Estudio de formulaciones de ketorolaco de trometamina para aplicación sobre mucosas y piel

[spa] En los últimos años, la investigación farmacéutica se ha centrado en mejorar el efecto de terapias actuales desarrollando nuevas formas farmacéuticas o vías de administración. Las rutas de administración transdérmica y transmucosa son una atractiva alternativa a la vía oral y a la parenteral, puesto que permiten evadir algunas desventajas que presentan estas vías tales como el efecto de primer paso hepático o disminuyendo efectos adversos como las irritaciones o ulceraciones gástricas. El Ketorolaco Trometamina es un fármaco anti-inflamatorio no esteroideo que por vía oral presenta dichas desventajas. Con el fin de obtener vehículos dérmicos de ketorolaco trometamina (KT) para el tratamiento local de la inflamación y restringir los efectos secundarios indeseables de los niveles sistémicos se desarrollaron hidrogeles (HGs) de poloxámero y carbómero y se caracterizaron. Se estudió la liberación in vitro, la permeación ex vivo y se estudió la distribución del fármaco en las diferentes capas de la piel. Finalmente, se evaluó también la eficacia antiinflamatoria in vivo y la tolerancia de las formulaciones en la piel. Los HGs fueron transparentes y estables durante 3 meses exhibiendo valores de pH biocompatibles. Ambos HGs presentaron un perfil de liberación rápida siguiendo una cinética de primer orden. La mayor cantidad de Ketorolaco trometamina se encontró en la superficie de la piel, seguido de la epidermis para KT-C940-HG y el estrato córneo para KT-P407-HG. La eficacia anti-inflamatoria de KT-P407-HG reveló suficiente biodisponibilidad de Ketorolaco trometamina para alcanzar fácilmente el sitio de acción. La aplicación de las formulaciones desarrolladas en voluntarios no indujo ninguna irritación visual de la piel. El KT-P407-HG se propuso como formulación dérmica adecuada para el tratamiento local anti-inflamatorio sin efecto secundario teórico sistémico. También se desarrollaron y estudiaron geles mucoadhesivos para la administración bucal; el KT se vehiculizó en dos excipientes mucoadhesivos, Carbopol y Carboximetil celulosa sódica, a una concentración del 2% de principio activo. La permeación los dos geles mucoadhesivos sobre mucosa bucal y sublingual de cerdo, mostró que ambas formulaciones eran capaces de alcanzar concentraciones plasmáticas teóricas suficientes para proporcionar efecto farmacológico sistémico, hecho que lleva a considerar el posible uso de dichas formulaciones mucoadhesivas como alternativa a la vía oral. La visión afecta significativamente la calidad de vida de las personas; las patologías asociadas al ojo son tanto molestas como difíciles de tratar. Las formulaciones tópicas oftálmicas convencionales son soluciones o suspensiones; las cuales han sido utilizadas durante siglos por su aceptación social y su bajo coste de fabricación, pero tienen ciertas limitaciones. El 98% dosis administrada en forma de colirio, es eliminada en pocos minutos. Además, los colirios son útiles para el tratamiento de enfermedades del segmento anterior del ojo, pero la mayoría de problemas visuales en los países industrializados están asociados al segmento posterior, cuyas necesidades no están bien cubiertas. Por este motivo, se han ido creando y mejorando nuevas formulaciones para el segmento posterior. Para la mayoría de los tratamientos para el segmento posterior, las formas de administración más utilizadas son las inyecciones intravitreales, este método es eficaz, seguro, pero poco cómodo para los pacientes. Por ello, surgen métodos nuevos que resuelvan estos problemas. En esta tesis doctoral se han desarrollado nanopartículas (NPs) con el fin de superar las limitaciones expuestas. Las NPs se caracterizaron, se llevaron a cabo estudios de liberación del KT de las NPs, estudio de la permeación ex vivo del KT a través de la córnea y tejido esclerótico y test de tolerancia ocular por métodos alternativos, HET-CAM. Las NPs poliméricas de ketoraolaco desarrollas y optimizadas presentaron un tamaño de partículas y características adecuadas para la administración ocular. La permeación del KT a través de la córnea y del tejido esclerótico fue mayor en las NPs que en el colirio comercial Acular®. Según demostró la permeación in vivo, las NPs penetran hasta el humor vítreo y el humor acuoso a las 8 horas de su administración. Dicha penetración fue superior al colirio Acular® usado como referencia.[eng] Recently, pharmaceutical research has focused on improving the effect of current therapies by developing new pharmaceutical forms or routes of administration. The transdermal and transmucosal routes are an attractive alternative to the oral and parenteral ones, since they allow avoiding some disadvantages that present these routes such as the First-pass hepatic effect or decreasing adverse effects for instance, gastric irritations or ulcerations. Ketorolac Tromethamine is a non-steroidal anti-inflammatory drug which exhibits the disadvantages abovementioned. In order to obtain dermal vehicles of ketorolac tromethamine (KT) for the local treatment of inflammation and restrict undesirable side effects of systemic levels hydrogels (HGs) of poloxamer and carbomer were developed and characterized. Moreover, in vitro release, ex vivo permeation and distribution of KT into the skin layers was evaluated. Finally, in vivo anti-inflammatory efficacy and skin tolerance were also assessed. HGs exhibit suitable physical-chemical and rheological properties. Rapid release profiles were observed through first order kinetics. Following the surface the highest concentration of KT from C940-HG was found in the epidermis and the stratum corneum for P407-HG. Relevant anti-inflammatory efficacy of KT-P407-HG revealed enough ability to provide sufficient bioavailability KT to reach easily the site of action. The application of developed formulations in volunteers did not induce any visual skin irritation. KT-P407-HG was proposed as suitable formulation for anti- inflammatory local treatment without theoretical systemic side effect. The permeation of two mucoadhesive gels (Carbopol and Carboxymethylcellulose Sodium) 2% Ketorolac tromethamine, on porcine mucosa, both buccal and sublingual, showed that these formulations would able to reach plasma concentrations within the therapeutic range. These results lead to consider the mucoadhesive formulations developed as an alternative to the oral route. Visual disturbances significantly affect people’s quality of life. Eye drops are the most common dosage forms however they present certain limitations; the 98% of the applied dose is eliminated in a few minutes. In addition, eye drops are useful for treatment of diseases of the anterior segment of the eye, but most visual impairments are associated with the posterior segment. In this doctoral thesis, we developed nanoparticles (NPs) in order to overcome these limitations. NPs were characterized, and in vitro release and ex vivo permeation studies through the cornea and sclerotic tissue were performed. Ocular tolerance test was also assessed by alternative methods, HET-CAM. The developed NPs were suitable for ocular administration. The permeation of KT through the cornea and sclerotic tissue was greater in NPs than in commercial Acular® eye drops. In vivo permeation demonstrated that NPs penetrated into the vitreous humor and aqueous humor within 8 hours of administration. Such penetration was superior to Acular® used as reference

Development, physical-chemical stability and release studies of four alcohol-free spironolactone suspensions for use in pediatrics

Dissolution studies have become of great significance because, in most cases, drug dissolution is the rate-limiting step in the absorption process. As occurs with solid oral dosage forms, heterogeneous disperse systems (suspensions) could also have some problems with their in vitro dissolution. The objective of this study was to evaluate influence of the excipients on the release of spironolactone from four alcohol free suspensions (pharmaceutical compounding) of spironolactone 5 mg/mL suitable for pediatric use. Also the comparison of the physical and chemical stability of the suspensions stored at 4, 25 and 40 ºC over a 60- day period has been studied. Rheological behavior, particle size, a prediction of long-term physical stability, pH and assay of spironolactone by HPLC were assessed at prefixed times. The dissolution profile of each suspension was determined and compared with that of the commercial tablets. A microbiological study of the best formula was also performed. Chemically, the four spironolactone suspensions were stable for 60 days stored at three temperatures; Suspension IV had optimum pH values and the highest recovery percentage. In terms of physical stability, sedimentation occurred in Suspension IV and flotation of spironolactone in Suspensions I, II and III. Suspension III had the highest viscosity and the slowest drug release. Suspension IV was also microbiologically stable for 60 days. In conclusion, Suspension IV had the best properties and the least suitable form was Suspension III, as its high viscosity made it difficult to achieve homogeneous redispersion, and it had the slowest dissolution profile

Ética en la docencia. El profesor universitario como modelo de actuación personal y profesional

Podeu consultar la Vuitena trobada de professorat de Ciències de la Salut completa a: http://hdl.handle.net/2445/66524El profesor universitario debe ser un modelo de actuación personal y profesional para sus alumnos; un ejemplo que estimule a los estudiantes tanto en el ejercicio de la profesión, como con el respeto por su entorno. De tal modo que el conocimiento que adquieran los alumnos puedan aplicarlo a la vida cotidiana. Esta práctica se ha llevado a cabo en la asignatura de Trabajo Dirigido. El profesor debe manifestar una coherencia entre acción y el pensamiento, debe ser justo y equitativo en la evaluación y tener en cuenta las necesidades particulares de los alumnos; también debe conseguir motivarlos, de forma amigable, con el fin que ellos se esfuercen para lograr las metas académicas. El objetivo es fomentar el logro de competencias transversales tales como responsabilidad, igualdad y capacidad de trabajo en equipo; mediante la realización de sesiones de debate entre el alumno, el tutor, y/o otros investigadores. Por otra parte, también se pretende un análisis reflexivo de nuestra propia actividad docente con el fin de tener en cuenta el potencial y necesidades particulares de cada alumno para lograr una mejora continua. Para alcanzar estos objetivos, el método consiste en la colaboración directa del alumno con los investigadores de la Unidad en proyectos reales y, sesiones semanales de discusión de los resultados que se van obteniendo. De forma que los alumnos desarrollan capacidad de trabajar en equipo, responsabilidad, respeto entre géneros, pensamiento crítico y una verdadera integración. Finalmente, creemos que la ética en la docencia también se pone de manifiesto a la hora de evaluar el aprendizaje de los alumnos. Por este motivo, es de vital importancia que el profesor universitario fomente un clima de integración, de comunicación y de trabajo en equipo en las sesiones docentes. El análisis reflexivo que ha realizado el grupo docente ha permitido examinar las debilidades, las fortalezas y oportunidades acaecidas de la actividad docente para potenciar mejoras en el nuevo curso

PV Lesions and Other Issues in the Oral Cavity Treatment and Removal without Pain

Abstract: Due to different oral and dental conditions, oral mucosa lesions such as those caused by the human papilloma virus and temporomandibular joint pathologies often have to be treated by surgical, ablative or extractive procedures. The treatment and control of pain and inflammation during these procedures is essential to guarantee the patient's well-being. For the foregoing reason, a hydrogel based on sodium alginate and hyaluronic acid containing 2% of ketorolac tromethamine has been developed. We characterized it physically, mechanically and morphologically. The rheological results suggest that the formulation can be easily and gently applied. Ex vivo permeation studies show that Ketorolac Tromethamine is able to penetrate through the buccal and sublingual mucosae, in addition to being retained in the mucosae's structure. Through an in vitro test, we were able to evaluate the role that saliva plays in the bioavailability of the drug, observing that more than half of the applied dose is eliminated in an hour. The histological and cytotoxic studies performed on pigs in vivo showed the excellent safety profile of the formulation, as well as its high tolerability. In parallel, a biomimetic artificial membrane (PermeaPad®) was evaluated, and it showed a high degree of correlation with the oral and sublingual mucosa

Validation of an Ex Vivo Permeation Method for the Intestinal Permeability of Different BCS Drugs and Its Correlation with Caco-2 In Vitro Experiments

The absorption study of drugs through different biological membranes constitutes an essential step in the development of new pharmaceutical dosage forms. Concerning orally administered forms, methods based on monolayer cell culture of Caco-2 (Caucasian colon adenocarcinoma) have been developed to emulate intestinal mucosa in permeability studies. Although it is widely accepted, it has disadvantages, such as high costs or high technical complexity, and limitations related to the simplified structure of the monolayer or the class of molecules that can be permeated according to the transport mechanisms. The aim of this work was to develop a new ex vivo methodology which allows the evaluation of the intestinal apparent permeability coefficient (Papp) while using fewer resources and to assess the correlation with Caco-2. To this end, pig (Sus scrofa) duodenum segments were mounted in Franz diffusion cells and used to permeate four different drugs: ketorolac tromethamine (Kt), melatonin (Mel), hydrochlorothiazide (Htz), and furosemide (Fur). No statistically significant differences (p > 0.05) were observed corelating Papp values from Franz diffusion cells and Caco-2 cell experiments for Kt, Htz, and Fur. However, there were statistically significant differences (p < 0.05) correlating Papp values and Mel. The difference is explained by the role of Mel in the duodenal epithelial paracellular permeability reduction. Ex vivo permeation may be an equivalent method to Caco-2 for drugs that do not produce intestinal membrane phenomena that could affect absorption

Nano-engineering of ketorolac tromethamine platforms for ocular treatment of inflammatory disorders

Aim: The development and optimization of Ketorolac tromethamine-loaded polylactic-co-glycolic acid nanoparticles (KT-NPs) for the treatment of inflammatory processes of the eye. Materials & methods: KT-NPs were developed by factorial design and characterized by assessing their physicochemical properties. Biopharmaceutical behavior studies, ocular tolerance, anti-inflammatory efficacy and bioavailability tests were performed on pigs. Results: Optimized KT-NPs of 112 nm, narrow distribution with encapsulation efficiency near 100% were obtained. KT release followed the Weibull model and there was significantly greater retention in the cornea and sclera than in the commercial reference. KT-NPs showed no signs of ocular irritancy and similar anti-inflammatory efficacy to the commercial reference. Conclusion: KT-NPs were a suitable alternative for the treatment of inflammatory disorders of the anterior and posterior segments of the eye as an alternative to conventional topical formulations

Characterization and In Vivo Anti-Inflammatory Efficacy of Copal (Dacryodes peruviana (Loes.) H.J. Lam) Essential Oil

Essential oils are natural aromatic substances that contain complex mixtures of many volatile compounds frequently used in pharmaceutical and cosmetic industries. Dacryodes peruviana (Loes.) H.J. Lam is a native species from Ecuador whose anti-inflammatory activity has not been previously reported, thus the aim of this study was to evaluate the anti-inflammatory activity of D. peruviana essential oil. To that end, essential oil from D. peruviana fruits was isolated by hydrodistillation and characterized physically and chemically. The tolerance of the essential oil was analyzed by cytotoxicity studies using human keratinocytes. The anti-inflammatory activity was evaluated by an arachidonic acid-induced edema model in mouse ear. The predominant compounds in D. peruviana essential oil were α-phellandrene, limonene, and α-pinene, with the three compounds reaching approximately 83% of the total composition. Tolerance studies showed high biocompatibility of this essential oil with human keratinocytes. In vivo studies demonstrated a moisturizing effect and an alleviation of several events occurred during the inflammatory process after topical treatment with D. peruviana essential oil such as decline in skin edema; reduction in leukocytic infiltrate; and decrease in inflammatory cytokines TNFα, IL-8, IL-17A, and IL-23. Therefore, this essential oil could be an attractive treatment for skin inflammation

Baricitinib Liposomes as a New Approach for the Treatment of Sjögren's Syndrome

Sjögren's syndrome is a chronic systemic autoimmune disease affecting from 0.2 to 3% of the general population. The current treatment for Sjögren's syndrome is aimed at controlling symptoms such as dry eyes and xerostomia. Systemic therapy with glucocorticoids or immunosuppressants is also used. Baricitinib is an immunosuppressant drug, specifically a Janus kinases 1 and 2 selective inhibitor. We propose ocular liposomal formulations loaded with baricitinib for the management of Sjögren's syndrome. The novelty of the work relies on the fact that, for the first time, baricitinib is intended to be used for topical delivery. Two liposomal formulations were prepared with different lipids: (i) L-α-phosphatidylcholine (Lα-PC) and (ii) a combination of lipids 1-palmitoyl-2-oleoyl-phosphatidylethanolamine: s1-Palmitoyl-2-oleoyl-sn-glycerol-3-phosphoglycerol (3:1, mol/mol) (POPE:POPG), and they were physicochemically characterized. The in vitro drug release and the ex vivo permeation through corneal and scleral tissues were also assessed. Finally, the tolerance of the formulations on the ocular tissues was evaluated by the HET-CAM technique, as well as through the histological analysis of the cornea and sclera and the cornea transparency. Both liposomes resulted in small, spherical shapes, with suitable physicochemical properties for the ocular administration. Lα-PC led to higher flux, permeation, and retention in the sclera, whereas POPE:POPG led to higher flux and permeation in the cornea. The formulations showed no irritant effects on the chorioallantoic membrane. Additionally, the liposomes did not affect the cornea transparency when they were applied, and the histological analysis did not reveal any structural alteratio

Semi-Solid Dosage Forms Containing Pranoprofen-Loaded NLC as Topical Therapy for Local Inflammation: In Vitro, Ex Vivo and In Vivo Evaluation

Pranoprofen (PRA)-loaded nanostructured lipid carriers (NLC) have been dispersed into blank gels composed of 1% of Carbomer 940 (PRA-NLC-Car) and 3% of Sepigel® 305 (PRA-NLC-Sep) as a novel strategy to refine the biopharmaceutical profile of PRA, for dermal administration in the treatment of skin inflammation that may be caused by possible skin abrasion. This stratagem intends to improve the joining of PRA with the skin, improving its retention and anti-inflammatory effect. Gels were evaluated for various parameters such as pH, morphology, rheology, and swelling. In vitro drug release research and ex vivo permeation through the skin were carried out on Franz diffusion cells. Additionally, in vivo assays were carried out to evaluate the anti-inflammatory effect, and tolerance studies were performed in humans by evaluating the biomechanical properties. Results showed a rheological profile common of semi-solid pharmaceutical forms for dermal application, with sustained release up to 24 h. In vivo studies using PRA-NLC-Car and PRA-NLC-Sep in Mus musculus mice and hairless rats histologically demonstrated their efficacy in an inflammatory animal model study. No signs of skin irritation or modifications of the skin's biophysical properties were identified and the gels were well tolerated. The results obtained from this investigation concluded that the developed semi-solid formulations represent a fitting drug delivery carrier for PRA's transdermal delivery, enhancing its dermal retention and suggesting that they can be utilized as an interesting and effective topical treatment for local skin inflammation caused by a possible abrasion

Assessing the Solubility of Baricitinib and Drug Uptake in Different Tissues Using Absorption and Fluorescence Spectroscopies

The low water solubility of baricitinib (BCT) limits the development of new formulations for the topical delivery of the drug. The aims of this study were to assess the solubility of BCT in different solvents, including Transcutol, a biocompatible permeation enhancer that is miscible in water, to evaluate the drug uptake in human skin and porcine tissues (sclera, cornea, oral, sublingual, and vaginal), and to subsequently extract the drug from the tissues so as to determine the drug recovery using in vitro techniques. Analytical methods were developed and validated for the quantification of BCT in Transcutol using absorption and fluorescence spectroscopies, which are complementary to each other and permit the detection of the drug across a broad range of concentrations. Results show that Transcutol permits an increased drug solubility, and that BCT is able to penetrate the tissues studied. The solutions of BCT in Transcutol were stable for at least one week. Hence, Transcutol may be a suitable solvent for further development of topical formulations