5-aminosalicylic Acid Derivatives Research Articles

Topical issues of therapy for patients with ulcerative colitis

Ulcerative colitis is an autoimmune disease characterized by ulcerative destructive processes in the mucous membrane of the colon. Despite advances in the pharmaceutical industry, its prevalence in the world is increasing every year. The etiology of UC is currently unknown to the end. According to modern concepts, ulcerative colitis is considered as a multifactorial disease, in the pathogenesis of which genetic determinism, disorders of the intestinal microbiota with a decrease in populations of anaerobic bacteria in combination with the trigger action of environmental factors are discussed. With high probability, the leading pathogenetic mechanisms of the disease are associated with the polarization of the Th2-type immune response, which is characterized by the synthesis of IL-4, IL-5, IL-9 and IL-13, which is regulated by STAT-5 and Gata-3. During the development of the disease, Th17, a type of immune response, is also involved in the immunopathological process, but with the participation of transcription factors STAT-3 and ROR-yt and the synthesis of IL-17, IL-2, IL-6, IL-26 and IL-22, as well as chemokine CCL20. Diet and lifestyle are part of the global guidelines for the treatment of patients with ulcerative colitis. Derivatives of 5-aminosalicylic acid are used as basic therapy preparations: combined preparations and preparations of pure 5-aminosalicylic acid. Nevertheless, the administration of systemic glucocorticosteroids is indicated to control the activity of the disease. However, as our practice shows, they are effective, but only at the first attack and subsequent 2-3 relapses of the disease, followed by a high incidence of hormone resistance. To date, there are modern medicines with a different mechanism of action, allowing achieving stable remission and improving the quality of life of patients. Among them, JAK -tofacitinib inhibitors are of particular interest in the treatment of ulcerative colitis. This is the first oral drug capable of inducing and maintaining steroidal remission. The choice of a particular drug is determined by the experience of use, cost and national recommendations.

A New Gold(III) Complex, TGS 703, Shows Potent Anti-Inflammatory Activity in Colitis via the Enzymatic and Non-Enzymatic Antioxidant System-An In Vitro, In Silico, and In Vivo Study.

Inflammatory bowel diseases (IBD) and their main representatives, Crohn's disease and ulcerative colitis, are worldwide health-care problems with constantly increasing frequency and still not fully understood pathogenesis. IBD treatment involves drugs such as corticosteroids, derivatives of 5-aminosalicylic acid, thiopurines, and others, with the goal to achieve and maintain remission of the disease. Nowadays, as our knowledge about IBD is continually growing, more specific and effective therapies at the molecular level are wanted. In our study, we tested novel gold complexes and their potential effect on inflammation and IBD in vitro, in silico, and in vivo. A series of new gold(III) complexes (TGS 404, 512, 701, 702, and 703) were designed and screened in the in vitro inflammation studies. In silico modeling was used to study the gold complexes' structure vs. their activity and stability. Dextran sulphate sodium (DSS)-induced mouse model of colitis was employed to characterize the anti-inflammatory activity in vivo. Lipopolysaccharide (LPS)-stimulated RAW264.7 cell experiments proved the anti-inflammatory potential of all tested complexes. Selected on the bases of in vitro and in silico analyses, TGS 703 significantly alleviated inflammation in the DSS-induced mouse model of colitis, which was confirmed by a statistically significant decrease in the macro- and microscopic score of inflammation. The mechanism of action of TGS 703 was linked to the enzymatic and non-enzymatic antioxidant systems. TGS 703 and other gold(III) complexes present anti-inflammatory potential and may be applied therapeutically in the treatment of IBD.

Probiotic-Assisted Colon-Specific Delivery of Anti-Inflammatory Drug – 5 ASA

Background: Mesalamine, one derivative of 5-aminosalicylic acid (5-ASA), has been recommended as the first-line medicine to induce and maintain remission in patients with mild-to-moderately active ulcerative colitis on account of its efficacy and safety. Objective: To evaluate the efficacy and safety of mesalamine in conjunction with probiotics for ulcerative colitis an ideal colon targeting system aims to deliver a therapeutic agent, selectively and effectively, to the colon. This system should ideally retain the drug release in the upper GI tract (stomach and small intestine); while trigger the drug release in the colon. Several approaches have been used to fabricate formulations to achieve a colon specific delivery of mesalamine such as; time dependent, enzymatic/microbial responsive approaches. This overview outlines the recent advances in mesalamine-colon delivery approaches for the potential treatment of ulcerative colitis and Crohn’ disease. Method: The matrix tablets of guar gum were prepared by wet granulation method Lactose, guar gum, talc and magnesium stearate were sifted separately through sieve number 60 to obtain particles of uniform size. Weighed quantity of Mesalamine was sifted through sieve number 100. Result: Matrix tablets containing Mesalamine were prepared by wet granulation method using guar gum as the colon targeting polymer and varying concentrations of probiotics Sporlac and Vivaflora to assist in colon targeting.

Застосування препаратів 5-аміносаліцилової кислоти в лікуванні запальних захворювань кишечника

Стаття присвячена порівняльній характеристиці різних похідних 5-аміносаліцилової кислоти. Дослідження останніх десятиліть змінили уявлення про можливості застосування аміносаліцилатів у терапії різних запальних захворювань кишечника. У зв’язку з невідомою етіологією хвороби Крона та неспецифічного виразкового коліту етіотропної терапії цих захворювань немає. Сутність лікування зводиться до гальмування активності запалення при загостреннях і проведенні курсів протирецидивної терапії. Численні дослідження, проведені протягом останніх 20 років, показали, що основу базисної терапії хронічних неспецифічних запальних захворювань кишечника становлять препарати 5-аміносаліцилової кислоти, або саліцилати. При виборі лікарської форми слід ураховувати відмінності між препаратами месалазину залежно від типу оболонки. Показано, що з точки зору фармакокінетики найбільш ефективними лікарськими формами месалазину для лікування неспецифічного виразкового коліту та хвороби Крона з ураженням товстої кишки є таблетки з кишковорозчинним покриттям, що забезпечує рН-залежне поступове вивільнення 5-аміносаліцилової кислоти на протязі усієї товстої кишки. Наявні на сьогодні на фармацевтичному ринку препарати 5-аміносаліцилової кислоти здатні контролювати перебіг виразкового коліту та хвороби Крона з ураженням товстої кишки в переважної більшості пацієнтів. Застосування препаратів 5-аміносаліцилової кислоти не обмежується терапією неспецифічного виразкового коліту та хвороби Крона. Препарат широко застосовується при інших захворюваннях кишечника, таких як дивертикулярна хвороба товстої кишки, банальні коліти, променеві ураження ободової кишки, а також для лікування такої поширеної хвороби, як синдром подразненого кишечника. Результати дослідження, що було проведено у відділенні захворювань кишечника ДУ «Інститут гастроентерології НАМН України» упродовж 2 років, показали позитивний ефект 20-денного лікування Месаколом неускладненої дивертикулярної хвороби. Месакол у дозі 1600 мг на добу призвів до повного купірування абдомінальної симптоматики у 68,7 % хворих.

Pharmacokinetics in Wistar Rats of 5-[(4-Carboxybutanoyl)Amino]-2-Hydroxybenzoic Acid: A Novel Synthetic Derivative of 5-Aminosalicylic Acid (5-ASA) with Possible Anti-Inflammatory Activity.

5-[(4-carboxybutanoyl)amino]-2-hydroxybenzoic acid (C2) is a novel synthetic derivative of 5-aminosalicylic acid (5-ASA), which is currently being evaluated ex vivo as an anti-inflammatory agent and has shown satisfactory results. This study aimed to obtain the pharmacokinetic profiles, tissue distribution and plasma protein binding of C2 in Wistar Rats. Additionally, an HPLC method was developed and validated to quantify C2 in rat plasma. The pharmacokinetic profiles of intragastric, intravenous and intraperitoneal administration routes at singles doses of 100, 50, and 100 mg/kg, respectively, were studied in Wistar rats. The elimination half-life of intravenously administered C2 was approximately 33 min. The maximum plasma level of C2 was reached approximately 24 min after intragastric administration, with a Cmax value of 2.5 g/mL and an AUCtot value of 157 μg min-1/mL; the oral bioavailability was approximately 13%. Following a single intragastric or oral dose (100 mg/kg), C2 was distributed and detected in all examined tissues (including the brain and colon). The results showed that C2 accumulates over time. The plasma protein binding results indicated that the unbound fraction of C2 at concentrations of 1 to 20 μg/mL ranged from 89.8% to 92.5%, meaning that this fraction of C2 is available to cross tissues. Finally, the blood-plasma partitioning (BP ratio) of C2 in rat plasma was 0.71 and 0.6 at concentrations of 5 and 10 μg/mL, respectively, which indicates that C2 is free in the plasmatic phase and not inside blood cells. The results of this study suggest that a fraction of the administered C2 dose is absorbed in the stomach, and the fraction that is not absorbed reaches the small intestine and colon. This distribution constitutes the main advantage of C2 compared with 5-ASA for the treatment of ulcerative colitis (UC) and Crohn's disease (CD).

Synthesis, bioactivity evaluation, and docking study of 5-aminosalicylic acid’s fatty acid derivatives

Some new oleic acid, linoleic acid, lauric acid derivatives of 5-aminosalicylic acid were produced in order to enhance bioactivity properties of 5-aminosalicylic acid. All new compounds’ structures were confirmed by spectroscopic methods. Moreover, in vitro antibacterial, anticancer, and anti-inflammatory activities of new synthesized compounds were investigated. Antibacterial activity was studied against pathogenic Gram-negative bacteria, Escherichia coli and Gram-positive bacteria, Staphylococcus aureus via disc diffusion method. Additionally, all derivatives’ anti-inflammatory activity were evaluated through NO suppression assay using interferon gamma (IFN-γ)/lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Furthermore, in vitro cytotoxicity assay was probed using MTT test against 3T3 and HT-29 cell lines. In another effort, docking studies were performed to predict the possible interactions and binding energy of new compounds against cyclooxygenase (COX-1/COX-2) and lipoxygenase (5-LOX) proteins. In conclusion, all new compounds exhibited moderate to better bioactivity improvements in comparison with parent drug. Also study of interactions between the new derivatives with active sites of proteins presented greater binding affinities than 5-aminosalicylic acid.

Synthesis and in vitro bioactivity evaluation of new glucose and xylitol ester derivatives of 5-aminosalicylic acid

Synthesis,in vitroanti-bacterial, anti-inflammatory and anti-cancer activity evaluations andin silicostudy of monosaccharide derivatives of mesalazine in comparison with parent drug.

Investigation of pH-sensitive galactopyranoside glycol hydrogels as effective vehicles for oral drug delivery

Abstract High-loading-capacity pH-sensitive glycolhydrogels were developed using allyl α- D -galactopyranosideas a biodegradable and biocompatible carbohydrate. Thesenew pH-sensitive glycol polymers were obtained through thefree-radical polymerization of methacrylic acid and allyl α- D -galactopyranoside using 1,6-hexanediol diacrylate and 1,6-hexanediol propoxylate diacrylate as crosslinker. The novelsugar-bearing galactopyranoside-based hydrogels were ana-lyzed to test their hydrolytic behavior in vitro, consideringtheir potential application as drug delivery systems.Equilibrium swelling studies were carried out in enzyme-free simulated gastric and intestinal fluids (SGF and SIF;pH 8 and pH 1, respectively). A model drug, olsalazine (anazo derivative of 5-aminosalicylic acid), was entrapped inthese gels, and their in vitro release profiles were establishedseparately in SGF and SIF at 37 °C. The swelling and drugrelease profiles revealed that the amount of drug released andswelling of the hydrogels depended on the methacrylic acidcontent and the crosslinker type and content.Keywords Glycolhydrogel .Oraldrugdelivery .Methacrylicacid(MAA) .Allylα-

In vitro digestion and fermentation of 5-formyl-aminosailcylate-inulin: A potential prodrug of 5-aminosalicylic acid

Many carbohydrate polymers that have been used as carriers for colon-targeted drugs have shown benefits against colonic diseases. The objectives of this project were to (1) synthesize a derivative of 5-aminosalicylic acid (5-ASA), a drug used to treat inflammatory bowel disease, containing inulin, a carbohydrate polymer that has shown benefits against inflammatory bowel disease; (2) quantify the release of 5-ASA from the conjugate during in vitro digestion and fermentation; and (3) determine the in vitro fermentation properties of the conjugated inulin. Inulin was esterified with 5-formyl-aminosalicylic acid (5-fASA), a derivative of 5-ASA, with a degree of substitution of 0.185±0.014. During in vitro digestion and fermentation, 56.2±6.5% of 5-fASA was released in 24 h. Gut bacteria did not deformylate 5-fASA to 5-ASA as anticipated. Though conjugation of inulin with 5-fASA reduced bifidogenicity at 24 h compared with native inulin (8.26±0.03 log cfu/g versus 8.59±0.09 log cfu/g, respectively, p<0.01), conjugated 5-fASA-inulin showed protracted fermentation with higher short chain fatty acid (SCFA) and equivalent butyrate concentration at 24 h (9.02±0.68 μmol SCFA/mg carbohydrate versus 7.54±0.53 μmol SCFA/mg carbohydrate, p<0.01; 2.16±0.22 μmol butyrate/mg carbohydrate versus 2.34±0.17 μmol butyrate/mg carbohydrate, respectively, p=0.09). These data suggest that conjugation of inulin with 5-fASA may support SCFA and especially butyrate-producing bacteria through inulin fermentation in the distal colon, an important site of inflammation, together with delivery of 5-fASA. However, gut bacteria were unable to hydrolyze the formyl group from 5-fASA; thus alternative strategies to conjugate 5-ASA to inulin or remove the formyl group from 5-fASA are needed.

Novel pH-sensitive hydrogels for colon-specific drug delivery

The purpose of this study is to develop novel intestinal specific drug delivery systems with pH-sensitive swelling and drug release properties. Acryloyl ester of 5-[4-(hydroxy phenyl) azo] salicylic acid (HPAS) as an azo derivative of 5-amino salicylic acid (5-ASA) was prepared under mild conditions. The HPAS was covalently linked with acryloyl chloride, abbreviated as APAS. Cubane-1,4-dicarboxylic acid (CDA), linked to two 2-hydroxyethyl methacrylate (HEMA) groups, was the cross-linking agent (CA). Methacrylic-type polymeric prodrugs were synthesized by free radical copolymerization of methacrylic acid, poly(ethyleneglycol monomethyl ether methacrylate), and APAS in the presence of cubane cross-linking agent. The effect of copolymer composition on the swelling behavior and hydrolytic degradation were studied in simulated gastric (SGF, pH 1) and intestinal fluids (SIF, pH 7.4). The composition of the cross-linked three-dimensional polymers was determined by FTIR spectroscopy. The hydrolysis of drug–polymer conjugates was carried out in cellophane membrane dialysis bags containing aqueous buffer solutions (pH 1 and pH 7.4) at 37°C. Detection of the hydrolysis product by UV spectroscopy shows that the azo prodrug (HPAS) was released by hydrolysis of the ester bond located between the HPAS and the polymer chain. Drug release studies showed that the increasing content of MAA in the copolymer enhances hydrolysis in SIF. These results suggest that pH-sensitive systems could be useful for preparation of a muccoadhesive system and controlled release of HPAS as an azo derivative of 5-amino salicylic acid (5-ASA).

Application of 2-hydroxyethyl methacrylate polymers in controlled release of 5-aminosalicylic acid as a colon-specific drug

Acrylic type polymeric systems having degradable ester bonds linked to 5-aminosalicylic acid were synthesized and evaluated as materials for drug delivery. 5-Aminosalicylic acid, as an important drug in the treatment of inflammatory bowel diseases, was linked to 2-hydroxyethyl methacrylate by activated ester methodology in two-step and one-pot procedures to obtain methacryloyloxyethyl 5-amino salicylate. The resulting methacrylic derivative of 5-aminosalicylic acid was copolymerized with methacrylamide, 2-hydroxyethyl methacrylate and methyl methacrylate (in 1:3 mole ratio) by free radical polymerization method in N,N-dimethylformamide solution, utilizing α,ά-azoisobutyronitrile as initiator at the temperature range of 65–70 °C. The obtained polymers were characterized by FT-IR, 1H NMR, 13C NMR and elemental analysis. The average molecular weights of the polymers bearing drug units as side substituents of the acrylic backbone were determined by gel permeation chromatography and their polydispersity indices resulted in the range of 1.6–1.8. Release studies of 5-aminosalicylic acid were performed into dialysis bags by hydrolysis in buffered solutions (pH 1, 7 and 8) at 37 °C. Detection of hydrolysis by UV spectroscopy at selected intervals showed that the drug can be released by selective hydrolysis of the ester bond at the side of drug moiety. 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 systems could be useful for preparation of a controlled release formulation of 5-aminosalicylic acid in colon.

New pH-Sensitive Glycopolymers for Colon-Specific Drug Delivery

pH-sensitive hydrogels are suitable candidates for oral delivery of therapeutic peptides, proteins, and drugs, due to their ability to respond to environmental pH changes. New pH-sensitive glycopolymers have been developed by free-radical polymerization of methacrylic acid and 6-acryloyl-glucose-1, 2, 3, 4-tetraacetate, using 1, 6-hexandiol diacrylate and 1, 6-hexandiol propoxylate diacrylate as cross-linking agents. The hydrogels were characterized by differential scanning calorimetry and FTIR. Equilibrium swelling studies were carried out in enzyme-free simulated gastric and intestinal fluids (SGF and SIF, respectively). A model drug, olsalazine [3, 3′-azobis (6-hydroxy benzoic acid)] as an azo derivative of 5-aminosalicylic acid, was entrapped in these gels and the in vitro release profiles were established separately in both enzyme-free SGF and SIF. The drug-release profiles indicated that the amount of drug released depended on the degree of swelling. The hydrogels containing polar propoxylate groups were hydrolyzed rather easily.

Synthesis and evaluation of pH-sensitive glycopolymers for oral drug delivery systems

AbstractSucrose esters (SE) are surfactants with potential pharmaceutical applications because of their low toxicity, biocompatibility, and excellent biodegradability. Biodegradable and biocompatible copolymeric hydrogels based on glucose-6-acrylate-1, 2, 3, 4-tetraacetate (GATA) and methacrylic acid (MAA) were designed and synthesized. Because of the growing importance of sugar-based hydrogels as drug delivery systems, these new pH-responsive glucose-containing copolymeric hydrogels were investigated for oral drug delivery. The GATA monomer was synthesized and characterized. The copolymeric hydrogel was synthesized by free-radical polymerization. Azobisisobutyronitrile (AIBN) was the free-radical initiator employed and Cubane-1, 4-dicarboxylic acid (CDA) linked to two 2-hydroxyethyl methacrylate (HEMA) group was the crosslinking agent (CA) used for hydrogel preparations. The hydrogels were characterized by differential scanning calorimetry and FT-IR. Equilibrium swelling studies were carried out in enzyme-free simulated gastric and intestinal fluids (SGF and SIF, respectively). A model drug, olsalazine [3, 3-َazobis (6-hydroxy benzoic acid)] (OSZ) an azo derivative of 5-aminosalicylic acid (5-ASA), was entrapped in these gels and the in vitro release profiles were established separately in both enzyme-free SGF and SIF. The drug release was found to be faster in SIF. The drug-release profiles indicated that amount of drug release depends on their degree of swelling and crosslinking.

Synthesis and Degradation Characteristics of Polyurethanes Containing AZO Derivatives of 5-Amino Salicylic Acid

New types of biodegradable and pH sensitive polyurethanes containing azo derivatives of 5-aminosalicylic acid (5-ASA) were synthesized by condensation of hexamethylene diisocyanate (HDI) with 4, 4-dihydroxy azobenzene-3, 3-dicarboxylic acid (AZO I) or 4, 4-dihydroxy 3-formyl azobenzene-3-carboxylic acid (AZO II). They contained both hydrolysable urethane bonds and enzymatically degradable azo-aromatic links. Degradation of polyurethanes (PU-AZO I and PU-AZO II) in phosphate buffer solutions was pH dependant. In basic conditions AZO I or AZO II was rapidly released over 48h. Incubation of PU-AZO I and PU-AZO II with rat cecal contents at 37°C gradually released 5-ASA, and the amount of drug released was 85% and 78% in 48h respectively. These polyurethane derivatives are being investigated for colon-specific drug delivery systems for treating inflammatory bowel disease based on the pH-dependant degradation of the polymer.

Synthesis and Evaluation of Biocompatible pH-Sensitive Hydrogels as Colon-Specific Drug Delivery Systems

Because of the growing importance of pH-sensitive hydrogels as drug delivery systems, biocompatible copolymeric hydrogels based N-vinyl-2-pyrrolidinone (NVP) and methacrylic acid (MAA) were designed and synthesized. These hydrogels were investigated for oral drug delivery. Radical copolymerizations of N-vinyl-2-pyrrolidinone (NVP) and methacrylic acid (MAA) with the various ratios of cross-linking agent were carried out at 70 °C. Azabisisobutyronitrile (AIBN) was the free-radical initiator employed and Cubane-1,4-dicarboxylic acid (CDA) linked to two 2-hydroxyethyl methacrylate (HEMA) group was the crosslinking agent (CA) used for hydrogel preparations. The hydrogels were characterized by differential scanning calorimetry and FT-IR. Equilibrium swelling studies were carried out in enzyme-free simulated gastric and intestinal fluids (SGF and SIF, respectively). A model drug, olsalazine [3,3′-azobis (6-hydroxy benzoic acid)] (OSZ) as an azo derivative of 5-aminosalicylic acid (5-ASA), was entrapped in these gels and the in-vitro release profiles were established separately in both enzyme-free SGF and SIF. The drug-release profiles indicated that the amount of drug released depended on the degree of swelling. The swelling was modulated by the amount of crosslinking of the polymer bonded drug (PBDs) prepared. Based on the great difference in hydrolysis rates at pH 1 and 7.4, these pH-sensitive hydrogels appear to be good candidates for colon-specific drug delivery.

Synthesis and characterization of acrylic type hydrogels containing azo derivatives of 5-amino salicylic acid for colon-specific drug delivery

pH-sensitive hydrogels are suitable candidates for oral delivery of therapeutic peptides, proteins and drugs, due to their ability to respond to environmental pH changes. Terephthalic acid was covalently linked with 2-hydroxyethyl methacrylate (HEMA), abbreviated as cross-linking agent (CA). Acryloyl ester of 5-[4-(hydroxy phenyl) azo] salicylic acid (HPAS) as an azo derivative of 5-amino salicylic acid (5-ASA) was prepared under mild conditions. The HPAS was covalently linked with acryloyl chloride, abbreviated as APAS. Free radical cross-linking copolymerization of polymerizable azo derivative of 5-ASA (APAS) and methacrylic acid (MAA) in two different molar ratios, with the various ratios CA as cross-linking agent were carried out with using 2, 2'-azobisisobutyronitrile (AIBN) as initiator at the temperature range 60-70 degrees C. The composition of the cross-linked three-dimensional polymers was determined by FTIR spectroscopy. Glass transition temperature (Tg) of the network polymers was determined calorimetrically. The hydrolysis of drug-polymer conjugates was carried out in cellophane membrane dialysis bags containing aqueous buffer solutions (pH 7.4 and pH 1) at 37 degrees C. The effect of copolymer composition on the hydrolytic degradation was studied in simulated gastric fluid (SGF, pH 1) and simulated intestinal fluid (SIF, pH 7.4) at 37 degrees C. Monitoring of the hydrolysis process by HPLC and UV spectroscopy shows that the azo prodrug (HPAS) was released by hydrolysis of the ester bond located between the HPAS and the polymer chain. The drug-release profiles indicate that amount drug release dependent on the content of MAA groups and crosslinking.

Inducción de tolerancia en la hipersensibilidad a mesalazina (5-ASA)

Mesalazine is a derivative of 5-aminosalicylic acid (5-ASA), which is useful in the treatment of intestinal inflammatory disease. Sulfasalazine is formed by two parts, sulfapyridine and 5-ASA, the latter being the active part of the molecule. The new preparatives derived from 5-ASA were developed in an attempt to avoid the traditionally associated side effects to sulfapyridine, although they are still observed and new effects appear. We present two cases. The first is a man diagnosed of inflammatory intestinal disease, with background of two previous reactions of urticaria and angioedema after acetyl salicylic acid, who presented urticaria after taking mesalazine. The second one had generalized urticaria after three months of initiating treatment with mesalazine. Given the need for treatment in both cases, a desensitization protocol to mesalazine was made. It was developed in 17 days in our service. Tolerance to that drug to therapeutic doses is reached. When faced with patients with hypersensitivity to different drugs, that are necessary to treat their disease, "desensitization" regimes, that assure good tolerance, can be made.

The Relation Between Swelling Properties and Cross-Linking of Hydrogels Designed for Colon-Specific Drug Delivery

Copolymers of 2-hydroxyethyl methacrylate (HEMA) and methacrylic acid (MAA)-based hydrogels containing 5% and 10% of a cross-linking agent were studied as drug delivery systems. Terephthalic acid was covalently linked with HEMA, abbreviated as CA (cross-linking agent). Free radical cross-linking copolymerization of HEMA and methacrylic acid (MAA) in three different molar ratios, mixed with a particulate 3, 3-azobis (6-hydroxy benzoic acid) (ABHB) as an azo derivative of 5-aminosalicylic acid with the various ratios CA as cross-linking agent were carried out with using 2, 2, Azobisisobutyronitrile as initiator at the temperature range 60–70°C. The compositions of the cross-linked three-dimensional polymers were determined by FTIR spectroscopy. Glass transition temperature of the network polymers was determined calorimetrically. The hydrolysis of drug-polymer conjugates was carried out in cellophane membrane dialysis bags containing an aqueous buffer solution (pH 7.4 and pH 1) at 37°C. The drug-release profiles indicate that the amount of drug release depends on its degree of swelling and cross-linking.

Controlled Release of Biomolecules from pH-Sensitive Hydrogels Prepared by Radiation Polymerization

Copolymers of 2-hydroxyethyl methacrylate and methacrylic acid based hydrogels were studied as hydrogel drug delivery systems. Radiation copolymerization of 2-hydroxyethyl methacrylate and methacrylic acid (mixed with 3,3'-azobis(6-hydroxy benzoic acid)(ABHB) as an azo derivative of 5-aminosalicylic acid were carried out with various amounts of methacryloyloxyethyl esters of terephthalic acid for crosslinking. The polymer structures were characterized by FTIR, 1H NMR, 13C NMR spectroscopy and glass transition temperature (Tg). The hydrolysis of the drug–polymer conjugates were carried out in dialysis bags containing aqueous buffer solutions (pH 1 and 7.4) at 37°C. The drug-release profiles indicate that the amount of drug release depended on the degree of swelling and crosslinking.

Synthesis and characterization of methacrylic derivatives of 5-amino salicylic acid with pH-sensitive swelling properties

The purpose of this study is to develop novel colon-specific drug delivery systems with pH-sensitive swelling and drug release properties. Methacrylic-type polymeric prodrugs with different content levels of 5-amino salicylic acid (5-ASA) were synthesized by free radical copolymerization of metacrylic acid (MAA), polyethylene glycol monomethacrylate (PEGMA), and a methacrylic derivative of 5-ASA (methacryloyloxyethyl 5-amino salicylate [MOES]). The copolymers were characterized, and the drug content of the copolymers was determined. The effect of copolymer composition on the swelling behavior and hydrolytic degradation was studied in simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.2). The swelling and hydrolytic behavior of the copolymers was dependent on the content of MAA groups and caused a decrease in gel swelling in SGF or an increase in gel swelling in SIF. Drug release studies showed that increasing content of MAA in the copolymer enhances the hydrolysis in SIF but has no effect in SGF. The results suggest that hydrogen-bonded complexes are formed between MAA and PEG pendant groups and that these pH-sensitive systems could be useful for preparation of a controlled-release formulation of 5-ASA.