(543e) Coated Microneedles for Transdermal Drug Delivery

INTRODUCTION Transdermal drug delivery has the advantage of eliminating the first pass effect of the liver and providing a large and easily accessible surface area for drug administration. However, to date transdermal drug delivery for systemic effects is limited to very few drugs, all of which have low molecular weights and high to moderate lipophilicity. Skin's topmost layer called the stratum corneum offers most resistance to transport of drugs across the skin. Different chemical and physical methods like chemical enhancers, ultrasound, electric energy, pressure driven flow, and lasers have been tried to disrupt the mass transfer resistance barrier of stratum corneum to deliver larger molecular weight and/or hydrophilic compounds. However, these methods have found limited clinical success.

To increase the repertoire of drugs deliverable via the skin, and to achieve it in a painless manner, microneedles were developed. Microneedles are micron-dimensioned needles that can pierce the skin in a minimally invasive manner without causing pain. Upon piercing skin they create micro-conduits across stratum corneum and provide a direct route for transport of drugs and vaccines into the skin. Microneedles can be used in a variety of modes for achieving this delivery. One of the modes is to coat the drug onto solid microneedles and insert them into the skin where the coated drug then dissolves upon contact with water present in the skin tissue.

However, coating drug onto solid microneedles in a controlled manner is extremely challenging. The main characteristics that the microneedle coating process should have are 1) uniformity of coating over the microneedle and across microneedles of an array, 2) spatial control over the length being coated, and 3) localizing the drug coating only to the microneedles and not their supporting surface for minimizing drug loss and standardizing the delivery dose. Of the different coating processes available, the dip coating process is most suitable for achieving these coating characteristics. But, at the small sub-millimeter length scale of microneedles the surface tension of the coating liquid, capillary forces and viscous forces become dominant. This makes the coating process difficult to control, especially to prevent coating of the microneedle supporting surface.

In this study we sought to address these challenges by developing a dip coating method and to understand the factors affecting mass of drug coated onto microneedles.

EXPERIMENTAL METHODS Single microneedles or arrays of stainless steel microneedles with 700 µm length, 180 µm width and 50 µm thickness were fabricated by first laser cutting a stainless steel sheet using an infrared laser and then electropolishing it in a solution containing water, phosphoric acid and glycerin in a ratio of 1:3:6 (v/v) at 70˚C. Next, drugs were coated onto single microneedles or arrays of microneedles using a novel dip coating device designed and fabricated in the laboratory. The device was designed to prevent the coating solution from coating the microneedle supporting surface. This was achieved by physically preventing access of the coating solution to the other surface of the microneedle array. To achieve a uniform coating on microneedles, the coating solution viscosity, and surface tension were controlled by adding a viscosity enhancer (carboxymethyl cellulose) and a surfactant (poloxamer 188) to the formulation.

To characterize the coating process, calcein, vitamin-B, bovine serum albumin, luciferase DNA plasmid, modified vaccinia virus, and microparticles were used as representative molecules for dip coating the microneedles. Fluorescent imaging or brightfield imaging was performed to visually examine the uniformity of microneedle coatings.To quantify the amount of drug coated on microneedles, vitamin-B was used as a model drug. Vitamin-B concentration in the coating solution, number of dips, and number of microneedles in the array were used to study the amount of drug that can be coated on microneedles. The amount of vitamin-B in the coatings was determined by dissolving the vitamin-B containing coatings off the microneedles and measuring vitamin-B concentration using fluorescence spectroscopy.

In vitro characterization of coated microneedle was done using porcine or human skin. Release kinetics of coatings was examined using an aqueous solution. Post insertion histological examination of porcine skin was also done to assess the success of delivery from coated microneedles.

RESULTS AND DISCUSSION Sharp and clean edged microneedles of different geometries were fabricated using the laser cutting and electropolishing method. The fabrication process was found to be extremely versatile and was used to make microneedles with intricate designs that could potentially incorporate different functionalities into microneedles like improved retention in skin.

Single microneedles, linear rows of 5 microneedles, and arrays with grids of 50 microneedles were successfully dip coated with the target molecule with good uniform coatings, spatial control and without contaminating the microneedle supporting surfaces. The target molecules that were uniformly dip coated onto the microneedles were calcein, vitamin-B, bovine serum albumin, luciferase DNA plasmid, modified vaccinia virus, and microparticles. Microparticles with diameter as large as 20 microns were successfully coated onto microneedles. Therefore, the coating device and formulation were very versatile in their ability to coat a large variety of molecules onto microneedles.

The mass of vitamin-B coated onto microneedles was found to increase with vitamin-B concentration in the coating solution, number of dips, and number of microneedles in the array. A high drug loading of 2.2 µg per microneedle was achieved. This suggests that drug up to 1 mg could be delivered into the skin using microneedle arrays containing hundreds of microneedles. Therefore, vaccines and drugs with sub-milligram doses are ideal candidates for coated microneedle based delivery. The release kinetics of the coatings in aqueous solution or skin in vitro was found to be 20 seconds, indicating that the coated microneedles can be used for fast delivery of drugs.

Imaging the delivery profile of drug from coated microneedles into porcine or human skin was done using histology. From the histological sections it was found that the drug coated onto microneedles was delivered into the skin without wiping off on the skin surface during insertion. Barium sulfate particles (<2 µm) and latex beads (10 µm diameter) were also found to have been delivered into the skin. However, the majority of the 20 µm diameter beads were wiped off on the skin surface during microneedle insertion. To achieve delivery of such large beads, the microneedle surface was modified to include through holes which we call ?pockets', that acted as protective cavities for beads during insertion of microneedles. The ability to deliver particles is relevant to the delivery of microparticle-based formulations into the skin either for controlled delivery or for vaccination or for delivery of water insoluble therapeutics.

CONCLUSION In conclusion, stainless steel microneedles were fabricated and dip coated with different water-soluble molecules with uniformity in coating, spatial control and preventing coating of surfaces other than the microneedles. A high drug loading of 2.2 µg of vitamin-B per microneedle was obtained using the dip coating method developed. Histological examination confirmed insertion of microneedles and delivery of coated drugs. Thus, coated microneedles can be used to deliver drugs to the skin requiring sub-milligram doses, such as vaccines and protein therapeutics.

ACKNOWLEDGEMENTS This work was supported in part by the National Institutes of Health and took place in the Center for Drug Design, Development and Delivery and the Microelectronics Research Center at Georgia Tech.