Pore blocking: An innovative formulation strategy for the design of alcohol resistant multi-particulate dosage forms

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Abstract

In this work calcium stearate (CaSt) multi-particulates loaded with codeine phosphate (COP) were developed in an attempt to provide extended release (ER) combined with alcohol dose dumping (ADD) resistance. The pellets were prepared via wet/extrusion spheronization and ER characteristics were obtained after fluid bed drying at 30 °C. Pore blockers (i.e., xanthan, guar gum and TiO2) were integrated to control the uptake of ethanolic media, the CaSt swelling and consequently, the COP release. While all three pore blockers are insoluble in ethanol, xanthan dissolves, guar gum swells and TiO2 does not interact with water. The incorporation of 10 and 15% TiO2 still provided ER characteristics and yielded ADD resistance in up to 40 v% ethanol. The in-vitro data were subjected to PK simulations, which revealed similar codeine plasma levels when the medication is used concomitantly with alcoholic beverages. Taken together the in-vitro and in-silico results demonstrate that the incorporation of appropriate pore blockers presents a promising strategy to provide ADD resistance of multi-particulate systems.

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