Biopharmaceutical profile of pranoprofen-loaded PLGA nanoparticles containing hydrogels for ocular administration

Two optimized pranoprofen-loaded poly-L-lactic-co glycolic acid (PLGA) nanoparticles (PF-F1NPs; PF- 39 F2NPs) have been developed and further dispersed into hydrogels for the production of semi-solid formu- 40 lations intended for ocular administration. The optimized PF-NP suspensions were dispersed in freshly 41 prepared carbomer hydrogels (HG_PF-F1NPs and HG_PF-F2NPs) or in hydrogels containing 1% azone 42 (HG_PF-F1NPs-Azone and HG_PF-F2NPs-Azone) in order to improve the ocular biopharmaceutical profile 43 of the selected non-steroidal anti-inflammatory drug (NSAID), by prolonging the contact of the pranopro- 44 fen with the eye, increasing the drug retention in the organ and enhancing its anti-inflammatory and 45 analgesic efficiency. Carbomer 934 has been selected as gel-forming polymer. The hydrogel formulations 46 with or without azone showed a non-Newtonian behavior and adequate physicochemical properties for 47 ocular instillation. The release study of pranoprofen from the semi-solid formulations exhibited a sus- 48 tained release behavior. The results obtained from ex vivo corneal permeation and in vivo anti-inflamma- 49 tory efficacy studies suggest that the ocular application of the hydrogels containing azone was more 50 effective over the azone-free formulations in the treatment of edema on the ocular surface. No signs of 51 ocular irritancy have been detected for the produced hydrogels

Quality by Design of Pranoprofen Loaded Nanostructured Lipid Carriers and Their Ex Vivo Evaluation in Different Mucosae and Ocular Tissues

Transmucosal delivery is commonly used to prevent or treat local diseases. Pranoprofen is an anti-inflammatory drug prescribed in postoperative cataract surgery, intraocular lens implantation, chorioretinopathy, uveitis, age-related macular degeneration or cystoid macular edema. Pranoprofen can also be used for acute and chronic management of osteoarthritis and rheumatoid arthritis. Quality by Design (QbD) provides a systematic approach to drug development and maps the influence of the formulation components. The aim of this work was to develop and optimize a nanostructured lipid carrier by means of the QbD and factorial design suitable for the topical management of inflammatory processes on mucosal tissues. To this end, the nanoparticles loading pranoprofen were prepared by a high-pressure homogenization technique with Tween 80 as stabilizer and Lanette® 18 as the solid lipid. From, the factorial design results, the PF-NLCs-N6 formulation showed the most suitable characteristics, which was selected for further studies. The permeability capacity of pranoprofen loaded in the lipid-based nanoparticles was evaluated by ex vivo transmucosal permeation tests, including buccal, sublingual, nasal, vaginal, corneal and scleral mucosae. The results revealed high permeation and retention of pranoprofen in all the tissues tested. According to the predicted plasma concentration at the steady-state, no systemic effects would be expected, any neither were any signs of ocular irritancy observed from the optimized formulation when tested by the HET-CAM technique. Hence, the optimized formulation (PF-NLCs-N6) may offer a safe and attractive nanotechnological tool in topical treatment of local inflammation on mucosal diseases

Development of Pranoprofen Loaded Nanostructured Lipid Carriers to Improve Its Release and Therapeutic Efficacy in Skin Inflammatory Disorders

Abstract: Pranoprofen (PF)-loaded nanostructured lipid carriers (NLCs), prepared using a high-pressure homogenization method, have been optimized and characterized to improve the biopharmaceutical profile of the drug. The optimized PF-NLCs exhibited physicochemical characteristics and morphological properties that were suitable for dermal application. Stability assays revealed good physical stability, and the release behavior of PF from these NLCs showed a sustained release pattern. Cell viability results revealed no toxicity. Ex vivo human skin permeation studies in Franz diffusion cells were performed to determine the influence of different skin penetration enhancers (pyrrolidone, decanol, octanoic acid, nonane, menthone, squalene, linoleic acid, and cineol) on skin penetration and retention of PF, being the highest dermal retention in the presence of linoleic acid. The selected formulations of NLCs exhibited a high retained amount of PF in the skin and no systemic effects. In vivo mice anti-inflammatory efficacy studies showed a significant reduction in dermal oedema. NLCs containing linoleic acid presented better anti-inflammatory efficacy by decreasing the production of interleukins in keratinocytes and monocytes. The biomechanical properties of skin revealed an occlusive effect and no hydration power. No signs of skin irritancy in vivo were detected. According to these results, dermal PF-NLCs could be an effective system for the delivery and controlled release of PF, improving its dermal retention, with reduced dermal oedema as a possible effect of this drug KEYWORDS: anti-inflammatory activity; linoleic acid; nanostructured lipid carriers; penetration enhancers; pranoprofen; skin deliver

In Vitro Cytotoxicity of Oleanolic/Ursolic Acids-Loaded in PLGA Nanoparticles in Different Cell Lines

Oleanolic (OA) and ursolic (UA) acids are recognized triterpenoids with anti-cancer properties, showing cell-specific activity that can be enhanced when loaded into polymeric nanoparticles. The cytotoxic activity of OA and UA was assessed by Alamar Blue assay in three different cell lines, i.e., HepG2 (Human hepatoma cell line), Caco-2 (Human epithelial colorectal adenocarcinoma cell line) and Y-79 (Human retinoblastoma cell line). The natural and synthetic mixtures of these compounds were tested as free and loaded in polymeric nanoparticles in a concentration range from 2 to 32 µmol/L. The highest tested concentrations of the free triterpene mixtures produced statistically significant cell viability reduction in HepG2 and Caco-2 cells, compared to the control (untreated cells). When loaded in the developed PLGA nanoparticles, no differences were recorded for the tested concentrations in the same cell lines. However, in the Y-79 cell line, a decrease on cell viability was observed when testing the lowest concentration of both free triterpene mixtures, and after their loading into PLGA nanoparticles

Asociación de pranoprofeno a sistemas nanoestructurados para administración tópica

[spa] En el presente trabajo, pranoprofeno (PF) fue asociado a nanopartículas (NPs) poliméricas de ácido poli-láctico-co-glicólico (PLGA), preparadas por la técnica de desplazamiento del disolvente. Las PF-NPs fueron optimizadas usando un diseño factorial. Las formulaciones optimizadas fueron aquellas que se prepararon con un pH de la fase acuosa de 4.5 ó 5.5; una concentración de PF de 1.0 ó 1.50 mg/mL; tensoactivo 5 ó 10 mg/mL y PLGA 9.0 ó 9.5 mg/mL. En estas condiciones experimentales, las PF-NPs optimizadas (PF-F1NPs y PF-F2NPs) mostraron un tamaño de partícula apropiado para la administración ocular y/o dérmica (alrededor de 350 nm) y una alta eficiencia de encapsulación del fármaco en el polimero (80%). Para asegurar la estabilidad de las PF-NPs durante un largo período de almacenamiento las formulaciones optimizadas fueron sometidas a un proceso de liofilización. Las características fisicoquímicas de las PF-NPs antes y después de liofilizar fueron similares entre sí. Las interacciones fármaco – polímero fueron evaluadas a través de difracción de rayos X, mediciones espectrales FTIR y análisis de DSC. Los resultados obtenidos sugieren la ausencia de interacciones químicas y confirman que el fármaco se dispersó en el interior de la matriz polimérica. Las PF-NPs optimizadas fueron incorporadas en un hidrogel de Carbómero (HG_PF-F1NPs y HG_PF-F2NPs) o hydrogel en presencia de un 1% ó 3% de azona (HG_PF-F1NPs-Azona y HG_PF-F2NPs-Azona), con la finalidad de obtener formulaciones semisólidas que permitan prologar el tiempo de contacto del fármaco en la superficie ocular y/o dérmica, incrementar la retención del fármaco y aumentar la eficacia analgésica y antiinflamatoria de PF. El análisis morfológico de las PF-NPs incorporadas en el hidrogel mostro que el diámetro de partícula fue similar al observado para las PF-NPs en suspensión. La evaluación del perfil de liberación in vitro de PF reveló que las formulaciones PF-NPs, HG_PF-NPs y HG_PF-NPs-Azona exhiben una liberación sostenida del fármaco comparado con la solución de fármaco libre. Por otra parte, los resultados obtenidos a partir de los ensayos de permeación transcorneal ex vivo y eficacia antiinflamatoria in vivo pone de manifiesto que las formulaciones de HG_PF-NPs-Azona (azona 1% p/p) pueden ser un sistema más efectivo y apropiado en el tratamiento del edema ocular. Adicionalmente, estas formulaciones mostraron una tolerancia ocular óptima por el método HET-CAM y el test de Draize. Los resultados observados a partir de la permeación transdérmica ex vivo y la eficacia antiinflamatoria in vivo de PF sugieren que la aplicación dérmica de la formulación HG_PF-F2NPs puede ser un sistema más apropiado para tratar el edema de la superficie de la piel, respecto al resto de formulaciones ensayadas. Ningún signo de irritación fue detectado tras la aplicación démica de las formulaciones semisólidas de PF en ausencia o en presencia de un 3% de azona.[eng] In the present work, pranoprofen (PF)-loaded poly (lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) were prepared and optimized by the solvent displacement technique. The optimized formulations were those prepared at aqueous phase pH values of 4.5 and 5.5, PF concentrations of 1.0 and 1.5 mg/mL, surfactant concentration of 5.0 and 10 mg/mL and PLGA concentration of 9.00 and 9.50 mg/mL. Under these conditions, the optimized NPs (PF-F1NPs y PF-F2NPs) showed a size appropriate particle size for topical administration (350 nm) and high entrapment efficiency (80%). Lyophilization assays was performed to ensure the long- term stability of these systems. The physicochemical properties of the NPs before and after freeze-drying were similar between them. The evaluation of the interactions between the drug and the polymer revealed that there is no evidence of any chemical interaction. The optimized PF-NPs formulations were incorporated into Carbomer hydrogel (HG_PF-F1NPs and HG_PF-F2NPs) or hydrogel with 1% or 3% azone (HG_PF-F1NPs-Azone and HG_PF-F2NPs-Azone), in order to obtain semisolid formulations that prolonging the contact of the PF with the eye or skin. The morphological analysis of the PF-NPs after incorporated into hydrogel revealed that the diameter of particle was similar to those of the NPs suspension. The in vitro release assay of PF from PF-NPs, HG_PF-NPs and HG_PF-NPs-Azone formulations revealed that these formulations exhibited sustained release behaviour with a slower release of PF compared to the free drug solution. The results obtained from the ex vivo corneal permeation and in vivo anti-inflammatory efficacy suggest that the ocular application of the semisolid formulations with a 1% azone could be appropriate in the treatment ocular oedema. In addition, these formulations showed an optimal ocular tolerance by HET-CAM method and Draize test. Otherwise, the results observed from the ex vivo transdermal permeation and in vivo anti-inflammatory efficacy assays of the PF indicate that the administration of the HG_PF-F2NPs may be more effective in the treatment of edema on the skin surface respect to the others formulations. No signs of skin irritancy were detected for all the semisolid formulations without or with a 3% azone

Biopharmaceutical profile of pranoprofen-loaded PLGA nanoparticles containing hydrogels for ocular administration

Two optimized pranoprofen-loaded poly-L-lactic-co glycolic acid (PLGA) nanoparticles (PF-F1NPs; PF- 39 F2NPs) have been developed and further dispersed into hydrogels for the production of semi-solid formu- 40 lations intended for ocular administration. The optimized PF-NP suspensions were dispersed in freshly 41 prepared carbomer hydrogels (HG_PF-F1NPs and HG_PF-F2NPs) or in hydrogels containing 1% azone 42 (HG_PF-F1NPs-Azone and HG_PF-F2NPs-Azone) in order to improve the ocular biopharmaceutical profile 43 of the selected non-steroidal anti-inflammatory drug (NSAID), by prolonging the contact of the pranopro- 44 fen with the eye, increasing the drug retention in the organ and enhancing its anti-inflammatory and 45 analgesic efficiency. Carbomer 934 has been selected as gel-forming polymer. The hydrogel formulations 46 with or without azone showed a non-Newtonian behavior and adequate physicochemical properties for 47 ocular instillation. The release study of pranoprofen from the semi-solid formulations exhibited a sus- 48 tained release behavior. The results obtained from ex vivo corneal permeation and in vivo anti-inflamma- 49 tory efficacy studies suggest that the ocular application of the hydrogels containing azone was more 50 effective over the azone-free formulations in the treatment of edema on the ocular surface. No signs of 51 ocular irritancy have been detected for the produced hydrogels

Development of Pranoprofen Loaded Nanostructured Lipid Carriers to Improve Its Release and Therapeutic Efficacy in Skin Inflammatory Disorders

Abstract: Pranoprofen (PF)-loaded nanostructured lipid carriers (NLCs), prepared using a high-pressure homogenization method, have been optimized and characterized to improve the biopharmaceutical profile of the drug. The optimized PF-NLCs exhibited physicochemical characteristics and morphological properties that were suitable for dermal application. Stability assays revealed good physical stability, and the release behavior of PF from these NLCs showed a sustained release pattern. Cell viability results revealed no toxicity. Ex vivo human skin permeation studies in Franz diffusion cells were performed to determine the influence of different skin penetration enhancers (pyrrolidone, decanol, octanoic acid, nonane, menthone, squalene, linoleic acid, and cineol) on skin penetration and retention of PF, being the highest dermal retention in the presence of linoleic acid. The selected formulations of NLCs exhibited a high retained amount of PF in the skin and no systemic effects. In vivo mice anti-inflammatory efficacy studies showed a significant reduction in dermal oedema. NLCs containing linoleic acid presented better anti-inflammatory efficacy by decreasing the production of interleukins in keratinocytes and monocytes. The biomechanical properties of skin revealed an occlusive effect and no hydration power. No signs of skin irritancy in vivo were detected. According to these results, dermal PF-NLCs could be an effective system for the delivery and controlled release of PF, improving its dermal retention, with reduced dermal oedema as a possible effect of this drug KEYWORDS: anti-inflammatory activity; linoleic acid; nanostructured lipid carriers; penetration enhancers; pranoprofen; skin deliver

Development of Pranoprofen Loaded Nanostructured Lipid Carriers to Improve Its Release and Therapeutic Efficacy in Skin Inflammatory Disorders

Abstract: Pranoprofen (PF)-loaded nanostructured lipid carriers (NLCs), prepared using a high-pressure homogenization method, have been optimized and characterized to improve the biopharmaceutical profile of the drug. The optimized PF-NLCs exhibited physicochemical characteristics and morphological properties that were suitable for dermal application. Stability assays revealed good physical stability, and the release behavior of PF from these NLCs showed a sustained release pattern. Cell viability results revealed no toxicity. Ex vivo human skin permeation studies in Franz diffusion cells were performed to determine the influence of different skin penetration enhancers (pyrrolidone, decanol, octanoic acid, nonane, menthone, squalene, linoleic acid, and cineol) on skin penetration and retention of PF, being the highest dermal retention in the presence of linoleic acid. The selected formulations of NLCs exhibited a high retained amount of PF in the skin and no systemic effects. In vivo mice anti-inflammatory efficacy studies showed a significant reduction in dermal oedema. NLCs containing linoleic acid presented better anti-inflammatory efficacy by decreasing the production of interleukins in keratinocytes and monocytes. The biomechanical properties of skin revealed an occlusive effect and no hydration power. No signs of skin irritancy in vivo were detected. According to these results, dermal PF-NLCs could be an effective system for the delivery and controlled release of PF, improving its dermal retention, with reduced dermal oedema as a possible effect of this drug KEYWORDS: anti-inflammatory activity; linoleic acid; nanostructured lipid carriers; penetration enhancers; pranoprofen; skin deliver