## 1 Introduction  
It is well known fact that transdermal delivery is considered an alternative route to both oral and parenteral drug administration [1]. The transdermal route has the advantages of avoiding liver metabolism, providing constant plasma drug concentration and avoids GIT irritation than oral route and shows better patient compliance than parenteral administration [2,3]. However, extremely low permeability of the skin to water soluble molecules secondary to the formidable barrier property of the lipophilic stratum corneum has been an obstacle to its use [4,5]. The barrier effect of the skin further makes it difficult to prepare transdermal systems capable to effectively deliver drugs in high concentrations into the blood. Therefore, transdermal systems with enhancing skin permeability and increasing drug delivery are of great interest nowadays. Transdermal drug-delivery systems including emulsions, gels and their combination (emulgels) have been found to increase skin permeability for drugs and thereby improve systemic absorption and drug effectiveness [6,7]. Due to its greaseless and thixotropic behavior, emulgel demonstrates an enhanced drug release profile, facilitates spreadability on the skin and increases absorption while preventing typical stability problems associated with emulsions, such as phase separation, creaming and coalescence [6]. In addition, novel drug-carrier systems such as liposomes, niosomes, and microemulsions have demonstrated encouraging results in skin, cutaneous and transdermal delivery of various drugs [8, 9, 10]. On the other hand, transdermal delivery of protein pharmaceuticals has also been extensively studied [11,12]. Incorporation of nanovesicles into transdermal vehicles has proved to enhance percutaneous drug absorption [13]. Niosomes are liquid dispersions that require gelling agents to be suitable for transdermal application. The backbone of this system is the non-ionic surfactant. Being amphiphilic in nature, niosomes can accommodate drug molecules with diverse physicochemical characteristics. They may increase the fluidity of the skin membranes through their interaction with the lipophilic layer--which reduces membrane resistance to drug permeation [14]. Moreover, several studies indicated that the niosomes may diffuse deep in the skin [15] and can deliver drugs into the systemic circulation [16,17]. The combination of niosomes with emulgels has resulted in the emergence of new drug-delivery system called the niosome emulgel. This system demonstrates superior transdermal perfusion compared to niosomes, which may be attributed to the dual effect of surfactants presented in niosome formulation and emulsion preparation. Moreover, they have the ability to diffuse across the narrow pores in the skin [6]. Recently, our group succeeded in enhancing the transdermal permeability of ketorolac tromethamine (water soluble drug) by novel niosome emulgel combination [6]. In the same context, the purpose of the current investigation was to maximize the transdermal permeability of insulin via utilizing niosome emulgel combination. Insulin is a well-known therapy for treatment of insulin-dependent diabetes mellitus. Insulin is a hormone formed of two peptide chains and has a molecular weight about 5.7 kDa [18]. Subcutaneous administration is considered as the main route for insulin delivery into the human body; however it has several drawbacks [19]. Literature suggests that various skin-permeation approaches--including chemical enhancers, nano or micro vesicles, low electric current, ultrasound, jet injection and micro needles--have been assessed to enhance the delivery of insulin [20,21]. In the last two decades, several research groups have successfully developed various devices capable of biosensing and deliver insulin through the skin [22]. In the current investigation, an optimized insulin-loaded niosome emulgel combination was investigated as a safe, painless and high-patient compliant drug-delivery system.