NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) ARE COMMONLY USED FOR THE TREATMENT OF CHRONIC INFLAMMATORY DISEASES, SUCH AS ARTHRITIS. PROLONGED ADMINISTRATION OF THESE DRUGS EXHIBIT SEVERAL UNDESIRED SIDE EFFECTS; THE MOST IMPORTANT ARE GASTRO-INTESTINAL (GI) IRRITATION AND ULCERATION WHICH REPRESENT STILL AN UNSOLVED THERAPEUTIC PROBLEM [1]. CONSIDERABLE ATTENTION HAS BEEN FOCUSED ON DEVELOPMENT OF BIOREVERSIBLEDERIVATIVES, SUCH AS PRODRUGS, TO TEMPORARILY MASK THE ACIDIC GROUP OF NSAIDS AS A PROMISING MEANS OF REDUCING OR ABOLISHING THE GI TOXICITY DUE TO THE LOCAL ATTENTION MECHANISM [2, 3].IN THIS RESEARCH WORK, 2-HYDROXYETHYL METHACRYLATE WAS FIRST COPOLYMERIZED WITH VARIOUS HYDROPHILIC OR HYDROPHOBIC ACRYLIC-TYPE MONOMERS BY FREE RADICAL POLYMERIZATION METHOD, USING AZOBISISOBUTYRONITRILE AS AN INITIATOR. THE AVERAGE MOLECULAR WEIGHTS AND MOLE COMPOSITIONS OF THE RESULTED COPOLYMERS WERE DETERMINED BY GEL PERMEATION CHROMATOGRAPHY AND1H-NMR SPECTRADATA, RESPECTIVELY. THEN, DICLOFENAC AS ANSAID WAS CHEMICALLY ATTACHED TO COPOLYMERS BY ESTER METHODOLOGY TO GIVE MACROMOLECULAR PRODRUGS. THE POLYMER-DRUG CONJUGATES WERE HYDROLYZED IN CELLOPHANE MEMBRANE DIALYSIS BAGS CONTAINING AQUEOUS BUFFERED SOLUTION (PH 8) AT 37OC AND THE HYDROLYSIS SOLUTIONS WERE DETECTED BY UV SPECTROPHOTOMETER ATSELECTED INTERVALS. THE RESULTS SUGGESTED THAT THE SYNTHESIZED COPOLYMERS COULD BE USEFUL CARRIERS FOR RELEASE OF DICLOFENAC IN CONTROLLED RELEASE SYSTEMS.

THE THERAPEUTIC USE OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) IS OFTEN RESTRICTED BYTHE NECESSITY TO DELIVER THE DRUG TO SPECIFIC SITES OF TARGET ORGAN OR TISSUE. THE USE OF NSAIDS IS ALSO LIMITED BY THEIR IRRITANT SIDE EFFECTS ON THE GASTRO-ENTERIC MUCOUS AND BY THEIR FREQUENT POORWATER SOLUBILITY [1]. THESE PROBLEMS CAN BE SOLVED BY THE PREPARATION OF POLYMERIC PRODRUG BACKBONES VIA HYDROLYZABLE BONDS. POLYMER-DRUG CONJUGATES OF NSAIDS HAVE BEEN DEVELOPED INORDER TO MINIMIZE DELIVERY PROBLEMS AND REDUCE GASTROINTESTINAL SIDE EFFECTS BY CONTROLLING THERATE, DURATION, AND SITE OF RELEASE [2, 3].THIS PRESENT WORK DEVELOPS AN EFFICIENT CHEMICAL METHOD TO DESIGN AND SYNTHESIS OF ACRYLIC TYPE POLYMERIC CARRIERS FOR RELEASE OF IBUPROFEN IN CONTROLLED RELEASE SYSTEMS. ([1- (4- CHLOROBENZOYL) -5-METHOXY-2-METHYL-1H-INDOLE-3-YL] ACETIC ACID), SO CALLED INDOMETHACIN, AS AN NSAID USED IN MANY PHARMACEUTICAL PREPARATIONS, WAS REACTED WITH 2-HYDROXYETHYL METHACRYLATE BY ESTERIFICATION METHODOLOGY TO GIVE AN ACRYLIC-TYPE POLYMERIZABLE DERIVATIVE OF INDOMETHACIN. THE OBTAINED MATERIAL WAS THEN COPOLYMERIZED WITH 2-HYDROXYETHYL METHACRYLATE OR METHYL METHACRYLATE BY FREE RADICAL POLYMERIZATION TECHNIQUE. THE RELEASE OF DRUG FROM THE OBTAINED POLYMERIC PRODRUGS WAS CARRIED OUT IN VITRO BY HYDROLYSISIN BUFFERED SOLUTIONS AT VARIOUS PH VALUES AND THE QUANTITY OF THE RELEASED DRUG DETECTED BY UV SPECTROSCOPY. THE EFFECTS OF NEIGHBORING GROUPS AND PH VALUES ON RELEASE OF INDOMETHACIN ARE DISCUSSED.

BACKGROUND: IN THE LAST DECADES MUCH ATTENTION HAS BEEN DIRECTED TO SPECIALITY POLYMERS FOR BIOMEDICAL APPLICATION. ONE PARTICULAR APPROACH TOWARDS THE IMPROVED USE OF DRUGS IS THE DESIGN OF POLYMER-DRUG CONJUGATES OR POLYMERIC PRODRUGS [1]. THE CHEMICAL ATTACHMENT OF LOW MOLECULAR WEIGHT DRUGS TO SYNTHETIC OR NATURAL POLYMERS HAS BEEN FREQUENTLY INVESTIGATED AS A MEANS OF IMPROVING THE EFFICACY OF DRUG CONTROL RELEASE DEVICES THROUGH A CONSTANT BUT PROLONGED RELEASE OF DRUGS WITH MINIMUM SIDE EFFECTS [2].METHODS: INDOMETHACIN, AS A NON-STEROIDAL ANTI- INFLAMMATORY DRUG, WAS LINKED TO 2-HYDROXYETHYL METHACRYLATE BY ACTIVATED ESTER METHODOLOGY. THE RESULTING METHACRYLIC DERIVATIVE OF INDOMETHACIN WAS COPOLYMERIZED WITH 2-HYDROXYETHYL METHACRYLATE AND N-BUTYL ACRYLATE BY FREE RADICAL POLYMERIZATION METHOD IN N, N-DIMETHYLFORMAMIDE SOLUTION, UTILIZING AZOISOBUTYRONITRILE AS INITIATOR AT 65-70OC. ALL OF THE OBTAINED COMPOUNDS WERE CHARACTERIZED BY FT-IR, 1H NMR, 13C NMR SPECTROSCOPY AND ELEMENTAL ANALYSIS TECHNIQUE. THE AVERAGE MOLECULAR WEIGHTS OF THE POLYMERS BEARING INDOMETHACIN WERE DETERMINED BY GEL PERMEATION CHROMATOGRAPHY AND THEIR POLYDISPERSITY INDICES RESULTED IN THE RANGE OF 1.8-1.9. RELEASE STUDIES OF IBUPROFEN WERE PERFORMED INTO DIALYSIS BAGS BY HYDROLYSIS IN BUFFERED SOLUTIONS (PH 1, 7.4 AND 10) AT 37OC.RESULTS: THE RELEASE PROFILES INDICATED THAT THESE MACROMOLECULAR PRODRUGS COULD BE USEFUL FOR RELEASING INDOMETHACIN IN DRUG DELIVERY SYSTEMS.CONCLUSION: THE RELEASE PROFILES INDICATED THAT THE HYDROLYTIC BEHAVIOR OF POLYMERIC PRODRUGS IS STRONGLY BASED ON THE POLYMER HYDROPHILICITY AND THE PH VALUE OF THE HYDROLYSIS SOLUTION. THE RESULTS SUGGEST THAT THESE POLYMERIC PRODRUGS COULD BE USEFUL FOR RELEASE OF IBUPROFEN IN CONTROLLED RELEASE SYSTEMS.

BACKGROUND: 4-CHLOROMETHYL STYRENE (CMS) HAS BEEN COPOLYMERIZED WITH MANY DIFFERENT COMONOMERS BY THE RADICAL METHOD AND THE RESULTING COPOLYMERS COULD PROVIDE NEW PRODUCTS BY NUCLEOPHILIC SUBSTITUTIONS OF THE CHLORINE ATOM [1]. THESE POLYMERS WITH VARIOUS FUNCTIONAL GROUPS HAVE WIDE POTENTIAL APPLICATIONS, SUCH AS FOR ION EXCHANGE RESINS, POLYMER SUPPORTS OF CATALYSTS AND RESINS FOR MICROLITHOGRAPHY [2]. VALPROIC ACID IS A BROAD-SPECTRUM ANTIEPILEPTIC DRUG WITH UNIQUE ANTI-CONVULSANT PROPERTIES AND IS USED IN THE TREATMENT OF PRIMARY GENERALIZED SEIZURES, PARTIAL SEIZURES AND MYOCLONIC SEIZURES [3].METHODS: IN THE PRESENT RESEARCH, THE HOMOPOLYMER OF CMS AND ITS COPOLYMERS WITH 2-HYDROXYETHYL METHACRYLATE OR METHYL METHACRYLATE WERE FIRST SYNTHESIZED BY BULK AND SOLUTION FREE RADICAL POLYMERIZATION, AT 70±2OC USING A, A’-AZOISOBUTYRONITRILE AS AN INITIATOR. VALPROIC ACID SODIUM SALT WAS THEN COVALENTLY LINKED TO THE OBTAINED HOMOPOLYMER AND COPOLYMERS WITH REPLACEMENT OF ALL THE CHLORINE ATOMS IN CMS UNITS. THE RESULTANT POLYMERIC PRODRUGS WERE CHARACTERIZED BY FTIR, 1HNMR, DIFFERENTIAL SCANNING CALORIMETRY (DSC) AND GEL PERMEATION CHROMATOGRAPHY. THE HYDROLYSIS OF DRUG-POLYMER CONJUGATES WAS CARRIED OUT IN CELLOPHANE MEMBRANE DIALYSIS BAGS CONTAINING AQUEOUS BUFFER SOLUTIONS (PH 1, 7.4 AND 10) AT 37OC FOR 24 H.RESULTS: DETECTION OF HYDROLYSIS SOLUTION AT SELECTED INTERVALS SHOWED THAT THE DRUG CAN BE RELEASED BY HYDROLYSIS OF THE ESTER BOND BETWEEN THE DRUG AND POLYMER BACKBONE.CONCLUSION: THE RELEASE PROFILES INDICATED THAT THE HYDROLYTIC BEHAVIOR OF POLYMERIC PRODRUGS IS STRONGLY BASED ON THE POLYMER HYDROPHILICITY AND THE PH VALUE OF THE HYDROLYSIS SOLUTION.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) ARE FREQUENTLY USED FOR THE TREATMENT OF INFLAMMATORY CONDITIONS AND THE MECHANISM OF THE ACTION IS MAINLY RELATED TO THE INHIBITION OF THE CYCLOOXYGENASE-2 ENZYME (COX-2) [1]. IN RECENT YEARS, A GROWING BODY OF EXPERIMENTAL AND EPIDEMIOLOGICAL EVIDENCE HAS DEMONSTRATED THAT NSAIDS ALSO DISPLAY PROMISING CHEMOPREVENTIVE ACTIVITIES, ESPECIALLY FOR COLORECTAL CANCER WITH HIGH COX-2 EXPRESSION [2, 3].THE MAIN PURPOSE OF THIS STUDY, IS SYNTHESIZE AND IN-VITRO EVALUATION OF ACRYLIC-TYPE POLYMERIC SYSTEMS HAVING DEGRADABLE ESTER BONDS LINKED TO INDOMETHACIN AS MATERIALS FOR APPLICATION IN DRUG DELIVERY SYSTEMS. INDOMETHACIN WAS FIRST LINKED TO 2-HYDROXYLETHYL METHACRYLATE BY ESTERIFICATION METHOD TO OBTAIN METHACRYLOYLOXYETHYL-DERIVATIVE OF INDOMETHACIN. THE RESULTING ACRYLIC DERIVATIVE WAS THEN COPOLYMERIZED WITH VARIOUS HYDROPHILIC AND HYDROPHOBIC ACRYLIC MONOMERS BY FREE RADICAL POLYMERIZATION METHOD IN N, N´-DIMETHYLFORMAMID SOLUTION, UTILIZING AZOBISISOBUTYRONITRILE AS AN INITIATOR AT 70±2OC. AFTER CHARACTERIZATION OF THE OBTAINED COMPOUNDS BY FT-IR, 1H-NMR, ELEMENTAL ANALYSIS, AND GEL PERMEATION CHROMATOGRAPHY, THE RELEASE STUDY OF DRUG FROM THE POLYMERIC PRODRUGS WAS CARRIED OUT IN-VITRO BY HYDROLYSIS IN BUFFERED SOLUTIONS AT VARIOUS PH VALUES. THE QUANTITY OF THE RELEASED INDOMETHACIN WAS DETECTED BY UV SPECTROSCOPY IN SELECTED INTERVALS. THE RELEASE PROFILES INDICATED THAT THESE MACROMOLECULAR PRODRUGS COULD BE USEFUL FOR RELEASING INDOMETHACIN IN DRUG DELIVERY SYSTEMS.

THERE IS A CONSIDERABLE INTEREST IN THE COLON SPECIFIC DRUG DELIVERY IN ORDER TO TREAT DISEASES OF THE LARGE INTESTINE, SUCH AS COLITIS, COLON CANCER, IRRITABLE BOWEL SYNDROME, CROHN AND INFECTIOUS DISEASES [1]. COLON TARGETING MAY BE ACHIEVED BY DIFFERENT DELIVERY SYSTEMS. IN RECENT YEARS, MACROMOLECULAR PRODRUGS OF THE ANTI-INFLAMMATORY AGENT OF 5-AMINOSALISYLIC ACID (5-ASA) HAS BEEN PREPARED AND STUDIED AS DRUG DELIVERY SYSTEMS FOR COLON TREATMENTS [2].IN THIS RESEARCH STUDY, SOME POLYMERIC PRODRUGS OF 5-ASA WERE SYNTHESIZED AND EVALUATED IN AN IN VITRO MODEL. FIRST, 5-ASA WAS LINKED TO 2-HYDROXYPROPYL METHACRYLATE BY AN ACTIVATED ESTER METHODOLOGY IN THE PRESENCE OF N, N-DICYCLOHEXYL CABODIIMIDE REAGENT. THE NOVELTY OF THIS SYNTHESIS IS THAT, IN JUST ONE STEP, THE HYDROLYZABLE-5ASA PENDANT GROUP ACRYLIC MONOMER IS OBTAINED WITH A HIGH YIELD. THE OBTAINED MATERIAL WAS THEN COPOLYMERIZED WITH VARIOUS ACRYLIC-TYPE MONOMERS BY THE FREE RADICAL POLYMERIZATION TECHNIQUE, AND THEIR DETAILED MOLECULAR STRUCTURES WERE CHARACTERIZED VIA FTIR, 1NMR, AND ELEMENTAL ANALYSIS. THE RELEASE OF 5-ASA FROM THE OBTAINED POLYMERIC PRODRUGS WAS CARRIED OUT IN VITRO BY HYDROLYSIS IN BUFFERED SOLUTIONS INTO CELLOPHANE DIALYSIS BAGS AT VARIOUS PH VALUES, AND THE QUANTITY OF THE RELEASED DRUG WAS DETECTED BY UV SPECTROSCOPY AT SELECTED INTERVALS. THE EFFECTS OF NEIGHBORING GROUPS AND PH VALUES ON THE RELEASE OF 5-ASA FROM THE SYNTHESIZED POLYMERIC PRODRUGS ARE DISCUSSED.

DICLOFENAC IS ONE OF THE MOST IMPORTANT NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) AND IS WIDELY USED FOR THE TREATMENT OF RHEUMATOID ARTHRITIS [1]. THE THERAPEUTIC USE OF NSAIDS IS OFTEN RESTRICTED BY THE NECESSITY TO DELIVER THE DRUG AT SPECIFIC SITES OF TARGET ORGAN OR TISSUE. THE USE OF...