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Background: Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in several tissues and organs causing, among others, severe eye symptoms. The high instability of cysteamine eye drops makes it difficult to develop formulations with an acceptable shelf life to be prepared in hospital pharmacy departments. Previously, a new compounded formulation of cysteamine eye drops in hyaluronic acid (HA) packaged in innovative single-dose systems was developed. Methods: Long-term stability at -20 °C of this formulation was studied considering the content of cysteamine, pH, osmolality, viscosity, and microbiological analysis. The oxygen permeability of single-dose containers was also studied and an ocular biopermanence study was conducted in healthy volunteers measuring lacrimal stability and volume parameters. Results: Data confirm that cysteamine concentration remained above 90% for 120 days, all parameters remaining within the accepted range for ophthalmic formulations. The permeability of the containers was reduced over time, while ocular biopermanence was maintained despite the freezing process and storage time. Conclusions: 0.55% cysteamine hydrochloride formulation in HA and packaged in single-dose containers preserved at -20 °C is stable for 120 days protected from light, presenting high potential for its translation into clinical practice when commercial presentations are not available

Nephropathic cystinosis is a rare autosomal recessive metabolic disease due to mutations in the CTNS gen codifying for cystinosin, a lysosomal symporter. It is characterized by the accumulation of cystine crystals in lysosomes causing end-stage renal damage and blindness in patients under ten years of age. Currently, there is no cure and the only palliative treatment, cysteamine, presents several limitations including the lack of cure for the disease, the adverse effects, and the complexity of the indicated treatment for life. Recent findings indicate that the intra-lysosomal accumulation of cystine alters key processes such as phagocytosis, redox balance, and autophagy, causing a molecular imbalance that, to date, has not been characterized in detail.

This doctoral thesis focuses on offering therapeutic alternatives through pharmaceutical compounding and drug repositioning from the hospital pharmacy to cover therapeutic gaps. An ophthalmic compounded formulation of cysteamine in hyaluronic acid packaged in novel single-dose containers was developed for the treatment of ocular cystinosis. On the other hand, an inhaled compounded formulation of ethanol was developed for the treatment of SARS-CoV-2 infection, and subsequently studied for efficacy and safety in the phase II clinical trial ALCOVID-19. In both cases, appropriate galenic development and characterisation has been performed in conjunction with preclinical pharmacokinetic studies prior to appropriate translation into clinical practice.

[Resumen]: Introducción: existe una amplia variedad de fórmulas o preparados de nutrición enteral y fórmulas o preparados infantiles. La consulta de información relacionada debe hacerse en las herramientas propias de cada laboratorio, lo que dificulta la visión crítica y la comparativa entre las mismas. Objetivo: describir el desarrollo de NEmecum como la primera web que permite realizar una búsqueda dirigida e independiente de fórmulas de nutrición o preparados infantiles, analizar el abanico nutricional actual en España y evaluar los datos de uso de la herramienta. Métodos: se desarrolló la estructura de una base de datos que unifica los parámetros de todas las fórmulas y se analizó el abanico nutricional español. Posteriormente, se seleccionaron los principales algoritmos de búsqueda dirigida y se codificó la herramienta digital. Se llevó a cabo una intensa difusión y se evaluó el impacto obtenido. Se analizaron el perfil de usuarios y centros registrados y los datos de uso de la herramienta y se evaluó su usabilidad mediante el cuestionario System Usability Scale (SUS). Resultados: se obtuvo una web responsive de acceso gratuito (http://nemecum.com) que permite realizar búsquedas dirigidas en base a unos filtros de búsqueda preestablecidos. La herramienta permitió analizar detalladamente el abanico nutricional en España, observándose la gran variedad de fórmulas disponibles de similares características. La campaña de difusión consiguió incrementar su uso de forma exponencial y cuenta actualmente con 1.370 usuarios y 79 centros registrados. La usabilidad fue valorada como excelente. Conclusión: el desarrollo de NEmecum supone una herramienta valiosa en la búsqueda y consulta de datos de fórmulas o preparados de nutrición enteral y fórmulas o preparados infantiles., [Abstract]: Introduction: there is a wide variety of enteral nutrition and infant formulas preparations. When there is a need to find infomation on a product, only the infomation from industy is available. Comparison amomg products becomes then ardous. Objective: to describe the development of NEmecum as the first website that allows a directed and independent search for enteral nutrition products and infant formulas, currently available in Spain, and to evaluate the initial use of NEmecum. Methods: the structure of a database that unifies the parameters of all formulas was developed, and the nutritional composition of all formulas was analyzed. Subsequently, the main search algorithms were selected and the digital tool was codified. Intensive dissemination was performed and the impact was evaluated. The profile of users and registered centers and the use of the tool were analyzed, and its usability was evaluated using the System Usability Scale (SUS) questionnaire. Results: a free-access responsive website (http://nemecum.com) that allows searches based on pre-established search filters was obtained. This tool allows for a detailed analysis avalaible formulas in Spain by observing a wide variety of formulas with similar characteristics. The dissemination campaign managed to increase its use exponentially, currently reaching 1,370 users and 79 registered centers. Usability was rated as excellent. Conclusion: the development of the NEmecum represents a valuable tool in the search and consultation of the characteristics of enteral nutrition formulas and infant preparations.

[Abstract] In the last decades, personalized medicine has been increasing its presence in different fields of medicine, including ophthalmology. A new factor that can help us direct medicine towards the challenge of personalized treatments is the microbiome. The gut microbiome plays an important role in controlling immune response, and dysbiosis has been associated with immune-mediated diseases such as non-infectious uveitis (NIU). In this review, we gather the published evidence, both in the pre-clinical and clinical studies, that support the possible role of intestinal dysbiosis in the pathogenesis of NIU, as well as the modulation of the gut microbiota as a new possible therapeutic target. We describe the different mechanisms that have been proposed to involve dysbiosis in the causality of NIU, as well as the potential pharmacological tools that could be used to modify the microbiome (dietary supplementation, antibiotics, fecal microbiota transplantation, immunomodulators, or biologic drugs) and, consequently, in the control of the NIU. Furthermore, there is increasing scientific evidence suggesting that the treatment with anti-TNF not only restores the composition of the gut microbiota but also that the study of the composition of the gut microbiome will help predict the response of each patient to anti-TNF treatment.

In the present thesis, the research, development, and characterization processes of controlled drug delivery systems intended for the treatment of two different ocular pathologies were described. Firstly, different types of lactoferrin-loaded nanoparticles intended for topical ophthalmic administration were developed and proposed as the first pharmacological alternative for the Keratoconus (KC) treatment. On the other hand, idebenone-loaded polymeric implants and microparticles were designed and proposed as new therapeutic strategies for the treatment of Leber's Hereditary Optic Neuropathy (LHON).

Nanostructured lipid carriers (NLC) are novel lipidic nanosystems that provide significant improvements in terms of high drug loading capacity and controlled drug release. The purpose of the present work was based on the design, development, and physicochemical characterization of lactoferrin-loaded NLCs as a new therapeutic alternative for the keratoconus treatment. Lactoferrin-loaded NLCs were successfully prepared by a double emulsion/solvent evaporation method. The resultant NLC were assessed in terms of particle size, size distribution, surface charge, morphology, encapsulation efficiency (EE), loading capacity (LC), stability, cytotoxicity, in vitro release, and ocular surface retention. Resulting data showed a size of 119.45 ± 11.44 nm, a 0.151 ± 0.045 PDI value and a surface charge of −17.50 ± 2.53 mV. Besides, high EE and LC values were obtained (up to 75%). The in vitro release study demonstrated a lactoferrin controlled release pattern. NLCs were also stable, non-toxic and show mucoadhesive properties. Thus, a consistent preclinical base was obtained, where NLC may be considered as a potential controlled release novel drug delivery system of lactoferrin for the keratoconus treatment