SOLID DOSAGE FORMULATIONS OF TELCAGEPANT POTASSIUM
A solid dosage pharmaceutical formulation comprising as an active ingredient the potassium salt of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (telcagepant), arginine, and a pharmaceutically acceptable surfactant. The invention is also directed to an amorphous form of the potassium salt of telcagepant.
1 . A solid dosage pharmaceutical formulation comprising
(1) N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium, or the hydrate or ethanolate thereof, or an amorphous form thereof,
(2) arginine; and
(3) a pharmaceutically acceptable surfactant.
2 . The solid dosage pharmaceutical formulation of claim 1 , wherein arginine is present in the amount of at least about 10% by weight of the formulation.
3 . The solid dosage pharmaceutical formulation of claim 1 or 2 , comprising about 100 to about 500 mg of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium.
4 . The solid dosage pharmaceutical formulation of any of claims 1 to 3 , comprising about 35 to about 55% by weight of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium.
5 . The solid dosage pharmaceutical formulation of any of claims 1 to 4 ,
wherein the pharmaceutically acceptable surfactant is a nonionic surfactant.
6 . The solid dosage pharmaceutical formulation of claim 5 wherein the nonioinic surfactant is a polyoxypropylene block copolymer.
7 . The solid dosage pharmaceutical formulation of any of claims 1 to 6
wherein the surfactant is present in the amount of up to about 10% by weight of the formulation.
8 . The solid dosage pharmaceutical formulation of any of claims 1 to 7 , which comprises N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium ethanolate Form I.
9 . The solid dosage pharmaceutical formulation of any of claims 1 to 7 , which comprises N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium ethanolate Form II.
10 . The solid dosage pharmaceutical formulation of any of claims 1 to 7 , which comprises N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium hydrate.
11 . The solid dosage pharmaceutical formulation of any of claims 1 to 7 , which comprises amorphous N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium.
12 . The solid dosage pharmaceutical formulation of claim 8 , wherein the N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium ethanolate Form I displays solid-state carbon-13 NMR spectra peaks of one or more of 109.1 ppm, 55.8 ppm and 54.6 ppm.
13 . The solid dosage pharmaceutical formulation of claim 8 , wherein the Raman spectra of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium ethanolate Form I displays peaks (cm −1 ) of one or more of 646.3, 707.4, 761.5, 832.9, 1063.3, 1365.5, 1402.0, 1445.7 and 1455.3
14 . The solid dosage pharmaceutical formulation of claim 10 , wherein the N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-2-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium hydrate displays solid-state carbon-13 NMR spectra peaks of one or more of 126.1 ppm, 54.4 ppm and 36.6 ppm.
15 . The solid dosage pharmaceutical formulation of claim 10 , wherein the Raman spectra of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium hydrate displays peaks (cm −1 ) of one or more of 646.8, 707.0, 753.7, 832.7, 1064.7, 1364.3, 1403.0 and 1441.0
16 . The solid dosage pharmaceutical formulation of claim 11 , wherein the N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium amorphous form displays solid-state carbon-13 NMR spectra peaks of one or more of 126.0 ppm, 53.7 ppm and 29.1 ppm.
17 . The solid dosage pharmaceutical formulation of claim 11 , wherein the Raman spectra of the N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium amorphous form displays peaks (cm −1 ) of one or more of 646.8, 706.8, 752.3, 832.4, 1063.6, 1365.2 and 1437.6.
18 . The solid dosage pharmaceutical formulation of any of claims 1 to 17 , which comprises about 280 mg or about 300 mg of the active ingredient N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide.
19 . The solid dosage pharmaceutical formulation of any of claims 1 to 18 , which is a tablet.
20 . The solid dosage pharmaceutical formulation of any of claims 1 to 19 , which provides Cmax in the blood of at least 2.75 μM.
21 . The solid dosage pharmaceutical formulation of any of claims 1 to 19 ,
which achieves a Tmax at a time point of no more than 1.0 hour after administration.
22 . The solid dosage pharmaceutical formulation of any of claims 1 to 19 ,
which achieves an AUC 0-Tmax in the blood of no more than 2.5 μM.
23 . The solid dosage pharmaceutical formulation of any of claims 1 to 19 ,
which achieves an AUC 0-2 hr in the blood of no more than 5.5 μM.
24 . The solid dosage pharmaceutical formulation of any of claims 1 to 19 ,
which achieves an AUC 0-4 hr in the blood of no more than 10.0 μM.
25 . The solid dosage pharmaceutical formulation of any of claims 1 to 19 ,
which achieves an AUC 0-∞ in the blood of no more than 15.5 μM.
26 . An amorphous form of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium, said amorphous form produced by the step of spray drying of the ethanolate or hydrate of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium in an organic solution.
27 . The amorphous form of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium of claim 26 , said amorphous form having a mean particle size of less than 15 μm.
28 . An amorphous form of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium, said amorphous form produced by the step of dissolving N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium ethanolate or hydrate in methanol, and precipitating the amorphous form.
29 . The amorphous form of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide potassium of claim 28 , said amorphous form having a mean particle size of less than 150 μm.