GB2041958A

GB2041958A - Medical preparations containing salicylazosulfa pyridine

Info

Publication number: GB2041958A
Application number: GB8001484A
Authority: GB
Original assignee: Individual
Current assignee: Individual
Priority date: 1979-01-29
Filing date: 1980-01-16
Publication date: 1980-09-17
Also published as: SE431937B; DE3003107A1; SE7900738L; GB2041958B

Abstract

A salicylazosulfa pyridine containing medical preparation, principally intended for treatment of ulcerous colitis, comprises salicylazosulfa pyridine chemically bonded, absorbed or adsorbed in a hydrophilic, cross-linked hydroxyl group containing polymer which is insoluble in water but has a capability of swelling in water containing liquids while forming a gel with chromatographic qualities. The polymer is preferably a cross-linked cellulose, starch, inulin, dextran or derivative, eg ethylhydroxyethyl cellulose, hydroxypropyl starch or hydroxyethyl dextran, or a polymerized and cross- linked carbohydrate, eg. dextrin, saccharose, maltose, glucose, fructose, sorbitol or inositol.

Description

SPECIFICATION Improvements in or relating to a medical preparation THE PRESENT INVENTION relates to a medi cal preparation, and more particularly to a medical preparation containing salicylazosulfa pyridine such as a preparation intended for the treatment of ulcerous colitis.

Salicylazosulfa pyridine is a sulfa preparation, which has been used extensively for the treatment of ulcerous colitis unspecified colitis and acute and chronic rheumatoid arthritis for example. One prior proposed way of making such a preparation is described in Swedish Patent Specification No. 130,524. As disclosed in this prior specification sulfapyridine is diazotized, and the diazonium salt of sulfapyridine thus formed is reacted with salicylic acid to form salicylazosulfa pyridine. Salicylazosulfa pyridine made in this way is presently marketed in the form of tablets in which starch is used as a filler and disintegrating agent.

Salicylazosulfa pyridine has a strong affinity to mucous membranes, which means that a good distribution of the salicylazosulfa pyridine in the intestinal canal, especially the lower regions of the intestinal canal is rendered difficult. This can be understood when it is appreciated that the salicylazosulfa pyridine tends to adhere on the mucous membrane surfaces, that it first encounters, namely the mucous membrane surfaces in the upper part of the intestinal canal. This can result in undesirable side effects.

Well known side effects caused by the unsatisfactory distribution of salicylazosulfa pyridine in the intestinal canal include indisposition or nausea, lack of appetite, pruritus, exanthem, urticaria, stomattis, parotitis, pancreatitis, and hepatitis.

The present invention seeks to provide a medical preparation in which the above described disadvantages of prior preparations are obviated or reduced.

According to this invention there is provided a salicylazosulfa pyridine containing medical preparation, which comprises salicylazosulfa pyridine chemically bonded, absorbed or adsorbed in a hydrophilic, cross-linked polymer containing hydroxyl groups, which polymer is insoluble in water but has a capability of swelling in water containing liquids to form a gel.

The preparation may be principally intended for the treatment of ulcerous colitis.

Examples of the said cross-linked three dimensional polymers are known per se and are presently utilised as gel chromatographic materials. Thus the preferred materials have chromatographic qualities.

Preferably the polymer may comprise a cross-linked polyalcohol polymer, a cross linked polymer carbohydrate a cross-linked polymerized carbohydrate, a cross-linked po lymer sugar alcohol, a cross-linked polymer ized sugar alcohol or a derivative thereof.

Cross-linked cellulose, starch, inulin and dex tran and derivatives thereof, such as ethylhy droxyethyl cellulose, hydroxypropyl starch and hydroxyethyl dextran are examples of suitable cross-linked polymers.

Alternatively cross-linked, polyermised, car bohydrates, preferably of low molecular weight such as dextrin, saccharose, maltose, glucose, fructose, sorbitol or inositol, can be used.

The above compounds may be cross-linked for example, by reacting and/or polymerizing the starting product with a bifunctional sub stance, such as epichlorohydrin.

Such cross-linked polymers are known per se, for example from the Swedish Patent Specifications 169,293, 204,906, 209,018, 222,291 and 358,894.

However, it is also possible to use polymers other than the above mentioned ones, on condition that they have similar properties. As examples of such polymers, a cross-linked polyvinyl pyrrolidone or a cross-linked polya crylamide can be mentioned.

Hydrophilic, cross-linked, water insoluble polymers suitable for use in forming prepara tions in accordance with the invention with gel chromatographic qualities are character ized by their swelling ability in water. The swelling ability can be measured for example by by letting one gram of dry cross-linked po- lymer swell fully in a surplus of distilled water whereupon the volume of the gel is measured.

The swelling ability may thus be expressed in terms of ml/g. Preferably the cross-linked polymer has a swelling ability of 1.5 to 100 ml/g, for example 1.5 to 50 ml/g.

The cross-linked polymer can contain ion exchanging groups. In one preferred embodi ment of the invention the cross-linked polymer contain anionic groups. For example, these can consist of carboxy groups, sulphonic acid groups or phosphoric acid groups. The princi ple of bonding anionic and cationic groups to different polymers is well known per se, for example from the U.S.A. Patent Specifications Nos. 3,275,576, and 3,277,025 and the Swedish Patent Specification No. 222,291.

Phosphoric acid groups can be bonded to hydroxyl groups, for instance in carbohydrate polymers, by esterification reactions.

The proportion of ion exchanging groups in the cross-linked polymer can be expresed by the equivalent weight or by the ion exchang ing capacity expressed in mekv/g. The ion exchanging capacity of the cross-linked po lymer can amount to 5 mekv/g.

In one preferable embodiment of the inven tion, the salicylazosulfa pyridine is absorbed and/or adsorbed in the cross-linked polymer, and this material can subsequently be used to make tablets. This absorption and/or adsorption is preferably be carried out before the tablet production process. Thus sulfapyridine is first diazotized, whereupon the diazonium salt is reacted with salicylic acid in an alkaline solution. The salicylazosufla pyridine formed is soluble in alkaline solutions, and the resultant solution containing the salicylazosulfa pyridine is suitably filtered, and then a cross-linked polymer is added to the filtered solution. The salicylazosulfa pyridine is allowed to diffuse into the cross-linked polymer whilst the solution is stirred.When an equilibrium has been obtained the salicylazosulfa pyridine is precipitated, for example by acidification with hydrochloric acid. In this process the salicylazosulfa pyridine is precipitated on large surfaces of the three dimensional polymer, whereby an effective purification of the crude product can be achieve. After a washing, and possible drying, one can make tablets directly from the product thus obtained, together with additives if required.

Alternatively salicylazosulfa pyridine in the form of a solution may be absorbed and/or adsorbed in the cross-linked polymer, which is thereafter possibly dried.

Alternatively again the salicylazosulfa pyridine can be chemically bonded in such a way to the cross-linked polymer that the salicylazosulfa pyridine will split off from the crosslinked polymer a contact with intestinal juice.

For example, such a chemical bonding can be brought about if hydroxyl groups of the crosslinked polymer are reacted with carboxy groups of the salicylazolsulfa pyridine so that an esterification takes place.

It has been found that advantages may are obtained by using a preparation in accordance with the invention as compared to previously known preparations containing salicylazosulfa pyridine. Thus, the preferred three dimensional polymer has turned out to make an excellent filler and disintegrating agent for example in tablets. Furthermore, as a very substantial advantage, a better distribution of the salicylazosulfa pyridine in the intestinal canal has been obtained. This results in a reduction of the above mentioned side effects.

As a result of the ability of the three dimensional polymer to swell in water containing liquids, a volume increase of the evacuation or stool is obtained, which has a positive influence on the peristaltic waves of the intestine.

This promotes the healing process in connection with ulcerous colitis for instance.

If the cross-linked polymer is formed as irregular particles tablets of good mechanical strength may be obtained.

In certain cases a further prolongation of the release of salicylazosulfa pyridine can be desirable. This can be obtained if anionic groups in acid form are bonded to the crosslinked polymer. Sometimes it has turned out to be valuable if at least a part of the anionic groups are present in the form of a zinc salt, which has a positive effect on the healing process in connection with ulcerous colitis for example.

The preparation according to the invention can, together with other additives if required, be produced in the form of example tablets, dragees, suppositories and suspensions.

The invention will be explained further in connection with the examples given below.

Example 1 A. A cross-linked carboxymethyl starch polymer was produced by adding 800 g carboxymethyl starch (Stadex, Malmoe, Sweden) with a substitution degree of 0.25 in respect of carboxy groups to 2000 ml toluene. 200 ml epichlorohydrin and 500 ml 6 N sodium hydroxide solution were added with stirring to the suspension obtained. The reaction was continued at 55 C for 1 5 hours. The reaction mixture was cooled, whereupon the toluene was separated. The product was washed with water, neutralized with 1 N hydrochloric acid and washed with distilled water. The product was shrunk with ethanol, dried and ground.

750 g cross-linked polymer with a swelling ability of 4.8 ml/g were obtained.

B. Salicylazosulfa pyridine was produced by dissolving 250 g sulfapyridine (Sigma Chemical Company, St. Louis, USA) in a mixture of 250 ml concentrated hydrochloric acid and 500 ml distilled water. The solution was cooled to 0 C and the sulfapyridine was diazotized with a solution of 80 g sodium nitrite in 250 ml distilled water. The temperature was kept at 0 C during the reaction that was continued for 3 hours. The reaction mixture had to be diluted during the reaction with 500 ml cold distilled water to permit an effective stirring. The diazonium salt formed above was introduced into a solution consisting of 1 59 g salicyclic acid dissolved in 1100 ml 5 N sodium hydroxide solution having a temperature of O"C. The reaction was continued at 0 C for 60 minutes. The solution was filtered. Then 5 N hydrochloric acid was added to the solution so that a pH of 2.7 was obtained. The precipitated suspension obtained was separated by filtration, washed with distilled water and sucked dry. The damp product was dissolved in 2000 ml 0.7 N sodium hydroxide solution and into two equal parts. One-part was treated as will be described in paragraph C and the other part as will be described in paragraph D below.

C. 375 g of the cross-linked polymer as described in paragraph A were added to one part of the solution as described in paragraph B, whereupon the salicylazosulfa pyridine solution was allowed to diffuse into the crosslinked polymer for 30 minutes while the solution was stirred. The suspension thus obtained was acidified with 1 N hydrochloric acid to a pH of 2.8. The precipitated product was sepa rated by filtration. It was washed until neutral with distilled water. Then it was dried. In this way 250 g product, which consisted of a cross-linked carboxymethyl starch polymer containing salicylazosulfa pyridine, were obtained.

D. 375 g of the cross-linked polymer as described in paragraph A were added to the other part of the solution as described in paragraph B, whereupon the salicylazosulfa pyridine solution was allowed to diffuse into the cross-linked polymer for 30 minutes while the solution was stirred. The suspension thus obtained was acidified with 1 N hydrochloric acid to a pH of 2.9. The precipitated product was separated by filtration. It was washed until neutral with distilled water. Then it was sucked dry. The product was treated on the filter with a solution of 20 g zinc chloride in 500 ml distilled water. The solution was allowed to pass slowly through the product bed.

The product was washed until neutral with distilled water, whereupon it was dried. Then 526 g product, which consisted of a crosslinked carboxymethyl starch polymer containing salicylazosulfa pyridine, where obtained.

The proportion of zinc in the product was 16%.

Example 2 A cross linked hydroxyethyl cellulose polymer was produced by dissolving 300 g hydroxyethyl cellulose (Natrosol 250 J R, Hercules Inc., Wilmington, USA) in 1 300 ml distilled water containing 75 g sodium hydroxide and 5 g sodiumboron hydride. The solution thus obtained was introduced into another solution consisting of 1 500 ml ethylenedichloride and 90 g stabilizer (Bayer Cellite BP 900) while the solution was stirred.

The mixture was heated to 70"C with stirring and 50 ml epichlorohydrin were added for the cross-linking reaction. The cross-linking reaction was carried out for 5 hours at 70"C with stirring. The reaction mixture was cooled to 22"C and the cross-linked polymer was cleaned by a treatment with acetone and 50 % ethanol/water. Finally the product was neutralized and shrunk in ethanol. The product was dried for 14 hours at 70"C in a drying chamber. Then 253 g cross-linked hydroxyethyl cellulose polymer with a bed volume of 18 ml/g were obtained.

50 g salicylazosulfa pyridine (National Formulary XIV Edition, American Pharmaceutical Association, Washington, USA) were dissolved in 500 ml 0.7 N sodium hydroxide solution with stirring. 50 g of the above cross-linked polymer were introduced into the solution obtained with stirring. The mixture obtained was stirred for 30 minutes at 22"C, whereupon 1 N hydrochloric acid was added to bring the solution a pH of 2.8. The precipitated product formed was separated on a suction funnel and washed with neutral with distilled water. The product was dried in a drying chamber for 11 hours at 70"C. Then 96 g product consisting of a cross-linked hydroxyethyl cellulose polymer containing salicylazosulfa pyridine were obtained.

The invention is not limited to the embodiments shown, since these can be modified in different ways within the scope of the present invention, as defined by the following claims.

Claims

1. A salicylazosulfa pyridine containing medical preparation, which comprises salicylazosulfa pyridine chemically bonded, absorbed or adsorbed in a hydrophilic, cross-linked polymer containing hydroxyl groups, which polymer is insoluble in water but has a capability of swelling in water containing liquids to form a gel.

2. A preparation according to claim 1, wherein the polymer comprises a cross-linked polyalcohol polymer, a cross-linked polymer carbohydrate, a cross-linked polymerized carbohydrate, a cross-linked polymer sugar alcohol, a cross-linked polymerized sugar alcohol or a derivative thereof.

3. A preparation according to claim 1 or 2, wherein the polymer comprises cross-linked cellulose, starch, inulin, dextran or a derivative thereof.

4. A preparation according to claim 3 wherein the polymer consists of ethylhydroxyethyl cellulose, hydroxypropyl starch or hydroxyethyl dextran.

5. A preparation according to claim 1 or 2, wherein the polymer comprises a polymerized and cross-linked carbohydrate.

6. A preparation according to claim 5 wherein said polymer comprises dextrin, saccharose, maltose, glucose, fructose, sorbitol or inositol.

7. A preparation according to any one of claims 1 to 6, wherein the polymer is crosslinked by means of a bifunctional substance.

8. A preparation according to claim 7 wherein said bifunctional substance is epichlorohydrin.

9. A preparation according to any one of claims 1 to 8, wherein the polymer contains ion exchanging groups.

10. A preparation according to claim 9, wherein the ion exchanging groups consist of anionic groups.

11. A preparation according to claim 10 wherein said anionic groups comprise carl oxy groups, sulphonic acid groups or phosphoric acid groups.

12. A preparation according to claim 10, wherein the anionic groups at least partially are present in acid form and/or in the form of zinc salts.

1 3. A preparation according to any one of claims 1 to 12, wherein the polymer is present in the form of particles with irregular shape.

14. A preparation substantially as herein described in Example 1.

1 5. A preparation substantially as herein described in Example II.

1 6. Any novel feature or combination of features disclosed herein.