Formulation development and in vitro evaluation of extemporaneous mucoadhesive in situ forming orals gels for localized therapy.

Abstract

Oral mucositis is a debilitating complication of head and neck cancer therapy, characterized by ulceration and moderate to severe pain, often leading to treatment de-escalation, malnutrition, and reduced quality of life. Bupivacaine-loaded thermosensitive mucoadhesive in situ gels have previously demonstrated prolonged oral residence and superior localized analgesia. The goal of this study is to develop a systematic and scalable formulation development approach to prepare hospital-compoundable mucoadhesive in situ forming oral gels using a pre-approved bupivacaine HCl injection. Sodium carboxymethyl cellulose (sodium CMC) was selected as the mucoadhesive polymer, while Pluronic^® F127 served as the thermosensitive component. A comprehensive evaluation of formulation variables, including polymer concentration, viscosity grade, and the degree of substitution revealed significant effects on the critical quality attributes. Increasing sodium CMC concentration initially enhanced mucoadhesion; however, excessive levels increased viscosity, reduced polymer hydration, and consequently decreased mucoadhesion and gelation temperature. Higher Pluronic^® F127 concentrations increased gel consolidation within hexagonal liquid crystalline structures, thereby slowing drug release. Converse to the conventional understanding, low-viscosity sodium CMC exhibited higher steady-state viscosity and more sustained drug release compared to the oral gels containing medium viscosity and high viscosity sodium CMC. The cumulative drug release at 8 h and the release kinetics were directly proportional to the degree of substitution of sodium CMC. This study represents one of the earliest systematic investigations into the complex interplay between formulation parameters and performance characteristics of mucoadhesive thermosensitive oral gels and establishes a novel structured approach for their rational formulation development. The knowledge and insight gained through this research will inform cost effective and accelerated formulation development of extemporaneous mucoadhesive in situ forming gels for different drug delivery applications.