Idea Transcript
US005 69 1343A
United States Patent [19]
[11] [45]
Sandborn [54] USE OF TOPICAL AZATHIOPRINE TO TREAT INFLAMMATORY BOWEL DISORDERS
Patent Number: Date of Patent:
5,691,343 Nov. 25, 1997
AB. Hawthorne et al., “Randomised controlled trial of
azathioprine withdrawal in ulcerated colitis”, Brit. J. Med.,
305, 20-22 (1992). M. Klein et al., ‘Treatment of Crohn’s Disease with Aza
[75] Inventor: William J. Sandborn, Rochester, Minn.
[73] Assignee: Mayo Foundation for Medical Education and Research, Rochester, Minn.
[51]
Disease Study: The Exclusion of Azathioprine Without B1. Korelitz et al., “Favorable Effect of 6-Mercaptopurine on Fistulae of Crohn’s Disease”, Digestive Diseases and
Sciences, 30, 58-64 (Jan. 985).
Mar. 30, 1995
Int. Cl.6 ................................................... .. A61K SD52
[52] US. Cl. [58]
B1. Korelitz et al., “Shortcomings of the National Crohn’s
Adequate Trial”, Gastroenterology, 80, 193-194 (1981).
[21] Appl. No.: 413,505 [22] Filed:
thioprine: A Controlled Evaulation”, Gastroenterology, 66, 916-922 (1974).
514/262
Field of Search ............................................. .. 514/262‘
L. Lennard et al., “Azathioprine metabolism in kidney transplant recipients”, Br J. Clin. Phamrac, 18, 693-700
(1984). J. Markowitz et al., “Long-Tenn 6-Mercaptopurine Treat ment in Adolescents with Crohn’s Disease”, Gastroenterol
[56]
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FOREIGN PATENT DOCUMENTS W094I28911 12/1994
WIPO.
OTHER PUBLICATIONS
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Crohn’s disease,” Gastmenterolog); 106, A659 (Apr. 1994). R. Capr‘illi et aL, “A double-blind comparison of the e?ec tiveness of azathioprine and sulfasalazine in idiopathic proc
tocolitis. Preliminary Report,” Dig. Dis., 20, 115-120
(197 5). K. Ewe et al., “Azathioprine combined with prednisolone or
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20, 1197-1203 (Nov. 10, 1985). B. Odlind et al., “Serum Azathioprine and 6-Mercaptopu rine Levels and Irnmunosuppressive Activity after Azathio prine in Uremic Patients”, Int. J. Immunopharmaa, 8, 1-11
(1986). D.P. O’Donoghue et al., “Double-Blind Withdrawal Trial of Azathioprine as Maintenance Treatment for Crohn’s Dis
ease”, The Lancet, 955-957 (Nov. 4, 1978). J. Perrault et al., “6-Mercaptopurine Therapy in Selected Cases of Corticosteroid-Dependent Crohn’s Disease”, Mayo Clin. Prom, 66, 480-484 (1991). D.H. Present et al., ‘Treatment of Crohn’s Disease with
6-Mercaptopurine”, N. Eng. J. Med., 302, 981-987 (May 1,
1980). D.H. Present et al., “6-Mercaptopurine in the Management of in?ammatory Bowel Disease: Short-and Long-Tenn
Gastroenterology, 105, 367-372 (Aug. 1993).
Toxicity”, Annals of Internal Medicine, 111, 641-649 (Oct.
D.P. Jewell et al., “Azathioprine in ulcerative colitis: ?nal report on controlled therapeutic trial,” Br Med. J., 4,
J. Rhodes et al., “Controlled Trial of Azathioprine in Crohn’s
627-639 (1974). A.P. Kirk et al., “Controlled trial of azathiopn'ne in chronic
ulcerative colitis,” Br. Med. J., 284, 1291-1292 (1982). IL Rosenberg et al., “A controlled trial of azathioprine in the management of chronic ulcerative colitis,” Gastmenter
ology, 69, 96-99 (1975). LR. Sutherland, ‘Topical treatment of ulcerative colitis,” Med. Clin. North Am., 74,'1l9-13l (Jan. 1990). Y. Takeichi et al., “Improvement of aqueous solubility and
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15, 1989). Disease”, The Lancet‘, 1273-1276 (Dec. 11, 1971). IL. Rosenberg et al., “A Controlled Trial of Azathioprine in
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1975). LW. Singleton, “Azathioprine Has a Very Limited Role in the Treatment of Crohn’s Disease”, Digestive Diseases and
Sciences, 26, 368-371 (Apr. 1981). R.W. Summers et al., “National Cooperative Crohn’s Dis ease Study: Results of Drug Treatmen ”, Gastroenterology
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A method is provided to treat in?ammatory bowel disease by topically administering to the colon an effective amount of
o-Thioguanine Mucleotides in Renal Transplant Patients”, J. Clin. PharmacoL, 30, 358-363 (1990). W.R. Connell et al., “Bone Marrow Toxicity caused by azathioprine in in?ammatory bowel disease: 27 years of
azathioprine or a pharmaceutically acceptable salt thereof, preferably Via formulations adapted for delayed-release oral
experience”, Gut, 34, 1081-1085 (1993).
Agent,
or
Firm-Schwegman,
Lundberg,
ABSTRACT
or rectal administration.
5 Claims, N0 Drawings
5,691,343 Page 2 OTHER PUBLICATIONS M. Verhave et al., “Azathioprine in the treatment of children
with in?ammatory bowel disease”, J. Pediatrics, 117,
809-814 (Nov. 1990). J.M.T. Willoughby et al., “Controlled Trial of Azathioprine
S. Zimm et al., “Phase I and Clinical Pharmacological Study of Mercaptopurine Administered as a Prolonged Intravenous
Infusion”, Cancer Research, 45, 1869-1873 (Apr. 1985). S. Zimm et a1._. “Variable Bioavailability of Oral Mercap
topurine”, N. Eng. J. Med., 308, 1005-1009 (1983).
in Crohn’s Disease”, The Lancet, 944-946 (Oct. 30, 1971). WP. Wilson et al., “Azathioprine” in Analytical Pro?les of Drug Substances, vol. 10; K. Florey, Ed.; Academic Press:
Abstract of Japanese Patent Application No. 62 072618, issued Apr. 3, 1987, (Takada) from Database WPI, Derwent
New York; PP. 30-53; 1981.
Publications Ltd., London.
5,691,343 1
2
USE OF TOPICAL AZATHIOPRINE TO TREAT INFLAMMATORY BOWEL DISORDERS
al., Med. Clin. North Amer., 74, 119 (1990)); rectal foams
(Drug. ?ier. 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
BACKGROUND OF THE INVENTION
al., New Engl. J. Med., 317, 1625 (1987)). The effective amount of azathioprine (AZA) can be
In?ammatory bowel disorders or diseases (IBD) encom pass a spectrum of overlapping clinical diseases that appear to lack a common etiology. IBD, however, are characterized by chronic intimation at various sites in the gastrointestinal (GI) tract. Illustrative IBD are regional enteritis (or Crohn’s
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 ?om 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 indi vidually 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.
disease), idiopathic ulcerative colitis, idiopathic proctocolitis, and infectious colitis. Most hypotheses regard ing the pathogenesis of IBD concern the implication of
immunologic, infectious, and dietary factors. 6-mercaptopurine (6MP) and its prodr'ug azathioprine (AZA) have been used in the treatment of in?ammatory bowel disease (IBD) for over 25 years. Multiple controlled trials and a recent meta-analysis support the e?icacy of 6MP andAZAin Crohn’s disease. See, J. M. T. Willoughby et al., lancel; ii 944 (1971); J. L. Rosenberg et at, Dig. Dis., 20,
Alternatively, the azathioprine may be combined with adju vants employed in solid unit dosage forms, such as ?llers
and binders, compressed into shaped, solid dosage forms such as pills or tablets, and the pills or tablets treated so as 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). 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.
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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-e?iects of AZA can be avoided or mini mized. 30 Thus, a useful enteric coating is one that remains undis
sociated in the low pH environment of the stomach, but readily ionizes when the pH rises to about 4 or 5. The most
SUNIMARY OF THE INVENTION
effective enteric polymers are polyacids having a pH, of 3 The present invention provides a therapeutic method of
treating in?ammatory bowel disease (IBD) comprising topi
to 5. 35
The most extensively use polymer is cellulose acetate
cally 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. Preferably the azathio prine is administered orally, by means of an enteric-coated unit dosage form that selectively releases AZA in the ter minal ileum and/or colon of the patient. The AZA can also be effectively administered to the colon by rectal adminis
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 ?uid, more stable to hydrolysis and able to ionize at a lower
tration 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 or
45
ulcerative colitis, 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>