Design of Swollen Lipidic Cubic Phase to Increase Transcutaneous Penetration of Biomacromolecules

Lipidic cubic phase (LCP) is a self-assembled system composed of lipids with interpenetrated aqueous channels, and its potential in drug delivery systems has been investigated. Although LCP was shown to improve transcutaneous penetration of hydrophilic molecules of up to 1203 Da so far, the transcutaneous delivery of larger molecules such as proteins has not been achieved. This is likely because proteins are usually larger than the aqueous channels of LCP (∼37.2 Å in diameter), which limits the molecular diffusion in LCP. In this report, we overcome this issue by adding N-octyl-β-d-glucopyranoside to glyceryl monooleate-water-based LCP to give swollen LCP (SLCP), which has larger aqueous channel diameters (∼65.6 Å). First, we systemically evaluated the effect of swelling on drug diffusion in LCP/SLCP. The release kinetics of various peptides and proteins whose sizes ranged from 9.14 to 55.28 Å in diameter were evaluated, and the diffusion coefficients (D) were calculated by the Fickian diffusion model. As expected, all peptides and proteins diffused faster in SLCP than in LCP. A more detailed analysis revealed a negative linear relationship between log D and the ratio of the radius of gyration of the proteins to the aqueous channel radius, indicating that swelling of a cubic nanostructure is an effective strategy to enhance D. Next, the skin penetration of proteins encapsulated in LCP and SLCP was evaluated. The skin penetration of ovalbumin (42.9 kDa), for example, was enhanced by SLCP but not by LCP, and a positive correlation between D and the amount of skin penetration was found. Collectively, this study provides an effective measure for designing LCP systems that enhance transcutaneous penetration of biomacromolecules.