Preferential π–π complexation between tamoxifen and borage oil/γ linolenic acid: Transcutaneous delivery and NMR spectral modulation

Abstract

The effect of different proportions of borage oil on the in vitro transcutaneous delivery of tamoxifen were studied, with the aim of developing a gel capable of the simultaneous delivery of tamoxifen and γ linolenic acid across (breast) skin. Supplementary work probed 1H NMR spectral data for tamoxifen in the presence of different proportions of polyunsaturated or unsaturated fatty acids. Typical, non-aqueous gels were modified to contain 1% tamoxifen and three levels of borage oil (∼25% γ linolenic acid) and the transcutaneous delivery of both tamoxifen and GLA across full thickness skin determined in vitro. Both tamoxifen and γ linolenic acid permeated the skin with the ratio of moles being consistent at approximately 4:1. This was irrespective of time, amount of borage oil contained in the formulation (above a minimum) and the presence of other (unsaturated) excipients: mineral oil, Miglyiol 810N, white soft paraffin, PEG400 and Cabosil M5. Dose-dependent downfield shifts of tamoxifen aromatic protons were observed in the presence of borage oil and linolenic acid (γ and α), but not saturated triacyl glycerol. The permeation data suggested vehicular complexation between tamoxifen and polyunsaturated constituents of borage oil and that such complexes permeated the skin intact. The 1H NMR data supported the hypothesis that such complexation was a consequence of preferential π–π orbital interactions between the phenyl groups of tamoxifen and the multiple double bonds of GLA. The mechanism for the permeation of intact complexes across skin remains to be elucidated.