Facultad de Ciencias de la Salud

Giardiasis is a parasitism produced by the protozoa Giardia intestinalis that lives as trophozoite in the small intestine (mainly in the duodenum) attached to the intestinal villus by means of billed discs. The first line treatment is metronidazole, a drug with high bioavailability, which is why to obtain therapeutic concentrations in duodenum, it is necessary to administer high doses of drug to patients with the consequent occurrence of side effects. It is necessary to developed new therapeutical approaches to achieve a local delivery of the drug. In this sense, we have developed gated mesoporous silica microparticles loaded with metronidazole and with a molecular gate pH dependent. In vitro assays demonstrated that the metronidazole release is practically insignificant at acidic pHs, but in duodenum conditions, the metronidazole delivery from the microparticles is effective enough to produce an important parasite destruction. In vivo assays indicate that this microparticulate system allows to increase the concentration of the drug in duodenum and reduce the concentration in plasma avoiding systemic effects. This system could be useful for other intestinal local treatments in order to reduce doses and increase drug availability in target tissues.

Purpose: The aim of this study was to evaluate the chemomechanical properties, antibacterial activity, and cytotoxicity of an experimental adhesive resin containing halloysite nanotubes (HNT), doped with alkyl trimethyl ammonium bromide (ATAB). Materials and Methods: A filler of HNT doped with ATAB was obtained (ATAB:HNT) and incorporated (5 wt%) into a resin blend made of bisphenol A glycerolate dimethacrylate, 2-hydroxyethyl methacrylate and a photoinitiator/co-initiator system (GATAB:HNT). The same resin blend without ATAB:HNT was used as control (Ctrl). The ATAB:HNT filler was assessed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The two tested adhesives were evaluated for degree of conversion (DC) in vitro and in situ, softening in alcohol, dentin microtensile bond strength (μTBS), antibacterial activity, and cytotoxicity (n = 5). Results: SEM showed that the nanotubes had a characteristic tubular-needle morphology, while the TEM analysis confirmed the presence of ATAB inside the lumens of HNT. The incorporation of ATAB:HNT induced no reduction (p > 0.05) of the DC either in situ or in vitro. No difference was encountered after the softening challenge test (p > 0.05) and no difference was found in μTBS between the two adhesives, both at 24 h (p > 0.05) and after 6 months of storage in distilled water (p > 0.05). However, ATAB:HNT reduced Streptococcus mutans viability (p < 0.05) without a cytotoxic effect on pulp cells (p > 0.05). Conclusions: GATAB:HNT adhesive demonstrated appropriate polymerization without significant differences in softening after solvent immersion, while concomitantly maintaining reliable bond strength after 6 months of water aging. Moreover, the ATAB:HNT filler can provide antibacterial activity to the adhesive resin without affecting pulp cell viability.

Nano-enabled lipid based drug delivery systems offer a platform to overcome challenges encountered with current failed leads in the treatment of parasitic and infectious diseases. When prepared with FDA or EMA approved excipients, they can be readily translated without the need for further toxicological studies, while they remain affordable and amenable to scale-up. Buparvaquone (BPQ), a hydroxynapthoquinone with in vitro activity in the nanomolar range, failed to clinically translate as a viable treatment for visceral leishmaniasis due to its poor oral bioavailability limited by its poor aqueous solubility (BCS Class II drug). Here we describe a self-nanoemulsifying system (SNEDDS) with high loading and thermal stability up to 6 months in tropical conditions able to enhance the solubilisation capacity of BPQ in gastrointestinal media as demonstrated by flow-through cell and dynamic in vitro lipolysis studies. BPQ SNEDDS demonstrated an enhanced oral bioavailbility compared to aqueous BPQ dispersions (probe – sonicated) resulting in an increased plasma AUC0-24 by 55% that is four fold higher than any previous reported values for BPQ formulations. BPQ SNEDDS can be adsorbed on low molecular glycol chitosan polymers forming solid dispersions that when compressed into tablets allow the complete dissolution of BPQ in gastrointestinal media. BPQ SNEDDS and BPQ solid SNEDDS demonstrated potent in vitro efficacy in the nanomolar range (<37 nM) and were able to near completely inhibit parasite replication in the spleen and 48 ± 48 and 56 ± 23% inhibition of the parasite replication in the liver respectively compared to oral miltefosine after daily administration over 10 days. The proposed platform technology can be used to elicit a range of cost-effective and orally bioavailable non-invasive formulations for a range of antiparasitic and infectious disease drugs that are needed for closing the global health innovation gap.

The aims of this study were to assess, in vitro, the possibility of administering propranolol transdermally and to evaluate the usefulness of the dermatopharmacokinetic (DPK) method in assessing the transport of drugs through stratum corneum, using propranolol as a model compound. Four chemical enhancers (decenoic and oleic acid, laurocapram, and R-(+)-limonene) and iontophoresis at two current densities, 0.25 and 0.5 mA/cm2 were tested. R-(+)-limonene, and iontophoresis at 0.5 mA/cm2 were proven to be the most efficient in increasing propranolol transdermal flux, both doubled the original propranolol transdermal flux. Iontophoresis was demonstrated to be superior than the chemical enhancer because it allowed faster delivery of the drug. The DPK method was sufficiently sensitive to detect subtle vehicle-induced effects on the skin permeation of propranolol. The shorter duration of these experiments and their ability to provide mechanistic information about partition between vehicle and skin and diffusivity through skin place them as practical and potentially insightful approach to quantify and, ultimately, optimize topical bioavailability.