M. Seiller

Surface activity and association of ABA polyoxyethylene—polyoxypropylene block copolymers in aqueous solution

Abstract The surface tension of aqueous solutions of a range of ABA polyoxyethylene-polyoxypropylene nonionic copolymers has been measured over a wide range of concentrations. The surface tension versus concentration plots show an inflection typical of that shown by conventional surfactants, but this occurs at very low concentrations (0.5–5 × 10 −6 M liter −1 ) and it is thought to be the result of monomolecular micelle formation. At higher concentrations (0.5 × 10 −4 to 1.5 × 10 −2 M liter −1 ) polymolecular aggregation probably takes place. The extent of uptake of benzopurpurine and iodine in aqueous solutions increases at high concentrations but the inflection points do not agree with any observable in the surface tension plots. Areas per molecule calculated using the simple form of the Gibbs equation indicate that there is considerable folding of the polymers at the air-water interface. For a given hydrophobic polyoxypropylene block, increasing the size of the hydrophilic polyoxyethylene chains causes an increase in interfacial molecular area. Increasing the length of the central hydrophobic moiety allows the molecule to fold more extensively and results in a decrease in the occupied area per molecule. Raising the temperature causes an increase in solution viscosity, especially near the lower consolute temperature (cloud point) of the system, a further indication of polymolecular association in these systems.

Influence of lipophilic surfactant on the release kinetics of water-soluble molecules entrapped in a W/O/W multiple emulsion

Abstract The aim of this work was to study the release kinetics of a water-soluble drug from two different W/O/W multiple emulsions prepared with two lipophilic surfactants at different concentrations. The study of the kinetics under both iso-osmotic and hypo-osmotic conditions allowed us to distinguish between two possible release mechanisms: swelling-breakdown or facilitated diffusion. The results obtained indicate that water-soluble drug release occurs by a mechanism of swelling followed by a breakdown of the oil globules, in which the lipophilic surfactant is a decisive factor. It appears that the globules swelling capacity is considerably increased when the lipophilic surfactant concentration increases, and the more the oil globule swells, the less the water-soluble drug releases. It seems that the stability could be improved by increasing the lipophilic surfactant concentration which could strengthen the interfacial film. In contrast, an excess of hydrophilic surfactant destabilized the emulsion.

A topical W/O/W multiple emulsion containing several active substances: formulation, characterization and study of release

Abstract W/O/W multiple emulsions are vesicular systems which can be used in many ways. They are made of small oily drops (intermediate phase) dispersed in an aqueous medium (outer phase) and in which very small aqueous droplets (inner phase) are encapsulated. These systems protect the substances encapsulated in the inner phase and can prolong their release to the outer phase. This work has developed a W/O/W emulsion containing active substances in each of the phases. The study of the release of the substance encapsulated in the inner aqueous phase, using rheometry and conductimetry, has shown that two simultaneous release mechanisms can exist: a breakdown of the oily membrane followed by the expulsion of the encapsulated substance and a diffusion of this substance through this oily membrane. These observations should allow to control the release of the entrapped substance.

Transdermal delivery of glucose through hairless rat skin in vitro: effect of multiple and simple emulsions

Abstract Three types of oil–water emulsions (W/O/W, O/W and W/O emulsions) were obtained and evaluated on hairless rat skin biopsies, using Franz diffusion cells. Natural emulsifiers (soybean phospholipids) were used to formulate stable multiple and simple emulsions. The qualitative and quantitative composition of the three emulsions was the same. In order to compare the emulsions that have been prepared with this new utilization of soybean phospholipids as emulsifier for vesicular systems and to achieve the importance of application conditions on the diffusion of glucose, a finite dose in open-cap and an infinite dose with occlusion were evaluated. After 24 h of diffusion, the maximum flux (0.69±0.21 μ g/cm 2 /h) for a finite dose was obtained with simple O/W emulsion, with a rank order of emulsions identical when compared to an infinite dose application: O/W>W/O/W>W/O.

Kinetics of swelling-breakdown of a W/O/W multiple emulsion: possible mechanisms for the lipophilic surfactant effect.

The properties and behavior of a W/O/W multiple emulsion formulation were analyzed during a swelling-breakdown process. Various experimental analyses, such as granulometry, rheology and conductimetry were performed, as well as a micropipette aspiration method. The predominant role of the lipophilic surfactant during the swelling phase confirmed. Two different mechanism can be proposed. Both imply the migration of the lipophilic surfactant from one interface to another and probably take place successively. The lipophilic surfactant could diffuse from the first to the second interface, thus rigidifying the membrane, or from the oily phase to the first interface, resulting in delayed coalescence of the aqueous droplets during swelling.

Optimization of a thermally reversible W/O/W multiple emulsion for shear-induced drug release.

PURPOSEnThe present work aimed at improvement of the formulation of a previously developed thermo-reversible W/O/W multiple emulsion by increasing the emulsion stability and reaching a higher fraction of an encapsulated drug released under shear. The emulsion was based on high molecular weight graft-copolymers of poly(acrylic acid) and Pluronic F127 as stabilizing agents.nnnMETHODSnOnce a stable W/O/W thermo-reversible multiple emulsion was obtained via a fine-tuning of the formulation, rheological, granulometric and conductometric tests were performed to assess the thermo-reversible behavior and the fragmentation-release characteristics of the new W/O/W multiple emulsion.nnnRESULTSnThe emulsion exhibited a 10(3) fold increase in viscosity over a range of temperatures from 20 to 40 degrees C. At moderate shearing, a complete release of the marker encapsulated in the internal aqueous phase was observed (99.6%) at 35 degrees C, whereas only 30% was released at 20 degrees C. Under similar conditions at 35 degrees C, slightly more than 50% was released for the initial formula.nnnCONCLUSIONnAdditionally, the ease of fabrication of the thermo-reversible W/O/W multiple emulsion combined with the complete release under shear at body temperature and the superior emulsion stability suggest numerous applications in the controlled release of drugs.

Rheology: how to characterize and to predict the evolution of W/O/W multiple emulsions

The purpose of this work was to compare the evolution of three multiple emulsions (ME) by different controls. The series of water‐in‐oil‐in‐water (W/O/W) multiple emulsions were elaborated and controlled by both the usual analyses which permitted the classification of the multiple emulsions with respect to their thermal stability, and the rheological oscillatory and flow analyses which are polyvalent methods. Further, these allow the ‘identity card’ of the multiple emulsion to be drawn, its evolution to be followed, and moreover, its behaviour being foreseen by simulating ageing by shear. Three different behaviours are observed; a destructuration, a phase inversion and stability.

The stability and in vitro release kinetics of a clofibride emulsion

Abstract Soybean and MCT submicron emulsions of clofibride were prepared using an optimal combination of phosphatidylcholine to poloxamer (molar ratio of 1:1). Both emulsions exhibited a mean droplet size in the range of 100–150 nm, and displayed identical Newtonian rheological behavior. The results of the accelerated stability tests indicated that the soybean emulsion was more resistant to various mechanical and thermal stresses than the MCT emulsion. The soybean emulsion remained stable even after an 18 month examination while the MCT emulsion showed signs of phase separation after 13 months storage at 25°C, confirming the findings of the accelerated tests. It was noted that the mean droplet size was not markedly altered by pH variation from 1.0 to 7.4 following 60 min of contact with the emulsion. Furthermore, the droplets of both emulsions remained practically unchanged as a function of contact time in artificial gastric medium. Whereas in artificial intestinal medium an increase in droplet size was observed only with the MCT emulsion. The in vitro release of clofibride from the emulsions was examined using various kinetic approaches. The dialysis sac technique was shown to be inadequate for drug release mechanism identification. However, two recent methods, the bulk-equilibrium reverse dialysis sac technique and the centrifugal ultrafiltration procedure, yielded rapid in vitro release profiles of clofibride from the emulsion. 70–90% of the clofibride content was released from the emulsion within 15–30 min, revealing that the kinetic process was probably controlled by the oil-water partition rate of the emulsion under perfect sink conditions. It was deduced from the overall results that the soybean emulsion of clofibride was definitely suitable for oral administration, since the presence of surface active agents may alter the drug absorption profile resulting in bioavailability enhancement.

Absorption and efficiency of insulin after oral administration of insulin-loaded nanocapsules in diabetic rats.

Poly(isobutylcyanoacrylate) nanocapsules have been shown to decrease the blood glucose level after oral administration to streptozotocin-induced diabetic fasted rats after 2 days [Diabetes 37 (1988) 246]. Yet, the absorption of insulin in the blood of rats has not been characterised. The aim of this work was to evaluate the biological activity of insulin given orally as nanocapsules. Humalog-loaded nanocapsules (50 IU/kg) were administered by gavage to streptozotocin-induced diabetic rats. Thirty minutes to 1 h after oral administration, significant levels of human insulin were detected in rat plasma. However, the concentrations were very heterogenous from one rat to another and no decrease of glycemia could be observed. In addition, parenteral injection of insulin in solution showed that high levels of the protein are necessary to decrease blood glucose concentration in diabetic rats. These concentrations were not reached after oral administration. The same dose of insulin decreased glycemia by 50% in normal rats and by only 25% in diabetics. This suggested that an insulino-resistance was developed by streptozotocin-induced diabetic rats.

An in vitro release kinetic examination and comparative evaluation between submicron emulsion and polylactic acid nanocapsules of clofibride

Polylactic acid nanocapsules of clofibride containing soybean oil (SO) or medium-chain triglycerides (MCT) as the oil core were prepared. The in-vitro drug release kinetic profiles were determined and compared to those of a clofibride submicron emulsion using two different kinetic techniques: the bulk equilibrium reverse dialysis sac technique, and the centrifugal ultrafiltration technique. The former technique was shown to be inadequate for in-vitro kinetic comparison purposes as a result of drug diffusion limitations through the dialysis membrane. The latter technique yielded rapid in-vitro release profiles of clofibride from both emulsion and nanocapsule delivery systems under perfect sink conditions although a consistent lower maximum drug amount was released from the MCT nanocapsules as compared to the corresponding emulsion. This was attributed to the relatively higher aqueous solubility of MCT as compared to SO. This comparative study, carried out, to the best of our knowledge, for the first time, clearly showed that both colloidal carriers behave similarly with respect to drug release despite their different morphological characteristics. The kinetic results clearly exclude either the use of submicron emulsion or of nanocapsules as colloidal controlled release delivery systems for any administration route where perfect sink conditions should prevail.