Design and characterization of monoacylglycerol lipid cubic phase systems for the effective delivery of small molecule pharmaceuticals

To be effective, a drug must be efficiently delivered in sufficient quantities over a period of time long enough for it to carry out its desired effect. A major challenge in this sense is poor retention and bioavailability of drugs, particularly those that display poor solubility. The number of newly discovered drugs is disproportionate to the number that make it to market because of less than desirable solubility and permeability profiles, but smart drug delivery systems, such as lipid-based systems, are capable of overcoming these challenges. One particular system, the amphiphilic, biocompatible, and biodegradable lipid cubic phase, has shown promise as an effective carrier system for the controlled release of drugs varying in solubility. This work explores the behaviour of a variety of industrially relevant small molecule pharmaceuticals in lipid cubic phases formulated with different host lipids for potential controlled delivery applications. An understanding of the molecular mechanisms underlying the process of dissolution/diffusion from these phases was elucidated to support the field of controlled drug delivery using in silico molecular dynamic modelling and empirical approaches. A comprehensive characterization approach was taken both macroscopically and microscopically using small-angle X-ray scattering and polarized light to ascertain the mesophase accessed upon incorporation of molecules of varying solubilities and size. In the first instance, the influence of environmental conditions on the release profile of four antihistamine molecules was studied to establish in vitro models that might assist in predicting the dissolution behaviour of a given pharmaceutical with known physicochemical properties. Two model first-generation and two model second-generation H1 antagonist antihistamine drugs were selected and formulated in two separate monoacyglycerol-derived matrices. The impact of encapsulating the molecules in the lipid cubic systems on their mucoadhesive properties was demonstrated using multi-parametric surface plasmon resonance (MP-SPR). With a potential application in developing therapies for the treatment of allergic reactions, the ability of the formulations to inhibit mediator release utilizing RBL-2H3 mast cells with the propensity to release histamine upon induction was presented. Lipid cubic formulations can enhance the intestinal solubility and subsequent bioavailability of notoriously hydrophobic drug entities by reducing drug precipitation and facilitating mass transport to the intestinal surface for absorption. In this context, the aims of the second study were twofold: to evaluate an approach to regulate the rate of degradation of lipid cubic phase drug delivery systems by targeting the enzyme interactions responsible for their demise; and to study the subsequent drug release profiles from bulk lipid cubic gels using model drugs of contrasting hydrophobicity. In a novel approach, monoacylglycerol cubic phases were formulated with a potent lipase inhibitor tetrahydrolipstatin displaying controlled degradation with at least a 4-fold longer release compared to the blank systems. Sustained release of a model hydrophobic pharmaceutical (a clofazimine salt) was studied over 30 days to highlight the advantage of incorporating an inhibitor into the cubic network to achieve tunable lipid release systems. The final aspect of this thesis deals with the interplay between the lipolysis rate and the interfacial interaction of porcine pancreatic lipase with lipid cubic substrates encapsulating the THL. In the final chapter, inhibitor-modified monoolein lipid cubic formulations designed to encapsulate and control the release of a model BCS class IV drug paclitaxel (PTX) were examined under simulated lipolysis in the presence of lipase and its cofactors colipase and calcium. We present a combination of thermodynamic and molecular dynamics simulations of the competitive inhibition with experimental dynamic digestion studies to reveal the role and mode of action of the studied lipase effectors in designing a degradation-controlled release system for the poorly soluble drug PTX. These studies facilitated a deeper understanding of the approach described in the previous chapter, expanding the study to open new important possibilities in the field of pharmaceutical transport especially where difficult-to-formulate drugs are concerned.