Capillary Video-Microscopy on the Release of Water-Soluble Drugs from Double-Emulsion Globules into Giant Liposomes

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ABSTRACTCTS-0075712K. PapadopoulosTulane UniversityThis is an exploratory grant for which the hypotheses is that Capillary Video-microscopy can uniquely reveal key aspects of the release mechanisms of water-soluble drugs from double-emulsion globules and their transport into neighboring giant liposomes that mimic biological cells. The goal is to elucidate the phenomena which govern these mechanisms and the control of which will ultimately decide the successful application of soluble emulsions as drug-delivery systems.Ephedrine hydrochloride (EPH HCI) will be used as the model water-soluble drug, encapsulated in the W1 compartment of a W1/0/W2 globule, and the oil membrane will be paraffin oil. Oil-soluble, nonionic surfactant Span-80 (sorbitan monooleate) and water-soluble, non-ionic surfactant Tween-80 will be studied as factors of both globule stability and drug release. The osmotic pressure gradients in the double-emulsion globules will be adjusted through NaCl.Microcapillaries (~200 um i.d., 10 200 um) will be fabricated from melting point tubes (1.1-1.2 mm i.d. x 100 mm) by pulling them in the middle using a Narishige PB-7 micropipette puller (see Picture 2). Injection and micromanipulation pipettes with fine tip will be shaped by pulling microtubes (Microcapes. 0.688 mm i.d. X 78 mm) from one of their ends so as to produce a tip of outside diameter 10-15 um. Micropipettes will be future fashioned with a microgorge (Narishige MF-9, see picture 3), thus allowing us to polish the end of the pipette or to bend it to a desired shape.To prepare a W1/0/W2 globule, a microcapillary will be filled with pure water or a saline solution at first. A micropipette filled with oil (containing oil-soluble surfactants) will then be inserted and will inject a large oil drop. Subsequently, and internal ephedrine-hydrochloride-solution droplet will be formed into the oil via the same procedure as the one that produces the oil drop. This globule preparation procedure will lead to an osmotic pressure gradient between W1 and W2 phases, which will cause the release of the water-soluble drug. A single globule will be used in each experiment and the complete transport process in this globule will be observed microscopically. In those experiments that will monitor the transfer of EPH HCI to a vessel, a giant vesicle will first be prepared with 1-palmitoyl-2oleoyl-sn-glycero-3-phosphocholine through electroformation.By using different salinities in W1 and W2 and EOPH HCI concentrations in W1 we will know under their conditions the water-soluble is delivered by a "swelling-breakdown" mechanism. The time needed before rupture will be used as a measure of the drug release rate. An obvious geometrical factor that will effect the time of rupture is the size of the W1 droplets. Since smaller W1 droplets will take longer to burst, polydisperity in such droplets should lead to prolonged release, and thus will be studied as a tool to control delivery.Under those salinity conditions that will not produce swelling and breakdown, water will transport from W1 and W2 via some diffusion-facilitating mechanisms, such as reverse micellization, spontaneous emulsification, hydrated-surfactant or lamellar-facilitated transport. We will determine the kinetics of such drug release as effected by various surfactant combinations and formulations that will favor certain mechanisms over others under different conditions.To visualize the transport of the released material from the W1/0/W2 globule to the neighboring giant vesicle, aqueous fluorescent dye (N-Methylhdroxy-quinolinium iodide) will be added to ephedrine hydrochloride solution. In order to simulate possible release situations in the body, both contact and non-contact a configuration of a double-emulsion globule and a giant vesicle will be studied. To study drug transfer under globule-vesicle contact, the giant vesicle will be pushed gently so as to visually touch the W1/0/W2 globule.