Soluplus® as an effective absorption enhancer of poorly soluble drugs in vitro and in vivo

a b s t r a c t As many new active pharmaceutical ingredients are poorly water soluble, solubility enhancers are one possibility to overcome the hurdles of drug dissolution and absorption in oral drug delivery. In the present work a novel solubility enhancing excipient (Soluplus Ò ) was tested for its capability to improve intestinal drug absorption. BCS class II compounds danazol, fenofibrate and itraconazole were tested both in vivo in beagle dogs and in vitro in transport experiments across Caco-2 cell monolayers. Each drug was applied as pure crystalline substance, in a physical mixture with Soluplus Ò , and as solid solution of the drug in the excipient. In the animal studies a many fold increase in plasma AUC was observed for the solid solutions of drug in Soluplus Ò compared to the respective pure drug. An effect of Soluplus Ò in a physical mixture with the drug could be detected for fenofibrate. In vitro transport studies confirm the strong effect of Soluplus Ò on the absorption behavior of the three tested drugs. Furthermore, the increase of drug flux across Caco-2 monolayer is correlating to the increase in plasma AUC and C max in vivo. For these poorly soluble substances Soluplus Ò has a strong potential to improve oral bioavailability. The applicability of Caco-2 monolayers as tool for predicting the in vivo transport behavior of the model drugs in combination with a solubility enhancing excipient was shown. Also the improvement of a solid dispersion compared to physical mixtures of the drugs and the excipient was correctly reflected by Caco-2 experiments. In the case of fenofibrate the possible improvement by a physical mixture was demonstrated, underscoring the value of the used tool as alternative to animal studies

Conjugation of Hot-Melt Extrusion with High-Pressure Homogenization: a Novel Method of Continuously Preparing Nanocrystal Solid Dispersions

Over the past few decades, nanocrystal formulations have evolved as promising drug delivery systems owing to their ability to enhance the bioavailability and maintain the stability of poorly water-soluble drugs. However, conventional methods of preparing nanocrystal formulations, such as spray drying and freeze drying, have some drawbacks including high cost, time and energy inefficiency, traces of residual solvent, and difficulties in continuous operation. Therefore, new techniques for the production of nanocrystal formulations are necessary. The main objective of this study was to introduce a new technique for the production of nanocrystal solid dispersions (NCSDs) by combining high-pressure homogenization (HPH) and hot-melt extrusion (HME). Efavirenz (EFZ), a Biopharmaceutics Classification System class II drug, which is used for the treatment of human immunodeficiency virus (HIV) type I, was selected as the model drug for this study. A nanosuspension (NS) was first prepared by HPH using sodium lauryl sulfate (SLS) and Kollidon® 30 as a stabilizer system. The NS was then mixed with Soluplus® in the extruder barrel, and the water was removed by evaporation. The decreased particle size and crystalline state of EFZ were confirmed by scanning electron microscopy, zeta particle size analysis, and differential scanning calorimetry. The increased dissolution rate was also determined. EFZ NCSD was found to be highly stable after storage for 6 months. In summary, the conjugation of HPH with HME technology was demonstrated to be a promising novel method for the production of NCSDs

Drug-Induced Dynamics of Bile Colloids.

Bile colloids containing taurocholate and lecithin are essential for the solubilization of hydrophobic molecules including poorly water-soluble drugs such as Perphenazine. We detail the impact of Perphenazine concentrations on taurocholate/lecithin colloids using analytical ultracentrifugation, dynamic light scattering, small-angle neutron scattering, nuclear magnetic resonance spectroscopy, coarse-grained molecular dynamics simulations, and isothermal titration calorimetry. Perphenazine impacted colloidal molecular arrangement, structure, and binding thermodynamics in a concentration-dependent manner. At low concentration, Perphenazine was integrated into stable and large taurocholate/lecithin colloids and close to lecithin. Integration of Perphenazine into these colloids was exothermic. At higher Perphenazine concentration, the taurocholate/lecithin colloids had an approximately 5-fold reduction in apparent hydrodynamic size, heat release was less exothermic upon drug integration into the colloids, and Perphenazine interacted with both lecithin and taurocholate. In addition, Perphenazine induced a morphological transition from vesicles to wormlike micelles as indicated by neutron scattering. Despite these surprising colloidal dynamics, these natural colloids successfully ensured stable relative amounts of free Perphenazine throughout the entire drug concentration range tested here. Future studies are required to further detail these findings both on a molecular structural basis and in terms of in vivo relevance