Systemic formulation of a pyridinone derivate for TG2-related diseases
The present invention relates to a formulation in particular an oral formulation for the prophylaxis and treatment of TG2-related disorders like fibrosis in particular diabetic nephropathy and/or diabetic associated non-alcoholic steatohepatitis (NASH) and/or non-alcoholic steatohepatitis, and its use in the prophylaxis and/or treatment of fibrosis in particular nephropathy, NASH, idiopathic pulmonary fibrosis, and cystic fibrosis. Further, the present application relates also to the use 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 as hepatoprotectant, i.e. as hepatoprotective agent. In addition the present invention relates to a pharmaceutical composition comprising (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 for use as hepatoprotective agent and for use in the protection of the liver against liver toxicity, the improvement of liver function, and/or in the prophylaxis or treatment of a liver disease or liver disorder.
1 . A systemic formulation containing Compound 1 of the formula (I):
or an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof, and at least one polymeric precipitation inhibitor, wherein the mass ratio of the at least one polymeric precipitation inhibitor relative to Compound 1 ranges from 0.05 to 10 m/m.
2 . The systemic formulation according to claim 1 , wherein the systemic formulation is an oral formulation.
3 . The systemic formulation according to claim 1 , wherein the systemic formulation further comprises at least one acidifier, at least one binder, or a combination of at least one acidifier and at least one binder.
4 . The systemic formulation according to claim 1 , wherein the at least one polymeric precipitation inhibitor is selected from the group consisting of L-hydroxypropyl cellulose, hydroxypropyl cellulose, a combination of L-hydroxypropyl cellulose and hydroxypropyl cellulose, polyethylene glycol, poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and sodium carboxymethyl cellulose.
5 . The systemic formulation according to claim 3 , wherein the at least one acidifier is selected from the group consisting of ascorbic acid, organic di-carboxylic acid, and organic tri-carboxylic acid.
6 . The systemic formulation 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.
7 . The systemic formulation according to claim 1 , wherein Compound 1 is in the form of particles having a particle size distribution which is defined by d(0.95)≤25 μm.
8 . The systemic formulation according to claim 1 , wherein the systemic formulation is a tablet, coated tablet, capsule, powder, or granule.
9 . The systemic formulation according to claim 3 , wherein the systemic formulation comprises 1 to 15 m/m acidifier, 0.1 to 7 m/m polymeric precipitation inhibitor, wherein m/m (mass ratio) of said acidifier and polymeric precipitation inhibitor is calculated relative to mass of Compound 1.
10 . The systemic formulation according to claim 1 , wherein the formulation comprises 0.1 wt % to 45 wt % Compound 1, 3 wt % to 75 wt % acidifier, 2 wt % to 35 wt % polymeric precipitation inhibitor, 0 wt % to 12 wt % binder, 2 wt % to 35 wt % disintegrant, and 1 wt % to 9 wt % lubricant/glidant.
11 . The systemic formulation according to claim 1 , wherein the systemic formulation comprises 0.1 wt % to 45 wt % Compound 1, 3 wt % to 75 wt % adipic acid, 2 wt % to 35 wt % L-hydroxypropyl cellulose and/or hydroxypropyl cellulose, 0 wt % to 12 wt % povidone K25, 2 wt % to 35 wt % sodium croscarmellose, and 1 wt % to 9 wt % talc or silicon dioxide.
12 . A method for the treatment of a liver disorder or disease comprising administering to a subject an effective amount of Compound 1 of formula (I):
an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound 1, wherein the liver disorder or disease is fibrotic liver diseases, cholestatic liver diseases, autoimmune hepatitis, or alcoholic steatohepatitis.
13 . The method according to claim 12 , wherein the liver disorder or disease is non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, cirrhosis, primary sclerosing cholangitis, or primary biliary cholangitis.
14 . The method according to claim 12 , wherein the liver disorder or disease is diabetes related fibrosis.
15 . A method for the protection of the liver against hepatotoxicity comprising administering to a subject an effective amount of Compound 1 of formula (I):
or an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof, as a hepatoprotectant,
wherein the protection of the liver against hepatotoxicity comprises the improvement of liver function, the protection against a liver injury, or the repair of a liver injury.
16 . The method according to claim 15 , wherein the hepatotoxicity or the liver injury is caused by at least one hepatotoxicant, celiac disease, or a viral infection.
17 . The method according to claim 16 , wherein the at least one hepatotoxicant is selected from the group consisting of a toxic chemical, a xenobiotic, an anticancer drug, an immunosuppressant drug, an analgesic drug, an anti-inflammatory drug, an anti-tubercular drug, a biological, radiation, a heavy metal, mycotoxin, galactosamine, a lipopolysaccharide, a celiac disease associated with a specific genetic phenotype, a pathobiology promoted by transglutaminase 2, and a viral infection with hepatitis A, B, or C virus.
18 . The method according to claim 15 , wherein the compound is administered orally.
19 . A method for the protection of the liver against hepatotoxicity comprising administering to a subject an effective amount of a pharmaceutical composition comprising Compound 1 of the formula (I):
or an enantiomer, a solvate, a hydrate or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, as a hepatoprotectant,
wherein the protection of the liver against hepatotoxicity comprises the improvement of liver function, the protection against a liver injury, the repair of a liver injury, or treatment of a liver disorder or disease.
20 . The method according to claim 19 , wherein the compound reduces serum levels of at least one hepatic enzyme.
21 . The method according to claim 20 , wherein the at least one hepatic enzyme is selected from the group consisting of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP).
22 . The method according to claim 19 , wherein the liver disorder or disease is liver fibrosis, alcoholic hepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, cirrhosis, primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, alcoholic steatohepatitis, or liver inflammation.
23 . The method according to claim 19 , wherein the hepatotoxicity, liver injury, the liver disease or the liver disorder is caused by at least one hepatotoxicant, celiac disease, or a viral infection.
24 . The method according to claim 23 , wherein the at least one hepatotoxicant is selected from the group consisting of a toxic chemical, a xenobiotic, an anticancer drug, an immunosuppressant drug, an analgesic drug, an anti-inflammatory drug, an anti-tubercular drug, a biological, a radiation, a heavy metal, mycotoxin, galactosamine, a lipopolysaccharide, a celiac disease associated with a specific genetic phenotype, a pathobiology promoted by transglutaminase 2 and a viral infection with hepatitis A, B, or C virus.
25 . The method according to claim 19 , wherein the pharmaceutical composition further comprises at least one polymeric precipitation inhibitor.
26 . The method according to claim 19 , wherein the pharmaceutical composition further comprises at least one acidifier and/or at least one binder.
27 . The method according to claim 25 , wherein the at least one polymeric precipitation inhibitor is selected from the group consisting of L-hydroxypropyl cellulose, hydroxypropyl cellulose, a combination of L-hydroxypropyl cellulose and hydroxypropyl cellulose, polyethylene glycol, poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, and sodium carboxymethyl cellulose.
28 . The method according to claim 26 , wherein the at least one acidifier is selected from the group consisting of ascorbic acid, organic di-carboxylic acid, and organic tri-carboxylic acid.
29 . The method according to claim 26 , 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.
30 . The method according to claim 19 , wherein Compound 1 is in the form of particles having a particle size distribution which is defined by d (0.95)≤25 μm.
31 . The method according to claim 19 , wherein the pharmaceutical composition is an oral formulation.
32 . The method according to claim 31 , wherein the oral formulation is a tablet, coated tablet, capsule, powder, or granule.
33 . The method according to claim 25 , wherein the pharmaceutical composition comprises 1 to 15 m/m acidifier, 0.1 to 7 m/m polymeric precipitation inhibitor, wherein m/m (mass ratio) of said acidifier and polymeric precipitation inhibitor compounds is calculated relative to mass of Compound 1.
34 . The method according to claim 25 , wherein the pharmaceutical composition comprises 0.1 wt % to 45 wt % Compound 1, 3 wt % to 75 wt % acidifier, 2 wt % to 35 wt % polymeric precipitation inhibitor, 0 wt % to 12 wt % binder, 2 wt % to 35 wt % disintegrant, and 1 wt % to 9 wt % lubricant/glidant.
35 . The method according to claim 25 , wherein the pharmaceutical composition comprises 0.1 wt % to 45 wt % Compound 1, 3 wt % to 75 wt % adipic acid, 2 wt % to 35 wt % L-hydroxypropyl cellulose and/or hydroxypropyl cellulose, 0 wt % to 12 wt % povidone K25, 2 wt % to 35 wt % sodium croscarmellose, and 1 wt % to 9 wt % talc or silicon dioxide.
36 . The method according to claim 19 , wherein the liver disease or disorder is liver fibrosis.
37 . The systemic formulation according to claim 3 , wherein the at least one acidifier is selected from the group consisting of ascorbic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid, glutamic acid, citric acid, and sodium hydrogen citrate.
38 . The method according to claim 26 , wherein the at least one acidifier is selected from the group consisting of ascorbic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid, glutamic acid, citric acid, and sodium hydrogen citrate.