It is known to use sequestering agent resins to bind non-absorbed bile acids in the intestinal tract to form complexes which are excreted in the feces whereby bile acids which would otherwise be reabsorbed and returned to the liver are removed from the system. This interrupts the enterohepatic cycle and leads to increased oxidation of cholesterol to bile acids and reduction in plasma cholesterol level. Such sequestering agent resins have been recognized for use for treatment of hypercholesterolemia especially primary hypercholesterolemia (i.e. elevated low density lipoproteins). Recently, it has been recognized that reducing serum cholesterol has a beneficial effect on protecting against the occurrence of atherosclerosis including heart disease. Thus, sequestering agent resins for bile acids have recently assumed increased importance.
Cholestyramine is one sequestering agent resin currently being used to lower blood cholesterol levels in humans by binding bile acids in the intestinal tract. Since it is orally administered, the fact that it has an undesirable odor and taste requires use in combination with masking excipients. Moreover, while cholestyramine is quite effective in binding bile acids in vitro, binding at between 50 and 80% of its theoretical capacity, in vivo much of the bile acid is stripped off in the ileum so that cholestyramine has a low gram potency. This low gram potency in combination with bulk added by the need for masking excipients has resulted in need for a daily intake of 27-54 grams per day which has inhibited widespread use of the drug.
Colestipol is another resin orally administered to sequester bile acids to reduce blood cholesterol level. It has a potency about 50% of cholestyramine.
Recently sequestering agent resins, including cholestyramine and colestipol, have been considered to protect against or treat diarrhea. Numerous clinical reports during the past 10 years have shown cholestyramine to be beneficial in treatment of certain chronic infantile diarrheas. This alternative is significant because infantile diarrhea leads to water and essential salt loss with the consequent risk of dehydration and the normal treatment of hydration and administration of essential salts sometimes is ineffective. Oral administration of cholestyramine has also been beneficial in instances where diarrhea is considered to be caused by the cathartic effect of bile acids reaching the colon in increased amounts, such as occurs in ileal resection and by-pass. There is also some indication that cholestyramine may be useful in the treatment of bacterial-induced diarrheas by binding bacterial enterotoxins.
USPTO Backgrounds
USPTO Backgrounds