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

María Rincón,María-José Fabrega,Marta Espina,María Rodríguez-Lagunas,Ana Calpena,María García,María Garduño-Ramírez,Guadalupe Abrego

doi:10.3390/nano8121022

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.

Highlights

Skin provides protection from environmental injuries, prevents microbial invasion, regulates temperature, and maintains hydration
PF was supplied by Alcon Cusi (Barcelona, Spain); LAS (PEG-8 Caprylic/Capric Glycerides) and PAT (Precirol® ATO 5) were gifted by Gattefossé (Gennevilliers, France); and Castor oil and Tween® 80 were purchased from Sigma-Aldrich
The use of nanocarriers to localize the drug in the inflamed areas of the skin can be considered of great importance in limiting the side effects of drugs on the uninvolved healthy skin areas, as well as the systemic circulation

Summary

Introduction

Skin provides protection from environmental injuries, prevents microbial invasion, regulates temperature, and maintains hydration. The skins infrastructure provides the necessary components to form a protective barrier. The outer epidermal layer, the stratum corneum (SC), normally retains enough water and acts as a hydro-lipid film constituting an effective first-line of defense against the outside world molecules [1]. The cutaneous permeability barrier resides in the extracellular lipids, mainly ceramides, free fatty acids, and cholesterol, which form extracellular lipid-enriched lamellar membranes between the corneocytes that block the movement of water and the electrolytes [2]. The lipid layers are anisotropic, meaning that the layers permeability is direction-dependent. This property greatly affects the diffusion characteristics in the skin, since diffusion through the SC is intercellular [3,4]

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