PREFORMULATION STUDIES FOR TOPICAL ADMINISTRATION OF A NITROSYL RUTHENIUM COMPLEX BY IONTOPHORESIS

TF22

Danielle Cristine Almeida Silva de Santana, Talitha de Wit, Renata Galvão de Lima, Antônio Cláudio Tedesco, Roberto Santana da Silva, Renata Fonseca Vianna Lopez

Faculdade de Ciências Farmacêuticas de Ribeirão Preto - Universidade de São Paulo (USP)

Introduction: The use of compounds capable of releasing NO, as the nitrosyl ruthenium complex [Ru(terpy)(Bdq)NO](PF₆)₃ (Bdq = 1,2 benzoquinonediimine; terpy = terpyridine), has recently become a very active area of research. This ruthenium complex is able to release NO under light or electrochemical stimulation, and its topical application is an alternative for skin cancer treatment. However, the physical chemical characteristics of this compound, as high molecular weight (947g.mol^-1) and positive charge, limits its skin passive diffusion, but the iontophoresis technique may improves its skin penetration. Therefore, the purpose of this work was to verify the drug stability in the presence of a weak electrical current as used in iontophoresis experiments and to evaluate NO delivery from a solution (pH 7.4) and from a hydrophilic gel containing this complex. Methods: The stability of [Ru(terpy)(Bdq)NO](PF₆)₃ at 200µg.mL^-1 in aqueous solution at different pHs (7.4, 5.0 and 4.0) was evaluated in the presence of an electrical current of 0.4 mA and Ag/AgCl electrodes. The drug was put in contact with the positive electrode and its remaining concentration was analyzed after 6 h of the current passage. NO release from nitrosyl ruthenium complex formulations (solution and hydrophilic gel at 40µg.mL^-1) under laser irradiation at 355nm and at 532nm was also evaluated by UV-Vis spectrum variation analysis and by an amperometric technique that detects directly the NO released. Results: Stability studies showed that [Ru(terpy)(Bdq)NO](PF₆)₃ solutions at pH 7.4 are electrically stable for at least 6h. Nevertheless, a decrease of ~10% in the drug remained concentration was observed in pH 4 and in pH 5 solutions. The UV-vis absorption spectral change after different doses of irradiation of the complex solution with a laser at 355nm or 532nm showed a decrease on the shoulder at 360nm and an increase in 510nm peak with the improvement of dose irradiation. This peak is concerning to the aqua complex [Ru(H₂O)(bdq)(terpy)] formed after NO release. Therefore, NO release from the complex with light irradiation was demonstrated. Its also shows that NO is released easier (with low irradiation doses) when the complex solution is irradiated at 355 nm. In situ NO formation after nitrosyl ruthenium complex formulations irradiation is showed by the NO sensor. The signal recorded by the NO sensor rose quickly when photolysis was initiated, then decreased when the light was turned off. Conclusion: The NO is released from the complex after light irradiation at 355nm and at 532nm. Moreover the [Ru(terpy)(Bdq)NO](PF₆)₃  is stable in the presence of a weak electrical current when its dispersed in a pH 7.4 formulation suggesting the possibility to delivery this drug topically using iontophoresis (supported by FAPESP).