Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ortho-hydroxybenzoic acid or derivative doai
Patent
1985-01-28
1986-05-27
Friedman, Stanley J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ortho-hydroxybenzoic acid or derivative doai
534660, A61K 3160
Patent
active
045915849
DESCRIPTION:
BRIEF SUMMARY
This invention is concerned with compounds having a pharmaceutically acceptable degree of purity, and with formulations thereof for the treatment of inflammatory disorders in the intestine (IBD), especially ulcerative colitis. The invention comprises also a method of treating inflammatory disorders in the intestine, especially ulcerative colitis. The method comprises oral or rectal administration of a compound according to the invention suitably formulated for its contemplated use; e.g. for oral administration in the form of a tablet or capsule, and for rectal administration in the form of an enema or suppository. The invention finally also comprises a novel method for producing 4,5'-azo-bis-salicylic acid (I) or its salt with a degree of purity that is pharmaceutically acceptable.
Medical treatments of ulcerative colitis have been carried out in various different ways. In particular two methods are now in use to a considerable extent:
Corticosteroids are relied on in severe acute cases, but they have highly objectionable side effects and are therefore unsuitable for more general use. Sulfasalazine is the compound that is being used most generally and most extensively. It is used both in acute phase treatments and prophylactically for preventing an acute condition (relapse prevention effect). Sulfasalazine is believed to exert its effect by being cleared to sulfapyridine and 5-aminosalicylic acid (5-ASA) in the patient's large intestine. The clerage product 5-ASA is believed to be responsible for the therapeutical effect, by direct local action on the intestinal mucosa, while the other clearage product, sulfapyridine, can hardly be considered to have any positive effect against the disease at all but is responsible for most of the side effects of sulfasalazine treatments.
Other methods of treating inflammatory disorders of the intestine comprise local treatment with 5-ASA and oral treatment with 5,5'-azo-bis-salicylic acid (A), carboxyphenylazosalicylic acid (B) and its carboxymethylamide (C). It is believed that when any of these three compounds are administered orally they can be transported to the large intestine where they are then subject to being split in a manner analogous to the splitting of sulfasalazine, to thus form 5-aminosalicylic acid plus another compound: p-aminobenzoic acid or p-aminohippuric acid, respectively. Compounds (A), (B) and (C) may be considered to act as carriers of 5-ASA during transport through the digestive tract. Splitting of the compound 5,5'-azo-bis-salicylic acid gives only 5-ASA.
Moreover it has been found that 4-aminosalicylic acid, PAS, a well-known anti-tuberculosis agent, may be useful in the treatment of ulcerative colitis by rectal administration. Oral administration of PAS or of 5-ASA is not considered to be recommendable because both of these substances are absorbed long before reaching that diseased region of the large intestine which is their desired target region for exerting their local effect.
In the 1950's it was believed that 4,5'-azo-bis-salicylic acid would be a potential tuberculostatic compound in view of the fact that it contains the PAS structure. However, Buchi, J. et al. (Helv. Chim. Acta 34 (1951), p. 2076-83) have shown by in vitro tests that the compound 4,5'-azo-bis-salicylic acid, among others, has a very low tuberculostatic effect--only 1/100 of the effect of PAS. For this reason it seemed out of the question that 4,5'-azo-bis-salicylic acid could be useful as a tuberculostatic agent. Buchi's work also indirectly showed that in his tests 4,5'-azo-bis-salicylic acid was not split to form 5-ASA and PAS: If indeed such splitting had occurred a tuberculostatic effect would have been obtained due to the action of PAS.
It has now surprisingly been found that in contrast to what is inferrable from the work of Buchi the 4,5'-azo-bis-salicylic acid and its salts are split, in the intestine with liberation of PAS and 5-ASA (see Example 6). The discovery of this splitting has been conducive to the elaboration of the present invention, objects of which
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patent: 1157169 (1915-10-01), Mettler
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Helvetica Chimica Acta. 34 (1951), pp. 2076-2083.
Willoughby et al., Gut. 1982, 23, pp. 1081-1087.
Friedman Stanley J.
Pharmacia AB
Philpitt Fred
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