ABSTRACT
Transdermal delivery cannot and need not be used in every situation. A rationale to explore this route typically exists for drugs that are subject to an extensive •rstpass metabolism when given orally or must be taken several times per day. Even then, only potent drugs can be administered through this route, because there are economical and cosmetic reasons that restrict the patch size. Though it is hard to make generalizations, the maximum patch size has been suggested to be about 50 cm2, and the maximum possible dose that can be delivered may be around 50 mg per day (11). Furthermore, the drugs should be moderately lipophilic (typically, log P of about 1 to 3) to be able to have signi•cant passive permeation into the skin and then be able to diffuse out from the skin into the aqueous systemic circulation. Lipophilic drugs with log P > 3, such as some antifungals and corticosteroids, tend to form a reservoir or depot in the skin. Passive permeation is also generally considered to be limited to drugs with a molecular weight (MW) less than 500 Da (12). Other factors that are important include solubility in the skin (13) and other parameters based on the physicochemical properties of the drug, including melting point, water solubility, number of atoms available for hydrogen bonding, as well as the previously mentioned MW and octanol-water partition coef•cient (14). As the melting point decreases, solubility in skin increases, and therefore, šux increases. Because enantiomers may have different melting points, the lower melting form enantiomer may have higher šux than the other enantiomer or as compared to the racemic mixture. Similarly, eutectic mixtures have lower melting points and therefore may have higher šux (e.g., EMLA cream) (see Section 7.4.1.1). One of the factors limiting more molecules from being commercialized as skin patches is skin irritation, which is discussed in Chapter 10. Hydrophilic molecules and macromolecules do not normally permeate through the skin, and their delivery by physical enhancement technologies is the primary focus of this book.
