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Esta tesis se centra en el diseño y evaluación de hidrogeles de polisacáridos para la administración colónica de fármacos. Estos hidrogeles tienen como objetivo mejorar el tratamiento de enfermedades colónicas como la colitis ulcerosa y la enfermedad de Crohn. La investigación aborda la preparación y caracterización de estos hidrogeles basados en gomas naturales (xantana y garrofina), evaluando su bioadhesión y capacidad de liberación de fármacos como el acetónido de triamcinolona y el ciprofloxacino. Además, explora el impacto de las ciclodextrinas en las propiedades de liberación de los hidrogeles y su eficacia en modelos animales de colitis. Concluye discutiendo los resultados y sugiriendo futuras direcciones de investigación para el desarrollo de hidrogeles inteligentes y nuevas aplicaciones terapéuticas.

Diabetes mellitus has emerged as one of the most prevalent chronic diseases of the 21st century with serious complications worsening its progression. This doctoral thesis is divided into four chapters focused on improving the treatment of complications associated with diabetes mellitus. In the first chapter, the subcutaneous administration of biopharmaceuticals is adressed as an effective and patientpreferred alternative to intravenous infusions. In the second chapter, supercritical foaming technology was utilised to manufacture PLGA implants loaded with dexamethasone and bevacizumab. The third chapter develops a drug delivery system to enhance the penetration of antifungal drugs into nails with onychomycosis. The fourth chapter develops an inert coating for in vitro testing with 3D printed devices.

[Abstract] 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 -20ºC 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 -20ºC is stable for 120 days protected from light, presenting high potential for its translation into clinical practice when commercial presentations are not available.

The study assesses the potential of combining xanthan gum and locust bean gum to create controlled-release hydrogels and also examines how compressing the polysaccharide blends affects their behavior. The research involved evaluating the rheological properties of aqueous dispersion of these gums and their mixtures using a rotational rheometer. Xanthan gum displayed a pseudoplastic Bingham behavior, while locust bean gum exhibited lower viscosity and shear thinning behavior. Gum blends showed an intermediate behavior with varying yield shear stress based on the gum proportions in the mixture. The flow index (n) and the consistency index (K) were calculated using the Power Law model (Ostwald de Waele relationship). The values of n are between 0.6 (Xanthan gum) and 0.1 (locust bean gum), with the blends showing intermediate values. These values are characteristic of shear-thinning systems and show a higher deviation of Xanthan gum from Newtonian behavior than LBG. Additionally, the k values indicate higher consistency for the Xanthan dispersions and similar behavior for the mixtures of the two polysaccharides, regardless of their proportion. Precompression at 433.6 MPa for 5 min reduced the dispersion viscosity of xanthan gum by 50% at a shear rate of 2s−1, decreasing it from 70 Pa s to 34 Pa s, while having a minimal impact on the rheological behavior of locust bean gum, which changed from 0.18 Pa s to 0.23 Pa s at a shear rate of 2s−1. Temperature also decreased the xanthan gum dispersion viscosity. Oscillatory rheology tests highlighted differences between xanthan gum and locust bean gum dispersions. Xanthan gum formed a durable three-dimensional network with bonds, while locust bean gum exhibited a network with a shorter shelf life. Precompression significantly altered the rheological behavior of the gum blends, increasing the storage and loss moduli. Drug diffusion tests developed in Franz-Chien cells showed no significant differences in diffusion profiles between

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

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.

In the present thesis, different topical-ophthalmic formulations of antifungals and cyclodextrins were developed for the treatment of fungal keratitis. In addition, the safety and permanence on the ocular surface of different cyclodextrins were evaluated in order to know their behavior in the eye and to optimize their use in the development of new ophthalmic formulations.

Liquid crystals (LCs) possess unique physicochemical properties, translatable into a wide range of applications. To date, lipidic lyotropic LCs (LLCs) have been extensively explored in drug delivery and imaging owing to the capability to encapsulate and release payloads with different characteristics. The current landscape of lipidic LLCs in biomedical applications is provided in this review. Initially, the main properties, types, methods of fabrication and applications of LCs are showcased. Then, a comprehensive discussion of the main biomedical applications of lipidic LLCs accordingly to the application (drug and biomacromolecule delivery, tissue engineering and molecular imaging) and route of administration is examined. Further discussion of the main limitations and perspectives of lipidic LLCs in biomedical applications are also provided