Concentration and composition dependent aggregation of Pluronic- and Poly-(2-oxazolin)-Efavirenz formulations in biorelevant media

Sebastian Endres,Emil Karaev,Simon Hanio,Jonas Schlauersbach,Christian Kraft,Tim Rasmussen,Robert Luxenhofer,Bettina Böttcher,Lorenz Meinel,Ann-Christin Pöppler

doi:10.1016/j.jcis.2021.08.040

Sebastian Endres, Emil Karaev + Show 8 more

Open Access

https://doi.org/10.1016/j.jcis.2021.08.040

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Abstract

Many drugs and drug candidates are poorly water-soluble. Intestinal fluids play an important role in their solubilization. However, the interactions of intestinal fluids with polymer excipients, drugs and their formulations are not fully understood. Here, diffusion ordered spectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY), complemented by cryo-TEM were employed to address this. Efavirenz (EFV) as model drug, the triblock copolymers Pluronic® F-127 (PF127) and poly(2-oxazoline) based pMeOx-b-pPrOzi-b-pMeOx (pOx/pOzi) and their respective formulations were studied in simulated fed-state intestinal fluid (FeSSIF). For the individual polymers, the bile interfering nature of PF127 was confirmed and pure pOx/pOzi was newly classified as non-interfering. A different and more complex behaviour was however observed if EFV was involved. PF127/EFV formulations in FeSSIF showed concentration dependent aggregation with separate colloids at low formulation concentrations, a merging of individual particles at the solubility limit of EFV in FeSSIF and joint aggregates above this concentration. In the case of pOx/pOzi/EFV formulations, coincident diffusion coefficients for pOx/pOzi, lipids and EFV indicate joint aggregates across the studied concentration range. This demonstrates that separate evaluation of polymers and drugs in biorelevant media is not sufficient and their mixtures need to be studied to learn about concentration and composition dependent behaviour.

Highlights

40% of worldwide approved drugs are poorly water-soluble and categorized as class II and class IV in the Biopharmaceutics Classification system (BCS).[1,2] The even higher amount in drug candidates has increased from 60% reported in 2013 [1] to 70% À 90% in 2017 [2]
The behaviour of two triblock copolymers, PluronicÒ F127 (PF127) and a pOx/ pOzi, as well as their formulations with the HIV-drug efavirenz in biorelevant media simulating the fed state intestinal fluids (FeSSIF) was investigated in detail using NMR spectroscopy in solution complemented by cryo-TEM
While the polymers alone could be straightforwardly classified as bile interacting polymers (PF127) and bile non-interacting based on 1H NMR spectra and observations from DOSY experiments, the situa

Summary

Introduction

40% of worldwide approved drugs are poorly water-soluble and categorized as class II and class IV in the Biopharmaceutics Classification system (BCS).[1,2] The even higher amount in drug candidates has increased from 60% reported in 2013 [1] to 70% À 90% in 2017 [2] In this context, drug delivery systems (DDS) such as nano- or microparticles based on lipids and polymers are investigated to overcome solubility challenges or generally alter physicochemical properties and influence pharmacokinetics.[3] Since the mid-1990 s, the number of publications on this topic strongly increased (Figure S1).

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