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 vacc ines and drugs. The application/wear time associated with sMTS-hand is less than 30 seconds. For vacc ine 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 uti lize a polymeric microstructured array to deliver a variety of therapeutics, inc luding local delivery of l idocane, intradermal delivery of vaccines and systemic delivery of peptides and proteins. MTS can prov ide fast and efficac ious delivery of compounds that are not usually compatible with transdermal delivery.

MTS delivery may be fac il itated 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 l idocane can provide almost immediate delivery of lidocane into the sk in to enable medical procedures such as minor dermal surgery and needle placement; peak tissue levels are achieved much more rapidly than conventional l idocane delivery systems from creams or gels . These results are intriguing when considered next to ex isting techniques of topical or iontophoretic application of l idocane. The sMTS-hand technology uti l izes a coated array to prov ide 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 s implicity and efficacious vacc ine delivery and removes the risk and fear associated with conventional needle use.

As with all MTS technologies, these capabil i ties are built around a manufacturable, polymeric microstructured array, des igned and engineered us ing various 3M technologies and expertise.

Polymeric microstructured microneedle arrays that can be hand inserted (sMTS-hand) have been developed and used to demonstrate efficac ious delivery of vacc ines and drugs intended for extended release. The application/wear time associated with sMTS-hand is less than 30 seconds, approx imately 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 sk in; 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 seroconvers ion.

The microneedle array has also been used as a sk in 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 hydrophil ic drugs to cross the s tratum 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.

Immunogenic ity and pharmacokinetic s tudies were conducted in-v ivo 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 s imple, non-threatening way to provide efficient delivery of vaccines and a means of providing an extended release for molecules typically confined to bolus delivery v ia syringe.

A tolerabil i ty s tudy in humans us ing sMTS-hand with no API showed excellent tolerabil i ty to the pre-treatment. Slight ery thema was observed in a small number of subjects , but the results were trans ient 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 EMLAAbstract

Lidocane hydrochlordie was coated onto the sMTS array (500µm tall, square pyramid s tructures). Us ing 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 sk in was swabbed to remove drug on the surface and the application s ite was biops ied. The biopsy was cut to separate the dermal tissue from the underlying fat. The dermal tissue was extracted and analyzed quantitatively for l idocane.

Results show that tissue levels of l idocane 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 s ite was prepared and analyzed in exactly the same manner as the s ite to which the sMTS array was applied. We estimate that approx imately 0.5 grams of EMLA were applied. At 2.5% w/w l idocane, this corresponds to an application of approx imately 12mg of l idocane, nearly 200 times more API than that applied v ia sMTS.

These data indicate that an sMTS-lidocane product may prov ide an alternative to EMLA pretreatment in patients that require local anesthes ia prior to IV placement, injection or minor dermal surgeries.

AcknowledgmentsThe authors wish to thank Ken Brown, Ryan Simmers, Stan Rendon, Kevin Puckett, David Wirtanen, Lester Harrison, Kraig Kroells, Ron Krienke, Jim Chris tensen, 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 dev ice, 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 infus ion device that prov ides rapid

delivery of high volume l iquid formulations of small molecules, and proteins, inc luding

antibodies

sMTS: effic ient deliveryof potent proteins, peptides and vaccines with

a ful ly 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 sk in pre-treatment dev ice to penetrate the s tratum corneum

sMTS-hand: a hand-applied system for s imple, fast, efficac ious

delivery of vaccines

Parathyroid hormone, 1-34 (PTH) was coated onto a patch that was secured to an occ lus ive, adhesive patch. The coated patch was dried and stored with des iccant unti l use.

Prior to patch application, the hams of swine were c lipped, shaved and washed with soap and water. MTS arrays with 700µm tall square pyramid s tructures were applied by hand, a s ingle time, with approx imately five pounds of force. The PTH patches were applied immediately after MTS pre-treatment. In the untreated group, PTH patches were applied to uncompromised sk in. Patches were removed after 6 hours.

Blood samples were collected prior to patch application and at des ignated time point following application. PTH levels were quantitatively assessed us ing 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.