Systemic formulation of a pyridinone derivate for coeliac disease
The present invention relates to a systemic formulation, in particular an oral formulation, for the prophylaxis and/or treatment of coeliac disease, i.e. for use in the prophylaxis and/or treatment of coeliac disease.
1 . A method for the prophylaxis or treatment of coeliac disease in a subject, comprising:
administering to the subject a systemic formulation comprising
an effective amount of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate of the formula (I):
or an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof, and at least one acidifier,
wherein the mass ratio of the at least one acidifier relative to (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof ranges from 15 to 0.1 m/m.
2 . The method according to claim 1 , wherein the systemic formulation is an oral formulation.
3 . The method according to claim 1 , wherein the systemic formulation further comprises at least one binder, at least one polymeric precipitation inhibitor, or a combination of at least one binder and at least one polymeric precipitation inhibitor.
4 . The method according to claim 1 , wherein the acidifier is selected from the group consisting of ascorbic acid, organic di-carboxylic acids.
5 . The method according to claim 3 , wherein the at least one binder is selected from the group consisting of sugar, sucrose, polysaccharides, xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice, or potatoes, preagglutinated (modified) starch derived from wheat, corn, rice, or potatoes, sodium starch glycolate, natural gums, acacia gum, gelatin, tragacanth, derivatives of sea weed, alginic acid, sodium alginate, ammonium calcium alginate, cellulose, cellulose derivatives, and polyvinylpyrrolidone.
6 . The method according to claim 3 , wherein the acidifier is adipic acid and the at least one polymeric precipitation inhibitor is selected from the group consisting of polyvinyl alcohol, polyvinyl-caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, L-hydroxypropyl cellulose, hydroxypropyl cellulose and a combination of L-hydroxypropyl cellulose and hydroxypropyl cellulose.
7 . The method according to claim 1 , wherein the (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxo-hept-2-enoate is in the form of particles having a particle size distribution which is defined by d (0.95)≤25 μm.
8 . The method according to claim 1 , wherein the systemic formulation comprises 0.1 wt % to 80 wt % (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, 1 wt % to 75 wt % acidifier, and wherein the systemic formulation further comprises 0.1 wt % to 40 wt % polymeric precipitation inhibitor, 0 wt % to 30 wt % binder, 0.1 wt % to 35 wt % disintegrant, and 0.1 wt % to 10 wt % lubricant/glidant.
9 . The method according to claim 1 , wherein the systemic formulation comprises 4.5 wt % to 55 wt % adipic acid.
10 . The method according to claim 8 , wherein the polymeric precipitation inhibitor is selected from the group consisting of polyvinyl alcohol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, L-hydroxypropyl cellulose, hydroxypropyl cellulose and a combination of L-hydroxypropyl cellulose and hydroxypropyl cellulose.
11 . The method according to claim 9 , wherein the systemic formulation further comprises 3.5 wt % to 30.5 wt % L-hydroxypropyl cellulose, 3.5 wt % to 30.5 wt % hydroxypropyl cellulose, or 3.5 wt % to 30.5 wt % of a combination of L-hydroxypropyl cellulose and hydroxypropyl cellulose.
12 . The method according to claim 3 , wherein the systemic formulation comprises 0.1 wt % to 80 wt % (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, 4.5 wt % to 55 wt % adipic acid, 3.5 wt % to 30 wt % L-hydroxypropyl cellulose, 0 wt % to 30 wt % mannitol, 2 wt % to 35 wt % sodium croscarmellose, and 1 wt % to 9 wt % talc or silicon dioxide.
13 . The method according to claim 1 , wherein the systemic formulation is in the form of a tablet, coated tablet, capsule, powder, or granules.
14 . The method according to claim 13 , wherein the systemic formulation is a capsule comprising 2.5 wt % to 30.5 wt % (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, 4.5 wt % to 55 wt % adipic acid, 3.5 wt % to 30 wt % L-hydroxypropyl cellulose, 2 wt % to 35 wt % sodium croscarmellose, and 1 wt % to 9 wt % talc.
15 . The method according to claim 13 , wherein the systemic formulation is a tablet comprising 0.1 wt % to 30 wt % (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, 35 to 50 wt % microcrystalline cellulose, 5 wt % to 50 wt % adipic acid, 3.5 wt % to 30 wt % L-hydroxypropyl cellulose, 0.01 wt % to 30 wt % mannitol, 3.7 wt % to 15 wt % sodium croscarmellose, and 0.5 wt % to 4.00 wt % silicon dioxide.
16 . The method according to claim 2 , wherein the oral formulation is an oral solid formulation.
17 . The method according to claim 1 , wherein the mass ratio of the at least one acidifier relative to (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof ranges from 11.5 to 1.8 m/m.
18 . The method according to claim 1 , wherein the mass ratio of the at least one acidifier relative to (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate or an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof ranges from 2 to 1 m/m.
19 . The method according to claim 1 , wherein the systemic formulation is an oral dosage form containing 10 mg of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof.
20 . The method according to claim 1 , wherein the systemic formulation is an oral dosage form containing 20 mg of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof.
21 . The method according to claim 1 , wherein the systemic formulation is an oral dosage form containing 50 mg of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof.
22 . The method according to claim 1 , wherein the systemic formulation is an oral dosage form containing 100 mg of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof.
23 . The method according to claim 1 , wherein the systemic formulation is administered to the subject once daily.
24 . The method according to claim 1 , wherein the acidifier is ascorbic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid, glutamic acid, citric acid, or sodium hydrogen citrate.