Dendrimers as ophthalmic vehicles

The majority of topically applied ocular drug-delivery systems are formulated either as solutions, ointments, or suspensions and suffer from various disadvantages such as quick elimination from the precorneal region, poor bioavailability, or failure to deliver the drug in a sustained fashion. Several research advances have been made in ocular drug delivery systems by using specialized delivery systems such as polymers, liposomes, or dendrimers to overcome some of these disadvantages. Ideal ocular drug-delivery systems should be nonirritating, sterile, isotonic, biocompatible, and biodegradable. The viscosity of the final product should be optimized so that the dosage form does not run out of the eye. Dendrimers provide solutions to some complex delivery problems for ocular drug delivery.

Some recent research efforts in dendrimers for ocular drug delivery include PAMAM dendrimers that were studied by Vandamme and Brobeck as ophthalmic vehicles for controlled delivery of pilocarpine and tropicamide to the eye (52). In the New Zealand albino rabbit model, the residence time of pilocarpine in the eye was increased by using dendrimers with carboxylic or hydroxyl surface groups. These surface-modified dendrimers were predicted to enhance pilocarpine bioavailability.

In another study, lipophilic amino-acid dendrimers were used to study the long-term effect of use of dendrimer for delivery of an antivascular endothelial growth factor (VEGF) oligonucleotide (ODN-1) to the eye of rats with the aim of inhibiting laser-induced choroidal neovascularization (CNV). It was shown that dendrimer containing ODN-1 showed significantly greater inhibition of CNV over a 4–6 month period compared with ODN-1 alone (54). Immunohistochemistry of the eye tissue after long-term treatment with dendrimers was conducted to determine if an immune response was generated after use of the dendrimer as a drug conjugate for treating eye diseases. It was determined that there was no significant increase in inflammatory response, proving that dendrimers could be used as a viable option for delivery of oligonucleotide to the eye for treating angiogenic eye diseases without concern of generating unwanted biological response.

Topical and transdermal delivery

Dendrimers have found recent applications in novel topical and transdermal delivery systems, providing benefits such as improved drug solubilization, controlled release, and drug-polymer conjugates (pro-drugs). The viscosity-generation-number property of a dendrimer solution allows for ease of handling of highly concentrated dendrimer formulations for these applications. Dendrimers have been shown to be useful as transdermal and topical drug delivery systems for nonsteroidal anti-inflammatory drugs (NSAIDs), antiviral, antimicrobial, anticancer, or antihypertensive drugs. PAMAM dendrimers have been studied as carrier transdermal systems for the model NSAIDs: ketoprofen and diflunisal (55). It was found that the PAMAM dendrimer-drug formulations showed increased transdermal drug delivery compared with formulations lacking dendrimers. In vivo studies in mice showed prolonged pharmacodynamic responses and 2.73-fold higher bioavailability over 24 h for certain dendrimer-containing drug solutions.

In another study, transport of indomethacin through intact skin was enhanced in vitro and in vivo (56). The bioavailability of indomethacin was increased by usingG4-PAMAM dendrimers with terminal amino groups. There have also been studies where dendrimers failed to show enhancement in drug transport through intact skin. It is well known that the molecular diffusion through intact skin is related to the molecular weight of the permeant molecule. Because of their high molecular weights, dendrimers generally have low diffusion coefficients. Diffusion through skin is more favorable for molecules that have solubility in lipids as well as in water. It could be possible to synthesize dendrimers with appropriate physical-chemical properties to facilitate drug transport through intact skin. Dendrimers with such favorable physicochemical properties could enhance transdermal transport of drugs by this mechanism. More research is warranted in this area to understand the structural-activity relationship of dendrimers in relation to skin transport.

In contrast to transdermal delivery, the use of dendrimers for topical delivery to the skin has shown to be more promising. Two different kinds of dendrimers were shown to have antiviral activity in vitro when the dendrimers were added to the cells before being challenged with the viruses. The dendrimers studied were either PAMAM or polylysine dendrimers. In contrast, dendrimers added to the cells after they were challenged with the virus showed no antiviral activity. The study was carried out in an in vitro assay to determine dendrimer activity against herpes simplex virus (HSV) types 1 and 2 (43). When tested in human foreskin fibroblast cells, both PAMAM and polylysine dendrimers showed activity against the virus. This study suggested that dendrimers could potentially be used as topical microbicides to be applied to the vaginal or rectal mucosa to protect against sexually transmitted diseases such as HIV or genital herpes. When tested against genital HSV infection in mice, two of the compounds showed significant reduction in infection rates when applied prior to intravaginal challenge.