1. K.J. Hansen, D. Duan, A. Determan, J. Gysbers, D. Brandwein, C. Moeckly, P. Johnson., G. Prochnow, T. Alston, K. Siebenaler 3M Drug Delivery Systems, 3M Center, St. Paul, MN 55144 A hand-insertable sMTS array (sMTS-hand) has been developed for the delivery of vaccines and drugs. The application/wear time associated with sMTS-hand is less than 30 seconds. For vaccine delivery, an integrated design of antigen coated onto the hand-inserted array was evaluated, and the resulting immune response was equivalent to that of IM injection. Building on 3M’s MTS foundation, several systems have been developed that utilize a polymeric microstructured array to deliver a variety of therapeutics, including local delivery of lidocane, intradermal delivery of vaccines and systemic delivery of peptides and proteins. MTS can provide fast and efficacious delivery of compounds that are not usually compatible with transdermal delivery. MTS delivery may be facilitated by use of an external applicator or require only hand application of a coated – or uncoated - microneedle array. When used in combination with a patch, the applicator-free MTS Press&Patch technology demonstrates delivery of peptides, proteins and small molecules not typically compatible with transdermal delivery. An sMTS array coated with a small amount of lidocane can provide almost immediate delivery of lidocane into the skin to enable medical procedures such as minor dermal surgery and needle placement; peak tissue levels are achieved much more rapidly than conventional lidocane delivery systems from creams or gels. These results are intriguing when considered next to existing techniques of topical or iontophoretic application of lidocane. The sMTS-hand technology utilizes a coated array to provide delivery of vaccines that may result in comparable, or improved immune response when considered versus a conventional IM syringe injection. The sMTS-hand system embodies the potential for simplicity and efficacious vaccine delivery and removes the risk and fear associated with conventional needle use. As with all MTS technologies, these capabilities are built around a manufacturable, polymeric microstructured array, designed and engineered using various 3M technologies and expertise. Polymeric microstructured microneedle arrays that can be hand inserted (sMTS-hand) have been developed and used to demonstrate efficacious delivery of vaccines and drugs intended for extended release. The application/wear time associated with sMTS-hand is less than 30 seconds, approximately the same time required for syringe administration. The microstructures are less than 1 mm in length and do not reach the nerve endings in the skin; less than 3 pounds of force is required for insertion. The array is well-tolerated in humans. The immune response generated upon delivery of protein antigen coated on the sMTS-hand is equivalent to that achieved when the same antigen is administered via a conventional IM route and, in some cases, may decrease the time required to achieve seroconversion. The microneedle array has also been used as a skin pre-treatment prior to application of transdermal patches containing proteins, peptides or water soluble small molecules (Press & Patch). With Press & Patch, the pre-treatment allows hydrophilic drugs to cross the stratum corneum and enter the systemic circulation. The transdermal patch maintains the channels during wear and provides a reservoir to achieve extended release of the API from the patch. Immunogenicity and pharmacokinetic studies were conducted in-vivo to demonstrate the potential for a hand-applied, polymeric, microstructured array to deliver molecules not typically compatible with transdermal delivery. The sMTS-hand and the Press & Patch systems offer a simple, non-threatening way to provide efficient delivery of vaccines and a means of providing an extended release for molecules typically confined to bolus delivery via syringe. A tolerability study in humans using sMTS-hand with no API showed excellent tolerability to the pre-treatment. Slight erythema was observed in a small number of subjects, but the results were transient and the skin quickly recovered. The 3M solid Microstructured Transdermal System (sMTS) consists of an application device which can place a drug-coated patch onto the skin for transdermal delivery of vaccines and drugs (photo at left). The patch contains a plastic microstructured array (diameter approximately 1cm), having up to 1300 microstructures (upper photo at right). Depending upon the desired depth of drug delivery, microstructure heights can range from 250 – 900 microns. A precision coating technology is used to place the drug on the upper half of the microstructures (lower photo at right). 3M Drug Delivery Systems Transdermal Delivery of Vaccines and Proteins using a Hand-Applied, Polymeric Microstructured Array (sMTS-hand and Press&Patch) Systemic Availability of Drugs Delivered via 3M solid Microstructured Transdermal System ( sMTS ) Extended Release Delivery of Peptides MTS Press & Patch Fast, Local Delivery of Lidocaine sMTS versus EMLA Abstract Lidocane hydrochlordie was coated onto the sMTS array (500µm tall, square pyramid structures). Using 3M’s POC applicator system, the array was applied to the ribs of an anesthetized swine (approx 30kg). The array was held in place on the swine for 1 minute and then removed. The skin was swabbed to remove drug on the surface and the application site was biopsied. The biopsy was cut to separate the dermal tissue from the underlying fat. The dermal tissue was extracted and analyzed quantitatively for lidocane. Results show that tissue levels of lidocane after 1 minute of exposure to an array coated with 78µg of lidocane are nearly double those measured in the tissue following a 60 minute application of EMLA cream. The EMLA site was prepared and analyzed in exactly the same manner as the site to which the sMTS array was applied. We estimate that approximately 0.5 grams of EMLA were applied. At 2.5% w/w lidocane, this corresponds to an application of approximately 12mg of lidocane, nearly 200 times more API than that applied via sMTS. These data indicate that an sMTS-lidocane product may provide an alternative to EMLA pretreatment in patients that require local anesthesia prior to IV placement, injection or minor dermal surgeries. Acknowledgments The authors wish to thank Ken Brown, Ryan Simmers, Stan Rendon, Kevin Puckett, David Wirtanen, Lester Harrison, Kraig Kroells, Ron Krienke, Jim Christensen, Pat Young, Joann Oesterich, Chris Webb, Mary Hopp and Tonya Grunwald A comparison of immune response for model antigen (8µg- ovalbumin) delivered to hairless guinea pigs by the sMTS integrated device, sMTS-hand and IM injection. Blood samples were drawn at 3 weeks post-prime and 3 weeks post- boost, and then tested for antigen-specific antibody. Immunogenicity of Antigens sMTS and sMTS-hand vs IM Injection Conclusions Coated microstructures, 8µg (top) and 25 µg (bottom) of antigen per array MTS hMTS: an integrated application, reservoir and infusion device that provides rapid delivery of high volume liquid formulations of small molecules, and proteins, including antibodies sMTS: efficient delivery of potent proteins, peptides and vaccines with a fully integrated or reusable applicator Press&Patch: a 2-step system for delivery of small molecule salts and proteins, offering local delivery or sustained release sMTS-device: a skin pre-treatment device to penetrate the stratum corneum sMTS-hand: a hand-applied system for simple, fast, efficacious delivery of vaccines Parathyroid hormone, 1-34 (PTH) was coated onto a patch that was secured to an occlusive, adhesive patch. The coated patch was dried and stored with desiccant until use. Prior to patch application, the hams of swine were clipped, shaved and washed with soap and water. MTS arrays with 700µm tall square pyramid structures were applied by hand, a single time, with approximately five pounds of force. The PTH patches were applied immediately after MTS pre- treatment. In the untreated group, PTH patches were applied to uncompromised skin. Patches were removed after 6 hours. Blood samples were collected prior to patch application and at designated time point following application. PTH levels were quantitatively assessed using an ELISA assay. Results show that blood levels of PTH in pigs pre- treated with MTS greatly exceed those in pigs who were not pre-treated with MTS.