T.L. Whateley

Poloxamer association in aqueous solution

Abstract Aqueous solutions of the surface active poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) block copolymers (poloxamers) were studied using photon correlation spectroscopy (quasi-elastic light scattering) and viscosity measurements. Poloxamers 184 and 237 showed detectable aggregates at 25° only at concentrations above about 6% with size increasing with concentration and with significant polydispersity, probably indicating a multiple association process. At 35°, however, essentially invariant values for the hydrodynamic radius were found over a wide concentration range and the systems were essentially monodisperse: these systems are more likely to be represented by a closed association model. The more hydrophilic poloxamer 188, however, retained its concentration dependence of aggregate size up to 55°. The variation with temperature of both the hydrodynamic radius of aggregates and the intrinsic viscosity of several poloxamers was rationalized by relating the temperature-dependency curves to the cloud point of the poloxamer. In some cases only certain sections of the curve are observable when the cloud point is high, e.g., >100°, or low, e.g.,

The Nature of the Oil Phase and the Release of Solutes from Multiple (w/o/w) Emulsions

The effect of the nature of the oil phase of w/o/w emulsions stabilized by interfacial complexation between span 80 (sorbitan mono‐oleate) and albumin has been studied. The long‐term stability of the systems has been assessed by photomicrography and by measuring the quantity of an internal marker (NaCl) remaining entrapped with time. The number of multiple oil drops and the diameters of the internal aqueous droplets were determined over 6 weeks, and the amounts of NaCl entrapped over the same period were followed. There were no significant changes in w/o/w emulsions prepared with a range of hydrocarbons (octane, dodecane, hexadecane, toluene and cyclohexane), indicating stable multiple emulsions. The release of NaCl and 5‐fluorouracil (5‐FU) separately entrapped in the internal aqueous phase of w/o/w emulsions was measured. Diffusion of the un‐ionized species of 5‐FU across the oil phase or through localized thin oil lamellae is the primary transport mechanism. In the presence of surface active agents, water is solubilized in inverse micelles which would possess the ability to solubilize other water‐soluble components, such as NaCl and 5‐FU. The mixed inverse micellar units of Span 80 and polysorbate (Tween) 80 therefore act as solute carriers across the liquid hydrocarbon membrane separating the two aqueous phases of the emulsions. The main factor in determining the differences in rates of release from the hydrocarbon emulsions appears to be the droplet size of the internal aqueous phase.

Methotrexate transport from the internal phase of multiple w/o/w emulsions

Release rates of Methotrexate (MTX) encapsulated in the internal phase of w/o/w emulsions stabilized by the interfacial interaction between albumin and sorbitan mono-oleate(Tween 80) were measured as functions of two formulation variables--the oil phase and the secondary emulsifier composition. The release rate was significantly affected by the nature of the oil phase and decreased in the order isopropyl myristate greater than octadecane greater than hexadecane greater than dodecane greater than octane, which was a reflection of the increasing internal droplet size of the emulsions. The release rate data conform with first order kinetics. Comparison of the effective permeability coefficients calculated from the experimental apparent first-order rate constants, with the effective permeability coefficient of water in planar oil layers, containing non-ionic surfactants, determined by a microgravimetric method supported the hypothesis of diffusion of MTX in water loaded inverse micelles. Surfactants with high HLB values, used as the secondary hydrophilic emulsifier increased the release rates, primarily by increasing the rate of diffusion of MTX through the non-aqueous liquid membrane.

The stabilization of w/o/w emulsions by interfacial interaction between albumin and non-ionic surfactants

Abstract The stability of w/o/w emulsions has been improved by means of interfacial interaction between Span 80 (sorbitan mono-oleate) and bovine serum albumin (BSA). The formation of an interfacial complex was demonstrated by the production of a visible film at the planar oil/water interface and by the increased stability of the w/o/w emulsions. The stability of each w/o/w emulsion was assessed in terms of the amount of internal aqueous phase remaining entrapped. This was dependent on the concentrations of both the Span 80 and the BSA, although increasing the BSA concentration above 0.2% only produced a minimal increase in stability. The release of sodium chloride from the internal aqueous phase and the changes in the physical structure of the w/o/w emulsions subjected to different osmotic pressure gradients were studied. Osmotic swelling of the internal aqueous phase induced thinning of the oil layer and explains the observed increase in the rate of solute release from the internal phase under high osmotic pressure gradients.

Release rate profiles of theophylline and insulin from stable multiple w/o/w emulsions

Abstract Stable multiple w/o/w emulsions have been prepared using various Pluronic F127:PAA complexes in the internal aqueous phases of these emulsions. Theophylline and 125 I-insulin were incorporated into the internal aqueous phases of these stable multiple emulsions and their release rates studied. The release rates of theophylline from these emulsions were found to be related to the droplet sizes of the emulsions which in turn was dependent on the particle sizes of the Pluronic:PAA complex in the internal aqueous phase, and the type of lipophilic surfactant in the oil phase. The use of surfactants with different HLB values in the external aqueous phase did not affect the entrapment efficiency of these emulsions. The release rate of 125 I-insulin from one of these emulsions was significantly slower than from 125 I-insulin solution. The release pattern of 125 I-insulin from this same emulsion after storage for three days was not significantly different from the newly-prepared emulsion. The results indicate that it is possible to formulate drugs such as theophylline and insulin in multiple w/o/w emulsions where we have found them to be stable and could thus be formulated for rapid onset of action or as sustained drug delivery system, depending on the choice of Pluronic:PAA complex in the internal aqueous phase and the type of lipophilic surfactant in the oil phase.

Stabilisation of w/o/w multiple emulsions by interfacial complexation of macromolecules and nonionic surfactants

Abstract A new approach to obtain stable w/o/w multiple emulsions has been developed; the basis is the interfacial interaction between a macromolecule, e.g. albumin or polyacrylic acid in the internal aqueous, and a lipophilic poloxamer surfactant in the dispersed oil phase. Lipophilic poloxamer surfactants of high molecular weight, e.g. Poloxamer 331, were preferable in forming a stable w/o and the subsequent w/o/w emulsions. Similarly, hydrophilic poloxamer surfactants of high molecular weight could enhance the stability of the w/o/w multiple emulsions when used to emulsify the initial w/o emulsions, e.g. poloxamer 403. A water soluble, internal marker, Sulphane Blue, was encapsulated within the emulsion droplets and the release rate studies were carried out. The results revealed that both the mass transfer rate and stability of the oil membrane could be influenced by the combination of external (secondary) hydrophilic surfactants used. The secondary surfactant affected release rate primarily by control of mass transfer through the oil liquid membrane. In optimising a stable multiple emulsion formulation, both the HLB (hydrophilic-lipophilic balance) values and surface activities of the surfactants have to be considered.

Nonaqueous foam structures from osmotically swollen w/o/w emulsion droplets

The inherent instability of w/o/w multiple emulsions can be partly overcome by the formation of a stable interfacial membrane through the interfacial interaction of a macromolecule such as bovine serum albumin in the aqueous phase and a lipophilic nonionic surfactant such as Poloxamer 331 in the oil phase of of the primary water/oil emulsion. A high-molecular-weight hydrophilic poloxamer (Poloxamer 403) used to form the multiple emulsion from this primary system was shown to strengthen the membrane so that it could withstand extensive thinning caused by the osmotically driven influx of water and swelling of the internal droplets. The oil-continuous stabilizing film at its thinnest can only be observed under phase-contrast or dark-field illumination. Single droplets carrying such a thin oil membrane were stable for several weeks. After equilibration of osmotic pressure across the membrane, i.e., after storage, the membrane appeared to have sufficient elasticity that it could respond to osmotic changes in the external aqueous phase. The new structures formed in these osmotically swollen systems are possibly analogs of aqueous foam bubbles in air and are the biliquid foams or “aphrons” described by F. Sebba (J. Colloid Interface Sci.40, 468, 1972).

Potentially biodegradable microcapsules with poly (alkyl 2-cyanoacrylate) membranes

currents measured at -1.5 V; drop time, 3 s; current density, 5 x 10-8 A mm-2. The diffusion currents were expressed as pen response in mm. The dificulty of the methyl nitrate being reduced at approximately the same potential as the glyceryl trinitrate was overcome as follows. The response, i,, of 1 ml standard methyl nitrate solution was measured; the response, i,, for the mixture of 1 ml of internal standard and 1 ml unknown trinitrate solution was then corrected for i, giving

Absorption and lymphatic uptake of 5-fluorouracil in the rat following oral administration of w/o/w multiple emulsions

Abstract The influence of the nature of the oil phase of w/o/w emulsions on the oral absorption of 5-fluoro[ 3 H]uracil in the rat is described. Liver levels and lymphatic accumulation of the drug following oral administration of w/o/w emulsions were studied. The absorption of 5-fluoro[ 3 H]uracil orally administered in a water/isopropyl myristate/water emulsion was enhanced compared to an aqueous solution while a w/o/w emulsion prepared with octane as the oil phase reduced intestinal uptake. The suggested mechanism underlying the enhancement noted with isopropyl myristate emulsions may be attributed to the inhibitory effect of the oil on the gastric emptying processes. Both emulsion systems showed potential as lymphotropic carriers of water-soluble drugs to the mesenteric lymph nodes following oral administration.

Some chemically modified poloxamer hydrogels: preparation, morphology and swelling properties

Abstract Polymerizable diacryloyl derivatives of a series of commercial poly(oxyethylene)-poly(oxypropylene)-poly(pxyethylene) block copolymeric surfactants have been prepared and polymerized to form cross-linked hydrogels whose properties can be varied by controlling the proportions of hydrophilic and hydrophobic monomers (e.g. Pluronic F68, poloxamer 188 and Pluronic L61, poloxamer 181). Morphology and spherulite formation of the hydrogels prepared from pure monomer and mixtures of the modified monomers were studied using optical and scanning electron microscopy, Spherulite formation in these mixtures was used as a probe of mixing compatibility and the imbibition of water, acting as a selective solvent, revealed different states of heterogeneity in the various cross-linked gels. Swelling of the gels in aqueous media increased in a non-liner fashion with increasing proportion of the modified, more hydrophilic, poloxamer 188 in the gel.