Dual Delivery from a Multilayer Buccal Film: Rational Design of a Combination Product for Localized Treatment of Oral Fibrosis.

Abstract

Oral submucous fibrosis (OSF) is a chronic, progressive, and potentially malignant disorder characterized by severe oral cavity remodeling. The condition is driven by a painful burning sensation and a pathognomonic restriction of mouth opening (trismus), severely diminishing patients' quality of life. Current clinical management represents a critical bottleneck in patient care, as conventional strategies rely heavily on painful intralesional injections or systemic regimens plagued by localized toxicity and poor compliance. Consequently, there is an urgent demand for localized, noninvasive, and patient-compliant delivery systems capable of sustaining therapeutic drug levels directly at the fibrotic site. To address this challenge, we developed, optimized, and characterized a multilayered buccal film ("sandwich" architecture) combining bupivacaine (Bupi) and pirfenidone (PFD) to achieve an immediate anesthetic effect followed by sustained antifibrotic action. A Design of Experiments (DoE) approach optimized both formulation composition and the critical process parameter (drying rate), yielding a fast-dissolving (FD) layer engineered for rapid Bupi release alongside a slow-dissolving (SD) layer tailored for prolonged PFD dissolution. The resulting monolithic system successfully immobilizes both therapeutics in a stable amorphous state, leveraging macromolecular free volume and modulated surface microtopography to regulate biphasic release kinetics. This work demonstrates the feasibility of engineering kinetically distinct, multilayered buccal films through rational design, providing a translationally viable therapeutic platform for localized management of oral fibrosis.