Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2003-01-22
2004-03-02
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S025000, C514S042000, C536S123100, C536S004100, C536S022100
Reexamination Certificate
active
06699848
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel anti-inflammatory compounds useful in the treatment of gastrointestinal inflammation. The invention further relates to a method of controlling the delivery of anti-inflammatory compounds, particularly mesalamine (5-amino salicylic acid, 5-ASA), 4-amino salicylic acid (4-ASA), and 3-amino salicylic acid (3-ASA) to the entire gastrointestinal (GI) tract in patients suffering from inflammatory bowel disease. The present invention principally relates to the treatment of inflammatory bowel diseases and functional bowel disorders with anti-inflammatory drugs such as mesalamine (5-ASA). Unlike conventional and well established treatments, which rely on timed-release, bacteria-mediated hydrolysis and/or pH dependent release formulations that have restricted access to gastrointestinally inflamed tissue, the compositions of the present invention can target a site throughout the length of the gastrointestinal intestinal tract to consistently deliver the medicine where it will be clinically most effective.
The ability of mesalamine to reduce inflammation is well established; however, its clinical efficacy for the treatment of certain inflammatory bowel diseases is not compelling because its pharmacological activity is dependent on where the drug is released in the intestinal tract. It is believed that mesalamine inhibits the production of leukotrienes and prostaglandins from arachidonic acid through a local effect at the sites of bowel inflammation; however, pre-clinical and clinical studies with current mesalamine products suggest these formulations have a variable release throughout the intestinal tract and are not retained at the inflammatory sites for a time sufficient to reduce inflammation. Moreover, the differences in the site of drug release (duodenum, jejunum, ileum or colon) from these formulations results in dramatically different absorption and metabolism of the drug. The variations in drug release and drug retention at different locations within the bowel from these commercial formulations makes it particularly difficult to treat patients having locally induced inflammation that differs from the release location.
Treating patients with anti-inflammatory compounds with gastrointestinal inflammation is not new, and the Food and Drug Administration (FDA) has already approved treating patients with mesalamine for certain types of inflammatory bowel disease that occur in the colon, namely ulcerative colitis. A number of different oral or rectal mesalamine formulations are commercially available for the treatment of inflammation in ulcerative colitis; however, each has met with limited success in ameliorating the symptoms of Crohn's disease. The principal difficulties with currently available mesalamine formulations include the inability to consistently release mesalamine at the inflamed tissue in different patients and the inability to locally deliver mesalamine to the site of inflammation for a time effective in reducing inflammation. The latter is due, in part, to extensive absorption and deactivation of mesalamine in the proximal ileum. Ironically, the clinical success of mesalamine formulations in treating inflammation in the colon has fostered the development of additional mesalamine formulations that only release the drug in the colon.
In the treatment of distal colitis, an enema preparation of mesalamine (Rowasa® enema) is considered efficacious. In the initial study to identify the active moiety in sulfasalazine, patients with distal ulcerative colitis were treated with sulfasalazine, mesalamine, or sulfapyridine enemas. Three quarters of the patients in the sulfasalazine and mesalamine groups showed improvement, while only about one third of patients in the sulfapyridine group improved. These data supported the hypothesis that mesalamine was the active therapeutic moiety, and subsequent studies confirmed the efficacy of mesalamine enemas in distal colitis. (Azad Khan et al. Lancet 2;892-895 (1977); Physician's Desk Reference 55
th
Edition pp 3160-3162, publ. Medical Economics (2001); U.S. Pat. No. 4,496,553).
Mesalamine, rectally administered through an enema, has limited systemic absorption and consequently good topical effectiveness in treating inflammation in the colon; however, rectally administered mesalamine acts only locally on the recto-sigmoidal colon so that more proximal inflammation cannot be treated in this manner. Moreover, patient compliance with rectally administered mesalamine is low, and has been associated with an increase colon cancer. Oral delivery of mesalamine is the preferred route of administration; however, suitable formulations have been elusive. Oral delivery of mesalamine to sites of inflammation located above the transverse colon, and particularly to the proximal small bowel, is more complex and successful delivery and therapeutic benefit depends upon factors such as gastric emptying time and retention time in the intestinal lumen. Gastric emptying time varies from one individual to another and in the same individual may vary according to the size of (orally taken) particles (or tablets) and according to whether the patient is in a fasting or non-fasting state. Dwell time in the ileum is also variable and particularly important in previously surgically treated Crohn's patients having a shortened small bowel. Luminal retention is related to the absorption and metabolism of mesalamine in the upper portion of the small intestine.
Another difficulty in formulating oral mesalamine for accurate targeting is stomach acidity, which destroys the drug preparations before they reach the bowel. The development and commercialization of both enterically coated drug dosage forms and prodrugs resistant to hydrolysis in the stomach have addressed this.
Enterically coated mesalamine dosage forms include Asacol®, Claversal®, and Pentasa®. Asacol® is coated with a delayed release acrylic resin (Eudrogit-S) that releases the drug in the distal ileum and colon. The resin on Asacol® releases mesalamine in a pH-dependent manner at pH 6 or above, causing release of mesalamine in the distal small bowel and colon making this drug ideal for the treatment of ulcerative colitis. Claversal® is also coated with a delayed release acrylic resin (Eudrogit-L) that releases the drug in the distal ileum and colon. Pentasa® contains ethylcellulose-coated, controlled-release microgranules of mesalamine that release mesalamine in a time-release manner throughout the distal portion of the small and the entire large intestine. Accordingly, Pentasa® would appear suitable for the treatment of Crohn's disease when the distal ileum is affected in addition to its use in ulcerative colitis. Each of these formulations uses a different mechanism to deliver the mesalamine to the sites of inflammation such as distal ileum and colon; however, they were all designed to bypass the areas of rapid absorption and inactivation of mesalamine in the duodenum and the jejunum by releasing the drug lower in the small intestine and colon. Innovative approaches in the development of orally administered mesalamine and its attendant problems are illustrated in U.S. Pat. Nos. 4,980,173, 4,496,553, 4,880,794, and 5,010,069; and the review by Prakash, A and Markham, A in Drugs 57(3): 383-408 (1999).
Attempts to overcome this acidity problem have also included use of the prodrugs sulfasalazine (Azulfidine®), olsalazine (Dipentum®) and balasalazide (Colazide®) that resist stomach acidity to yield free 5-ASA after cleavage by bacterial enzymes in the colon. In addition to the reported adverse side effects, accurate targeting of diseased sites with sulfasalazine, olsalazine and balasalazide is limited by the variations in colonic bacterial flora required for bacterial cleavage of these compounds.
The toxic effects of sulfapyridine are the limiting factor in using sulfasalazine. Common adverse reactions include headache, nausea, anorexia, and dyspepsia. These symptoms relate to plasma levels of sulfapyridine and usually occur at d
Barts Samuel
Henry Michael C.
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