Tracey Hanley

Nanostructure of liquid crystalline matrix determines in vitro sustained release and in vivo oral absorption kinetics for hydrophilic model drugs.

Nanostructured lipid-based liquid crystalline systems have been proposed as sustained oral drug delivery systems, but the interplay between their intrinsic release rates, susceptibility to digestive processes, and the manner in which these effects impact on their application in vivo, are not well understood. In this study, two different bicontinuous cubic phases, prepared from glyceryl monooleate and phytantriol, and a reversed hexagonal phase formed by addition of a small amount of vitamin E to phytantriol (Q(II GMO), Q(II PHYT) and H(II PHYT+VitEA), respectively) were prepared. The release kinetics for a number of model hydrophilic drugs with increasing molecular weights (glucose, Allura Red and FITC-dextrans) was determined in in vitro release experiments. Diffusion-controlled release was observed in all cases as anticipated from previous studies with liquid crystalline systems, and it was discovered that the release rates of each drug decreased as the matrix was changed from Q(II GMO) to Q(II PHYT) to H(II PHYT+VitEA). Formulations containing (14)C-glucose, utilized as a rapidly absorbed marker of drug release, were then orally administered to rats to determine the relative in vivo absorption rates from the different formulations. The results showed a trend by which the rate of absorption of (14)C-glucose followed that observed in the corresponding in vitro release studies, providing the first indication that the nanostructure of these materials may provide the ability to tailor the absorption kinetics of hydrophilic drugs in vivo, and hence form the basis of a new drug delivery system.

A general review of polymeric insulation for use in HVDC cables

The authors present a review article of the properties of XLPE and an examination of the origins of space charge and how it is measured. The space charge in the insulation and the conduction current can affect the electric stress distribution in the insulation. The effect of morphology on the electrical properties of polyethylene is discussed in detail.

Nanostructured liquid crystalline particles provide long duration sustained-release effect for a poorly water soluble drug after oral administration

This study is the first to demonstrate the ability of nanostructured liquid crystal particles to sustain the absorption of a poorly water soluble drug after oral administration. Cubic (V(2)) liquid crystalline nanostructured particles (cubosomes) formed from phytantriol (PHY) were shown to sustain the absorption of cinnarizine (CZ) beyond 48h after oral administration to rats. Plasma concentrations were sustained within the range of 21.5±1.5ng/mL from 12 to 48h. In stark contrast, cubosomes prepared using glyceryl monooleate (GMO) did not sustain the absorption of CZ and drug concentrations fell below quantifiable levels after 24h. Sustained absorption of CZ from PHY cubosomes lead to a significant enhancement (p<0.05) in oral bioavailability (F%=21%) compared to a CZ suspension (9%) and oleic acid emulsion (12%). Analysis of the nanostructured particles in simulated gastric and intestinal fluids using small angle x-ray scattering (SAXS) revealed that the V(2)Pn3m nanostructure of PHY cubosomes was maintained for extended periods of time, in contrast to GMO cubosomes where the V(2)Im3m nanostructure was lost within 18h after exposure, suggesting that degradation of the LC nanostructure may limit sustained drug release. In addition, PHY cubosomes were shown to be extensively retained in the stomach (>24h) leading to the conclusion that in the case of non-digestible PHY cubosomes, the stomach may act as a non-sink reservoir that facilitates the slow release of poorly water soluble drugs, highlighting the potential use of non-digestible LC nanostructured particles as novel sustained oral drug delivery systems.

Evaluating the link between self-assembled mesophase structure and drug release

Lipid-based liquid crystalline materials are of increasing interest for use as drug delivery systems. The intricate nanostructure of the reversed bicontinuous cubic (V(2)) and inverse hexagonal (H(2)) liquid crystal matrices have been shown to provide diffusion controlled release of actives of varying size and polarity. In this study, we extend the understanding of release to other self-assembled phases, the micellar cubic phase (I(2)) and inverse micelles (L(2)). The systems are comparable as they were all prepared from the one lipid, glyceryl monooleate (GMO), which sequentially forms all four phases with increasing hexadecane (HD) content in excess water. Phase identity was confirmed by small angle X-ray scattering (SAXS). SAXS data indicated that four mesophases were formed with increasing HD content at 25°C: V(2) phase (Pn3m space group) formed at 0-4% (w/w) HD, H(2) phase formed at 4-25% (w/w) HD, I(2) phase (Fd3m space group) formed at 25-40% (w/w) HD and finally L(2) phase formed at >40% (w/w) HD. Analogous compositions using phytantriol rather than GMO as the core lipid did not produce the I(2) phase, with only V(2) to H(2) to L(2) transitions being apparent with increasing HD concentration. In order to relate the liquid crystal phase structure to drug release rate, in vitro release tests were conducted by incorporating radio-labelled glucose as a model hydrophilic drug into the four GMO-based mesophases. It was found that the drug release followed first-order diffusion kinetics and was fastest from V(2) followed by L(2), H(2), and I(2). Drug release was shown to be significantly faster from bicontinuous cubic phase than the other mesophases, indicating that the state of the water compartments, whether open or closed, has a great influence on the rate of drug release. It is envisioned that liquid crystalline mesophases with slower release characteristics will more likely have potential applications as sustained release drug delivery systems, and hence that the bicontinuous cubic phase is not necessarily the best choice for a sustained release matrix.

Preparation of phytantriol cubosomes by solvent precursor dilution for the delivery of protein vaccines

Different delivery strategies to improve the immunogenicity of peptide/protein-based vaccines are currently under investigation. In this study, the preparation and physicochemical characterisation of cubosomes, a novel lipid-based particulate system currently being explored for vaccine delivery, was investigated. Cubosomes were prepared from a liquid precursor mixture containing phytantriol or glycerylmonooleate (GMO), F127 for particle stabilisation, and a hydrotrope (ethanol or polyethylene glycol (PEG(200)) or propylene glycol (PG)). Several liquid precursors were prepared, and the effect of varying the concentrations of F127 and the hydrotrope on cubosome formation was investigated. Formulations were prepared by fragmentation for comparison. The model protein ovalbumin (Ova) was also entrapped within selected formulations. Submicron-sized particles (180-300 nm) were formed spontaneously upon dilution of the liquid precursors, circumventing the need for the preformed cubic phase used in traditional fragmentation-based methods. The nanostructure of the phytantriol dispersions was determined to be cubic phase using SAXS whilst GMO dispersions had a reverse hexagonal nanostructure coexisting with cubic phase. The greatest entrapment of Ova was within phytantriol cubosomes prepared from liquid precursors. Release of Ova from the various formulations was sustained; however, release was significantly faster and the extent of release was greater from fragmented dispersions compared to liquid precursor formulations. Taken together, these results suggest that phytantriol cubosomes can be prepared using liquid precursors and that it is a suitable alternative to GMO. Furthermore, the high entrapment and the slow release of Ova in vitro highlight the potential of phytantriol cubosomes prepared using liquid precursors as a novel vaccine delivery system.

Liquid Crystalline Systems of Phytantriol and Glyceryl Monooleate Containing a Hydrophilic Protein: Characterisation, Swelling and Release Kinetics

Swelling and phase behaviour of phytantriol and glyceryl monooleate (GMO) matrices with varying water loadings were investigated. Release of a model protein, FITC-Ova was subsequently examined. Polarised light microscopy and small angle X-ray scattering analysis showed that the addition of FITC-Ova only altered the liquid crystalline structure of phytantriol matrices at low water loadings, and that postrelease study, the phase structure of matrices at both low and high loading reflected that of the binary system. Addition of FITC-Ova to GMO matrices also altered the liquid crystalline structure when compared to the respective binary system at low but not at high loading. All samples analysed after the release study had transformed to the reverse hexagonal phase (H(II)). Swelling studies revealed a faster and more extensive swelling of GMO when compared to phytantriol. Release of FITC-Ova from phytantriol matrices was faster and occurred to a greater extent most likely due to the conversion of GMO matrices into the H(II) phase. No effect on release as a function of initial water content was observed for either lipid. We have confirmed that phytantriol based liquid crystalline matrices can sustain the release of a hydrophilic protein, suggesting its suitability as a potential sustained antigen-delivery system.

Impurities in Commercial Phytantriol Significantly Alter Its Lyotropic Liquid-Crystalline Phase Behavior

The lyotropic liquid-crystalline phase behavior of phytantriol is receiving increasing interest in the literature as a result of similarities with glyceryl monooleate, despite its very different molecular structure. Some differences in the phase-transition temperature for the bicontinuous cubic to reverse hexagonal phase have been reported in the literature. In this study, we have investigated the influence that the commercial source and hence the purity has on the lyotropic phase behavior of phytantriol. Suppression of the phase-transition temperatures (by up to 15 degrees C for the bicontinuous cubic to reverse hexagonal phase transition) is apparent with lower-purity phytantriol. In addition, the composition boundaries were also found to depend significantly on the source and purity of phytantriol, with the bicontinuous cubic phase + excess water boundary occurring at a water content above that reported previously (i.e., >5% higher). Both the temperature and compositional changes in phase boundaries have significant implications on the use of these materials and highlight the impact that subtle levels of impurities can play in the phase behavior of these types of materials.

Experimental validation of proton transverse relaxivity models for superparamagnetic nanoparticle MRI contrast agents

Analytical models of proton transverse relaxation rate enhancement by magnetic nanoparticles were tested by making measurements on model experimental systems in a field of 1.4 T. Proton relaxivities were measured for five aqueous suspensions of iron oxide (maghemite) nanoparticles with nominal mean particle sizes of 6, 8, 10, 11, and 13 nm. Proton relaxivity increased with mean particle size ranging from 13 s(-1) mM Fe(-1) for the 6 nm sample, up to 254 s(-1) mM Fe(-1) for the 13 nm sample. A strong correlation between the measured and predicted values of the relaxivity was observed, with the predicted values being consistently higher than the measured values. The results indicate that the models give a reasonable agreement with experimental results and hence can be used as the basis for the design of new magnetic resonance imaging contrast and labelling agents.

Cubosomes containing the adjuvants imiquimod and monophosphoryl lipid A stimulate robust cellular and humoral immune responses.

New generation vaccines increasingly utilize highly purified peptides and proteins as the target antigen, however these are often poorly immunogenic. One of the most promising strategies for improving immunogenicity of such subunit vaccines is through incorporation into particulate carriers. Here we report the preparation, physicochemical characterization and in vivo immunological activity of cubosomes, a novel lipid-based nanostructured particulate carrier, modified to include the Toll-like receptor agonists monophosphoryl lipid A and imiquimod. The immunological activity of cubosome formulations was compared to that of liposome and alum formulations. Sustained release of the model antigen ovalbumin (Ova) was observed in vitro and in vivo from cubosomes. Cubosomes+adjuvants induced robust CD8⁺ and CD4⁺ T cell proliferation and interferon-γ production, as well as the production of Ova-specific antibodies. Cubosomes+adjuvants were more efficient at generating Ova-specific cellular responses and were equally as effective in generating humoral responses when compared to liposomes+adjuvants and alum. Overall, the results show that cubosomes have the potential to act as effective sustained release vaccine delivery systems.

Phytantriol and glyceryl monooleate cubic liquid crystalline phases as sustained-release oral drug delivery systems for poorly water-soluble drugs II. In-vivo evaluation

Objectives  Lipid‐based liquid crystals formed from phytantriol (PHY) and glyceryl monooleate (GMO) retain their cubic‐phase structure on dilution in physiologically relevant simulated gastrointestinal media, suggesting their potential application as sustained‐release drug‐delivery systems for poorly water‐soluble drugs. In this study the potential of PHY and GMO to serve as sustained‐release lipid vehicles for a model poorly‐water‐soluble drug, cinnarizine, was assessed and compared to that of an aqueous suspension formulation.