Development of a thermostable oxytocin microneedle patch.

Oxytocin is a nonapeptide hormone used in labor to initiate uterine contractions and to prevent and treat postpartum hemorrhage. Oxytocin is currently administered by injection and requires refrigerated transport and storage, which limits access, especially during home birth in developing countries. Here, we propose a thermostable, simple-to-administer microneedle (MN) patch for rapid delivery of oxytocin suitable for use by healthcare workers with limited training, like traditional birth attendants. Oxytocin (10 IU, 16.8 µg) coated onto stainless steel MN arrays was released into skin within 1-5 min after manual insertion. Among tested excipients, polyacrylic acid was best at stabilizing oxytocin stored at 75% relative humidity, with no significant loss for up to 2 months at 40 °C. Under desiccated conditions, MNs coated with formulations containing trehalose in a mixture of citrate buffer and ethanol retained 75% oxytocin potency at 40 °C for 12 months; the commercial oxytocin product Pitocin® was reduced to 35% potency under these conditions. These findings support development of MN patches for oxytocin administration with improved ease of use, extended thermostability and simplified logistics to enable greater access to this life-saving medicine.

Plasmonic Paper Microneedle Patch for On-Patch Detection of Molecules in Dermal Interstitial Fluid.

Minimally invasive devices to detect molecules in dermal interstitial fluid (ISF) are desirable for point-of-care diagnostic and monitoring applications. In this study, we developed a microneedle (MN) patch that collects ISF for on-patch biomarker analysis by surface-enhanced Raman scattering (SERS). The micrometer-scale MNs create micropores in the skin surface, through which microliter quantities of ISF are collected onto plasmonic paper on the patch backing. The plasmonic paper was prepared by immobilizing poly(styrenesulfonate) (PSS) coated gold nanorods (AuNRs) on a thin strip of filter paper using plasmonic calligraphy. Negatively charged PSS was used to bind positively charged rhodamine 6G (R6G), which served as a model compound, and thereby localize R6G on AuNR surface. R6G bound on the AuNR surface was detected and quantified by acquiring SERS spectra from the plasmonic paper MN patch. This approach was used to measure pharmacokinetic profiles of R6G in ISF and serum from rats in vivo. This proof-of-concept study indicates that a plasmonic paper MN patch has the potential to enable on-patch measurement of molecules in ISF for research and future medical applications.

Monitoring drug pharmacokinetics and immunologic biomarkers in dermal interstitial fluid using a microneedle patch.

Minimally invasive point-of-care diagnostic devices are of great interest for rapid detection of biomarkers in diverse settings. Although blood is the most common source of biomarkers, interstitial fluid (ISF) is an alternate body fluid that does not clot or contain red blood cells that often complicate analysis. However, ISF is difficult to collect. In this study, we assessed the utility of a microneedle patch to sample microliter volumes of ISF in a simple and minimally invasive manner. We demonstrated the use of ISF collected in this way for therapeutic drug monitoring by showing similar vancomycin pharmacokinetic profiles in ISF and serum from rats. We also measured polio-specific neutralizing antibodies and anti-polio IgG in ISF similar to serum in rats immunized with polio vaccine. These studies demonstrate the potential utility of ISF collected by microneedle patch in therapeutic drug monitoring and immunodiagnostic applications.

Recruitment and Collection of Dermal Interstitial Fluid Using a Microneedle Patch.

Interstitial fluid (ISF) that surrounds cells in tissues of the body is a novel source of biomarker that complements conventional sources like blood, urine, and saliva. To overcome difficulties in harvesting ISF, a minimally invasive, rapid, simple-to-use, cost-effective method is developed to collect ISF from the skin involving a microneedle (MN) patch. By pressing 650 µm long MNs at an angle just below the skin surface, blood-free ISF flows through micropores to the skin surface and is absorbed into a thin strip of paper on the MN patch backing for subsequent analysis. An optimized method in rat skin in vivo is well tolerated and able to collect >2 µL of ISF within 1 min. Brief skin pretreatment with MNs followed by a 5 min delay dramatically increases subsequent ISF collection by a mechanism believed to involve increased skin hydration. ISF collection using an MN patch has the potential to simplify access to biomarkers in ISF for research and future medical diagnostic and monitoring applications.

Development of a thermostable microneedle patch for polio vaccination.

The aim of this study was to develop a dissolving microneedle (MN) patch for administration of inactivated polio vaccine (IPV) with improved thermal stability when compared with conventional liquid IPV. Excipient screening showed that a combination of maltodextrin and D-sorbitol in histidine buffer best preserved IPV activity during MN patch fabrication and storage. As determined by D-antigen ELISA, all three IPV serotypes maintained > 70% activity after 2 months and > 50% activity after 1-year storage at 5 °C or 25 °C with desiccant. Storage at 40 °C yielded > 40% activity after 2 months and > 20% activity after 1 year. In contrast, commercial liquid IPV types 1 and 2 lost essentially all activity within 1 month at 40 °C and IPV type 3 had < 40% activity. Residual moisture content in MN patches measured by thermogravimetric analysis was 1.2-6.5%, depending on storage conditions. Glass transition temperature measured by differential scanning calorimetry, structural changes measured by X-ray diffraction, and molecular interactions measured by Fourier transform infrared spectroscopy showed changes in MN matrix properties, but they did not correlate with IPV activity changes during storage. We conclude that appropriately formulated MN patches can exhibit thermostability that could enable distribution of IPV with less reliance on cold chain storage.