P1.146 Drug targeting to skin and hair follicle: investigation of an antiandrogen and a fluorescent marker

U. Münster¹, S. Lombardi Borgia¹, C. Nakamura¹, A. Haberland¹, W. Mehnert², H.C. Korting³, U. Blume-Peytavi⁴, R. Sivaramakrishnan⁵, K.D. Kramer⁵, M. Schäfer-Korting¹

¹Institut für Pharmazie, Pharmakologie und Toxikologie and ²Institut für Pharmazie, Pharmazeutische Technologie, Freie Universität, Berlin, Germany; ³Klinik und Poliklinik für Dermatologie und Allergologie, Ludwig-Maximilians Universität, München, Germany; ⁴Dermatologische Klinik, Experimentelle und angewandte Physiologie der Haut, Humboldt Universität zu Berlin, Germany; ⁵Institut für Physik, Freie Universität, Berlin, Germany.

Objectives: Acne and androgenetic alopecia are linked to androgen effects and therefore should improve following topical application of antiandrogens. Serious side effects due to a systemic absorption, however, exclude this treatment in men. Drug targeting to the sebum gland and dermal papillae, however, may allow topical antiandrogen treatment in men, too. This may become possible by particulate carrier systems such as solid lipid nanoparticles (SLN), which are known to support dermal targeting¹⁾. Cutaneous uptake was also visualised by fluorescence microscopy using dye loaded SLN.

Methods: The new antiandrogen prodrug, RU 58841-myristate (RUM) was developed for topical therapy. Ester cleavage was proved, receptor affinity and local tolerability were compared to RU 58841. In contrast to native RU 58841, the more lipophilic RUM and nile red can be loaded to SLN by hot homogenisation. Particles were characterised for their physico-chemical properties, drug/dye loading²⁾ and stability. Permeation tests both on full-thickness pig skin and reconstructed epidermis were carried out on RUM loaded SLN using Franz diffusion cells. With porcine and human scalp skin targeting to the skin and hair follicle was visualised by fluorescence microscopy. A cream and nanoemulsion served for comparison.

Results: While receptor binding experiments proved the almost complete loss of binding to the androgen receptor by ester formation, RUM is rapidly metabolised to the potent antiandrogen RU 58841 by cultured human skin cells. Cellular viability was not impaired.

Physically stable RUM and nile red loaded SLN were obtained, the dye was adsorbed to the particle surface. Permeation studies proved only negligible antiandrogen permeation through reconstructed epidermis and excised skin, implying a more topical action of the drug. Fluorescence microscopy showed that both SLN and nanoemulsion increased dye uptake into the skin as compared to the cream. There was also an extensive follicular uptake and the dye was to be detected the sebaceous gland. Yet the nanoemulsion and cream did not appear inferior with respect to the hair follicle targeting.

Conclusions: RUM loaded SLN should be considered for topical antiandrogen therapy of acne and androgenetic alopecia.