Lamellar liquid crystalline phases for cutaneous delivery of Paclitaxel: impact of the monoglyceride.

PURPOSE: To develop liquid crystalline phases with monoglycerides, and assess whether the monoglyceride type favors cutaneous over transdermal paclitaxel delivery. METHODS: BRIJ-based lamellar phases were prepared with 0.5% paclitaxel and 20% of either monocaprylin (LP-MC), monomyristolein (LP-MM) or monoolein (LP-MO). Skin electrical resistance, drug release and cutaneous delivery in vitro and in vivo were assessed. Viability of skin equivalents and release of IL-1α were assessed as indexes of irritation potential. RESULTS: An inverse relationship between monoglyceride acyl chain length and amount of paclitaxel delivered was observed. Although the largest paclitaxel amounts were delivered by LP-MC, all formulations delivered higher levels of drug in the skin (56-64-fold) than across the tissue. The superiority of LP-MC seems related to a stronger decrease in skin resistance (as an index of permeability), and not to increased drug release. LP-MC displayed similar penetration-enhancing ability in vivo, and a much lower irritation potential than Triton-X100 (a moderate irritant), leading to 3-fold higher skin equivalent viability and release of 60-fold less IL-1α. CONCLUSIONS: Even though LP-MC delivered the largest amounts of paclitaxel, all formulations provided similar cutaneous/transdermal delivery ratios, suggesting that changing the monoglyceride acyl chain length did not affect the balance between cutaneous and transdermal delivery.

Influence of internal structure and composition of liquid crystalline phases on topical delivery of paclitaxel.

This study aimed to evaluate whether and how the internal structure and composition of liquid crystalline systems can be tailored to maximize paclitaxel cutaneous delivery. Liquid crystalline phases of water, Brij-97, and medium-chain mono/diglycerides (MCG) were characterized by polarized light microscopy. Lamellar phases containing 20% (w/w) water and MCG at 10% (LP-10) or 20% (LP-20), and a hexagonal phase (HP) with 45% water and 10% MCG were selected; paclitaxel was incorporated at 0.5% (w/w). Compared with drug solution in myvacet oil, LP-20 provided the highest paclitaxel cutaneous delivery (threefold), and LP-10 the highest transdermal delivery (fourfold). Using a fluorescent drug derivative [at 0.5%, (w/w)], we observed that penetration occurred through intact stratum corneum. To evaluate whether penetration results relate to drug release differences, paclitaxel self-diffusion coefficient (D) and in vitro release were studied. D was the highest in LP-20, but release from LP-20 and LP-10 was similar. The low D in HP was associated with the lowest drug release. As an index of efficacy, we assessed the cytotoxicity of paclitaxel-loaded LP-20 against fibroblasts. Cell viability was 1.3-2 times smaller with LP-20 than with drug solution. Our results demonstrate that LP-20 provides optimization of paclitaxel cutaneous delivery and efficient cytotoxicity.

Topical delivery of lycopene using microemulsions: enhanced skin penetration and tissue antioxidant activity.

Topical delivery of lycopene is a convenient way to supplement cutaneous levels of antioxidants. In this study, lycopene was incorporated (0.05%, w/w) in two microemulsions containing BRIJ-propylene glycol (2:1, w/w, surfactant blend) but different oil phases: mono/diglycerides of capric and caprylic acids (MG) or triglycerides of the same fatty acids (TG). Microemulsions containing MG and TG were isotropic, fluid, and clear, with internal phase diameters of 27 and 52 nm, respectively. Both MG- or TG-containing microemulsions markedly increased lycopene penetration in the stratum corneum (6- and 3.6-fold, respectively) and in viable layers of porcine ear skin (from undetected to 172.6 +/- 41.1 and 103.1 +/- 7.2 ng/cm(2), respectively) compared to a control solution. To assure that lycopene delivered to the skin was active, the antioxidant activity of skin treated with MG-containing microemulsion was determined by CUPRAC assay, and found to be 10-fold higher than untreated skin. The cytotoxicity of MG-containing microemulsion in cultured fibroblasts was similar to propylene glycol (considered safe) and significantly less than of sodium lauryl sulfate (a moderate-to-severe irritant) at 1-50 microg/mL. These results demonstrate that the MG-containing microemulsion is an efficient and safe system to increase lycopene delivery to the skin and the antioxidant activity in the tissue.

Microemulsions containing medium-chain glycerides as transdermal delivery systems for hydrophilic and hydrophobic drugs.

We evaluated the ability of microemulsions containing medium-chain glycerides as penetration enhancers to increase the transdermal delivery of lipophilic (progesterone) and hydrophilic (adenosine) model drugs as well as the effects of an increase in surfactant blend concentration on drug transdermal delivery. Microemulsions composed of polysorbate 80, medium-chain glycerides, and propylene glycol (1:1:1, w/w/w) as surfactant blend, myvacet oil as the oily phase, and water were developed. Two microemulsions containing different concentrations of surfactant blend but similar water/oil ratios were chosen; ME-lo contained a smaller concentration of surfactant than ME-hi (47:20:33 and 63:14:23 surfactant/oil/water, w/w/w). Although in vitro progesterone and adenosine release from ME-lo and ME-hi was similar, their transdermal delivery was differently affected. ME-lo significantly increased the flux of progesterone and adenosine delivered across porcine ear skin (4-fold or higher, p < 0.05) compared to progesterone solution in oil (0.05 +/- 0.01 microg/cm(2)/h) or adenosine in water (no drug was detected in the receptor phase). The transdermal flux of adenosine, but not of progesterone, was further increased (2-fold) by ME-hi, suggesting that increases in surfactant concentration represent an interesting strategy to enhance transdermal delivery of hydrophilic, but not of lipophilic, compounds. The relative safety of the microemulsions was assessed in cultured fibroblasts. The cytotoxicity of ME-lo and ME-hi was significantly smaller than sodium lauryl sulfate (considered moderate-to-severe irritant) at same concentrations (up to 50 microg/mL), but similar to propylene glycol (regarded as safe), suggesting the safety of these formulations.