Study of Rheology and Polymer Adsorption Onto Drug Nanoparticles in Pharmaceutical Suspensions Produced by Nanomilling.

Nanosuspensions provide a drug delivery approach to cope with erratic absorption of poorly water-soluble compounds. Despite extensive research over the last years, there are still open pharmaceutical challenges so it is often unclear how quality attributes such as viscosity and physical stability are generated, which requires a more thorough study of the colloidal structures and interactions in nanosuspensions. In this study, diffusing wave spectroscopy and microfluidics-based rheology were used for the first time to assess pharmaceutical nanosuspensions that were obtained by wet milling. Further sample characterization following centrifugation was based on optical rotatory dispersion and conductivity experiments. Ketoconazole was selected as model drug in the presence of sodium dodecyl sulfate and hydroxypropyl cellulose as anionic and steric stabilizer, respectively. The results unexpectedly showed that the investigated nanosuspensions did not behave as Einstein-like suspensions because a viscosity decrease was evidenced for increased drug load. This effect was attributed to the polymer that formed a dominating network in the bulk solution from where adsorption occurred onto particle surfaces. This depletion of bulk polymer caused the observed rheological finding. Further colloidal research should be invested into different pharmaceutical nanosuspensions to gain a more complete structural understanding and to harness their full technological potential.

Application of superabsorbent polymers (SAP) as desiccants to dry maize and reduce aflatoxin contamination.

The ability of superabsorbent polymers (SAP) in drying maize and controlling aflatoxin contamination was studied under different temperatures, drying times and SAP-to-maize ratios. Temperature and drying time showed significant influence on the aflatoxin formation. SAP-to-maize ratios between 1:1 and 1:5 showed little or no aflatoxin contamination after drying to the optimal moisture content (MC) of 13 %, while for ratios 1:10 and 1:20, aflatoxin contamination was not well controlled due to the overall higher MC and drying time, which made these ratios unsuitable for the drying process. Results clearly show that temperature, frequency of SAP change, drying time and SAP-to-maize ratio influenced the drying rate and aflatoxin contamination. Furthermore, it was shown that SAP had good potential for grain drying and can be used iteratively, which can make this system an optimal solution to reduce aflatoxin contamination in maize, particular for developing countries and resource-lacking areas.

Responsive self-assembled nanostructured lipid systems for drug delivery and diagnostics.

While stimuli-responsive polymers have received a huge amount of attention in the literature, responsive lipid-based mesophase systems offer unique opportunities in biomedical applications such as drug delivery and biosensing. The different mesophase equilibrium structures enables dynamic switching between nanostructures to facilitate drug release or as a transducer for recognition events. In drug delivery, this behavior offers researchers the means to deliver a therapeutic payload at a specific rate and time i.e. 'on-demand'. This review summarizes the distinctive features of these multifaceted materials and aggregates the current state of the art research from our groups and others into the use of these materials as bulk gels and nanostructured dispersions for drug delivery, biosensing and diagnostics.

pH-responsive lyotropic liquid crystals and their potential therapeutic role in cancer treatment.

A weak amphiphilic base, pyridinylmethyl linoleate, is blended with monolinolein, yielding mesophases with a pH-induced hexagonal-to-cubic transition at pH ≤ 5.5. We show the potential therapeutic role of this mesophase in treating cancerous tissues exploiting their more acidic pH compared to healthy tissues. In vitro release studies with doxorubicin on HT29 human colon cancer cells show a 10-fold faster release and 3-fold increased efficiency for killing cancer cells at pH 5.5 versus pH 7.4, demonstrating the potential of this strategy in cancer treatment.

Influence of electrostatic interactions on the release of charged molecules from lipid cubic phases.

The release of positive, negative, and neutral hydrophilic drugs from pH responsive bicontinuous cubic phases was investigated under varying conditions of electrostatic interactions. A weak acid, linoleic acid (LA), or a weak base, pyridinylmethyl linoleate (PML), were added to the neutral monolinolein (ML) in order to form lyotropic liquid-crystalline (LLC) phases, which are negatively charged at neutral pH and positively charged at acidic pH. Release studies at low ionic strength (I = 20 mM) and at different pH values (3 and 7) revealed that electrostatic attraction between a positive drug, proflavine (PF), and the negatively charged LLC at pH = 7 or between a negative drug, antraquinone 2-sulfonic acid sodium salt (AQ2S), and the positively charged LLC at pH = 3 did delay the release behavior, while electrostatic repulsion affects the transport properties only to some extent. Release profiles of a neutral drug, caffeine, were not affected by the surface charge type and density in the cubic LLCs. Moreover, the influence of ionic strength was also considered up to 150 mM, corresponding to a Debye length smaller than the LLC water channels radius, which showed that efficient screening of electrostatic attractions occurring within the LLC water domains results in an increased release rate. Four transport models were applied to fit the release data, providing an exhaustive, quantitative insight on the role of electrostatic interactions in transport properties from pH responsive bicontinuous cubic phases.

Reconstitution of OmpF membrane protein on bended lipid bilayers: perforated hexagonal mesophases.

Membrane proteins have been reconstituted on lipid bilayers with zero mean-curvature (cubic phases or vesicles). Here we show that reconstitution of pore-forming membrane proteins can also occur on highly curved lipidic bilayers of reverse hexagonal mesophases, for which the mean-curvature is significantly different from zero. We further show that the membrane protein provides unique topological interconnectivities between the aqueous nanochannels, significantly enhancing mesophase transport properties.

Perforated bicontinuous cubic phases with pH-responsive topological channel interconnectivity.

Lipidic lyotropic liquid crystals are at the frontline of current research for release of target therapeutic molecules due to their unique structural complexity and the possibility of engineering stimuli-triggered release of both hydrophilic and hydrophobic molecules. One of the most suitable lipidic mesophases for the encapsulation and delivery of drugs is the reversed double diamond bicontinuous cubic phase, in which two distinct and parallel networks of ∼4 nm water channels percolate independently through the lipid bilayers, following a Pn3m space group symmetry. In the unperturbed Pn3m structure, the two sets of channels act as autonomous and non-communicating 3D transport pathways. Here, a novel type of bicontinuous cubic phase is introduced, where the presence of OmpF membrane proteins at the bilayers provides unique topological interconnectivities among the two distinct sets of water channels, enabling molecular active gating among them. By a combination of small-angle X-ray scattering, release and ion conductivity experiments, it is shown that, without altering the Pn3m space group symmetry or the water channel diameter, the newly designed perforated bicontinuous cubic phase attains transport properties well beyond those of the standard mesophase, allowing faster, sustained release of bioactive target molecules. By further exploiting the pH-mediated pore-closing response mechanism of the double amino acid half-ring architecture in the membrane protein, the pores of the perforated mesophase can be opened and closed with a pH trigger, enabling a fine modulation of the transport properties by only moderate changes in pH, which could open unexplored opportunities in the targeted delivery of bioactive compounds.

Controlling anisotropic drug diffusion in lipid-Fe3O4 nanoparticle hybrid mesophases by magnetic alignment.

We present a new strategy to control the anisotropic diffusion of hydrophilic drugs in lyotropic liquid crystals via the dispersion of magnetic nanoparticles in the mesophase, followed by reorientation of the mesophase domains via an external magnetic field. We select a lipid reverse hexagonal phase doped with magnetic iron oxide nanoparticles and glucose and caffeine as model hybrid mesophase and hydrophilic drugs, respectively. Upon cooling through the disorder-order phase transition of the hexagonal phase and under exposure to an external moderate magnetic field (1.1 T), both the nanoparticles and the hexagonal domains align with their columnar axes along the field direction. As a result, the water nanochannels of the inverted hexagonal domains also align parallel to the field direction, leading to a drug diffusion coefficient parallel to the field direction much larger than what was measured perpendicularly: in the case of glucose, for example, this difference in diffusion coefficients approaches 1 order of magnitude. Drug diffusion of the unaligned reverse hexagonal phase, which consists of randomly distributed domains, shows values in between the parallel and transversal diffusion values. This study shows that modifying the overall alignment of anisotropic mesophases via moderate external fields is a valuable means to control the corresponding transport tensor of the mesophase and demonstrates that the orientation of the domains plays an important role in the diffusion process of foreign hydrophilic molecules.

Diffusion, molecular separation, and drug delivery from lipid mesophases with tunable water channels.

Lyotropic liquid crystals characterized by a bicontinuous cubic phase (BCP) have a structure characterized by interpenetrated water channels following triply periodic minimal surfaces, which can be stable in excess water conditions and thus suitable in a multitude of applications. The control of the water channels size in these systems has a direct impact on their use for drug delivery, crystallization, and membrane separation processes. In this work we carry out systematic diffusion studies to show how the control on the water channel dimensions directly correlates with the release and separation performance of bicontinuous cubic phases. Specifically, we tune the water channels diameter of the monolinolein/water system by adding different amounts of sucrose stearate, which, having hydration-enhancing properties, can shift the boundaries of the phase diagram. We then design a model bicontinuous cubic phase lipidic membrane of the Im3m space group, having a sugar ester to monolinolein ratio of 20%, and we follow the diffusion within its water channels, by using molecules that differ systematically in size and molecular conformation, and we demonstrate, for each class of molecules, a diffusion-enhanced process upon increase of the water channel diameter. Finally, we also show the ability of the bicontinuous cubic phase to efficiently and selectively separate nanoparticles of a target size, by choosing an amount of sucrose stearate for which the water channel diameter and the nanoparticle dimensions match, demonstrating the possible use of these systems as filtering membranes of tunable molecular cutoff.

pH-responsive lyotropic liquid crystals for controlled drug delivery.

We present a food-grade lyotropic liquid crystal system, capable of responding to pH variations with a reversible switch in both the structure and physical properties. The system, which is composed by monolinolein and linoleic acid (97:3 wt % ratio) in the presence of excess water at 37 °C and 150 mM ionic strength, is specifically designed to reversibly change from a Im3m reverse bicontinuous cubic phase to a H(II) reverse columnar hexagonal phase, when changing the pH from neutral (pH 7) to acidic (pH 2) conditions, to simulate intestine and stomach conditions, respectively. The pH responsiveness is provided by the linoleic acid, which, being a weak acid (pK(a) ≈ 5), is essentially in the deprotonated charged state at pH 7 and mainly protonated and neutral at pH 2, imposing changes in the critical packing parameter (CPP) of the lyotropic liquid crystal. The use of this system as an efficient controlled-release delivery vehicle is demonstrated on the model hydrophilic drug phloroglucinol, by both release and diffusion studies at different pH, as followed by ultraviolet-visible (UV-vis) spectroscopy. The Im3m cubic phase at pH 7 is shown to release 4 times faster than the H(II) phase at pH 2, making this system an ideal candidate for oral administration of drugs for targeted delivery in intestine or colon tracts.