A PHARMACEUTICAL COMPOSITION CONTAINING AZO-BIS-SALICYLIC ACID OR A SALT THEREOF AND A METHOD FOR TREATMENT OF INFLAMMATORY CONDITIONS IN THE INTESTINE

Abstract: Novel composition for the treatment of inflammatory disorders in the intestine (IBD), especially ulcerative colitis. The composition contains 4,4'-azo-bis-salicylic acid and/or a pharmacologically acceptable and therapeutically active salt thereof. The invention also provides a novel method for the treatment of inflammatory disorders in the intestine, especially ulcerative colitis.

Description: - A pharmaceutical composition containing azo-bis-salicylic acid or a -_alt thereof and a method for treatment of inflammatory conditions in the intestine. This invention is concerned with a novel composition for the treatment of inflammatory disorders in the intestine, especially ulcerative colitis. The composition contains 4,4'-azo-bis-salicylic acid or its pharmacologically acceptable salts, in particular the disodium salt. The present invention also provides a novel method for treating inflammatory disorders in the intestine (IBD) , especially ulcerative colitis. The method comprises oral or rectal administration of a compound suitably formu¬ lated for its contemplated use? e.g. for oral administration in the form of a tablet or capsule, and for rectal adminis¬ tration in the form of an- enema or suppository. 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 cleaved to sulfapyridine and 5-aminosalicylic acid (5-ASA) in the patient's large intestine. The cleavage product 5-ASA is believed to be responsible for the thera¬ peutical effect, by direct local action on the intestinal mucosa, while the other cleavage 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. As regards 5-ASA, its only known side effect is a toxic effect on the kidneys. Other methods of treating inflammatory disorders of the intestine comprise rectal or oral treatment with 5-ASA ( P-A-8102671) , 5,5'-azo-bis-saliσylic acid (A) (EP-A-0036637) , carboxyphenylazosalicylic acid (B) (ΞP-A-0045006) and its carboxymethylamide (C) (GB-A-2080796) . It is believed that when the three last-mentioned 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-amino- salic lic acid plus another compound: p-aminobenzoiσ 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 (EP-A-62000) . Oral administration of PAS or of 5-ASA is not 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. It is known that such splitting of azo compounds in the intestine as will occur with e.g. sulfasalazine will proceed satisfactorily as long as the azo compound contains a hydroxy group in position para or ortho to an azo group. Upon chemical reduction of azo compounds containing such hydroxy groups, the split amines are formed immediately. If the azo compound does not contain hydroxy groups in ortho or para position (note that amino groups give the same effect) , . reduction will proceed with the formation of stable hydrazo compounds. Much more vigorous reductive conditions are then required for further reducing the hydrazo compounds to form amines. ___ OMH The compund 4,4'-azo-bis-salicylic acid was once considered to be potentially effective against tuberculosis. However, this compound was shown to be inactive against that disease, according to pharmacological testing (Ind. J. Med. Res. 40 (1952), p. 4-5, and Ind. J. Pharm. 13 (1951), p. 3-5). These early results moreover show that under the conditions employed in the in vivo tests no (or very little) free PAS can have formed by splitting: If it had formed, the " results obtained ought to have been good ones, that is, the PAS if it had formed would have shown a very good tuberculostatic effect in the animal model chosen. There is nothing remark¬ able about the results actually obtained, inasmuch as splitting of 4,4'-azo-bis-salicylic acid to PAS was not to be expected because of the greater resistance of the 4,4' compound to reduction as compared to for example the isomeric 5,5'-azo-bis-salicylic acid. Surprisingly, it has now been found that in contrast to the evidence provided by earlier results the 4,4'-azo-bis-salicylic acid (as well as salts thereof) is split reductively in vivo, with the formation of PAS. The reduction takes place in the large intestine or corresponding organ under the action of the- reducing conditions of the local environment. The splitting is a necessary prerequisite for the 4,4'-azo- bis-salicylic acid to become effective as an agent against the intestinal disorders, and the present invention is based on the highly surprising discovery that splitting actually does take place. Cόrroboration of this discovery is illustrated in Example 5. The invention relates to compositions which are novel for treating inflammatory disorders in the intestine. In addition to a therapeutically active amount of 4,4'-azo-bis-salicylic acid and/or a salt thereof which is pharmaceutically acceptable and therapeutically active, the compositions according to OMPI the invention may optionally contain a pharmaceutically acceptable carrier and/or a suitable adjuvant. Examples of suitable salts include salts of said acid with pharma¬ ceutically acceptable alkali or alkaline earth metals, and salts with positively charged and pharmaceutically acceptable carriers. The compositions according to the invention may take the form of tablets, drag€es, capsules, enemas etc. They are produced in a known per se manner in that 4,4'-azo-bis- salicylic acid is mixed with the desired carrier material and/or appropriate auxiliary substances to thus give a suitable galenic form. For example, the composition may be coated with a film that is resistant to gastric juice and is dissolved only after it has reached the intestine. When a composition according to the invention is prepared the free acid may be replaced by one or more of its salts which are suitable for the purpose in question. The amount of acid or its salt per dosage unit will vary, depending in each case on inter alia the number of administrations per day, and the individual and total dosages per day. By analogy with what is known about 5-aminosalic lic acid, it is expected that only a minor portion of the PAS and Ac-PAS as formed will be absorbed from the large intestine and secreted in the urine. The release of PAS moreover proceeds relatively slowly, which is an advantage especially in cases where the site of the inflammatory intestinal disorder is in the lower portion of the large intestine. The toxicity of 4,4'-azo-bis-salicylic acid, PAS and Ac-PAS is remarkably low. Therefore, 4,4'-azo-bis-salicylic acid and its pharmacologically tolerable salts are potentially useful agents for the treatment of inflammatory disorders of the intestine, in particular ulcerative colitis. The present invention is also concerned with a novel method of treating inflammatory conditions in the intestine, especially in the large intestine, and in particular ulcerative colitis. The method is σharacterixed by rectally or orally administering a therapeutically active dose of 4,4'-azo-bis- salicylic acid " or a salt thereof which is pharmaceutically acceptable and therapeutically active. This of course also includes the possibility of administering the free acid together with one or more of such salts. According to a preferred embodiment, the acid is administered in salt form, and such a salt may advantageously be an alkali or alkaline earth metal salt, e.g. sodium salt of the acid. Administration is usually performed together with a pharmaceutically acceptable carrier and/or a suitable .adjuvant. The daily dose of the active substance, 4,4*-azo-bis-salicylic acid, will vary from case to case and may amount to for instance- about 0,1 to abo.ut 10 g per day and adult weighing 75 kg. In normal therapy cases, a preferred dosage will as a rule give a good therapeutical effect while at the same time side effects are kept at an acceptable low level. The total daily dose may be portioned out among a plurality of admin¬ istrations per day, for instance 1 to 5 administrations. Where the drug is administered in the form of the salt of the acid, the doses, mentioned above refer to the corresponding amount of free 4,4'-azo-bis-salicylic acid. - Production of 4,4'-azo-bis-salicylic acid is known per se. The compound may thus be produced according to e.g. Budziarek, R. et al. (J. Chem. Soc. (1955), part III p. 3158-63). In accordance with this method methyl 4-aminosalicylate is subjected to an oxidative self-coupling reaction so as to form 3,3'-dihydroxy-4,4'-dimethoxycarbonyl-azooxybenzene. The azooxy group of the coupling reaction product is reduced whereupon the methyl ester groups are hydrolyzed to thus form the desired 4,4'-azo-bis-salicylic acid. It will be appreciated of course that also other types of syntheses may be chosen, but an important point to be noted is that the synthesis method chosen should give a product of such purity as to be pharmaceutically acceptable. This "pharmaceutically acceptable degree of purity" means that the product must not contain impurities which give rise to unacceptable side effects. Normally an absolute purity of 98 % (w/w) is suitable in this respect, the product having at the same time to f lfill the ordinary quality requirements of -medicines. A number of non-limitative working examples are set out below. Example 1 4,4-azo-bis-salic lic acid (produced 250 mg according to J. Chem. Soc (1955) part III p. 3158-63) starch 125 mg Mg stearate 20 mg Aerosil^ 200 (silica particles, Degussa, 5 mg Federal Republic of Germany) are mixed homogeneously. Water is added, whereupon the mixture is granulated at 60 C and compressed to form tablets weighing 400 mg. If desired the tablet may be provided in a manner known per se with a coating of a film that is soluble in the stomach or in the small intestine. Example 2 disodiu 4,4 r -azo-bis-salic late 250 mg starch 110 mg Mg stearate 15 mg are mixed homogeneously and compressed to form tablets weighing 375 mg. Disodium 4,4'-azo-bis-salicylic acid is produced in a manner known per se by means of acidifying an alkaline aqueous solution of 4,4'-azo-bis-salicylic acid to pH 6-7. Example 3 The pH of ' a 10.0 lit. aqueous solution containing 100 g of disodium 4,4'-azo-bis-salicylate is adjusted to pH 7,5, whereupon the solution is filled into 100 ml bottles for rectal administration. The bottles are then sterilized. Example 4 Gelatin capsules containing 200 mg of disodium 4,4'-azo-bis- salicylate are produced by automatic filling with crystalline salt of particle size 0.15 - 2.0 mm obtained by sieve screening. Example 5 Sglitting_of ^ 4 Λ 4^-azo-bis-^ After a single dose of 100 mg/kg given orally to mice, urine was collected during a period of 24 hours. The amount of p-aminosalicylic acid (PAS and Ac-PAS, that is, N-acetyl-p- aminosalicylic acid) present in the urine was measured by means of chemical analysis (Willonghby, C.P. et al. ; but 23 (1982) p. 1081 - 87) . The results are set forth in the table below. OMPI Amount secreted, % of dose administered Ac-PAS PAS Mouse No. 1 10 0.3 2 15 3.2 3 8 0.3 4 12 0.8 Average 11.3 1.2

Claims: C L A I M S A Composition for oral or rectal treatment of inflammatory conditions in the intestine, comprising a therapeutically active amount of 4,4'-azo-bis-salicylic acid or a therapeutically active and pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and/or a pharmaceutically adjuvant. A method of treating inflammatory conditions in the intestine, comprising administering to a patient suffering from such condition a therapeutically active amount of 4,4'-azo-bis-salicylic acid or a therapeutically active amount of a pharmaceutically and therapeutically acceptable salt thereof.

Inventors: AGBACK HUBERT, TRUELOVE SIDNEY CHARLES, AGBACK, HUBERT, TRUELOVE, SIDNEY, CHARLES
Applicants: PHARMACIA AB
Application year: 1984
Main classification: A61K31
IPC codes: A61K31