Local Delivery of Imiquimod to Buccal Mucosa

Objectives: Imiquimod, an immune response modifier approved for market (Aldara), has been successfully used to treat acitinic keratosis and superficial basal cell carcinomas. A small number of case studies showed that off-label use of imiquimod was successful in stopping progression of oral dysplasia to oral squamous cell carcinoma.  However, use of commercially available cream may be undesirable to use in oral cavity. The objective of this work was to determine the efficiency of previously designed mucoadhesive system in delivering imiquimod to epithelium and to confirm bioactivity of released imiquimod.

Methods: Mucoadhesive films with backing layer were attached to mucosal surface of 500µm thick porcine buccal tissue contained in a Franz cell. Samples were collected from receptor compartment at predetermined intervals, and drug quantity was measured using HPLC. Permeability and transport kinetics of imiquimod control solutions and imiquimod-loaded films were compared. Bioactivity of imiquimod released from film supernatants was assessed by measuring TNF-α produced by RAW 264.7 cells via ELISA.

Results: Flux rates of imiquimod through buccal mucosal tissue were 1.25µg/cm²/hr and 4.98µg/cm²/hr for mucoadhesive films and control solutions, respectively.  This result demonstrates that transport of imiquimod through tissue into simulated saliva was controlled by the films. The mucoadhesive films also decreased permeability of imiquimod through tissue by 50% compared to control solutions, resulting in accumulation of more drug in 500µm thick mucosal tissue. Imiquimod was found to retain bioactivity after undergoing all the processing steps of making films. No significant difference in amounts of TNF-α produced by macrophagic cells was observed using film supernatants and control solutions of same concentration.

Conclusions: Mucoadhesive films were able to control drug release and may limit systemic absorption of drug. Decreased permeability of bioactive imiquimod through tissue following release from films may increase localization of drug in cancerous lesions and increase effectiveness of treatment.