Transdermal Drug Delivery

Kim et al.

Microneedles are an effective compromise between topical application and injection.

Drug delivery into the skin for local or systemic effects is extremely difficult due to the highly effective barrier properties of skin’s outer layer, the stratum corneum. The human stratum corneum is only 10-15 μm thick, but precludes absorption of most drugs at therapeutic levels. The approximately 20 drugs with approval from the Food and Drug Administration (FDA) as transdermal patches all have molecular weights below 400 Da, are relatively lipophilic and require low doses. Because the barrier layer of skin is just microns thick, microneedles have been developed to cross the stratum corneum without going deeply into the skin, thereby avoiding pain and bleeding. By by-passing the stratum corneum barrier, microneedles have been shown to dramatically increase the number of compounds that can be administered across the skin, including low molecular weight drugs, biotherapeutics, vaccines and other materials.

Interestingly, you can buy several types of dermaroller (some say "FDA listed") from amazon (or a similar microneedle stamp) for under $30. They are sold as cosmetic devices, e.g., for the treatment of acne scars. In general, skin damage (including skin tattooing) seems to help with evoking an immune response.

While the above studies employed microneedles fabricated as research prototypes, the Dermaroller® and other similar FDA-registered devices are sold commercially for cosmetic purposes and have also been investigated a transdermal drug delivery tool by pretreating the skin with microneedle punctures generated by a cylindrical roller of metal microneedles. Microneedle rollers have also been applied to enhance optical skin clearing by glycerol and increased skin permeability to chondroitin sulfate.

Prausnitz and Langer

This paper summarizes several ways to achieve transdermal delivery.

The third generation of transdermal delivery systems is poised to make significant impact on drug delivery because it targets its effects to the stratum corneum. This targeting enables stronger disruption of the stratum corneum barrier, and thereby more effective transdermal delivery, while still protecting deeper tissues. In this way, novel chemical enhancers, electroporation, cavitational ultrasound and more recently microneedles, thermal ablation and microdermabrasion (Arora, Prausnitz and Mitragotri31) have been shown to deliver macromolecules, including therapeutic proteins and vaccines, across the skin in human clinical trials.

One delivery method that is missing from the list, since it's not strictly transdermal, is sublingual delivery (see thin film drug delivery, which can also be buccal). For example, you can buy TheraFlu as "thin strips" that dissolve in your mouth. Listerine breath strips apparently use the same polymer as many thin film drugs.

Sublingual delivery is more like injection than ingestion, since it delivers drugs into the bloodstream without first passing through the liver (first-pass metabolism). I don't know if there are limitations on the size of molecule that can be delivered this way, though there are vaccines in development.

Wang et al.

Wang et al., linked from Prausnitz, is an example of using microneedles to inject an influenza vaccine. The authors of the paper made their own microneedle array using an infrared laser!

After electropolishing, the thickness of the microneedles reduced to 50 μm, and each microneedle in the array measured 700 μm in length and 160 μm in width at the base, tapering to a sharp tip.

Dermarollers actually have similar dimensions to the Wang et al. microneedle array, though definitely thicker (according to the product page, one dermaroller's needles are 0.5mm to 1.5mm in length and 0.2mm thick)

Bachy et al.

Bachy et al. also have an interesting paper on creating microneedle arrays for the delivery of a vaccine. The microneedle array is made of Na-CMC-sucrose (Na-CMC is mechanically strong and sucrose is a protein stabilizer). The needles dissolve after 5 minutes in contact with the mouse's skin. Apparently, the desiccated virus did not lose immunogenicity. This is pretty amazing...