SOLID PHARMACEUTICAL FORMULATIONS OF 6-(2-CHLORO-6-METHYLPYRIDIN-4-YL)-5-(4-FLUOROPHENYL)-1,2,4-TRIAZIN-3-AMINE

Abstract

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

Claims

1. A solid pharmaceutical formulation comprising 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.

2. The formulation of claim 1, wherein: the polymeric stabilizer includes polyvinylpyrollidone; the ionic surfactant includes sodium docusate; and the non-ionic surfactant includes a poloxamer or a PEGylated phospholipid.

3. The formulation of any one of claims 1 to 2, wherein: the polymeric stabilizer is polyvinylpyrollidone K-30; the ionic surfactant is sodium docusate; and the non-ionic surfactant is poloxamer 407.

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

5. The formulation of any one of claims 1 to 4, wherein the composition comprises, on a w/w % basis: from 20 to 75% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; from 1 to 20% of polyvinylpyrollidone K-30; from 0.01 to 1.00% of sodium docusate; and from 20 to 60% of poloxamer 407.

6. The formulation of any one of claims 1 to 5, wherein the formulation includes, on a w/w % basis: from 10 to 50% of microcrystalline cellulose; from 20 to 50% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; from 0.1 to 10% of polyvinylpyrollidone K-30; from 0.01 to 1.00% of sodium docusate; and from 10 to 40% of poloxamer 407.

7. The formulation of any one of claims 1 to 6, wherein the formulation further comprises a lubricant.

8. The formulation of claim 7, wherein the lubricant includes sodium stearyl fumarate.

9. The formulation of any one of claims 7 to 8, wherein the formulation includes, on a w/w % basis: from 25 to 40% of microcrystalline cellulose; from 25 to 45% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; from 3 to 7% of PVP K30; from 0.05 to 0.50% of sodium docusate; from 15 to 35% of poloxamer 407; and from 0.01 to 0.5% of sodium stearyl fumarate.

10. The formulation of any one of claims 1 to 9, wherein the formulation includes, on a w/w % basis: from 30 to 35% of microcrystalline cellulose; from 33 to 39% of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; from 4.2 to 5.2% of PVP K30; from 0.2 to 0.3% of sodium docusate; from 22 to 28% of poloxamer 407; and from 0.15 to 0.25% of sodium stearyl fumarate.

11. A solid pharmaceutical formulation comprising a plurality of microcrystalline cellulose pellets each individually coated with a composition, wherein the composition consists essentially of, 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% of PVP K30; 0.38% of sodium docusate; and 38.1% of poloxamer 407.

12. A solid pharmaceutical formulation comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine wherein an oral dose of 50 mg 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine to a human subject provides an AUC.sub.0-48 of 1850 ng.Math.h/mL±30%.

13. A solid pharmaceutical formulation comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine wherein an oral dose of 50 mg 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine to a human subject provides a C.sub.max of 352 ng/mL±30%.

14. A solid pharmaceutical formulation comprising 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine wherein an oral dose of 50 mg 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine to a human subject provides an AUC.sub.0-48 of 1850 ng.Math.h/mL±30% and a C.sub.max of 352 ng/mL±30%.

15. 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 according to any one of claims 1 to 14, wherein the unit dosage form includes 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.

16. 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 according to any one of claims 1 to 15, wherein the unit dosage form includes 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.

Description

[0049] FIG. 1 is a graph showing particle size distributions for milled (right bars) and re-dispersed (left bars) API.

[0050] FIG. 2 is a graph showing particle size distributions for two different nanosuspension formulations.

[0051] FIG. 3 is a graph showing % release of API from four different tablet formulations.

[0052] FIGS. 4A-4C are graphs showing time courses of API plasma concentration in dogs of Formulation 1 (FIG. 4A), Formulation 3 (FIG. 4b), and Formulation 4C (FIG. 4C).

[0053] FIG. 5 is a process flow chart for preparation of capsules, e.g., of Formulation 8a.

[0054] FIGS. 6A-6D are graphs showing time courses of API plasma concentration in dogs of Formulation 1 (FIG. 6A), Formulation 8b (FIG. 6B), Formulation 8a (FIG. 6C), and Formulation 7b (FIG. 6D).

[0055] Described herein are solid pharmaceutical formulations of Compound 1. The solid pharmaceutical formulations are suitable for oral dosing and provide suitable qualities, e.g., dissolution and absorption so as to afford desired pharmacokinetic behavior in subjects.

[0056] The inventors investigated multiple strategies to make an effective solid formulation, including: [0057] Conventional immediate release tablets. Overall drug exposure was limited by low solubility of Compound 1; not considered feasible. [0058] Salt form/co-crystal: Salt screen only showed formation of salt with strong acids which then rapidly dissociated on contact with water. Screen of co-crystal former molecules was unsuccessful in identifying a suitable co-crystal form. [0059] Lipid formulation: Compound 1 is a neutral molecule, and not lipophilic. Lipidic screen did not show significant solubility in suitable excipients for making a true lipidic formulation. [0060] Mesoporous silica formulation: Such formulations require adequate solubility of API in suitable solvent and amorphous stability. Solubility of Compound 1 inadequate. [0061] Spray-dried amorphous solid dispersion: Compound 1 has limited solubility in solvents suitable for spray drying. [0062] Hot melt extruded amorphous solid dispersion: Screening demonstrated stability of such solid dispersions at low drug loading levels. Microdissolution and dissolution showed increased and sustained release of Compound 1 compared to crystalline Compound 1. [0063] Crystalline nanoparticles: Nanocrystalline Compound 1 coated on an insoluble core. Demonstrated enhanced dissolution rate by increasing surface area.

[0064] Hot melt extrusion amorphous solid dispersion formulations and crystalline nanoparticle formulations were further developed as described below.

EXAMPLE 1

Phase 1a Formulation

[0065] For Phase la studies, a mix-and-drink formulation (Formulation 1) was developed. Compound 1 was wet bead milled to achieve sub-micron particle size. A range of polymeric, non-ionic and ionic surfactant/nanosuspension stabilising systems were evaluated. Spray drying was chosen as the method to transform the nanosuspension into a solid product. Sucrose was added to the nanosuspension formulation prior to spray drying as a matrix former, to prevent agglomeration of the API nanoparticles and maintain the rapid dissolution characteristics of the particles on reconstitution of the suspension. A 1.0% w/w suspension was developed for use in the spray drying process to yield a 5.5% w/w Compound 1 powder for oral suspension. The dried powder was reconstituted in water containing 2 mg/mL simethicone before dosing.

TABLE-US-00001 TABLE 1 Formulation 1 (nanosuspension) Component % w/w Function Compound 1 5.5 Drug substance HPMC 27.6 Polymeric stabilizer sucrose 38.7 Matrix former docusate sodium 0.6 Surfactant Poloxamer 188 27.6 Surfactant

EXAMPLE 2

Formulation 2 Nanosuspension

Example 2A

Feasibility Study

[0066] A slurry was made by first adding sodium docusate then dissolving PVP K30, then adding Compound 1, followed by milling in a planetary ceramic vessel mill into a nano-sized suspension. See FIG. 1. This experiment showed that it was possible to mill Compound 1 to nanosize particles with this formulation.

TABLE-US-00002 TABLE 2 Formulation 2 (nanosuspension) Milled suspension Pellet coating composition composition (dry based) % w/w (dry based) % w/w Compound 1 87.2 Compound 1 46.6 PVP K30 12.2 PVP K30 6.5 Docusate Sodium 0.6 Docusate Sodium 0.3 Solid matrix former 46.6 (Trehalose or PVP K17)

[0067] It also proved it was possible (but with process difficulties) to spraycoat the suspension on MCC cores using trehalose as matrix former. Redispersion of spraycoated pellets showed the same particle size distribution as post-milled suspension.

Example 2B

Particle Size Distribution

[0068] Particle size distributions for nanosuspensions of Formulation 3 and Formulation 1 were compared. See FIG. 2. Formulation 3 had a smaller average size and was more monodisperse than Formulation 1.

TABLE-US-00003 TABLE 3 Formulation 3 (nanosuspension) Component % w/w Function Compound 1 78.8 Drug substance PVP 5.1 Polymeric stabilizer Docusate sodium 0.3 surfactant DSPE-PEG2000 15.8 surfactant

[0069] Formulation 3 was found to dissolve rapidly (>90% in 10 min) and completely (98%) under USP2 conditions, pH 1.2, 2% SDS, 50 rpm, using 100 mg of Compound 1.

Example 2C

Extrudate

[0070] A series of extrudate tablet formulations according to Tables 4A-4D were prepared. Dissolution profiles in Fasted state simulated intestinal fluid (FaSSIF V2) of corresponding Tablets 1-4 are shown in FIG. 3.

TABLE-US-00004 TABLE 4A Formulation 4A (Tablet 1) Component % w/w Function Extrudate (15:85 50 Drug substance:polymer carrier Compound 1:Soluplus) Lactose 38 Soluble filler Crospovidone 10 Disintegrant CSD 1 Glidant SSF 1 lubricant

TABLE-US-00005 TABLE 4B Formulation 4B (Tablet 2) Component % w/w Function Extrudate (15:85 50 Drug substance:polymer carrier Compound 1:Soluplus) Mannitol 30.4 Soluble filler DCPA 7.6 Soluble filler Crospovidone 10 Disintegrant CSD 1 Glidant SSF 1 lubricant

TABLE-US-00006 TABLE 4C Formulation 4C (Tablet 3) Component % w/w Function Extrudate (15:85 50 Drug substance:polymer carrier Compound 1:Soluplus) Mannitol 19 Soluble filler MCC 19 Insoluble filler Crospovidone 10 Disintegrant CSD 1 Glidant SSF 1 lubricant Extrudate particle size (μm): D.sub.0.5 = 47.6; D.sub.0.9 = 194 Tablet disintegration time < 1 min

TABLE-US-00007 TABLE 4D Formulation 4D (Tablet 4) Component % w/w Function Extrudate (15:85 70 Drug substance:polymer carrier Compound 1:Soluplus) Mannitol 14.4 Soluble filler DCPA 3.6 Soluble filler Crospovidone 10 Disintegrant CSD 1 Glidant SSF 1 lubricant

[0071] Tablets 1-4 achieved less than 70% release within 30 min, and a maximum of ˜80% release within 90 min. See FIG. 3.

EXAMPLE 3

Dog Study 1

[0072] Pharmacokinetic parameters of Formulation 1 (FIG. 4A) and Formulation 3 (FIG. 4B) and Formulation 4C (FIG. 4C) were compared in dogs. Formulation 4C showed poor and inconsistent pharmacokinetics. Results for Formulations 1 and 3 are summarized in Table 4, expressed as relative ratios for Formulation 3:Formulation 1.

TABLE-US-00008 TABLE 4 Dog study 1 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 0.71 0.89

[0073] Formulation 3 had lower exposure compared to Formulation 1. Possible causes were surmised to be: [0074] Aggregation of Formulation 3 in stomach and small intestine leading to decreased dissolution rate which limits absorption. [0075] The excipients of Formulation 1 provided additional solubilisation of Compound 1 which increased transport to cell wall (Ullevi effect). [0076] The excipients of Formulation 1 enhanced absorption of Compound 1.

EXAMPLE 4

Process Flow for Pellets

[0077] FIG. 5 illustrates the process flow for manufacture of coated microcrystalline pellets, and, where applicable, subsequent loading of the pellets into capsules. Initially, the API (Compound 1) can be dry milled in an optional PIN milling process. The milled Compound 1 was then mixed with water, ionic surfactant, and polymeric stabilizer to form a slurry. The slurry was wet milled, yielding a nanosuspension. The nanosuspension was then mixed with additional water and non-ionic surfactant. The resulting suspension was then coated on microcrystalline cellulose in a fluid bed coating process. The pellets can then be used as-is, or where applicable, further processed for loading in capsules. For capsule loading, pellets were blended with lubricant (e.g., sodium stearyl fumarate or magnesium stearate) prior to capsule filling.

EXAMPLE 5

Formulation 5 Pellets

[0078] A pellet formulation (Formulation 5) was developed based on Formulation 3, changing DSPE-PEG2000 for Poloxamer 407, and adjusting ratios of components. Formulation 5 was then formed into pellets by coating on microcrystalline cellulose.

TABLE-US-00009 TABLE 5 Formulation 5 Pellet coating suspension composition (dry based) % w/w Compound 1 31.9 PVP K30 4.1 Docusate Sodium 0.2 Poloxamer 407 31.9 Trehalose 31.9

EXAMPLE 6

Microcrystalline Cellulose Nanopellet

[0079] Following the method of Example 4, a coating suspension was prepared (Formulation 6), and coated on to microcrystalline cellulose (Vivapur 350, approx. particle size 450 μm) in a fluid-bed coating process, either as-is (Formulation 7a) or with trehalose (Formulation 7b). Suitable particle sizes for milled API are particles D.sub.90<5 μm and D.sub.50<2 μm, and smaller.

TABLE-US-00010 TABLE 6 Formulation 6 Component % w/w Function Compound 1 54.44 Drug substance PVP K30 7.08 Polymeric stabilizer Sodium Docusate 0.38 Ionic surfactant Poloxamer 407 38.1 Non-ionic surfactant

TABLE-US-00011 TABLE 7 Formulation 7a and Formulation 7b Component 7a, % w/w 7b, % w/w Function API, % 36.29 25.28 Drug substance PVP K30, % 4.72 3.29 Polymeric stabilizer Sodium Docusate 0.25 0.177 Ionic surfactant Poloxamer 407 25.40 25.28 Non-ionic surfactant Trehalose 0.00 12.641 Matrix former mcc pellets 33.33 33.33 Pellet core

[0080] The pellets of Formulations 7a and 7b were blended with lubricant (sodium stearyl fumarate) according to Formulations 8a and 8b and loaded encapsulated in a gelatin capsule, with a dose of 50 mg of Compound 1 per capsule.

TABLE-US-00012 TABLE 8 Formulation 8a and Formulation 8b Component 8a, % w/w 8b, % w/w Function Compound 1 36.220 25.232 Drug substance PVP K30 4.709 3.28 Polymeric stabilizer sodium docusate 0.254 0.177 Ionic surfactant Poloxamer 407 25.354 25.232 Non-ionic surfactant trehalose 0.000 12.616 Matrix former mcc pellets 33.263 33.263 Pellet core sodium stearyl 0.200 0.200 Lubricant fumarate

Example 7

Dog Study 2

[0081] The pharmacokinetic properties of Formulation 1, the capsules of Formulation 8a, the capsules of Formulation 8b, and Formulation 7b as a nanosuspension were measured in dogs (oral dosing, dogs pretreated with omeprazole). Results are summarized in Table 9 (AUC, expressed as F.sub.rel % compared to Formulation 1) and Table 10 (C.sub.max, expressed as % compared to Formulation 1). Time courses are shown in FIG. 6A (Formulation 1), FIG. 6B (Formulation 8b), FIG. 6C (Formulation 8a), and FIG. 6D (Formulation 7b).

TABLE-US-00013 TABLE 9 Dog Study 2, AUC F.sub.rel, % Dog 1 Dog 2 Dog 3 Dog 4 mean 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

TABLE-US-00014 TABLE 10 Dog Study 2, C.sub.max, % Dog 1 Dog 2 Dog 3 Dog 4 mean 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

[0082] Both capsule formulations 8a and 8b had relative AUC>0.7 compared to Formulation 1, and had relative C.sub.max>0.7 compared to Formulation 1. Formulation 8a showed higher AUC than 8b. In addition, Formulation 8b exhibited degradation when upon storage at temperatures of 50° C. The pellets of Formulation 8a re-dispersed to smaller particles than those of Formulation 8b. Formulation 8a was progressed to a human relative bioavailability study.

Example 8

Human Relative Bioavailability Study

[0083] Following administration of AZD4635 nanosuspension (Formulation 1) to human subjects in the fasted state, plasma AZD4635 concentrations were quantifiable from the first sampling time point of 0.25 hour post-dose in all subjects. Thereafter, concentrations remained quantifiable until 24 to 48 hours post-dose. Maximum plasma concentrations occurred between 0.5 hour and 2 hours post-dose (median t.sub.max of 1 hour). Geometric mean (CV %) values for C.sub.max, AUC.sub.0-t and AUC were 276 ng/mL (16.7), 1670 ng.Math.h/mL (29.4), and 1760 ng.Math.h/mL (29.8), respectively (see Table 11).

[0084] Following administration of AZD4635 solid oral capsule formulation (Formulation 8a capsule) to human subjects in the fasted state, plasma AZD4635 concentrations were quantifiable from between 0.25 hour and 0.5 hour post-dose. Thereafter, concentrations remained quantifiable until the last sampling occasion at 48 hours post-dose. Maximum plasma concentrations occurred between 1 hour and 2 hours post-dose (median t.sub.max of 1.5 hours). Geometric mean (CV %) values for C.sub.max, AUC.sub.0-t and AUC were 352 ng/mL (31.0), 1850 ng.Math.h/mL (28.3) and 1940 ng.Math.h/mL (29.0), respectively (see Table 11).

[0085] The relative bioavailability of AZD4635 based on C.sub.max and AUC.sub.0-48 were 128% and 110%, respectively. Statistical comparisons of geometric mean ratios (GMRs) for C.sub.max and AUC.sub.0-48 were 126.71% (90% confidence interval [CI]: 111.12% to 144.48%) and 110.21% (104.33% to 116.42%), respectively, indicating the peak and overall exposure levels for the solid oral capsule formulation (Formulation 8a) were on average 27% and 10% higher than the nano-suspension (Formulation 1). The absorption rate was higher for the solid formulation and resulted in higher peak concentrations.

TABLE-US-00015 TABLE 11 Summary of Human Relative Bioavailability Study Nanosuspension Capsule (Formulation 1) (Formulation 8a) t.sub.max.sup.a (h)  1.00 (0.50-2.00)  1.50 (1.00-2.00) C.sub.max (ng/mL)  276 (16.7)  352 (31.0) AUC.sub.0-t (ng .Math. h/mL) 1670 (29.4) 1850 (28.3) AUC.sub.0-48 (ng .Math. h/mL) 1690 (28.4) 1860 (27.7) AUC (ng .Math. h/mL) 1760 (29.8) 1940 (29.0) t.sub.1/2λZ (h)  11.3 (24.9)  11.4 (20.7) F.sub.rel C.sub.max (%) —  128 (33.6) F.sub.rel AUC.sub.0-t (%) —  110 (12.5) F.sub.rel AUC.sub.0-48 (%) —  111 (12.9) F.sub.rel AUC (%) —  110 (12.9) .sup.a Median(range) t.sub.max = time of maximum observed concentration sampled during a dosing interval C.sub.max = maximum concentration occurring at t.sub.max AUC.sub.0-t = area under the drug concentration-time curve from zero to last time point AUC.sub.0-48 = area under the drug concentration-time curve from zero time to 48 hours AUC = area under the drug concentration-time curve t.sub.1/2λz = half-life associated with the z component of a polyexponential equation F.sub.rel = relative bioavailability

[0086] Other embodiments are within the scope of the following claims.