Solid pharmaceutical formulation of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine

Abstract

Solid pharmaceutical formulations comprising AZD4635 are described. The solid formulation may include a polymeric stabilizer (such as polyvinyl pyrrolidone), an ionic surfactant (such as docusate sodium) and a non-ionic surfactant (such as a poloxamer).

Description

[0001] Adenosine regulates a variety of physiological functions. Intracellularly, adenosine is involved in energy metabolism, nucleic acid metabolism, and the methionine cycle; extracellular adenosine participates in intercellular signaling. For example, extracellular adenosine is a potent immunosuppressant that prevents excessive immune responses during inflammation and infection. Adenosine also acts on other systems, including the cardiovascular system and the central nervous system.

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

[0003] In the immune system, engagement of A2a and A2b adenosine receptors is an important regulatory mechanism that protects tissues from excessive immune responses. In tumors, this pathway is hijacked and hinders anti-tumor immunity, thereby promoting cancer development. In addition, in many cases, the tumor microenvironment contains high levels of extracellular adenosine. Therefore, adenosine receptors (especially A2aR and A2bR) have been identified as targets for cancer treatment.

[0004] Compound 1 (6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine) has the following structure:

[0005]

[0006] and disclosed in WO 2011 / 095625. 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.

[0007] Compound 1 is weakly alkaline, with the triazine moiety showing a pKa value of 1.78. Its logP value is 2.8. In aqueous media, compound 1 has poor solubility, ranging from less than 5 μg / mL at neutral pH to 29.8 μg / mL at pH 1.2; in simulated fasting intestinal fluid, the solubility is 5.8 μg / mL.

[0008] Due to its poor solubility, the bioavailability of Compound 1 is limited. It can be made into a powder for administration in the form of a mixed drink. However, the administration of mixed drink formulations is relatively complicated, causing an unpleasant user experience for patients. Therefore, there is still a need for a solid pharmaceutical formulation of Compound 1 that can be conveniently administered while maintaining suitable pharmacokinetic properties.

[0009] In one aspect, a solid pharmaceutical formulation comprises a plurality of microcrystalline cellulose spheroids, each spheroid being individually coated with a composition comprising: 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; a polymer stabilizer; an ionic surfactant; and a nonionic surfactant.

[0010] The polymer stabilizer may include polyvinyl pyrrolidone.

[0011] The ionic surfactant may include docusate sodium.

[0012] Nonionic surfactants may include poloxamers or pegylated phospholipids.

[0013] In some embodiments, the polymer stabilizer may include polyvinyl pyrrolidone, the ionic surfactant may include docusate sodium, and the nonionic surfactant may include poloxamer or pegylated phospholipids.

[0014] The polymer stabilizer may be polyvinylpyrrolidone K-30.

[0015] The ionic surfactant may be docusate sodium.

[0016] The nonionic surfactant may be poloxamer 407.

[0017] In some embodiments, the polymer stabilizer may be polyvinylpyrrolidone K-30, the ionic surfactant may be docusate sodium, and the nonionic surfactant may be poloxamer 407.

[0018] The composition may further comprise trehalose.

[0019] Based on w / w %, the composition may comprise: 20% to 75% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine.

[0020] Based on w / w %, the composition may comprise: 1% to 20% of polyvinylpyrrolidone K-30.

[0021] Based on w / w %, the composition may comprise: 0.01% to 1.00% docusate sodium.

[0022] Based on w / w %, the composition may comprise: 20% to 60% Poloxamer 407.

[0023] In some embodiments, based on w / w%, the composition may include: 20% to 75% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 1% to 20% polyvinylpyrrolidone K-30; 0.01% to 1.00% docusate sodium; and 20% to 60% poloxamer 407.

[0024] Based on w / w %, the formulation may include: 10% to 50% microcrystalline cellulose.

[0025] Based on w / w %, the formulation may include: 20% to 50% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.

[0026] Based on w / w %, the formulation may include: 0.1% to 10% of polyvinylpyrrolidone K-30.

[0027] Based on w / w %, the formulation may include: 0.01% to 1.00% docusate sodium.

[0028] Based on w / w %, the formulation may include: 10% to 40% Poloxamer 407.

[0029] In some embodiments, the formulation comprises, based on w / w%, 10% to 50% microcrystalline cellulose; 20% to 50% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 0.1% to 10% polyvinylpyrrolidone K-30; 0.01% to 1.00% docusate sodium; and 10% to 40% poloxamer 407.

[0030] The formulation may further comprise a lubricant. The lubricant may include sodium stearyl fumarate.

[0031] Based on w / w %, the formulation may include: 25% to 40% microcrystalline cellulose.

[0032] Based on w / w %, the formulation may include: 25% to 45% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.

[0033] Based on w / w %, the formulation may include: 3% to 7% PVP K30.

[0034] Based on w / w %, the formulation may include: 0.05% to 0.50% docusate sodium.

[0035] Based on w / w %, the formulation may include: 15% to 35% Poloxamer 407.

[0036] Based on w / w %, the formulation may include: 0.01% to 0.5% sodium stearyl fumarate.

[0037] In some embodiments, the formulation may include, based on w / w%, 25% to 40% microcrystalline cellulose; 25% to 45% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 3% to 7% PVPK30; 0.05% to 0.50% docusate sodium; 15% to 35% poloxamer 407; and 0.01% to 0.5% sodium stearyl fumarate.

[0038] Based on w / w %, the formulation may include: 30% to 35% microcrystalline cellulose.

[0039] Based on w / w %, the formulation may include: 33% to 39% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.

[0040] Based on w / w %, the formulation may include: 4.2% to 5.2% PVP K30.

[0041] Based on w / w %, the formulation may include: 0.2% to 0.3% docusate sodium.

[0042] Based on w / w %, the formulation may include: 22% to 28% Poloxamer 407.

[0043] Based on w / w %, the formulation may include: 0.15% to 0.25% sodium stearyl fumarate.

[0044] In some embodiments, the formulation may include, based on w / w%, 30% to 35% microcrystalline cellulose; 33% to 39% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 4.2% to 5.2% PVPK30; 0.2% to 0.3% docusate sodium; 22% to 28% poloxamer 407; and 0.15% to 0.25% sodium stearyl fumarate.

[0045] In another aspect, a solid pharmaceutical formulation comprises a plurality of microcrystalline cellulose spheroids, each spheroid being individually coated with a composition, wherein the composition consists essentially of, on a w / w % basis: 54.44% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 7.08% PVP K30; 0.38% docusate sodium; and 38.1% poloxamer 407.

[0046] In another aspect, a solid pharmaceutical formulation comprises 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine, wherein an oral dose of 50 mg 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine administered to a human subject provides an AUC of 1850 ng·h / mL±30%. 0-48 . The solid pharmaceutical formulation may include a plurality of microcrystalline cellulose spherical particles, each of which is coated with a composition comprising: 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; a polymer stabilizer; an ionic surfactant; and a non-ionic surfactant. The polymer stabilizer may include polyvinyl pyrrolidone. The ionic surfactant may include sodium docusate. The non-ionic surfactant may include poloxamer or a pegylated phospholipid. In some embodiments, the polymer stabilizer may include polyvinyl pyrrolidone, the ionic surfactant may include sodium docusate, and the non-ionic surfactant may include poloxamer or a pegylated phospholipid. In some embodiments, the formulation comprises, based on w / w%, 10% to 50% microcrystalline cellulose; 20% to 50% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 0.1% to 10% polyvinylpyrrolidone K-30; 0.01% to 1.00% docusate sodium; and 10% to 40% poloxamer 407.

[0047] In another aspect, a solid pharmaceutical formulation comprises 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine, wherein an oral dose of 50 mg 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine administered to a human subject provides a C max. The solid pharmaceutical formulation may include a plurality of microcrystalline cellulose spherical particles, each of which is coated with a composition comprising: 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; a polymer stabilizer; an ionic surfactant; and a non-ionic surfactant. The polymer stabilizer may include polyvinyl pyrrolidone. The ionic surfactant may include sodium docusate. The non-ionic surfactant may include poloxamer or a pegylated phospholipid. In some embodiments, the polymer stabilizer may include polyvinyl pyrrolidone, the ionic surfactant may include sodium docusate, and the non-ionic surfactant may include poloxamer or a pegylated phospholipid. In some embodiments, the formulation comprises, based on w / w%, 10% to 50% microcrystalline cellulose; 20% to 50% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 0.1% to 10% polyvinylpyrrolidone K-30; 0.01% to 1.00% docusate sodium; and 10% to 40% poloxamer 407.

[0048] In another aspect, a solid pharmaceutical formulation comprises 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine, wherein an oral dose of 50 mg 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine administered to a human subject provides an AUC of 1850 ng·h / mL±30%. 0-48 and 352ng / mL±30% C max . The solid pharmaceutical formulation may include a plurality of microcrystalline cellulose spherical particles, each of which is coated with a composition comprising: 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; a polymer stabilizer; an ionic surfactant; and a non-ionic surfactant. The polymer stabilizer may include polyvinyl pyrrolidone. The ionic surfactant may include sodium docusate. The non-ionic surfactant may include poloxamer or a pegylated phospholipid. In some embodiments, the polymer stabilizer may include polyvinyl pyrrolidone, the ionic surfactant may include sodium docusate, and the non-ionic surfactant may include poloxamer or a pegylated phospholipid. In some embodiments, the formulation comprises, based on w / w%, 10% to 50% microcrystalline cellulose; 20% to 50% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 0.1% to 10% polyvinylpyrrolidone K-30; 0.01% to 1.00% docusate sodium; and 10% to 40% poloxamer 407.

[0049] In another aspect, a solid unit dosage form of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine comprises 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. A solid unit dosage form of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine may comprise 50, 75, or 100 mg of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine.

[0050] Other features, objects, and advantages will be apparent from the description, and from the claims.

[0051] Figure 1 is a graph showing the particle size distribution of the milled (right column) and redispersed (left column) API.

[0052] Figure 2 is a graph showing the particle size distribution of two different nanosuspension formulations.

[0053] Figure 3 is a graph showing the % release of API for four different tablet formulations.

[0054] Figures 4A-4C It is shown that the preparation 1 ( Figure 4A ), Formulation 3 (Figure 4b) and Formulation 4C ( Figure 4C ) Graph of the time course of API plasma concentrations in dogs.

[0055] Figure 5 is a flow chart for preparing capsules (eg, formulation 8a).

[0056] Figures 6A-6D It is shown that the preparation 1 ( Fig. 6A )、Preparation 8b( Figure 6B )、Preparation 8a( Figure 6C ) and preparation 7b( Fig.6D ) Graph of the time course of API plasma concentrations in dogs.

[0057] Described herein is a solid pharmaceutical formulation of Compound 1. The solid pharmaceutical formulation is suitable for oral administration and provides suitable qualities, such as solubility and absorbability, to provide a desired pharmacokinetic behavior in a subject.

[0058] The inventors investigated a variety of strategies to prepare effective solid formulations, including:

[0059] - Conventional immediate release tablets. Low solubility of Compound 1 limits overall drug exposure; not considered feasible.

[0060] - Salt forms / co-crystals; Salt screening showed only strong acid salts to form, which then dissociated rapidly on contact with water. Co-crystal forming molecular screening was unsuccessful in identifying a suitable co-crystal form.

[0061] - Lipid formulation: Compound 1 is a neutral molecule and is not lipophilic. Lipid screening did not show significant solubility in suitable excipients for the preparation of a true lipid formulation.

[0062] - Mesoporous silica formulations: This type of formulation requires sufficient solubility of the API in a suitable solvent and amorphous stability. Compound 1 has insufficient solubility.

[0063] - Spray-dried amorphous solid dispersion: Compound 1 has limited solubility in solvents suitable for spray drying.

[0064] - Hot melt extruded amorphous solid dispersion: Screening showed that this solid dispersion was stable at low drug loading levels. Microdissolution and dissolution showed enhanced and sustained release of Compound 1 compared to crystalline Compound 1.

[0065] - Crystalline nanoparticles: Nanocrystalline Compound 1 coated on an insoluble core. Shows increased surface area and enhanced dissolution rate.

[0066] Hot melt extruded amorphous solid dispersion formulations and crystalline nanoparticle formulations were further developed as described below.

[0067] Example 1: Phase 1a Formulation

[0068] For Phase 1a studies, a mixed drink formulation (Formulation 1) was developed. Compound 1 was wet bead milled to obtain submicron particle size. A range of polymeric, nonionic and ionic surfactant / nanosuspension stabilization systems were evaluated. Spray drying was selected as a method to convert the nanosuspension into a solid product. Sucrose was added to the nanosuspension formulation as a matrix former before spray drying to prevent agglomeration of the API nanosuspension and maintain the rapid dissolution properties of the particles when the suspension was reconstituted. A 1.0% w / w suspension was developed for the spray drying process to produce a 5.5% w / w Compound 1 powder for oral suspension. Prior to administration, the dry powder was reconstituted in water containing 2 mg / mL simethicone.

[0069] Table 1: Formulation 1 (nanosuspension)

[0070] Components %w / w Function Compound 1 5.5 Drug substances HPMC 27.6 Polymer Stabilizer sucrose 38.7 Matrix forming agent Docusate Sodium 0.6 Surfactants Poloxamer 188 27.6 Surfactants

[0071] Example 2: Formulation 2 Nanosuspension

[0072] Example 2A: Feasibility Study

[0073] The slurry was made by first adding docusate sodium, then dissolving PVP K30, and then adding compound 1, followed by grinding in a planetary ceramic vessel mill to a nano-size suspension. Figure 1 This experiment shows that compound 1 can be ground into nano-sized particles using this formulation.

[0074] Table 2: Formulation 2 (nanosuspension)

[0075]

[0076] It was also demonstrated that it is possible (but difficult) to spray a suspension onto MCC cores using trehalose as a matrix former. The redispersion of the sprayed spheres showed the same particle size distribution as the suspension after grinding.

[0077] Example 2B: Particle Size Distribution

[0078] Compare the particle size distribution of the nanosuspensions of Formulation 3 and Formulation 1. Figure 2 Compared with Formulation 1, Formulation 3 has a smaller average size and better monodispersity.

[0079] Table 3: Formulation 3 (nanosuspension)

[0080] Components %w / w Function Compound 1 78.8 Drug substances PVP 5.1 Polymer Stabilizer Docusate Sodium 0.3 Surfactants DSPE-PEG2000 15.8 Surfactants

[0081] Formulation 3 was found to dissolve rapidly (within 10 min, >90%) and completely (98%) under USP2 conditions (pH 1.2, 2% SDS, 50 rpm, using 100 mg of Compound 1).

[0082] Example 2C: Extrudate

[0083] A series of extruded tablet formulations were prepared according to Tables 4A-4D. Figure 3 The dissolution profiles of the fasted state simulated intestinal fluid (FaSSIF V2) are shown in the corresponding Tables 1-4.

[0084] Table 4A: Formulation 4A (Tablet 1)

[0085] Components %w / w Function Extrudate (15:85 compound 1:Soluplus) 50 Polymer carriers for drug substances lactose 38 Soluble fillers Crospovidone 10 Disintegrants CSD 1 Glidants SSF 1 Lubricant

[0086] Table 4B: Formulation 4B (Tablet 2)

[0087] Components %w / w Function Extrudate (15:85 compound 1:Soluplus) 50 Polymer carriers for drug substances Mannitol 30.4 Soluble fillers DCPA 7.6 Soluble fillers Crospovidone 10 Disintegrants CSD 1 Glidants SSF 1 Lubricant

[0088] Table 4C: Formulation 4C (Tablet 3)

[0089] Components %w / w Function Extrudate (15:85 compound 1:Soluplus) 50 Polymer carriers for drug substances Mannitol 19 Soluble fillers MCC 19 Insoluble fillers Crospovidone 10 Disintegrants CSD 1 Glidants SSF 1 Lubricant

[0090] Extrudate particle size (μm): D 0.5 =47.6; D 0.9 =194

[0091] Tablet disintegration time <1min

[0092] Table 4D: Formulation 4D (Tablet 4)

[0093]

[0094]

[0095] Tablets 1-4 achieved less than 70% release within 30 min and approximately 80% maximum release within 90 min. Figure 3 .

[0096] Example 3: Dog Study 1

[0097] The dog formulation 1 ( Figure 4A ) and Preparation 3( Figure 4B ) and preparation 4C( Figure 4C ) pharmacokinetic parameters of Formulation 4C. Formulation 4C showed poor and inconsistent pharmacokinetics. Table 4 summarizes the results of Formulations 1 and 3, expressed as the relative ratio of Formulation 3:Formulation 1.

[0098] Table 4: Dog Study 1

[0099] animal Rel Cmax* Rel AUC 0-t* Rel AUC 0-inf* 1 0.74 0.61 1.04 2 0.52 0.78 0.81 3 0.54 0.91 0.98 4 0.44 0.54 0.68 average value 0.71 0.89

[0100] The exposure of Formulation 3 was lower than that of Formulation 1. It is speculated that the possible reasons are:

[0101] • Formulation 3 aggregates in the stomach and small intestine resulting in a decrease in dissolution rate, which limits absorption.

[0102] • The excipients of Formulation 1 provide additional solubilization of Compound 1, which increases transport to the cell wall (Ullevi effect).

[0103] The excipients of Formulation 1 enhance the absorption of Compound 1.

[0104] Example 4: Process flow of pellets

[0105] Figure 5A process flow for producing coated microcrystalline spheroids and, if applicable, subsequently loading the spheroids into capsules is described. Initially, the API (Compound 1) may be dry-milled in an optional PIN milling process. The ground Compound 1 is then mixed with water, an ionic surfactant, and a polymer stabilizer to form a slurry. The slurry is wet-milled to obtain a nanosuspension. The nanosuspension is then mixed with additional water and a nonionic surfactant. The resulting suspension is then coated on microcrystalline cellulose in a fluidized bed coating process. The spheroids may then be used as is, or, if applicable, further processed and loaded into capsules. For capsule loading, the spheroids are blended with a lubricant (such as sodium stearyl fumarate or magnesium stearate) before filling the capsules.

[0106] Example 5: Formulation 5 Pellets

[0107] A pellet formulation (Formulation 5) was developed based on Formulation 3 by changing DSPE-PEG2000 to Poloxamer 407 and adjusting the ratio of each component. Formulation 5 was then made into pellets by coating with microcrystalline cellulose.

[0108] Table 5: Formulation 5

[0109] Pellets coated with suspension composition (dry basis) %w / w Compound 1 31.9 PVP K30 4.1 Docusate Sodium 0.2 Poloxamer 407 31.9 Trehalose 31.9

[0110] Example 6: Microcrystalline cellulose nanospheres

[0111] The coating suspension (Formulation 6) was prepared according to the method of Example 4 and coated on microcrystalline cellulose (Vivapur 350, particle size about 450 μm) in a fluidized bed coating process, either as such (Formulation 7a) or together with trehalose (Formulation 7b). The API after grinding is preferably of particle size D 90 <5μm and D 50 <2μm and smaller.

[0112] Table 6: Formulation 6

[0113] Components %w / w Function Compound 1 54.44 Drug substances PVPK30 7.08 Polymer Stabilizer Docusate Sodium 0.38 Ionic surfactants Poloxamer 407 38.1 Nonionic surfactants

[0114] Table 7: Formulations 7a and 7b

[0115]

[0116]

[0117] According to Formulations 8a and 8b, the pellets of Formulations 7a and 7b were blended with a lubricant (sodium stearyl fumarate) and encapsulated into gelatin capsules at a dose of 50 mg of Compound 1 per capsule.

[0118] Table 8: Formulations 8a and 8b

[0119] Components 8a, %w / w 8b, %w / w Function Compound 1 36.220 25.232 Drug substances PVPK30 4.709 3.28 Polymer Stabilizer Docusate Sodium 0.254 0.177 Ionic surfactants Poloxamer 407 25.354 25.232 Nonionic surfactants Trehalose 0.000 12.616 Matrix forming agent mcc pellets 33.263 33.263 Spherule core Sodium Stearoyl Fumarate 0.200 0.200 Lubricant

[0120] Example 7: Dog Study 2

[0121] The pharmacokinetic properties of Formulation 1, Formulation 8a capsules, Formulation 8b capsules, and Formulation 7b as a nanosuspension were measured in dogs (oral administration, dogs pretreated with omeprazole). The results are summarized in Table 9 (AUC, F rel %) and Table 10 (C max , compared to Formulation 1, expressed as %). The time course is shown in Fig. 6A (Preparation 1), Figure 6B (Preparation 8b), Figure 6C (Formulation 8a) and Fig.6D (Preparation 7b).

[0122] Table 9: Dog Study 2, AUC F rel , %

[0123] Dog 1 Dog 2 Dog 3 Dog 4 average value 8b 0.76 0.78 0.78 0.77 0.77 8a 0.91 0.98 0.76 0.91 0.89 7b 1.22 1.32 0.93 1.14 1.15

[0124] Table 10: Dog Study 2, C max , %

[0125] Dog 1 Dog 2 Dog 3 Dog 4 average value 8b 0.82 0.56 0.85 0.82 0.76 8a 1.02 0.77 0.51 0.89 0.80 7b 1.43 1.38 0.87 1.13 1.21

[0126] The relative AUCs of both capsule formulations 8a and 8b were > 0.7 compared to formulation 1, and the relative C max >0.7. Formulation 8a showed a higher AUC than 8b. In addition, Formulation 8b degraded when stored at 50°C. The pellets of Formulation 8a were redispersible into smaller particles than the pellets of Formulation 8b. A human relative bioavailability study was conducted on Formulation 8a.

[0127] Example 8: Human relative bioavailability study

[0128] Following administration of AZD4635 nanosuspension (Formulation 1) to human subjects in the fasting state, plasma AZD4635 concentrations were quantified from the first sampling time point of 0.25 hours post-dose for all subjects. Thereafter, concentrations remained quantifiable until 24 to 48 hours post-dose. Maximum plasma concentrations occurred between 0.5 and 2 hours post-dose (median t max for 1 hour). C max , AUC 0-t The geometric mean (CV%) values ​​of AUC 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).

[0129] Following administration of the AZD4635 solid oral capsule formulation (Formulation 8a capsules) to human subjects in the fasting state, plasma AZD4635 concentrations were quantified between 0.25 and 0.5 hours post-dose. Thereafter, concentrations remained quantifiable until the last sampling at 48 hours post-dose. Maximum plasma concentrations occurred between 1 and 2 hours post-dose (median t max for 1.5 hours). C max , AUC 0-t The geometric mean (CV%) values ​​of AUC 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).

[0130] C-based max and AUC 0-48 The relative bioavailability of AZD4635 was 128% and 110% respectively. max and AUC 0-48 The statistical comparison of the geometric mean ratios (GMR) of the solid oral capsule formulation (Formulation 8a) 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 overall exposure levels of the solid oral capsule formulation (Formulation 8a) were 27% and 10% higher on average than those of the nanosuspension (Formulation 1). The absorption rate of the solid formulation was higher and resulted in higher peak concentrations.

[0131] Table 11: Summary of Human Relative Bioavailability Studies

[0132]

[0133] a Median (range)

[0134] t max = time of maximum observed concentration during dosing interval sampling

[0135] C max =t max The maximum concentration at

[0136] AUC 0-t = drug concentration - area under the time curve from zero to the last time point

[0137] AUC 0-48 = Area under the drug concentration-time curve from zero to 48 hours

[0138] AUC = Area under the drug concentration-time curve

[0139] t1 / 2λZ = half-life associated with the z component of the multi-exponential equation

[0140] F rel =Relative bioavailability

[0141] Other embodiments are within the scope of the following claims.

Claims

1. A solid pharmaceutical formulation comprising a plurality of microcrystalline cellulose spheroids, each spheroid being individually coated with a composition comprising, on a w / w % basis: 20% to 75% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 1% to 20% polyvinylpyrrolidone K-30; Docusate sodium 0.01% to 1.00%; and 20% to 60% Poloxamer 407, The coating is carried out in the form of a nanosuspension.

2. The formulation according to claim 1, wherein the composition further comprises trehalose.

3. The formulation according to claim 1 or 2, wherein based on w / w%, the formulation comprises: 10% to 50% microcrystalline cellulose; 20% to 50% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 1% to 10% polyvinylpyrrolidone K-30; 0.01% to 1.00% docusate sodium; and 20% to 40% Poloxamer 407.

4. The formulation according to claim 1 or 2, wherein the formulation further comprises a lubricant.

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

6. The formulation according to claim 5, wherein based on w / w%, the formulation comprises: 25% to 40% microcrystalline cellulose; 25% to 45% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3% to 7% PVPK30; 0.05% to 0.50% docusate sodium; 20% to 35% Poloxamer 407; and 0.01% to 0.5% sodium stearyl fumarate.

7. The formulation according to claim 6, wherein based on w / w%, the formulation comprises: 30% to 35% microcrystalline cellulose; 33% to 39% 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 4.2% to 5.2% PVPK30; 0.2% to 0.3% docusate sodium; 22% to 28% Poloxamer 407; and 0.15% to 0.25% sodium stearyl fumarate.

8. A solid pharmaceutical formulation comprising a plurality of microcrystalline cellulose spheroids, each spheroid being individually coated with a composition, wherein on a w / w % basis, the composition consists of: 54.44% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 7.08% PVPK30; 0.38% docusate sodium; and 38.1% Poloxamer 407; The coating is carried out in the form of a nanosuspension.

9. A solid pharmaceutical formulation comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine, wherein the solid pharmaceutical formulation is as described in claim 1, and wherein an oral dose of 50 mg 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine administered to a human subject provides an AUC of 1850 ng·h / mL±30% 0-48 .

10. A solid pharmaceutical formulation comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine, wherein the solid pharmaceutical formulation is as described in claim 1, and wherein an oral dose of 50 mg of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine administered to a human subject provides a C max .

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

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

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

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