Ophthalmic wild olive (ACEBUCHE) oil nanoemulsions exert oculoprotective effects against oxidative stress induced by arterial hypertension.

Oxidative stress plays a key role in several systemic and ocular diseases, including hypertensive eye diseases. In this context, we previously showed that oral administration of wild olive (acebuche, ACE) oil from Olea europaea var. sylvestris can counteract ocular damage secondary to arterial hypertension by modulating excess reactive oxygen species (ROS) produced by the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Therefore, this work describes the development of an ACE oil-based formulation for ocular administration as a local therapy to counteract hypertension-related oxidative damage. Specifically, ACE oil nanoemulsions (NEs) were successfully produced and characterized, exhibiting appropriate features for ophthalmic administration, including a nanometer size (<200 nm), moderate negative ZP, adequate osmolality and pH, and colloidal stability in biorelevant fluids. Likewise, the NEs presented a shear thinning behavior, especially convenient for ocular instillation. In vivo evaluation was performed through either intravitreal injection or topical ophthalmic administration in mice with hypertension induced via administration of Nω-nitro-L-arginine-methyl-ester (L-NAME). Both routes of administration reduced hypertensive morphological alterations and demonstrated a noticeable antioxidant effect thanks to the reduction of the activity/expression of NADPH oxidase in cornea and retina. Thus, an ACE oil ophthalmic formulation represent a promising therapy for ocular pathologies associated with arterial hypertension.

Lentes de contacto para vehiculizar principios activos: una prometedora herramienta terapéutica / Contact lenses as drug-delivery systems: a promising therapeutic tool

La administración ocular de fármacos utilizando formas farmacéuticas tradicionales, como las gotas oftálmicas o pomadas entre otras, proporciona una baja biodisponibilidad de los fármacos así como múltiples administraciones al día con el consiguiente peligro de incumplimiento terapéutico. Aunque la tecnología farmacéutica ha intentado proponer diversas soluciones para aumentar la biodisponibilidad en las formas farmacéuticas más comunes, no ha sido del todo satisfactorio. En este contexto, las lentes de contacto se presentan como sistemas de liberación de fármacos que subsanan en gran medida estos dos grandes problemas y ofrecen otras ventajas adicionales. Por ello, en los últimos años, se ha investigado con más empeño el uso de lentes de contacto como sistemas portadores de fármacos, ya que pueden aumentar la biodisponibilidad de los mismos, proporcionando un aumento de la eficacia y cumplimiento terapéuticos. En la presente revisión se han referenciado las principales técnicas utilizadas para alcanzar dicho fin: inmersión en soluciones de fármaco, uso de barreras de vitamina E, impresión molecular, sistemas coloidales, etc. A continuación se recogen los resultados más interesantes encontrados en función de las distintas patologías oculares. El uso de lentes de contacto para la vehiculización y liberación de principios activos es una estrategia relativamente novedosa aunque ya tiene muchos estudios y ensayos que lo sustentan. De todas formas se deben seguir investigando para alcanzar finalmente un producto eficaz, seguro y estable, y que pueda llegar a ser comercializado

The ocular administration of drugs using traditional pharmaceutical forms, including eye drops or ointments, results in low bioavailability, as well as requiring multiple administrations per day, with the consequent danger of therapeutic non-compliance. Although, through the use of pharmaceutical technology, attempts have been made to use various solutions in order to increase bioavailability in the most common pharmaceutical forms, it has not been entirely satisfactory. In this context, contact lenses are presented as drug delivery systems that largely remedy these two major problems and offer other additional advantages. Therefore, the use of contact lenses as drug carrying systems has been increasingly investigated in recent years, as they can increase the bioavailability of these drugs, leading to an increase in therapeutic efficacy and compliance. The main techniques used to achieve this goal are included in this review, including immersion in drug solutions, use of vitamin E barriers, molecular printing, colloidal systems, etc. The most interesting results, depending on the different eye pathologies, are presented. Although the use of contact lenses as a vehicle for the release of active ingredients is a relatively novel strategy, there are already many studies and trials that support it. In any case, further research needs to be carried out to finally reach an effective, safe, and stable product that can be marketed

Contact lenses as drug-delivery systems: a promising therapeutic tool. / Lentes de contacto para vehiculizar principios activos: una prometedora herramienta terapéutica.

The ocular administration of drugs using traditional pharmaceutical forms, including eye drops or ointments, results in low bioavailability, as well as requiring multiple administrations per day, with the consequent danger of therapeutic non-compliance. Although, through the use of pharmaceutical technology, attempts have been made to use various solutions in order to increase bioavailability in the most common pharmaceutical forms, it has not been entirely satisfactory. In this context, contact lenses are presented as drug delivery systems that largely remedy these two major problems and offer other additional advantages. Therefore, the use of contact lenses as drug carrying systems has been increasingly investigated in recent years, as they can increase the bioavailability of these drugs, leading to an increase in therapeutic efficacy and compliance. The main techniques used to achieve this goal are included in this review, including immersion in drug solutions, use of vitamin E barriers, molecular printing, colloidal systems, etc. The most interesting results, depending on the different eye pathologies, are presented. Although the use of contact lenses as a vehicle for the release of active ingredients is a relatively novel strategy, there are already many studies and trials that support it. In any case, further research needs to be carried out to finally reach an effective, safe, and stable product that can be marketed.

In vivo biodistribution of venlafaxine-PLGA nanoparticles for brain delivery: plain vs. functionalized nanoparticles.

Background: Actually, no drugs provide therapeutic benefit to approximately one-third of depressed patients. Depression is predicted to become the first global disease by 2030. So, new therapeutic interventions are imperative.Research design and methods: Venlafaxine-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were surface functionalized with two ligands against transferrin receptor to enhance access to brain. An in vitro blood-brain barrier model using hCMEC/D3 cell line was developed to evaluate permeability. In vivo biodistribution studies were performed using C57/bl6 mice. Particles were administered intranasal and main organs were analyzed.Results: Particles were obtained as a lyophilized powder easily to re-suspend. Internalization and permeability studies showed the following cell association sequence: TfRp-NPs>Tf-NPs>plain NPs. Permeability studies also showed that encapsulated VLF was not affected by P-gP pump efflux increasing its concentration in the basolateral side after 24 h. In vivo studies showed that 25% of plain NPs reach the brain after 30 min of one intranasal administration while less than 5% of functionalized NPs get the target.Conclusions: Plain NPs showed the highest ability to reach the brain vs. functionalized NPs after 30 min by intranasal administration. We suggest plain NPs probably travel via direct nose-to-brian route whereas functionalized NPs reach the brain by receptor-mediated endocytosis.

Role of Nanotechnology for Enzyme Replacement Therapy in Lysosomal Diseases. A Focus on Gaucher's Disease.

Lysosomal storage diseases (LSDs) comprise a group of rare inherited chronic syndromes that cause deficiency of specific native enzymes within the lysosomes. The macromolecular compounds that are usually catabolized by lysosomal enzymes are accumulated within these organelles, causing progressive damage to tissues, skeleton and organs and, in several cases, the central nervous system (CNS). The damage caused by substrate accumulation finally results in physical deterioration, functional impairment and potential death. Up to date, the most promising therapy for most LSDs is enzyme-replacement therapy (ERT), which provides patients with the corresponding active enzyme. However, these enzymes do not have enough stability in blood, the treatment must be therefore periodically administrated by i.v. infusion under medical supervision, and immunogenicity issues are frequent. In addition, affected areas within the CNS, where the blood-brain barrier (BBB) is a major obstacle, cannot be reached by the enzymes. Nanotechnology can provide useful carriers to successfully protect and preserve enzymes, and transport them through the BBB towards brain locations. Several strategies based on targeting specific receptors on the BBB have led to nanoparticles that successfully carry sensitive molecules to the brain. Then, the main LSDs are described and a thorough review of nanotechnology strategies for brain delivery studied up to date is presented.

Lipid nanoparticles as an emerging platform for cannabinoid delivery: physicochemical optimization and biocompatibility.

This work aims at developing and optimizing a valuable oral delivery carrier for the cannabinoid derivative CB13, which presents a high therapeutic potential in chronic pain states that respond poorly to conventional analgesics, but also shows highly unfavorable physicochemical properties. CB13-loaded lipid nanoparticles (LNP) formulations were developed through solvent-emulsion evaporation and optimized in terms of physicochemical properties, long-term stability, integrity under gastric simulated conditions and in vitro interaction with NIH 3T3, HEK 293T and Caco-2 cells. An optimized formulation of LNP containing CB13 was obtained from a wide range of conditions assayed and analyzed. The selection of the lipid core, production conditions and the inclusion of lecithin proved to be key factors for the final properties of encapsulation, integrity and performance of the carriers. The LNP formulation proposed proved to be a promising carrier for the oral delivery of CB13, a cannabinoid with high therapeutic potential in chronic pain states that currently lack a valid oral treatment.

In vitro and in vivo evaluation of Δ9-tetrahidrocannabinol/PLGA nanoparticles for cancer chemotherapy.

Nanoplatforms can optimize the efficacy and safety of chemotherapy, and thus cancer therapy. However, new approaches are encouraged in developing new nanomedicines against malignant cells. In this work, a reproducible methodology is described to prepare Δ(9)-tetrahidrocannabinol (Δ(9)-THC)-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles against lung cancer. The nanoformulation is further improved by surface functionalization with the biodegradable polymers chitosan and poly(ethylene glycol) (PEG) in order to optimize the biological fate and antitumor effect. Mean nanoparticle size (≈ 290 nm) increased upon coating with PEG, CS, and PEG-CS up to ≈ 590 nm, ≈ 745 nm, and ≈ 790 nm, respectively. Surface electrical charge was controlled by the type of polymeric coating onto the PLGA particles. Drug entrapment efficiencies (≈ 95%) were not affected by any of the polymeric coatings. On the opposite, the characteristic sustained (biphasic) Δ(9)-THC release from the particles can be accelerated or slowed down when using PEG or chitosan, respectively. Blood compatibility studies demonstrated the adequate in vivo safety margin of all of the PLGA-based nanoformulations, while protein adsorption investigations postulated the protective role of PEGylation against opsonization and plasma clearance. Cell viability studies comparing the activity of the nanoformulations against human A-549 and murine LL2 lung adenocarcinoma cells, and human embryo lung fibroblastic MRC-5 cells revealed a statistically significant selective cytotoxic effect toward the lung cancer cell lines. In addition, cytotoxicity assays in A-549 cells demonstrated the more intense anticancer activity of Δ(9)-THC-loaded PEGylated PLGA nanoparticles. These promising results were confirmed by in vivo studies in LL2 lung tumor-bearing immunocompetent C57BL/6 mice.

Building functional materials for health care and pharmacy from microfluidic principles and Flow Focusing.

In this review, we aim at establishing a relationship between the fundamentals of the microfluidics technologies used in the Pharmacy field, and the achievements accomplished by those technologies. We describe the main methods for manufacturing micrometer drops, bubbles, and capsules, as well as the corresponding underlying physical mechanisms. In this regard, the review is intended to show non-specialist readers the dynamical processes which determine the success of microfluidics techniques. Flow focusing (FF) is a droplet-based method widely used to produce different types of fluid entities on a continuous basis by applying an extensional co-flow. We take this technique as an example to illustrate how microfluidics technologies for drug delivery are progressing from a deep understanding of the physics of fluids involved. Specifically, we describe the limitations of FF, and review novel methods which enhance its stability and robustness. In the last part of this paper, we review some of the accomplishments of microfluidics when it comes to drug manufacturing and delivery. Special attention is paid to the production of the microencapsulated form because this fluidic structure gathers the main functionalities sought for in Pharmacy. We also show how FF has been adapted to satisfy an ample variety of pharmaceutical requirements to date.

Functional PLGA NPs for oral drug delivery: recent strategies and developments.

This article presents the potential of PLGA nanoparticles for the oral administration of drugs. Different strategies are used to improve oral absorption of these nanoparticles. These strategies are based on modification of nanoparticle surface properties. They can be achieved either by coating the nanoparticle surface with stabilizing hydrophilic bioadhesive polymers or surfactants, or by incorporating biodegradable copolymers containing a hydrophilic moiety. Some substances such as chitosan, vitamin E, methacrylates, lectins, lecithins, bile salts and RGD molecules are employed for this purpose. Of especial interest are nanoparticles production methods and, in order to improve oral bioavailability, the mechanism of each additive.

Development and validation of an RP-HPLC method for CB13 evaluation in several PLGA nanoparticle systems.

A simple, fast, and reversed-phase high-performance liquid chromatographic (RP-HPLC) method has been developed and validated for determining of a cannabinoid derivate, which displays potent antihyperalgesic activity, 1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone (CB13) into PLGA nanoparticles. Separation was achieved in a C18 column using a mobile phase consisting of two solvents: solvent A, consisting of acetonitrile : water : acetic acid (75 : 23.7 : 1.3 v/v), and solvent B, consisting of acetonitrile. An isocratic method (70 : 30 v/v), with a flow rate of 1.000 mL/min, and a diode array detector were used. The developed method was precise, accurate, and linear over the concentration range of analysis with a limit of detection and a limit of quantification of 0.5 and 1.25 µg/mL, respectively. The developed method was applied to the analysis of CB13 in nanoparticles samples obtained by three different procedures (SEV, FF, and NPP) in terms of encapsulation efficiency and drug release. Nanoparticles size and size distribution were also evaluated founding that NPP method presented the most lowest particle sizes with narrow-size distribution (≈320 nm) and slightly negative zeta potential (≈-25 mV) which presumes a suitable procedure for the synthesis of PLGA-CB13 nanoparticles for oral administration.

Drug targeting to cancer by nanoparticles surface functionalized with special biomolecules.

Nanoparticulate-based drug carriers have been developed to overcome the problems of conventional anticancer pharmacotherapy, i.e., the little specificity and low accumulation of the drug into the tumor interstitium, and the extensive biodistribution leading to severe toxicity. Unfortunately, conventional nanoparticles have been demonstrated to merely accumulate the loaded drug into organs associated to the reticuloendothelial system, e.g., the liver. Recently, drug delivery strategies involving the use of nanoplatforms surface decorated with unique biomolecules have demonstrated their potential in concentrating the chemotherapy agent specifically into the malignant cells. This review will be focused on the analysis of the current state of the art and future perspectives of such passive and active targeting strategies based on the enhanced permeability and retention effect and on a ligand-mediated transport, respectively. Special attention will be given to the use of these surface functionalized nanocarriers to overcome multi-drug resistances in cancer cells.

Nanostructures for drug delivery to the brain.

This review aims to summarize present approaches employed in delivering drugs to the central nervous system. Changes in blood-brain barrier (BBB) function have been reported in several neurological disorders. A brief description of the blood brain barrier and the main pathologies related to this barrier disfunction are described. Treatments for these disorders are based on several available strategies for delivering drugs into the brain, through circumvention of the BBB, as disruption of the BBB, prodrugs, molecular Trojan horses, among others. Particular attention will be placed on nanocarriers and more specifically on polymeric nanoparticles, which are presented as the most promising strategy for CNS delivery, helping drugs to be targeted more efficiently to the brain. This also allows attacking previously untreatable disorders such as brain tumors and other neurodegenerative diseases. New strategies and technologies commercialized by different pharmaceutical companies are also included.

Insulin-loaded PLGA microparticles: flow focusing versus double emulsion/solvent evaporation.

CONTEXT: Oral administration of insulin is severely limited by very low bioavailability. Biocompatible polymeric nanocarriers have been investigated to overcome this problem. Flow focusing (FF) has revolutionized current engineering of poly(D,L-lactide-co-glycolide) (PLGA) based micromedicines. This technique has never been used to formulate insulin-loaded PLGA microparticles. OBJECTIVE: Investigation of the benefits rising from the synthesis of insulin-loaded PLGA microplatforms by FF, compared to double emulsion/solvent evaporation method. MATERIALS AND METHODS: Both synthesis methodologies were compared in terms of geometry, surface physicochemical properties and insulin vehiculization capabilities. The stability of the peptide during the formulation procedure was further analysed. RESULTS: FF permitted the preparation of insulin-loaded microcarriers with better geometry and physicochemical properties for the oral route, along with greater insulin loading capabilities and sustained insulin release kinetics. DISCUSSION AND CONCLUSION: Results have lead to the identification of the best formulation conditions for the engineering of insulin-loaded PLGA microparticles against diabetes.

Straightforward production of encoded microbeads by Flow Focusing: potential applications for biomolecule detection.

Fluorescently encoded polymeric microparticles are acquiring great importance in the development of simultaneous multianalyte screening assays. We have developed a very versatile and straightforward method for the production of dye-labeled microparticles with a very reproducible size distribution and freely-chosen and discernible fluorescent properties. Our method combines Flow Focusing technology with a solvent evaporation/extraction procedure in a single step, yielding spherical, non-aggregate and non-porous particles. We have designed a multi-coloured bead array which includes the possibility of modifying the surface properties of the microparticles, which offer excellent properties for covalent attachment of biomolecules such as peptides, oligonucleotides, proteins, etc. We also show the potential of the fluorescently labeled microspheres for the detection of biomolecule (peptides and oligonucelotides) interactions using flow cytometry.

Microcápsulas de famotidina de liberaciónprogramada para administración oral / Alginate beads of famotidine for oral controlled release

Se han ensayado distintas formulaciones de microcápsulas de famotidina para administración oral, elaboradas mediante el método de gelificación iónica. Los resultados obtenidos para el porcentaje de atrapamiento variaron en función del empleo de una solución o suspensión de fármaco, así como de los polímeros empleados y de sus proporciones. Por otro lado, estos resultados no estuvieron influenciados por empleo o no de aguja hipodérmica en la formación de las microcápsulas. También se estudió la influencia de estos polímeros sobre la liberación de famotidina desde los sistemas ensayados, así como el empleo de Eudragit® S-100 como material de recubrimiento de las microcápsulas con el objetivo de conseguir una adecuada eficacia de liberación del fármaco desde estos sistemas (AU)

Optimización de un proceso de complejación para obtener un nuevo sistema de liberación controlada de morfina. II: Influencia de la concentración de polímero en el medio de reacción y determinación del exceso de morfina / Optimization of a complexation process to obtain a new morphine control release system. II. Influence of the polymer concentration in the reaction medium and determination of the excess of morphine

En esta segunda parte, se continua con el estudio de la optimización de la técnica de complejación propuesta, determinando la influencia de la cantidad total de Eudragit® L en el medio de complejación. También se cuantifica el exceso de morfina necesario para conseguir los mejores valores del rendimiento del proceso. A su vez, se inicia la etapa de escalado del proceso de complejación. Durante esta etapa, se determina la conveniencia de invertir el orden de reacción sobre la técnica propuesta inicialmente. Además, se realiza un estudio comparativo entre los distintos lotes de complejos obtenidos en la etapa de escalado, con objeto de determinar la repetitividad del proceso. (AU)

Optimización de un proceso de complejación para obtener un nuevo sistema de liberación controlada de morfina. I. Influencia de la fuerza iónica y de la cantidad de morfina a utilizar / Optimization of a complexation process to obtain a new morphine control release system I. Influence of the ionic strength and the quantity of morphine required

En el presente trabajo se resumen los pasos seguidos para optimizar un proceso de formación de complejos entre el Eudragit® L 30D y el clorhidrato de morfina con el fin de elaborar formas farmacéuticas de liberación controlada del citado fármaco y mejorar en lo posible, la calidad de vida de miles de pacientes aquejados de dolor severo crónico, pacientes a los que la morfina va dirigida. En esta primera parte se llevó a cabo un estudio sobre la posible influencia de la fuerza iónica sobre el rendimiento del proceso. Así mismo, se determinó la necesidad de emplear un exceso de fármaco respecto a la cantidad estequiométrica de grupos carboxílicos neutralizados del polímero en vista a optimizar la técnica de complejación (AU)

Administración oral de proteínas terapéuticas para liberación colónica: estrategias tecnofarmacéuticas / Oral administration of therapeutic proteins for colonic release: technopharmaceutical strategies

La posibilidad que ofrece el colon como lugar de absorción de fármacos, hace que en los últimos años esté aumentando el interés por conseguir una vía alternativa para aquellos principios activos, como los péptidos y las proteínas, que hasta ahora sólo podían ser administrados por la vía parenteral. En este artículo se intenta dar una visión general acerca de las características fisiológicas y anatómicas del colon así como una recopilación de las diferentes estrategias que se usan para conseguir la liberación y la absorción a nivel colónico (AU)

Erradicación de Helicobacter pylori en el tratamiento de la úlcera péptica / Helicobacter Pylori eradication in peptic ulcer treatment

La erradicación de Helicobacter pylori, causa principal de la úlcera péptica, no está indicada en todos los casos donde se confirme la existencia de esta bacteria. Hay que tener en cuenta una serie de factores antes de indicar la erradicación de H. pylori como tratamiento de las úlceras duodenal y gástrica. En este trabajo de revisión se pretende resumir y describir en qué casos está indicada la erradicación de H. pylori, así como las ventajas e inconvenientes que presenta este tratamiento respecto a los tratamientos tradicionalmente empleados en este tipo de patologías. (AU)

Evolución en el tratamiento de la úlcera péptica / Evolution in peptic ulcer

Cuando en 1983 se confirmó que H. pylory era la causa del 100 por ciento de las úlceras duodenales y del 80 por ciento de las úlceras gástricas, el tratamiento de estas enfermedades relacionadas con la secreción ácida del estómago sufrió un importantísimo cambio. Así, de ser tratadas de forma sintomática; han pasado a ser tratadas como una enfermedad infecciosa mediante el empleo conjunto de un antiácido y antibióticos. En este trabajo de revisión se pretende describir y resumir cómo ha ido cambiando el tratamiento de estas enfermedades, hasta ahora crónicas, en los últimos años (AU)