1. John K. Simons, Kris J. Hansen, Tim A. Peterson As the results show, delivery of naloxone via a sMTS patch is comparable to a SQ injection with regard to bioavailability and PK profile. Relative to traditional passive transdermal technologies, 3M’s hMTS and sMTS technologies can provide rapid transdermal delivery of liquid (1000 µL) or solid formulations. Intradermal delivery of a small molecular salt (naloxone), not compatible with traditional transdermal delivery, was achieved with both technologies with measured PK profiles similar to those obtained with SQ injections. The hollow, polycarbonate MSs penetrate the stratum corneum and provide infusion up to 1 mL in less than 20 minutes, at approximately 250µm beneath the surface of the skin. The PK profile resulting from the naloxone infusion can be affected by the infusion profile. Coated sMTS arrays demonstrates fast (<1 minute) and efficient transdermal delivery of solid, dried API formulations. ACKNOWLEDGEMENTS The authors acknowledge the contributions of A. Determan, G. Prochnow, H. Lewin, N. Johnson, S. Burton, R. Simmers, K. Brown, T. Fenn, C. Moeckly, P. Sackett, D. Brandwein, J. Gysbers, K. Puckett, J. Oesterich, K. Siebenaler, L. Robinson, R. Krienke, D. Heidebrink, J. Moseman, P. Johnson and B. Haldin REFERENCES 1. S.R. Rosenthal, Multiple Injector Puncture Device. US Patent 3,675,766 (1972). 2. J.B. McConnell, H.E. Zangenberg, and M.S. Cooper, Intracutaneous Injection Device. US Patent 3,034,507 (1962). 3. M.R. Prausnitz, Microneedles for Transdermal Drug Delivery. Advanced Drug Delivery Reviews. 56: 581-587 (2004). 4. S. Kaushik, D.D. Denson, D.V. McAllister, S. Smitra, M.G. Allen, M.R. Prasunitz. Lack of Pain Associated with Microfabricated Microneedles. Anesthesia and Analgesia. 92:502-504 (2001). 3M Drug Delivery Systems has designed proof of concept (POC) devices that utilize either hollow (hMTS) or solid (sMTS) microsturctures (MSs) for intradermal delivery of molecules not typically compatible with traditional transdermal delivery technologies. T he use of MS devices has long been proposed as a minimally invasive method for drug delivery. (1-3) MSs, usually less than 2 mm in length, can penetrate the stratum corneum with minimal patient discomfort (4), providing a delivery route for drugs typically available only via injection. In this work, 3M characterizes the in vivo performance of the hMTS and sMTS technologies to deliver naloxone, a small, molecular salt, systemically. To fully characterize the performance of the hMTS device, three sets of experiments were conducted: depth of penetration (DOP) studies, infusion of placebo formulations, and infusion of a naloxone solution. The DOP studies were conducted to determine the average penetration depth of the MSs into the skin. The infusion studies with placebo formulations were conducted to evaluate site reactions and visualize the delivery of the formulation. Finally, the naloxone infusion was conducted to establish the pharmacokinetic (PK) profile of a molecule delivered intradermally via the hMTS device. To characterize the performance of the sMTS device, DOP studies, release studies of coated naloxone formulations from the sMTS array, and systemic delivery studies were all completed. DOP – The results of the hMTS, DOP studies are reported in table below. On average the MS arrays penetrated more deeply in pigs as compared to HGPs. The photograph shown below (left side) illustrates how the HGP skin looked following the application of the hMTS patch coated with rhodamin B. Marks from all 18 MSs can be seen. Infusion of Placebo Formulations - Several infusions of up to 1mL were conducted using a sterile 5% dextrose or 0.001% methylene blue solution. Once the formulation had been delivered, the device was allowed to stay in place for up to 10 minutes. The photograph shown below (right side) shows the results of an 800µL intradermal infusion of a 0.001% methylene blue formulation into pig. The skin was dry to the touch after patch removal; the deep blue of the infused formulation provides a visual assessment of the treatment. Each blue spot on the skin corresponds to one of the eighteen hollow microstructures on the array. With domestic pigs, a red, array-sized blotch was observed immediately after patch removal, but faded to be non-perceptible within 5 minutes. A small wheal was also observed on the pig skin immediately following patch removal but was resolved visually and to the touch within 40 minutes. Naloxone Infusion - Four different animals were used for the study comparing the PK profiles generated after hMTS infusion, subcutaneous (SQ) injection and IV injection. The pigs weighed between 10-22 kg at the time of dosing and ranged in age from 1.5-3 months. Similar volumes of the same naloxone formulation were administered to three pigs to directly compare the PK profiles associated with hMTS, SQ, and IV administration. In the fourth case, 200 µL of formulation were delivered via hMTS using a faster infusion profile to evaluate the effect of infusion rate on the PK profile. Naloxone levels detected in the sera were normalized to approximate the blood volume of the dosed animal based on a conversion of 62mL of blood per kg of pig. All results are shown at the top of the next column. The results indicate comparable delivery and bioavailability of naloxone via hMTS infusion and SQ injection. As expected, both T max and C max are affected by the hMTS infusion rate. In the case of the 200 µL hMTS infusion, T max is comparable to the SC injection. In the case of the 435 µL hMTS infusion (slower infusion rate), Tmax is delayed by ~25 minutes. DOP – When applied to pigs, the average DOP for the sMTS arrays was 109 ± 9 µm when applied to the ham and 93 ± 8 µm when applied to the abdomen. Naloxone Time Release - The graph below shows the results of the time release study where the array content values are plotted against the time the array patches were worn. The initial (T=0 min) array content of 15.6 µg/array drops to ~1.6 µg/array within 30 seconds. The results confirm that very fast, efficient delivery is possible with coated MSs. Although this data set does not demonstrate that the dose was actually delivered versus being simply wiped off on top of the skin, the systemic delivery study (data discussed below) clearly demonstrates that the formulation is being delivered efficiently. Systemic Delivery - The results of the naloxone systemic delivery studies are shown in the graph at the top of the next column. The results are plotted with those obtained with a SQ control. To ensure adequate sensitivity of the assay, the arrays were coated with ~68 µg/array and four arrays were applied per animal. Higher loadings can be achieved but are dependent on the physical properties of the API. As an example 325 µg/array of ovalbumin have been successfully coated. For direct comparison, 250 µg of naloxone were delivered subcutaneously. 3M Drug Delivery Systems Drug Delivery using 3M’s Hollow/Solid Microstructured Transdermal Systems Results and Discussion - hMTS The DOP studies were conducted on both hairless guinea pigs (HPGs) and domestic pigs. The DOP was determined using a water soluble dye (rhodamine B) coated on the MSs which were assessed microscopically both before and after application. The micrograph to the right shows the array after application. Prior to application the MSs are uni- formly coated along their full length with rhodamine B. The hMTS array consisted of a MS disk (18 MSs/array) connected to a commercial syringe pump through which up to 1mL of liquid formulation was administered intradermally. The hollow MSs were applied to the skin to a depth sufficient to penetrate the stratum corneum and the epidermis and create direct access to the dermis. With domestic pigs, the hMTS device was used to deliver up to 1000 µL of formulation in about 18 minutes. Blood samples were drawn prior to infusion and at specified time points during and post infusion from the ear vein of the pigs and analyzed by LC/MS. The sMTS arrays (~1200 MSs/array, 250 µm) were coated with naloxone form- ulation. For the time release studies (~16 µg/array), the naloxone contents of the MS arrays were determined before and after specified wear times on the HGPs (T=0, 0.5, 1. 2, 3, and 10 minutes). The amount of naloxone removed from the array provided an indirect measure of how much drug had been delivered. For the systemic delivery studies on pigs (270 µg/four arrays), blood samples were drawn before and at specified times following patch application. The higher dose/ mulitiple arrays were used to ensure an adequate concentration of naloxone in the blood to be accurately quantified. Arrays were also analyzed post application to determine an upper limit of how much naloxone was actually dosed (224 µg ). Experimental Methods Results and Discussion - sMTS Conclusions Introduction DOP in HGPsDOP in Pigs Number of MSs6 arraysx18 MSs/array= 108 MSs 6 arraysx18MSs/array= 108 MSs Average DOP (µm)210250 Standard Deviation (µm)3040