Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Patent
1995-02-02
1999-08-24
Rose, Shep K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
424468, 424469, 424474, 424475, A61K 922, A61K 926, A61K 952
Patent
active
059422483
DESCRIPTION:
BRIEF SUMMARY
This invention relates to pharmaceutical compositions. In preferred embodiments, the invention relates to pharmaceutical compositions of drugs which undergo biliary excretion and/or enterohepatic recycling. The invention also relates to a method of formulating a pharmaceutically active agent into a pharmaceutical composition and to a method of administering drugs, as well as to the use of drugs and certain other ingredients in the preparation of pharmaceutically useful compositions. The invention also provides a means of avoiding hepatic and gastrointestinal toxicity due to drug administration.
It is in general known to formulate surfactants with pharmaceutical agents for the purpose of solubilizing them as in, for example, EP-A-0179583 and WO-A-9012583. EP-A-0274870 teaches that non-steroidal anti-inflammatory drugs (NSAIDs), which are in general poorly water soluble, can be administered, as well as solubilized, as micelles and that this has advantages of (a) potentially protecting the drug from the acidic and enzymatic environment of the stomach and (b) protecting the gastrointestinal mucosa from adverse effects of the drug (such as gastrointestinal bleeding, which is induced by NSAIDs including aspirin, indomethacin and piroxicam). Bile acids (or bile salts--the exact nature and proportion of the species present will depend on the pH of the environment and so the terms are used interchangeably in this specification) are naturally occurring surractants. They are a group of compounds with a common "backbone" structure based on cholanic acid found in all mammals and higher vertebrates. The detergent properties of bile acids are largely determined by the number and orientation of hydroxyl groups substituted onto a steroidal nucleus. Bile acids may be mono-, di- or tri-hydroxylated; they always contain a 3-.alpha. hydroxyl group, whereas the other hydroxyl groups, most commonly found at C.sub.6, C.sub.7 or C.sub.12, may be positioned above (.beta.) or below (.alpha.) the plane of the molecule. Many permutations of hydroxyl configuration are possible, but certain configurations are very much more common in nature than others. In most animal species there is a recognised pattern to the usual composition of the bile acids found in the bile acid pool of individual animals.
Bile acids are synthesized in vivo from cholesterol in the liver by hydroxylation and other modifications. Virtually all bile acids found in the bile of mammals and higher vertebrates are amidated at the C.sub.24 position with either taurine or glycine. The extent to which various bile acids are amidated with either glycine or taurine shows considerable variation between species and depends on the availability of taurine as a substrate for the conjugating enzyme. The term "bile acids" as used herein includes such amidated moieties.
In its role as an exocrine gland the liver secretes bile, a solution of detergent bile acids, which may be stored and further concentrated by the gall-bladder between meals. Following gall-bladder contraction in response to the gastrointestinal hormone cholecystokinin, when food is consumed, the bile acids enter the duodenum where they perform their major role as surfactants: they function to enhance the digestion and absorption of dietary lipids and lipid soluble vitamins. Bile acids also increase the action of pancreatic lipases. After completing their role in digestion bile acids are avidly conserved by the body: they are efficiently reabsorbed by an active receptor mediated process from the terminal ileum and returned to the lever, via the hepatic portal vein, and undergo further receptor enhanced extraction prior to resecretion into the bile. Thus the almost continuous flow of bile acids is topographically localized and limited to the liver, biliary tree, intestine, enterocytes and hepatic portal venous system, and thus comprises the enterohepatic circulation. The enterohepatic circulation functions not only to conserve valuable detergent bile acid molecules, by allowing their many times repeated use, but also
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Cortecs Limited
Rose Shep K.
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