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

Abstract

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.

Keywords::

• Hot-melt extrusion
• solid dispersion
• CB-1 antagonist
• dissolution test sink conditions
• supersaturation
• bioavailability

Acknowledgments

The authors would like to thank all the people who have collaborated in the performance of this article either all people involved directly or indirectly in the project and especially the people part of preformulation area for their ability, effort and dedication. Andreas and Catherine from Evonick Gmbh for their collaboration.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. All the experimental has been done in ESTEVE lab.