Estudio de la permeación ex vivo e in vivo de antidepresivos tricíclicos en tejido biológico. Estudio de la actividad anestésica y analgésica

Abstract

La tesis doctoral consta de 3 artículos desarrollados a lo largo de varios años. El primer trabajo tiene el título de “Transdermal delivery of imipramine and doxepin from newly oil-in-water nanoemulsions for an analgesic and anti-allodynic activity: Development, characterization and in vivo evaluation”. Los antidepresivos y más concretamente los antidepresivos tricíclicos por su mayor eficacia y actividad analgésica han sido objeto de numerosos estudios. En este primer artículo, hemos estudiado la actividad analgésica y anestésica de dos antidepresivos tricíclicos (imipramina y doxepina). Con el fin de investigar formulaciones analgésicas de aplicación cutánea, hemos desarrollado una nanoemulsión compuesta por propilenglicol, Transcutol® , agua, Labrasol®, Plurol Oleico®, isostearato de isoestearilo, ácido oleico y D-limoneno. La concentración final de imipramina o doxepina en el sistema de la nanoemulsión fue del 3% (p/p) En este trabajo, las nanoemulsiones han sido caracterizadas en función de su pH, viscos

PERMEATION STUDY EX VIVO AND IN VIVO OF TRICYCLIC ANTIDEPRESSANT IN BIOLOGICAL TISSUES. STUDY OF ANESTHETIC AND ANALGESIC ACTIVITY This study is based on three papers published between 2013 and 2014. The first paper has the title: “Transdermal delivery of imipramine and doxepin from newly oil-in-water nanoemulsions for an analgesic and anti-allodynic activity: Development, characterization and in vivo evaluation”. We study the local analgesic and anesthetic properties of nanoemulsions with imipramine and doxepin. The concentration of these tricyclic antidepressants in the nanoemulsion system was 3% (w/w). The composition of optimized nanoemulsion is 45% of aqueous phase, 40% mixture of surfactants and 15% oil phase. The second study was published in 2014 in the European Journal of Pharmaceutical Sciences and has the title:”An improved cryopreservation method for porcine buccal mucosa in ex vivo drug permeation studies using Franz diffusion cells”. We study a cryopreservation method for porcine buccal mucosa based in the mixture of phosphate buffer saline (PBS) with 10% DMSO and 4% albumin as cryoprotective agents. The porcine buccal mucosa has been proposed as a substitute for the buccal mucosa barrier on ex vivo permeability studies avoiding unnecessary sacrifice of animals. We used a Franz diffusion cell system and HPLC as detection method. The freezing effects on drug permeability parameters were evaluated. Equally histological studies were performed. Furthermore, the use of the parameter transmucosal water loss (TMWL) as an indicator of the buccal mucosa integrity was evaluated just as transepidermal water loss (TEWL) is utilized for skin integrity. The results showed no difference between fresh and frozen mucosal flux, permeability coefficient or lag time. However, statistical significant difference in TMWL between fresh and frozen mucosa was observed. The last paper:” Transbuccal delivery of doxepin: Studies on permeation and histological investigation” evaluated a model of buccal permeation to determine the depth of delivery of doxepin into excised porcine buccal mucosa following topical application of a saturated aqueous doxepin solution. Buccal mucosa permeation studies were performed using Franz diffusion cells, Cumulative amounts of doxepin permeated were plotted as a function of time. Finally, a histological evaluation of the buccal mucosa was performed to test potential damage due to the permeation phenomenon. This study lays the foundation for further research within this area with a view to potentially adopting alternative strategies for enhanced buccal absorption of doxepin in clinical practice.