KJ Hansen, JK Simons, TA Peterson 3M Drug Delivery Systems Transdermal delivery of non-traditional APIs for systemic delivery using solid microstructures KJ Hansen, JK Simons, TA Peterson Introduction Systemic Delivery of Salts and Macromolecules Release Profile: sMTS Delivery of 60kDa Protein Different Lengths and Densities to Optimize Delivery A variety of APIs, from salts to proteins, were coated on sMTS arrays and delivered to swine. PK profiles, generally indicate a Cmax comparable to or earlier than that observed following subcutaneous injection of the same compound. Purpose. A small diameter polycarbonate array containing ~1200 solid microstructures has been developed to enable rapid transdermal delivery of several non-traditional transdermal APIs. The API formulations were coated on the microstructures prior to insertion into the skin with a specially designed applicator. The effectiveness of the solid microstructured transdermal system (sMTS) has been tested in-vivo, demonstrating efficient systemic delivery Methods. The sMTS arrays were coated with concentrated solutions of the targeted APIs, such as naloxone hydrochloride, dried, and packaged. The coated sMTS arrays, configured in an adhesive patch, were inserted into domestic swine and allowed to remain in contact with the skin for several minutes. Blood samples were collected and assayed via ELISA or HPLC/MS. Results were compared to levels of the APIs detected in blood samples collected after traditional subcutaneous or IV injection of the same amount of API. Indirect delivery studies were also conducted where the coated sMTS arrays were applied to hairless guinea pigs for varying amounts of time to evaluate the release characteristics of the coated formulations from the array patches. Results. Tested in domestic swine, the pharmacokinetic profiles resulting from sMTS delivery of naloxone hydrochloride were comparable, with respect to Cmax and bioavailability, to those measured following subcutaneous injections. In the formulation release studies, up to 150µg of a protein-based API have been coated on the arrays. Depending on the formulation, 60-70% delivery was typically achieved in less than 5 minutes. The short wear time associated with the sMTS patch, along with the relative bioavailability achieved using sMTS, far exceed those achievable using traditional (patch) transdermal technologies. Conclusions. The sMTS has been used to demonstrate systemic delivery of naloxone hydrochloride with pharmacokinetic characteristics similar to those achieved using subcutaneous injection. These results along with the formulation release results demonstrate the potential utility of sMTS to transdermally deliver a range of small molecules and protein formulations that typically require injection. The sMTS technology is compatible with a wide variety of water-soluble or partially water-soluble APIs. These characteristics provide faster, more complete, and more versatile delivery than can be achieved using existing passive (patch) transdermal technologies. Approximately 18µg of ovalbumin was coated onto sMTS arrays and applied to swine for a pre-determined time between 30 seconds and ten minutes. After removal, arrays were analyzed for residual ovalbumin and compared to the initial loading. Coating and Release sMTS arrays are prepared using one of two coating processes. API is coated such that 90% of the active ingredient is placed on the top half of the microstructures. Depending on formulation characteristics and coating conditions, complete release (>75% of coated API) is achieved in less than 10 minutes and in some cases in as little as 30 seconds. Target loading is typically 1-500µg/array. The coating technologies have proven versatile and APIs over a large range of molecular weights and solubilities have been successfully coated onto and released from the microstructures. For some APIs, fine tuning of the release profile or PK profile may be accommodated using arrays of varying densities with microstructures ranging from 200-700µm. sMTS for systemic and vaccine delivery sMTS - Protein Vaccine Immunogenicity Data, 4 Weeks post Dose sMTS- Protein Vaccine Immunogenicity Data, 8 Weeks post Dose A model protein vaccine, ovalbumin, was coated on sMTS arrays with and without one of two 3M vaccine adjuvants and delivered to HGPs. Identical formulations in this dose titration study were also administered via IM injection. Blood samples were collected 4 weeks post dose and 8 weeks post dose (4 weeks post boost) and analyzed via ELISA. Quantitative, comparative results of anti-OVA titer at 4 weeks and 8 weeks post –dose are presented. 3M’s sMTS is a versatile systemic delivery device for potent proteins and salts. Salts or macromolecules are coated on to arrays and delivered intradermally when the microstructures penetrate the skin and provide direct transfer through the skin to the intradermal tissue. Transport of the API off the microstructure and into the systemic circulation is fast and efficient. PK profiles resulting from sMTS delivery of a variety of molecules show comparable performance to administration of the API by subcutaneous injection. 3M’s sMTS is also an optimal platform for the delivery of vaccines, alone or in concert with 3M vaccine adjuvants that are compatible with intradermal delivery. Delivery of the antigen and adjuvant directly to the specialized dermal dendritic cells provide significant potential for improved antibody response even while decreasing the usage of antigen. 3M’s sMTS is painless and greatly reduces the potential for accidental needle stick injuries. Because the system cannot be reloaded, the risk of disease transmission resulting from “shared needles” is also virtually eliminated. Under extreme force, 3M’s sMTS polymeric arrays bend, but not break, all but eliminating the risk of structure loss in the application site. Release and Stability for Adjuvant and Antigen Dosed formulations and coated sMTS arrays were packaged dry and stored for 10 weeks at 4C. Results of this study indicate good stability of the antigen, and 3M Adjuvant #1 (no stability data were collected for Adjuvant #2). A study characterizing protein stability at 25C/60%RH will be conducted.