Claims for Patent: 11,365,182

Summary for Patent: 11,365,182

Title:	Crystal modifications of odevixibat
Abstract:	The present invention relates to crystal modifications of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N--{(R)-.alpha.-[N--((S)-1- -carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrah- ydro-1,2,5-benzothiadiazepine (odevixibat), more specifically crystal modifications 1 and 2 of odevixibat. The invention also relates to a process for the preparation of crystal modification 1 of odevixibat, to a pharmaceutical composition comprising crystal modification 1, and to the use of this crystal modification in the treatment of various conditions as described herein.
Inventor(s):	Lundqvist; Robert (Halso, SE), Ymen; Ingvar (Saltsjo-boo, SE), Bohlin; Martin (Johanneshov, SE), Byrod; Eva (Molndal, SE), Gillberg; Per-Goran (Molndal, SE), Tivert; Anna-Maria (Gothenburg, SE), Bryland; Rikard (Limhamn, SE), Dahlquist; Ann-Charlotte (Lund, SE), Elversson; Jessica (Dalby, SE), Gustafsson; Nils Ove (Loddekopinge, SE)
Assignee:	Albireo AB (Gothenburg, SE)
Application Number:	17/065,245
Patent Claims:	1. A method for treating a liver disease or disorder comprising orally administering to a subject in need of such treatment a therapeutically effective amount of a crystalline hydrate of odevixibat, or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein the crystalline hydrate of odevixibat is a channel hydrate. 3. The method of claim 1, wherein the crystalline hydrate of odevixibat comprises from about 0 to about 2 moles of water associated with the crystal per mole of odevixibat. 4. The method of claim 1, wherein the crystalline hydrate of odevixibat is a sesquihydrate. 5. The method of claim 1, wherein the crystalline hydrate of odevixibat has an XRPD pattern, obtained with CuK.alpha.1-radiation, with peaks at .degree. 2.theta.positions 5.6.+-.0.2, 6.7.+-.0.2 and/or 12.1.+-.0.2. 6. The method of claim 5, wherein the crystalline hydrate of odevixibat has an XRPD pattern, obtained with CuK.alpha.1-radiation, with specific peaks at .degree. 2.theta.positions 5.6.+-.0.2, 6.7.+-.0.2 and 12.1.+-.0.2 and one or more of the characteristic peaks: 4.1.+-.0.2, 4.6.+-.0.2, 9.3.+-.0.2, 9.4.+-.0.2 and 10.7.+-.0.2. 7. The method of claim 5, wherein the crystalline hydrate of odevixibat has a crystallinity of greater than about 99%. 8. The method of claim 1, wherein the liver disease or disorder is selected from the group consisting of: an inherited metabolic disorder of the liver; inborn errors of bile acid synthesis; congenital bile duct anomalies; biliary atresia; neonatal hepatitis; neonatal cholestasis; hereditary forms of cholestasis; cerebrotendinous xanthomatosis; a secondary defect of BA synthesis; Zellweger's syndrome; cystic fibrosis-associated liver disease; alpha1-antitrypsin deficiency; Alagilles syndrome (ALGS); a primary defect of bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC); benign recurrent intrahepatic cholestasis (BRIC); autoimmune hepatitis; primary biliary cirrhosis (PBC); liver fibrosis; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); portal hypertension; cholestasis; Down syndrome cholestasis; drug-induced cholestasis; intrahepatic cholestasis of pregnancy; jaundice during pregnancy; intrahepatic cholestasis; extrahepatic cholestasis; parenteral nutrition associated cholestasis (PNAC); low phospholipid-associated cholestasis; lymphedema cholestasis syndrome 1 (LSC1); primary sclerosing cholangitis (PSC); immunoglobulin G4 associated cholangitis; primary biliary cholangitis; cholelithiasis; gall stones; biliary lithiasis; choledocholithiasis; gallstone pancreatitis; Caroli disease; malignancy of bile ducts; malignancy causing obstruction of the biliary tree; biliary strictures; AIDS cholangiopathy; ischemic cholangiopathy; pruritus due to cholestasis or jaundice; pancreatitis; chronic autoimmune liver disease leading to progressive cholestasis; hepatic steatosis; alcoholic hepatitis; acute fatty liver; fatty liver of pregnancy; drug-induced hepatitis; iron overload disorders; congenital bile acid synthesis defect type 1 (BAS type 1); drug-induced liver injury (DILI); hepatic fibrosis; congenital hepatic fibrosis; hepatic cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis sclerosing cholangitis (NISCH); erythropoietic protoporphyria (EPP); idiopathic adulthood ductopenia (IAD); idiopathic neonatal hepatitis (INH); non syndromic paucity of interlobular bile ducts (NS PILBD); North American Indian childhood cirrhosis (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; serum bile acid-caused toxicities; viral hepatitis; hepatocellular carcinoma (hepatoma); cholangiocarcinoma; bile acid-related gastrointestinal cancers; and cholestasis caused by tumours and neoplasms of the liver, of the biliary tract and of the pancreas. 9. The method of claim 8, wherein the liver disease or disorder is selected from the group consisting of: biliary atresia, ALGS, PFIC, PBC, and PSC. 10. The method of claim 9, wherein the liver disease or disorder is biliary atresia. 11. The method of claim 10, wherein the biliary atresia is post-Kasai biliary atresia or post-liver transplantation biliary atresia. 12. The method of claim 10, wherein the biliary atresia comprises an accumulation of bile acids in the extrahepatic biliary tree. 13. The method of claim 10, wherein the biliary atresia comprises an accumulation of bile acids in the intrahepatic biliary tree. 14. The method of claim 9, wherein the liver disease or disorder is PFIC. 15. The method of claim 14, wherein the PFIC is selected from PFIC Type 1, PFIC Type 2, PFIC Type 3, non-specified PFIC, post-biliary diversion PFIC, and post-liver transplant PFIC. 16. The method of claim 8, wherein the liver disease or disorder is pruritus due to cholestasis or jaundice. 17. The method of claim 8, wherein the liver disease or disorder is NASH. 18. The method of claim 1, wherein treatment of the liver disease or disorder comprises decreasing the level of serum bile acids.