Compositions and methods for the treatment or prevention of oxalate-related disorders

Abstract

The present disclosure is related to pharmaceutical compositions and methods for treating and/or preventing oxalate-related disorders. More particularly, the present disclosure pertains to compositions comprising an oxalate-degrading bacteria Oxalobacter formigenes particularly suitable for the treatment and/or prevention of late stage hyperoxaluria characterized by high plasma-oxalate levels and a progressing decrease in kidney function.

1 .- 38 . (canceled) 
     
     
         39 . A pharmaceutical composition comprising:
 (i) about 10% to about 25% by dry weight of  Oxalobacter formigenes,      (ii) about 50% to about 65% by dry weight of sucrose;   (iii) about 10% to about 30% by dry weight of one or more cryopreserving agents and/or excipients.   
     
     
         40 . The pharmaceutical composition according to  claim 39 , comprising about 15% to about 25% by dry weight of  Oxalobacter formigenes.    
     
     
         41 . The pharmaceutical composition according to  claim 39 , comprising about 17% to about 22% by dry weight of  Oxalobacter formigenes.    
     
     
         42 . The pharmaceutical composition according to  claim 39 , wherein the cryopreserving agents and/or excipients are selected from maltodextrin, oligofructose, and alginate. 
     
     
         43 . The pharmaceutical composition according to  claim 42 , comprising about 15% to about 21% by dry weight of maltodextrin as a cryopreserving agent. 
     
     
         44 . The pharmaceutical composition according to  claim 42 , comprising about 16% to about 19% by dry weight of maltodextrin as a cryopreserving agent. 
     
     
         45 . The pharmaceutical composition according to  claim 42 , comprising about 1% to about 5% by dry weight of oligofructose as a cryopreserving agent and about 0.5% to about 2% by dry weight of alginate as an excipient. 
     
     
         46 . The pharmaceutical composition according to  claim 45 , wherein said pharmaceutical composition further comprises about 1% to about 5% by weight of water. 
     
     
         47 . The pharmaceutical composition according to  claim 42 , comprising about 0.5% to about 1.5% by dry weight of alginate as an excipient. 
     
     
         48 . The pharmaceutical composition according to  claim 39 , wherein said composition comprises:
 about 17% to about 22% by dry weight of  Oxalobacter formigenes,      about 52% to about 62% by dry weight of sucrose;   about 17% to about 25% by dry weight of one or more cryopreserving agents and/or excipients.   
     
     
         49 . The pharmaceutical composition according to  claim 39 , wherein said pharmaceutical composition comprises:
 (i) about 19% by dry weight of  Oxalobacter formigenes,      (ii) about 57% by dry weight of sucrose;   (iii) about 21% by dry weight of one or more cryopreserving agents and/or excipients, and   (iv) q.s. water.   
     
     
         50 . The pharmaceutical composition according to  claim 49 , wherein said about 21% by dry weight of one or more cryopreserving agents and/or excipients comprises about 1% by dry weight of alginate, about 17% by dry weight of maltodextrin and about 3% by dry weight of oligofructose. 
     
     
         51 . The pharmaceutical composition according to  claim 39 , wherein the in vitro oxalate-degrading activity of the  Oxalobacter formigenes  present in said pharmaceutical composition is such that at least 100 picograms/colony forming unit are degraded after incubation in 60 mM oxalate-containing medium at 37° C. for at least 8 hours. 
     
     
         52 . An enteric-coated capsule for oral administration of  Oxalobacter formigenes  to a subject and delivery of  Oxalobacter formigenes  to the small intestine and/or to the ileum, comprising the pharmaceutical composition according to  claim 39 , wherein said capsule contains  Oxalobacter formigenes  in an amount of from about 10 9  to about 10 10  CFUs, wherein said capsule shows essentially no disintegration within one hour of incubation in Simulated Gastric Fluid (SGF) having a pH of about 1.2±0.1 and comprising about 3.2 mg/ml of pepsin at a temperature of about 37° C., and wherein said capsule shows a start of disintegration within about one hour of incubation in Simulated Intestinal Fluid (SIF) having a pH of about 6.8±0.1 and comprising about 10 mg/ml of pancreatin at about 37° C. 
     
     
         53 . The enteric-coated capsule according to  claim 52 , wherein the oxalate-degrading activity in vitro of the  Oxalobacter formigenes  present in said capsule is no less than (NLT) 100 mmol/capsule/19 hours. 
     
     
         54 . A method for preparing a pharmaceutical composition according to  claim 39 , comprising:
 (a) mixing a cell paste of  Oxalobacter formigenes  with said excipients and/or cryopreserving agents and optionally water; and   (b) lyophilizing the composition obtained in step (a).   
     
     
         55 . The method according to  claim 54 , wherein the in vitro oxalate-degrading activity of the  Oxalobacter formigenes  present in said pharmaceutical composition is such that at least 100 picograms/colony forming unit are degraded after incubation in 60 mM oxalate-containing medium at 37° C. for at least 8 hours. 
     
     
         56 . A method for treating or preventing an oxalate-related disorder, said method comprising administering a pharmaceutically effective amount of a pharmaceutical composition according to  claim 39  to a subject in need thereof. 
     
     
         57 . The method of  claim 56 , wherein said oxalate-related disorder is selected from a calcium-oxalate deposition related disorder involving hyperoxalemia, hyperoxaluria with hyperoxalemia, primary hyperoxaluria, secondary hyperoxaluria, hyperoxalemia, accumulation of oxalate in blood plasma, oxalosis associated with Chronic Kidney Disease (CKD) or end stage renal disease (ESRD), bariatric surgery with jejunal/ileal resection or Roux-en-Y procedures, Zellweger's disease, cancers with jejunal/ileal resection, renal infections with  Aspergillus niger , end stage renal disease (ESRD) in patients on dialysis, oxalate-related inflammation, cardiac conductance disorders, vulvodynia, idiopathic calcium oxalate kidney stone disease (urothiliasis), inflammatory bowel disease (IBS), Small Intestine Bacterial Overgrowth (SIBS), gastroenteritis, gastritis, enteritis, enterocolitis, ulcerative colitis, Crohn's disease, or an oxalate-related disorder in a patient treated with a gastrointestinal lipase inhibitor. 
     
     
         58 . The method of  claim 56 , wherein the method is effective to increase systemic oxalate excretion in said subject. 
     
     
         59 . The method of  claim 56 , wherein said pharmaceutically effective amount comprises  Oxalobacter formigenes  in an amount of about 10 9  to about 10 10  CFUs. 
     
     
         60 . The method of  claim 59 , wherein said method comprises administering said pharmaceutically effective amount at least twice a day for a continuous period of months or years, or until the levels of plasma oxalate have been lowered, and are maintained at a level of about 1-3 μmon. 
     
     
         61 . A method for treating or preventing an oxalate-related disorder, said method comprising administering a pharmaceutically effective amount of an enteric-coated capsule according to  claim 52  to a subject in need thereof. 
     
     
         62 . The method of  claim 61 , wherein said oxalate-related disorder is selected from a calcium-oxalate deposition related disorder involving hyperoxalemia, hyperoxaluria with hyperoxalemia, primary hyperoxaluria, secondary hyperoxaluria, hyperoxalemia, accumulation of oxalate in blood plasma, oxalosis associated with Chronic Kidney Disease (CKD) or end stage renal disease (ESRD), bariatric surgery with jejunal/ileal resection or Roux-en-Y procedures, Zellweger's disease, cancers with jejunal/ileal resection, renal infections with  Aspergillus niger , end stage renal disease (ESRD) in patients on dialysis, oxalate-related inflammation, cardiac conductance disorders, vulvodynia, idiopathic calcium oxalate kidney stone disease (urothiliasis), inflammatory bowel disease (IBS), Small Intestine Bacterial Overgrowth (SIBS), gastroenteritis, gastritis, enteritis, enterocolitis, ulcerative colitis, Crohn's disease, or an oxalate-related disorder in a patient treated with a gastrointestinal lipase inhibitor. 
     
     
         63 . The method of  claim 61 , wherein said method is effective to increase systemic oxalate excretion in said subject. 
     
     
         64 . The method of  claim 61 , wherein said method comprises administering said pharmaceutically effective amount at least twice a day for a continuous period of months or years, or until the levels of plasma oxalate have been lowered, and are maintained at a level of about 1-3 μmol/L.