Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Patent
1989-12-19
1992-04-28
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
424479, 424488, 424489, 424493, 424499, 536102, A61K 922, A61K 936, C08B 3100
Patent
active
051087588
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to delayed release formulations, especially those in which the delayed release characteristic is due to a coating. The term "coating" is used herein to encompass coatings for solid supports and also capsules enclosing fluids and/or solids and the term "coated" is used similarly.
In many situations it is desirable to coat an active substance in such a way that the active substance is released from the coating only after a predetermined interval or only after a change in environment. For example, pesticides may be microencapsulated in 10 .mu.m polyurea-polyamide coatings, which gradually degrade when applied to a surface, thereby gradually releasing the pesticide. In a medical context, it is particularly advantageous to be able to administer orally a medicament which is coated so that it passes through the stomach and is released only when the coated material reaches the small intestine. Such coatings are called "enteric" coatings and are relatively easy to formulate taking advantage of the fact that the stomach contents are acid and the intestinal contents are alkaline.
A harder task has been to provide a coated medicament which will survive both the stomach and the small intestine and will release the active ingredient only when the material reaches the large intestine or colon.
Many diseases of the colon, for example ulcerative colitis and Crohn's disease and potentially also cancer of the colon, could be better treated if site-specific delivery of the therapeutic agent could be effected. Therapeutic agents include corticosteroids, for example hydrocortisone and prednisolone, mesalazine, bisocodyl, phenolphthalein, rhein, sulphasalazine, cholestyramine and azathioprine. Few effective oral therapies are available, and administration via the rectum is messy and relatively expensive. If drugs for the treatment of colonic disease are encapsulated in an enteric coating, absorption of the drug from the small intestine is very rapid, and only small amounts of the drug reach the required site of action. If site-specific release could be obtained, smaller doses would be required, with a reduction in undesirable side effects.
There are also situations other than the treatment of diseases of the colon where it is desirable to deliver a drug to the colon before it is released. Thus, in certain conditions such as arthritis the release of drugs in the ileum can cause problems and it is desirable for laxatives and anti-diarrhoeal drugs to be selectively released in the colon. Other drugs may also benefit from such a form of release depending upon their absorption characteristics.
A number of approaches have been suggested for site-specific release to the colon. Thus, glycoside derivatives of steroid drugs are reported to be poorly absorbed in the stomach and small intestine but to be released in the large intestine through microbial action (Friend, D. R. and Chang, G. W., J. Med. Chem., 1984, 27, 261). Moreover, coating of peptide drugs with polymers cross-linked with azoaromatic groups is reported to protect the drugs from digestion in the stomach and small intestine but allow their release in the large intestine by the action of the indigenous microflora to effect reduction of the azo bonds (Saffron, M. et al., Science, 1986, 233, 1081).
It has now been found that certain types of amylose coatings are particularly suitable for the purpose of site-specific release in the colon. For a long time it was thought that starch was almost entirely degraded by .alpha.-amylase, a digestive enzyme present in the small intestine, but recently it has been reported in papers concerned with studies on foodstuffs that a proportion of starch is not degraded until it reaches the colon (Englyst and Cummings, Cereals in a European Context, edited by Morton, First European Conference on Food Science and Technology, Ellis Harwood, Chichester, England, 1987, page 221 and Ring et al, Food Chemistry, 1988, 28, 97).
However, papers concerned with the use of starch materials in a medical context have reported that a
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Allwood Michael C.
Archer David B.
Ring Stephen G.
Kishore G. S.
National Research Development Corporation
Page Thurman K.
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