Estudio de la absorción transdérmica de memantina clorhidrato y tizanidina clorhidrato

Zusammenfassung

The administration of drugs via the transdermal pathway is becoming a regular option, but only very few drug candidates with appropriate physicochemical properties have been approved for transdermal delivery. The aim of this thesis was to develop a transdermal formulation that could allow reaching therapeutic plasma levels for the treatment of two chronic diseases: Alzheimer and Spasticity. Both are chronic diseases that require chronically drug administration. Alzheimer¿s disease is a neurodegenerative brain disorder that leads to major debilitating cognitive deficits in the elderly. Memantine (a noncompetitive N-methyl-D-aspartate [NMDA] receptor antagonist) is used as a pharmacological treatment for patients with mild to moderate vascular dementia and has been approved for the treatment of the symptoms that characterize the moderate-serious state of the Alzheimer¿s disease. Patients suffering Alzheimer are usually of an advanced age and have many memory and cognitive problems, as well as deglution problems; in addition, they have numerous co-morbidities that demand multiple medications. In this sense, the transdermal route of administration constitutes an alternative by which the inconveniences related with oral drug administration can be overcome and facilitates multiple drug administration. Memantine has no chromophoric groups that could be detected by an UV detector, so it was necessary to extract the drug contained in the samples and to perform a dansylation reaction. On Chapter 1 we validated demonstrating accuracy, precision and linearity a high-performance liquid chromatography (HPLC) method involving ultraviolet detection for the quantitative analysis of memantine hydrochloride. This validation allowed us to evaluate the molecule transdermal administration by means of the performance of in vitro transdermal studies (Chapter 2). It is important to highlight that iontophoresis exhibited the greatest ability to enhance the flux of drug with respect to the control; nevertheless, the results obtained with a skin pre-treatment with R-(+)-limonene indicate that this compound could be of great use as a percutaneous enhancer in a memantine transdermal delivery system. In addition, we have compared results obtained with memantine with those obtained with other compounds and satisfactory correlations have been obtained between the optimum lipophilicity of the enhancer and n-octanol/water partition coefficient of drug. Finally, on Chapter 3, various memantine hydrochloride occlusive transdermal systems (TS) were formulated with different polymeric matrixes and with chemical enhancers. The in vitro permeation of the memantine across porcine skin and the physical characteristics, stability, moisture uptake, mechanical properties and in vivo bioadhesion of the TS were evaluated. Iontophoretic studies were carried out with human skin and the results compared with those obtained in the pig model. Our results demonstrated that the presence of limonene or laurocapram in a formulation enhances the transdermal flux of memantine with respect to controls. According to our results, a TS of a reasonable size (97 cm2) formulated with PVP and R-(+)-limonene could be capable of providing therapeutic plasma concentrations of memantine. In addition, iontophoresis was found to enhance the flux of the drug with respect to controls in a higher extent than chemical enhancers; this would enable to achieve therapeutic plasma concentrations more rapidly and with a smaller patch (15 cm2). Our results need to be verified in vivo. On the other hand, Spasticity is a motor disorder characterized by a velocity dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyper excitability of the stretch reflexes, as one component of the upper motoneuron syndrome. One of the pharmaco-therapeutic agents approved by the FDA for the spasticity treatment is the tizanidine hydrochloride, an a2-adrenergic agonist that acts mainly at spinal and supraspinal levels to inhibit excitatory interneurons. Because of poor tizanidine absorption and bioavailability, the transdermal route of administration constitutes an alternative to the oral drug administration. On Chapter 4 we expose an ultra-performance liquid chromatography (UPLC) method involving ultraviolet detection. The validated method was simple, accurate, precise, rapid and useful for determining the transdermal absorption of tizanidine. The co-treatment effect of several chemical enhancers on the transdermal absorption of tizanidine was evaluated (Chapter 5). Among those, Tween 20® (2% in ethanol-water 40%, v/v; and incorporated into a transdermal gel) showed the greatest capacity to enhance the flux of tizanidine across pig skin. In order to improve those findings, Chapter 6 includes different strategies that bypass or remove the stratum corneum and the effect of those on the molecule transdermal flux (tape stripping, laser microporation and heat separated dermis). The evaluation of the effect of those techniques showed that is much more important the depth of the treatment applied than a complete epidermis removal, but a balance should be kept in between both. The application of a transdermal formulation of tizanidine into Abstract a laser microporated skin (900 pores with a depth of 32 ¿m) showed promising results but, not good enough from a practical point of view. Finally, on Chapter 7, the effect of a physical enhancer like iontophoresis to increase tizanidine delivery across skin was evaluated in vitro and in vivo. The effect of drug concentration, current density and ion competition were studied. The in vitro results suggested that applying a current density of 0.5 mA¿cm-2 to a transdermal gel containing tizanidine it could be possible to reach therapeutic plasma levels. That was confirmed with the in vivo studies, which have also shown that therapeutic concentrations can be reached in a short period of time (about 15 minutes in rats). Th