Stability, cutaneous delivery, and antioxidant potential of a lipoic acid and α-tocopherol codrug incorporated in microemulsions

Abstract

The aim of this study was to assess the skin penetration, stability, and antioxidant effects of a α-tocopherol-lipoic acid codrug. To enhance penetration, we evaluated three microemulsions varying in water content and composition of the oil phase (isopropyl myristate with either monocaprylin or oleic acid). The codrug was incorporated at 1% (w/w). Codrug hydrolysis in the microemulsion increased with increases in time (up to 48 h) and formulation water content (10%-30%, w/w). Microemulsions increased the codrug delivery into viable layers of porcine ear skin by 2.9-7.8-fold compared with a control formulation (20% monocaprylin in isopropyl myristate) after 24 h. Penetration enhancement was influenced by the oil phase, with the formulation containing monocaprylin displaying the most pronounced effect. Antioxidant activity, assessed in skin bioequivalents using the thiobarbituric acid-reactive substances (TBARS) assay, demonstrated that TBARS levels decreased by 39% after treatment with the codrug-containing microemulsion compared with the unloaded formulation. In addition to the codrug, tocopherol (8.2 ± 0.6 μg/cm(2)) was detected in the viable bioequivalent tissues, suggesting that the codrug was partly hydrolyzed after 12 h. Taken together, these results support the potential of nanodispersed formulations containing a tocopherol-lipoic acid codrug to improve skin antioxidant activity.

Keywords: antioxidant; codrugs; formulations; lipoic acid; microemulsion; permeation enhancers; skin; transdermal; α-tocopherol.

Figure 1

Representation of the co-drug structure.

Figure 2

Phase behavior of mixtures containing various surfactant blends, aqueous and oil phases. As oil phases, isopropyl myristate (IPM) was mixed with either monocaprylin or oleic acid (1:1, w/w). Phase diagrams were constructed using DG:DT:propylene glycol (PG) as surfactant blend at 1:1:2 (A) or 1:1:1 (B, w/w/w) with IPM and monocaprylin as oil phase or DG:DT:PG with IPM and oleic acid as oil phase (C). The dark shaded area in phase diagrams represents formation of fluid, transparent, single-phase formulations classified as microemulsions, whereas the grey line represent the dilution line used to study changes on formulation electrical conductivity. Changes on conductivity and viscosity of mixtures of surfactant and oil phase containing monocaprylin (D) or oleic acid (E) at 1:1 (w/w) as a function of aqueous content are also depicted. The percolation threshold of samples containing monocaprylin was confirmed in the plot of dconductivity/dwater as a function of water content (F).

Figure 3

Variations in the content of the co-drug in microemulsions as a function of time and formulation aqueous content. Each point represents average of 3 replicates ± standard deviation.

Figure 4

Penetration of the co-drug from control vehicle (isopropyl myristate containing 20% of monocaprylin), ME10-MC, ME20-MC and ME20-OA in the stratum corneum (SC) or viable skin layers (ED) as a function of time. Each point represents average of 3–5 replicates ± standard deviation.

Figure 5

Influence of microemulsion composition on skin penetration rates and tissue permeability. (A): Penetration rates of the co-drug as a function of time; (B): Δ transepidermal water loss induced by treatment with control vehicles, ME20-MC and ME20-OA. Values were calculated as difference in transepidermal water loss after treatment (4 or 8 h) and 5 minutes of formulation application. Each point represents average of 3-7 replicates ± standard deviation. *p < 0.05 compared to skin treated with control vehicles (IPM+MC or IPM+OA).

Figure 6

Influence of microemulsion treatment on TBARS levels in bioengineered cutaneous tissues. TBARS levels were calculated by normalizing levels in microemulsion-treated skin to values in untreated skin. *p < 0.01 compared to skin treated with the unloaded (not containing co-drug) formulation.