The Stability Of W/O/W Multiple Emulsion And Its Application In Loading Insulin

Water-in-oil-in-water(W/O/W) multiple emulsions have great potentials for application in many fields, especially in pharmacy because of their special character of encapsulating water-soluble substances. W/O/W multiple emulsions loading protein drugs in the internal phase have three functions: protecting protein drugs from being degraded by enzymes in stomach and intestine; releasing drug slowly through oil phase to achieve the aim of sustained release; realizing oral administer so as to relieve the pain of patients. However, multiple emulsions have not been commercially available due to one main reason of their instability. Therefore, it is significant to study the stability of multiple emulsions.The W/O/W multiple emulsions are composed of liquid paraffin, span-80(sorbitan monooleate) and tween-80(polyoxyethylene sorbitan monooleate). The two-step preparation method is applied to prepare multiple emulsions. Several properties influencing the stability of multiple emulsions are investigated, such interfacial property, viscous property, and water transport and so on. In this study, some methods controlling the stability of multiple emulsions are given and some mechanisms about the stability of emulsion are explained.Firstly, properties of the oil and water interface are studied. The CMC of tween-80 in water and that of span-80 in oil measured through interfacial tension are 1.34×10^-3mol/l and 4.15×10^-5mol/l, respectively. And the minimum concentrations of tween-80 in water and span-80 in oil are calculated. The dilational viscoelasticity of interface with different surfactants are tested, which encompasses interfacial viscosity is a main means to resist the deformation under low deformation rate and at the same time interfacial elasticity is a main means to recover the deformation under fast deformation rate. Furthermore, modulating the proportion of surfactants can adjust the dilational viscoelasticity of interface.Secondly, the effects of viscosity on stability of W/O/W multiple emulsions are investigated from two aspects: viscosity of primary emulsion, viscosity of polymer. Meanwhile, the feasibility of viscosity model calculating the swelling ratio of multiple emulsions is evaluated. The studies indicate that the viscosity of primary emulsion has little effect on that of multiple emulsions, polymers increase the viscosity of multiple emulsions obviously and that the viscosity model can be used to calculate the swelling ratio of multiple emulsions. Thirdly, an important mass transfer, water transport, related to the stability of multiple emulsion system is investigated. For the W/O/W multiple emulsion system in this study, several factors evoking water transport are researched one by one, such as micelle water carrying, osmotic pressure facilitating, and coalescence. Experimental studies indicate that the coalescence under osmotic pressure is obvious and the control of water transport is needed so as to keep the stability of multiple emulsions. In order to control water transport, two simple models are established,(ⅰ) one droplet model, giving the criterion to judge the water transport direction, and(ⅱ) statistic mean droplet radius, helping to control water transport when the second-composite is added into the internal phase. Models are proved by experimental phenomena.Fourthly, technical conditions preparing multiple emulsions are optimized. Orthogonal experiments are used to fix on the optimized operation condition, such as the concentration of surfactants, the ratio of oil to water, the temperature of preparation. Based on the orthogonal experiments, range analysis, variance analysis and single factor analysis, the best experiment conditions preparing stable emulsion are determined as follows: 12wt% of span-80, 4wt% of tween-80, preparation at 50℃, the volume ratio of oil to water 5:3, and the volume ratio of emulsion to water 1:2. The mean droplet size of multiple emulsions prepared is 14.6μm, and the coherence is 0.24. The water transport is controlled when 0.0205 mol/l potassium chloride is added into the internal phase and 0.0184 mol/l potassium chloride is in the external phase. An intensity synergistic effect of konjac gum and xanthan gum has been found to prepare the gel system. The optimal proportion is that the complex gelatin consisted of 20wt% konjac gum and 80wt% xanthan gum while the complex gelatin is lwt% in the external phase. A gelatin multiple emulsions system is prepared making the multiple emulsions much more stable.Finally, insulin is taken as model drug encapsulated into the internal phase of W/O/W multiple emulsions. The encapsulated efficiency is up to 90% and sustained release is attained to some extent. W/O/W multiple emulsion can protect insulin against proteolytic enzymes in the gastrointestinal tract and it can release insulin in artificial intestinal juice. At the same time, external phase is dealt with by gel making the multiple emulsions keep the stability on shelf life. The experiments show that the gelled multiple emulsions can renew its fluidity when taking orally, which is advantageous to release and absorption of drugs.