine cycle; extracellular adenosine is involved in intercellular signaling. For example, extracellular adenosine is a potent immunosuppressant, preventing excessive immune responses during inflammation and infection. Adenosine also acts in other systems, including the cardiovascular system and central nervous system. [Background technology]

[0002] The actions of adenosine are mediated by a family of G-protein-coupled receptors. At least four subtypes of adenosine receptors have been identified: A1R, A2aR, A2bR, and A3R. The A1R and A3 subtypes inhibit the activity of the enzyme adenylate cyclase, while the A2a and A2b subtypes stimulate its activity, thereby regulating the levels of cyclic AMP in cells.

[0003] In the immune system, the interaction of A2a and A2b adenosine receptors is an important regulatory mechanism that protects tissues from excessive immune responses. In tumors, this pathway is hijacked, hindering antitumor immunity and promoting cancer progression. Furthermore, the tumor microenvironment often contains high levels of extracellular adenosine. Therefore, adenosine receptors, particularly A2aR and A2bR, have been identified as targets for cancer therapy.

[0004] Compound 1, 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, has the following structure: [ka] and is disclosed in Patent Document 1. Compound 1 is a potent A2aR antagonist in clinical trials for the treatment of cancer. Compound 1 is also known as AZD4635 or HTL-1071.

[0005] Compound 1 is weakly basic, with the triazine moiety exhibiting a pKa of 1.78. Its logP value is 2.8. In aqueous media, Compound 1 is poorly soluble, with solubilities ranging from less than 5 μg / mL at neutral pH to 29.8 μg / mL at pH 1.2; in fasted simulated intestinal fluid, the solubility is 5.8 μg / mL.

[0006] Due to its low solubility, the bioavailability of Compound 1 is limited. It can be formulated as a powder for administration in a mix-and-drink form. However, mix-and-drink formulations are relatively complicated to administer and can be an unpleasant experience for patients. Therefore, there remains a need for a solid dosage formulation of Compound 1 that facilitates administration while maintaining suitable pharmacokinetic properties. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2011 / 095625 Brochure Summary of the Invention [Means for solving the problem]

[0008] In one embodiment, the solid dosage formulation comprises a plurality of microcrystalline cellulose pellets, each individually coated with a composition comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; a polymeric stabilizer; an ionic surfactant; and a non-ionic surfactant.

[0009] The polymeric stabilizer may include polyvinylpyrrolidone.

[0010] The ionic surfactant may include docusate sodium.

[0011] The non-ionic surfactant may include a poloxamer or a PEGylated phospholipid.

[0012] In some embodiments, the polymeric stabilizer can include polyvinylpyrrolidone, the ionic surfactant can include sodium docusate, and the non-ionic surfactant can include poloxamer or PEGylated phospholipid.

[0013] The polymeric stabilizer can be polyvinylpyrrolidone K-30.

[0014] The ionic surfactant can be docusate sodium.

[0015] The non-ionic surfactant may be poloxamer 407.

[0016] In some embodiments, the polymeric stabilizer can be polyvinylpyrrolidone K-30, the ionic surfactant can be docusate sodium, and the non-ionic surfactant can be poloxamer 407.

[0017] The composition may further comprise trehalose.

[0018] The composition may comprise, on a w / w % basis: 20 to 75% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.

[0019] The composition may comprise, on a % w / w basis: 1-20% polyvinylpyrrolidone K-30.

[0020] The composition may contain, on a w / w% basis: 0.01 to 1.00% docusate sodium.

[0021] The composition may contain, on a w / w% basis: 20-60% poloxamer 407.

[0022] In some embodiments, the composition may include, on a w / w% basis: 20-75% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 1-20% polyvinylpyrrolidone K-30; 0.01-1.00% docusate sodium; and 20-60% poloxamer 407.

[0023] The formulation contains, on a w / w% basis: 10-50% microcrystalline cellulose.

[0024] The formulation may contain, on a w / w % basis: 20-50% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.

[0025] The formulation may contain, on a w / w% basis: 0.1-10% Polyvinylpyrrolidone K-30.

[0026] The formulation may contain, on a w / w% basis: 0.01 to 1.00% docusate sodium.

[0027] The formulation may contain, on a w / w% basis: 10-40% poloxamer 407.

[0028] In some embodiments, the formulation includes, on a w / w% basis: 10-50% microcrystalline cellulose; 20-50% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 0.1-10% polyvinylpyrrolidone K-30; 0.01-1.00% docusate sodium; and 10-40% poloxamer 407.

[0029] The formulation may further comprise a lubricant, which may include sodium stearyl fumarate.

[0030] The formulation may contain, on a w / w% basis: 25-40% microcrystalline cellulose.

[0031] The formulation may contain, on a w / w % basis: 25-45% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.

[0032] The formulation may contain, on a w / w% basis: 3-7% PVP K30.

[0033] The formulation may contain, on a w / w% basis: 0.05-0.50% docusate sodium.

[0034] The formulation may contain, on a w / w% basis: 15-35% poloxamer 407.

[0035] The formulation may contain, on a w / w% basis: 0.01 to 0.5% sodium stearyl fumarate.

[0036] In some embodiments, the formulation may include, on a w / w% basis: 25-40% microcrystalline cellulose; 25-45% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-7% PVP K30; 0.05-0.50% docusate sodium; 15-35% poloxamer 407; and 0.01-0.5% sodium stearyl fumarate.

[0037] The formulation may contain, on a w / w% basis: 30-35% microcrystalline cellulose.

[0038] The formulation may comprise, on a w / w % basis: 33-39% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.

[0039] The formulation may contain, on a % w / w basis: 4.2-5.2% PVP K30.

[0040] The formulation may contain, on a w / w% basis: 0.2-0.3% docusate sodium.

[0041] The formulation may contain, on a w / w% basis: 22-28% poloxamer 407.

[0042] The formulation may contain, on a w / w% basis: 0.15-0.25% sodium stearyl fumarate.

[0043] In some embodiments, the formulation may include, on a w / w% basis: 30-35% microcrystalline cellulose; 33-39% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 4.2-5.2% PVP K30; 0.2-0.3% docusate sodium; 22-28% poloxamer 407; and 0.15-0.25% sodium stearyl fumarate.

[0044] In another embodiment, the solid dosage formulation comprises a plurality of microcrystalline cellulose pellets, each individually coated with a composition, the composition consisting essentially of, on a w / w% basis: 54.44% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 7.08% PVP K30; 0.38% docusate sodium; and 38.1% poloxamer 407.

[0045] In another embodiment, a solid dosage formulation comprises 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, wherein a 50 mg oral dose of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine in a human subject has an AUC of 1850 ng·h / mL ± 30% 0-48The solid dosage formulation may include a plurality of microcrystalline cellulose pellets, each individually coated with a composition comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; a polymeric stabilizer; an ionic surfactant; and a non-ionic surfactant. The polymeric stabilizer may include polyvinylpyrrolidone. The ionic surfactant may include docusate sodium. The non-ionic surfactant may include a poloxamer or a PEGylated phospholipid. In some embodiments, the polymeric stabilizer may include polyvinylpyrrolidone, the ionic surfactant may include docusate sodium, and the non-ionic surfactant may include a poloxamer or a PEGylated phospholipid. In some embodiments, the formulation includes, on a w / w% basis: 10-50% microcrystalline cellulose; 20-50% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 0.1-10% polyvinylpyrrolidone K-30; 0.01-1.00% docusate sodium; and 10-40% poloxamer 407.

[0046] In another embodiment, a solid dosage formulation comprises 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, wherein an oral dose of 50 mg of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine to a human subject has a C of 352 ng / mL ± 30%. maxThe solid dosage formulation may include a plurality of microcrystalline cellulose pellets, each individually coated with a composition comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; a polymeric stabilizer; an ionic surfactant; and a non-ionic surfactant. The polymeric stabilizer may include polyvinylpyrrolidone. The ionic surfactant may include docusate sodium. The non-ionic surfactant may include a poloxamer or a PEGylated phospholipid. In some embodiments, the polymeric stabilizer may include polyvinylpyrrolidone, the ionic surfactant may include docusate sodium, and the non-ionic surfactant may include a poloxamer or a PEGylated phospholipid. In some embodiments, the formulation includes, on a w / w% basis: 10-50% microcrystalline cellulose; 20-50% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 0.1-10% polyvinylpyrrolidone K-30; 0.01-1.00% docusate sodium; and 10-40% poloxamer 407.

[0047] In another embodiment, a solid dosage formulation comprises 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, wherein an oral dose of 50 mg of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine in a human subject has an AUC of 1850 ng·h / mL±30%. 0-48 and 352 ng / mL ± 30% C maxThe solid dosage formulation may include a plurality of microcrystalline cellulose pellets, each individually coated with a composition comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; a polymeric stabilizer; an ionic surfactant; and a non-ionic surfactant. The polymeric stabilizer may include polyvinylpyrrolidone. The ionic surfactant may include docusate sodium. The non-ionic surfactant may include a poloxamer or a PEGylated phospholipid. In some embodiments, the polymeric stabilizer may include polyvinylpyrrolidone, the ionic surfactant may include docusate sodium, and the non-ionic surfactant may include a poloxamer or a PEGylated phospholipid. In some embodiments, the formulation includes, on a w / w% basis: 10-50% microcrystalline cellulose; 20-50% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 0.1-10% polyvinylpyrrolidone K-30; 0.01-1.00% docusate sodium; and 10-40% poloxamer 407.

[0048] In another embodiment, the solid unit dosage form of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine contains 1 to 200 mg of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine in a gelatin capsule. The solid unit dosage form of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine can contain 50, 75, or 100 mg of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.

[0049] Other features, objects, and advantages will be apparent from the description and drawings, and from the claims. [Brief explanation of the drawings]

[0050] [Figure 1] FIG. 1 is a graph showing the particle size distribution of milled (right bar) and redispersed (left bar) API. [Figure 2] FIG. 2 is a graph showing particle size distribution for two different nanosuspension formulations. [Figure 3] FIG. 3 is a graph showing the % API release from four different tablet formulations. [Figures 4A-4C] 4A-4C are graphs showing the time course of API plasma concentration in dogs for Formulation 1 (FIG. 4A), Formulation 3 (FIG. 4B), and Formulation 4C (FIG. 4C). [Figure 5] FIG. 5 is a flow chart of steps for preparing capsules of, for example, Formulation 8a. [Figures 6A-6D] 6A-6D are graphs showing the time course of API plasma concentration in dogs for Formulation 1 (FIG. 6A), Formulation 8b (FIG. 6B), Formulation 8a (FIG. 6C), and Formulation 7b (FIG. 6D). DETAILED DESCRIPTION OF THE INVENTION

[0051] Described herein are solid pharmaceutical formulations of Compound 1. The solid pharmaceutical formulations provide appropriate qualities, such as solubility and absorption, such that they are suitable for oral administration and result in the desired pharmacokinetic behavior in subjects.

[0052] The inventors have investigated several strategies to create effective solid formulations, including: - Traditional immediate release tablets. Overall drug exposure is limited by the poor solubility of Compound 1; it is not considered feasible. - Salt forms / co-crystals: The salt screen only showed the formation of salts with strong acids, which then rapidly dissociated upon contact with water. The screen for co-crystal formers was unsuccessful in identifying suitable co-crystal forms. Lipid formulations: Compound 1 is a neutral molecule and is not lipid soluble. A lipid screen showed no significant solubility in suitable excipients to create a true lipid formulation. - Mesoporous silica formulations: Such formulations require adequate solubility and amorphous stability of the API in a suitable solvent. Compound 1 has inadequate solubility. - Spray-dried amorphous solid dispersion: Compound 1 has limited solubility in solvents suitable for spray drying. Hot-melt extruded amorphous solid dispersions: Screening demonstrated the stability of such solid dispersions at low drug loading levels. Microdissolution and dissolution demonstrated sustained and increased release of Compound 1 compared to crystalline Compound 1. -Crystalline nanoparticles: Nanocrystalline compound 1 was coated onto an insoluble core. Increasing the surface area was shown to improve dissolution rates.

[0053] The hot melt extruded amorphous solid dispersion and crystalline nanoparticle formulations were further developed as follows. [Example]

[0054] Example 1: Phase 1a Formulation A mix-and-drink formulation (Formulation 1) was developed for Phase 1a trials. Compound 1 was wet bead milled to submicron particle size. A series of polymeric, nonionic, and ionic surfactant / nanosuspension stabilization systems were evaluated. Spray drying was selected as the method for converting the nanosuspension to a solid product. Sucrose was added as a matrix-forming agent to the nanosuspension formulation prior to spray drying to prevent aggregation of the API nanoparticles and maintain the rapid dissolution characteristics of the particles upon suspension reconstitution. A 1.0% w / w suspension was developed for use in the spray drying process to obtain a 5.5% w / w Compound 1 powder for oral suspension. Prior to administration, the dried powder was reconstituted in water containing 2 mg / mL simethicone.

[0055] [Table 1]

[0056] Example 2: Formulation 2 Nanosuspension Example 2A: Feasibility Study A slurry was made by first adding docusate sodium, then dissolving PVP K30, then adding Compound 1, and then grinding to a nano-sized suspension in a flat-bed ceramic container mill. See Figure 1. This experiment demonstrated that it was possible to grind Compound 1 into nano-sized particles using this formulation.

[0057] [Table 2]

[0058] This also demonstrated that it was possible to spray coat MCC cores with a suspension using trehalose as the matrix former (although the process is difficult). Redispersions of the spray-coated pellets showed the same particle size distribution as the suspension after milling.

[0059] Example 2B: Particle Size Distribution The particle size distributions for the nanosuspensions of Formulation 3 and Formulation 1 were compared. See Figure 2. Formulation 3 had a smaller mean particle size and was more monodisperse than Formulation 1.

[0060] [Table 3]

[0061] Formulation 3 was found to dissolve rapidly (>90% in 10 minutes) and completely (98%) using 100 mg of Compound 1 under USP2 conditions, pH 1.2, 2% SDS, 50 rpm.

[0062] Example 2C: Extrudate A series of extruded tablet formulations according to Tables 4A-4D were prepared, and the dissolution profiles of the corresponding tablets 1-4 in fasted simulated intestinal fluid (FaSSIF V2) are shown in Figure 3.

[0063] [Table 4]

[0064] [Table 5]

[0065] [Table 6]

[0066] Extrusion particle size (μm): D 0.5 =47.6;D 0.9 =194 Tablet disintegration time <1 minute

[0067] [Table 7]

[0068] Tablets 1-4 achieved less than 70% release within 30 minutes and a maximum of 80% release within 90 minutes. See Figure 3.

[0069] Example 3: Dog Study 1 The pharmacokinetic parameters of Formulation 1 (Figure 4A), Formulation 3 (Figure 4B), and Formulation 4C (Figure 4C) were compared in dogs. Formulation 4C demonstrated poor and inconsistent pharmacokinetics. The results for Formulations 1 and 3 are summarized in Table 4 and expressed as a relative ratio of Formulation 3 to Formulation 1.

[0070] [Table 8]

[0071] The exposure of Formulation 3 was lower compared to Formulation 1. The possible reasons were speculated to be: Aggregation of Formulation 3 in the stomach and small intestine leading to a slow dissolution rate that limits absorption. The excipients in formulation 1 provided additional solubilization of compound 1, thereby increasing its transport into the cell wall (Ullevi effect). The excipients in Formulation 1 enhanced the absorption of Compound 1.

[0072] Example 4: Process flow for pellets FIG. 5 illustrates a process flow for the production of coated microcrystalline pellets and, if applicable, subsequent filling of the pellets into capsules. First, the API (Compound 1) can be dry-milled in an optional PIN milling process. The milled Compound 1 was then mixed with water, an ionic surfactant, and a polymeric stabilizer to form a slurry. The slurry was wet-milled to obtain a nanosuspension. The nanosuspension was then mixed with additional water and a nonionic surfactant. Microcrystalline cellulose was then coated with the resulting suspension in a fluidized-bed coating process. The pellets can then be used as is or further processed as needed for filling into capsules. For capsule filling, the pellets were mixed with a lubricant (e.g., sodium stearyl fumarate or magnesium stearate) before capsule stuffing.

[0073] Example 5: Formulation 5 pellets A pellet formulation (Formulation 5) was developed based on Formulation 3 by exchanging DSPE-PEG2000 for Poloxamer 407 and adjusting the ratio of ingredients. Formulation 5 was then formed into pellets by coating with microcrystalline cellulose.

[0074] [Table 9]

[0075] Example 6: Microcrystalline cellulose nanopellets Following the method of Example 4, a coating suspension was prepared (Formulation 6) and either directly (Formulation 7a) or with trehalose (Formulation 7b) was coated onto microcrystalline cellulose (Vivapur 350, particle size approximately 450 μm) in a fluidized bed coating process. The appropriate particle size for the milled API was Particle D 90 <5 μm and D 50<2 μm and smaller.

[0076] [Table 10]

[0077] [Table 11]

[0078] According to formulations 8a and 8b, the pellets of formulations 7a and 7b were mixed with lubricant (sodium stearyl fumarate), filled into gelatin capsules and sealed to give a dose of 50 mg of Compound 1 per capsule.

[0079] [Table 12]

[0080] Example 7: Dog Study 2 The pharmacokinetic properties of Formulation 1, Formulation 8a capsules, Formulation 8b capsules, and Formulation 7b as nanosuspensions were measured in dogs (oral administration, dogs pretreated with omeprazole). The results are shown in Table 9 (AUC, F compared to Formulation 1). rel % and Table 10 (C max , expressed as % compared to Formulation 1). The time courses are shown in Figure 6A (Formulation 1), Figure 6B (Formulation 8b), Figure 6C (Formulation 8a) and Figure 6D (Formulation 7b).

[0081] [Table 13]

[0082] [Table 14]

[0083] The relative AUC of both capsule formulations 8a and 8b was >0.7 compared to formulation 1, and the relative Cmax was >0.7 compared to Formulation 1. Formulation 8a showed a higher AUC than 8b. Furthermore, Formulation 8b showed degradation when stored at a temperature of 50°C. The pellets of Formulation 8a redispersed into smaller particles than Formulation 8b. Formulation 8a was advanced to human relative bioavailability studies.

[0084] Example 8: Human relative bioavailability study Following administration of AZD4635 nanosuspension (Formulation 1) to fasted human subjects, plasma AZD4635 concentrations were quantifiable in all subjects from the first sampling time point, 0.25 hours post-dose. Concentrations then remained quantifiable for up to 24-48 hours post-dose. Maximum plasma concentrations occurred between 0.5 and 2 hours post-dose (median t max 1 hour). C max , AUC 0-t The geometric mean (CV%) values ​​for CI and AUC were 276 ng / mL (16.7), 1670 ng·h / mL (29.4), and 1760 ng·h / mL (29.8), respectively (see Table 11).

[0085] Following administration of the AZD4635 solid oral capsule formulation (Formulation 8a capsule) to fasted human subjects, plasma AZD4635 concentrations were quantifiable between 0.25 and 0.5 hours post-dose. Concentrations then remained quantifiable until the final sampling occasion, 48 hours post-dose. Maximum plasma concentrations occurred between 1 and 2 hours post-dose (median t max 1.5 hours). C max , AUC 0-t The geometric mean (CV%) values ​​for CI and AUC were 352 ng / mL (31.0), 1850 ng·h / mL (28.3), and 1940 ng·h / mL (29.0), respectively (see Table 11).

[0086] C max and AUC 0-48 The relative bioavailability of AZD4635 based on C was 128% and 110%, respectively. max and AUC 0-48Statistical comparison of the geometric mean ratios (GMR) for the solid oral capsule formulation (Formulation 8a) and nanosuspension (Formulation 1) was 126.71% (90% confidence interval [CI]: 111.12% to 144.48%) and 110.21% (104.33% to 116.42%), respectively, indicating that the peak and total exposure levels for the solid oral capsule formulation (Formulation 8a) were on average 27% and 10% higher than those for the nanosuspension (Formulation 1). The absorption rate was higher for the solid formulation, resulting in higher peak concentrations.

[0087] [Table 15]

[0088] Other embodiments are within the scope of the following claims.

Claims

1. On a w / w% basis: 20-75% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 1-20% polyvinylpyrrolidone K-30; 0.01 to 1.00% docusate sodium; 20-60% Poloxamer 407; 1. A solid dosage formulation comprising a plurality of microcrystalline cellulose pellets, each individually coated with a composition in the form of a nanosuspension, comprising:

2. 10. The formulation of claim 1, wherein the composition further comprises trehalose.

3. 3. A formulation according to claim 1 or 2, comprising on a w / w% basis: 10-50% microcrystalline cellulose; 20-50% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 1-10% polyvinylpyrrolidone K-30; 0.01 to 1.00% docusate sodium; 20-40% Poloxamer 407; A formulation comprising:

4. The formulation of any one of claims 1 to 3, wherein the formulation further comprises a lubricant.

5. 5. The formulation of claim 4, wherein the lubricant comprises sodium stearyl fumarate.

6. 6. A formulation according to claim 4 or 5, comprising on a w / w % basis: 25-40% microcrystalline cellulose; 25-45% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; with 3-7% PVP K30; 0.05 to 0.50% docusate sodium; 20-35% Poloxamer 407; 0.01 to 0.5% sodium stearyl fumarate; A formulation comprising:

7. A formulation according to any one of claims 1 to 6, comprising on a w / w% basis: 30-35% microcrystalline cellulose; 33-39% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 4.2-5.2% PVP K30; 0.2-0.3% docusate sodium; 22-28% Poloxamer 407; 0.15 to 0.25% sodium stearyl fumarate; A formulation comprising:

8. A solid pharmaceutical formulation comprising a plurality of microcrystalline cellulose pellets, each individually coated with a composition in the form of a nanosuspension, said composition comprising, on a w / w% basis: 54.44% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 7.08% PVP K30; 0.38% docusate sodium; 38.1% Poloxamer 407, A solid dosage formulation consisting of:

9. 1. A solid pharmaceutical formulation comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, said solid pharmaceutical formulation being as defined in claim 1, wherein an oral dose of 50 mg of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine in a human subject has an AUC of 1850 ng·h / mL±30%. ０－４８ A solid dosage formulation resulting in

10. 1. A solid pharmaceutical formulation comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, said solid pharmaceutical formulation being as defined in claim 1, wherein an oral dose of 50 mg of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine to a human subject has a C of 352 ng / mL ± 30%. ｍａｘ A solid dosage formulation resulting in

11. 1. A solid pharmaceutical formulation comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, said solid pharmaceutical formulation being as defined in claim 1, wherein an oral dose of 50 mg of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine to a human subject has an AUC of 1850 ng·h / mL±30%. ０－４８ and 352 ng / mL ± 30% C ｍａｘ A solid dosage formulation resulting in

12. 12. A solid unit dosage form of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine comprising the formulation of any one of claims 1 to 11, comprising 1 to 200 mg of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine in a gelatin capsule.

13. 12. A solid unit dosage form of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine comprising the formulation of any one of claims 1 to 11, wherein the solid unit dosage form comprises 50, 75, or 100 mg of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine in a gelatin capsule.

Images