**4.2 Novel formulation approaches for improving skin delivery of NSAIDs 4.2.1 Micromemulsions**

Microemulsions are transparent liquid dispersions with a droplet size of 20-200 nm. Their formulations include four fundamental components, which are water, oil, surfactant and co-surfactant. The advantages of microemulsions include enhancing solubility of drugs, thermodynamic stability, ease of preparation and low costs (Neubert, 2011). Microemulsions have recently attracted attention in enhancing dermal permeation of lypophilic drugs as well as hydrophilic drugs. The oils and surfactants included in the composition of microemulsions also act as penetration enhancers. Besides, the composition of formulation and the internal structure of phases enhance diffusion of the drug inside the carrier and improve the partition of drug to SC (Kogan & Garti, 2006). The most important disadvantage of microemulsions is potential risk of skin irritation due to their high content of surfactants. Kantarc et al. (2007) prepared microemulsion formulations containing diclofenac sodium, and optimized it in with vitro tests. The irritant effect of formulations was investigated on healthy volunteers, and their safety was demonstrated. In another study, lecithin microemulsions of ketoprofen were developed (Paolino et al., 2002). Permeation of drug from microemulsion formulation was compared to the conventional dermal ketoprofen formulation. In this study performed with healthy volunteers, it was demonstrated that ketoprofen microemulsions enhanced the permeation of drug and has good skin tolerability (Amrish & Kumar, 2009). Dalmora et al. (2001) administered microemulsions loaded with piroxicam to rats in vivo, and demonstrated that dermal anti-inflammatory effect was extended, and inflammation inhibition lasted for nine days following single-dose administration. In vivo antiinflammatory activity study has also demonstrated that microemulsions containing flurbiprofen performed better than conventional gel formulation (Ambade et al., 2008). In another study, nano/submicron emulsions of flurbiprofen were suggested as dermal carriers (Fang et al., 2004).

#### **4.2.2 Vesicular carriers**

Vesicular systems such as liposomes, niosomes and transfersomes have been developed for optimization of dermal penetration of drugs and particularly for dermal targeting. Vesicular systems have the advantages of controlling release rate of the active ingredient and to ensure localization of dermally administered drugs in dermal layers. Besides, transdermal administration of vesicular systems helps to carry drug molecules into systemic circulation (El Sayed et al., 2007; Ceve, 2004).

#### 4.2.2.1 Liposomes

Liposomes are described as lipidic vesicles containing water. Cholesterol and phospholipids or amphiphilic ingredients of these compounds are typically used as lipids. Liposomes can capture hydrophilic molecules or contain lipophilic molecules in their membranes. Some liposomes can be adsorbed in the skin surface or may go into fusion. Fusion of liposomes may increase the drag force required for permeation of the molecule and facilitate dermal penetration of the drug. However, fusion of liposomes on the skin surface does not apply for macromolecular drugs. Another mechanism is penetration of liposomes to SC before fusion with SC lipids and releasing the drug there. With this mechanism, particularly the drug in liposomes that are dermally administered can be localized in different layers of the skin (El Magraby et al., 2008; Williams, 2003).

Mezei & Gulasekharam (1980) used liposomes as "dermal drug carrier system" for the first time. However, liposomes are localized in the outermost layer of the skin (SC). Therefore, it is advantageous in cases where retaining drug in SC is desirable. It does not seem possible with these systems to penetrate the drug to deeper tissues of the skin or into systemic circulation. Therefore, it is rather preferred to increase dermal moisture for cosmetic purposes (El Magraby et al., 2008; Williams, 2003).
