Composite Dissolving Microneedles for Coordinated Control of Antigen and Adjuvant Delivery Kinetics in Transcutaneous Vaccination

Abstract

Transcutaneous administration has the potential to improve therapeutics delivery, providing an approach that is safer and more convenient than traditional alternatives, while offering the opportunity for improved therapeutic efficacy through sustained/controlled drug release. To this end, we demonstrate a microneedle materials platform for rapid implantation of controlled-release polymer depots into the cutaneous tissue. Arrays of microneedles comprised of drug-loaded poly(lactide-co-glycolide) (PLGA) microparticles or solid PLGA tips were prepared with a supporting and rapidly water-soluble poly(acrylic acid) (PAA) matrix. Upon application of microneedle patches to the skin of mice, the microneedles perforated the stratum corneum and epidermis. Penetration of the outer skin layers was followed by rapid dissolution of the PAA binder on contact with the interstitial fluid of the epidermis, implanting the microparticles or solid polymer microneedles in the tissue, which were retained following patch removal. These polymer depots remained in the skin for weeks following application and sustained the release of encapsulated cargos for systemic delivery. To show the utility of this approach we demonstrated the ability of these composite microneedle arrays to deliver a subunit vaccine formulation. In comparison to traditional needle-based vaccination, microneedle delivery gave improved cellular immunity and equivalent generation of serum antibodies, suggesting the potential of this approach for vaccine delivery. However, the flexibility of this system should allow for improved therapeutic delivery in a variety of diverse contexts.

Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination

“…Thus, an important next step for the concepts presented here will be implementation of vaccine delivery methods that allow vaccine exposure patterns as described here to be achieved following a single administration. Methods that may be suitable include the use of microneedle patches, biodegradable microparticles, or other controlled-release devices (52)(53)(54)(55). Such delivery systems have been shown to be able to deliver large proteins and other vaccine components in increasing dose profiles.…”

Beyond antigens and adjuvants: formulating future vaccines

“…Several types of microneedle patches that can tailor vaccine kinetics have been designed and tested in mice, NHPs, and early clinical trials, including microneedles composed of polymers that swell or dissolve at controlled rates when applied to the skin, releasing encapsulated vaccines (refs. 123-125 and Figure 2A); microneedles composed of polymer microparticles or nanoparticles carrying encapsulated vaccine supported in a dissolving matrix, which rapidly deposit vaccine-loaded particles into the skin for subsequent tunable release kinetics from the implanted particles (126,127); and microneedles composed of a solid tip or polymer coating on a dissolving base, in which the vaccine-releasing tip is rapidly implanted into the skin upon patch application (refs. 126, 128, 129, and Figure 2B).…”

Multifunctional particle-constituted microneedle arrays as cutaneous or mucosal vaccine adjuvant-delivery systems

“…The PLGA microparticles had a size of about 1580 nm in diameter and zeta potential of ¡26 mV and were fabricated to form the MPMAs which had conical microneedles of 700-mm in height and 250-mm in diameter at the base with water-soluble poly(acrylic acid) (PAA) as a supporting pedestal. 64 The MA microneedles proved thermostable and able to perforate the stratum corneum and implant the antigen/adjuvant-loaded PLGA microparticles in the epidermal compartment following patch removal due to rapid separation of microneedles from PAA pedestal (Fig. 7).…”