A mucoadhesive biodissolvable thin film for localized and rapid delivery of lidocaine for the treatment of vestibulodynia.

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.

Biodegradable polymeric solid implants for ultra-long-acting delivery of single or multiple antiretroviral drugs.

Lack of adherence is a key barrier to a successful human immunodeficiency virus (HIV) treatment and prevention. We report on an ultra-long-acting (ULA) biodegradable polymeric solid implant (PSI) that can accommodate one or more antiretrovirals (e.g., dolutegravir (DTG) and rilpivirine (RPV)) at translatable human doses (65% wt.) in a single implant. PSIs are fabricated using a three-step process: (a) phase inversion of a drug/polymer solution to form an initial in-situ forming solid implant, (b) micronization of dried drug-loaded solid implants, and (c) compression of the micronized drug-loaded solid powder to generate the PSI. DTG and RPV can be pre-combined in a single PLGA-based solution to make dual-drug PSI; or formulated individually in PLGA-based solutions to generate separate micronized powders and form a bilayer dual-drug PSI. Results showed that in a single or bilayer dual-drug PSI, DTG and RPV exhibited physicochemical properties similar to their pure drug analogues. PSIs were well tolerated in vivo and effectively delivered drug(s) over 180 days with concentrations above 4× PA-IC90 after a single subcutaneous administration. While biodegradable and do not require removal, these PSIs can safely be removed to terminate the treatment if required. The versatility of this technology makes it attractive as an ULA drug delivery platform for HIV and various therapeutic applications.

2'-Behenoyl-paclitaxel conjugate containing lipid nanoparticles for the treatment of metastatic breast cancer.

The aim of these studies was to develop a novel 2'-behenoyl-paclitaxel (C22-PX) conjugate nanoparticle (NP) formulation for the treatment of metastatic breast cancer. A lipophilic paclitaxel derivative C22-PX was synthesized and incorporated into lipid-based NPs. Free C22-PX and its NP formulation were evaluated in a series of in vitro and in vivo studies. The results demonstrated that C22-PX NPs were much better tolerated and had significantly higher plasma and tumor AUCs compared to Taxol at the maximum tolerated dose (MTD) in a subcutaneous 4T1 mouse mammary carcinoma model. These benefits resulted in significantly improved antitumor efficacy with the NP-based formulation.