Self-assembled mPEG-hexPLA polymeric nanocarriers for the targeted cutaneous delivery of imiquimod

mPEG-hexPLA micelles have shown their ability to improve delivery and cutaneous bioavailability of a wide range of poorly water soluble and lipophilic molecules. Although poorly water soluble, imiquimod (IMQ) is only moderately lipophilic and it was decided to investigate whether mPEG-hexPLA polymeric micelles could be used as a drug delivery system for this less than ideal candidate for encapsulation. Nanosized IMQ micelles (d(n) = 27 nm) were formulated and characterized. Moreover, the innovative use of size exclusion chromatography allowed the exact drug localization inside the formulation to be determined; it appeared that the use of acetic acid to solubilize IMQ led to a higher IMQ content outside the micelle than inside. IMQ micelles (0.05%) were formulated in a gel using carboxymethyl cellulose (CMC). In vitro application of this formulation to porcine and human skin led to promising delivery results. IMQ deposition in human skin was 1.4 +/- 0.4 mu g/cm(2) while transdermal permeation was only 79 +/- 19 ng/cm(2): the formulation displayed > 17-fold selectivity for cutaneous deposition over transdermal permeation. The optimized 0.05% gel significantly outperformed Aldara. cream (containing 5% IMQ) formulation in terms of delivery efficiency to human skin (2.85 +/- 0.74% vs 0.04 +/- 0.01%). Despite IMQ being only partially incorporated in the micelles, the biodistribution profile showed that the optimized 0.05% gel delivered as much as 518.2 +/- 173.3 ng/cm(2) (1.04 +/- 0.35% of the applied dose) to the viable epidermis and 236.4 +/- 88.2 ng/cm(2) (0.47 +/- 0.18% of the applied dose) to the upper dermis where the target antigen presenting cells reside. In contrast, for Aldara cream, the delivery efficiencies in those layers were less than 0.02%. The optimal 0.05% gel thus allowed therapeutically relevant drug levels to be achieved in target tissues despite a 100-fold dose reduction.