Stimuli-Responsive Polymers for Transdermal, Transmucosal and Ocular Drug Delivery

Abstract

Despite their conventional and widespread use, oral and intravenous routes of drug administration face several limitations. In particular, orally administered drugs undergo enzymatic degradation in the gastrointestinal tract and first-pass metabolism in the liver, which tend to decrease their bioavailability. Intravenous infusions of medications are invasive, painful and stressful for patients and carry the risk of infections, tissue damage and other adverse reactions. In order to account for these disadvantages, alternative routes of drug delivery, such as transdermal, nasal, oromucosal, ocular and others, have been considered. Moreover, drug formulations have been modified in order to improve their storage stability, solubility, absorption and safety. Recently, stimuli-responsive polymers have been shown to achieve controlled release and enhance the bioavailability of multiple drugs. In this review, we discuss the most up-to-date use of stimuli-responsive materials in order to optimize the delivery of medications that are unstable to pH or undergo primary metabolism via transdermal, nasal, oromucosal and ocular routes. Release kinetics, diffusion parameters and permeation rate of the drug via the mucosa or skin are discussed as well.

Keywords: mucoadhesive properties; nasal drug delivery; ocular drug delivery; oromucosal drug delivery; stimuli-responsive polymers; transdermal drug delivery.

Figure 1

Barriers to transdermal drug delivery and strategies to overcome them. Skin structure and organization represent major hurdles for effective transdermal drug delivery. The multilayered structure of the epidermis and small pore size provide a physical barrier for drug penetration. Furthermore, the highly lipophilic upper layer of the skin prevents the entrance of polar and charged molecules, while the hydrophilic inner layer stops the transfer of hydrophobic compounds. Active and passive techniques have been proposed to overcome the aforementioned barriers. Active strategies use electric, sound, light and mechanical energy to force the penetration of medications through the skin. Passive strategies, in turn, attempt to optimize the composition of drug formulations by adding nanoparticles, liposomes, dendrimers, polymers and other compounds.

Figure 2

Barriers to nasal and oromucosal drug delivery and strategies to overcome them. Nasal anatomy and physiology significantly limit the absorption of drugs delivered intranasally. The nasal mucosa has a thickness of 5–15 µm and is covered with multiple cilia and degradative enzymes. The ciliary beating and action of enzymes cause rapid clearance of nasally administered medications. Similarly, the oral cavity contains multiple obstacles for drug delivery via an oromucosal route, including a thick multilayered mucosal layer (thickness of 400–700 μm), continuous saliva production and degradative enzymes. In order to enhance the retention and absorption of drugs delivered via the two routes, cationic polymers, thiolated polymers, in situ gels and a variety of nanocarriers have been successfully tested.

Figure 3

Barriers to ocular drug delivery and strategies to overcome them. The complex structure of the eye reduces the efficiency of ocular drug delivery. Specifically, the tear film, multilayered cornea, anionic vitreous humor and blood–ocular barrier impede the penetration of medications administered via an ocular route. In situ gels, microneedles and nanocarriers have been shown to address the hurdles mentioned above and enhance the efficiency of ocular drug transfer. In situ gels provide an example of “smart” polymers, i.e., they can respond to a variety of stimuli such as change in pH, temperature, electroconductivity, etc.