Effect of monoacyl phosphatidylcholine content on the formation of microemulsions and the dermal delivery of flufenamic acid

Abstract

The choice of appropriate excipients is crucial for the success of a dermal drug delivery system. Especially surfactants should be chosen carefully, because of their possible interactions with the skin or the applied drug. Since monoacyl phosphatidylcholine (MAPL) exhibits great emulsification properties and can be derived from natural sources, it is of great interest as surfactant in microemulsions. Therefore, the aim of the present study was to investigate the effect of the MAPL content on the formation of microemulsions. The great emulsification power of MAPL was confirmed by increased isotropic areas with increasing MAPL content. Moreover, a decrease in particle size, particle size distribution and viscosity with increasing MAPL content was determined. Besides its effects on microemulsion structure, MAPL exhibited a significant influence on the skin permeation of flufenamic acid. Interestingly, the higher the MAPL content, the lower was the skin permeation of flufenamic acid. A possible explanation might be that the hydrophilic MAPL could hinder the permeation of the lipophilic drug. In contrast, the skin permeation enhancing effects of the microemulsion with the lowest MAPL content might be attributed to formation of a patch-like structure and therefore better contact between the formulation and the skin.

Introduction

The outermost layer of the skin, the stratum corneum, represents the major barrier to dermal drug delivery. It has evolved to protect us from the excessive loss of water and the ingress of foreign materials. As a consequence, this unique barrier is hard to be overcome by conventional means (Lane, 2013).

In comparison to traditional vehicles, so called ‘microemulsions’ are known to exhibit increased cutaneous drug delivery (Kreilgaard, 2002). Microemulsions are thermodynamically stable transparent systems consisting of water, oil and surfactants. Mostly, the addition of a co-solvent, such as a short- or medium-chain alcohol, is required for further decrease of the interfacial tension (Santos et al., 2008, Heuschkel et al., 2008). The exact mechanism of permeation enhancement of these promising colloidal drug carrier systems is not totally understood yet. Clearly, the composition of microemulsions significantly influences the delivery of the active. For example, an enhanced dermal delivery of drugs with increasing water content of microemulsions was determined in a number of previous studies and is mainly attributed to increased skin hydration levels (Santos et al., 2008, Hoppel et al., 2014, Hathout et al., 2010). Besides the ratio of the main components, variations in types of excipients can alter interactions of the vehicle with the skin or the applied drug (Santos et al., 2008).

Microemulsion components such as surfactants, alcohols and fatty acids can promote the delivery of drugs by acting as penetration enhancers. Although a large variety of chemicals were identified as skin permeation enhancers, their use is often limited by toxicity issues (Lane, 2013).

Especially surfactants may exhibit strong influences on the skin and even so on the structure of a vehicle and its performance in terms of dermal drug delivery (Lane, 2013). Additionally, care has to be taken to avoid skin irritation often associated with the use of surfactants (Wilhelm et al., 1993).

Lecithin is one of the most widely used natural emulsifying agent. It is a mixture of different phospholipids with phosphatidylcholine as the quantitatively most important fraction. Since lecithins are components of cell membranes of plants and animals, they can be derived from natural sources. Vegetable lecithin is mainly obtained from oil-bearing seed such as soybean and canola seed (Klang and Valenta, 2011). Diacyl phosphatidylcholine derived from these natural raw materials can be manufactured to monoacyl phosphatidylcholine (MAPL) by enzymatic hydrolysis. The major benefit of this phospholipid is a greater emulsification power compared to diacyl phosphatidylcholine (Kim et al., 2001, Trotta et al., 1996).

Since natural lecithins are among the safest emulsifying agents on the market with a low incidence of allergic reactions (Klang and Valenta, 2011), numerous studies on lecithin-based microemulsions were performed over the last years (Trotta et al., 1996, Paolino et al., 2002, Bonina et al., 1995, Hoeller et al., 2008, Dreher et al., 1997, Schwarz et al., 2012). However, the influence of the MAPL content on internal structure of microemulsion and dermal delivery of actives is not yet fully elucidated.

Recently, we investigated a significant influence of the composition of MAPL-based microemulsions on the dermal delivery of flufenamic acid (Hoppel et al., 2014). To deepen the already acquired knowledge, the present study addresses the question how the microemulsion structure and dermal delivery of flufenamic acid are affected by different MAPL amounts. For this purpose, pseudoternary phase diagrams were constructed for phospholipid products differing in their respective MAPL content. The structure of one promising mixture that led to the formation of a stable microemulsion with all MAPL fractions was characterized by particle size measurements and rheology. In order to compare the performance of the microemulsions in terms of dermal delivery of flufenamic acid, Franz-type diffusion cell experiments with porcine skin as model membrane were carried out.