Enhanced in vivo absorption of CB-1 antagonist in rats via solid solutions prepared by hot-melt extrusion.

The aim of the present work was to investigate in vitro dissolution properties of three binary solid solutions prepared by a hot-melt extrusion (HME) process with vinyl pirrolidone--vinyl acetate copolymer (Kollidon VA 64), ethyl acrylate, methyl methacrylate polymer (Eudragit E) polyetilenglicol 8000 (PEG 8000) with a cannabinoid type 1 (CB-1) antagonist. Hansen solubility parameters were calculated from the chemical structures of the drug and the individual polymers in order to predict miscibility. Solid state characterizations of drug substance, physical blends and HME formulations were performed with differential scanning calorimetry. The dissolution testing conducted under sink conditions revealed that the dissolution rate of HME formulations improved around 1.8-fold vs drug substance. Supersaturation dissolution study demonstrated that HME formulations composed by Eudragit E and Kollidon VA64 increased drug solubility between 30- and 35-fold, respectively comparing to the drug substance. Physical and chemical stability of formulations were studied at 40°C/75%HR with open dish during 15 days. The formulation composed by the drug and Eudragit E at 10:90 was evaluated for in vivo drug absorption in male Wistar-Hannover rats and it was found to increase CB-1 absorption threefold greater than pure drug oral suspension.

Pair distribution function X-ray analysis explains dissolution characteristics of felodipine melt extrusion products.

Solid solutions of felodipine with EUDRAGIT E and EUDRAGIT E/NE were shown to dramatically increase the dissolution rate of felodipine in biorelevant media. Of the two polymer systems, extrudates containing 5% EUDRAGIT NE showed a faster dissolution rate and less recrystallization (no precipitation within 2 h). Although differential scanning calorimetry (DSC) and conventional X-ray powder diffraction (XRPD) were able to verify the amorphous state of the drug after melt extrusion, it was not possible to differentiate the two extrudate compositions further with these methods. We then applied pair distribution function (PDF) analysis to investigate extrudates. It was possible to more closely characterize the solid state of the amorphous extrudates in terms of local structural order: PDF analysis revealed that addition of minor amounts of EUDRAGIT NE to the main component EUDRAGIT E during extrusion changed the local structure of EUDRAGIT E in a nonadditive way. We conclude that local ordering can be important to the release characteristics of extrudates, even when the components are present in the amorphous state.