Permeação cutânea e vaginal de fármacos: rotas alternativas

Abstract

In Chapter 1, the objective was to insert taxifoline (TAX) into a semi-solid dosage form and to evaluate its ex vivo permeation in human skin. TAX was incorporated into an oil-in-water emulsion. Analysis Method was developed and validated using high performance liquid chromatography (HPLC) to active principle quantification during the experiments and permeation through the human skin was conducted in Franz-type cells. In the chromatographic method the following conditions were used: octadecylsilane (C18) column; mobile phase consisting of water and acetonitrile (45:55, v/v), acidified with 0.1 % formic acid (pH = 2,4); column compartment temperature to 45 ° C; an isocratic flow system at 0,5 mL.min-1 and detection at 288 nm. The method was precise (CV<5 %), accurate (recovery between 98 % and 102 %), linear (R2>0,99), specific, and robust. Permeation experiment through human skin presented permeated percentage equal to 48,09 % (per dose). The results described suggest that, in the studied matrix, TAX may be able to permeate up to the dermis and that, possibly, TAX achieved concentrations may be sufficient for the same to exert its therapeutic effect systemically. In Chapter 2, the objective of the study was to evaluate the feasibility of using formulations containing dienogest (DNG), gestrinone (GTN), nimesulide (NMS) and piroxicam (PRX) for vaginal administration in patients with pelvic pain associated with endometriosis. Intravaginal creams were individually composed of active pharmaceutical ingredients incorporated into Pentravan® base (0,2 % DNG, 0,5 % GTN, 2,0 % NMS and 2,0 % PRX). Methods of quantification using HPLC were validated for the quantification of active principles, vaginal permeation profiles were determined using porcine vaginal mucosa in Franz type diffusion cells and kinetic parameters were determined. Methods were precise (CV <5 %), exact (recovery between 98 % and 102 %), linear (R2> 0,99) and specific. Diffusion experiments demonstrated fluxes of 15,98 μg.cm- 2.h-1 for DNG, 3,91 μg.cm-2.h-1 for PRX, 3,72 μg.cm-2.h-1 for GTN and 2,26 μg.cm-2.h-1 for NMS. Fluxes required to release the recommended daily dose for the treatment of pelvic pain associated with endometriosis were calculated and established as 0,87 μg.cm-2.h-1 for DNG, 0,69 μg.cm-2.h-1 for GTN, 70,45 μg.cm-2.h-1 for NMS and 9,64 μg.cm-2.h-1 for PRX. DNG and GTN had permeation fluxes and quantities of drug absorbed hypothetically compatible with therapeutic effect in vivo, whereas NMS and PRX studies showed a great amount of these drugs retained in the vaginal mucosa which could explain a local effect for these two substances. The results suggest that the matrix evaluated appears to be a viable intravaginal vehicle for the systemic therapeutic use of DNG and GTN. However, NMS and PRX demonstrated the possibility of use for an effect on the local tissue. Further studies should be performed in the formulation for systemic therapeutic use of NMS and PRX.