Intradermal delivery of vaccine nanoparticles using hollow microneedle array generates enhanced and balanced immune response.

Hollow microneedles can help overcome the skin permeation barrier imposed by the stratum corneum and facilitate transcutaneous delivery of nanoparticle delivery systems. In the present study, we investigated the use of the hollow microneedle array for intradermal delivery of polymeric nanoparticles (NPs) in rats. Compared to intravenous and subcutaneous routes of administration, intradermal delivery of polymeric NPs via a hollow microneedle array resulted in a unique pharmacokinetic profile, characterized by an early burst transit through the draining lymph nodes and a relatively limited overall systemic exposure. Based on high local lymphatic concentrations achieved, we investigated the use of this modality for vaccine delivery. A model antigen ovalbumin (OVA) and TLR agonists imiquimod and monophosphoryl Lipid A encapsulated in poly(d,l-lactide-co-glycolide) (PLGA) NPs were used as the vaccine formulation. Compared to soluble OVA-based vaccine, OVA loaded NPs demonstrated faster antibody affinity maturation kinetics. Moreover, antigen loaded NPs delivered via a hollow microneedle array elicited a significantly higher IgG2a antibody response and higher number of interferon (IFN)-γ secreting lymphocytes, both markers of Th1 response, in comparison to antigen loaded NPs delivered by intramuscular injection and soluble antigen delivered through hollow microneedle array. Overall, our results show that hollow microneedle mediated intradermal delivery of polymeric NPs is a promising approach to improve the effectiveness of vaccine formulations.

Enhanced Stability of Inactivated Influenza Vaccine Encapsulated in Dissolving Microneedle Patches.

PURPOSE: This study tested the hypothesis that encapsulation of influenza vaccine in microneedle patches increases vaccine stability during storage at elevated temperature. METHODS: Whole inactivated influenza virus vaccine (A/Puerto Rico/8/34) was formulated into dissolving microneedle patches and vaccine stability was evaluated by in vitro and in vivo assays of antigenicity and immunogenicity after storage for up to 3 months at 4, 25, 37 and 45°C. RESULTS: While liquid vaccine completely lost potency as determined by hemagglutination (HA) activity within 1-2 weeks outside of refrigeration, vaccine in microneedle patches lost 40-50% HA activity during or shortly after fabrication, but then had no significant additional loss of activity over 3 months of storage, independent of temperature. This level of stability required reduced humidity by packaging with desiccant, but was not affected by presence of oxygen. This finding was consistent with additional stability assays, including antigenicity of the vaccine measured by ELISA, virus particle morphological structure captured by transmission electron microscopy and protective immune responses by immunization of mice in vivo. CONCLUSIONS: These data show that inactivated influenza vaccine encapsulated in dissolving microneedle patches has enhanced stability during extended storage at elevated temperatures.

Separable arrowhead microneedles.

Hypodermic needles cause pain and bleeding, produce biohazardous sharp waste and require trained personnel. To address these issues, we introduce separable arrowhead microneedles that rapidly and painlessly deliver drugs and vaccines to the skin. These needles are featured by micron-size sharp tips mounted on blunt shafts. Upon insertion in the skin, the sharp-tipped polymer arrowheads encapsulating drug separate from their metal shafts and remain embedded in the skin for subsequent dissolution and drug release. The blunt metal shafts can then be discarded. Due to rapid separation of the arrowhead tips from the shafts within seconds, administration using arrowhead microneedles can be carried out rapidly, while drug release kinetics can be independently controlled based on separable arrowhead formulation. Thus, drug and vaccine delivery using arrowhead microneedles are designed to offer a quick, convenient, safe and potentially self-administered method of drug delivery as an alternative to hypodermic needles.

Fabrication of dissolving polymer microneedles for controlled drug encapsulation and delivery: Bubble and pedestal microneedle designs.

Dissolving microneedle patches offer promise as a simple, minimally invasive method of drug and vaccine delivery to the skin that avoids the need for hypodermic needles. However, it can be difficult to control the amount and localization of drug within microneedles. In this study, we developed novel microneedle designs to improve control of drug encapsulation and delivery using dissolving microneedles by (i) localizing drug in the microneedle tip, (ii) increasing the amount of drug loaded in microneedles while minimizing wastage, and (iii) inserting microneedles more fully into the skin. Localization of our model drug, sulforhodamine B in the microneedle tip by either casting a highly concentrated polymer solution as the needle matrix or incorporating an air bubble at the base of the microneedle achieved approximately 80% delivery within 10 min compared to 20% delivery achieved by the microneedles encapsulating nonlocalized drug. As another approach, a pedestal was introduced to elevate each microneedle for more complete insertion into the skin and to increase its drug loading capacity by threefold from 0.018 to 0.053 microL per needle. Altogether, these novel microneedle designs provide a new set of tools to fabricate dissolving polymer microneedles with improved control over drug encapsulation, loading, and delivery.