Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ortho-hydroxybenzoic acid or derivative doai
Reexamination Certificate
1999-12-17
2002-07-30
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ortho-hydroxybenzoic acid or derivative doai
C166S163000
Reexamination Certificate
active
06426338
ABSTRACT:
This application is a 371 of PCT/AU98/00332 filed May 7, 1998.
1. Technical Field
This invention relates to methods and compositions for the treatment of bowel disorders characterised by constipation. Such disorders include segments of Irritable Bowel Syndrome (IBS) characterised by constipation, chronic pseudo-obstruction, chronic abdominal bloating syndrome and functional constipation. Symptoms include abdominal pain, constipation, bloating, acid reflux, flatulence, nausea and vomiting, chronic lethargy and sleep disorders.
2. Background Art
Constipation is a very common condition in the west, affecting about 20% of the population. Yet, to date no effective therapy is available. Chronic constipation is a condition largely confined to women and is of unknown etiology. Diet, psychology, motility disturbances and enteric nervous dysplasia have been identified as possible causes or factors. However, for the majority of patients the cause of constipation remains obscure. The pathogenesis of irritable bowel syndrome has also hitherto been unknown. Conventional treatments have been unsatisfactory as instanced by the very large number of therapies available and recommended from time to time. These have included psychotherapy, dietary regimens, and laxatives. To date, there is no evidence that any such therapies influence the underlying mechanism of the disorder and certainly cure is not possible.
In general, therefore, the treatment of constipation and bloating as well as pseudo-obstruction and functional constipation depends still on chronic usage of laxatives. There has indeed been little attempt to treat any underlying pathophysiologic condition, since the underlying condition is not yet understood. However, as described by Borody T J et al (Oral vancomycin can reverse idiopathic constipation,
Gastroenterology
(1989) 96 52A) there is some evidence that in constipated patients abnormal bowel flora may be invaded by yet uncharacterised pathogenic bacteria which manufacture false neurotransmitters which bind to the nerves and muscle fibres of the enteric nervous system and affect intestinal motility. Constipation and pseudo-obstruction may ensue from such an infection. From clinical observations and response to antibiotics it is apparent that more often than not constipation is caused by an infection of the normal enteric flora by bacteria which manufacture endorphin-like substances.
However, use of antibiotics on a long-term basis has been of little help in solving the problem of constipation because of potential side-effects. For example, vancomycin is neurotoxic. Furthermore, costs of such antibiotics to the patient would be prohibitive.
More recently, colchicine, a drug used for several decades in the treatment of gout and one known to cause diarrhoea, has been trialed in severe constipation (Verne G N et al: Colchicine is an effective treatment for patients with severe idiopathic constipation,
Gastroenterology
(1995) 108 A705). However, colchicine given alone in the doses described in the paper is dangerous long-term since it can cause muscle and nerve damage (myopathy and neuropathy) and is therefore of no practical use in chronic constipation. In a lower dose it is insufficient in most patients to stimulate defecation. Hence, on its own colchicine is clinically of interest but of no practical use for this group of conditions.
Australian patent no. 652191 discloses the usefulness of salicylic acid derivatives in the treatment of bowel disorders including constipation. However, only larger doses of 1.0 to 1.5 g amino-salicylic acid derivatives effectively relieved the symptoms of constipation and the percentage of patients whose constipation is actually ameliorated by administration of amino-salicylic acid derivatives alone is relatively low.
Accordingly, there remains a need for an effective therapy for constipation. It is an object of the present invention to provide a composition and method for the treatment of constipation.
DISCLOSURE OF THE INVENTION
The present invention arose from observations by the inventor that treatment of patients with colchicine for constipation, although effective, requires high doses as does treatment with amino-salicylic acid derivatives. It was only upon combining both these agents at lower doses that it was observed that such a combination produces the best results to date for the patient. The clinical effect on the symptoms of bowel disorders characterised by constipation, by combined administration of low doses of an amino-salicylic acid derivative and colchicine, is surprisingly greater than would be expected from a summation of the known effects of administering the same doses of either the amino-salicylic acid derivative or colchicine alone.
Thus, in a first embodiment, the invention provides a pharmaceutical composition for the treatment or prophylaxis of constipation, the composition including or consisting of colchicine and at least one amino-salicylic acid derivative.
In a second embodiment, the invention provides a method for the treatment or prophylaxis of constipation in a mammal in need of said treatment or prophylaxis, including administering to said mammal an effective amount of colchicine and an effective amount of at least one amino-salicylic acid derivative.
The invention further provides a process of manufacturing a medicament for the treatment or prophylaxis of constipation, the composition including or consisting of colchicine and at least one amino-salicylic acid derivative; use of a composition including or consisting of colchicine and at least one amino-salicylic acid derivative for the treatment or prophylaxis of constipation; and use of colchicine with at least one amino-salicylic acid derivative for the manufacture of a medicament for the treatment or prophylaxis of constipation.
As used herein, the expression “amino-salicylic acid derivative” means 4-amino salicylic acid, 5-amino salicylic acid, or a pharmaceutically acceptable salt or prodrug thereof.
In the compositions, methods, processes and uses in accordance with the invention, the amino-salicylic acid derivative is typically selected from the group consisting of mesalazine (5-amino salicylic acid), olsalazine, sulfasalazine, ipsalazide, balsalazide, benzalazine, para-amino salicylic acid (4-amino salicylic acid) and pharmaceutically acceptable salts thereof.
Preferably, the amino-salicylic acid derivative is one of a group consisting of sulfasalazine, olsalazine and the amino salicylic acids including 5-amino salicylic acid and 4-amino salicylic acid or a pharmaceutically acceptable salt thereof. Still more preferably, the amino-salicylic acid derivative is selected from mesalazine, olsalazine and pharmaceutically acceptable salts thereof. Advantageously, the amino-salicylic acid derivative may be selected by reference to the particular disorder involved. For example, pain-predominant constipation may benefit more from administration of a preparation including mesalazine as opposed to olsalazine. Compositions which include colchicine and more than one amino-salicylic acid derivative are also within the scope of the present invention. Similarly, a method of the second embodiment of the invention may include administering more than one amino-salicylic acid derivative.
Compositions of the invention may be prepared by means known in the art for the preparation of pharmaceutical compositions including blending, grinding, homogenising, suspending, dissolving, emulsifying, dispersing and, where appropriate, mixing of the colchicine and amino-salicylic acid derivative(s), optionally together with one or more selected excipients, diluents, carriers and adjuvants.
The pharmaceutical composition of the invention may be in the form of a tablet, lozenge, pill, troche, capsule, soft-gel capsule, sachet or other combining vehicle, elixir, powder, including lyophilised powder, solution, granule, suspension, emulsion, syrup or tincture. Slow-release, or delayed-release, forms may also be prepared, for example in the form of coated particles, multi-layer tablets or microg
Jagoe Donna
Krass Frederick
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