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El objetivo general es acompañar al grupo piloto de estudiantes que han iniciado el proceso de constituir una ETCu dentro de la UCM así como despertar entre los nuevos estudiantes de máster y doctorado nuevas vocaciones emprendedoras, especialmente dentro de las disciplinas STEM donde existe una mayor brecha de género y en donde se fomente el trabajo en equipo entre hombres y mujeres.

Las infecciones protésicas articulares o PJIs (periprosthetic joint infections) son una complicación frecuente de las artroplastias. La prevalencia para las artroplastias de cadera es superior al 4% lo que produce un gran impacto negativo en los pacientes y en los sistemas de salud. Actualmente, la intervención más común consiste en un procedimiento quirúrgico, en el que se retira la prótesis infectada y se aplica un cemento óseo cargado con antibióticos que se mantiene en la articulación durante varias semanas antes de colocar una nueva prótesis. Sin embargo, la cantidad liberada de antibióticos no es suficiente y el cemento óseo puede alterar las propiedades biomecánicas de la articulación. Además, tanto este como otros tratamientos convencionales no son eficaces frente a todos los patógenos que pueden producir las PJIs. Como alternativa se están desarrollando nuevos abordajes para el tratamiento de las PJIs. Sin embargo, debido a que aún se encuentran en fases iniciales, su traslación clínica no podrá llevarse a cabo en un futuro cercano. Una forma de acelerar este proceso es desarrollando modelos in vitro en 3D que sean más complejos y representativos de las condiciones in vivo, en este caso del espacio articular, con el fin de obtener resultados más fiables y predictivos. El uso de estos modelos puede ayudar también a la reducción del número de animales empleados en investigación, una tendencia al alza en los últimos años, debido a su elevado coste y por cuestiones éticas..., Periprosthetic joint infections (PJIs) are a common complication of arthroplasties, with a prevalence of more than 4% for hip arthroplasties, which has a negative impact on both patients and healthcare systems. The main current treatment consists of a surgical procedure, where the infected prosthesis is removed and an antibiotic-loaded bone cement is placed, remaining at the joint for several weeks before replacement with a new prosthesis. However, drug release is not adequate, and additionally, the bone cement can alter the biomechanical properties of the joint. Hence, conventional treatments are far from ideal and are not effective against all the pathogens that cause PJIs and cannot be used simultaneously as prophylaxis and treatment. As an alternative, new strategies are under development for the treatment of PJIs, and most of them are in early stages, requiring further in vitro and in vivo evaluation. These studies can take several years, so their clinical translation will not take place soon. One way to speed up this process is the development of advanced in vitro 3D models that are more complex and representative of in vivo conditions, in this case of the joint space, being able to obtain more reliable and predictive results. The use of these models can also help to reduce the number of animals used in research, an upward trend in recent years, due to its high cost and ethical concerns...

Los elevados tiempos de análisis de estabilidad de medicamentos y la estrecha ventana de caducidad de preparados oficinales y fórmulas magistrales, han supuesto un reto para la industria farmacéutica y la farmacia comunitaria a lo largo de los años. Según el Consejo Internacional para la Armonización de los Requisitos Técnicos para Productos Farmacéuticos de Uso Humano (ICH) junto con la Organización Mundial de la Salud (OMS), se han proporcionado un conjunto de directrices (ICH Q1A-F, Q3A-B, Q5C, Q6A-B) con la intención de unificar los estándares para la Unión Europea, Japón y los Estados Unidos. Los estudios de estabilidad de una sustancia farmacológica deben incluir condiciones de almacenamiento que evalúen diferentes aspectos de temperatura y humedad durante un mínimo de 12 meses. Por este motivo, han surgido como un enfoque novedoso para predecir la estabilidad a largo plazo de forma más eficiente, los estudios de Estabilidad Predictiva Acelerada (APS) que son llevados a cabo durante un período de 3-4 semanas combinando temperaturas extremas (> 40 °C) y condiciones de humedad relativa (HR > 50 %)..., The long drug stability analysis times and the narrow expiry date of official preparations and compounding formulations have been a challenge for the pharmaceutical industry and community pharmacies over the years.According to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) together with the World Health Organization (WHO), a set of guidelines have been provided (ICH Q1A-F, Q3A-B, Q5C, Q6A-B) with the intention of unifying standards for the European Union, Japan and the United States.Stability studies of a drug substance must include storage conditions that evaluate different aspects of temperature and humidity for a minimum of 12 months. For this reason, Accelerated Predictive Stability (APS) studies have emerged as a novel approach to predict long-term stability more efficiently, which are carried out over a period of 3-4 weeks combining extreme temperatures (> 40 °C) and relative humidity conditions (RH > 50%).Currently, industrially fabricated medicines have a well-defined expiry date supported by rigorous studies before they are approved to be commercialised. However, the expiry date of topical, oral and parenteral formulations prepared in both hospital and community pharmacies of compounding formulations and tends to be shorter, especially when data demonstrating a longer stability period are not available...

Pharmaceutical stability studies continue to be a key parameter in the development and manufacture of both drug substance and drug pruducts. The data collected from stability studies across the entire life cycle of drug development can be used to identify optimum formulation and manufacturing strategies, determine packaging and storage requirements, assign shelf-life or retest dates. Currently this information serves as both a key learning tool for industry as well as fulfilling a regulatory requirement for drug approval.Predictive modelling tools such as Accelerated Predictive Stability (APS), Risk Based Predictive Stability (RBPS) and the Accelerated Stability Assessment Program (ASAP) have gained prominence in the pharmaceutical industry as a means to improve understanding of drug degradation mechanisms and other key stability characteristics. Amorphous solid dispersions are currently one of the most common approaches utilised by the pharmaceutical industry to overcome solubility and dissolution issues when tackling the formulation of a poorly water-soluble drug for oral administration. Enhancing the solubility of hydrophobic drugs remains a challenge for oral delivery as their low solubility often results in reduced bioavailability being required for the administration of higher doses to ensure that a therapeutic dose is delivered to the target organ. Dispersing an active pharmaceutical ingredient (API) within an amorphous carrier – namely a polymer that controls drug release is one of the most common strategies to increase the dissolution rate of hydrophobic drugs. Several methods exist that may be used to produce amorphous solid dispersions but only a few, such as spray drying (SD) and hot melt extrusion (HME), are easily scalable..., Los estudios de estabilidad farmacéutica siguen siendo un parámetro clave en el desarrollo y la fabricación tanto de sustancias farmacológicas como de medicamentos y producto terminado. Los datos recopilados de los estudios de estabilidad a lo largo de todo el ciclo de vida del desarrollo de fármacos se pueden utilizar para identificar estrategias óptimas de formulación y fabricación, determinar los requisitos de acondicionamiento y almacenamiento, asignar fechas de vida útil o de testeo. Actualmente, esta información sirve tanto como una herramienta de aprendizaje clave para la industria como para cumplir con un requisito regulatorio para la aprobación de medicamentos. Las herramientas de predicción como la Estabilidad Predictiva Acelerada (APS), la Estabilidad Predictiva Basada en el Riesgo (RBPS) y el Programa de Evaluación de Estabilidad Acelerada (ASAP) han ganado importancia en la industria farmacéutica como un medio para mejorar la comprensión de los mecanismos de degradación de fármacos y otras características clave de estabilidad de medicamentos. Las dispersiones sólidas amorfas son actualmente uno de los enfoques más comunes utilizados por la industria farmacéutica para superar los problemas de solubilidad y disolución al abordar la formulación de un fármaco poco soluble en agua para su administración oral. Mejorar la solubilidad de los fármacos hidrofóbicos sigue siendo un desafío para su administración oral, ya que su baja solubilidad a menudo conlleva una biodisponibilidad muy baja siendo necesaria la administración de dosis más elevadas. La dispersión de un ingrediente farmacéutico activo (API) dentro de un vehículo amorfo, es decir, un polímero que controla la liberación del fármaco, es una de las estrategias más comunes para aumentar la velocidad de disolución de los fármacos hidrofóbicos. Existen varios métodos que se pueden usar para producir dispersiones sólidas amorfas, pero solo unos pocos, como el secado por atomización (SD) y la extrusión por

La anfotericina B (AmB) es un fármaco caracterizado por presentar un amplio espectro antifúngico y antiparasitario. Se administra por vía parenteral debido a su escasa absorción oral. A pesar de su eficacia, su uso clínico se ve limitado por la aparición de eventos adversos, principalmente nefrotoxicidad y hemólisis. La Fungizona® fue el primer medicamento comercializado, pero, en la mayoría de los países, ha sido desplazada por formulaciones lipídicas de AmB (Abelcet® Amphocil® y Ambisome®) que presentan un balance beneficio/riesgo más favorable, sin embargo, tienen un coste muy elevado y requieren de condiciones ambulatorias/ hospitalarias para administrarlos al paciente. Por este motivo, existe una necesidad clínica de desarrollar formulaciones de AmB que presenten una buena relación coste-eficacia y que sean seguras para tratar infecciones fúngicas y parasitarias. Con este objetivo se desarrollaron nuevas formulaciones orales de AmB combinando diferentes excipientes mediante el recubrimiento de pellets con formulaciones líquidas micelares de AmB. Con estas nuevas formulaciones se consigue mejorar el índice terapéutico en comparación con la AmB convencional, mejorando la actividad in vitro frente a candida y disminuyendo su toxicidad hemolítica, lo que se debe, principalmente a los excipientes utilizados en la formulación líquida que recubre los pellets, así como de la proporción de los mismos..., Amphotericin B (AmB) is a broad antifungal and antiparasitic drug, usually administered by intravenous infusion due to its low aqueous solubility and low oral absorption. AmB clinical use is limited by its acute toxicity presenting, mainlys fever and gastrointestinal symptoms as well as chronic toxicity related to haemolysis and nephrotoxicity. Fungizone’s low therapeutic index is responsible for its replacement by novel lipid AmB formulations (Abelcet®, Amphocil® y Ambisome®) with more favourable risk-benefit ratio, but witha very high cost, which limits their use in developing countries. Thus, there is an increased need to engineer cost-effective and safe AmB formulations for the treatment of fungal and parasitic diseases.Novel oral AmB formulations were developed combining different excipients by spray coated beads with AmB micellar formulations. These new formulations improve the therapeutic index compared to conventional AmB as well as thein vitro activity against candida. The AmB pellets formulations showed a reduction in AmB haemolytic toxicity. These advantages are mainly due to the excipients used in the liquid formulation to the coated layer and the ratio between beads and coating excipients...

Background: College students are vulnerable to suffering from anxiety and depression. Moreover, mental disorders can contribute to drug consumption or inappropriate use of prescribed drugs. Studies on this topic in Spanish college students are limited. This work analyses anxiety and depression and psychoactive drug intake pattern in the post-COVID era in college students. Methods: An online survey was conducted among college students from UCM (Spain). The survey collected data including demographic, academic student perception, GAD-7 and PHQ-9 scales, and psychoactive substances consumption. Results: A total of 6,798 students were included; 44.1% (CI95%: 42.9 to 45.3) showed symptoms of severe anxiety and 46.5% (CI95%: 45.4 to 47.8) symptoms of severe or moderately severe depression. The perception of these symptoms did not change after returning to face-to-face university classes in the post-COVID19 era. Despite the high percentage of cases with clear symptoms of anxiety and depression, most students never had a diagnosis of mental illnesses [anxiety 69.2% (CI95%: 68.1 to 70.3) and depression 78.1% (CI95%: 77.1 to 79.1)]. Regarding psychoactive substances, valerian, melatonin, diazepam, and lorazepam were the most consumed. The most worrying issue was the consumption of diazepam, 10.8% (CI95%: 9.8 to 11.8), and lorazepam, 7.7% (CI95%: 6.9 to 8.6) without medical prescription. Amongst illicit drugs, cannabis is the most consumed. Limitations: The study was based on an online survey. Conclusions: The high prevalence of anxiety and depression aligned with poor medical diagnosis and high intake of psychoactive drugs should not be underestimated. University policies should be implemented to improve the well-being of students., Observatorio del Estudiante, Universidad Complutense de Madrid, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

The incidence and prevalence of invasive fungal infections have increased significantly over the last few years, leading to a global health problem due to the lack of effective treatments. Amphotericin B (AmB) and itraconazole (ITR) are two antifungal drugs with different mechanisms of action. In this work, AmB and ITR have been formulated within granules to elicit an enhanced pharmacological effect, while enhancing the oral bioavailability of AmB. A Quality by Design (QbD) approach was utilised to prepare fixed-dose combination (FDC) granules consisting of a core containing AmB with functional excipients, such as inulin, microcrystalline cellulose (MCC), chitosan, sodium deoxycholate (NaDC) and Soluplus® and polyvinyl pyrrolidone (PVP), coated with a polymeric layer containing ITR with Soluplus® or a combination of Poloxamer 188 and hydroxypropyl methyl cellulose-acetyl succinate (HPMCAS). A Taguchi designs of experiments (DoE) with 7 factors and 2 levels was carried out to understand the key factors impacting on the physicochemical properties of the formulation followed by a Box-Behnken design with 3 factors in 3 levels chosen to optimise the formulation parameters. The core of the FDC granules was obtained by wet granulation and later coated using a fluidized bed. In vitro antifungal efficacy was demonstrated by measuring the inhibition halo against different species of Candida spp., including C. albicans (24.19-30.48 mm), C. parapsilosis (26.38-27.84 mm) and C. krusei (11.48-17.92 mm. AmB release was prolonged from 3 to 24 hours when the AmB granules were coated. In vivo in CD-1 male mice studies showed that these granules were more selective towards liver, spleen and lung compared to kidney (up to 5-fold more selective in liver, with an accumulation of 8.07 µg AmB/g liver after twice-daily 5 days administration of F2), resulting in an excellent oral administration option in the treatment of invasive mycosis. Nevertheless, some biochemical alterations were found, Banco Santander, Science Foundation Ireland, Ministerio de Ciencia, Innovación y Universidades (España), Unión Iberoamericana de Universidades, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, FALSE, pub

Ministerio de Ciencia e Innovacion de España, Science Foundation Ireland, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

Sulfur and nitrogen mustards, bis(2-chloroethyl)sulfide and tertiary bis(2-chloroethyl) amines, respectively, are vesicant warfare agents with alkylating activity. Moreover, oxidative/nitrosative stress, inflammatory response induction, metalloproteinases activation, DNA damage or calcium disruption are some of the toxicological mechanisms of sulfur and nitrogen mustard-induced injury that affects the cell integrity and function. In this review, we not only propose melatonin as a therapeutic option in order to counteract and modulate several pathways involved in physiopathological mechanisms activated after exposure to mustards, but also for the first time, we predict whether metabolites of melatonin, cyclic-3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and N1-acetyl-5-methoxykynuramine could be capable of exerting a scavenger action and neutralize the toxic damage induced by these blister agents. NLRP3 inflammasome is activated in response to a wide variety of infectious stimuli or cellular stressors, however, although the precise mechanisms leading to activation are not known, mustards are postulated as activators. In this regard, melatonin, through its anti-inflammatory action and NLRP3 inflammasome modulation could exert a protective effect in the pathophysiology and management of sulfur and nitrogen mustard-induced injury. The ability of melatonin to attenuate sulfur and nitrogen mustard-induced toxicity and its high safety profile make melatonin a suitable molecule to be a part of medical countermeasures against blister agents poisoning in the near future., Sección Deptal. de Farmacología y Toxicología (Veterinaria), Sección Deptal. de Farmacia Galénica y Tecnología Alimentaria (Veterinaria), Fac. de Veterinaria, TRUE, pub, Descuento UCM

El emprendimiento como disciplina científica se asienta sobre dos pilares fundamentales: la transversalidad y la internacionalización. Son estos los que requieren una planificación para la aplicación de metodologías que fortalezcan el emprendimiento., Entrepreneurship as a scientific discipline is based on two fundamental pillars: transversality and internationalisation. transversality and internationalisation. It is these that require planning for the application of methodologies application of methodologies that strengthen entrepreneurship.

Chagas disease (CD) is a parasitic zoonosis endemic in Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective when received at the early stages of the disease and it involved two drugs (nifurtimox (NFX) and benznidazole (BNZ)). Both treatments require multiple daily administrations of high doses, suffer from variable efficacy and insufficient efficacy in chronic CD, many side effects, and a very long duration of treatment that results in poor compliance, while combined available therapies that lead to reduced duration of treatment are not available and polypharmacy reduces compliance and increases the cost further. Here we present self-nanoemulsified drug delivery systems (SNEDDS) able to produce easily scalable combined formulations of NFX and BNZ that can allow for tailoring of the dose and can be easily converted to oral solid dosage form by impregnation on mesoporous silica particles. SNEDDS demonstrated an enhanced solubilisation capacity for both drugs as demonstrated by flow-through studies and in vitro lipolysis studies. High loading of SNEDDS to Syloid 244 and 3050 silicas (2:1 w/w) allowed clinically translatable amounts of both NFX and BNZ to be loaded. Tablets prepared from NFX-BNZ combined SNEDDS loaded on Syloid 3050 silicas demonstration near complete dissolution in the flow through cell apparatus compared to NFX and BNZ commercial tablets respectively (Lampit® and Rochagan®). NFX-BNZ-SNEDDS demonstrated nanomolar efficacy in epimastigotes and amastigotes of T. cruzi with acceptable selectivity indexes and demonstrated enhanced survival and reduced parasitaemia in acute murine experimental models of CD. Thus, the results presented here illustrate the ability for an easily scalable and personalised combination oral therapy prepared from GRAS excipients, enabling treatment access worldwide for the treatment of CD.

Oily excipients are vital components of dermatological products. In this study, the in vitro and in vivo characteristics of Wild Olive Oil (WOO) were compared with two other types of olive oils: Extra Virgin Olive Oil (EVOO) and Virgin Olive Oil (VOO). This work has also included Liquid Paraffin (LP) and Rosehip Oil (RO) as reference oils. Melatonin was used in the study as a model drug to demonstrate the antioxidant capacity of the oils. The melatonin carrier capacity and antioxidant performance was related to the degree of unsaturation of the oils and was highest for RO and WOO and lowest for LP. However, the most stable oil to oxidation was LP. The in vivo performance of the oils in the skin of eight healthy volunteers was investigated with a dermoanalyser. The highest increment of oil and hydration in the skin was obtained with RO. The lowest perception of oiliness was described for WOO, which produced the highest increase in elasticity of the skin area where it was applied. An in vitro-in vivo correlation was therefore performed through multivariable analysis (MVA)., Universidad Complutense de Madrid, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, Instituto Universitario de Farmacia Industrial, TRUE, pub

The combination of lopinavir/ritonavir remains one of the first-line therapies for the initial antiretroviral regimen in pediatric HIV-infected children. However, the implementation of this recommendation has faced many challenges due to cold-chain requirements, high alcohol content, and unpalatability for ritonavir-boosted lopinavir syrup. In addition, the administration of crushed tablets has shown a detriment for the oral bioavailability of both drugs. Therefore, there is a clinical need to develop safer and better formulations adapted to children’s needs. This work has demonstrated, for the first time, the feasibility of using direct powder extrusion 3D printing to manufacture personalized pediatric HIV dosage forms based on 6 mm spherical tablets. H-bonding between drugs and excipients (hydroxypropyl methylcellulose and polyethylene glycol) resulted in the formation of amorphous solid dispersions with a zero-order sustained release profile, opposite to the commercially available formulation Kaletra, which exhibited marked drug precipitation at the intestinal pH., Institutional Fund Projects, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

La anfotericina B (AmB) es un fármaco caracterizado por presentar un amplio espectro antifúngico y antiparasitario. Se administra por vía parenteral debido a su escasa absorción oral. A pesar de su eficacia, su uso clínico se ve limitado por la aparición de eventos adversos, principalmente nefrotoxicidad y hemólisis. La Fungizona® fue el primer medicamento comercializado, pero, en la mayoría de los países, ha sido desplazada por formulaciones lipídicas de AmB (Abelcet® Amphocil® y Ambisome®) que presentan un balance beneficio/riesgo más favorable, sin embargo, tienen un coste muy elevado y requieren de condiciones ambulatorias/ hospitalarias para administrarlos al paciente. Por este motivo, existe una necesidad clínica de desarrollar formulaciones de AmB que presenten una buena relación coste-eficacia y que sean seguras para tratar infecciones fúngicas y parasitarias. Con este objetivo se desarrollaron nuevas formulaciones orales de AmB combinando diferentes excipientes mediante el recubrimiento de pellets con formulaciones líquidas micelares de AmB. Con estas nuevas formulaciones se consigue mejorar el índice terapéutico en comparación con la AmB convencional, mejorando la actividad in vitro frente a candida y disminuyendo su toxicidad hemolítica, lo que se debe, principalmente a los excipientes utilizados en la formulación líquida que recubre los pellets, así como de la proporción de los mismos...

“Introducción “ La elevada incidencia y prevalencia de las infecciones fúngicas y parasitarias supone un grave problema de salud pública a nivel global debido a la complejidad de dichos tratamientos, así como a la aparición de resistencias. Los tratamientos existentes actualmente engloban desde la administración parenteral de anfotericina B (AmB), con efectos nefrotóxicos y hemolíticos, hasta el uso oral de miltefosina, que puede resultar elevadamente tóxica a nivel gastrointestinal y además es teratogénica. AmB es el fármaco de referencia en la terapia antifúngica y antiparasitaria desde hace décadas, aunque afortunadamente el uso de la presentación Fungizona® ha sido desplazado por la formulación liposomal de AmB (AmBisome®) y otras presentaciones lipídicas, reduciendo su toxicidad. Además, la AmB presenta tres estados de agregación en solución y desarrolla su actividad a través de dos mecanismos de acción. La modulación del estado de agregación para desencadenar uno u otro mecanismo de acción es una estrategia prometedora en el tratamiento de estas infecciones. Los mecanismos de acción que permiten la actividad antiinfecciosa de la AmB consisten en la ruptura de la membrana plasmática y la inducción del estrés oxidativo. La ruptura de la membrana plasmática se produce debido a la unión del fármaco al ergosterol presente en células fúngicas y parasitarias, que dan lugar a la formación de poros que liberan iones, produciendo una alteración electrolítica que finaliza con la muerte celular; mientras que la inducción del estrés oxidativo tiene lugar debido a un aumento de la concentración de radicales libres que provocan daños en la célula, conllevando la pérdida de la actividad metabólica de ésta. Actualmente, sólo existen formulaciones de AmB de administración intravenosa disponibles en el mercado debido a la baja biodisponibilidad del fármaco a través de otras vías. Por ello, es necesario desarrollar formulaciones que permitan incrementar su biodisponibilidad. Así, “Introduction” An increase in the incidence and prevalence of fungal and parasitic infections has been reported, causing a global health problem due to the complexity of treatments, as well as the appearance of resistances. Current treatments involve parenteral administration of amphotericin B (AmB), with nephrotoxic and hemolytic effects, and also, the oral utilization of miltefosine, which can result highly toxic and teratogenic. AmB has been the reference drug in antifungal and anti-parasitic therapy for decades. The use of the Fungizone® has been downgraded by the liposomal formulation of AmB (AmBisome®) and other lipid formulations, decreasing its toxicity. Moreover, it is well-known that AmB presents three different aggregation states in solution and its activity takes place through two mechanisms of action. Modulating its aggregation state to trigger one or another mechanism of action is a promising strategy in the treatment of these infections. The mechanisms of actions that enable the anti-infective activity of AmB consist on the disruption of plasma membrane and producing oxidative stress. Membrane disruption is produced by the binding of AmB to ergosterol in fungal and parasitic cells, triggering the formation of pores that generate the leakage of ions, resulting in an electrolytic disturbance which finalizes with cell death; while oxidative stress induction is produced due to an increase in the concentration of free radicals which cause cell damage, and hence a loss in the metabolic activity. Nowadays, only intravenous formulations containing AmB are available in the market due to its low bioavailability through other pathways. Thus, there is an increased clinical need to engineer formulations that promote and enhance its bioavailability. Thereby, topical or oral administration of AmB formulations could be a therapeutic alternative to parenteral formulations. In the last few years, formulations based on liposomes have been developed to improve transderma

Antifungal drugs such as amphotericin B (AmB) interact with lipids and phospholipids located on fungal cell membranes to disrupt them and create pores, leading to cell apoptosis and therefore efficacy. At the same time, the interaction can also take place with cell components from mammalian cells, leading to toxicity. AmB was selected as a model antifungal drug due to the complexity of its supramolecular chemical structure which can self-assemble in three different aggregation states in aqueous media: monomer, oligomer (also known as dimer) and poly-aggregate. The interplay between AmB self-assembly and its efficacy or toxicity against fungal or mammalian cells is not yet fully understood. To the best of our knowledge, this is the first report that investigates the role of excipients in the supramolecular chemistry of AmB and the impact on its biological activity and toxicity. The monomeric state was obtained by complexation with cyclodextrins resulting in the most toxic state, which was attributed to the greater production of highly reactive oxygen species upon disruption of mammalian cell membranes, a less specific mechanism of action compared to the binding to the ergosterol located in fungal cell membranes. The interaction between AmB and sodium deoxycholate resulted in the oligomeric and polyaggregated forms which bound more selectively to the ergosterol of fungal cell membranes. NMR combined with XRD studies elucidated the interaction between drug and excipient to achieve the AmB aggregation states, and ultimately, their diffusivity across membranes. A linear correlation between particle size and the efficacy/toxicity ratio was established allowing to modulate the biological effect of the drug and hence, to improve pharmacological regimens. However, particle size is not the only factor modulating the biological response but also the equilibrium of each state which dictates the fraction of free monomeric form available. Tuning the aggregation state of AmB formu, European Regional Development Fund, European Society of Clinical Microbiology an Infection Diseases (ESCMID), Engineering and Physical Sciences Research Council, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, Instituto Universitario de Farmacia Industrial, TRUE, pub

Blister or vesicant chemical warfare agents (CWAs) have been widely used in different military conflicts, including World War I and the Iran-Iraq War. However, their mechanism of action is not fully understood. Sulfur and nitrogen mustard exert toxic effects not only through the alkylation of thiol-bearing macromolecules, such as DNA and proteins, but also produce free radicals that can develop direct toxic effects in target organs such as the eyes, skin, and respiratory system. The lack of effective treatments against vesicant CWAs-induced injury makes us consider, in this complex scenario, the use and development of melatonin-based therapeutic strategies. This multifunctional indoleamine could facilitate neutralization of the oxidative stress, modulate the inflammatory response, and prevent the DNA damage, as well as the long-term health consequences mediated by vesicant CWAs-induced epigenetic mechanisms. In this context, it would be essential to develop new galenic formulations for the use of orally and/or topically applied melatonin for the prophylaxis against vesicant CWAs, as well as the development of post-exposure treatments in the near future., DGAM-Office Weapons and Material of the Spanish Ministry of Defense for the MELVES project, UCJC (QUIMELTER), Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

Transferosomes, also known as transfersomes, are ultradeformable vesicles for transdermal applications consisting of a lipid bilayer with phospholipids and an edge activator and an ethanol/aqueous core. Depending on the lipophilicity of the active substance, it can be encapsulated within the core or amongst the lipid bilayer. Compared to liposomes, transferosomes are able to reach intact deeper regions of the skin after topical administration delivering higher concentrations of active substances making them a successful drug delivery carrier for transdermal applications. Most transferosomes contain phosphatidylcholine (C18) as it is the most abundant lipid component of the cell membrane, and hence, it is highly tolerated for the skin, decreasing the risk of undesirable effects, such as hypersensitive reactions. The most common edge activators are surfactants such as sodium deoxycholate, Tween® 80 and Span® 80. Their chain length is optimal for intercalation within the C18 phospholipid bilayer. A wide variety of drugs has been successfully encapsulated within transferosomes such as phytocompounds like sinomenine or apigenin for rheumatoid arthritis and leukaemia respectively, small hydrophobic drugs but also macromolecules like insulin. The main factors to develop optimal transferosomal formulations (with high drug loading and nanometric size) are the optimal ratio between the main components as well as the critical process parameters for their manufacture. Application of quality by design (QbD), specifically design of experiments (DoE), is crucial to understand the interplay among all these factors not only during the preparation at lab scale but also in the scale-up process. Clinical trials of a licensed topical ketoprofen transferosomal gel have shown promising results in the alleviation of symptons in orthreothritis with non-severe skin and subcutaneous tissue disorders. However, the product was withdrawn from the market which probably was related to the higher c, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, Instituto Universitario de Farmacia Industrial, TRUE, pub

Fuse deposition modelling (FDM) has emerged as a novel technology for manufacturing 3D printed medicines. However, it is a two-step process requiring the fabrication of filaments using a hot melt extruder with suitable properties prior to printing taking place, which can be a rate-limiting step in its application into clinical practice. Direct powder extrusion can overcome the difficulties encountered with fabrication of pharmaceutical-quality filaments for FDM, allowing the manufacturing, in a single step, of 3D printed solid dosage forms. In this study, we demonstrate the manufacturing of small-weight (<100 mg) solid dosage forms with high drug loading (25%) that can be easily undertaken by healthcare professionals to treat hypertension. 3D printed nifedipine minitablets containing 20 mg were manufactured by direct powder extrusion combining 15% polyethylene glycol 4000 Da, 40% hydroxypropyl cellulose, 19% hydroxy propyl methyl cellulose acetate succinate, and 1% magnesium stearate. The fabricated 3D printed minitablets of small overall weight did not disintegrate during dissolution and allowed for controlled drug release over 24 h, based on erosion. This release profile of the printed minitablets is more suitable for hypertensive patients than immediate-release tablets that can lead to a marked burst effect, triggering hypotension. The small size of the minitablet allows it to fit inside of a 0-size capsule and be combined with other minitablets, of other API, for the treatment of complex diseases requiring polypharmacy within a single dosage form., Universidad Complutense de Madrid, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

Science Foundation Ireland/FEDER, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

Leishmaniasis affects around 12 million people worldwide and is estimated to cause the ninth-largest disease burden. There are three main forms of the disease, visceral (VL), cutaneous (CL), and mucocutaneous (MCL), leading to more than one million new cases every year and several thousand deaths. Current treatments based on chemically synthesized molecules are far from ideal. In this study, we have tested the in vitro and in vivo efficacy of ursolic acid (UA), a multifunctional triterpenoid with well-known antitumoral, antioxidant, and antimicrobial effects on different Leishmania strains. The in vitro antileishmanial activity against the intracellular forms was six and three-fold higher compared to extracellular forms of L. amazonensis and L. infantum, respectively. UA also showed to be a potent antileishmanial drug against both VL and CL manifestations of the disease in experimental models. UA parenterally administered at 5 mg/kg for seven days significantly reduced the parasite burden in liver and spleen not only in murine acute infection but also in a chronic-infection model against L. infantum. In addition, UA ointment (0.2%) topically administered for four weeks diminished (50%) lesion size progression in a chronic infection model of CL caused by L. amazonensis, which was much greater than the effect of UA formulated as an O/W emulsion. UA played a key role in the immunological response modulating the Th1 response. The exposure of Leishmania-infected macrophages to UA led to a significant different production in the cytokine levels depending on the Leishmania strain causing the infection. In conclusion, UA can be a promising therapy against both CL and VL., University CEU-Cardenal Herrera, Agencia Española de Cooperación Internacional para el Desarrollo, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

Universidad Complutense de Madrid, Fondo Colaborativo de Unión Iberoamericana de Universidades, Universidad de São Paulo, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

Fungal and parasitic diseases affect more than a billion people across the globe, one-sixth of the world’s population, mostly located in developing countries. The lack of effective and safer treatments combined with a deficient diagnosis lead to serious chronic illness or even death. There is a mismatch between the rate of drug resistance and the development of new medicines. Formulation of antifungal and antiparasitic drugs adapted to different administration routes is challenging, bearing in mind their poor water solubility, which limits their bioavailability and efficacy. Hence, there is an unmet clinical need to develop vaccines and novel formulations and drug delivery strategies that can improve the bioavailability and therapeutic effect by enhancing their dissolution, increasing their chemical potency, stabilising the drug and targeting high concentration of drug to the infection sites. This Editorial regards the ten research contributions presented in the Special Issue “Antifungal and Antiparasitic Drug Delivery”., Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

A stronger Th1 (cellular) immune response in canine leishmaniosis (CanL) leads to a better prognosis. Dietary nucleotides plus AHCC® have shown beneficial e ects in dogs with clinical leishmaniosis and in clinically healthy Leishmania-infected dogs. The potential leishmanicidal activity of nucleotides and AHCC was assessed by quantifying nitric oxide (NO) production and replication of parasites. Their e ects on lymphocyte proliferation were studied with and without soluble Leishmania infantum antigen (SLA) stimulation. Cytokine level variations were assessed using naïve and L. infantum-infected macrophages/lymphocytes cocultures. Promastigotes and amastigotes proliferation and NO macrophage production were not directly a ected. Lymphocyte proliferation was significantly enhanced by nucleotides, AHCC, and their combinations only after SLA stimulation. Nucleotides and AHCC significantly increased the production of IL-1 , IL-2, IL-5, IL-9, IL-10, and IL-12 by naïve immune cells. In naïve and L. infantum-infected macrophage/lymphocyte cocultures, nucleotides with or without AHCC led to significant increases in IFN- and TNF- . Given that these cytokines are involved in the e ective Th1 immune response against Leishmania parasites, these mechanisms of action could explain the previously reported in vivo clinical e cacy of such combination and further support the use of nucleotides with or without AHCC in the management of CanL patients.

Leishmaniasis a ects around 12 million people worldwide and is estimated to cause the ninth-largest disease burden. There are three main forms of the disease, visceral (VL), cutaneous (CL), and mucocutaneous (MCL), leading to more than one million new cases every year and several thousand deaths. Current treatments based on chemically synthesized molecules are far from ideal. In this study, we have tested the in vitro and in vivo e cacy of ursolic acid (UA), a multifunctional triterpenoid with well-known antitumoral, antioxidant, and antimicrobial e ects on di erent Leishmania strains. The in vitro antileishmanial activity against the intracellular forms was six and three-fold higher compared to extracellular forms of L. amazonensis and L. infantum, respectively. UA also showed to be a potent antileishmanial drug against both VL and CL manifestations of the disease in experimental models. UA parenterally administered at 5 mg/kg for seven days significantly reduced the parasite burden in liver and spleen not only in murine acute infection but also in a chronic-infection model against L. infantum. In addition, UA ointment (0.2%) topically administered for four weeks diminished (50%) lesion size progression in a chronic infection model of CL caused by L. amazonensis, which was much greater than the e ect of UA formulated as an O/W emulsion. UA played a key role in the immunological response modulating the Th1 response. The exposure of Leishmania-infected macrophages to UA led to a significant di erent production in the cytokine levels depending on the Leishmania strain causing the infection. In conclusion, UA can be a promising therapy against both CL and VL.

“Introducción “ La elevada incidencia y prevalencia de las infecciones fúngicas y parasitarias supone un grave problema de salud pública a nivel global debido a la complejidad de dichos tratamientos, así como a la aparición de resistencias. Los tratamientos existentes actualmente engloban desde la administración parenteral de anfotericina B (AmB), con efectos nefrotóxicos y hemolíticos, hasta el uso oral de miltefosina, que puede resultar elevadamente tóxica a nivel gastrointestinal y además es teratogénica. AmB es el fármaco de referencia en la terapia antifúngica y antiparasitaria desde hace décadas, aunque afortunadamente el uso de la presentación Fungizona® ha sido desplazado por la formulación liposomal de AmB (AmBisome®) y otras presentaciones lipídicas, reduciendo su toxicidad. Además, la AmB presenta tres estados de agregación en solución y desarrolla su actividad a través de dos mecanismos de acción. La modulación del estado de agregación para desencadenar uno u otro mecanismo de acción es una estrategia prometedora en el tratamiento de estas infecciones. Los mecanismos de acción que permiten la actividad antiinfecciosa de la AmB consisten en la ruptura de la membrana plasmática y la inducción del estrés oxidativo. La ruptura de la membrana plasmática se produce debido a la unión del fármaco al ergosterol presente en células fúngicas y parasitarias, que dan lugar a la formación de poros que liberan iones, produciendo una alteración electrolítica que finaliza con la muerte celular; mientras que la inducción del estrés oxidativo tiene lugar debido a un aumento de la concentración de radicales libres que provocan daños en la célula, conllevando la pérdida de la actividad metabólica de ésta. Actualmente, sólo existen formulaciones de AmB de administración intravenosa disponibles en el mercado debido a la baja biodisponibilidad del fármaco a través de otras vías. Por ello, es necesario desarrollar formulaciones que permitan incrementar su biodisponibilidad. Así

Creación de un nuevo recurso educativo virtual para estudiantes de grado en Farmacia sobre la serialización de los medicamentos y los procesos de mezclado.

Los objetivos de esta tesis son: 1.- Obtención de comprimidos (núcleos) de ibuprofeno con una mínima cantidad de excipientes (<7%) mediante compactación por rodillos. 2.- Determinación de la consistencia de los parámetros críticos del proceso: materia prima, dosis, estudio del efecto de diferentes fuerzas de compactación y de compresión en las características de dichos núcleos. 3.- Determinación de la bioequivalencia de una de estas formulaciones. Para la consecución de estos objetivos se divide el trabajo en varias fases que fueron el planteamiento de la tesis: 1. Estudio de las diferentes formulaciones de comprimidos de ibuprofeno (dosis 600 mg) comercializadas en España entre los años 2011 y 2015. 2. Estudio del efecto de la materia prima y de la fuerza de compactación con la mínima cantidad de excipientes en la granulación de ibuprofeno. 3. Estudio del efecto de la fuerza de compresión en las características de comprimidos de 200 y 600 mg de ibuprofeno obtenidos a partir de granulados con diferentes fuerzas de compactación. 4. Estudio de bioequivalencia de una formulación de ibuprofeno obtenido por compactación..., The main aims of this thesis are: 1.- Development of an ibuprofen tablet formulation containing less than 7% of excipients using roller compaction. 2.- Consistency of the process. Effect of batch raw material, dose, different roller with the minimum excipients quantity and tableting forces on the quality of the granules and tablets. 3.- Bioequivalent assay of one of this tablet formulations.The experimental work is divided in the following phases: 1. Characteristics of marketed ibuprofen tablet generic formulations in Spain (2011 and 2015). 2. Effect of force compaction on the quality of granules obtained by roller compaction. 3. Effect of force tableting on the quality of 200 and 600 mg ibuprofen tablets obtained with granulates elaborated at different roller compaction forces. 4. Bioequivalence study of a coated ibuprofen formulation obtained by roller compaction...

Invasive pulmonary aspergillosis represents one of the most serious fungal infections among immunocompromised patients. In this study, we aimed to analyze the in vivo e_cacy of prophylactic oral amphotericin B (AMB) encapsulated in modified chitosan-nanoparticles (Nanomerics’ Molecular Envelope Technology (MET)) supplemented with a standardized extract of cultured Lentinula edodes mycelia (AHCC®) in a murine model of pulmonary aspergillosis. We determined fungal burden and survival of mice and additionally, we carried out a cytokine analysis in an attempt to understand the immunomodulation of the extract. Our results evidenced equivalent e_cacy between orally administered AMB-MET and the intravenous liposomal AMB marketed formulation. Addition of the AHCC® supplement significantly improved e_cacy in terms of burden reduction and survival increase of both oral and intravenous AMB therapies compared to the untreated control group. Moreover, a protective e_ect of the extract was observed in terms of weight loss. Regarding the cytokine profiles, the Th1 immune response was stimulated in treated animals when compared to the control group. This response was marked by an enhancement in the MCP-1, GM-CSF, VEGF, RANTES and IL-17 levels and a decrease in the IL-6, a biomarker related to the severity of the infection., Universidad Complutense de Madrid, UCL School of Pharmacy, University of London, Generalitat de Catalunya, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

Leishmaniasis is a neglected tropical disease a_ecting more than 12 million people worldwide, which in its visceral clinical form (VL) is characterised by the accumulation of parasites in the liver and spleen, and can lead to death if not treated. Available treatments are not well tolerated due to severe adverse e_ects, need for parenteral administration and patient hospitalisation, and long duration of expensive treatments. These treatment realities justify the search for new e_ective drugs, repurposing existing licensed drugs towards safer and non-invasive cost-e_ective medicines for VL. In this work, we provide proof of concept studies of butenafine and butenafine self-nanoemulsifying drug delivery systems (B-SNEDDS) against Leishmania infantum. Liquid B-SNEDDS were optimised using design of experiments, and then were spray-dried onto porous colloidal silica carriers to produce solid-B-SNEDDS with enhanced flow properties and drug stability. Optimal liquid B-SNEDDS consisted of Butenafine:Capryol 90:Peceol:Labrasol (3:49.5:24.2:23.3 w/w), which were then sprayed-dried with Aerosil 200 with a final 1:2 (Aerosil:liquid B-SNEDDS w/w) ratio. Spray-dried particles exhibited near-maximal drug loading, while maintaining excellent powder flow properties (angle of repose <10_) and sustained release in acidic gastrointestinal media. Solid-B-SNEDDS demonstrated greater selectivity index against promastigotes and L. infantum-infected amastigotes than butenafine alone. Developed oral solid nanomedicines enable the non-invasive and safe administration of butenafine as a cost-e_ective and readily scalable repurposed medicine for VL., Unión Iberoamericana de Universidades, Fundação de Amparo à Pesquisa do Estado de São Paulo, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

Blended learning has risen in popularity over the last two decades as it has shown to be an effective approach for accommodating an increasingly diverse student population in Higher Education as well as enriching the learning environment through the incorporation of online teaching resources. The act of blending significant elements of the learning environment such as face-to-face, online and self-paced learning leads to better student experiences and outcomes, and more efficient teaching and course management practices if combined appropriately. For this reason, an appropriate systematic and dynamic approach of blended learning design is crucial for a positive outcome starting with planning for integrating blended elements into a course followed by creating blended activities and implementing them. Evaluating their effectiveness and knowing in which environments they work better and finally improving the blended activities designed from both the student’s and instructor’s perspective is critical for the next delivery of the course. This work aims to provide useful examples and increase awareness of Higher Education educators about how traditional face-to-face learning can be transformed into blended courses with the aim of increasing student engagement with both in-class and online approaches while being time effective for the instructor.

Amphotericin B possesses high activity against Candida spp. with low risk of resistance. However, Amphotericin B’s high molecular weight compared to other antifungal drugs, such as miconazole and clotrimazole, and poor water solubility hampers its e_cacy at the physiological conditions of the oropharyngeal cavity (saliva pH, limited volume for dissolution) and thereby limits its clinical use in oropharyngeal candidiasis. We have prepared fast-dissolving orodispersible films with high loading (1% w/w) using solvent casting that enables amphotericin B to remain solubilised in saliva in equilibrium between the monomeric and dimeric states, and able to produce a local antifungal e_ect. Optimisation of the amphotericin B-loaded orodispersible films was achieved by quality by design studies combining dextran and/or maltodextrin as dextrose-derived-polymer film formers with cellulose-derived film formers (hydroxypropylmethyl/hydroxypropyl cellulose in a 1:4 weight ratio), sorbitol for taste masking, microcrystalline cellulose (Avicel 200) or microcrystalline cellulose-carboxymethylcellulose sodium (Avicel CL-611) for enhancing the mechanical strength of the film, and polyethylene glycol 400 and glycerol (1:1 w/w) as plasticizers. The optimised amphotericin B orodispersible films (containing 1% AmB, 25% dextran, 25% maltodextrin, 5% sorbitol, 10% Avicel 200, 10% polyethylene glycol 400, 10% glycerol, 3% hydroxypropylmethyl cellulose acetate succinate, 12% hydroxypropyl cellulose) possessed a fast disintegration time (60 _ 3 s), quick release in artificial saliva (>80% in 10 min), high burst strength (2190 mN mm) and high e_cacy against several Candida spp. (C. albicans, C. parapsilosis and C. krusei) (>15mminhibition halo). Amphotericin B orodispersible films are stable for two weeks at room temperature (25 _C) and up to 1 year in the fridge. Although further toxicological and in vivo e_cacy studies are required, this novel Amphotericin B orodispersible films is a promising, Science Foundation Ireland/FEDER, University of Portsmouth, Research and Development Fund, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

Leishmaniasis is a neglected tropical disease a_ecting more than 12 million people worldwide, which in its visceral clinical form (VL) is characterised by the accumulation of parasites in the liver and spleen, and can lead to death if not treated. Available treatments are not well tolerated due to severe adverse e_ects, need for parenteral administration and patient hospitalisation, and long duration of expensive treatments. These treatment realities justify the search for new e_ective drugs, repurposing existing licensed drugs towards safer and non-invasive cost-e_ective medicines for VL. In this work, we provide proof of concept studies of butenafine and butenafine self-nanoemulsifying drug delivery systems (B-SNEDDS) against Leishmania infantum. Liquid B-SNEDDS were optimised using design of experiments, and then were spray-dried onto porous colloidal silica carriers to produce solid-B-SNEDDS with enhanced flow properties and drug stability. Optimal liquid B-SNEDDS consisted of Butenafine:Capryol 90:Peceol:Labrasol (3:49.5:24.2:23.3 w/w), which were then sprayed-dried with Aerosil 200 with a final 1:2 (Aerosil:liquid B-SNEDDS w/w) ratio. Spray-dried particles exhibited near-maximal drug loading, while maintaining excellent powder flow properties (angle of repose <10_) and sustained release in acidic gastrointestinal media. Solid-B-SNEDDS demonstrated greater selectivity index against promastigotes and L. infantum-infected amastigotes than butenafine alone. Developed oral solid nanomedicines enable the non-invasive and safe administration of butenafine as a cost-e_ective and readily scalable repurposed medicine for VL., Unión Iberoamericana de Universidades (ENF03-2017), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP processes: 2016/00468-0 and 2017/09405-4), Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

Los objetivos de esta tesis son: 1.- Obtención de comprimidos (núcleos) de ibuprofeno con una mínima cantidad de excipientes (<7%) mediante compactación por rodillos. 2.- Determinación de la consistencia de los parámetros críticos del proceso: materia prima, dosis, estudio del efecto de diferentes fuerzas de compactación y de compresión en las características de dichos núcleos. 3.- Determinación de la bioequivalencia de una de estas formulaciones. Para la consecución de estos objetivos se divide el trabajo en varias fases que fueron el planteamiento de la tesis: 1. Estudio de las diferentes formulaciones de comprimidos de ibuprofeno (dosis 600 mg) comercializadas en España entre los años 2011 y 2015. 2. Estudio del efecto de la materia prima y de la fuerza de compactación con la mínima cantidad de excipientes en la granulación de ibuprofeno. 3. Estudio del efecto de la fuerza de compresión en las características de comprimidos de 200 y 600 mg de ibuprofeno obtenidos a partir de granulados con diferentes fuerzas de compactación. 4. Estudio de bioequivalencia de una formulación de ibuprofeno obtenido por compactación...

Las aplicaciones de la impresión 3D se han desarrollado notablemente en los últimos años. Desde su aparición en los años ochenta, surgieron nuevas técnicas de impresión 3D para satisfacer el interés creciente demostrado por diferentes industrias, incluida la industria farmacéutica. La técnica de impresión 3D podría ser revolucionaria en el proceso de fabricación de medicamentos. La facilidad y flexibilidad que presenta, puede resolver algunas limitaciones que demuestra la fabricación tradicional en cuanto a productos farmacéuticos con un proceso de formulación complejo, tales como productos con perfiles de liberación modificada. Al basarse sobre un proceso de fabricación por capas siguiendo las instrucciones minuciosas de un modelo diseñado digitalmente, la diversidad de los productos obtenidos es impresionante. Las posibilidades que parece ofrecer esta nueva tecnología al proceso de fabricación de medicamentos no tienen fin. Esta revisión trata fundamentalmente los sistemas de administración de medicamentos de liberación controlada obtenidos mediante impresión 3D. Se aborda las posibilidades de personalización de tratamiento y fabricación a demanda que ofrece esta tecnología., The wide spread applications of 3D manufacturing has grown substantially in last few years. Since its appearance in the eighties, many 3D printing techniques have developed in order to satisfy the growing interest demonstrated by many industries including the pharmaceutical industry. The 3D printing technique could prove to be revolutionary in the drug manufacturing process. The ease and flexibility presented, may resolve some limitations that traditional manufacturing shows with pharmaceutical products which require a complex formulation process, such as drugs with modified release profiles. Given that the basic principle, on which this technique relies on, is a layer by layer manufacturing process following instructions of a digitally designed model, the diversity of the products obtained is tremendous. Whether it’s a drug with a specific shape or a combination of drugs designed in particular to meet a patient’s needs, the possibilities that this technique appears to offer for the drug manufacturing process can be described as endless. Although this review, is widely focused in the field of controlled-release drug delivery systems, personalized treatment and on-demand drug manufacturing are also discussed.

Glioblastoma multiforme is one of the most prevalent and malignant forms of central nervous system tumors. The treatment of glioblastoma remains a great challenge due to its location in the intracranial space and the presence of the blood–brain tumor barrier. There is an urgent need to develop novel therapy approaches for this tumor, to improve the clinical outcomes, and to reduce the rate of recurrence and adverse effects associated with present options. The formulation of therapeutic agents in nanostructures is one of the most promising approaches to treat glioblastoma due to the increased availability at the target site, and the possibility to co-deliver a range of drugs and diagnostic agents. Moreover, the local administration of nanostructures presents significant additional advantages, since it overcomes blood–brain barrier penetration issues to reach higher concentrations of therapeutic agents in the tumor area with minimal side effects. In this paper, we aim to review the attempts to develop nanostructures as local drug delivery systems able to deliver multiple agents for both therapeutic and diagnostic functions for the management of glioblastoma., Unión Europea. H2020, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

One of the main objectives of the WHO is controlling transmission of parasitic protozoa vector-borne diseases. A quick and precise diagnosis is critical in selecting the optimal therapeutic regime that avoids unnecessary treatments and the emergence of resistance. Molecular assays based on loopmediated isothermal amplification (LAMP) techniques are a good alternative to light microscopy and antigen-based rapid diagnostic tests in developing countries, since they allow for a large amount of genetic material generated from a few copies of DNA, and use primers that lead to high sensitivity and specificity, while the amplification process can be performed in isothermal conditions without the need of sophisticated equipment to interpret the results. In this review, the main advances in the development of LAMP assays for the diagnosis of malaria, leishmaniasis and Chagas' disease are discussed as well as the feasibility of their implementation in developing countries and use as point- of-care diagnostic tests.

Engineering of pharmaceutical cocrystals is an advantageous alternative to salt formation for improving the aqueous solubility of hydrophobic drugs. Although, spray drying is a well-established scale-up technique in the production of cocrystals, several issues can arise such as sublimation or stickiness due to low glass transition temperatures of some organic molecules, making the process very challenging. Even though, fluidised bed spray coating has been successfully employed in the production of amorphous drug-coated particles, to the best of our knowledge, it has never been employed in the production of cocrystals. The feasibility of this technique was proven using three model cocrystals: sulfadimidine (SDM)/4-aminosalicylic acid (4ASA), sulfadimidine/nicotinic acid (NA) and ibuprofen (IBU)/ nicotinamide (NAM). Design of experiments were performed to understand the critical formulation and process parameters that determine the formation of either cocrystal or coamorphous systems for SDM/4ASA. The amount and type of binder played a key role in the overall solid state and in vitro performance characteristics of the cocrystals. The optimal balance between high loading efficiencies and high degree of crystallinity was achieved only when a binder: cocrystal weight ratio of 5:95 or 10:90 was used. The cocrystal coated beads showed an improved in vitro-in vivo performance characterised by: (i) no tendency to aggregate in aqueous media compared to spray dried formulations, (ii) enhanced in vitro activity (1.8-fold greater) against S. aureus, (iii) larger oral absorption and bioavailability (2.2-fold higher Cmax), (iv) greater flow properties and (v) improved chemical stability than cocrystals produced by other methods derived from the morphology and solid nature of the starter cores.

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.

La impresión 3D pretende adaptar la fabricación de los medicamentos a los requerimientos específicos de cada paciente, atendiendo a su edad, peso, perfil farmacogenético, comorbilidades, así como a su farmacocinética característica. Para ello, la fabricación aditiva dispone de diferentes técnicas como la impresión 3D por inyección de tinta, a demanda o en continuo; la tecnología por deposición de material, que engloba la deposición de material fundido y la tecnología PAM y; la impresión 3D por láser, que incluye la estereolitografía. Así pues, un objetivo concreto de esta revisión es dar una visión general sobre las ventajas, desventajas y exigencias que demandan cada una de las técnicas. Del mismo modo, se contrastan las perspectivas competitivas que ofrece la impresión 3D, evidenciadas con la aprobación de Spritam® por parte de la FDA, con la aparición de dispositivos personalizados para diversos tratamientos y, con el Bioprinting como aplicación concreta a la Ingeniería de tejidos., 3D Printing aims to adapt drug’s manufacture to the specific requirements of each patient, taking into account their age, weight, pharmacogenetic profile, comorbidities, as well as their characteristic pharmacokinetics. For that, additive manufacturing has different techniques such as printing-based inkjet systems, in a continuous way or on demand; nozzlebased deposition systems, which includes fused-deposition modeling and pressure-assisted microsyringes and; laser-based writing systems that constitutes the stereolithography technique. Thus, a definite objective of this review is an overview of the advantages, disadvantages and requests required by each of the technologies. Likewise, the competitive perspective offered by 3D printing are going to be mentioned like the approval of Spritam® by the FDA, the appearance of custom devices for various treatments and, Bioprinting as the specific device to the Tissue engineering.

La estabilidad de los fármacos depende en buena parte de las condiciones de almacenamiento, exposición a la luz, así como cambios importantes de temperatura y humedad siendo uno de los principales criterios para determinar la aceptación o rechazo de cualquier medicamento. Por este motivo, los estudios de estabilidad son una parte fundamental de todo el proceso de investigación y desarrollo de un producto farmacéutico. Los estudios clásicos de estabilidad de medicamentos se dividen en tres categorías: estudios a largo plazo (12 meses), estudios intermedios (6 meses) y estudios acelerados (6 meses). Los acelerados son estudios con condiciones de temperatura y humedad más extremas y se utilizan generalmente para determinar el efecto a corto plazo de la exposición fuera de las condiciones de almacenamiento establecidas, mientras que el objetivo de los estudios a largo plazo consiste en establecer el periodo de validez y las condiciones de conservación del medicamento. El problema principal de estos estudios clásicos es su elevado tiempo de duración y por lo tanto, al alto coste asociado al mismo. Para resolver este problema se han desarrollado nuevos modelos de predicción de estabilidad de medicamentos, como el Programa de Evaluación de Estabilidad Acelerada, o ASAP, con el cuál se pueden realizar estimaciones precisas de la vida útil mediante un protocolo específico durante un tiempo entre 2 y 4 semanas, permitiendo así determinar de una forma más efectiva y rápida que formulaciones son más estables, qué material de acondicionamiento es más apto, el período de validez y las condiciones de conservación más adecuadas., The stability of the drugs specially depends on the conditions of storage, exposure to light, as well as important changes in temperature and humidity. Stability is one of the most important criteria for determining acceptance or rejection of any medication. For this reason stability studies are a fundamental part of the whole process of research and development of a pharmaceutical product. Classical studies of drug stability are divided into three categories: long-term studies (12 months), intermediate studies (6 months) and accelerated studies (6 months). Accelerated studies are perfromed using more extreme temperature and humidity conditions and are generally used to determine the short-term effect of exposure outside of the established storage conditions by regulatory agencies, whereas the objective of long-term studies is to establish the shelf life and the Este trabajo tiene una finalidad docente. La Facultad de Farmacia no se hace responsable de la información contenida en el mismo. - 4 - conditions of preservation of the drug. The principal problem of these classic studies is their long duration and thus, their high cost. To solve this problem, new models of drug stability prediction have been developed, such as the Accelerated Stability Assessment Program, also denominated ASAP, which estimates the self life through a specific protocol of 2 to 4 weeks. This facilitates inan faster and most efective way the correct selection of the most stable formulation, the most conveninet packing material, the shelf life and the storage conditions more appropriate.