*3.7.2 Microemulsions*

Water in oil microemulsions are stable dispersions consist of small water droplets dispersed within a continuous oil layer stabilized by incorporating a high concentration of surfactant/emulsifying molecules. Lipophilic surroundings of the external phase of the microemulsion resemble the environment of the upper layer of skin. This resemblance makes microemulsions ideal for application on the skin surface [127]. Also, the ease of administering microemulsions on the skin makes these ideal for passive delivery of proteins or peptides across the skin [128].

The efficacy of topically applied protein formulated with a microemulsion was investigated [129]. Rapid penetration of the molecule into the skin immediately below the application site was observed. Another study performed with desmopressin not only validated the capability of microemulsion as a transdermal carrier system but also indicated its superiority over creams and gels in delivering drugs across the skin [130]. The superior transdermal delivery of microemulsion has been attributed to the high loading capacity of the microemulsion and penetration enhancing effect of the constituents. Microemulsions have the capacity of encompassing a large amount of drugs without an increase in vehicle affinity. This capacity leads to a higher concentration gradient and higher transdermal flux from microemulsions. Also, the surfactant (e.g., isopropyl palmitate) can augment permeation by disrupting the intracellular lipid structure of stratum corneum [131, 132].

#### **3.8 Prodrug**

A prodrug is a reversible chemical modification of the drug to enhance its solubility, bioavailability, and stability without altering its pharmacological properties [133]. There are many examples where prodrug has been synthesized for proteins or peptides. For example, the thyrotropin-releasing hormone (TRH) has been successfully transported through human skin [134]. This was done by using the lipophilic prodrug of TRH, N-octyloxycarbonyl-TRH (**Figure 18**). The good skin penetration

**Figure 18.** *TRH and its prodrug.*

behavior of this prodrug was attributed to its high water solubility and lipophilicity. Conjugation of proteins or peptides with carriers that selectively transport them across the biological membranes can be used to deliver protein or peptide therapeutics across the skin [135, 136]. For example, the toxic protein ricin is transported across the cell membrane via binding to the ricin B chain found on the surface, followed by internalization. The active component is liberated upon entering the cell, where it exerts its toxicological effects. Thus, ricin behaves essentially as a prodrug of the ricin A chain.
