Lipophilic compounds, transdermal drug

Generally, the stratum corneum is considered to be the rate limiting layer of the skin with regard to transdermal drug absorption. However, for the invasion of very lipophilic compounds, the bottleneck moves from the stratum corneum down to the viable, very hydrophilic layer of the epidermis, due to substances reduced solubility in this rather aqueous layer [14],... 

On the other hand, highly lipophilic compounds, such as hormones, can be solubilized via the prodrug approach. For example, the rate of transdermal absorption of the highly lipophilic drug, testosterone, was enhanced over 50-fold by forming water-soluble, yet lipophilic, prodrug ester.f The prodrug testoster-onyl-4-dimethylaminobutyrate was found to penetrate human skin tissue, in vitro, 54 times faster than... 

For example, the permeability coefficients of intact stratum corneum for lipophilic compounds such as corticosterone are in the order of 2 x lO cm/sec in an aqueous system. The aqueous solubility of corticosterone is approximately 0.3mg/mL.f A simple calculation using Eqs. (1) and (2) show why only potent drug of a required dose less than 1 mg per day can utilize the transdermal route via passive delivery. Physical and chemical transdermal enhancers are required for most drugs. Table 1 provides a list of transdermal enhancement methods and companies involved in the development of technologies related to these methods. The readers are encouraged to view the company websites listed in the table, but caution must be taken because the information and claims provided in a company website are subjective and not peer-reviewed. 

The capacity of the skin to absorb lipid-soluble chemicals is both a blessing and a curse. Transdermal medicated adhesive patches, for example, take advantage of the capacity of the skin to absorb small lipophilic compounds in order to administer chemicals such as scopolamine, the anti-sea sickness drug, and nicotine. Unfortunately, urushiol, the active ingredient found in poison ivy, poison oak, and poison sumac, also takes advantage of the skin s capacity to absorb small, lipophilic chemicals, and is absorbed via the dermal pathway. 

Ophthalmic, transmucosal, and transdermal products will be the most sensitive to the strength of binding. These routes of administration experience minimal dilution. However, this may not be a signiLcant concern because the drug typically can also be displaced from the CD cavity at the delivery site by competing lipophiles at the delivery site, such as triglycerides, cholesterol, bile salts, and other hydrophobic compounds, which are often in much higher concentrations (Thompson, 1997). 

Azone (laurocapram) is used extensively as a transdermal permeation enhancer, and has also found use in buccal drug delivery. It is a lipophilic surfactant in nature (Figure 10.4). Permeation of salicylic acid was enhanced by the pre-application of an Azone emulsion in vivo in a keratinized hamster cheek pouch model [35]. Octreotide and some hydrophobic compounds absorption have also been improved by the use of Azone [36], Azone was shown to interact with the lipid domains and alter the molecular moment on the surface of the bilayers [37], In skin it has been proposed that Azone was able to form ion pairs with anionic drugs to promote their permeation [38],... 

The stratum corneum basically contains a mixture of cholesterol, free fatty acids, and ceramides, placed in multilayers. They mediate both the epidermal permeability barrier and the transdermal delivery of both lipophilic and hydrophilic molecules. Studies have shown that each of the three key lipid classes is required for normal barrier function (32). These reports also show the potential of certain inhibitors of lipid synthesis to enhance the trans-dermal delivery of drugs like lido-caine or caffeine. Thus, the modulation of stratum corneum lipids is an important determinant of the barrier permeability to both hydrophobic and hydrophilic compounds transport and drug penetration. It has been reported that an inverse correlation exists between solute penetration and stratum corneum lipid content (33). 

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