A novel stimuli-synchronized alloy-treated matrix for space-defined gastrointestinal delivery of mesalamine in the Large White pig model.

The study focussed on designing a Stimuli-Synchronized Matrix (SSM) for space-defined colonic delivery of the anti-inflammatory drug mesalamine. The configured matrix provided time-independent delivery and stimuli targeting. Formulations were optimized according to a Box-Behnken experimental design that constituted mesalamine-loaded BaSO4-crosslinked chitosan dispersed within a pectin, carboxymethylcellulose and xanthan gum complex. The complex was compressed into matrices and subsequently alloy-treated with pectin and ethylcellulose. In vitro drug release was determined in the presence and absence of colonic enzymes and the mean dissolution time was used for formulation optimization. To mechanistically elucidate the synchronous catalytic action of the enzymes pectinase and glucosidase on the matrix, computer-aided 3D modelling of active fractions of the enzyme-substrate complexes was generated to predict the orientation of residues affecting the substrate domain. Drug release profiles revealed distinct colonic enzyme responsiveness with fractions of 0.402 and 0.152 of mesalamine released in the presence and absence of enzymes, respectively after 24h. The commercial comparator product showed irreproducible release profiles over the same period (SD=0.550) compared to the SSM formulation (SD=0.037). FTIR spectra of alloy-treated matrices showed no peaks from 1589 to 1512cm(-1) after colonic enzyme exposure. With increasing enzyme exposure there were also no peaks between 1646 and 1132cm(-1). This indicated polymeric enzyme cleavage for controlled and space-defined release of mesalamine. Plasma concentration profiles in the Large White pig model produced a Cmax of 3.77±1.375µg/mL compared to 10.604±2.846µg/mL for the comparator formulation. The SSM formulation proved superior over the comparator product by providing superiorly controlled enzyme-responsive colonic drug delivery.

A composite polyelectrolytic matrix for controlled oral drug delivery.

The purpose of this study was to formulate drug-loaded polyelectrolyte matrices constituting blends of pectin, chitosan (CHT) and hydrolyzed polyacrylamide (HPAAm) for controlling the premature solvation of the polymers and modulating drug release. The model drug employed was the highly water-soluble antihistamine, diphenhydramine HCl (DPH). Polyelectrolyte complex formation was validated by infrared spectroscopy. Matrices were characterized by textural profiling, porositometry and SEM. Drug release studies were performed under simulated gastrointestinal conditions using USP apparatus 3. FTIR spectra revealed distinctive peaks indicating the presence of -COO(-) symmetrical stretching (1,425-1,390 cm(-1)) and -NH (3) (+) deformation (1,535 cm(-1)) with evidence of electrostatic interaction between the cationic CHT and anionic HPAAm corroborated by molecular mechanics simulations of the complexes. Pectin-HPAAm matrices showed electrostatic attraction due to residual -NH(2) and -COO(-) groups of HPAAm and pectin, respectively. Textural profiling demonstrated that CHT-HPAAm matrices were most resilient at 6.1% and pectin-CHT-HPAAm matrices were the least (3.9%). Matrix hardness and deformation energy followed similar behavior. Pectin-CHT-HPAAm and CHT-HPAAm matrices produced type IV isotherms with H3 hysteresis and mesopores (22.46 nm) while pectin-HPAAm matrices were atypical with hysteresis at a low P/P(0) and pore sizes of 5.15 nm and a large surface area. At t (2 h), no DPH was released from CHT-HPAAm matrices, whereas 28.2% and 82.2% was released from pectin-HPAAm and pectin-CHT-HPAAm matrices, respectively. At t (4 h), complete DPH release was achieved from pectin-CHT-HPAAm matrices in contrast to only 35% from CHT-HPAAm matrices. This revealed the release-modulating capability of each matrix signifying their applicability in controlled oral drug delivery applications.