Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1998-09-23
2002-07-23
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S468000, C424S490000, C514S925000, C514S964000
Reexamination Certificate
active
06423340
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to oral pharmaceutical compositions for use in the treatment of inflammatory bowel diseases and the use of certain glucocorticosteroids in the preparation of pharmaceutical compositions for the treatment by the oral route of certain inflammatory bowel diseases.
BACKGROUND OF THE INVENTION
Inflammatory bowel disease is the term generally applied to two diseases, namely ulcerative colitis and Crohn's disease.
Ulcerative colitis is a chronic inflammatory disease of unknown aetiology afflicting only the large bowel and, except when very severe, limited to the bowel mucosa. The course of the disease may be continuous or relapsing, mild or severe. It is curable by total colectomy which may be needed for acute severe disease or chronic unremitting disease. Most patient with ulcerative colitis are managed medically rather than surgically.
Crohn's disease is also a chronic inflammatory disease of unknown aetiology but, unlike ulcerative colitis, it can affect any part of the bowel. Although lesions may start superficially, the inflammatory process extends through the bowel wall to the draining lymph nodes. As with ulcerative colitis, the course of the disease may be continuous or relapsing, mild or severe but, unlike ulcerative colitis it is not curable by resection of the involved segment of bowel. Most patients with Crohn's disease come to surgery at some time, but subsequent relapse is common and continuous medical treatment is usual.
For treatment of acute attacks of ulcerative colitis, glucocorticosteroids such as prednisone or prednisolone acetate are almost invariably used and given by mouth for the average acute attack or relapse, or locally, by enema.
After remission has been achieved, sulphasalazine is the maintenance treatment of choice in treating ulcerative colitis. This drug, however, has a significant number of side effects chiefly due to absorption of the sulphapyridine moiety from the colon. Recently compounds which contain only 5-aminosalicylic acid have been developed; these are as effective as sulphasalazine and do not have the sulphapyridine side effects but do have side effects of their own, notably diarrhoea.
Glucocorticosteroids are, however, not used for maintenance of remission in ulcerative colitis; doses that do not produce unacceptable side effects are ineffective, and patients who need chronic high dose glucocorticosteroids for control of their disease almost invariably are treated by colectomy.
As with ulcerative colitis, glucocorticosteroids are the treatment of choice for severe active Crohn's disease, but ideally only to achieve remission, after which they should be stopped. However, all too frequently the disease does not satisfactorily remit, and glucocorticosteroids may be necessary to maintain control of symptoms.
Sulphasalazine is also useful in less severe cases, particularly for disease involving the colon.
Very often in Crohn's disease, however, primary medical treatment of the disease process is ineffective, and only symptomatic treatment is of value i.e. analgesics for pain and opiates for diarrhoea. Most patients eventually require surgery.
DISCLOSURE OF THE INVENTION
Our studies indicate that the compositions according to the present invention may advantageously be used in the treatment of ulcerative colitis including idiopathic proctitis and certain aspects of Crohn's disease by the oral route.
In ulcerative colitis the compositions can be used for the treatment of both active and chronic continuous disease and for relapse preventing treatment (i.e. maintenance therapy once remission has been achieved).
In Crohn's disease the compositions can be used for the treatment of Crohn's colitis in its active phase and for relapse preventing therapy (i.e. maintenance therapy once remission has been achieved), and for the treatment of the small intestine for relapse preventing treatment (i.e. maintenance therapy).
It has been found that the diseases defined above can be treated using the anti-inflammatory steroids
(22RS)-16&agr;,17&agr;-butylidenedioxy-11&bgr;,21-dihydroxypregna-1,4-diene-3,20-dione [I],
the 22R-epimer of [I],
(22RS)-16&agr;,17&agr;-butylidenedioxy-9&agr;-fluoro-11&bgr;,21-di-hydroxy-pregna-1,4-diene-3,20-dione [II],
the 22R-epimer of [II],
(22RS)-16&agr;,17&agr;-butylidenedioxy-6&agr;,9&agr;-difluoro-11&bgr;,21-dihydroxy-pregna-1,4-diene-3,20-dione [III],
the 22R-epimer of [III],
(22RS)-21-acetoxy-16&agr;,17&agr;-butylidenedioxy-11&bgr;-hydroxy-pregna-1,4-diene-3,20-dione [IA],
the 22R-epimer of [IA],
(22RS)-21-acetoxy-16&agr;,17&agr;-butylidenedioxy-9&agr;-fluoro-11&bgr;-hydroxy-pregna-1,4-diene-3,20-dione [IIA],
the 22R-epimer of [IIA],
(22RS)-21-acetoxy-16&agr;,17&agr;-butylidenedioxy-6&agr;,9&agr;-difluoro-11&bgr;-hydroxy-pregna-1,4-diene-3,20-dione [IIIA],
the 22R-epimer of [IIIA],
(22RS)-16&agr;,17&agr;-butylidenedioxy-11&bgr;,21-dihydroxypregn-4-ene-3,20-dione [IV],
the 22R-epimer of [IV],
(22RS)-16&agr;,17&agr;-pentylidenedioxy-11&bgr;,21-dihydroxypregn-4-ene-3,20-dione [V],
the 22R-epimer of [IV],
(22RS)-21-acetoxy-16&agr;,17&agr;-butylidenedioxy-11&bgr;,hydroxypregn-4-ene-3,20-dione [IVA],
the 22R-epimer of [IVA],
(22RS)-21-acetoxy-16&agr;,17&agr;-pentylidenedioxy-11&bgr;,21-dihydroxypregn-4-ene-3,20-dione [VA],
the 22R-epimer of [VA],
methyl (20RS)-16&agr;,17&agr;-butylidenedioxy-11&bgr;-hydroxy-androsta-1,4-diene-3-one-17&bgr;-carboxylate [VI],
the 20R-epimer of [VI],
methyl (20RS)-16&agr;,17&agr;-butylidenedioxy-9&agr;-fluoro-11&bgr;-hydroxy-androsta-1,4-diene-3-one-17&bgr;-carboxylate [VII],
the 20R-epimer of [VII],
methyl (20RS)-16&agr;,17&agr;-butylidenedioxy-6&agr;,9&agr;-difluoro-11&bgr;-hydroxy-androsta-1,4-diene-3-one-17&bgr;-carboxylate [VIII],
the 20R-epimer of [VIII],
methyl (22RS)-16&agr;,17&agr;-butylidenedioxy-6&agr;,9&agr;-difluoro-11&bgr;-hydroxy-3,20-dioxopregna-1,4-diene-21-oate [IX] and
the 22R-epimer of [IX].
Compound [I] has the approved name “budesonide”.
Compound [I] and its 22R-epimer are particular preferred compounds.
Budesonide and compounds [II], [III], [IA], [IIA] and [IIIA] are described and claimed in Swedish Patent Specification 378 109. Budesonide is known to have an anti-inflammatory activity and, compared to prednisone, prednisolone and other glucocorticosteroids, an advantageous ratio between local and systemic effect when administered topically to the skin or to the lungs by inhalation.
Budesonide is a potent steroid, which is successfully used when locally treating (via aerosol) asthma and rhinitis. Also controlled trials of budesonide enema for locally treating proctitis and distal ulcerative colitis are in progress (Danielsson Å et al: A controlled randomized trial of budesonide versus prednisolone retention enemas in active distal ulcerative colitis, Scand. J. Gastroenterol. 22:987-992, 1987 and Danielsson Å et al: Controlled trial of budesonide enema and placebo in proctitis and distal ulcerative colitis. Scand. J. Gastroenterol. 24. supplement 159:88). The use of oral budesonide in the treatment of small bowel Crohn's disease in its active phase has been described (Wolman S L: Use of oral budesonide in a patient with small bowel Crohn's disease and previous pseudotumor cerebri secondary to steroids. Scand. J. Gastroenterol. 24, Supplement 158:146-147).
The characteristic profile of budesonide when used for the treatment of these diseases is a high anti-inflammatory effect at the place of application but a low degree of unwanted systemic glucocorticoid side effects. The low degree of systemic side effects of budesonide is a result of a high first pass liver metabolism transferring budesonide into substantially less active
Aktiebolaget Draco
Webman Edward J.
White & Case LLP
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