Transdermal Drug/Vaccine Delivery Using Microneedles and Microdermabrasion

Skin provides an attractive route of drug/vaccine delivery due to ease of accessibility, elimination of the liver's first pass effect and large surface area. However, to make use of this delivery route, a major transport barrier called stratum corneum (skin's outermost layer) must be overcome. A number of methods like chemical enhancers, ultrasound, electric fields and lasers have been explored to expand the number of drugs that can be delivered via the skin. Despite some success, such enhancement methods have made little impact on clinical drug delivery to date.

To overcome the resistance barrier of stratum corneum in a more consistent and versatile way, we are using two different strategies ? to ?bypass' and to ?remove' the resistance barrier. In the first strategy of ?bypassing' the resistance barrier, microneedles coated with drug/vaccine are inserted into the skin and the drug dissolves from the coating and is deposited beneath the stratum corneum. In the second strategy of ?removing' the stratum corneum, microdermabrasion is used. In the microdermabrasion process, micron-sized, inert particles are projected at the skin with high velocity under vacuum in a manner similar to sand blasting. The small particles ablate the cells of the stratum corneum, which are then sucked away under vacuum. With the removal of stratum corneum, opportunity then arises to deliver any molecule through the skin.

The development of these two methods has led to a number of collaborations with different research groups both within and outside the
US. A brief synopsis of my PhD thesis work and these additional collaborations is given below.

PhD thesis research:

Thesis title: Microneedle-based vaccine delivery: needle design and biological effects.

Results: A laser cutting and electropolishing-based fabrication process has been developed to make stainless steel microneedles. A pain study conducted on human subjects showed that microneedles are almost painless as compared to hypodermic needles, and an increase in microneedle length increases pain.

    A coating process has been developed that can coat microneedle arrays with good spatial control. As a model drug, riboflavin was coated onto microneedles at up to 2.2 ìg per microneedle. Microneedle insertion and rapid coating dissolution were demonstrated in pig cadaver skin. These data suggest that microneedles offer an attractive opportunity to deliver drugs and vaccines requiring sub-milligram doses.

Collaborative research:

1.      Project aim: Delivery of naltrexone derivative to treat alcohol and narcotic dependence using microneedles.

Collaborative researcher: Dr. Audra Stinchcomb,
College of
Pharmacy,
University of
Kentucky

Results: Microneedle treatment of in vitro hairless guinea pig skin showed enhancement of flux both for water soluble form and the base form of naltrexone. Permeability enhancement of the water soluble form was sufficient for delivery of naltrexone at therapeutic rates.

 2.      Project aim: Use microneedles to deliver chemicals into the skin that change skin's optical properties for imaging.

Collaborative researcher: Dr. A.J. Welch, Biomedical Engineering, University of Texas (
Austin).

Results: Microneedle treatment of in vitro hamster skin increased optical clarity by a factor of 5 as measured using optical coherence tomography.

3.      Project aim:  Deliver a novel hepatitis-C DNA vaccine through the skin using coated microneedles.

Collaborative researcher: Dr. Matti Sallberg, Division of Clinical Virology, Karolinska Institute,
Sweden

Results: Preliminary experiments have been conducted to coat microneedles with a plasmid expressing b-galactosidase with a dose of 1.6 mg on 5 microneedles. Further immunization experiments using hepatitis-C DNA vaccine coated microneedles will be conducted in
Sweden.

4.      Project aim: Delivery of novel AIDS vaccine to human subjects and non-human primates using microdermabrasion.

Collaborative researchers: Drs. Mark Feinberg and Silvija Staprans, Vaccine Research Center, Emory University, and Dr. Fran Priddy, The Hope Clinic, Emory University.

Results: A microdermabrasion process has been developed that partially removes stratum corneum both in humans and in monkeys (rhesus macaques). Skin electrical resistance was developed as a non-invasive predictor of stratum corneum removal. Greater than 80% drop in skin's electrical resistance was observed following microdermabrasion. Skin resistance values before microdermabrasion showed greater variability than following microdermabrasion. Further optimization of microdermabrasion parameters will be done to reach a point where complete stratum corneum is removed without damaging the underlying layers, and to find the skin resistance threshold value that corresponds to complete stratum corneum removal.