A lipid-based liquid crystalline matrix that provides sustained release and enhanced oral bioavailability for a model poorly water soluble drug in rats.

Liquid crystalline phases that are stable in excess water, formed using lipids such as glyceryl monooleate (GMO) and oleyl glycerate (OG), are known to provide a sustained release matrix for poorly water soluble drugs in vitro, yet there has been no report of the use of these materials to impart oral sustained release behaviour in vivo. In the first part of this study, in vitro lipolysis experiments were used to compare the digestibility of GMO with a second structurally related lipid, oleyl glycerate, which was found to be less susceptible to hydrolysis by pancreatic lipase than GMO. Subsequent oral bioavailability studies were conducted in rats, in which a model poorly water soluble drug, cinnarizine (CIN), was administered orally as an aqueous suspension, or as a solution in GMO or OG. In the first bioavailability study, plasma samples were taken over a 30 h period and CIN concentrations determined by HPLC. Plasma CIN concentrations after administration in the GMO formulation were only sustained for a few hours after administration while for the OG formulation, the plasma concentration of cinnarizine was at its highest level 30 h after dosing, and appeared to be increasing. A second study in which CIN was again administered in OG, and plasma samples taken for 120 h, revealed a Tmax for CIN in rats of 36 h and a relative oral bioavailability of 344% when compared to the GMO formulation (117%) and the aqueous suspension formulation (assigned a nominal bioavailability of 100%). The results indicate that lipids that form liquid crystalline structures in excess water, may have application as an oral sustained release delivery system, providing they are not digested rapidly on administration.

Hexosomes formed from glycerate surfactants--formulation as a colloidal carrier for irinotecan.

A new class of amphiphiles with a glycerate headgroup, recently shown to form reverse hexagonal phase in excess water, have been dispersed to form Hexosome dispersions comprising sub-200 nm particles retaining the internal nanostructure of the parent H(II) phase. The application of these novel materials to the development of a new injectable formulation of irinotecan was investigated. The formulation of irinotecan with a small percentage of oleic acid in oleyl glycerate permitted a clinically relevant dose of irinotecan to be dissolved in the glycerate surfactant and dispersed in aqueous medium to form an injectable particle-based dose form of irinotecan. Importantly, incorporation of irinotecan into Hexosomes at neutral pH did not result in conversion from the active lactone to the inactive carboxylate form on storage, and is hence a promising alternative to the current low pH formulation of irinotecan required to inhibit this conversion. Although release of irinotecan from the Hexosomes was shown to be virtually instantaneous from the Hexosomes on substantial dilution, the retention of the drug in lactone form at neutral pH demonstrates a potential application of these novel nanostructured particles in injectable drug delivery.

Lyotropic liquid crystalline phases formed from glycerate surfactants as sustained release drug delivery systems.

A new class of surfactants with glycerate headgroups, that form viscous lyotropic liquid crystalline phases in excess water, have been investigated for their potential to provide sustained release matrices for depot drug delivery. Oleyl glycerate and phytanyl glycerate were used as representative surfactants of this new class, and their behaviour compared with that of glyceryl monooleate (GMO). The surfactants were found to form reverse hexagonal phase (H(II)) in excess water, and the matrices were loaded with a series of model hydrophobic and hydrophilic drugs, (paclitaxel, irinotecan, glucose, histidine and octreotide), and the release kinetics determined. In all cases, the release behaviour obeyed Higuchi kinetics, with linear drug release versus square root of time. The H(II) phases released model drugs slower than the GMO cubic phase matrix. The oleyl glycerate matrix was found to consistently release drug faster than the phytanyl glycerate matrix, despite both matrices being based on H(II) phase. To further demonstrate the potential utility of these materials as drug depot delivery systems, an injectable precursor formulation for octreotide was also prepared and demonstrated to provide controlled release for the peptide. The stability of the H(II) phase to likely in vivo breakdown products was also assessed.