In vitro and in vivo assessment of hydroxypropyl cellulose as functional additive for enabling formulations containing itraconazole

Rafael D Bachmaier; Marius Monschke; Thilo Faber; Anna K Krome; Yann Pellequer; Edmont Stoyanov; Alf Lamprecht; Karl G Wagner

doi:10.1016/j.ijpx.2021.100076

In vitro and in vivo assessment of hydroxypropyl cellulose as functional additive for enabling formulations containing itraconazole

Int J Pharm X. 2021 Mar 17:3:100076. doi: 10.1016/j.ijpx.2021.100076. eCollection 2021 Dec.

Authors

Rafael D Bachmaier¹, Marius Monschke¹, Thilo Faber¹, Anna K Krome¹, Yann Pellequer², Edmont Stoyanov³, Alf Lamprecht^{1

2}, Karl G Wagner¹

Affiliations

¹ Department of Pharmaceutical Technology and Biopharmaceutics, University of Bonn, 53121 Bonn, Germany.
² UFR Santé, Laboratoire de Pharmacie Galénique, 19, rue Ambroise Paré, 25000 Besancon, France.
³ Nisso Chemical Europe GmbH, Berliner Allee 42, 40212 Düsseldorf, Germany.

Abstract

Using polymers as additives to formulate ternary amorphous solid dispersions (ASDs) has successfully been established to increase the bioavailability of poorly soluble drugs, when one polymer is not able to provide both, stabilizing the drug in the matrix and the supersaturated solution. Therefore, we investigated the influence of low-viscosity hydroxypropyl cellulose (HPC) polymers as an additive in HPMC based ternary ASD formulations made by hot-melt extrusion (HME) on the bioavailability of itraconazole (ITZ). The partitioning potential of the different HPC grades was screened in biphasic supersaturation assays. Solid-state analytics were performed using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD). The addition of HPCs, especially HPC-UL, resulted in a superior partitioned amount of ITZ in biphasic supersaturation assays. Moreover, the approach in using HPCs as an additive in HPMC based ASDs led to an increase in partitioned ITZ compared to Sporanox® in biorelevant biphasic dissolution studies. The results from the biphasic dissolution experiments correlated well with the in vivo studies, which revealed the highest oral bioavailability for the ternary ASD comprising HPC-UL and HPMC.

Keywords: API, active pharmaceutical ingredient; ASD, amorphous solid dispersion; AUC, area under the curve; AcN, acetonitrile; Amorphous solid dispersion; BCS, biopharmaceutical classification system; Biphasic dissolution; DMSO, dimethyl sulfoxide; DSC, differential scanning calorimetry; FaSSIF, fasted state simulated intestinal fluid; GI, gastrointestinal; HME, hot-melt extrusion; HPC; HPC, hydroxypropyl cellulose; HPMC; HPMC, hydroxypropyl methyl cellulose; Hot-melt extrusion; ITZ, itraconazole; KTZ, ketoconazole; NCE, new chemical entity; OH-ITZ, hydroxy-itraconazole; PM, physical mixture; SD, spray-drying; TG, glass transition temperature; XRPD, x-ray powder diffraction.