Purpose: Basal cell carcinoma (BCC) is a common malignant tumor in Caucasians and accounts for 95% of non-melanoma skin cancers in the United States. Non-surgical treatment of superficial BCC involves the use of AldaraTM cream containing 5% w/w imiquimod as the active ingredient. Imiquimod, a toll-like receptor (TLR) agonist, is an immune response modifier with potent indirect antiviral activity. Topical delivery of imiquimod is superior to oral administration, because first-pass metabolism of drug is avoided and the drug concentration is maximized at the affected area. However, the cream dosage form suffers from dose variability, poor drug availability due to the incomplete release of the drug and poor patient compliance. We hypothesized that the sustained release of imiquimod from a film would result in an effective treatment, while eliminating the need for daily cream application and the associated dosing variations.
Methods: Imiquimod-loaded chitosan (1.5%, w/v, medium molecular weight or practical grade chitosan) films were prepared by casting/solvent evaporation method using propylene glycol (5%, v/v) as a plasticizer. Mechanical properties of the films were investigated using mechanical tester equipment. X-ray crystallography was used to determine the physical stability of imiquimod in film formulations. Films were further analyzed for thickness, water vapor transmission rate, swelling index, and content uniformity. In addition, effect of varying concentrations of imiquimod and molecular weight of chitosan was studied on the release characteristics of the film. Finally, the bioactivity of imiquimod in film formulations was assessed by determining its growth inhibition potential against A375P and B16-F10 cells.
Results: Imiquimod-loaded chitosan films were readily formed by solvent evaporation, which resulted in an aesthetically appealing film formulation. Based on our results, the process resulted in a very uniform, reproducible films with respect to thickness with a CV of less than 1.5%. The X-ray diffraction data and content uniformity studies demonstrated the uniform imiquimod loading with no change in the physical form of the drug within the chitosan film matrix. The optimal film formulations demonstrated a good balance of sturdiness and flexibility, which is an essential characteristic of dressing materials. Our studies demonstrated that chitosan films were capable of releasing a defined dose of imiquimod over a period of six days and changes in imiquimod loadings in the films across a range of 8.5-85 µg/cm2 did not significantly affect the release pattern. As observed, the release profiles obtained from the different molecular weight films were almost identical with a slightly higher initial burst in the case of the medium molecular weight chitosan film. The results of in vitro bioactivity assay clearly demonstrate that the bioactivity of imiquimod was not affected by its entrapment in chitosan matrix or by the various manufacturing steps and comparable to the respective solution formulation.
Conclusion: Chitosan films exhibited excellent physicochemical properties and were capable of releasing intact and active drug at a specified dose over a period of six days.
Saif Rahman Nirzhor– University of Minnesota, Minneapolis, Minnesota
Timothy Wiedmann– Professor, University of Minnesota, Minneapolis, Minnesota
Swayam Prabha– Assistant Professor, University of Minnesota, Minneapolis, Minnesota