SE431937B - SALICYLAZOSULPHAPYRIDE CONTAINING MEDICAL PREPARATION - Google Patents

SALICYLAZOSULPHAPYRIDE CONTAINING MEDICAL PREPARATION

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Publication number
SE431937B
SE431937B SE7900738A SE7900738A SE431937B SE 431937 B SE431937 B SE 431937B SE 7900738 A SE7900738 A SE 7900738A SE 7900738 A SE7900738 A SE 7900738A SE 431937 B SE431937 B SE 431937B
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Sweden
Prior art keywords
polymer
crosslinked
composition according
groups
salicylazosulfapyridine
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SE7900738A
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Swedish (sv)
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SE7900738L (en
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J A O Johansson
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Perstorp Ab
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Priority to SE7900738A priority Critical patent/SE431937B/en
Priority to GB8001484A priority patent/GB2041958B/en
Priority to DE19803003107 priority patent/DE3003107A1/en
Publication of SE7900738L publication Critical patent/SE7900738L/en
Publication of SE431937B publication Critical patent/SE431937B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

7900738-1 På grund av den otillfredsställande distributionen uppträder de i sammanhanget välkända biverkningarna, såsom illamående, aptitlös- het, pruritus, exantem, urticaria, stomatit, parotit, pankreatit, hepatit m.m. Det har sedan länge förelegat ett stort behov att komma tillrätta med dessa problem. Enligt föreliggande uppfinning har det nu visat sig möjligt att i hög grad minska dessa biverk- ningsproblem. 7900738-1 Due to the unsatisfactory distribution, they appear in well-known side effects, such as nausea, loss of appetite het, pruritus, exantem, urticaria, stomatitis, parotitis, pancreatitis, hepatitis m.m. There has long been a great need to deal with these problems. According to the present invention it has now been shown that these side effects can be greatly reduced problem.

Man har därvid åstadkommit ett salicylazosulfapyridinhaltigt medi- cinskt preparat huvudsakligen avsett för behandling av ulcerös kolit. Preparatet kännetecknas av att det innehåller salicylazo- sulfapyridin kemiskt bundet till eller absorberat i en hydrofil, tvärbunden, hydroxylgruppshaltig polymer, som är olöslig i vatten, men har förmåga att svälla i vattenhaltiga vätskor under bildning av en gel med kromatografiegenskaper.A salicylazosulfapyridine-containing medium has been obtained. Chinese preparation mainly for the treatment of ulcerative colitis colitis. The preparation is characterized in that it contains salicylazo- sulfapyridine chemically bound to or absorbed in a hydrophilic, crosslinked, hydroxyl group-containing polymer, which is insoluble in water, but has the ability to swell in aqueous fluids during formation of a gel with chromatography properties.

Sådana tvärbundna polymerer är kända som gelkromatografiska material.Such crosslinked polymers are known as gel chromatographic materials.

Enligt uppfinningen kan man exempelvis använda en tvärbunden poly- alkoholpolymer, ett polymert eller polymeriserat kolhydrat, en polymer eller polymeriserad sockeralkohol eller ett derivat därav.According to the invention, for example, a crosslinked polymer can be used. alcohol polymer, a polymeric or polymerized carbohydrate, a polymer or polymerized sugar alcohol or a derivative thereof.

Tvärbunden cellulosa, stärkelse, inulin, dextran eller derivat av dessa, såsom hydroxietylcellulosa, etylhydroxietylcellulosa, kar- boximetylstärkelse, hydroxipropylstärkelse och hydroxietyldextran, utgör_exempel på lämpliga produkter hörande till ovanstående grupp. Även polymeriserad och tvärbunden dextrin, sackaros, maltos, glukos, fruktos, sorbitol eller inositol kan användas enligt uppfinningen.Crosslinked cellulose, starch, inulin, dextran or derivatives of these, such as hydroxyethylcellulose, ethylhydroxyethylcellulose, boximethyl starch, hydroxypropyl starch and hydroxyethyl dextran, constitutes_examples of suitable products belonging to the above group. Also polymerized and crosslinked dextrin, sucrose, maltose, glucose, fructose, sorbitol or inositol can be used according to the invention.

Ovanstående föreningar kan ha tvärbundits på olika sätt. Detta kan ha åstadkommits bl.a. genom att utgångsprodukten reagerats och/ åeller polymeriserats med ett bifunktionellt ämne, såsom epiklor- hydrin.The above compounds may have been crosslinked in various ways. This can have been achieved i.a. by reacting the starting product and / or polymerized with a bifunctional substance, such as epichloro- hydrin.

Sådana tvärbundna polymerer är i och för sig förut kända, exempel- vis från de svenska patenten 169.293, 204.906, 209,0lB, 222.291 samt 358.894. 7900738-1 Det är emellertid även möjligt att använda andra än ovanstående polymerer under förutsättning att de har liknande egenskaper. Som exempel på sådana polymerer kan nämnas en tvärbunden polyvinyl- pyrolidon eller en tvärbunden polyakrylamid.Such crosslinked polymers are known per se, e.g. wise from the Swedish patents 169,293, 204,906, 209,0lB, 222,291 and 358,894. 7900738-1 However, it is also possible to use other than the above polymers provided that they have similar properties. As examples of such polymers may be mentioned a crosslinked polyvinyl pyrolidone or a crosslinked polyacrylamide.

Hydrofila, tvärbundna, vattenolösliga polymerer med gelkromatogra- fiska egenskaper karakteriseras genom sin svällningsförmåga i vatten.Hydrophilic, crosslinked, water-insoluble polymers with gel chromatography fishing properties are characterized by their swelling ability in water.

Svällningsförmågan bestämmes genom att man låter t.ex. 1 g torr tvär- bunden polymer fullständigt svälla i överskott av destillerat vatten, varefter man avläser gelvolymen. Svällningsförmågan anges i ml per gram. Enligt uppfinningen skall den tvärbundna polymeren ha en sväll- ningsförmåga av 1,5 till 100 ml/g, t.ex. 1,5 till 50 ml/g.The ability to swell is determined by letting e.g. 1 g dry cross- bound polymer completely swells in excess distilled water, after which the gel volume is read. The swelling capacity is given in ml per gram. According to the invention, the crosslinked polymer should have a swellable 1.5 to 100 ml / g, e.g. 1.5 to 50 ml / g.

Den tvärbundna polymeren kan innehålla jonbytande grupper. Enligt en utföringsform av uppfinningen innehåller den tvärbundna poly- meren anjoniska grupper. Dessa kan bl.a. utgöras av karboxylgrupper, sulfonsyragrupper eller Fosforsyragrupper. Principen att anknyta anjoniska och katjoniska grupper till olika polymerer är i och för sig välkänd bl.a. genom de amerikanska patenten 3.275.576 och 3.277.025 samt det svenska patentet 222.291. Fosforsyragrupper kan anknytas till hydroxylgrupper i exempelvis kolhydratpolymerer genom förestringsreaktioner.The crosslinked polymer may contain ion exchange groups. According to one embodiment of the invention contains the crosslinked polymer more anionic groups. These can i.a. consist of carboxyl groups, sulfonic acid groups or Phosphoric acid groups. The principle of attachment anionic and cationic groups to different polymers are in and for is well known i.a. through U.S. Patents 3,275,576 and 3,277,025 and the Swedish patent 222,291. Phosphoric acid groups can attached to hydroxyl groups in, for example, carbohydrate polymers by esterification reactions.

Halten jonbytande grupper i den tvärbundna polymeren anges genom ekvivalentvikten eller genom jonbytarkapaciteten uttryckt i mekv/g.The content of ion exchange groups in the crosslinked polymer is indicated by the equivalent weight or by the ion exchange capacity expressed in meq / g.

Jonbytarkapaciteten hos den tvärbundna polymeren kan uppgå till 5 mekv/g.The ion exchange capacity of the crosslinked polymer can amount to 5 mekv / g.

Det nya preparatet enligt uppfinningen innefattar en kombination av salicylazosulfapyridin och en tvärbunden polymer enligt ovan.The new preparation according to the invention comprises a combination of salicylazosulfapyridine and a crosslinked polymer as above.

Salicylazosulfapyridinet och den tvärbundna polymeren kan därvid vara kombinerade på olika sätt med varandra. 7900738-1 Enligt en fördelaktig utföringsfom av uppfinningen är salicylazosulfa- pyridinet inkorporerat i den tvärbundna polymeren före tablettslagningen.The salicylazosulfapyridine and the crosslinked polymer can thereby be combined in different ways with each other. 7900738-1 According to an advantageous embodiment of the invention, salicylazosulphate is the pyridine incorporated into the crosslinked polymer prior to tableting.

Inkorporeringen kan därvid exempelvis ske redan under tillverknings- processen, varvid sulfapyridin först diazoteras, varefter diazoniumsaltet reageras med salicylsyra i alkalisk miljö. Det bildade salicylazosulfa- pyridinet är lösligt i alkalisk miljö och underkastas lämpligen filtrering.The incorporation can then take place, for example, already during the the process, in which the sulfapyridine is first diazotized, followed by the diazonium salt reacts with salicylic acid in an alkaline environment. The salicylazosulfate formed the pyridine is soluble in an alkaline environment and is suitably subjected to filtration.

Den -filtrerade lösningen försattes härefter med en tvärbunden polymer, varefter salicylazosulfapyridinet får diffundera in i den tvärbundna polymeren under omrörning. Sedan jämvikt inträtt utfälles salicylazo- sulfapyridinet genom surgöring med exempelvis saltsyra. Genom detta förfarande utfälles salicylazosulfapyridinet på stora ytor i den tre- dimensionella polymeren, varigenom en effektiv rening av råprodukten kan uppnås. Efter tvättning och eventuell torkning kan man direkt slå tabletter av den så, erhållna produkten med eventuella tillsatser.The filtered solution was then added with a crosslinked polymer, after which the salicylazosulfapyridine is allowed to diffuse into the crosslinked the polymer with stirring. After equilibrium has been established, salicylazo the sulfapyridine by acidification with, for example, hydrochloric acid. Through this method, the salicylazosulfapyridine precipitates on large areas in the dimensional polymer, whereby an effective purification of the crude product can achieved. After washing and possible drying, you can immediately beat tablets of the product thus obtained with any additives.

Enligt en annan utföringsform av uppfinningen kan färdigprodukten salicyl- azosulfapyridin i form av lösning absorberas in i den tvårbundna nolymeren, vilken därefter eventuellt torkas.According to another embodiment of the invention, the finished product may be salicylic. azosulfapyridine in the form of a solution is absorbed into the crosslinked polymer, which is then optionally dried.

Enligt en ytterligare utföringsform kan salicylazosulfapyridinet vara kemiskt bundet på. sådant sšítt till den tvärbundna polymeren, att salicyl- azosulfapyridinet vid kontakt med exempelvis tarmsaft avspaltas från den tvärbundna. polymeren. En sådan kemisk bindning kan exempelvis åstadkommas om hydroxylgrupper i den tvärbundna polymeren reageras med karboxylgrupner i salicylazosulfapyridinet på. i och för sig välkänt sätt, varigenom en förestring sker.In a further embodiment, the salicylazosulfapyridine may be chemically bound on. such as to the crosslinked polymer that the salicylic the azosulfapyridine on contact with, for example, intestinal juice is cleaved from it cross-linked. polymers. Such a chemical bond can be achieved, for example if hydroxyl groups in the crosslinked polymer are reacted with carboxyl groups in the salicylazosulfapyridine at. per se well-known manner, whereby a esterification takes place.

Enligt uppfinningen uppnår man en rad fördelar i relation till förut kända preparat innehållande salicylazosulfapyridin. Den tredimensionella polymeren har således visat sig utgöra ett utmärkt fyllnads~ och spräng- medel i exempelvis tabletter. Vidare erhålles som en mycket väsentlig fördel en bättre distribution av salicylazosulfapyridinet i tarmkanalen tack vare den tredimensionella polymeren. Detta resulterar i att man reducerar ovanstående biverkningar.According to the invention, a number of advantages are achieved in relation to the foregoing known preparations containing salicylazosulfapyridine. The three-dimensional the polymer has thus been found to be an excellent filling and blasting agent. agents in, for example, tablets. Furthermore, obtained as a very essential benefit a better distribution of the salicylazosulfapyridine in the intestinal tract thanks to the three-dimensional polymer. This results in that one reduces the above side effects.

Genom den tredimensionella polymerens förmåga att svälla i vattenhaltiga. vätskor erhålles en volymökning i avföringen; som positivt påverkar tarmperistaltiken, vilket gynnar läkningsprocessen i samband med exempel- vis ulcerös kolit . 7900738-i Om den tvärbundna polymeren utformas som oregelbundna partiklar erhålles en god hållfasthet hos tabletter.By the ability of the three-dimensional polymer to swell in aqueous. liquids a volume increase is obtained in the stool; which positively affects intestinal peristalsis, which favors the healing process associated with vis ulcerative colitis. 7900738-i If the crosslinked polymer is formed as irregular particles are obtained a good strength of tablets.

I vissa fa-ll kan en ytterligare förlängning av frigörandet av salicylazo- sulfapyridin vara önskvärt och detta kan då, uppnås om man anknyter an- joniska grupper i syraform till den tvärbundna polymeren. Det har även i vissa fall visat sig värdefullt att åtminstone en del av de anjoníska grupperna föreligger i form av zinksalt, som har en positiv effekt på läkningsprocessen exempelvis i samband med-ulcerös kolit.In some cases, a further extension of the release of salicylazo sulfapyridine may be desirable and this can then be achieved by attaching ionic groups in acid form to the crosslinked polymer. It has too in some cases proved valuable to at least some of the anionic the groups are in the form of zinc salt, which has a positive effect on the healing process, for example in connection with ulcerative colitis.

Medlet enligt uppfinningen kan eventuellt tillsammans med andra tillsatser ingå i exempelvis tabletter, dragêer, suppositorier samt suspensioner.The agent according to the invention may optionally together with other additives included in, for example, tablets, dragees, suppositories and suspensions.

Uppfinningen beskrivs närmare i anslutning till nedanstående utförings- exempel .The invention is described in more detail in connection with the following embodiments. example.

Exemgel l A. En tvärbunden karboxïmetylstärkelsepolymer tillverkades enligt följande 800 g karboæçymetylstärkelse (Stadex, Malmö, Sverige) med en substi- tutionsgrad avseende karbozqylgrupper av 0,25, försattes med 2000 ml toluen. Den erhållna suspensionen försattes med 200 ml epiklorhydrin och 500 ml 6 N natronlut under omröring.Exemgel l A. A crosslinked carboxymethyl starch polymer was made according to following 800 g carboeçymethyl starch (Stadex, Malmö, Sweden) with a substi- degree of carbozyl groups of 0.25, was added with 2000 ml toluene. The resulting suspension was added with 200 ml of epichlorohydrin and 500 ml of 6 N sodium hydroxide solution with stirring.

Reaktionen fick fortgå. vid 550 C under 15 timar. Reaktionsbland- ningen kyldes och toluenet avskíldes. Produkten tvättades med vatten, neutraliserades med l N saltsyra samt tvättades med destíllerat vatten.The reaction was allowed to continue. at 550 C for 15 hours. Reaction mixture The mixture was cooled and the toluene was separated. The product was washed with water, neutralized with 1 N hydrochloric acid and washed with distilled water.

Produkten krymptes med etanol, torkades och maldes. Man erhöll därvid '(50 g tvärbunden polymer med en svällningsfömåga. av 14,8 ml/ g.The product was shrunk with ethanol, dried and ground. It was obtained (50 g of crosslinked polymer with a swelling capacity of 14.8 ml / g.

B. Salicylazosulfapyridin tillverkades enligt följande 250 g sulfopyridin (Sigma Chemical Company, St. Louis, USA) löstes i en blandning av 250 ml konc. saltsyra och 500 ml destíllerat vatten.B. Salicylazosulfapyridine was prepared as follows 250 g of sulfopyridine (Sigma Chemical Company, St. Louis, USA) was dissolved in a mixture of 250 ml conc. hydrochloric acid and 500 ml of distilled water.

Lösningen kyldes till 00 C och sulfapyridinet diazoterades med en lösning av 80 g natriwnnitrit i_250 ml destillerat vatten. Tempera- turen hölls vid 00 C under reaktionen, som fick pågå i 3 timmar. m. 7900738-1 Reaktionsblandningen måste spädas under reaktionen med 500 ml kallt destillerat vatten för att uppnå. effektiv omröring.The solution was cooled to 0 ° C and the sulfapyridine was diazotized with one solution of 80 g of sodium nitrite in 250 ml of distilled water. Tempera- the tour was kept at 00 ° C during the reaction, which was allowed to proceed for 3 hours. m. 7900738-1 The reaction mixture must be diluted during the reaction with 500 ml of cold distilled water to achieve. efficient stirring.

Det bildade diazoniumsaltet enligt ovan fördes ner i en lösning bestående av 159 g salicylsyra löst i llOO ml 5 N natronlut och med temperaturen 00 C. Reaktíonen fick fortgå vid Oo C under 60 min. lösningen filtrerades och försattes med 5 N saltsyra så att :ett pH av 2,7 uppnåddes. Den så 'erhållna fällningssuspensionen avskildes genom filtrering, tvättades med destillerat vatten och sögs dropptorr.The diazonium salt formed as above was immersed in a solution consisting of 159 g of salicylic acid dissolved in 100 ml of 5 N sodium hydroxide solution and with the temperature 00 ° C. The reaction was allowed to proceed at 0 ° C for 60 minutes. the solution was filtered and added with 5 N hydrochloric acid so that: a pH of 2.7 was achieved. The precipitate suspension thus obtained was separated by filtration, washed with distilled water and sucked dry.

Den fuktiga produkten löstes i 2000 ml 0,7 N natronlut och delades i två lika delar. Den ena. delen bearbetades enligt avsnitt C och den andra enligt avsnitt D nedan.The moist product was dissolved in 2000 ml of 0.7 N sodium hydroxide solution and partitioned two equal parts. One. the part was processed according to section C and the others according to section D below.

Den ena lösningsdelen enligt avsnitt B försattes med 375 g av den tvärbundna polymeren enligt avsnitt A, varefter salicylazosulfapyri- dinlösningen fick diffundera in i- den tvärbmdna polymeren under om- röring i 30 minuter. Den så. erhållna suspensionen surgjordes med 1 N saltsyra till ett pHav 2,8. Produkten avskildes genom filtrering.One part of the solution according to section B was added with 375 g of it the crosslinked polymer of Section A, after which salicylazosulfapyri the solution was allowed to diffuse into the crosslinked polymer during the stirring for 30 minutes. It saw. the resulting suspension was acidified with 1 N hydrochloric acid to a pH of 2.8. The product was separated by filtration.

Därefter tvättades den till neutral reaktion med destillerat vatten och torkades. Härvid erhölls 520 g produkt, som utgjordes av sali- cylazosulfapyridin i kombination med tvârbunden karboacymetylstärkelse- polymer .Then it was washed to neutral reaction with distilled water and dried. 520 g of product were obtained, which consisted of cylazosulfapyridine in combination with cross-linked carboacymethyl starch polymer.

Den andra lösningsdelen enligt avsnitt B försattes med 375 g av den tvârbundna polymeren enligt avsnitt A, varefter salicylazosulfa- pyridinlösningen fick diffundera in i den tvärbundna polymeren under omröring i 30 minuter. Den så erhållna suspensionen surgjordes med l N saltsyra till ett pH av 2,9. Produkten avskildes genom filtrering.The second solution part according to section B was added with 375 g of it the crosslinked polymer of Section A, after which salicylazosulphate the pyridine solution was allowed to diffuse into the crosslinked polymer below stirring for 30 minutes. The suspension thus obtained was acidified with 1 N hydrochloric acid to a pH of 2.9. The product was separated by filtration.

Därefter tvättades den till neutral reaktion med destillerat vatten och sögs torr .Then it was washed to neutral reaction with distilled water and sucked dry.

Produkten behandlades på filtrezt med en lösning av 20 g zinkklorid i 500 ml destillerat vatten. Lösningen fick långsamt passera genom produktbädden. Produkten tvättades till neutral reaktion med destil- lerat vatten och torkades. Härvid erhölls 526 g produkt, som utgjordes av salicylazosulfapyridin i kombination med tvärbmden karboaqfmetyl- stärkelsepolymer. Zinkhalten i produkten var 1,6 %. 7900738 -1 Exe el 2 En tvärbunden hydroxyetylcellulosapolymer tillverkades enligt fëljande. 300 g hydroxyetylcellulosa (Hatrosol 250 J R, Hercules Inc., Wilmington, USA) löstes i 1300 ml dest. vatten, som innehöll 75 E natriumhydroxid och 5 g natriumborhydrid. Den så erhållna lösningen fördes neri en annan lösning bestående av 1500 ml etylendiklorid och 90 g stabilisator (Bayer Cellíte BP 900) under omröring. Blandningen värmdes till 700 C under omröring och försattes med 50 ml epiklorhydrin för tvärbindnings- reaktion. Tvärbindningsreaktionen fick ske under omröring vid 700 C i 5 timmar. Reaktionsblandningen kyldes till 220 C och den tvdrbundna polymeren renades genom behandling med aceton och 50 % etanol/vatten.The product was treated on a filter with a solution of 20 g of zinc chloride in 500 ml of distilled water. The solution had to slowly pass through the product bed. The product was washed until neutral with distillation. clay water and dried. This gave 526 g of product, which was of salicylazosulfapyridine in combination with the cross-linked carbomethylmethyl starch polymer. The zinc content of the product was 1.6%. 7900738 -1 Exe el 2 A crosslinked hydroxyethylcellulose polymer was prepared as follows. 300 g of hydroxyethylcellulose (Hatrosol 250 J R, Hercules Inc., Wilmington, USA) was dissolved in 1300 ml of dest. water, which contained 75 U of sodium hydroxide and 5 g of sodium borohydride. The solution thus obtained was taken down another solution consisting of 1500 ml of ethylene dichloride and 90 g of stabilizer (Bayer Cellíte BP 900) while stirring. The mixture was heated to 700 ° C with stirring and added with 50 ml of epichlorohydrin for crosslinking reaction. The crosslinking reaction was allowed to proceed with stirring at 700 DEG C. in 5 hours. The reaction mixture was cooled to 220 DEG C. and the crosslinked the polymer was purified by treatment with acetone and 50% ethanol / water.

Slutligen neutralíserades produkten och krymptes i etanol. Produkten torkaaes i torkskåp via 7o° c i 11+ timmar. Man erhöll därvid 253 g tvärbunden hydroxyetylcellulosa-polymer med bäddvolymen 18 ml/g. 50 g salicylazosulfapyridin (National Formulary XIV Edition, American Pharmaeeutical Association, Washington, USA) löstes i 500 ml 0,7 N natronlut under omröring. I den så erhållna lösningen nerfördes 50 g tvärbunden polymer enligt ovan under omröring. Den så erhållna bland- ningen omrördes i 30 minuter vid 220 C och försattes med 1 N saltsyra till ett pH av 2,8. Den bildade produkten avskildes på sugtratt och tvättades till neutral reaktion med destillerat vatten. Produkten torkades i torkskåp vid 700 C i ll timmar. Men erhöll därvid 96 g produkt, som utgjordes av salicylazosulfapyridin i kombination med en tvärbunden hydroxyetylcellulosapolymer.Finally, the product was neutralized and shrunk in ethanol. The product dried in a drying cabinet via 7o ° c for 11+ hours. 253 g were obtained crosslinked hydroxyethylcellulose polymer with a bed volume of 18 ml / g. 50 g salicylazosulfapyridine (National Formulary XIV Edition, American Pharmaceutical Association, Washington, USA) was dissolved in 500 ml of 0.7 N baking soda while stirring. In the solution thus obtained, 50 g were reduced crosslinked polymer as above with stirring. The mixture thus obtained The mixture was stirred for 30 minutes at 220 DEG C. and added with 1 N hydrochloric acid to a pH of 2.8. The product formed was separated on a suction funnel and was washed until neutral with distilled water. The product was dried in a drying cabinet at 700 C for 11 hours. However, 96 g of product were obtained, which consisted of salicylazosulfapyridine in combination with a crosslinked hydroxyethylcellulose polymer.

Exempel 3 En tvärbunden sorbitolpolymer tillverkades enligt följande 400 g sorbitol löstes i 200 ml 50-viktprocentíg natriumhyd- roxid-vattenlösning. Till blandningen sattes droppvis vid 50” C 350 g epiklorhydrin under loppet av 2 timmar. Efter ca 30 minuter inträdde gelbildning. Den bildade produkten härdades vid 60° C under 24 timmar. Produkten finfördelades genom mal- ning, slammades upprepade gånger i destillerat vatten och neu- traliserades med saltsyra. 7900738-1 Därefter avlägsnades vatten från produkten med hjälp av sug- filtrering under vakuum. Sedan torkades produkten vid 6U° C i vakuum. Produkten hade en svällningsförmåga av 6,3 ml/g. 25 g salicylazosulfapyridin (National Formulary XIV Edition, American Pharmaceutical Association, Washington, USA) löstes i 250 ml 0,7 N natronlut under omrörning. I den så erhållna lösningen nerfördes 70 g tvärbunden polymer enligt ovan under omrörning. Den så erhållna blandningen omrördes i 30 minuter vid 22" C och försattes med l N saltsyra till ett pH av 2,5.Example 3 A crosslinked sorbitol polymer was made as follows 400 g of sorbitol were dissolved in 200 ml of 50% strength by weight sodium oxide oxide solution. To the mixture was added dropwise 50 ”C 350 g epichlorohydrin over the course of 2 hours. After approx Gel formation occurred for 30 minutes. The product formed was cured at 60 ° C for 24 hours. The product was comminuted by grinding were repeatedly slurried in distilled water and tralized with hydrochloric acid. 7900738-1 Thereafter, water was removed from the product by suction. filtration under vacuum. Then the product was dried at 6U ° C in a vacuum. The product had a swelling capacity of 6.3 ml / g. 25 g salicylazosulfapyridine (National Formulary XIV Edition, American Pharmaceutical Association, Washington, USA) was dissolved in 250 ml of 0.7 N sodium hydroxide solution with stirring. In the so obtained to the solution was dropped 70 g of crosslinked polymer as above stirring. The mixture thus obtained was stirred for 30 minutes at 22 ° C and added with 1 N hydrochloric acid to a pH of 2.5.

Den bildade produkten avskildes på sugtratt och tvättades till neutral reaktion med destillerat vatten. Produkten torkades i torkskåp vid 70” C i 14 timmar. Man erhöll därvid 91 g produkt, som utgjordes av en tvärbunden sorbitolpolymer innehållande salicylazosulfapyridin.The product formed was separated on a suction funnel and washed neutral reaction with distilled water. The product was dried in drying cabinet at 70 ”C for 14 hours. 91 g of product were obtained, which consisted of a crosslinked sorbitol polymer containing salicylazosulfapyridine.

Uppfinningen är inte begränsad till de visade utföringsformerna, då dessa kan modifieras på olika sätt inom uppfinningens ram.The invention is not limited to the embodiments shown, as these can be modified in various ways within the scope of the invention.

Claims (10)

7900738-1 PATENTKRAV7900738-1 PATENT CLAIMS l. Salicylazosulfapyridinhaltigt medicinskt preparat, huvudsakligen avsett för behandling av ulcerös kolit, k ä n n e t e c k n a t därav, att det innehåller salioylazosulfapyridin kemiskt bundet till eller absorberat i en hydrofil, tvärbunden, hydroxylgrupps- haltig polymer, som är olöslig i vatten, men har Förmåga att svälla i vattenhaltiga vätskor under bildning av en gel med kro- matografiegenskaper.Salicylazosulfapyridine-containing medicinal product, mainly intended for the treatment of ulcerative colitis, characterized in that it contains salioylazosulfapyridine chemically bound to or absorbed in a hydrophilic, crosslinked, hydroxyl group-containing polymer, which is insoluble in water, but has in aqueous liquids to form a gel with chromatographic properties. 2. Preparat enligt patentkrav l, k ä n n e t e c k n a t därav, att polymeren utgöres av en tvärbunden polyalkoholpolymer, ett polymert eller polymeriserat kolhydrat, en polymer eller polyme- riserad sockeralkohol eller ett derivat därav.2. A composition according to claim 1, characterized in that the polymer consists of a crosslinked polyalcohol polymer, a polymeric or polymerized carbohydrate, a polymer or polymerized sugar alcohol or a derivative thereof. 3. Preparat enligt patentkrav l eller 2, k ä n n e t e c k n a t därav, att polymeren utgöres av_tvärbunden cellulosa, inulin, stärkelse, dextran, eller derivat av dessa, såsom hydroxietylcellulosa, etylhydroxietylcellulosa, karboximetylstärkelse, hydroxipropyl- stärkelse eller hydroxietyldextran.3. A composition according to claim 1 or 2, characterized in that the polymer is a crosslinked cellulose, inulin, starch, dextran, or derivatives thereof, such as hydroxyethylcellulose, ethylhydroxyethylcellulose, carboxymethyl starch, hydroxypropyl starch or hydroxypropyl starch. 4. Preparat enligt patentkrav 1 eller 2, k ä n n e t e c k n a t därav, att polymeren utgöres av polymeriserad och tvärbunden dextrin, sackaros, maltos, glukos, fruktos, sorbitol eller ino- sitol.Preparation according to Claim 1 or 2, characterized in that the polymer consists of polymerized and crosslinked dextrin, sucrose, maltose, glucose, fructose, sorbitol or inositol. 5. Preparat enligt något av patentkraven l-4, k ä n n e t e c k - n a t därav, att polymeren är tvärbunden med hjälp av ett bifunk- tionellt ämne, såsom epiklorhydrin.5. A composition according to any one of claims 1-4, characterized in that the polymer is crosslinked by means of a bifunctional substance, such as epichlorohydrin. 6. Preparat enligt något av patentkraven l-5, k ä n n e t e c k - n a t därav, att polymeren innehåller jonbytande grupper. _ 7900738-1 10Preparation according to one of Claims 1 to 5, characterized in that the polymer contains ion-exchanging groups. _ 7900738-1 10 7. Preparat enligt patentkrav 6, k ä n n e t e c k n a t därav, att de jonbytande grupperna utgöres av anjoniska grupper, exempel- vis karboxylgrupper, sulfonsyragrupper eller fosforsyragrupper.7. A composition according to claim 6, characterized in that the ion exchange groups are anionic groups, for example carboxyl groups, sulfonic acid groups or phosphoric acid groups. 8. Preparat enligt patentkrav 7, k ä n n e t e c k n a t därav, att de anjoniska grupperna åtminstone delvis Föreligger i form av zinksalter.8. A composition according to claim 7, characterized in that the anionic groups are at least partially present in the form of zinc salts. 9. Preparat enligt patentkrav 7 eller 8, k ä n n e t e c k n a t därav, att de anjoniska grupperna åtminstone delvis föreligger i syraform.9. A composition according to claim 7 or 8, characterized in that the anionic groups are at least partially in acid form. 10. Preparat enligt något av patentkraven l-9, k ä n n e t e c k - n a t därav, att polymeren föreligger i form av partiklar med oregelbunden form. 7900738-1 SAMMANDRAG Salicylazosulfapyridinhaltigt medicinskt preparat, huvudsakligen avsett För behandling av ulcerös kolit. Preparatet innehåller salícylazosulfapyridin kemiskt bundet till eller absorberat i en hydrofil, tvärbunden, hydroxylgruppshaltig polymer, som är olöslig i vatten, men har förmåga att svälla i vattenhaltiga vätskor under bildning av en gel med kromatografiegenskaper.10. A composition according to any one of claims 1 to 9, characterized in that the polymer is in the form of particles of irregular shape. 7900738-1 SUMMARY Medicinal product containing salicylazosulfapyridine, mainly intended for the treatment of ulcerative colitis. The composition contains salicylazosulfapyridine chemically bound to or absorbed in a hydrophilic, crosslinked, hydroxyl group-containing polymer, which is insoluble in water but capable of swelling in aqueous liquids to form a gel having chromatographic properties.
SE7900738A 1979-01-29 1979-01-29 SALICYLAZOSULPHAPYRIDE CONTAINING MEDICAL PREPARATION SE431937B (en)

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SE7900738A SE431937B (en) 1979-01-29 1979-01-29 SALICYLAZOSULPHAPYRIDE CONTAINING MEDICAL PREPARATION
GB8001484A GB2041958B (en) 1979-01-29 1980-01-16 Medical preparations containing salicylazosulpha pyridine
DE19803003107 DE3003107A1 (en) 1979-01-29 1980-01-29 SALICYLAZOSULFAPYRIDINE CONTAINING MEDICINAL PRODUCT

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988006893A1 (en) * 1987-03-13 1988-09-22 Benzon Pharma A/S An oral composition containing particles comprising an active substance

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1131833B (en) * 1980-06-20 1986-06-25 Crinos Industria Farmaco EXCIPIENTS FOR SPERMICIDE SUBSTANCES
US5288500A (en) * 1987-03-13 1994-02-22 Benzon Pharma A/S Oral composition containing particles comprising an active substance
DK110188D0 (en) * 1988-03-02 1988-03-02 Claus Selch Larsen HIGH MOLECULAR WEIGHT PRODRUG DERIVATIVES OF ANTI-FLAMMATORY DRUGS
CN104130186A (en) * 2014-06-30 2014-11-05 江苏瑞克医药科技有限公司 Method for improving salicylazosulfapyridine refining production efficiency
CN105348184B (en) * 2015-11-26 2020-12-29 苏州统华药品有限公司 Preparation method of sulfasalazine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988006893A1 (en) * 1987-03-13 1988-09-22 Benzon Pharma A/S An oral composition containing particles comprising an active substance

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DE3003107A1 (en) 1980-08-07
GB2041958B (en) 1982-11-24
GB2041958A (en) 1980-09-17

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