Balanced lipase interactions for degradation-controlled paclitaxel release from lipid cubic phase formulations

Michele Dully,Shayon Bhattacharya,Vivek Verma,David Murray,Damien Thompson,Tewfik Soulimane,Sarah P Hudson

doi:10.1016/j.jcis.2021.09.024

Michele Dully, Shayon Bhattacharya + Show 5 more

Open Access

https://doi.org/10.1016/j.jcis.2021.09.024

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Abstract

Lipid cubic phase (LCP) formulations enhance the intestinal solubility and bioavailability of hydrophobic drugs by reducing precipitation and facilitating their mass transport to the intestinal surface for absorption. LCPs with an ester linkage connecting the acyl chain to the glycerol backbone (monoacylglycerols), are susceptible to chemical digestion by several lipolytic enzymes including lipases, accelerating the release of hydrophobic agents from the lipid bilayers of the matrix. Unlike regular enzymes that transform soluble substrates, lipolytic enzymes act at the interface of water and insoluble lipid. Therefore, compounds that bind to this interface can enhance or inhibit the activity of enzymes to varying extent. Here, we explore how the lipolysis rate can be tuned by the interfacial interaction of porcine pancreatic lipase with monoolein LCPs containing a known lipase inhibitor, tetrahydrolipstatin. Release of the Biopharmaceutical Classification System (BCS) class IV drug, paclitaxel, from the inhibitor-modified LCP was examined in the presence of lipase and its effectors colipase and calcium. By combining experimental dynamic digestion studies, thermodynamic measurements and molecular dynamics simulations of the competitive inhibition of lipase by tetrahydrolipstatin, we reveal the role and mode of action of lipase effectors in creating a precisely-balanced degradation-controlled LCP release system for the poorly soluble paclitaxel drug.

Highlights

We have recently shown that lipolytic enzyme interactions can be modulated through the incorporation of known lipase inhibitor tetrahydrolipstatin (THL) into the lipid cubic phase to control the release of a model small hydrophobic drug clofazimine (CFZ) from Lipid cubic phase (LCP) [57]
The influence of the complex and competitive interactions between lipase, its effectors/inhibitors and lipid substrates can be mapped with a goal to modulating the degradation rate of the lipid matrix and corresponding release profile of incorporated hydrophobic drugs
The modulation of the lipolysis of a lipid cubic phase is characterised by studying the impact of the inhibitor tetrahydrolipstatin (THL), effector colipase and calcium ion co-factor, and hydrophobic therapeutic agents on the enzymatic activity of lipases

Summary

Introduction

Identified a large number of poorly soluble, high molecular weight drug candidates with presumed poor ability to permeate biological membranes [1]. Their physiochemical properties place them in the most difficult class IV category of the Biopharmaceutical Classification system (BCS) [2]. Efforts to improve their bioavailability may require reverting back to the lead optimisation phase to alter the chemical structure in an attempt to improve the physiochemical properties of the active pharmaceutical ingredient (API) [3]. Significant effort has been expended towards developing carrier systems to deliver poorly soluble APIs [10,11,12,13,14], which can be engineered to achieve a targeted release in response to environmental stimuli and changes [15,16,17,18,19]

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