Controlled Release from Zein Matrices: Interplay of Drug Hydrophobicity and pH.

PURPOSE: In earlier studies, the corn protein zein is found to be suitable as a sustained release agent, yet the range of drugs for which zein has been studied remains small. Here, zein is used as a sole excipient for drugs differing in hydrophobicity and isoelectric point: indomethacin, paracetamol and ranitidine. METHODS: Caplets were prepared by hot-melt extrusion (HME) and injection moulding (IM). Each of the three model drugs were tested on two drug loadings in various dissolution media. The physical state of the drug, microstructure and hydration behaviour were investigated to build up understanding for the release behaviour from a zein based matrix for drug delivery. RESULTS: Drug crystallinity of the caplets increases with drug hydrophobicity. For ranitidine and indomethacin, swelling rates, swelling capacity and release rates were pH dependent as a consequence of the presence of charged groups on the drug molecules. Both hydration rates and release rates could be approached by existing models. CONCLUSION: The drug state and pH dependant electrostatic interactions are hypothesised to influence release kinetics. Both factors can potentially be used to influence release kinetics release, thereby broadening the horizon for zein as a tuneable release agent.

Creating Drug Solubilization Compartments via Phase Separation in Multicomponent Buccal Patches Prepared by Direct Hot Melt Extrusion-Injection Molding.

Creating in situ phase separation in solid dispersion based formulations to allow enhanced functionality of the dosage form, such as improving dissolution of poorly soluble model drug as well as being mucoadhesive, can significantly maximize the in vitro and in vivo performance of the dosage form. This formulation strategy can benefit a wide range of solid dosage forms for oral and alternative routes of delivery. This study using buccal patches as an example created separated phases in situ of the buccal patches by selecting the excipients with different miscibility with each other and the model drug. The quaternary dispersion based buccal patches containing PEG, PEO, Tween 80, and felodipine were prepared by direct hot melt extrusion-injection molding (HME-IM). The partial miscibility between Tween 80 and semicrystalline PEG-PEO led to the phase separation after extrusion. The Tween phases acted as drug solubilization compartments, and the PEG-PEO phase had the primary function of providing mucoadhesion and carrier controlled dissolution. As felodipine was preferably solubilized in the amorphous regions of PEG-PEO, the high crystallinity of PEG-PEO resulted in an overall low drug solubilizing capacity. Tween 80 was added to improve the solubilization capacity of the system as the model drug showed good solubility in Tween. Increasing the drug loading led to the supersaturation of drug in Tween compartments and crystalline drug dispersed in PEG-PEO phases. The spatial distribution of these phase-separated compartments was mapped using X-ray micro-CT, which revealed that the domain size and heterogeneity of the phase separation increased with increasing the drug loading. The outcome of this study provides new insights into the applicability of in situ formed phase separation as a formulation strategy for the delivery of poorly soluble drugs and demonstrated the basic principle of excipient selection for such technology.

The Development of Direct Extrusion-Injection Moulded Zein Matrices as Novel Oral Controlled Drug Delivery Systems.

PURPOSE: To evaluate the potential of zein as a sole excipient for controlled release formulations prepared by hot melt extrusion. METHODS: Physical mixtures of zein, water and crystalline paracetamol were hot melt extruded (HME) at 80°C and injection moulded (IM) into caplet forms. HME-IM Caplets were characterised using differential scanning calorimetry, ATR-FTIR spectroscopy, scanning electron microscopy and powder X-ray diffraction. Hydration and drug release kinetics of the caplets were investigated and fitted to a diffusion model. RESULTS: For the formulations with lower drug loadings, the drug was found to be in the non-crystalline state, while for the ones with higher drug loadings paracetamol is mostly crystalline. Release was found to be largely independent of drug loading but strongly dependent upon device dimensions, and predominately governed by a Fickian diffusion mechanism, while the hydration kinetics shows the features of Case II diffusion. CONCLUSIONS: In this study a prototype controlled release caplet formulation using zein as the sole excipient was successfully prepared using direct HME-IM processing. The results demonstrated the unique advantage of the hot melt extruded zein formulations on the tuneability of drug release rate by alternating the device dimensions.

Coating formation during drying of ß-lactoglobulin: gradual and sudden changes.

The drying dynamics of protein coatings is of importance for many applications. The main focus of research so far was to investigate macroscopic properties of protein coatings, leaving drying dynamics virtually unexplored. A unique combination of techniques is used to monitor drying of a coating containing the protein ß-lactoglobulin. The techniques used cover both macroscopic and microscopic aspects of the drying process. For all water fractions amenable to diffusing wave spectroscopy analysis (xw > 0.2 w/w), the tracer particles diffuse in the coating as in a Newtonian viscous medium. Magnetic resonance imaging shows both protein and water are distributed homogeneously over the coating during drying, up to water fractions above 0.2 w/w. When drying continues to lower water fractions, sudden transitions in drying behavior are observed by both dynamic vapor sorption and IR spectroscopy, which we suggest are due to changes in molecular interactions caused by dehydration of the protein backbone.

Influence of protein hydrolysis on the growth kinetics of ß-lg fibrils.

Recently it was found that protein hydrolysis is an important step in the formation of ß-lactoglobulin fibrils at pH 2 and elevated temperatures. The objective of the present study was to further investigate the influence of hydrolysis on the kinetics of fibril formation. Both the hydrolysis of ß-lactoglobulin and the growth of the fibrils were followed as a function of time and temperature, using SDS polyacrylamide gel electrophoresis and a Thioflavin T fluorescence assay. As an essential extension to existing models, the quantification of the effect of the hydrolysis on the fibrillar growth was established by a simple polymerization model including a hydrolysis step.