The effect of drug ionization on lipid-based formulations for the oral delivery of anti-psychotics.

Tahlia R Meola,Paul Joyce,Clive A Prestidge,Kara Paxton,Hayley B Schultz

doi:10.5599/admet.830

Abstract

Lipid-based formulations (LBFs) are well-known to improve the oral bioavailability of poorly water-soluble drugs (PWSDs) by presenting the drug to the gastrointestinal environment in a molecularly dispersed state, thus avoiding the rate-limiting dissolution step. Risperidone and lurasidone are antipsychotics drugs which experience erratic and variable absorption, leading to a low oral bioavailability. The aim of this research was to develop and investigate the performance of risperidone and lurasidone when formulated as an emulsion and silica-lipid hybrid (SLH). Lurasidone and risperidone were dissolved in Capmul® MCM at 100% and 80% their equilibrium solubility, respectively, prior to forming a sub-micron emulsion. SLH microparticles were fabricated by spray-drying a silica stabilised sub-micron emulsion to form a solid powder. The performances of the formulations were evaluated in simulated intestinal media under digesting conditions, where the emulsion and SLH provided a 17-fold and 23-fold increase in LUR solubilisation, respectively. However, the performance of RIS was reduced by 2.2-fold when encapsulated within SLH compared to pure drug. Owing to its pKa, RIS adsorbed to the silica and thus, dissolution was significantly hindered. The results reveal that LBFs may not overcome the challenges of all PWSDs and physiochemical properties must be carefully considered when predicting drug performance.

Highlights

Adherence to antipsychotic medication is a significant challenge for patients, whereby research suggests at least half of patients are non-compliant, leading to illness relapse, hospital remittance or suicide [1]
The enhanced performance provided by lipid-based formulations (LBFs) can be attributed to the following proposed mechanisms: (i) lipids in the gastrointestinal tract hinder gastric emptying from the stomach, increase transit time of the drug in the small intestine, allowing greater absorption to occur [6, 7]; (ii) drug can be encapsulated and pre-solubilised in lipid and presented to the gastrointestinal tract in its molecularly dispersed state, drug absorption is no longer limited by its dissolution rate [8, 9], and (iii) exogenous lipids stimulate the release of bile and pancreatic lipase from the gall bladder and pancreas, respectively, which triggers the production of solubilising species that can further solubilise the drug and be transported across the epithelium via enterocytes [6, 7]
Fabrication and physicochemical characterisation of RIS and LUR formulations The drug loading levels of LBFs is dependent on the solubilising capacity of the active pharmaceutical ingredient in the lipid reservoir

Summary

Introduction

Adherence to antipsychotic medication is a significant challenge for patients, whereby research suggests at least half of patients are non-compliant, leading to illness relapse, hospital remittance or suicide [1]. As a class, antipsychotic drugs are generally poorly water-soluble, resulting in limited absorption and sub-optimal oral bioavailability when administered as a conventional tablet [2, 3]. Despite the magnitude of advantages, LBFs account for only 2-4 % of commercialised pharmaceutical formulations [10, 11]. This is likely attributed to disadvantages associated with their liquid-state, such as poor physical stability, drug leakage, oxidation of lipid excipients and drug precipitation [12, 13]

Objectives

Results

Conclusion