Potential of Non-aqueous Microemulsions to Improve the Delivery of Lipophilic Drugs to the Skin

Abstract

In this study, non-aqueous microemulsions were developed because of the challenges associated with finding pharmaceutically acceptable solvents for topical delivery of drugs sparingly soluble in water. The formulation irritation potential and ability to modulate the penetration of lipophilic compounds (progesterone, α-tocopherol, and lycopene) of interest for topical treatment/prevention of skin disorders were evaluated and compared to solutions and aqueous microemulsions of similar composition. The microemulsions (ME) were developed with BRIJ, vitamin E-TPGS, and ethanol as surfactant-co-surfactant blend and tributyrin, isopropyl myristate, and oleic acid as oil phase. As polar phase, propylene glycol (MEPG) or water (MEW) was used (26% w/w). The microemulsions were isotropic and based on viscosity and conductivity assessment, bicontinuous. Compared to drug solutions in lipophilic vehicles, MEPG improved drug delivery into viable skin layers by 2.5-38-fold; the magnitude of penetration enhancement mediated by MEPG into viable skin increased with drug lipophilicity, even though the absolute amount of drug delivered decreased. Delivery of progesterone and tocopherol, but not lycopene (the most lipophilic compound), increased up to 2.5-fold with MEW, and higher amounts of these two drugs were released from MEW (2-2.5-fold). Both microemulsions were considered safe for topical application, but MEPG-mediated decrease in the viability of reconstructed epidermis was more pronounced, suggesting its higher potential for irritation. We conclude that MEPG is a safe and suitable nanocarrier to deliver a variety of lipophilic drugs into viable skin layers, but the use of MEW might be more advantageous for drugs in the lower range of lipophilicity.

Nanocarriers Provide Sustained Antifungal Activity for Amphotericin B and Miltefosine in the Topical Treatment of Murine Vaginal Candidiasis

“…For comparison, other ME containing larger amounts of non-ionic surfactants caused no significant reduction on the viability of fibroblasts when used at 10-50 µg/ml (Hosmer et al, 2009;Phelps et al, 2011), indicating that the ME developed here should be safer. ME swelling and transition to gel in vivo is important to prolong drug release (Carvalho et al, 2017;Phelps et al, 2011). Thus, we verified if the ME used here would swell upon contact with an aqueous environment and undergo phase transition to gel.…”

“…A non-aqueous microemulsion (ME), in which water was replaced by propyleneglycol, was prepared as previously described (Carvalho et al, 2017), by mixing 20% propyleneglycol, 24.8% phosphatidylcholine, 5.6% tricaprilin, and 49.6% monoolein in a 37 • C water bath until completely dissolved. Then, 1.25% AMB (AMB-ME) or 2% MFS (MFS-ME) were incorporated into the microemulsion.…”

Development of a method for quantitative determination of the cytotoxic agent piplartine (piperlongumine) in multiple skin layers

“…It is generally used in concentrations up to 10% (more frequently at 5%) to avoid the irritation associated with skin barrier disruption (Karande, Jain, Ergun, Kispersky, & Mitragotri, ; Moghadam et al, ), but because our goal was to assess whether the method enabled detection of differences in the cutaneous piplartine delivery when different formulation were used, we selected the highest concentration generally used (10%). It is well known that composition, penetration enhancer type and concentration affect drug release and skin penetration, and thus, this result is useful to guide formulation development (Carvalho et al, ; Mah, Kochhar, Ong, & Kang, ; Pepe et al, ; Phelps, Bentley, & Lopes, ). Finally, in addition to detecting the effect of the penetration enhancer, the method developed also enabled us to distinguish the influence of time on cutaneous drug delivery.…”

“…The remaining VS was cut into very small pieces (<2 mm) and placed in a different conical tube (V. F. Carvalho, de Lemos, Vieira, Migotto, & Lopes, ; Pepe, McCall, Zheng, & Lopes, ). Then, a piplartine solution in methanol was added to the vials containing SC and VS so that the theoretical final piplartine concentration in homogenates would range from 0.15 to 5 μg/mL.…”

Method Development and Validation for Analysis of Deoxyarbutinin Anhydrous Emulsion System Using High-Performance Liquid Chromatography

“…Instability in water is a problem if formulated in conventional emulsions. Therefore, to enhance the stability, the aqueous phase formulated to an anhydrous, non-aqueous, oil-in-oil or oil-polar solvent emulsion system [13][14]. In this preparation, we choose polyol-in-oil anhydrous emulsions for the analysis.…”