Developing Transdermal Applications of Ketorolac Tromethamine Entrapped in Stimuli Sensitive Block Copolymer Hydrogels

Purpose: 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. / Methods: KT poloxamer based HG (KT-P407-HG) and KT carbomer based HG (KT-C940-HG) were elaborated and characterized in terms of swelling, degradation, porosity, rheology, stability, in vitro release, ex vivo permeation and distribution skin layers. Finally, in vivo anti-inflammatory efficacy and skin tolerance were also assessed. / Results: HGs were transparent and kept stable after 3 months exhibiting biocompatible near neutral pH values. Rheological patterns fitted to Herschel-Bulkley for KT-C940-HG and Newton for KT-P407-HG due to its low viscosity at 25°C. 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. / Conclusions: KT-P407-HG was proposed as suitable formulation for anti-inflammatory local treatment without theoretical systemic side effect

The influence of freeze drying and ϒ-irradiation in pre-clinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using D-(+)-trehalose and polyethylene glycol

Gladys Rosario Ramos Yacasi, María Luisa García López, Marta Espina García, Alexander Parra Coca, Ana Cristina Calpena Campmany Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, Spain Abstract: This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen’s egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over .30 days. This study concludes that both formulations meet the Goldman’s criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials. Keywords: nanoparticles, flurbiprofen, polyethylene glycol 3350, d-(+)-trehalose, freeze-drying, γ-irradiatio

PPARγ agonist-loaded PLGA-PEG nanocarriers as a potential treatment for Alzheimer’s disease: in vitro and in vivo studies

Marcelle Silva-Abreu,1,2 Ana Cristina Calpena,1,2 Pol Andrés-Benito,3,4 Ester Aso,3,4 Ignacio A Romero,5 David Roig-Carles,5 Radka Gromnicova,5 Marta Espina,1,2 Isidre Ferrer,3,4 María Luisa García,1,2 David Male5 1Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; 2Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain; 3Servei d’Anatomia Patològica, Institut d’Investigació Biomèdica de Bellvitge-Hospital Universitari de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Spain; 4Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain; 5School of Life, Health and Chemical Sciences, Faculty of Science, The Open University, Walton Hall, Milton Keynes, UK Objective: The first aim of this study was to develop a nanocarrier that could transport the peroxisome proliferator-activated receptor agonist, pioglitazone (PGZ) across brain endothelium and examine the mechanism of nanoparticle transcytosis. The second aim was to determine whether these nanocarriers could successfully treat a mouse model of Alzheimer’s disease (AD). Methods: PGZ-loaded nanoparticles (PGZ-NPs) were synthesized by the solvent displacement technique, following a factorial design using poly (lactic-co-glycolic acid) polyethylene glycol (PLGA-PEG). The transport of the carriers was assessed in vitro, using a human brain endothelial cell line, cytotoxicity assays, fluorescence-tagged nanocarriers, fluorescence-activated cell sorting, confocal and transmission electron microscopy. The effectiveness of the treatment was assessed in APP/PS1 mice in a behavioral assay and by measuring the cortical deposition of β-amyloid. Results: Incorporation of PGZ into the carriers promoted a 50x greater uptake into brain endothelium compared with the free drug and the carriers showed a delayed release profile of PGZ in vitro. In the doses used, the nanocarriers were not toxic for the endothelial cells, nor did they alter the permeability of the blood–brain barrier model. Electron microscopy indicated that the nanocarriers were transported from the apical to the basal surface of the endothelium by vesicular transcytosis. An efficacy test carried out in APP/PS1 transgenic mice showed a reduction of memory deficit in mice chronically treated with PGZ-NPs. Deposition of β-amyloid in the cerebral cortex, measured by immunohistochemistry and image analysis, was correspondingly reduced. Conclusion: PLGA-PEG nanocarriers cross brain endothelium by transcytosis and can be loaded with a pharmaceutical agent to effectively treat a mouse model of AD. Keywords: nanoparticle, Alzheimer’s disease, blood–brain barrier, brain endothelium, pioglitazone, APP/PS1 transgenic mous

The elite athlete´s mental recovery

Att vila fysiskt är för många en självklarhet, däremot pratas det sällan om den mentala återhämtningen. Båda är viktiga och har stor påverkan på prestation och hälsa. I den här studien är syftet att undersöka elitidrottares upplevelser och erfarenheter av mental återhämtning. För att ta reda på detta har vi genomfört kvalitativa intervjuer. På vilket sätt respondenterna får återhämtning, hur de påverkas av frånvaro av mental återhämtning och om dessa idrottare upplever ett samband mellan frånvaron av mental återhämtning och psykisk ohälsa presenteras i resultatet. När vi analyserade resultaten av intervjuerna gjorde vi innehållsanalyser. Vi kom fram till att samtliga får återhämtning genom att tänka på annat än idrotten och genom att utöva aktiviteter som är roliga. Vid frånvaro av mental återhämtning upplevde majoriteten en försämrad prestation och att hälsan påverkades negativt. Respondenterna beskrev ett samband mellan psykisk ohälsa och frånvaro av mental återhämtning. Det finns relativt lite forskning inom detta område, däremot stämde resultaten med tidigare forskning som idag finns tillgänglig.To many people, resting physically is a matter of course, however, mental recovery is rarely talked about. Both are important and have major impact on performance and health. In this study, the aim is to investigate athletes experiences of mental recovery. In order to find out, we have conducted qualitative interviews. In what way the respondents receive recovery, how they are affected by the absence of mental recovery and if these athletes experience a connection between the absence of mental recovery and mental illness is presented in the results. When we analyzed the results of the interviews, we used content analyses. We concluded that all respondents receive recovery by thinking about other things than sport and by doing activities that are fun. In the absence of mental recovery, the majority experienced a deterioration in performance and a negative impact on health. The respondents described a link between mental illness and the absence of mental recovery. There is limited research in this area, but the results were consistent with previous research available today

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2