Application of novel chitosan derivatives in dissolution enhancement of a poorly water soluble drug.

Solid dispersions of the poorly water soluble drug dexamethasone and newly synthesized chitosan derivatives (chitosan succinate, CS, and chitosan phthalate, CP) were prepared by spray drying. The resulting microspheres were evaluated in terms of their drug loading or encapsulation efficiency as well as drug release profile. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and infrared spectroscopy (IR) were used to evaluate the solid dispersion for possible interactions between drug and polymers. The pure drug was evaluated in the same manner for comparison purposes. High loading levels (>74%) were achieved using CP and CS as polymer matrices. Drug release rate was accelerated significantly upon the formation of the solid dispersions; the drug release rate was increased with increasing percentage of the chitosan derivatives in the microspheres. IR studies showed no chemical interaction while the X-ray studies showed a significant change in the crystallinity of the drug upon formation of solid dispersions.

Synthesis of zinc-crosslinked thiolated alginic acid beads and their in vitro evaluation as potential enteric delivery system with folic acid as model drug.

The aim of this study is to explore the potential of synthetic modifications of alginic acid as a method to enhance the stability of its complexes with divalent cations under physiological conditions. A fraction of algin's carboxylic acid moieties was substituted with thiol groups to different substitution degrees through conjugating alginate to cysteine to produce alginate-cysteine (AC) conjugates. Infrared spectrophotometry and iodometry were used to characterize the resulting polymeric conjugates in terms of structure and degree of substitution. Moreover, zinc ions were used to crosslink the resulting AC polymers. Folic acid loaded beads were prepared from Zinc-crosslinked AC polymers (AC-Zn) of different cysteine substitution degrees. The generated beads were then investigated in vitro for their capacity to modify folic acid release. AC-Zn polymeric beads resisted drug release under acidic conditions (pH 1.0). However, upon transfer to a phosphate buffer solution (pH 7.0) they released most of their contents almost immediately. This change in drug release behavior is most probably due to the sequestering of zinc cations by phosphate ions within the buffer solution to form insoluble chelates and, to a lesser extent, the ionization of the carboxylic acid and thiol moieties. Removal of zinc ions from the polymeric matrix seems to promote polymeric disintegration and subsequent drug release. A similar behavior is expected in vivo due to the presence of natural zinc sequestering agents in the intestinal fluids. AC-Zn polymers provided a novel approach for enteric drug delivery as drug release from these matrices complied with the USP specifications for enteric dosage forms.

Synthesis of iron-crosslinked chitosan succinate and iron-crosslinked hydroxamated chitosan succinate and their in vitro evaluation as potential matrix materials for oral theophylline sustained-release beads.

Chitosan succinate (CS) and hydroxamated chitosan succinate (HCS) were prepared. The generated semisynthetic polymers were employed in the formation of drug-loaded, iron(III)-crosslinked polymeric beads. Infrared spectroscopy was employed to prove the crosslinking. The produced beads were evaluated in vitro as drug prolonging and potentially orally administered delivery system. Theophylline was used as the loaded model drug. The generated beads proved to be successful in prolonging drug release. Iron leaching from the generated beads was minimal (<2%), and it only took place under acidic conditions (pH 1).

Second derivative ultraviolet spectrophotometry and HPTLC for the simultaneous determination of vitamin C and dipyrone.

Two accurate, precise and sensitive thin layer chromatographic (TLC) and second derivative UV-spectrophotometric procedures are described for the simultaneous determination of ascorbic acid and dipyrone in pure form and in pharmaceutical dosage forms. The TLC method involved direct application of methanolic solutions of tested samples on silica gel TLC plates using water:methanol (95:5 v/v) as developing system. The developed plates were then directly scanned at 260 nm using a TLC scanner. The second method depends on second derivative UV-spectrophotometry with zero crossing technique of measurement. Second derivative amplitudes at 280 and 272 nm were selected for the determination of ascorbic acid and dipyrone, respectively. Both methods show good linearity, precision and reproducibility. They are simple and do not require manipulation prior to analysis. The proposed methods have been successfully applied to the determination of the drugs in various pharmaceutical dosage forms such as tablets and ampoules.

Synthesis of iron-crosslinked hydroxamated alginic acid and its in vitro evaluation as a potential matrix material for oral sustained-release beads.

Hydroxamated alginic acid (HAA) was prepared. The generated semisynthetic polymer was employed in the formation of drug-loaded, iron(III)-crosslinked polymeric beads. Infrared spectroscopy was employed to prove the crosslinking. The degree of hydroxamate substitution was determined by acid-base back titration, and it was found to be ca. 20%. The produced beads were evaluated in vitro as orally administered sustained release drug delivery system. Theophylline, paracetamol, and chlorpheniramine maleate were used as model drugs. The generated beads proved to be successful in prolonging drug release, particularly in the case of theophylline. Iron leaching from the generated beads was minimal (< 0.5% of the entire complexed iron), and took place during passage through the simulated gastric fluid.

Synthesis of chitosan succinate and chitosan phthalate and their evaluation as suggested matrices in orally administered, colon-specific drug delivery systems.

The naturally occurring polymer chitosan was reacted separately with succinic and phthalic anhydrides. The resulting semisynthetic polymers were assessed as potential matrices for colon-specific, orally administered drug delivery. Sodium diclofenac was used as the dispersed model drug. The prepared matrices were incorporated into tablets, which were evaluated in vitro. The evaluation included dissolution studies conducted under simulated gastrointestinal conditions of pH and transit times. The percentage fluid uptake was used to indicate the ability of the matrix to protect an embedded drug from gastric juices. The prepared matrices resisted dissolution under acidic conditions. On the other hand, improved drug release profiles were observed under basic conditions. Therefore, the results suggest the suitability of the prepared matrices in colon specific, orally administered drug delivery system. However, future in vivo testing is planned to fully establish the suitability of the prepared polymers for colon-specific drug delivery.

Chitosan microcapsules as controlled release systems for insulin.

This study analyses the use of chitosan for the production of surface crosslinked microparticulate systems containing insulin. The microcapsules were prepared by an innovative technique based on interfacial crosslinkage of different amounts of chitosan solubilized in the inner phase of a water/oil emulsion by means of ascorbyl palmitate. The correlation between the main formulation parameters and the functional properties of the microcapsules were analysed. Insulin is incorporated with high efficiency. The peptide release is constant for appreciable periods of time. The content of chitosan modulates the main physico-chemical properties of the matrix.

Indomethacin loaded chitosan microspheres. Correlation between the erosion process and release kinetics.

The preparation of chitosan microspheres covalently linked with citric acid and loaded with indomethacin is described. The release kinetics correlated with the concentration of chitosan in the microsphere preparative mixture and the pH of the release medium. Deviations from Fickian to zero order kinetics were observed at higher concentrations of chitosan and at pH 7.4. The variations induced by these parameters on drug diffusion and solubility in the matrix undergoing erosion were analyzed.

Microparticles of BSA substituted with deoxycholic acid and triethylene glycol glutarate. Correlations between the physico-chemical properties of the matrix and the release kinetics.

Bovine serum albumin or bovine serum albumin covalently linked to deoxycholic acid and triethylene glycol glutarate were used for the preparation of microspheres loaded with indomethacin. The presence of these residues on the bovine serum albumin molecule increased the loading levels. The kinetic analysis of release evidenced a zero order release period from the start of release in the microparticles obtained by bovine serum albumin linked to deoxycholic acid and triethylene glycol glutarate, followed by a decreasing rate release and a first Anomalous period followed by a zero order period in the albumin microparticles. These different release behaviours were correlated to the modifications induced by deoxycholic acid and triethylene glycol glutarate on the drug diffusivity and solubility in the matrix undergoing erosion.