Graduation Date

Spring 5-7-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Dr. Benson J. Edagwa

Second Advisor

Dr. Howard E. Gendelman

Abstract

Opioid use disorder (OUD) remains a major global public health crisis, characterized by high relapse rates, increasing overdose mortality, and significant barriers to sustained treatment engagement. Despite the effectiveness of medications such as buprenorphine (BUP), treatment success is limited by poor adherence to existing frequently administered formulations. These challenges are further exacerbated in individuals with co-morbid conditions such as chronic hepatitis B virus (HBV) infection, a leading cause of liver fibrosis, where overlapping social, behavioral, and structural barriers compromise long-term adherence to therapy. Consequently, there is a critical need for innovative treatment strategies that provide sustained efficacy for OUD and overlapping chronic conditions. We hypothesized that ultra-long-acting (ULA) prodrug formulations could address these limitations by maintaining therapeutic drug levels for months following a single administration. For OUD, we merged prodrug and ion pairing strategies to create an ultra-long-acting (ULA) BUP nanosuspension (NM6BUP-Pamoate). The dual prodrug-ion-pair approach enabled transformation of BUP into a ready-to-use organic solvent free and shelf stable formulation. Pharmacokinetic (PK) studies in Sprague–Dawley rats showed that a single dose of NM6BUP-Pamoate delivers efficacious plasma BUP levels for six months. Importantly, plasma BUP levels increase gradually before reaching sustained therapeutic concentrations, providing a PK profile that is well suited for initiation during early withdrawal while maintaining sustained therapeutic exposure. Brain BUP concentrations were stable and exceeded plasma levels. Safety evaluations confirmed no off-target pharmacology with favorable local and systemic tolerability. NM6BUP-Pamoate formulation represents a promising ultra-long-acting treatment for OUD with the potential to provide both early stabilization and durable protection. In parallel, given the high prevalence of viral hepatitis and liver fibrosis among individuals who inject drugs and the shared challenges of long-term treatment adherence, we designed a long-acting prodrug formulation of vonafexor (VON), a farnesoid X receptor agonist with antifibrotic activity. The resulting long-acting prodrug formulation suppressed profibrotic markers and precluded liver and lung damage in a model of chronic liver injury. The data demonstrates the potential of a LA VON prodrug formulation to combat liver and lung fibrosis. Collectively, this work demonstrates the successful application of prodrug and hydrophobic salt strategies to improve the PK and pharmacological properties of BUP and VON. The development of ultra-long-acting BUP and VON formulations could simultaneously prevent opioid overdose deaths and progression of lung and liver fibrosis.

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