Enema and enterically-coated oral dosage forms of azathioprine

Details Enema and enterically-coated oral dosage forms of azathioprine Enema and enterically-coated oral dosage forms of azathioprine

2000-12-21

2002-08-13

Jarvis, William R. A. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06432967

ABSTRACT:

BACKGROUND OF THE INVENTION
Inflammatory bowel disorders or diseases (IBD) encompass a spectrum of overlapping clinical diseases that appear to lack a common etiology. IBD, however, are characterized by chronic inflammation at various sites in the gastrointestinal (GI) tract. Illustrative IBD are regional enteritis (or Crohn's disease), idiopathic ulcerative colitis, idiopathic proctocolitis, and infectious colitis. Most hypotheses regarding the pathogenesis of IBD concern the implication of immunologic, infectious, and dietary factors.
Colorectal cancer is the most common visceral cancer in the United States. The colorectal cancer progresses through clinically recognizable stages from normal mucosa through enlarging and increasingly dyplastic polyps to carcinoma. The precursor relationship of colorectal adenomatous polyps to carcinoma and the high prevalence of adenomas make them an attractive target in chemoprevention trials. Furthermore, endoscopic or surgical removal of polyps does not change the pathogenetic milieu responsible for their growth and development. The recurrence rate for colorectal adenomas ranges from 20-60% by two years. Patients who have undergone surgical resection of a primary colorectal cancer have also been shown to be at high risk of developing metachronous adenomas. Chemoprevention by pharmacologic intervention remains to be established in clinical practice, and there is a continuing need to develop new chemopreventive treatments for colorectal adenomas. 6-mercaptopurine (6MP) and its prodrug azathioprine (AZA) have been used in the treatment of inflammatory bowel disease (IBD) for over 25 years. Multiple controlled trials and a recent meta-analysis support the efficacy of 6MP and AZA in Crohn's disease. See, J. M. T. Willoughby et al.,
Lancet
, ii 944 (1971); J. L. Rosenberg et al.,
Dig. Dis
., 20, 721 (1975). Several controlled trials support the use of AZA in ulcerative colitis, the most recent by Hawthorne and colleagues, in
Brit. Med. J
., 305, 20 (1992). Both azathioprine and 6-mercaptopurine have also demonstrated anti-tumor activity against a wide variety of transplantable rodent tumors and against hematologic malignancies in man. However, use of 6MP and AZA has been limited by concerns about their toxicities. Dose-related leukopenia is seen in 2-5% of patients treated long-term with 6MP or AZA for IBD. See, for example, D. H. Present et al.,
Am. Int. Med
., 111, 641 (1989); W. R. Connell et al.,
Gut
, 34, 1081 (1993).
Therefore, a need exits for effective, nontoxic therapies for IBD. Furthermore, there is also a need for new chemopreventative treatments for colorectal adenomas.
SUMMARY OF THE INVENTION
The present invention provides new therapeutic methods of treating inflammatory bowel disease (IBD) and colorectal adenomas comprising topically administering to the colon of a patient in need of such treatment, an amount of azathioprine (AZA) effective to relieve the symptoms of said IBD or to prevent colorectal adenomas, either prior to or following endoscopic or surgical removal. Preferably the azathioprine is administered orally, by means of an enteric-coated unit dosage form that selectively releases AZA in the terminal ileum and/or colon of the patient. The AZA can also be effectively administered to the colon by rectal administration of an enema formulation comprising AZA. Due to poor absorption of AZA in the bloodstream from the colon, relatively high doses of AZA can be administered to the afflicted tissue, i.e., in the case of Crohn's disease, ulcerative colitis, or colorectal adenomas without inducing systemic toxicities such as leukopenia, Therefore, effective AZA doses of from about 150-1000 mg can be delivered 1-4 times daily to adult patients (150 mg 1×day-1000 mg 4×day) without undue toxicities (about 2-20 mg/kg AZA doses are administered).
As used herein the term “azathioprine” includes the pharmaceutically acceptable salts thereof, as well as functionally equivalent analysis, derivatives, and metabolites, such as 6-MP and thioguanine. For example, see U.S. Pat. No. 3,056,785, and W. P. Wilson et al.,
Anal. Profiles of Drug Substances
, 10, 29-53 (1981).
DETAILED DESCRIPTION OF THE INVENTION
Colonic administration of drugs has been used to reduce the toxicity associated with oral or IV corticosteroids and oral 5-aminosalicyclate in patients with IBD. This decreased toxicity is believed to be due to reduced systemic bioavailability. Several types of colonic drug delivery systems are currently available, including enemas (L. R. Sutherland et al.,
Med. Clin. North Amer
., 74, 119 (1990)); rectal foams (
Drug. Ther. Bull
., 29, 66 (1991)); and delayed release oral formulations in the form of Eudragit-coated capsules which dissolve at pH 7 in the terminal ileum (K. W. Schroeder et al.,
New Engl. J. Med
., 317, 1625 (1987)).
The effective amount of azathioprine (AZA) can be topically administered to the colon of the patient by oral ingestion of a unit dosage form comprising an effective amount of AZA which is enterically coated so as to be released from the unit dosage form in the lower intestinal tract, e.g., in the terminal portion of the ileum and in the colon of the patient. Microparticles of AZA may be individually coated and delivered as a suspension in a liquid vehicle, may be encapsulated as a powder or may be compressed into a pill or tablet and swallowed. Alternatively, the azathioprine may be combined with adjuvants employed in solid unit dosage forms, such as fillers and binders, compressed into shaped, solid dosage forms such as pills or tablets, and the pills or tablets treated so as to apply an enteric coating of suitable thickness thereto.
Enteric coatings are those which remain intact in the stomach, but will dissolve and release the contents of the dosage form once it reaches the small intestine. The purpose of an enteric coating is to delay the release of the AZA until it reached the target site of action in the colon. Since the AZA topically-administered to the colonic tissue in this fashion is only about 10% absorbed into the bloodstream, the systemic side-effects of AZA can be avoided or minimized.
Thus, a useful enteric coating is one that remains undissociated in the low pH environment of the stomach, but readily ionizes when the pH rises to about 4 or 5. The most effective enteric polymers are polyacids having a pHa of 3 to 5.
The most extensively use polymer is cellulose acetate phthalate (CAP) which is capable of functioning effectively as an enteric coating. However, a pH greater than 6 usually is required for solubility and thus a delay in drug release may ensue. Another useful polymer is polyvinyl acetate phthalate (PVAP) which is less permeable to moisture and gastric fluid, more stable to hydrolysis and able to ionize at a lower pH, resulting in earlier release of actives in the duodenum.
A more recently available polymer is hydroxypropyl methylcellulose phthalate. This has similar stability to PVAP and dissociates in the same pH range. A further example of currently used polymers are those based on methacrylic acid, e.g., methacrylic acid ester copolymers with acidic ionizable groups, such as Eudragit S-100 (methacrylic acid copolymer). Various systems are available that allow each of these enteric polymers to be applied as aqueous dispersions, thus facilitating the use of aqueous film-coating technology for the enteric coating of pharmaceutical dosage forms.
Another preferred dosage form in the topical administration of AZA to the colon is an enema formulation, which is rectally administered to the lower colon. Useful formulations comprise an effective amount of AZA dissolved or dispersed in a suitable flowable carrier vehicle, such as water, alcohol or an aqueous-alcoholic fluid. The carrier vehicle is preferably thickened with natural or synthetic thickness such as gums, acrylates or modified celluloses. The formulation can also comprise an effective amount of a lubricant such as a natural or synthetic fat or oil, i.e., a tris-fatty acid glycerate or lecithin. N

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