Abstract
Lipid cubic phase formulations have gained recognition as potential controlled delivery systems for a range of active pharmaceutical and biological agents on account of their desirable physiochemical properties and ability to encapsulate both hydrophobic and hydrophilic molecules. The most widely studied lipid cubic systems are those of the monoacylglycerol lipid family. These formulations are susceptible to lipolysis by a variety of enzymes, including lipases and esterases, which attack the ester bond present on the lipid chain bridging the oleic acid component to the glycerol backbone. The release of poorly soluble molecules residing in the lipid membrane portions of the phase is limited by the breakdown of the matrix; thus, presenting a potential means for further controlling and sustaining the release of therapeutic agents by targeting the matrix stability and its rate of degradation. The aims of the present 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. Here, hybrid materials consisting of cubic phases with monoacylglycerol lipids of different chain lengths formulated with a potent lipase inhibitor tetrahydrolipstatin were designed. Modulation of the release of a hydrophobic model pharmaceutical, a clofazimine salt, was obtained by exploiting the matrices’ enzyme-driven digestion. A stable cubic phase is described, displaying controlled degradation with at least a 4-fold improvement compared to the blank systems shown in inhibitor-containing cubic systems. Sustained release of the model hydrophobic pharmaceutical was studied over 30 days to highlight the advantage of incorporating an inhibitor into the cubic network to achieve tunable lipid release systems. This is done without negatively affecting the structure of the matrix itself, as shown by comprehensive small-angle x-ray scattering experiments.
Highlights
Challenges in the delivery of therapeutic agents in vivo include controlling and maintaining their release at therapeutically effective doses over a sustained period of time, long enough for them to exhibit their desired effect
Lipid carrier systems have proven their potential in controlled delivery applications on account of their unique microstructure and amphiphilic character, as well as the biodegradable and biocompatible nature of the lipids used [3,4]
One can determine whether a test material is anisotropic or isotropic in nature and measure its birefringence by using cross-polarized microscopy (CPLM) [72]
Summary
Challenges in the delivery of therapeutic agents in vivo include controlling and maintaining their release at therapeutically effective doses over a sustained period of time, long enough for them to exhibit their desired effect. The lipid cubic phase, has generated interest as a sustained delivery vehicle over the past two decades [13] These systems possess a unique microstructure [14,15,16,17] that can be accessed under certain conditions of temperature and water content [4,18], and have demonstrated their capacity to encapsulate and control the delivery of a wide range of pharmaceuticals of different solubilities from enzymes and proteins to small molecule drugs. Numerous commercially available host lipids [3,14,28,31,32,33] capable of forming the cubic phase exist and the selection of a suitable host is key in developing the cubic phase for drug delivery applications
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