Abstract
Vestibulodynia (VBD), an idiopathic pain disorder characterized by erythema and pain of the vulvar vestibule (the inner aspect of the labia minora and vaginal opening), is the most common cause of sexual pain for women of reproductive age. Women also feel discomfort with contact with clothing and tampon use. As most women with this disorder only have pain with provocation of the tissue, topical anesthetics applied to the vestibule are the current first line treatment for temporary pain relief. Treatment options are limited due to anatomical constraints of the vestibular region, poor drug retention time, imprecise dosing, leakage, and overall product messiness. In this study we report a novel approach to treatment of VBD using thin film designed to fit the vulvar vestibule and deliver lidocaine locally. Two use cases for VBD treatment were identified 1) rapid drug release (<5 min), for use prior to intercourse and 2) long-acting release (≥120 min) for prolonged use and relief throughout the day. Cellulose-based mucoadhesive thin films were fabricated using a solvent casting method. Three polymers including hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethycellulose (HMPC), were selected owing to their biocompatibility and ideal properties for film casting. Films casted with HEC, HPC, and HPMC exhibited mucoadhesive properties relative to a control, with the highest mucoadhesive force recorded for films casted with HPC. Effect of media volume, pH, presence of mucin and presence of drug on film dissolution rates were investigated. Dissolution rates were independent of media volume, media pH or drug presence, whereas faster dissolution rates were obtained for all films in presence of mucin. In vitro lidocaine release kinetics were influenced by polymer type, percent drug loading and film casting thickness. Lidocaine release was based on a diffusion mechanism rather than through film dissolution and faster release (∼5 min) was observed for HEC films compared HPC films (∼120 min). Higher drug loading and film thickness resulted in slower and more prolonged release kinetics of lidocaine. All films were biocompatible and exhibited good mechanical properties. Two film formulations (9% w/w HPC with 12% w/w LHC, 5% w/w HEC with 6% w/w LHC) were optimized to meet the two use case scenarios for VBD treatment and moved into in vivo testing. In vivo testing demonstrated the safety of the films in BALB/c mice, and the pharmacokinetic analysis demonstrated the delivery of lidocaine primarily to the vaginal tissue. We demonstrate the ability to develop a mucoadhesive, biodissolvable thin film and fine-tune drug release kinetics to optimize local delivery of lidocaine to the vulva.