A. T. Florence

The effect of non‐ionic surfactant vesicle (niosome) entrapment on the absorption and distribution of methotrexate in mice

Non‐ionic surfactant vesicles (niosomes) prepared from a non‐ionic surfactant, cholesterol and dicetyl phosphate and containing methotrexate (MTX) have been administered to mice. Given intravenously the niosomes prolong the levels of MTX in the blood, large amounts of the drug being taken up by the liver. There was also an increased uptake of MTX into the brain, perhaps due to an effect of the niosome components on the permeability of the blood brain barrier. Absorption of the drug from the gastrointestinal tract following oral ingestion, appeared to be increased at some doses; most of the entrapped MTX was taken up by the liver, but uptake of MTX into the brain was also increased. The metabolic profile of the drug is altered by the niosomes which appear to prevent the rapid formation of 7‐hydroxy methotrexate.

Some features of breakdown in water-in-oil-in-water multiple emulsions

Abstract W/O/W multiple emulsions break down by several possible routes, for example by coalescence of the internal aqueous droplets or of the oil drops, by expulsion of the internal droplets following rupture of the oily lamella which surrounds them, or by passage of water through the oil phase by diffusion. This paper describes an investigation of the breakdown pathways associated with three different W/O/W systems using cinemicrography. Three types of multiple (oil) drops were identified in the systems prepared-these being identified by the number and size of the internal aqueous droplets. Type “A” drops contained one large internal droplet, type “B” contained several small internal droplets, and type “C” globules entrapped large numbers of internal droplets. One type predominates in a given multiple emulsion although all three types and simple oil drops can coexist. Hence, in general, we can refer to three main types of multiple emulsion systems, A, B, and C. The W/O/W emulsions were filmed over periods ranging from a few seconds after formation to 30 hr using time-lapse, continuous, and high-speed cinemicrography. The emulsions were also studied by conventional photomicrography. Attempts were made to predict which breakdown pathways would be followed taking into account surface area changes on coalescence and expulsion and, in general, experimental evidence was in agreement with these predictions. The results indicate that all the proposed mechanisms of breakdown occur in W/O/W systems but that some are more favored than others, their predominance depending on the type of multiple emulsion formed. A preliminary analysis of the attractive forces between multiple droplets has also been made.

The Distribution of Doxorubicin in Mice Following Administration in Niosomes

Abstract— Large multilamellar non‐ionic surfactant vesicles (niosomes) with diameters of around 800–900 nm prepared from a C16 triglyceryl ether with and without cholesterol and containing doxorubicin (Adriamycin) were administered to S180 tumour‐bearing NMRI mice by bolus injection. Although in‐vitro drug release from cholesterol‐containing niosomes is delayed, in‐vivo there was little difference between the two preparations when plasma levels were compared. As previously observed, half‐lives of the drug were prolonged compared with free solution profiles. Liver uptake was not significantly affected by niosome encapsulation of doxorubicin. There is minor accumulation of drug in the lung, perhaps because of aggregation of the vesicles and their physical entrapment. Tumour levels of drug were higher following administration of cholesterol‐containing niosomes and this was reflected in the more effective reduction in tumour growth. Metabolism of doxorubicin is altered by niosomal administration, but more studies are required before the significance of the metabolic data can be assessed.

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.,

Adriamycin-loaded niosomes: drug entrapment, stability and release

The effect of encapsulation of adriamycin into niosomes, and its resultant chemical purity, was studied by means of HPLC and high-speed scanning spectrophotometry (the simultaneous use of which allowed investigation of potential non-fluorescent drug degradation products), and the process shown not to adversely affect the drug. Efficiency of entrapment of aqueous solutions of the drug was apparently dependent on neither vesicle composition nor method of production, and evidence of a degree of surfactant-adriamycin association was provided by the high entrapment values. Light-induced drug degradation was reduced by niosome encapsulation, and efflux of entrapped adriamycin was decreased by inclusion of cholesterol into the vesicles, in a manner similar to that reported for liposome preparations. Thus only chemically pure adriamycin was entrapped in, and released from, niosomes.

Comparison of albumin and casein microspheres as a carrier for doxorubicin

Doxorubicin (Adriamycin)‐loaded casein and albumin microspheres, with diameters between 14 and 38 μm (50% weight average) were prepared by glutaraldehyde stabilization of the aqueous phase (containing protein and drug) of a water in oil emulsion. Physical properties, drug loading characteristics and release rates from microspheres in‐vitro have been compared and correlated with effects on tumour growth when injected intratumourally in rats. Compared with albumin, the surface charge of the casein system was more negative and the microspheres exhibited a slower release of drug in‐vitro. Both observations could be explained by the lower drug content of the casein system. There was evidence for the formation of a doxorubicin complex in the microspheres, the significance of which is not yet known. Casein microspheres containing 11 μg of doxorubicin had a similar inhibitory effect on tumour growth (growth delay = 20ṁ7 days) to 85 μg of drug incorporated into albumin microspheres (growth delay = 18ṁ6 days). The absence of a simple dose‐response relationship shows that carrier matrix can influence potency of incorporated drug. The results are consistent with release rate of the drug from microspheres (obversely, rate of drug delivery to the tumour), being a determinant of potency in these systems.

Changes in crystallinity and solubility on comminution of digoxin and observations on spironolactone and oestradiol

Using infrared spectroscopy, X‐ray diffractometry, differential thermal analysis, scanning electron microscopy, solubility and dissolution rate measurements, it was demonstrated that the comminution of digoxin results in the appearance of an amorphous phase. The examination of spironolactone and 17β‐oestradiol by infrared spectroscopy and differential thermal analysis showed that these compounds also undergo changes in their crystallinity on grinding. Since the dissolution characteristics of poorly soluble drugs may be complex functions of surface area and crystallinity, it is concluded that the most pertinent method for standardizing a sample of a polymorphic drug of low solubility is by means of a powder dissolution test, as the results embrace the influences of particle size, aggregation and polymorphism.

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.

Investigations into the formation and characterization of microemulsions. II. Light scattering conductivity and viscosity studies of microemulsions

Abstract Microemulsions formed with water—xylene—sodium alkyl benzene sulfonate (NaDBS)-hexanol have been investigated using time-average light scattering conductivity and viscosity measurements at 25°C. Four different concentrations of NaDBS were used, namely, 5, 10.9, 15, and 20 wt% and the molar ratio of n -hexanol:NaDBS was kept constant at 3.4, 3.24, 3.4, and 3.4, respectively. The light scattering results showed that at low volume fractions of water, φ H 2 O , the Rayleigh ratio, R 90 increased slowly with an increase in φ H 2 O but above a critical volume fraction of water, φ H 2 O S , R 90 increased almost linearly with increase of φ H 2 O , reached a maximum at another critical water volume fraction, φ H 2 O C , above which R 90 decreased with further increase in φ H 2 O . The results were interpreted qualitatively in terms of the possible aggregate units formed. A quantitative analysis of the light scattering data was carried out using a procedure based on the use of a hard sphere model for particle interactions. Using this approach, the water droplet radius R was calculated as a function of φ H 2 O for the four systems investigated. The results showed a linear increase of R with increase in φ H 2 O . Approximate values of the water radii were also calculated from the interfacial area and these were found to be in full agreement with the radii obtained from light scattering measurements. The conductance κ showed a non-monotonic variation as the water concentration was increased. A maximum in the κ-φ H 2 O was observed at a critical volume fraction of water φ H 2 O S above which κ decreased and then remained almost constant over a range of φ H 2 O values. The conductance then sharply increased at another φ H 2 O value, namely φ H 2 O C . This φ H 2 O C value was reduced with increase in NaDBS concentration. The conductance results indicate structural changes in the system as the water concentration increases and the transition observed correlate with those obtained from light scattering. Moreover, the low κ values found and the non-monotonic variation of κ with φ H 2 O are indicative of the presence of definitive water cores with an external surfactant film which acts as a barrier for ion transport. Viscosity results showed the behavior normally encountered with concentrated dispersions, the relative viscosity η r increasing exponentially with φ H 2 O . The viscosity data were fitted to the Mooney equation. The results showed an increase in the Einstein coefficient with increase in NaDBS concentration indicating an increase in the hydrodynamic volume of droplets. This was attributed to the increase of the ratio of the surfactant layer thickness to the droplet core radius as the NaDBS concentration is increased.