PHARMACEUTICAL COMPOSITION COMPRISING A POTENT INHIBITOR OF URAT1

Abstract

The present invention relates to pharmaceutical compositions containing 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid or a pharmaceutically acceptable salt (hereinafter referred to as the “Agent”), more particularly to orally deliverable compositions containing the Agent; to the use of said compositions as a medicament; and to processes for the preparation of said compositions.

Claims

1. A modified release pharmaceutical composition comprising the Agent, wherein said composition, after oral administration in the fasted state to a subject in need of treatment thereof exhibits at least one of the following: a. produces in the subject a geometric mean maximum plasma concentration (C.sub.max) of the Agent between 1 ng/ml and 50 ng/ml; and b. produces a ratio of C.sub.max/AUC.sub.0-24 between 0.04 and 0.4.

2. A modified release pharmaceutical composition according to claim 1, wherein said composition, after oral administration in the fasted state to a subject in need of treatment thereof produces in the subject a ratio of C.sub.max/AUC.sub.0-24 between 0.04 and 0.4.

3. A modified release pharmaceutical composition according to claim 1, wherein said composition, after oral administration in the fasted state to a subject in need of treatment thereof exhibits both of the following: a. produces in the subject a geometric mean maximum plasma concentration (C.sub.max) of the Agent between 1 ng/ml and 40 ng/ml; and b. produces a ratio of C.sub.max/AUC.sub.0-24 between 0.04 and 0.4.

4. A modified release pharmaceutical composition according to claim 2, wherein the ratio of C.sub.max/AUC.sub.0-24 is between 0.04 and 0.3.

5. A modified release pharmaceutical composition according to claim 2, wherein the ratio of C.sub.max/AUC.sub.0-24 is between 0.04 and 0.2.

6. A modified release pharmaceutical composition according to claim 2, wherein the ratio of C.sub.max/AUC.sub.0-24 is between 0.04 and 0.16.

7. A modified release pharmaceutical composition according to any one of claim 1, wherein the Agent is 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.

8. A modified release pharmaceutical composition according to any one of claim 1, wherein the oral composition is administered to the subject to provide a dose of the Agent selected from a range of 0.5-20 mg, for example 0.5, 0.67, 0.75, 0.83, 1, 1.25, 1.5, 2, 2.5, 3, 3.3, 4.5, 5, 6, 7.5, 9, 10, 12, 15 and 20 mg.

9. A modified release pharmaceutical composition according to any one of claim 1, wherein the oral composition is administered to the subject to provide a dose of the Agent selected from 4.5, 6, 9 and 12 mg and the ratio of C.sub.max/AUC.sub.0-24 is between 0.04 and 0.16.

10. A modified release pharmaceutical composition according to any one of claim 1, wherein after oral administration at a dose of 10 mg in the fasted state to a subject in need of treatment thereof produces a AUC.sub.0-24 of about 100 ng.Math.hr/mL or more.

11. A modified release pharmaceutical composition according to any one of claim 1, wherein the pharmaceutical composition is a matrix dosage form or a multiparticulate system.

12. A modified release pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is a matrix dosage form in the form of a tablet comprising a water erodible matrix.

13. A modified release pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is a multiparticulate composition comprising a plurality of pellets or beads, where in each pellet or bead comprises a seed core layered with the Agent and coated with a polymeric material of the type useful for providing modified release of the Agent.

14. A method for treating a human, suffering from a condition treatable by the Agent comprising administering thereto a pharmaceutical composition according to any one of claim 1.

15. A method for treating disorders of uric acid metabolism selected from polycythemia, myeloid metaplasia, gout, a recurrent gout attack, gouty arthritis, hyperuricaemia, hypertension, a cardiovascular disease, coronary heart disease, heart failure, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, acute or chronic kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis and sarcoidosisin, in a warm blooded animal, preferably a human, comprising administering thereto a pharmaceutical composition according to claim 1.

16. The method according to claim 15, wherein the disorder of uric acid metabolism is gout.

17. (canceled)

18. (canceled)

19. A pharmaceutical composition according to claim 1, further comprising a xanthine oxidase inhibitor.

20. A pharmaceutical composition according to claim 19, wherein the xanthine oxidase inhibitor is febuxostat.

Description

BRIEF DESCRIPTION OF FIGURES

[0139] FIG. 1 shows the mean dissolution profile for the 5 mg immediate release tablet formulation prepared as described in Example 1. The dissolution experiments were carried out in 900 mL SGF (simulated gastric fluid) without pepsin at 37° C. with a paddle speed of 50 rpm (n=6).

[0140] FIG. 2 shows the mean dissolution profiles for the MR formulations prepared as described in Example 2-6. The dissolution experiments for MR1, MR2 and MR4 were carried out in 900 mL pH 6.8 50 mM phosphate buffer solution at 37° C. with a paddle speed of 50 rpm (n=6 each). The dissolution experiments for MR3 and MR5 were carried out in a two stage dissolution method, the acid stage was 750 mL of 0.1N HCl and the buffer stage was 1000 mL of pH 6.8 buffer (both stages were at 37° C. with a paddle speed of 50 rpm, n=6).

[0141] FIG. 3a shows the mean 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid plasma concentration-time profile for the 5 mg immediate release formulations dosed under fasted and fed conditions.

[0142] FIG. 3b shows the mean 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid plasma concentration-time profile for immediate release formulations dosed at various levels under fasted conditions.

[0143] FIG. 4 shows the mean 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid plasma concentration-time profile for modified release tablet formulations described in Example 2 through Example 6 at a 5 mg dose in the fasted condition.

[0144] FIG. 5 shows the mean 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid plasma concentration-time profile for modified release tablet formulations described in Example 2 through Example 6 at a 5 mg dose in the fed condition.

[0145] FIG. 6 shows the mean 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid plasma concentration-time profile for the MR4 formulation modified release tablet described in Example 5 and Example 5a dosed as 4×2.5 mg tablets or 1×10 mg tablets in fasted condition and 1×10 mg tablets dosed with low-fat and high-fat meals.

[0146] FIG. 7 shows the dissolution profile for the 3-hour pellet formulation prepared as described in Examples 12. The dissolution experiments were carried out in various media with different pH values at 37° C. with a paddle speed of 100 rpm.

[0147] FIG. 8 shows the dissolution profile for the 5-hour pellet formulation prepared as described in Examples 13. The dissolution experiments were carried out in various media with different pH values at 37° C. with a paddle speed of 100 rpm.

[0148] FIG. 9 shows the dissolution profile for the 8-hour pellet formulation prepared as described in Examples 14. The dissolution experiments were carried out in various media with different pH values at 37° C. with a paddle speed of 100 rpm.

[0149] FIG. 10 shows the dissolution profile for the 15-hour pellet formulation prepared as described in Examples 15. The dissolution experiments were carried out in media with pH values of 6.8 or 6.5 at 37° C. with a paddle speed of 100 rpm.

[0150] FIG. 11 shows the dissolution profile for the mono-ethanolamine pellet formulation prepared as described in Example 16. The dissolution experiments were carried out in various media with different pH values at 37° C. with a paddle speed of 100 rpm.

[0151] FIG. 12 shows the dissolution profile for the mono-ethanolamine pellet formulation prepared in accordance with the process as described in Example 16, with the only exception that the weight amount of PVP and EC was changed from 24% PVP K30 (76% EC) to 23% PVP K30 (77% EC). The dissolution experiments were carried out in various media with different pH values and ionic strength at 37° C. with a paddle speed of 100 rpm.

[0152] FIG. 13 shows the mean 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid plasma concentration-time profile for an oral solution, the MR4 modified release tablet (described in Example 5) and four pellet formulations (as described in Examples 12-17) after administration to Labrador dogs with acidic stomach pH in the fasted state.

[0153] FIG. 14 shows the mean 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid plasma concentration-time profile pellet formulations described in Example 12-15 at a 5 mg 5 hr pellet, 10 mg 8 hr pellet and 10 mg 15 hr pellet dose in the fasted condition.

[0154] FIG. 15 shows the mean 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid plasma concentration-time profile pellet formulations described in Example 12-15 at a 5 mg 5 hr pellet, 10 mg 8 hr pellet and 10 mg 15 hr pellet dose in the fed condition.

[0155] FIG. 16 shows the mean 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid plasma concentration-time profile for the 8-hour pellet formulation described in Example 14 at a 10 mg dose in both the fasted and fed conditions.

[0156] FIG. 17 shows the dissolution profile for the pellet formulation prepared as described in Example 22. The dissolution experiment was carried out in pH 6.8 buffer (ionic strength 0.1, 50.0 mM KH2PO4+23.6 mM NaOH) at 37° C. using a paddle speed of 100 rpm.

[0157] FIG. 18 shows the dissolution profile for the pellet formulation prepared as described in Example 24. The dissolution experiment was carried out in pH 6.8 buffer (ionic strength 0.1, 50.0 mM KH2PO4+23.6 mM NaOH) at 37° C. using a paddle speed of 100 rpm.

EXAMPLE 1: PREPARATION OF IMMEDIATE RELEASE TABLET COMPOSITIONS CONTAINING THE AGENT

[0158] 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was prepared in accordance with the methods disclosed in WO 2013/067425 (Example No. 1).

[0159] This example formulation was prepared by a conventional direct compression and film coating process. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size D.sub.10 was less than 1 μm, D.sub.50 less than 5 μm and D.sub.90 less than 20 Microcrystalline cellulose (Avicel PH-102, FMC International, Philadelphia, Pa., USA), croscarmellose sodium (AcDiSol®, FMC International, Philadelphia, Pa., USA) and colloidal silicon dioxide (CabOSil M5P, Cabot Corporation, Alpharetta, Ga., USA) were all screened prior to use.

[0160] The micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid (23.0 g) and a portion of the microcrystalline cellulose were blended for 5 minutes. The remaining portion of microcrystalline cellulose was added and blended for 5 further minutes (total amount of microcrystalline cellulose is 416.3 g). The croscarmellose sodium (13.8 g) and colloidal silicon dioxide (4.6 g) raw materials were added to the micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/microcrystalline cellulose mixture, blended for 5 minutes and then passed through a Comil (Screening Mills) and further blended for an additional 15 minutes. 0.5% (w/w) Magnesium stearate (Hyqual™ 2257, Mallinckrodt Pharmaceuticals, St. Louis, Mo., USA) was screened prior to use and added to the blend and mixed for 5 minutes. The final blend was compressed on a rotary tablet press (Globe Pharma Mini-Press) as 100 mg tablets with a 6.1 mm diameter and approximately 3.5 mm thickness. Tablets were filmed coated in a perforated pan coating system with a hypromellose based aesthetic film coat (15% w/v dispersion of Opadry Blue 03K105000 in purified water) to a target weight gain of 3% w/w. The compositions for the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid immediate release tablets, at 5 mg and 20 mg strengths, are presented in Table 1.

TABLE-US-00002 TABLE 1 Formulation for 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4- yl)thio)-2-methylpropanoic acid Immediate Release Tablets 5 mg 20 mg Ingredient Grade mg/tablet mg/tablet % w/w Tablet Core 2-((3-(4- Micronized   5.0  20.0   4.83% cyanonaphthalen- 1-yl)pyridine-4- yl)thio)-2- methylpropanoic acid (micronized).sup.1 Microcrystalline Avicel PH-102  90.5  36.0  87.44% Cellulose.sup.2 Croscarmellose AcDiSol   3.0  12.0   2.90% Sodium Colloidal Silicon CabOSil M5P   1.0   4.0   0.97% Dioxide Magnesium Stearate Hyqual 2257   0.5   2.0   0.48% Coating Opadry Blue 03K105000   3.5  14.0   3.38% Purified Water.sup.3 USP — — — Total 103.5 414.0 100.00% .sup.1Adjusted based on water content and total related substances to provide 5 mg or 20 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid per tablet. .sup.2Adjusted after drug substance correction to maintain core tablet weight at 100 mg or 400 mg. .sup.3Processing aid; removed during manufacturing.

EXAMPLE 2: PREPARATION OF MODIFIED RELEASE HPMC HYDROPHILIC MATRIX TABLET COMPOSITION (MR1)

[0161] This example formulation was prepared by a conventional direct compression and film coating process. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size D.sub.10 was less than 1 μm, D.sub.50 less than 5 μm and D.sub.90 less than 20 μm.

[0162] With the exception of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid all raw materials were screen prior to use.

[0163] Micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid (12.50 g), and a portion of the microcrystalline cellulose were blended for 5 minutes. The remaining portion of microcrystalline cellulose was added and blended for 5 further minutes (total amount of microcrystalline cellulose is 381.75 g). The hypromellose (100.0 g, Methocel K100 Premium LV CR, Dow Chemical Company, Midland, Mich., USA) and colloidal silicon dioxide (2.0 g) were added to the micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/microcrystalline cellulose blend, mixed for 5 minutes, passed through a Comil (Screening Mills) and further blended for an additional 15 minutes. Magnesium stearate 0.75% (w/w) is added to the blend and mixed for 5 minutes. The final blend was compressed on a rotary tablet press (Manesty Beta Press) as 100 mg tablets with a 6.1 mm diameter and approximately 3.5 mm thickness. The resultant tablet cores were filmed coated in a perforated pan coating system with a hypromellose based aesthetic film coat (15% w/v dispersion of Opadry Blue 03K105000 in purified water) to a target weight gain of 3% w/w. The composition of the MR1 formulation is presented in Table 2.

TABLE-US-00003 TABLE 2 Composition of 2-((3-(4-cyanonaphthalen-1-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid modified release HPMC hydrophilic matrix tablet (MR1) Ingredients % w/w mg/tablet Tablet Core 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-   2.43   2.50 yl)thio)-2-methylpropanoic acid.sup.1 (Micronized) Hypromellose (Methocel K100 Premium LVCR)  19.42  20.00 Microcrystalline Cellulose.sup.2 (Avicel PH-102)  74.13  76.35 Colloidal Silicon Dioxide (CabOSil M5P)   0.39   0.40 Magnesium Stearate (Hyqual 2257)   0.73   0.75 Film Coat Opadry Blue (03K105000)   2.91   3.00 Purified Water.sup.3 (USP) — — Total Tablet Weight 100.00 103.0  .sup.1Adjusted based upon water content and total related substances to provide 2.5 mg per tablet .sup.2Quantity of microcrystalline cellulose to be adjusted after drug substance correction to maintain target core tablet weight at 100 mg .sup.3Purified water is removed during processing.

EXAMPLE 3: PREPARATION OF MODIFIED RELEASE HPMC/POLYETHYLENE OXIDE HYDROPHILIC MATRIX TABLET COMPOSITION (MR2)

[0164] This example formulation was prepared by a conventional direct compression and film coating process. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size D.sub.10 was less than 1 μm, D.sub.50 less than 5 μm and D.sub.90 less than 20 μm.

[0165] With the exception of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid all raw materials were screen prior to use.

[0166] Micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid (12.50 g) and a portion of microcrystalline cellulose were blended for 5 minutes. The remaining portion of microcrystalline cellulose was added and blended for 5 further minutes (total amount of microcrystalline cellulose used was 381.75 g). The lactose monohydrate (40.0 g, Foremost Farms, Rothschild, Wis., USA), hypromellose (75.0 g, Methocel K100 Premium LV CR, Dow Chemicals), Polyethylene Oxide (50.0 g, PolyOx WSR N750, Dow Chemicals) and colloidal silicon dioxide (1.5 g) were added to the micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/microcrystalline cellulose blend, blended for 5 minutes, passed through a Comil (Screening Mills) and further blended for an additional 15 minutes. Magnesium stearate 0.5% (w/w) was added to the blend and mixed. The final blend was compressed on a rotary tablet press (Manesty Beta Press) as 100 mg tablets with a 6.1 mm diameter and approximately 3.5 mm thickness. The resultant tablet cores were filmed coated in a perforated pan coating system with a hypromellose based aesthetic film coat (15% w/v dispersion of Opadry Blue 03K105000 in purified water) to a target weight gain of 3% w/w. The composition of the MR2 formulation is presented in Table 3.

TABLE-US-00004 TABLE 3 Composition of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4- yl)thio)-2-methylpropanoic acid modified release HPMC/Polyethylene Oxide hydrophilic matrix tablet (MR2) Ingredients % w/w mg/tablet Tablet Core 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-   2.43   2.50 yl)thio)-2-methylpropanoic acid.sup.1 (Micronized) Hypromellose (Methocel K100LV CR)  14.56  15.00 Polyethylene Oxide (PolyOx WSR N750)   9.71  10.00 Microcrystalline Cellulose.sup.2 (Avicel PH-102)  61.84  63.70 Lactose Monohydrate (FastFlo 316)   7.77   8.00 Colloidal Silicon Dioxide (CabOSil M5P)   0.29   0.30 Magnesium Stearate (Hyqual 2257)   0.49   0.50 Film Coat Opadry Blue (03K105000)   2.91   3.00 Purified Water.sup.3 (USP) — — Total Tablet Weight 100.00 103.0  .sup.1Adjusted based upon water content and total related substances to provide 2.5 mg per tablet .sup.2Quantity of microcrystalline cellulose to be adjusted after drug substance correction to maintain target core tablet weight at 100 mg .sup.3Purified water is removed during processing.

EXAMPLE 4: PREPARATION OF DELAYED RELEASE TABLET COMPOSITION (MR3)

[0167] This example formulation was prepared by a conventional direct compression and film coating process. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size D.sub.10 was less than 1 μm, D.sub.50 less than 5 μm and D.sub.90 less than 20 μm.

[0168] With the exception of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid all raw materials were screen prior to use.

[0169] The micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid (50.0 g) and a portion of the microcrystalline cellulose were blended for 5 minutes. The remaining portion of microcrystalline cellulose was added and blended for 5 further minutes (total amount of microcrystalline cellulose used was 1860.0 g). The croscarmellose sodium (60.0 g) and colloidal silicon dioxide (20.0 g) raw materials were added to the micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/microcrystalline cellulose mixture, blended for 5 minutes, passed through a Comil (Screening Mills) and further blended for an additional 15 minutes. Magnesium stearate 0.5% (w/w) was screened prior to use and added to the blend and mixed for 5 minutes. The final blend was compressed on a rotary tablet press (Manesty Beta Press) as 100 mg tablets with a 6.1 mm diameter and approximately 3.5 mm thickness.

[0170] The above tablets were film coated with an enteric polymer coating. The enteric polymer coating was comprised of hypromellose acetate succinate (Aqoat AS-HF, Shin-Etsu Chemical Company, Ltd., Tokyo, Japan) 29.8 g, triethyl citrate (Vertellus Performance Materials, Inc. Indianapolis, Ind., USA) 10.4 g, talc (Brenntag Specialties, Inc., Luzenac, Val Chisone, Italy) 9.0 g, and sodium lauryl sulfate (Spectrum Chemical Manufacturing Company, Gardena, Calif.) 0.9 g. The coating was applied to the tablets using a perforated pan coater to an approximately 10% weight gain. Tablets were subsequently film coated in a perforated pan coating system with a hypromellose based aesthetic film coat (15% w/v dispersion of Opadry Blue 03K105000 in purified water) to a target weight gain of 3% w/w. The compositions for the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid MR3 formulations are presented in Table 4.

TABLE-US-00005 TABLE 4 Composition of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4- yl)thio)-2-methylpropanoic acid delayed release tablet (MR3) Ingredients % w/w mg/tablet Tablet Core 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-   2.21   2.50 yl)thio)-2-methylpropanoic acid.sup.1 (Micronized) Microcrystalline Cellulose.sup.2 (Avicel PH-102)  82.08  93.00 Croscarmellose Sodium (Ac-Di-Sol)   2.65   3.00 Colloidal Silicon Dioxide (CabOSil M5P)   0.88   1.00 Magnesium Stearate (Hyqual 2257)   0.44   0.50 Enteric Coat Hypromellose Acetate Succinate (Aqoat AS-HF)   5.25   5.95 Triethyl Citrate (USP/EP)   1.84   2.08 Talc (Pharma M)   1.58   1.79 Sodium Lauryl Sulfate (USP/EP)   0.16   0.18 Purified Water.sup.3 (USP) — — Aesthetic Coat Opadry Blue (03K105000)   2.91   3.30 Purified Water.sup.3 (USP) — — Total Tablet Weight 100.00 113.3  .sup.1Adjusted based upon water content and total related substances to provide 2.5 mg per tablet .sup.2Quantity of microcrystalline cellulose to be adjusted after drug substance correction to maintain target core tablet weight at 100 mg .sup.3Purified water is removed during processing.

EXAMPLE 5: PREPARATION OF MODIFIED RELEASE HPMC HYDROPHILIC MATRIX TABLET COMPOSITION (MR4)

[0171] This example formulation was prepared by a conventional direct compression and film coating process. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size D.sub.10 was less than 1 μm, D.sub.50 less than 5 μm and D.sub.90 less than 20 μm.

[0172] With the exception of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid all raw materials were screen prior to use.

[0173] Micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid (625.0 g) and a portion of microcrystalline cellulose were blended for 8 minutes. The second portion of microcrystalline cellulose was added and blended for 8 minutes. The hypromellose (7500.0 g, Methocel K100M Premium DC), colloidal silicon dioxide (125 g) and a third portion of microcrystalline cellulose (total amount of microcrystalline cellulose used was 16687.5 g) were added to the micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/microcrystalline cellulose mixture, blended for 5 minutes and then passed through a Comil (Screening Mills) for further blending for an additional 24.4 minutes. Magnesium stearate 0.25% (w/w) was screened prior to use and added to the blend and mixed for 8 minutes. The final blend was compressed on a rotary tablet press (Manesty Beta Press) as 100 mg tablets with a 6.1 mm diameter and approximately 3.5 mm thickness. The resultant tablet cores were filmed coated in a perforated pan coating system with a hypromellose based aesthetic film coat (15% w/v dispersion of Opadry Blue 03K105000 in purified water) to a target weight gain of 3% w/w. The composition of the MR4 formulation is presented in Table 5.

TABLE-US-00006 TABLE 5 Composition of 2-((3-(4-cyanonaphthalen-1-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid modified release HPMC K100M hydrophilic matrix tablet (MR4) Ingredients % w/w mg/tablet Tablet Core 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-   2.43   2.50 yl)thio)-2-methylpropanoic acid.sup.1 (Micronized) Hypromellose (Methocel K100M Premium DC)  29.13  30.00 Microcrystalline Cellulose.sup.2 (Avicel PH-102)  64.81  66.75 Colloidal Silicon Dioxide (CabOSil M5P)   0.49   0.50 Magnesium Stearate (Hyqual 2257)   0.24   0.25 Film Coat Opadry Blue (03K105000)   2.91   3.00 Purified Water.sup.3 (USP) — — Total Tablet Weight 100.00 103.0  .sup.1Adjusted based upon water content and total related substances to provide 2.5 mg per tablet .sup.2Quantity of microcrystalline cellulose to be adjusted after drug substance correction to maintain target core tablet weight at 100 mg .sup.3Purified water is removed during processing.

EXAMPLE 5A: PREPARATION OF MODIFIED RELEASE HPMC HYDROPHILIC MATRIX TABLET COMPOSITION, 10 MG DOSE (MR4)

[0174] This example formulation was prepared by a conventional direct compression and film coating process. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size D.sub.10 was less than 1 μm, D.sub.50 less than 5 μm and D.sub.90 less than 20 μm.

[0175] With the exception of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid all raw materials were screened prior to use.

[0176] Micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid (25.0 g) and the microcrystalline cellulose (958.1 g) were blended for 5 minutes. Lactose monohydrate (506.0 g) hypromellose (396.0 g, Benecel K100M PHARM, Ashland) and colloidal silicon dioxide (5.0 g) were added to the micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/microcrystalline cellulose mixture, blended for 5 minutes then passed through a Comil (Screening Mills) and further blended for an additional 15 minutes. Magnesium stearate 0.25% (w/w) was screened prior to use and added to the blend and mixed for 5 minutes. The final blend was compressed on a rotary tablet press (Manesty Beta Press) as a 5×9.5 mm 180 mg tablets and approximately 4.1 mm thickness. The resultant tablet cores were filmed coated in a perforated pan coating system with a hypromellose based aesthetic film coat (15% w/v dispersion of Opadry White 03K18416 in purified water) to a target weight gain of 3% w/w. The composition of the 10 mg MR4 10 mg tablet formulation is presented in Table 6.

TABLE-US-00007 TABLE 6 Composition of 10 mg 2-((3-(4-cyanonaphthalen-1-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid modified release HPMC K100M hydrophilic matrix tablet (MR4) Ingredients % w/w mg/tablet 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-   5.39  10.00 yl)thio)-2-methylpropanoic acid.sup.2 (Micronized) Hypromellose (Methocel K100M Premium DC)  19.42  36.00 Microcrystalline Cellulose (Avicel PH-102)  46.98  87.10 Lactose Monohydrate (Foremost FastFlo 316)  24.81  46.00 Colloidal Silicon Dioxide (CabOSil M5P)   0.24   0.45 Magnesium Stearate (Hyqual 2257)   0.24   0.45 Opadry White (03K18416)   2.91   5.40 Purified Water.sup.2 (USP) — — Total Tablet Weight 100.0  185.40 .sup.1Adjusted based upon water content and total related substances to provide 10 mg per tablet .sup.2Purified water is removed during processing

EXAMPLE 6: PREPARATION OF DELAYED RELEASE HPMC HYDROPHILIC MATRIX TABLET COMPOSITION (MR5)

[0177] This example formulation was prepared by a conventional direct compression and film coating process. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size D.sub.10 was less than 1 μm, D.sub.50 less than 5 μm and D.sub.90 less than 20 μm.

[0178] With the exception of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid all raw materials were screen prior to use.

[0179] Micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid (25.0 g) and a portion of the microcrystalline cellulose were blended for 5 minutes. The remaining portion of microcrystalline cellulose was added (total amount used 672.5 g) and blended for 5 minutes. The hypromellose (300.0 g, Methocel K100M Premium DC) was added to the micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/microcrystalline cellulose mixture, blended for 5 minutes and then passed through a Comil (Screening Mills) and further blended for an additional 15 minutes. Magnesium stearate 0.25% (w/w) was screened prior to use and added to the blend and mixed for 8 minutes. The final blend was compressed on a rotary tablet press (Globe Pharma Mini Press) as 100 mg tablets with a 6.1 mm diameter and approximately 3.5 mm thickness.

[0180] The above tablets were film coated with an enteric polymer coating. The enteric polymer coating was comprised of Methacrylic Acid Copolymer Dispersion (Eudragit L30D-55, Evonik Industries AG, Germany) 43.1 g, Triethyl citrate 1.3 g, and Talc 2.5 g. The coating was applied to tablets using a perforated pan coater to an approximately 5% weight gain. The resultant tablets were then filmed coated in a perforated pan coating system with a hypromellose based aesthetic film coat (15% w/v dispersion of Opadry Blue 03K105000 in purified water) to a target weight gain of 3% w/w. The composition of the MR5 formulation is presented in Table 7.

TABLE-US-00008 TABLE 7 Composition of 2-((3-(4-cyanonaphthalen-1-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid delayed release HPMC K100M hydrophilic matrix tablet (MR5) Ingredients % w/w mg/tablet Tablet Core 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-   2.31   2.50 yl)thio)-2-methylpropanoic acid.sup.1 (Micronized) Hypromellose (Methocel K100M Premium DC)  27.74  30.00 Microcrystalline Cellulose.sup.2 (Avicel PH-102)  62.18  67.25 Magnesium Stearate (Hyqual 2257)   0.23   0.25 Enteric Coat Methacrylic Acid Copolymer (Eudragit L30D-55)   3.56   3.85 Triethyl Citrate (USP/EP)   0.37   0.40 Talc (Pharma M)   0.69   0.75 Purified Water.sup.3 (USP) — — Aesthetic Coat Opadry Blue (03K105000)   2.91   3.15 Purified Water.sup.3 (USP) N/A N/A Total Tablet Weight 100.00 108.15 .sup.1Adjusted based upon water content and total related substances to provide 2.5 mg per tablet .sup.2Quantity of microcrystalline cellulose to be adjusted after drug substance correction to maintain target core tablet weight at 100 mg .sup.3Purified water is removed during processing.

EXAMPLE 7: DISSOLUTION TESTING OF IMMEDIATE RELEASE AND MODIFIED RELEASE TABLET FORMULATIONS

Methods

[0181] Dissolution of immediate release tablets were performed according to the general procedure of the United States Pharmacopeia Apparatus II (paddle) for immediate release dosage forms. Aliquots of the dissolution test media were collected and filtered at specific time intervals and analyzed by reverse phase HPLC using isocratic elution and UV detection at 226 nm. The HPLC method conditions were: Analytical Column: Reverse phase HPLC Cig column, YMC ODS-AQ, 4.6×150 mm, 120 Å, 3 μm (Part # AQ12S031546WT); Eluent: 60% 10 mM KH.sub.2PO.sub.4, pH 2.4/40% Acetonitrile; 20 or 50 μL injection volume (depending on dosage strength), 1.0 mL/min flow rate, 35° C. column temperature; ambient sample temperature; 8 minute run time. The release of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was determined by comparing the peak responses of the sample chromatograms to the peak responses of the standard chromatograms. 900 mL SGF (simulated gastric fluid) without pepsin at 37° C. and a paddle speed of 50 rpm is used. The SGF was prepared by adding 12.0 g of sodium chloride to 42.0 mL of concentrated hydrochloric acid brought to 6 L with deionized water. The solution had a pH of about 1.2.

[0182] Dissolution of MR1, MR2 and MR4 tablets were performed according to the general procedure of the United States Pharmacopeia Apparatus II (paddle) for extended release dosage forms. Aliquots of the dissolution test media are collected and filtered at specific time intervals and analyzed by reverse phase HPLC using isocratic elution and UV detection at 226 nm. The HPLC method conditions were: Analytical Column YMC ODS-AQ, 4.6×150 mm, 120 Å, 3 μm (Part # AQ12S031546WT); Eluent: 60% 10 mM KH.sub.2PO.sub.4, pH 2.4/40% Acetonitrile; 20 or 50 μL injection volume (depending on dosage strength), 1.0 mL/min flow rate, 35° C. column temperature; ambient sample temperature; 8 minute run time. The release of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid is determined by comparing the peak responses of the sample chromatograms to the peak responses of the standard chromatograms obtained concomitantly. The method uses Spiral Stainless Steel Capsule Sinkers to hold the tablets or capsules. 900 mL pH 6.8 50 mM phosphate buffer solution was used at 37° C. and a paddle speed of 50 rpm is used. The buffer was prepared by adding 122.4 g of KH.sub.2PO.sub.4 dissolved in approximately 16 L of deionized water, pH adjusted to 6.8±0.1 with 1 N sodium hydroxide, then brought to a total of 18 L with deionized water.

[0183] Dissolution of MR3 tablets was performed according to the general procedure of the United States Pharmacopeia Apparatus II (paddle) for delayed release dosage forms using a two stage dissolution method. Aliquots of the dissolution test media were collected and filtered at specific time intervals and analyzed by reverse phase HPLC using isocratic elution and UV detection at 226 nm. The HPLC method conditions were: Analytical Column: YMC ODS-AQ, 4.6×150 mm, 120 Å, 3 μm (Part # AQ12S031546WT); Eluent: 60% 10 mM KH.sub.2PO.sub.4, pH 2.4/40% Acetonitrile; 20 or 50 μL injection volume (depending on dosage strength), 1.0 mL/min flow rate, 35° C. column temperature; ambient sample temperature; 8 minute run time. The release of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was determined by comparing the peak responses of the sample chromatograms to the peak responses of the standard chromatograms obtained concomitantly. The acid stage is 750 mL of 0.1N HCl and the buffer stage is 1000 mL of pH 6.8 buffer. Both stages are at 37° C. and use a paddle speed of 50 rpm. The acid stage is from the first 0 to 2 hours. At 2 hours, the pH is increased to 6.8 by addition of 250 mL of 0.20 M Na.sub.3PO.sub.4 buffer solution to the media. The buffer media was prepared by adding 152 g of Na.sub.3PO.sub.4.12H.sub.2O dissolved in 2 L of deionized water, pH adjusted as necessary with 2 N NaOH or 2 N HCl such that the final buffer solution (after addition to the 750 mL of acid stage media) is pH is 6.8±0.1.

[0184] Dissolution of MR5 tablets was performed according to the general procedure of the United States Pharmacopeia Apparatus II (paddle) for delayed release dosage forms using a two stage dissolution method. Aliquots of the dissolution test solutions were collected and filtered at specific time intervals and analyzed by reverse phase HPLC using isocratic elution and UV detection at 226 nm. The HPLC method conditions were: Analytical Column: YMC ODS-AQ, 4.6×150 mm, 120 Å, 3 μm (Part # AQ12S031546WT); Eluent: 60% 10 mM KH.sub.2PO.sub.4, pH 2.4/40% Acetonitrile; 20 or 50 μL injection volume (depending on dosage strength), 1.0 mL/min flow rate, 35° C. column temperature; ambient sample temperature; 8 minute run time. The release of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was determined by comparing the peak responses of the sample chromatograms to the peak responses of the standard chromatograms. The acid stage was 500 or 900 mL of 0.1N HCl (depending on dosage strength) and the buffer stage was 500 or 900 mL (depending on dosage strength) of pH 6.8 50 mM phosphate buffer solution (122.4 g of KH.sub.2PO.sub.4 dissolved in approximately 16 L of deionized water, pH adjusted to 6.8±0.1 with 1 N sodium hydroxide, then brought to a total of 18 L with deionized water). Both stages are at 37° C. and use a paddle speed of 50 rpm. The acid stage is from the first 0 to 2 hours followed by then the same dosage unit being transferred into the buffer stage medium. This might be accomplished by removing from the apparatus the vessel containing the acid and replacing it with another vessel containing the buffer and transferring the dosage unit to the vessel containing the buffer. Continue to operate the apparatus. As an alternative, a different dissolution apparatus prepared according to the conditions specified above could be used for the Buffer stage.

Dissolution Results

[0185] FIG. 1 shows the dissolution profile for the 5 mg immediate release formulation described in Example 1 (n=6). FIG. 2 shows the dissolution profile for the MR formulations described in Examples 2-6 (n=6).

[0186] The dissolution data for the immediate release tablets show that dissolution is rapid and >80% of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid is released within 15 minutes. Modified release matrix tablet formulation MR1 and MR2 show 80% of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid released in 3 hours and 4 hours respectively. The MR3 formulation showed no release over 2 hours at pH 1.1 with immediate release following the media pH change to 6.8. The MR4 formulation showed 80% of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid released in 12 hours. The MR5 formulation shows no 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid release for 2 hours at pH 1.1. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid dissolution profile from the MR5 formulation is similar to that seen for MR4 following the dissolution media pH change to pH 6.8.

EXAMPLE 8: SINGLE DOSE PHASE I CLINICAL TRIAL—IMMEDIATE RELEASE FORMULATIONS

[0187] A phase 1, randomized, double-blind, placebo-controlled study in healthy adult male volunteers evaluated single rising doses and the preliminary food effect for 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid at 6 dose groups with 8 subjects per group. Under fed conditions, the subjects were required to fast overnight for at least hours before dosing, then receive study medication 30 minutes after completing a standard moderate fat breakfast that did not include high fructose corn syrup. Subjects in each dose group were randomized to receive a single dose of either 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid (6 subjects) or placebo (2 subjects). 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was supplied as 1 mg oral solution, 2 mg oral solution, 5 mg tablets, or 20 mg tablets (depending on dose level).

[0188] Segment A evaluated single rising doses of 2 mg, 5 mg, 20 mg and 40 mg and the preliminary food effect of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid at the 5 mg and 20 mg doses followed by multiple ascending doses of 1 mg, 5 mg and 10 mg qd in Segment B.

TABLE-US-00009 Segment Group Dose (mg) Dietary State Dose Form A 1 20 mg Fasted 1 × 20 mg tablet 2 40 mg Fasted 2 × 20 mg tablet 3 20 mg Fed 1 × 20 mg tablet 4  5 mg Fasted 1 × 5 mg tablet  5  2 mg Fasted oral solution 6  5 mg Fed 1 × 5 mg tablet  B 1  5 mg qd Fasted 1 × 5 mg tablet  2 10 mg qd Fasted 2 × 5 mg tablet  3  1 mg qd Fasted oral solution

[0189] The oral solution was prepared by the clinical pharmacist in bulk within 24 hours of administration. The oral solution of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid (0.033 mg/mL concentration) was prepared as a mixture of the appropriate amount of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid powder, anhydrous dibasic sodium phosphate, and sterile water for irrigation; placebo oral solution was prepared as a vehicle using anhydrous dibasic sodium phosphate and sterile water for irrigation. The immediate release tablets were prepared as described in Example 1. Plasma samples were collected at the following time-points in relation to dosing on Day 1: pre-dose (within 30 minutes before dosing) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 30, 36, 48, 54, 60, and 72 hours post-dose, and were analysed for 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid content. A summary of the mean plasma pharmacokinetic parameters following administration of the immediate release compositions at various doses of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid are provided in Table 8.

TABLE-US-00010 TABLE 8 Geometric Mean (95% CI) Plasma Pharmacokinetics of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)- 2-methylpropanoic acid following a Single Dose at Various Dose Levels under Fed or Fasted Conditions Dose Food T.sub.max C.sub.max AUC.sub.0-24 AUC.sub.∞ t.sub.1/2 (mg) N Group (hr) (ug/mL) (pg-hr/mL) (μg .Math. hr/mL) (hr) 2 Fasted 5 Geomean 0.500 0.0364  0.0388  0.0450 12.1 N = 6 (95% CI) (0.250-0.500) (0.0224-0.0592) (0.0298-0.0506) (0.0347-0.0583) (7.61-19.2) 5 Fasted 4 Geomean 0.625 0.0729 0.102 0.121 14.2 N = 6 (95% CI) (0.500-0.750) (0.0537-0.0989) (0.0891-0.117)  (0.108-0.135) (10.7-18.8) Fed 6 Geomean 1.25  0.0457  0.0752  0.0928 12.7 N = 6 (95% CI) (0.750-2.50)  (0.0345-0.0606) (0.0595-0.0951) (0.0718-0.120)  (9.73-16.7) 20 Fasted 1 Geomean 0.500 0.384  0.463 0.540 10.9 N = 6 (95% CI) (0.250-1.50)  (0.268-0.550) (0.397-0.540) (0.469-0.623) (6.15-19.2) Fed 3 Geomean 1.25  0.181  0.350 0.415 13.8 N = 6 (95% CI) (1.00-2.50) (0.0921-0.357)  (0.234-0.523) (0.282-0.611) (7.88-24.0) 40 Fasted 2 Geomean 0.750 0.760  1.07  1.27   9.51 N = 6 (95% CI) (0.250-1.00)  (0.493-1.17)  (0.701-1.64)  (0.873-1.84)  (7.81-11.6) *T.sub.max is represented by median (range): .sup.$Body weight normalized parameter

[0190] The mean plasma concentration-time profiles for the IR formulations under fed and fasted conditions are depicted in FIGS. 3a and 3b. Absorption of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid following a single oral dose under fasted conditions was rapid. For example, at the 5 mg dose the geometric mean maximum plasma concentration (C.sub.max) achieved is approximately 73 ng/ml and the time at which the peak plasma concentration is observed (T.sub.max) is in the range of approximately 0.25-1.5 hours (median 0.6 hours). When 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was administered with food, slightly slower absorption and lower exposure were observed. Plasma exposures of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid displayed dose proportional increases in the 1 mg to 40 mg dose range. Important pharmacodynamic parameters related to the serum Uric Acid lowering effects are shown in the following two tables:

TABLE-US-00011 AUC.sub.0−24 Mean % Dose/ (ng .Math. hr/ change in sUA Condition mL) from predose.sup.1 (%)  2 mg/Fasted   38.8  8%  5 mg/Fasted  102   15% 20 mg/Fasted  463   43% 40 mg/Fasted 1070   58% .sup.1% sUA change mean maximum observed percentage change from pre-dose in serum urate concentrations (E.sub.max)

TABLE-US-00012 Urine Urate Excretion.sup.1 Dose/ AUC.sub.0-24 C.sub.max/ UUE UUE UUE 0-6 hrs/ Condition C.sub.max (ng .Math. hr/mL) AUC.sub.0-24 0-6 hrs 6-12 hrs 12-24 hrs 0-24 hrs 5 mg/Fasted 72.9 102 0.72 509 231 347 0.468 .sup.1Urine urate excretion (UUE) is measured as mg of urate per urine collection period.

EXAMPLE 9: PHASE I/II CLINICAL TRIALS—MODIFIED RELEASE FORMULATIONS (MR1-5)

[0191] A Phase 1, randomized study to evaluated the PK, PD, and safety and tolerability of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid MR formulations in n=12 healthy adult male subjects in fasted and fed states. This study evaluated a total of 5 MR formulations at a 5 mg dose. The MR formulations tested are those described in Examples 2-6. Plasma samples for PK analysis were collected at the following time points: Pre-dose (within 30 minutes before dosing) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 30, 36, 48, 54, 60 and 72 hours post-dose. A summary of the mean plasma pharmacokinetic parameters following administration of the MR compositions of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid are provided in Table 9.

TABLE-US-00013 TABLE 9 Summary Plasma Pharmacokinetics of 2-((3-(4-cyanonaphthalen-1-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid following a 5 mg Single Dose in various MR Formulations under Fed or Fasted Conditions (Geometric Mean (95% CI)) T.sub.max.sup.1 C.sub.max AUC.sub.0-24 AUC.sub.∞ t.sub.1/2 Form Food n (hr) (ng/mL) (ng .Math. hr/mL) (ng .Math. hr/mL) (hr).sup.2 MR1 Fasted 12 1.75 (1.00-3.00) 21.3 (16.6-27.3) 96.7 (77.3-121)  131 (96.1-178) 18.0 (11.0-29.3) Fed 5 2.00 (1.00-2.50) 27.1 (16.2-45.6) 91.9 (71.6-118)  128 (79.6-206) 19.0 (10.5-34.2) MR2 Fasted 12  1.50 (0.750-2.50) 32.2 (23.1-44.7) 116 (88.3-152) 145 (103-204)  13.4 (10.1-17.6) Fed 6 2.00 (1.00-4.00) 47.2 (31.5-70.7) 123 (88.7-171) 154 (97.3-243) 15.3 (9.78-23.8) MR3 Fasted 12  2.25 (0.750-6.00) 56.6 (42.4-75.6) 113 (91.8-139) 133 (107-165)  12.7 (10.2-15.8) Fed 10 5.00 (2.50-6.00) 45.8 (32.9-63.7) 114 (87.2-149) 134 (104-173)  15.3 (11.7-19.9) MR4 Fasted 12  2.25 (0.500-4.00) 7.40 (5.98-9.16) 46.2 (40.9-52.3) 68.5 (59.3-79.2) 15.4 (11.1-21.3) Fed 5 2.00 (1.00-3.00) 8.65 (4.87-15.4) 44.3 (30.2-65.1) 57.4 (36.0-91.6) 10.2 (6.08-17.2) MR5 Fasted 11 3.00 (1.00-4.00) 7.66 (5.67-10.4) 39.2 (29.2-52.7) 60.0 (44.6-80.8) 15.0.sup.2 (11.3-20.0).sup.  Fed 6 4.50 (2.00-5.00) 6.59 (4.62-9.38) 26.0 (21.7-31.1) 61.3 (34.6-109)  28.4 (11.5-70.3) .sup.1Values are presented as median (range); .sup.2Half lives in more than half subjects were calculated from a period of <2 calculated half-lives and deemed unreliable.

[0192] The mean plasma concentration-time profile for each formulation under fasted conditions is depicted in FIG. 4 and the profile for each formulation under fed conditions is depicted in FIG. 5.

[0193] As described above, a total of 5 modified-released formulations (MR1, MR2, MR3, MR4 and MR5) were evaluated in this study. Following a single oral 5 mg dose of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid in these formulations under fasted conditions, 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was readily absorbed from the MR1 and MR2 formulations (median T.sub.max 1.50-1.75 hours) and relatively slower from the MR4 and MR5 formulations (median T.sub.max 2.25-3.00 hours) (see Table 9 and FIG. 4). Both the MR3 and MR5 formulations showed a noticeable lag time in the absence or presence of food. Plasma concentrations of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid declined with average terminal half-life values of approximately 10-28 hours (Table 9).

[0194] Using the MR1 formulation as a reference, under fasted conditions, the MR2 and MR3 formulations generally exhibited higher (51-166% higher) C.sub.max values while the MR4 and MR5 formulations showed lower (approximately 64-65% lower) C.sub.max values (Table 9). AUC exposures for the MR2 and MR3 formulations were both comparable to MR1, while the MR4 and MR5 formulations showed only half (approximately 48-54%) of the AUC exposure of MR1. The ranking order across the five formulations is MR3>MR2>MR1>MR4=MR5 for C.sub.max and MR3=MR2=MR1>MR4=MR5 for AUC. Food had no impact on the rank order for the relative bioavailability (Table 9). Important pharmacodynamic parameters related to the serum Uric Acid lowering effects are shown in the following two tables:

TABLE-US-00014 AUC.sub.0−24 Mean % Dose/ (ng .Math. hr/ change in sUA Formulation Condition mL) from predose.sup.1 (%) MRI 5 mg/Fasted  96.7 23.7% MR2 5 mg/Fasted 116   24.7% MR3 5 mg/Fasted 113   18.6% MR4 5 mg/Fasted  46.2 14.8% MR5 5 mg/Fasted  39.2 12.4% .sup.1% sUA change mean maximum observed percentage change from pre-dose in serum urate concentrations (E.sub.max)

TABLE-US-00015 Urine Urate Excretion.sup.1 Formulation/ AUC.sub.0-24 Cmax/ UUE UUE UUE 0-6 hrs/ Condition Cmax (ng .Math. hr/mL) AUC 0-6 hrs 6-12 hrs 12-24 hrs 0-24 hrs MR1/Fasted 21.3 96.7 0.22 449 258 219 0.485 MR2/Fasted 32.2 116 0.28 423 259 229 0.464 MR3/Fasted 56.6 113 0.50 388 272 245 0.429 MR4/Fasted 7.4 46.2 0.16 324 276 251 0.381 MR5/Fasted 7.7 39.2 0.20 290 275 267 0.349 .sup.1Urine urate excretion (UUE) is measured as mg of urate per urine collection period.

[0195] Efficacy of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid in lowering serum uric acid is linearly related to the AUC. AUC achieved was formulation dependent.

EXAMPLE 10: PHASE I CLINICAL TRIALS—MODIFIED RELEASE FORMULATION MR4 BIOAVAILABILITY WHEN DELIVERED AS 4×2.5 MG TABLETS AND SINGLE 10 MG TABLET

[0196] A Phase 1, randomized, open label, 4 way crossover PK and PD study in healthy adult male subjects designed to assess the relative bioavailability of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid 2.5 mg MR tablets administered as a 10 mg dose (4×2.5 mg tablets) and a single 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid 10 mg MR tablet. The 10 mg MR tablet was prepared as described in Example 5a. This study also assessed the effect of a low fat and high fat meal on the PK and PD of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid 10 mg MR tablets. Sixteen subjects were randomized to 1 of 4 treatment sequences. The treatments administered on Days 1 or 5 according to the randomization schedule were as follows: [0197] Treatment A: 10 mg dose of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid, administered as 4×2.5 mg ER tablets, in the fasted state. [0198] Treatment B: 10 mg dose of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid, administered as a single 10 mg ER tablet, in the fasted state.

[0199] The treatments administered on Days 9 or 13 according to the randomization schedule were as follows: [0200] Treatment C: 10 mg dose of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid, administered as a single 10 mg ER tablet, in the fed state (low-fat, high-calorie meal). [0201] Treatment D: 10 mg dose of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid, administered as a single 10 mg ER tablet, in the fed state (high-fat, high-calorie meal).

[0202] During Treatments A and B subjects were fasted overnight for at least 10 hours prior to the start of PD collections. Subjects also fasted overnight for at least 10 hours prior to study medication dosing.

[0203] During Treatment C, subjects received the same standardized low-fat, high calorie breakfast (800 to 1000 calories and approximately 15% to 20% fat content consumed in 30 minutes or less), within the 30 minutes prior to dosing. During Treatment D, subjects received the same standardized high-fat, high calorie breakfast (800 to 1000 calories and approximately 50% fat content consumed in 30 minutes or less), within the 30 minutes prior to dosing. Subjects were instructed to consume 100% of the meal. Upon completion of the study breakfast, no food was allowed for 4 hours after the administration of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.

[0204] A summary of the mean plasma pharmacokinetic parameters following administration of the MR4 compositions are provided in Table 10.

TABLE-US-00016 TABLE 10 Summary Plasma Pharmacokinetics of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid in healthy adult male subjects following various treatments (Geometric Mean [95% Confidence Interval]) Treatment Group Tmax.sup.a C.sub.max AUC.sub.0-24 AUC.sub.last AUC.sub.∞ t.sub.1/2 (Treatment) N (hr) (ng/mL) (ng .Math. hr/mL) (ng .Math. hr/mL) (ng .Math. hr/mL) (hr) A (4 × 2.5 mg, 15 2.00 (1.00-6.00) 14.1 (11.7-16.8) 87.9 (74.1-104)  119 (96.8-146) 131 (105-164)  16.5 (11.6-23.4) Fasted) B (1 × 10 mg, 15 2.00 (1.00-4.00) 14.9 (11.9-18.8) 84.6 (66.6-107)  114 (85.7-153) 130 (95.9-176) 15.5 (10.6-22.5) Fasted) C (1 × 10 mg, 15 2.00 (1.00-6.00) 11.8 (9.23-15.1)  69.6 (55.9-86.7) 97.8 (77.3-124) 108 (84.4-139) 15.4 (11.6-20.4) Low-fat Fed.sup.b) D (1 × 10 mg, 15 4.00 (1.50-8.00) 27.2 (20.2-36.6) 128 (103-159) 160 (130-199) 173 (137-219)  16.6 (11.5-23.9) High-fat Fed.sup.c) Abbreviations: AUC.sub.0-24, area under the concentration-time curve from time zero up to 24 hours postdose; AUC.sub.last, area under the concentration-time curve from time zero to the quantifiable last sampling timepoint; AUC.sub.∞, area under the concentration-time curve from time zero to infinity, C.sub.max, maximum observed concentration; T.sub.max, time of occurrence of maximum observed concentration; t.sub.1/2, apparent terminal half-life; .sup.aT.sub.maxt values are represented by median (range). .sup.b15% to 20% fat, 800 to 1000 calories. .sup.c50% fat, 800 to 1000 calories.

[0205] The mean plasma concentration-time profile for the formulation under fed and fasted conditions is depicted in FIG. 6.

[0206] The relative bioavailability of the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid 10 mg MR tablet was 100% compared with the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid 2.5 mg MR tablets administered as a total 10 mg dose in the fasted state, based on AUC∞. Geometric mean ratios and corresponding 90% CI for C.sub.max and AUC∞ were within bioequivalence limits (80% to 125%). The sUA lowering following dosing with the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid 10 mg MR tablet in the fasted state was comparable to dosing with 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid 2.5 mg MR tablets at 10 mg total dose.

[0207] Compared with the fasted state, a low-fat meal decreased the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid C.sub.max and AUC∞ exposures by approximately 21% and 17%, respectively. The sUA lowering following dosing with the low-fat meal was comparable to sUA lowering in the fasted state.

[0208] A high-fat meal increased the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid C.sub.max and AUC∞ exposures by 82% and 34%, respectively, for the 10 mg MR tablet compared with the fasted state. A high-fat meal enhanced the sUA lowering effect (an approximate 44% maximum reduction from predose value) compared with the fasted state (an approximate 32% maximum reduction from predose value). The enhanced sUA lowering under high-fat conditions is consistent with higher plasma drug exposures.

[0209] The sUA lowering achieved by administration of the formulations is shown in the following table:

TABLE-US-00017 AUC.sub.0−24 Mean % (ng .Math. hr/ change in sUA Formulation Dose Condition mL) from predose.sup.1 MR4 4 × 2.5 mg tablets Fasted  87.9 30.7% MR4 1 × 10 mg tablet   Fasted  84.6 31.5% MR4 1 × 10 mg tablet   Low-Fat Fed  69.6 29.4% MR4 1 × 10 mg tablet   High-Fat Fed 128   43.6% .sup.1% sUA change mean maximum observed percentage change from predose in serum urate concentrations (E.sub.max)

[0210] Efficacy of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid in lowering serum uric acid is linearly related to the AUC.

EXAMPLE 11: PROCESS FOR PREPARATION OF PELLET FORMULATIONS

[0211] Pellet formulations were prepared by a drug layering process. An inert core of a solid material of a mean size of from 100-700 μm was coated with 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid in a drug layering process. A solution or suspension containing said compound was sprayed onto the solid material and the solvent was evaporated. Examples of inert cores that can be used include microcrystalline cellulose such as Celphere CP-203 (200-300 μm), Celphere CP-305 (300-500 μm) or Celphere 507 (500-700 μm), silicon dioxide (sand) or sucrose.

[0212] After 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid has been layered onto the inert core, a film layer is formed to provide a release rate controlling membrane. The film layer contains a polymer such as ethylcellulose (EC) and/or hydroxypropylcellulose (HPC). The amount of HPC to EC is between 1-99%, such as 10-60% or 25-45% of the total polymer weight.

Step 1: Coating of an Inert Core Pellet

[0213] A solution of the Agent is prepared in a concentration of from 1-30 w/w, such as from 5-15% w/w. The Agent is mixed with a binder, such as HPC, HPMC or other polymer and dispersed in a solvent. Examples of solvents that may be used are water or an alcohol such as ethanol, or a mixture thereof. The solution or suspension is held at a temperature of from 15° C. and 40° C. The solution or suspension of said compound is sprayed onto the core material in a fluidised bed equipment such as Aeromatic MP1, LabCC (Graniten LabCC) or Glatt GPCG at a temperature of from 50-100° C., such as from 35-80° C., or from 50-75° C., for example for s duration of 30-500 minutes. Batch sizes useful are typically from 10 g-400 kg. For a batch size of 1 kg, a spray rate of from 5-40 g/min is used.

[0214] It is also possible to use a crystallisation process without the need for a binder. In this case the crystalline compound can be dissolved in a solvent and then re-crystallised onto the cores/seeds in the fluid bed. This may be initiated or effected with or without seeding with crystals of said compound and can be performed in one step or be divided in several sub-bathes.

Step 2, Polymer Coating of Pellets from Step 1

[0215] The pellet granules formed in step 1 are coated with a polymer such as ethyl cellulose (EC), hydroxypropyl cellulose (HPC) or a mixture thereof. In one embodiment, the mixture contains HPC in a quantity of from 0 to 100%, such as 10 to 60%, or 20 to 50% of the total amount of the coating polymer. The polymer and/or the mixture thereof is dissolved in a solvent such as water, a ketone or an alcohol such as ethanol and/or mixtures thereof. The solution is sprayed onto the granules in fluidized bed equipment such as Aeromatic MP1, LabCC or Glatt GPCG at a temperature of from 60-120° C., such as from 75-100° C. The solution is sprayed onto the granules for a sufficient period of time, such as from 10 min to 400 minutes. The time required is dependent on the batch size and the desired thickness of the polymer film to achieve the desired Agent release profile. The batch size may be from 10 g up to 400 kg.

Step 3, Capsule Filling or Tableting

[0216] The pellets comprising the compound 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid prepared according to step 2 may be filled into a capsule. Examples of a capsule material that may be used in accordance with the invention is hydroxypropyl methylcellulose or gelatine. Alternatively, the pellets can be formed into a tablet.

EXAMPLE 12: PREPARATION OF PELLET FORMULATION (3-HOUR PROFILE)

[0217] A pellet formulation was prepared with the following composition:

TABLE-US-00018 Composition of modified release pellet capsules 5 mg Quantity (mg per Components capsule) Supplier Active compound.sup.1  5.0 MCC spheres 0.15-0.3 mm 22.2 Asahi Kasei HPMC 6 cps  0.6 Dow HPC LF  6.2 Ashland EC  9.3 Dow Ethanol, 95 per cent qs Kemetyl A Water purified qs HPMC capsule NA Qualicaps .sup.12-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid

[0218] This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size D.sub.10 was less than 1 μm, D.sub.50 less than 5 μm and D.sub.90 less than 20 μm.

[0219] A polymer solution of 15.0 g of HPMC 6 cps in 1350.0 g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was added. The resultant suspension was protected from light and stirred overnight. The suspension was held at RT ° C. Before spraying, the suspension was sieved through a 200 μm mesh. The spray rate was between 8-12 g suspension/min for the first 5 minutes and there after 10 to 20 g suspension/min for another 105 minutes. Inlet temperature was 72° C. 1250 g of the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/HPMC suspension was sprayed onto 500 g microcrystalline cellulose (MCC) powder spheres (Celphere CP-203 (150-300 μm)) in a fluidised bed equipment (LabCC3). The temperature of outlet air was approximately 30° C., fluidising air flow about 35 Nm.sup.3/h and an atomizer air pressure of approximately 2.5 bar. The product could be made in one or several steps depending on batch sizes.

[0220] A polymer solution of 57.6 g ethyl cellulose 10 cP (EC) and 38.4 g hydroxypropyl cellulose (HPC) dissolved in 1504 g of 95% ethanol was prepared. The drug layered pellets (150 g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42° C. with a spray rate of approximately 10-18 g/min. After spraying 1395 g of polymer solution the polymer coated pellets were dried for 10 minutes in fluidized bed equipment. See process parameters below.

TABLE-US-00019 Process parameters Ranges: Inlet temperature 72-74° C. Outlet temperature 42-60° C. Fluidizing air flow 35 Nm3/h Spray Rate 10-18 g/min Atomization air pressure 2.5 bar Atomization air flow 2.6-2.7 Nm.sup.3/h

[0221] The polymer coated pellets were screened through a 710 μm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver 5 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.

EXAMPLE 13: PREPARATION OF PELLET FORMULATION (5-HOUR PROFILE)

[0222] A pellet formulation was prepared with the following composition:

TABLE-US-00020 Composition of modified release pellet capsules 5 mg Quantity (mg per Components capsule) Supplier Active compound.sup.1  5.0 MCC spheres 0.15-0.3 mm 22.2 Asahi Kasei HPMC 6 cps  0.6 Dow HPC LF  5.6 Ashland EC  9.9 Dow Ethanol, 95 per cent qs Kemetyl A Water purified qs HPMC capsule NA Qualicaps .sup.12-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid

[0223] This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size D.sub.10 was less than 1 μm, D.sub.50 less than 5 μm and D.sub.90 less than 20 μm.

[0224] A polymer solution of 15.0 g of HPMC 6 cps in 1350.0 g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was added. The spray rate was between 5-12 g suspension/min for the first 5 minutes and there after 10-20 g suspension/min for another 105 minutes. Inlet temperature was 72° C. 1250 g of the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/HPMC suspension was sprayed onto 500 g microcrystalline cellulose (MCC) powder spheres (Celphere CP-305 (300-500 μm) in fluidized bed equipment. The temperature of outlet air was approximately 30° C., fluidizing air flow approximately 35 Nm.sup.3/h and an atomizer air pressure approximately 2.5 bar. The product could be made in one or several steps depending on batch sizes.

[0225] A polymer solution of 61.4 g ethyl cellulose 10 cP (EC) and 34.6 g hydroxypropyl cellulose (HPC) dissolved in 1504 g of 95% ethanol was prepared. The drug layered pellets (150 g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42° C. with a spray rate of approximately 10-18 g/min. After spraying 1302.9 g of polymer solution the polymer coated pellets were dried for 10 minutes in fluidized bed equipment. See process parameters below.

TABLE-US-00021 Process parameters: Ranges Inlet temperature 72-74° C. Outlet temperature 42-60° C. Fluidizing air flow 35 Nm3/h Spray Rate 10-18 g/min Atomization air pressure 2.5 bar Atomization air flow 2.6-2.7 Nm.sup.3/h

[0226] The polymer coated pellets were screened through a 710 μm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver 5 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.

EXAMPLE 14: PREPARATION OF PELLET FORMULATION (8-HOUR PROFILE)

[0227] A pellet formulation was prepared with the following composition:

TABLE-US-00022 Composition of modified release pellet capsules 10 mg Quantity Components (mg per capsule) Supplier Active Compound.sup.1 10.0 MCC spheres 0.15-0.3 mm 44.5 Asahi Kasei HPMC 6 cps 1.1 Dow HPC LF 10.1 Ashland EC 20.9 Dow Ethanol, 95 percent qs Kemetyl A Water purified qs HPMC capsule NA Qualicaps .sup.12-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid

[0228] This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size D.sub.10 was less than 1 μm, D.sub.50 less than 5 μm and D.sub.90 less than 20 μm.

[0229] A polymer solution of 15.0 g of HPMC 6 cps in 1350.0 g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was added. The spray rate was between 5-12 g suspension/min for the first 5 minutes and there after 10-20 g suspension/min for another 105 minutes. Inlet temperature was 72° C. 1250 g of the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/HPMC suspension was sprayed onto 500 g microcrystalline cellulose (MCC) powder spheres (Celphere CP-305 (300-500 μm)) in fluidized bed equipment. The temperature of outlet air was approximately 30° C., fluidizing air flow approximately 35 Nm.sup.3/h and an atomizer air pressure approximately 2.5 bar. The product could be made in one or several steps depending on batch sizes.

[0230] A polymer solution of 64.8 g ethyl cellulose 10 cP (EC) and 31.3 g hydroxypropyl cellulose (HPC) dissolved in 1504 g of 95% ethanol was prepared. The drug layered pellets (150 g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42° C. with a spray rate of approximately 10-18 g/min. After spraying 1395 g of polymer solution the polymer coated pellets were dried for 10 minutes in a fluidized bed equipment. See process parameters below.

[0231] Process parameters Ranges

[0232] Inlet temperature 72-74° C.

[0233] Outlet temperature 42-60° C.

[0234] Fluidizing air flow 35 Nm.sup.3/h

[0235] Spray Rate 10-18 g/min

[0236] Atomization air pressure 2.5 bar

[0237] Atomization air flow 2.6-2.7 Nm.sup.3/h

[0238] The polymer coated pellets were screened through a 710 μm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver 10 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.

EXAMPLE 15: PREPARATION OF PELLET FORMULATION (15-HOUR PROFILE)

[0239] A pellet formulation was prepared with the following composition:

TABLE-US-00023 Composition of modified release pellet capsules 10 mg Quantity Components (mg per capsule) Supplier Active compound.sup.1 10 MCC spheres 0.15-0.3 mm 44.5 Asahi Kasei HPMC 6 cps 1.1 Dow HPC LF 9.0 Ashland EC 22.0 Dow Ethanol, 95 percent qs Kemetyl A Water purified qs HPMC capsule NA Qualicaps .sup.12-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid

[0240] This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation. 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size D.sub.10 was less than 1 μm, D.sub.50 less than 5 μm and D.sub.90 less than 20 μm.

[0241] A polymer solution of 15.0 g of HPMC 6 cps in 1350.0 g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was added. The spray rate was between 5-12 g suspension/min for the first 5 minutes and there after 10-20 g suspension/min for another 105 minutes. Inlet temperature was 72° C. 1250 g of the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/HPMC suspension was sprayed onto 500 g microcrystalline cellulose (MCC) powder spheres (Celphere CP-305 (300-500 μm)) in fluidized bed equipment. The temperature of outlet air was approximately 30° C., fluidizing air flow approximately 35 Nm.sup.3/h and an atomizer air pressure approximately 2.5 bar. The product could be made in one or several steps depending on batch sizes.

[0242] A polymer solution of 68.2 g ethyl cellulose 10 cP (EC) and 27.8 g hydroxypropyl cellulose (HPC) dissolved in 1504 g of 95% ethanol was prepared. The drug layered pellets (150 g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42° C. with a spray rate of approximately 10-18 g/min. After spraying 1395 g of polymer solution the polymer coated pellets were dried for 10 minutes in a fluidized bed equipment. See process parameters below.

TABLE-US-00024 Process parameters: Inlet temperature 72-74° C. Outlet temperature 42-60° C. Fluidizing air flow 35 Nm3/h Spray Rate 10-20 g/min Atomization air pressure 2.5 bar Atomization air flow 2.6-2.7 Nm.sup.3/h

[0243] The polymer coated pellets were screened through a 425-710 μm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver 10 mg of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.

EXAMPLE 16: PREPARATION OF PELLET FORMULATION USING MONO-ETHANOLAMINE SALT

[0244] A pellet formulation was prepared with the following composition:

TABLE-US-00025 Composition of MEA modified release pellet capsules 5 mg Quantity Components (mg per capsule) Supplier Active Compound.sup.1 5 MCC spheres 0.3-0.5 mm 25.77 Asahi Kasei HPMC 6 cps 0.46 Dow PVP K30 4.04 Sigma-Aldrich EC 12.79 Dow Ethanol, 95 percent Qs Kemetyl A Magnesium stearate 0.06 Peter Greven Water purified Qs Milli Q HPMC capsule NA Qualicaps .sup.12-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid monoethanolamine

[0245] Cores from Celphere CP305 (Asahi Kasei, 0.3-0.5 mm) were used as the starting material. The API suspension used to coat the cores consisted of MilliQ water, micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid mono-ethanolamine salt (MEA salt, prepared as described below) and HPMC 6 cps.

[0246] The MEA salt layered core pellets were manufactured to an MEA salt concentration of between 165 and 176 mg/g. The dry content of the suspension was 22%, 20% MEA salt and 2% HPMC 6 cps.

[0247] The suspension for the MEA salt layer coating was prepared by first dissolving HPMC in purified water using a magnetic stirrer overnight. Thereafter the MEA salt was added and the suspension was stirred prior to use. The suspension was kept stirring during the coating process.

[0248] The MEA salt layered core pellets were manufactured in bottom sprayed fluid bed equipment (MiniGlatt). Typical scale of manufacturing was 25 g cores and 118 g of coating suspension.

[0249] The ethanol based solution for the MR-films was prepared by adding EC/PVP to 95% Ethanol during stirring. The materials were left over night to dissolve. The coating was performed in a fluid bed equipment (MiniGlatt). Process parameters are seen below.

[0250] Process parameters for MEA salt layered seed/core pellets

TABLE-US-00026 Tin 70-75° C. Tout 40-60° C. FF 13 Nm3/h Coat speed 2-4.0 g/min Atom. press 1.0 bar Atom. flow 1.1-1.3 Nm.sup.3/h

Process Parameters MR Coating of Pellets

[0251]

TABLE-US-00027 Tin 70-75° C. Tout 45-60° C. FF 11 Nm.sup.3/h Coat speed 4-6.0 g/min Atom. press 1.0 bar Atom. flow 0.4-0.5 Nm.sup.3/h

Preparation of the Mono-Ethanolamine Salt

[0252] 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid mono-ethanolamine salt was isolated from 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid n-butanolate according to the following procedure. To 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid n-butanolate ((34.80 g, 92.53 mmol) was added methyl ethyl ketone (167 mL) and dimethyl sulfoxide (42 mL). The resulting mixture was heated to 47-50° C. in order to form a solution. The solution was then clarified by filtration, and the resulting filtrate re-heated to 47-50° C. 2-Aminoethanol (6.1 mL, 100 mmol) was then added over at least 10 minutes, initiating the precipitation of the product from solution. The temperature was reduced to 0-10° C. over approximately 2 hours, and the product slurry stirred for 1 hour at this temperature range. The product was isolated by filtration, the filter cake washed twice with methyl ethyl ketone (2×70 mL) and dried in vacuo to constant weight at 60-65° C., yielding 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid mono-ethanolamine salt as a crystalline white solid (35.91 g, 86.37 mmol, 93.3%).

[0253] 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid mono-ethanolamine salt can also be isolated from 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid according to the following procedure. To 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid (64.81 g, 181 mmol) was added methyl ethyl ketone (311 mL) and dimethyl sulfoxide (78 mL). The resulting mixture was heated to 47-50° C. in order to form a solution. The solution was then clarified by filtration, and the resulting filtrate re-heated to 47-50° C. 2-Aminoethanol (11.5 mL, 191 mmol) was then added over at least 10 minutes, initiating the precipitation of the product from solution. The temperature was reduced to 0-10° C. over approximately 2 hours, and the product slurry stirred for at least 30 minutes at this temperature range. The product was isolated by filtration, the filter cake washed twice with methyl ethyl ketone (2×65 mL) and dried in vacuo to constant weight at 60° C., yielding 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid mono-ethanolamine salt as a crystalline white solid (71.73 g, 172.3 mmol, 95.1%).

[0254] .sup.1H NMR (400 MHz, DMSO-d6, 90° C.) 1.40 (d, J=9.6 Hz, 6H), 2.79 (t, J=5.5 Hz, 2H), 3.55 (t, J=5.5 Hz, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.65 (td, J=1.1, 6.9, 7.6 Hz, 1H), 7.77-7.84 (m, 2H), 8.17 (d, J=7.4 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.29 (s, 1H), 8.52 (d, J=5.4 Hz, 1H). Ratio of free acid: 2-aminoethanol by .sup.1H NMR 1:1.01.

EXAMPLE 17: PREPARATION OF PELLET FORMULATION USING WATER-BASED COATING

[0255] A pellet formulation was prepared with the following composition:

TABLE-US-00028 Composition of modified release pellet capsules 5 mg Quantity Components (mg per capsule) Supplier Active Compound.sup.1 5.0 MCC spheres 0.15-0.3 mm 22.2 Asahi Kasei HPMC 6 cps 0.54 Dow Eudragit NM30D 2.75 Evonik Kollicoat IR 0.775 BASF Talc 1.175 Sigma-Aldrich Magnesium stearate 0.06 Peter Greven Water purified Qs HPMC capsule NA Qualicaps .sup.12-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid

[0256] 2.47 g Kollicoat IR (polyvinyl alcohol/polyethylene glycol grafted copolymer, manufactured by BASF) and 3.75 g Talc powder was suspended in 64.52 g water. After stirring overnight, 29.25 g Eudragit NM30D dispersion was added. The dry content in the suspension was 15% w/w. The dispersion was held at RT ° C. Before spraying, the dispersion was sieved through a 200 μm mesh. The speed of the pump was between 1 and 2 g dispersion/min. Inlet temperature was 41° C. 35 g dispersion was sprayed onto 10 g of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid drug layered core seeds (produced as described in Example 14) in a fluidised bed drier (MiniGlatt). The temperature of outlet air was about 25° C., fluidising air flow about 14 Nm3/h and an atomizer air pressure of about 1.6 bar giving 8.5% (w/w) active drug/MR granules.

[0257] Process Parameters

TABLE-US-00029 Tin 38-43° C. Tout 25-35° C. FF 14 Nm.sup.3/h Coat speed 1-2 g/min Atom. press 1.6 bar Atom. flow 1.6-1.8 Nm.sup.3/h

EXAMPLE 18: DISSOLUTION TESTING OF PELLET FORMULATIONS

Methods

[0258] Dissolution of extended release pellets added as free pellets (not pellets in capsules) with a dose of 10 mg were performed in arrange of different pH media according to the general procedure of the United States Pharmacopeia Apparatus II (paddle). Aliquots of the dissolution test media were pumped in a closed loop for each individual vessel and filtered at specific time intervals and analyzed with a spectrophotometer equipped with 10 mm flow cell with UV detection at 303 nm with baseline correction by a three-point drop-line at 380-420 nm. The release of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was determined by comparing the UV responses of the sample chromatograms to the UV responses of a standard calibration curve. 500 mL dissolution media at 37° C. and a paddle speed of 100 rpm is used.

[0259] Dissolution media used with ionic strength (I) were applicable:

pH 6.8 I=0.1: 50.0 mM KH2PO4+23.6 mM NaOH

pH 6.8 I=0.025: 14.2 mM KH2PO4+5.4 mM NaOH

pH 6.5: 10.4 mM Na2PO4, 3.3 mM NaOH, 106 mM NaCl,

pH 6.0: 80.6 mM KH2PO4+9.7 mM NaOH

[0260] pH 5.5: 7.02 mM citric acid+19.91 mM Sodium citrate dihydrate
pH 4: 42.1 mM citric acid+27.3 mM Sodium citrate dihydrate

pH 1: 0.1 M HCl

Dissolution Results

[0261] FIG. 7 shows the dissolution profile for the 3-hour pellet formulation described in Example 12. Release rate is influenced by pH of the media. Note: the ionic strength of the pH 6.8 media was 0.1.

[0262] FIG. 8 shows the dissolution profile for the 5-hour pellet formulation described in Example 13. Release rate is influenced by pH of the media. Note: the ionic strength of the pH 6.8 media was 0.1.

[0263] FIG. 9 shows the dissolution profile for the 8-hour pellet formulation described in Example 14. Release rate is influenced by pH of the media. Note: the ionic strength of the pH 6.8 media was 0.1.

[0264] FIG. 10 shows the dissolution profile for the 15-hour pellet formulation described in Example 15. Release rate is influenced by pH of the media. Note: the ionic strength of the pH 6.8 media was 0.1.

[0265] FIG. 11 shows the dissolution profile for the mono-ethanolamine salt pellet formulation described in Example 16. Release is not significant influenced by the pH of the media. Note: the ionic strength of the pH 6.8 media was 0.1.

[0266] FIG. 12 shows the dissolution profile for a mono-ethanolamine salt pellet formulation prepared in accordance with Example 16 but with the one exception that the PVP and EC weight amounts were changed from 24% PVP K30 (76% EC) to 23% PVP K30 (77% EC). Release is not significantly influenced by the pH of the media or the ionic strengths tested.

EXAMPLE 19: PK STUDY IN DOG MODELS—PELLET FORMULATIONS AND MR4

[0267] A pharmacokinetic study in Labrador dogs was performed under fasted conditions to compare the relative bioavailability of four different Pellet formulations with the MR4 tablet and an oral solution at the dose of 2.5 and 5 mg, which is equivalent to a human dose of 5 and 10 mg, respectively. The MR4 tablet tested in the study is described in Example 5. The pellet formulations tested in the study are described in Examples 12-17.

[0268] A lower relative bioavailability for all formulations was observed compared to the reference solution (see Table 11 and FIG. 13). The relative bioavailability of the 5 hour and 8 hour pellets were comparable to that of the MR4 tablet while the mono-ethanolamine salt and the water based coated pellet had significantly lower relative bioavailability compared to the other 5 hour and 8 hour pellets formulations.

TABLE-US-00030 TABLE 11 Mean plasma PK parameters of different formulations of the Agent in Labrador dogs with acidic stomach pH under fasted conditions. Frel vs Frel vs Dosage Dose Tmax C.sub.max AUC.sub.0-24 Formulation A Solution Formulation form (mg) (hr) (nM) (nM*h) (%) (%) Solution solution 5 0.24 95.9 219.6 — 100 MR4 Tablet 5 1.9 17.4 110.4 100 55 (multiple) 5 hour pellet Capsule 2.5 3.8 13.5 52.7 109 54 8 hour pellet Capsule 5 4.8 12.2 72.4 76 36 MEA salt pellet Capsule 5 5.0 1.7 10.5 9 5 Pellet with water- Capsule 5 5.5 3.3 27 25 14 based coat

EXAMPLE 20: PHASE I CLINICAL TRIAL—PELLET FORMULATIONS AND MR4

[0269] A Phase 1, randomized, open-label, 5-way crossover pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy adult male subjects designed to assess the relative bioavailability of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid 5 mg and 10 mg capsules and 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid 2.5 mg MR4 tablets administered as a 10 mg dose (2.5 mg×4). This study assessed the effect of a high-fat meal on the PK and PD of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid. Plasma PK samples were collected at the following time points in relation to dosing of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid: within 30 minutes prior to dosing and at 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose. A summary of the mean plasma pharmacokinetic parameters following administration of the Pellet compositions of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid are provided in Table 12.

TABLE-US-00031 TABLE 12 Summary Plasma Pharmacokinetics of 2-((3-(4-cyanonaphthalen-1-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid following a Single Dose in various Pellet Formulations under Fed or Fasted Conditions (Geometric Mean (95% CI)) Geomean PK Food Effect Parameters Dose C.sub.max/AUC Ratio (Fed/Fasted) C.sub.max AUC.sub.0-24 Formulation Food (mg) Ratio C.sub.max AUC.sub.∞ (ng/mL) (ng .Math. hr/mL) 5 h release Fasted 5 0.19 98.9% 106% 14.9 80.1 Fed.sup.a 5 0.17 15.0 86.7 8 h release Fasted 10 0.15 99.9% 103% 23.4 155 Fed.sup.a 10 0.14 23.3 163 15 h release Fasted 10 0.12  116% 113% 14.0 118 Fed.sup.a 10 0.12 16.3 142 MR4, Cohort 1 Fasted 10 0.16 — — 12.9 82.0 MR4, Cohort 3 Fasted 10 0.15 — — 13.2 89.6 MR4 Fasted 10 0.18  182% 134% 14.9 84.6 (10 mg tablet) Fed.sup.a 10 0.21 27.2 128 IR tablet Fasted 5 0.72 62.7% 76.8%  72.9 102 Fed.sup.b 5 0.61 45.7 75.2 .sup.ahigh-fat meal; .sup.blow-fat meal

[0270] The mean plasma concentration-time profile for each formulation under fasted conditions is depicted in FIG. 14 and the profile for each formulation under fed conditions is depicted in FIG. 15. FIG. 16 shows the mean plasma concentration-time profile for the 8-hour pellet formulation described in Example 14 at a 10 mg dose in both the fasted and fed conditions.

[0271] Exposure of the 5 hr pellet formulation at a 5 mg dose was similar to that seen with a 10 mg dose of MR4. The 8 hr and 15 hr pellet formulations showed higher bioavailability than the same dose of the MR4 formulation, indicating an unexpectedly high extent of colonic absorption of the compound given its physicochemical properties. All pellet formulation showed no significant food effect and variability was similar to that for the MR4 formulation (measured as % CV). Rank order of C.sub.max/AUC ratios is as follows: IR cap>>5 h>8 h MR4>15 h release form. The 5 hr pellet formulation had a higher C.sub.max/AUC ratio to MR4 (0.19 versus 0.17 for MR4 in this study). Both the 8 hr and 15 hr pellet formulation had a lower C.sub.max/AUC ratio than MR4 in this study (0.15 and 0.12 respectively).

[0272] The sUA lowering achieved by administration of the formulations are shown in the following tables:

TABLE-US-00032 Mean % change Condition AUC.sub.0-24 in sUA from Formulation Dose (Fasted/Fed) (ng .Math. hr/mL) predose.sup.1 (%) MR4 (Cohort 10 mg Fasted 82.0 29.8% 1 and 3) 5 hr Pellet 5 mg Fasted 80.1 30.6% 8 hr Pellet 10 mg Fasted 155 42.5% 15 hr Pellet  10 mg Fasted 118 35.2% .sup.1% sUA change mean maximum observed percentage change from pre-dose in serum urate concentrations (E.sub.max)

EXAMPLE 21: PREPARATION OF VARIOUS PELLET FORMULATIONS BY DRUG LAYERING PROCESS

[0273] A number of pellet formulations were prepared in accordance with the process described In Example 11. Table 13 provides details of composition and process parameters along with the dissolution time to 80% release in pH 6.8 media (ionic strength 0.1, 900 ml media, 100 rpm), tested in accordance with the dissolution method described in Example 18.

TABLE-US-00033 TABLE 13 Composition and process parameters for preparation of various pellet formulations. Coating Amount Batch Coating Dose Time 80% composition of film size speed FF AP AF T.sub.in T.sub.out (mg/g released Coating % w/w ratio (wt %) (g) (g/min) (Nm.sup.3/h) (bar) (Nm.sup.3/h) (° C.) (° C.) pellets) (min) EC 10:HPC LF 72:28 10.4 20 5.6 15 1.2 0.7 75 46 171 252 EC 10:HPC LF 68:32 22.7 100 19 35 2.5 2.6 75 43 158 552 EC 10:HPC LF 71:29 14 200 40.6 35 4.3 4.3 100 48 101 438 EC 10:HPC LF 71:29 12.5 600 40 35 4.3 4.2 100 44 102 540 EC 10:HPC LF 68:32 20.9 100 20.7 35 2.5 2.6 75 42 150 507 EC 10:HPC LF 68:32 18.9 200 37 35 4.7 4.1 100 45 162 390 EC 10:HPC SSL 70:30 24.5 6 3.8 12.5 1 0.4 73 41 118 150 EC 10:HPCL 75:25 17.4 6 4 13 1 0.4 75 44 120 1050 EC 100:PVP K30 70:30 20 10 4.5 12 1 0.4 69 43 100 30 EC10:PVP K30 76:24 33.2 10 5.5 11 1 0.4 80 46 116 354 EC10:PVP K30 76:24 37.4 10 5.6 11 1 0.4 80 45 110 414 HPC LF supplied by Ashland. HPC L and SSL supplied by Nisso. Abbreviations: T.sub.in (Inlet temperature), T.sub.out (Outlet temperature), FF (Fluidizing air flow), AP (Pressure to atomise API or polymer solution) and AF (Atomizer air flow).

EXAMPLE 22: PREPARATION OF PELLET FORMULATION (8-HOUR PROFILE) AT DOSES 4.5, 6 AND 12 MG

[0274] Pellet formulations were prepared with the following compositions:

TABLE-US-00034 Compositions of modified release pellet capsules 4.5, 6 and 12 mg Quantity Quantity Quantity (mg per (mg per (mg per Components capsule) capsule) capsule) Supplier Active Compound.sup.1 4.5 6 12 MCC spheres 15.4 20.8 41.9 Asahi Kasei 0.3-0.5 mm HPMC 6 cps 0.44 0.6 1.2 Dow HPC LF 1.82 2.45 4.94 Ashland EC 3.9 5.25 10.6 Dow Ethanol, 95 percent Qs Qs Qs Kemetyl A Water purified Qs Qs Qs Magnesium Stearate 0.05 0.07 0.15 HPMC capsule NA NA NA Qualicaps .sup.12-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid

[0275] A polymer solution of 19.0 g of HPMC 6 cps in 1710.3 g water was prepared. After a clear solution was obtained, 171.0 g micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was added. The suspension was protected from light and stirred overnight. The suspension was held at RT ° C. Before spraying, the suspension was sieved through 200 μm mesh. The spray rate was between 8-11 g suspension/min for the first 5 minutes and there after 15-20 g suspension/min for another 111 minutes. Inlet temperature was 73° C. 1587.5 g the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/HPMC suspension was sprayed onto 500 g microcrystalline cellulose (MCC) powder spheres (Celphere CP-305 (300-500 μm)) in a fluidised bed equipment (LabCC3). The temperature of outlet air was approximately 30° C., fluidising air flow approximately 35 Nm.sup.3/h and an atomizer air pressure of approximately 2.5 bar. The product could be made in one or several steps depending on batch sizes.

[0276] 100 g of these granules were coated with a solution of 20.0 g ethyl cellulose 10 cP (EC) and 9.4 g hydroxypropyl cellulose (HPC) dissolved in 460 g of 95% ethanol in a fluidised bed equipment (LabCC3) at a temperature of outlet air of 42° C. with a spray rate of in average 20 g solution/min Process parameters were as follows:

[0277] Process Parameters

TABLE-US-00035 Tin 70-75° C. Tout 40-60° C. FF 35 Nm.sup.3/h Coat speed 18-22 g/min Atom. press 2.5 bar Atom. flow 2.6-2.7 Nm.sup.3/h

[0278] Dissolution testing of the pellet formulation was carried out in accordance with the methods disclosed in Example 8 using pH 6.8 buffer (ionic strength 0.1, 50.0 mM KH2PO4+23.6 mM NaOH) at 37° C. using a paddles speed of 100 rpm. FIG. 17 shows the dissolution profile for the pellets produced as described above in this Example 22.

EXAMPLE 23: PHASE I CLINICAL TRIAL—PELLET FORMULATIONS (8-HOUR PROFILE AT 4.5, 6 AND 12 MG DOSES)

[0279] A Phase 1, randomized, open-label, 3-way crossover pharmacokinetic (PK) study in healthy adult male subjects designed to assess the relative bioavailability of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid 4.5, 6 and 12 mg capsules was conducted using the 8-hour profile formulations described in Example 22. A study to assess the effect of a high-fat meal on the PK of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was also conducted. Plasma PK samples were collected at the following time points in relation to dosing of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid: within 30 minutes prior to dosing and at 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.
A summary of the mean plasma pharmacokinetic parameters following administration of the pellet compositions of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid are provided in the following table:

TABLE-US-00036 Geomean PK Parameters Dose C.sub.max/AUC C.sub.max AUC.sub.0-24 (mg) Food Ratio (ng/mL) (ng .Math. hr/mL) 4.5 Fasted 0.173 11.8 68.0 6 Fasted 0.166 13.4 80.8 12 Fasted 0.170 28.6 168
A summary of the mean plasma pharmacokinetic parameters following administration of the pellet compositions of 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4- yl)thio)-2-methylpropanoic acid in the food effect studies are provided in the following table:

TABLE-US-00037 Geomean PK Parameters Geomean Fed/ Dose C.sub.max/AUC C.sub.max AUC.sub.0-24 Fasted ratio (%) (mg) Food Ratio (ng/mL) (ng .Math. hr/mL) AUC.sub.last C.sub.max 6 Fasted 0.178 14.8 83.5 112 89.7 Fed 0.136 13.3 98.2
No significant food effect for the pellet formulations with regards to C.sub.max or AUC was observed. Furthermore, the C.sub.max/AUC ratio decreased with food.

EXAMPLE 24: PREPARATION OF A PELLET FORMULATION (8-HOUR PROFILE) AT DOSES 4.5, 6 AND 12 MG

[0280] Pellet formulations were prepared with the following compositions:

TABLE-US-00038 Compositions of modified release pellet capsules 4.5, 6 and 12 mg Quantity Quantity Quantity (mg per (mg per (mg per Components capsule) capsule) capsule) Supplier Active Compound.sup.1 4.5 6 12 MCC spheres 29.0 38.7 77.4 JRS 0.5-0.7 mm HPMC 6 cps 0.5 0.7 1.3 Dow HPC LF 2.7 3.6 7.2 Ashland EC 6.6 8.8 17.5 Dow Ethanol, 95 percent Qs Qs Qs Kemetyl A Water purified Qs Qs Qs Magnesium Stearate 0.1 0.1 0.2 HPMC capsule NA NA NA Qualicaps .sup.12-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid

[0281] A polymer solution of 155 g of HPMC 6 cps in 13950 g water was prepared in excess. After a clear solution was obtained, 1395 g micronized 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid was added. The suspension was protected from light and stirred. The suspension was held at RT ° C. Before spraying, the suspension was sieved through 200 μm mesh. The spray rate was between 90.0-95.0 g suspension/min for the first 18 minutes and there after 96.0-97.0 g suspension/min for another 144 minutes. Inlet temperature was 74° C. 15530.0 g the 2-((3-(4-cyanonaphthalen-1-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/HPMC suspension was sprayed onto 9000.0 g microcrystalline cellulose (MCC) powder spheres (Vivapur 500-700 μm (JRS Pharma)) in a fluidised bed equipment (FBC01). The temperature of outlet air was approximately 26.4° C. (24.4-39.2° C.), fluidising air flow approximately 183 Nm.sup.3/h and an atomizer air pressure of approximately 2.6 bar. The product could be made in one or several steps depending on batch sizes.

[0282] 9000 g of these granules were coated with a solution of 1640 g ethyl cellulose 10 cP (EC) and 670 g hydroxypropyl cellulose (HPC) dissolved in 36190 g of 95% ethanol in a fluidised bed equipment (FBC01) at a temperature of outlet air of 23-45° C. with a spray rate of in average 241.0 g solution/min Process parameters were as follows:

[0283] Process Parameters

TABLE-US-00039 Tin 100° C. Tout 23-45° C. FF 183 Nm.sup.3/h Coat speed 235.0-245.0 g/min (target 241.0 g/min) Atom. press 4.5-4.9 bar Atom. flow (measured) 21.5-23.0 Nm.sup.3/h
Resulting modified release pellets were lubricated with magnesium stearate and filled into HPMC capsules.
Dissolution testing of the pellet formulation was carried out in accordance with the methods disclosed in Example 8 using pH 6.8 buffer (ionic strength 0.1, 50.0 mM KH2PO4+23.6 mM NaOH) at 37° C. using a paddles speed of 100 rpm. FIG. 18 shows the dissolution profile for the pellets produced as described above in this Example 24.