Franco Pattarino

Emulsions containing partially water-miscible solvents for the preparation of drug nanosuspensions

The aim of this study was to investigate the feasibility of partially water-miscible solvents, such as benzyl alcohol, butyl lactate and triacetin, to prepare drug nanosuspensions by a solvent quenching technique. Mitotane, which possesses very poor water solubility and low bioavailability, was used as model drug. Preparation was by emulsifying an organic solution of the drug in an aqueous solution of a stabilising agent followed by rapid displacement of the solvent from the internal into the external phase, provoking solid particle formation. To verify the influence of emulsion droplet size on the drug particle size, 0.1 or 0.2% of different emulsifiers (Tween 80, caprylyl-capryl glucoside or lecithin) and different homogenisation conditions (Ultra Turrax or a high pressure homogenizer at 200 or 1000 bar for three cycles) were used. In general, emulsion droplet size decreased with high pressure homogenization and on increasing the number of cycles. The size of drug particles, obtained after adding water at a constant rate, was dependent on the droplet size in the emulsion. Drug particles of approximately 80 nm were obtained using butyl lactate, supporting the hypothesis that drug particle formation by the emulsification diffusion process involves generating regions of local supersaturation. Because of the increase in available surface area, the dissolution rate of diaultrafiltrated suspensions increased greatly compared to commercial product.

In vitro permeation of azelaic acid from viscosized microemulsions

Abstract The transport of azelaic acid, a bioactive molecule used in treating acne and many skin disorders, from a viscosized microemulsion and from a gel through full thickness abdominal skin was examined. A lag time was evident in both systems. The percentage of azelaic acid transported from the microemulsion was several times higher than that from the gel. The effect of dimethyl sulfoxide, chosen as a model enhancer, on transport was also investigated. After 8 h from the viscosized microemulsions, 43 and 64% of the initial amount passed through hairless skin in the presence of 1 and 2% of dimethyl sulfoxide, respectively.

Influence of counter ions on the skin permeation of methotrexate from water-oil microemulsions

The influence on the permeation of methotrexate across intact hairless mouse skin of different counter ions added to water--oil (w/o) microemulsions containing lecithin, as surfactant, and water--propylene glycol at different pH values, as internal phase, was studied. As counter ions, monooctyl phosphate, monodecyl phosphate, monodecyl glycerophosphate, taurodeoxycholate, dodecyl sulfate and dioctyl sulfosuccinate were used. At pH 4.0, the transport of methotrexate was enhanced by the counter ions and a marked increase in the flux of the drug was measured when dodecyl sulfate and dioctyl sulfosuccinate were used. At pH 5.0 only a slight increase of the flux was observed. The increased permeation was attributed to the lipophilization of methotrexate as a consequence of ion pair formation.

Stability of drug-carrier emulsions containing phosphatidylcholine mixtures

Lipid emulsion particles containing 10% of medium chain triglycerides were prepared using 2% w/w of a mixture 1:1 w/w of purified soya phosphatidylcholine and 2-hexanoyl phosphatidylcholine as emulsifier mixture, for use as drug carriers. The mean droplet sizes of emulsions, prepared using an Ultra Turrax or a high-pressure homogenizer, were about 288 and 158 nm, respectively, compared with 380 and 268 nm for emulsions containing lecithin, or 325 and 240 nm for those containing 6-phosphatidylcholine. The stability of the emulsions, determined by monitoring the decrease of a lipophilic marker at a specified level within the emulsion, and observing coalescence over time, was also greatly increased using the emulsifier mixture. The emulsion stability did not notably change in the presence of a model destabilizing drug, indomethacin. The use of a second hydrophilic surfactant to adjust the packing properties of the lecithin at the oil-water interface provided an increase in the stability of lipid emulsions, and this may be of importance in the formulation of drug delivery systems.

Investigation of the phase behaviour of systems containing lecithin and 2-acyl lysolecithin derivatives

A series of modified phospholipids (m-PC) possessing different acyl chains in position 2, from butanoyl to hexadecanoyl, were prepared by partial synthesis from soybean lysolecithin. They were used with soybean lecithin to construct phase diagrams containing ethanol as cosolvent, water and medium chain triglycerides (MCT) or isopropyl myristate (IPM) as oils. The weight ratios lecithin:m-PC and surfactants:ethanol were kept constant at 1:1. The results indicate that the m-PCs have a strong effect on the microemulsion (L) and liquid crystalline (LC) domains in the water-rich/oil-poor part of the phase diagrams, although all diagrams correspond to a single lecithin:m-PC ratio. On decreasing the acyl chain length, and thus increasing the hydrophilicity of the surfactant, there was a corresponding increase in the L area, which moved towards the aqueous corner of the phase diagrams. The LC phase was detected only in the presence of the hexadecanoyl derivative for the systems containing MCT, and it was not detected only in the presence of the butanoyl derivative for the systems containing IPM. The use of a second hydrophilic surfactant to adjust the packing properties of the lecithin-alcohol systems, and/or to increase the fluidity of the surfactant film, increased the region of existence of the isotropic systems. This may be of importance in the formulation of drug delivery systems, especially those which are diluted by biological fluids upon administration.

Experimental design and partial least squares in the study of complex mixtures: microemulsions as drug carriers

Abstract Four-component non-aqueous microemulsions, containing lecithin, taurodeoxycholic acid, ethyl oleate and 1,2-propylene glycol have been studied with chemometric techniques to emphasize the role of the components on the release of a drug. Since microemulsions can be obtained only for particular proportions of the constituents, their realm of existence was determined by using Doehlert experimental design. Successively, a mixture design technique was applied to select the set of microemulsions for the measurement of the diffusion rate of a model lipophilic drug, retinol, through a hydrophilic membrane. The drug permeability was modelled as a function of the mixture composition by partial least squares (PLS). The results emphasize the role of the cosurfactant and the oil phase of the system on the drug permeation behaviour from the waterless microemulsion.

Formation of lecithin-based microemulsions containing n-alkanol phosphocholines

Abstract The formation of microemulsion phases was studied at 25°C for systems containing soybean phosphatidylcholine (lecithin), medium-chain-triacylglycerol (MCT) or isopropyl myristate (IPM), water, alcohol and n-alkanol phosphocholines (Cn), with chain length between 6 and 12 carbon atoms, as second hydrophilic surfactant. The lecithin/Cn mixing ratio was 1:1, while the surfactant/alcohol mixing ratios were 1:1 and 2:1 for the systems containing MCT, and 1:1 for the systems containing IPM. Alcohols used were ethanol, 1-propanol and 1-butanol. The maximum extension of the region of existence of the microemulsion systems containing MCT was found with butanol, while in the presence of IPM it was found with propanol. Except for the system containing IPM and butanol, the size of the microemulsion phase increased on increasing the length of the Cn chain, and moved towards the aqueous corner of the phase diagram. The use of a second hydrophilic amphiphile to adjust the spontaneous packing properties of the lecithin–alcohol system, or to increase the fluidity of the surfactant film, provided an increase in the region of existence of the microemulsion systems.

OPTIMIZATION OF W/O-S EBHULSIONS AND STUDY OF THE QUANTITATIVE RELATIONSHIPS BETWEEN ESTER STRUCTURE AND EMULSION PROPERTIES

ABSTRACT Chemometric procedures were applied to water-in-oil-silicon (W/O-S) emulsions, used in cosmetic field. The optimization.performed by the strategy of Experimental Design and Response Surface method, led to an emulsion of very high stability. Quantitative relationships between two properties of emulsions)stability and viscosity) and chemical structure of 15 esters, employed as oil, were studied. By Partial Least Squares (PLS) method, properties and structure of acids and alcohols, from wich the esters derived, could be used to model the properties of the emulsion.

EFFECT OF ALCOHOL CDSURFACTANTS ON THE DIFFUSION COEFFICIENTS OF MICROEMULSIONS BY LIGHT SCATTERING

ABSTRACT The influence of increasing amounts of alcohol on the collective diffusion coefficient was investigated using a light scattering technique. Three components were mantained fixed (isopropyl myristate, sodium bis-S-ethylhexyl sulphosuccinate, water ) series of microemulsions were obtained adding increasing aliquots of alcohol (1-butane isobutanol, 2-pentanol, 3-pentanol, 3-methy1-2-butanol, tert-amylalcohol, cyclo-peintanol, 3-methy 1-3-pentano 1, cyclohexanol, benzyl alcohol( The behaviour was the same for all the series, a maximum of collective diffusion coefficient was noted for each alcohol. The collective diffusion coefficients at maximum could be related to the water solubilities of the alcohols.

COMBINED USE OF LECITHIN AND DECVL POLYGLUCOSIDE IN MICROEMULSIONS: DOMAIN OF EXISTENCE AND COSURFACTANT EFFECT

Abstract The phase diagram of a isopropyl myristate (IPM), water, leckhin/decyl polyglucoside (1:1), butanol mixture was constructed and the region of the o/w microemulsion was examinated. The realm of existence of this system was also investigated employing eight different, linear and branched short-chained alcohols as cosurfactants. The alcohol contribute to the extention of the microemulsion domain was explained in terms of lipophilicity and solubility. Moreover, the role of the cosurfactant was examined in a relationship study where the amount required to form the microemulsion of a series of twenty alcohols was related to a set of new structural descriptors of these molecules, the WHIM indices.