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The safety profile of new antidiabetic xanthine derivatives with thiazolidine‑4‑one scaffold (6, 7) and their new chitosan based formulations (CS-6, CS-7), administrated to diabetic rats, have been evaluated in terms of biochemical markers of liver and kidney function as well as of hematological markers. The effect on lipid profile and clinic parameters (body weight, food and water intake) has been also evaluated. The treatment of diabetic rats with xanthine derivatives (6, 7) and chitosan based formulations (CS-6, CS-7) was associated with lower liver enzymes (AST, ALT, LDH) and bilirubin (direct, total) values compared to the non-treated diabetic rats, that means the tested derivatives/formulations have improved the liver function injured in diabetes mellitus conditions. Also the kidney biochemical markers (creatinine, uric acid, urea) were significantly decreased in diabetic rats treated with 6, 7 and chitosan microparticles (CS-6, CS-7). The values of biochemical markers of liver and kidney functions were even better than the values recorded for pioglitazone, used as standard antidiabetic drug. The improving effect on kidney function was proved by the histopathological study. Moreover, the xanthine derivatives and their chitosan based formulation were associated with improved hematological markers compared to the non-treated diabetic rats which mean the improving of the hemorheological state. These results support the safety profile of new xanthine derivatives with thiazolidine‑4‑one scaffold (6, 7) and their new chitosan based formulations (CS-6, CS-7) and their potential applications for the treatment of diabetes mellitus syndrome., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chitosan is a non-toxic, biocompatible, biodegradable natural cationic polymer known for its low imunogenicity, antimicrobial, antioxidant effects and wound-healing activity. To improve its therapeutic potential, new chitosan-sulfonamide derivatives have been designed to develop new wound dressing biomaterials. The structural, morphological and physico-chemical properties of synthesized chitosan derivatives were analyzed by FT-IR, (1)H NMR spectroscopy, scanning electron microscopy, swelling ability and porosity. Antimicrobial, in vivo testing and biodegradation behavior have been also performed. The chitosan derivative membranes showed improved swelling and biodegradation rate, which are important characteristics required for the wound healing process. The antimicrobial assay evidenced that chitosan-based sulfadiazine, sulfadimethoxine and sulfamethoxazole derivatives were the most active. The MTT assay showed that some of chitosan derivatives are nontoxic. Furthermore, the in vivo study on burn wound model induced in Wistar rats demonstrated an improved healing effect and enhanced epithelialization of chitosan-sulfonamide derivatives compared to neat chitosan. The obtained results strongly recommend the use of some of the newly developed chitosan derivatives as antimicrobial wound dressing biomaterials., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The objective of this study was to develop new films based on chitosan functionalized with sulfonamide drugs (sulfametoxydiazine, sulfadiazine, sulfadimetho-xine, sulfamethoxazol, sulfamerazine, sulfizoxazol) in order to enhance the biological effects of chitosan. The morphology and physical properties of functionalized chitosan films as well the antioxidant effects of sulfonamide-chitosan derivatives were investigated. The chitosan-derivative films showed a rough surface and hydrophilic properties, which are very important features for their use as a wound dressing. The film based on chitosan-sulfisoxazol (CS-S6) showed the highest swelling ratio (197%) and the highest biodegradation rate (63.04%) in comparison to chitosan film for which the swelling ratio was 190% and biodegradation rate was only 10%. Referring to the antioxidant effects the most active was chitosan-sulfamerazine (CS-S5) which was 8.3 times more active than chitosan related to DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging ability. This compound showed also a good ferric reducing power and improved total antioxidant capacity.

New xanthine derivatives as antidiabetic agents were synthesized and new chitosan formulations have been developed in order to improve their biological and pharmacokinetic profile. Their physicochemical properties in terms of particle size, morphology, swelling degree, crystalline state, the loading efficiency as well as in vitro release and biodegradation rate were evaluated. According to the results the optimized formulations have a high drug loading efficiency (more than 70%), small particle size, a good release profile in the simulated biological fluids (the percentage of cumulative release being more than 55%) and improved biodegradation rate in reference with chitosan microparticles. The presence of xanthine derivatives (6, 7) in chitosan microparticles was demonstrated by means of FTIR analysis. The X-ray diffraction (XRD) proved that xanthine derivatives present a crystalline state. The biological evaluation assays confirmed the antioxidant and antidiabetic effects of the xanthine derivatives (6, 7) and their chitosan formulations (CS-6, CS-7). Xanthine derivative 6 showed a high antiradical scavenging effect (DPPH remaining=41.78%). It also reduced the glucose blood level with 59.30% and recorded level of glycosylated hemoglobin was 4.53%. The effect of its chitosan formulation (CS-6) on the level of blood glucose (114.5mg/dl) was even more intense than the one recorded by pioglitazone (148.5mg/dl) when used as standard antidiabetic drug. These results demonstrated the potential application of xanthine derivative 6 and its chitosan formulation (CS-6) in the treatment of the diabetes mellitus syndrome., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The aim of this paper is theophylline (THP) inclusion into xanthan-chitosan polyionic complex (Xa-CS) and the study of its in vitro and in vivo kinetic release. Xa-CS hydrogel was obtained by ionic complexation between two oppositely charged polysaccharides. THP was loaded into the Xa-CS matrix by diffusion of the drug solution. The obtained samples were characterized by FTIR spectroscopy, SEM microscopy and study of the swelling behavior. THP in vitro release experiments were carried out in conditions mimicking the gastrointestinal environment. The chosen drug dose for in vivo study was 15 mg THP/Kg body weight of THP powder or an equivalent dose in complex form. THP serum concentrations were determined by an HPLC assay. The THP peak serum concentration (C(max)) was 7.18 microg/ml for free THP and AUC(0-48) was 25.76 microg h/ml, while in the case of Xa-CS-THP, C(max) was of 5.72 microg/ml and AUC(0-48) = 45.72 microg h/ml. The in vivo study regarding the behaviour of the obtained formulation, showed an increase bioavailability of THP compared to the raw drug, suggesting the possible application of the complex Xa-CS as an oral controlled drug delivery system in the management of chronic pulmonary obstructive disease.

The study aim was to develop and validate a high-performance liquid chromatography–electrospray ionization mass spectrometry (HPLC-ESI-MS) method to simultaneously determine glibenclamide (Gli) and silymarin (Sil) released from chitosan (CS) microparticles in aqueous solutions. The CS microparticles were synthesized using an ionic gelation method, and their morphology, swelling degree, encapsulation efficiency and active substance release were investigated. Gli and Sil were loaded in different concentrations, and their identification and quantification were performed using the HPLC-ESI-MS method, which was further validated. The drugs' characteristic m/z was found in the higher intensity of retention time (Rt) (Gli, 8.909 min; Sil A, 5.41 min; and Sil B, 5.66 min). The method selectivity and precision are very good, and the blank solution proved no interference. The linearity of the answer function is very good for Sil A (R2 = 1), Sil B (R2 = 0.9998) and Gli (R2 = 0.9991). For Gli, we obtained a limit of detection (LOD) = 0.038 mg/mL and limit of quantification (LOQ) = 1.275 mg/mL; for Sil A, a LOD = 0.285 mg/mL and LOQ = 0.95 mg/mL; and for Sil B, a LOD = 0.045 mg/mL and LOQ = 0.15 mg/mL. A high-resolution HPLC-ESI-MS method was developed and validated, which allowed the simultaneous determination of Gli and Sil loaded in CS microparticles, in a concentration range of 0.025–1 mg/mL. [ABSTRACT FROM AUTHOR]

Featured Application: This article presents the development and characterization of new chitosan based polymeric systems containing glibenclamide and lipoic acid for diabetes mellitus therapy. The systems were designed as multi-target systems, aiming for optimal glycemic control, as well as the reactive oxygen species generated by hyperglycemia. Glibenclamide and lipoic acid are two drugs frequently recommended for the management of diabetes mellitus, and so, the development of a new formulation containing both substances has a great benefit in terms of efficiency and compliance, acting also as a multi-target drug system. Accordingly, the aim of this study was the formulation and physicochemicalcharacterization of new polymeric systems based on chitosan (CS) in whose matrix were encapsulated glibenclamide (Gly) and lipoic acid (LA). The polymeric systems were prepared as microparticles (CS–Gly, CS–LA, and CS–Gly–LA) through ionic gelation method, using pentasodium tripolyphosphate (TPP) as crosslinking agent. The polymeric systems obtained were characterized in terms of particle size and morphology, IR spectroscopy, entrapment efficiency and drug loading, swelling degree, and therelease of the active substances from the chitosan matrix. The polymeric systems obtained were stable systems; the presence of glibenclamide and lipoic acid into the polymer matrix were proved by IR spectroscopy. The entrapment efficiency was 94.66% for Gly and 39.68% for LA. The developed polymeric systems proved a favorable swelling degree and drug release profile, the percentage of release being 88.68% for LA and 75.17% for Gly from CS–Gly–LA systems. [ABSTRACT FROM AUTHOR]

Chitosan (CH) nanofibrous structures containing sulfadiazine (SDZ) or sulfadiazine modified chitosan (SCH) in the form of functional nanoparticles attached to nanofibers (hybrid nanostructures) were obtained by mono-axial and coaxial electrospinning. The mono-axial design consisted of a SDZ/CH mixture solution fed through a single nozzle while the coaxial design consisted of SCH and CH solutions separately supplied to the inner and outer nozzle (or in reverse order). The CH ability to form nanofibers assured the formation of a nanofiber mesh, while SDZ and SCH, both in form of suspensions in the electrospun solution, assured the formation of active nanoparticles which remained attached to the CH nanofiber mesh after the electrospinning process. The obtained nanostructures were morphologically characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The SDZ release profiles and kinetics were analyzed. The SDZ or SCH nanoparticles loosely attached at the surface of the nanofibers, provide a burst release in the first 20 min, which is important to stop the possible initial infection in a wound, while the SDZ and SCH from the nanoparticles which are better confined (or even encapsulated) into the CH nanofibers would be slowly released with the erosion/disruption of the CH nanofiber mesh. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop new films based on chitosan functionalized with sulfonamide drugs (sulfametoxydiazine, sulfadiazine, sulfadimetho-xine, sulfamethoxazol, sulfamerazine, sulfizoxazol) in order to enhance the biological effects of chitosan. The morphology and physical properties of functionalized chitosan films as well the antioxidant effects of sulfonamide-chitosan derivatives were investigated. The chitosan-derivative films showed a rough surface and hydrophilic properties, which are very important features for their use as a wound dressing. The film based on chitosan-sulfisoxazol (CS-S6) showed the highest swelling ratio (197%) and the highest biodegradation rate (63.04%) in comparison to chitosan film for which the swelling ratio was 190% and biodegradation rate was only 10%. Referring to the antioxidant effects the most active was chitosan-sulfamerazine (CS-S5) which was 8.3 times more active than chitosan related to DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging ability. This compound showed also a good ferric reducing power and improved total antioxidant capacity. [ABSTRACT FROM AUTHOR]

In the present study polyelectrolyte complexes (PECs) based on new sulfadiazine-chitosan conjugates with sodium hyaluronate have been developed with potential use in treatment of burn wounds. The PECs were chemically characterized using Fourier Transform-Infrared Spectroscopy, Scanning Electon Microscopy and Near Infrared Chemical Imaging Technique. The swelling behavior and in vitro sulfadiazine release were also investigated. The antimicrobial activity was evaluated towards three bacterial strains: Escherichia coli, Listeria monocytogenes and Salmonella thyphymurium. The developed PECs demonstrated their antimicrobial efficiency against tested bacterial strains, the PECs containing sulfadiazine-modified chitosan being more active than PECs containing unmodified chitosan. [ABSTRACT FROM AUTHOR]

Abstract: Chitosan biocomposite hydrogels were used as drug carriers for the delivery of some compounds with bronchodilatatory and anti-inflammatory activities. Chitosan nanocomposite hydrogels were prepared by crosslinking the chitosan nanocomposites with glutaraldehyde. The matrix was characterized by swelling experiments, X-ray diffraction and scanning electron microscopy. An intercalated structure was formed. The hydrogels were loaded with paracetamol, theophylline, two xanthine derivatives 7-[2-hydroxy-3-(4-acethyl-amino-phenoxy)-propyl]-8-R-1,3-dimethyl-xanthine derivatives with (R=H, NO2 for D1 and D2, respectively) and two corresponding novel nitric oxide donors compounds such as 7-[2-nitroxyacethyl-oxy-3-(4-acethyl-amino-phenoxy)-propyl]-8-R-1,3-dimethyl-xanthine (R=H, NO2 for 65 and respectively 77 compounds). Their controlled release was evaluated in acidic media (pH=2.2) simulating the gastric fluid. The effect of Cloisite 15A addition on the drug release was determined. A higher concentration of 9mass% Cloisite 15A significantly retarded the drug release. The kinetics of the drug release was studied in order to ascertain the type of release mechanism. Because the release of drugs from drug-intercalated montmorillonite was controllable, these new materials have a great potential as a delivery host in the pharmaceutical field. [Copyright &y& Elsevier]

The hydrogels of crosslinked chitosan with different glutaraldehyde amounts have been "in vitro" tested as carriers for prolonged release of some drugs for inflammatory and bronchopulomonary diseases. These hydrogels have been loaded with two novel nitric oxide donors, derivatives of 7-[2-nitroxyacethyl-oxy-3-(4-acethyl-amino-phenoxy)-propyl]-8-R-1,3-dimethyl-xanthine compounds (R=H, NO2 for 65 and respectively 77 compounds) designed as multitarget drugs and parent compounds as paracetamol, theophylline, two xanthine derivatives 7-[2-hydroxy-3-(4-acethyl-amino-phenoxy)-propyl]-8-R-1,3-dimethyl-xanthine derivatives with (R=H, NO2 for D1 and respectively D2) and their release was evaluated in an acidic solution (pH=2.2) simulating the gastric fluid. Results have been correlated with the swelling behaviour which was also followed in acidic media with pH=2.2. The relationships between the release profiles and kinetics and matrix characteristics and/or drug properties have been established. [ABSTRACT FROM AUTHOR]

Chitosan (CS) based microparticles for controlled release of theophylline (THP) were obtained by ionic gelation. The microparticles were characterized by laser diffraction analysis (particle size), scanning electron microscopy (SEM), FTIR spectroscopy, and thermogravimetric analysis. The average diameter of the CSTHP microparticles was 182 μm. The FTIR spectra confirmed that new hydrogen bonds had formed between the carbonylic group belonging to THP and the amino group of CS, while the thermogravimetric analysis showed a modified stability in the obtained particles and confirmed the presence of an interaction between the drug and CS. The THP release process was monitored for up to 24 h in simulated gastric fluid (pH 1.5) and in simulated intestinal fluid (pH 7.4). The release process of THP from microparticles was not influenced by the pH of dissolution media. In the first 30 min the drug was released in a rapid manner, and after this stage by a non-Fickian profile. [ABSTRACT FROM AUTHOR]

In recent decades, drug delivery systems (DDSs) based on nanotechnology have been attracting substantial interest in the pharmaceutical field, especially those developed based on natural polymers such as chitosan, cellulose, starch, collagen, gelatin, alginate and elastin. Nanomaterials based on chitosan (CS) or chitosan derivatives are broadly investigated as promising nanocarriers due to their biodegradability, good biocompatibility, non-toxicity, low immunogenicity, great versatility and beneficial biological effects. CS, either alone or as composites, are suitable substrates in the fabrication of different types of products like hydrogels, membranes, beads, porous foams, nanoparticles, in-situ gel, microparticles, sponges and nanofibers/scaffolds. Currently, the CS based nanocarriers are intensely studied as controlled and targeted drug release systems for different drugs (anti-inflammatory, antibiotic, anticancer etc.) as well as for proteins/peptides, growth factors, vaccines, small DNA (DNAs) and short interfering RNA (siRNA). This review targets the latest biomedical approaches for CS based nanocarriers such as nanoparticles (NPs) nanofibers (NFs), nanogels (NGs) and chitosan coated liposomes (LPs) and their potential applications for medical and pharmaceutical fields. The advantages and challenges of reviewed CS based nanocarriers for different routes of administration (oral, transmucosal, pulmonary and transdermal) with reference to classical formulations are also emphasized. [ABSTRACT FROM AUTHOR]