Relating Advanced Electrospun Fiber Architectures to the Temporal Release of Active Agents to Meet the Needs of Next-Generation Intravaginal Delivery Applications

pharmaceutics Review Relating Advanced Electrospun Fiber Architectures to the Temporal Release of Active Agents to Meet the Needs of Next-Generation Intravaginal Delivery Applications Kevin M. Tyo 1,2,† , Farnaz Minooei 3,† , Keegan C. Curry 4 , Sarah M. NeCamp 5 , Danielle L. Graves 5 , Joel R. Fried 3 and Jill M. Steinbach-Rankins 1,2,5,6, * 1 2 3 4 5 6 * † Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY 40202, USA; Center for Predictive Medicine, Louisville, KY 40202, USA Department of Chemical Engineering, University of Louisville, Louisville, KY 40292, USA; (F.M.); (J.R.F.) Department of Biology, University of Louisville, Louisville, KY 40292, USA; Department of Bioengineering, Speed School of Engineering, University of Louisville, Louisville, KY 40292, USA; (S.M.N.); (D.L.G.) Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40292, USA Correspondence: ; Tel.: +1-502-852-5486 Co-first authors. Received: 7 March 2019; Accepted: 30 March 2019; Published: 3 April 2019



 Abstract: Electrospun fibers have emerged as a relatively new delivery platform to improve active agent retention and delivery for intravaginal applications. While uniaxial fibers have been explored in a variety of applications including intravaginal delivery, the consideration of more advanced fiber architectures may offer new options to improve delivery to the female reproductive tract. In this review, we summarize the advancements of electrospun coaxial, multilayered, and nanoparticle-fiber architectures utilized in other applications and discuss how different material combinations within these architectures provide varied durations of release, here categorized as either transient (within 24 h), short-term (24 h to one week), or sustained (beyond one week). We seek to systematically relate material type and fiber architecture to active agent release kinetics. Last, we explore how lessons derived from these architectures may be applied to address the needs of future intravaginal delivery platforms for a given prophylactic or therapeutic application. The overall goal of this review is to provide a summary of different fiber architectures that have been useful for active agent delivery and to provide guidelines for the development of new formulations that exhibit release kinetics relevant to the time frames and the diversity of active agents needed in next-generation multipurpose applications. Keywords: electrospun fibers; fiber architecture; drug delivery; intravaginal delivery; delivery vehicle 1. Introduction Intravaginal delivery is an effective strategy to improve the localization of antiviral, antibacterial, antifungal, chemotherapeutic, and contraceptive agents within the female reproductive tract (FRT) [1,2]. Relative to oral administration routes, intravaginal delivery localizes agents to the FRT, avoiding both the harsh gastrointestinal environment and hepatic first pass effect. This results in an increase in drug bioavailability within target tissue and corresponding functional activity by decreasing off-target effects and systemic exposure [3]. The inherent characteristics of the FRT, including its large surface Pharmaceutics 2019, 11, 160; doi:10.3390/pharmaceutics11040160 www.mdpi.com/journal/pharmaceutics FRT, avoiding both the harsh gastrointestinal environment and hepatic first pass effect. This results in an increase in drug bioavailability within target tissue and corresponding functional activity by Pharmaceutics 2019, 11, 160 2 of 31 decreasing off-target effects and systemic exposure [3]. The inherent characteristics of the FRT, including its large surface area and low enzymatic activity, additionally make the FRT a favorable site for active agent administration targeting area andlocalized low enzymatic activity, additionally and make the FRT [4,5]. a favorable site for localized active agent Although and intravaginal administration targetingdelivery [4,5]. offers a variety of advantages to enhance the delivery of active agents [6], challenges unique to the FRT be overcome to provide efficacious prophylaxis and Although intravaginal delivery offersmust a variety of advantages to enhance the delivery of active treatment. One of the most important components of the FRTtoisprovide the mucus layer, which protectsand the agents [6], challenges unique to the FRT must be overcome efficacious prophylaxis epitheliumOne andof lamina propria from incoming pathogens (Figure However, it can also act as treatment. the most important components of the FRT is the 1). mucus layer, which protects thea barrier, impeding therapeutic to underlying epithelial and cells [7,8].also In addition epithelium and lamina propriatransport from incoming pathogens (Figure 1).immune However, it can act as a to theseimpeding challenges, the frequent shedding and production of cervicovaginal mucus decrease barrier, therapeutic transport to underlying epithelial and immune cells [7,8].can In addition active retention, while bacterial flora, and acidic environment created by to theseagent challenges, the frequent shedding andenzymes, production of the cervicovaginal mucus can decrease beneficial can contribute metabolization and of active agents, reducing active agentbacteria retention, while bacterialtoflora, enzymes, and thedegradation acidic environment created by beneficial efficaciousness. bacteria can contribute to metabolization and degradation of active agents, reducing efficaciousness. Figure 1. 1. Schematic Schematic depicting depicting the the structure structure and and specific specific layers layers of of the the vaginal vaginal mucosa mucosa that that can can act act as as aa Figure barrier to to active active agent agent transport transport (not (not to to scale). scale). The The mucus mucus layer layer of of the the female female reproductive tract (FRT) (FRT) barrier reproductive tract frequently sheds sheds and and can can immobilize immobilize active active agents agents (shown (shown in in red), red), leading leading to to decreased decreased efficacy efficacy of of frequently the administered administered agents. agents. The The bacterial bacterial flora flora normally normally present present within within the the FRT FRT can can also also metabolize metabolize and and the degrade agents, agents, further further contributing contributing to to decreased decreased efficacy. efficacy. Last, Last, the the squamous squamous epithelium epithelium can can hinder hinder degrade transport to to underlying underlyingimmune immunecells cellspresent presentnear nearthe theepithelial epithelialsurface surfaceand/or and/or in in the lamina lamina propria. propria. transport To To address address these these challenges, challenges, intravaginal intravaginal delivery delivery platforms platforms have have been been formulated formulated as as solid solid or or semi- (...truncated)