Development of Halobetasol-loaded nanostructured lipid carrier for dermal administration: Optimization, physicochemical and biopharmaceutical behavior, and therapeutic efficacy.

Halobetasol propionate (HB) is considered a super potent drug in the group of topical corticosteroids. HB has anti-inflammatory activity, vasoconstriction properties, and due to its high skin penetration, it can cause systemic side effects. To improve its characteristics, enhance topical effectiveness and reduce penetration to systemic circulation, a study to optimize and characterize a HB-loaded lipid nanocarrier (HB-NLC) has been made by high-pressure homogenization method. The formulation is composed by HB, surfactant, glyceryl distearate and capric glycerides. The optimized HB-NLC containing 0.01% of HB and 3% of total lipid shows an average size below 200 nm with a polydispersity index ≪0.2 and an encapsulation efficiency ≫90%. The in vitro and in vivo tests indicate that the HB-NLC is not toxic, is well tolerated and has an anti-inflammatory effect because they decrease the production of Interleukins in keratinocytes and monocytes. HB-NLC is considered an alternative treatment for skin inflammatory disorders.

Effect of Different Skin Penetration Promoters in Halobetasol Propionate Permeation and Retention in Human Skin.

Halobetasol propionate (HB) is a potent synthetic corticosteroid used against inflammatory skin diseases, such as dermatitis, eczema, and psoriasis, among others. The aim of this study is to define how the presence of different skin penetration enhancers (nonane, menthone, limonene, azone, carene, decanol, linoleic acid and cetiol) affects the penetration and retention in skin of HB. To determine drug penetration through skin, 5% of each promoter was used in an ex vivo system with human skin on Franz cells. The results showed that the highest permeation occurs in the presence of menthone, followed by nonane. Permeation parameters were determined. The in vivo test was assessed, and the formulation containing HB-menthone presented better anti-inflammatory efficacy. These results are useful to generate a specific treatment according to each patient's needs, and the inflammatory characteristics of the disease.

Semi-solid functionalized nanostructured lipid carriers loading thymol for skin disorders.

Acne constitutes one of the most prevalent skin disorder affecting both skin and mental health of patients. However, no cure has been developed so far. In this area, Thymol constitutes a potential candidate since it is able to restore the healthy microbiota of the skin. However, its permeation properties cause its fast elimination and, to avoid this problem, thymol has been loaded into nanostructured lipid carriers (TH-NLCs). Moreover, to increase the suitability of these systems for skin applications, several surface functionalization strategies of TH-NLCs had been assessed. Among the different molecules, phosphatidylcholine-TH-NLCs demonstrated to be safe as well as to provide high antioxidant activity in cellular studies. Therefore, to administer these systems to the skin, functionalized TH-NLCs were dispersed into a carbomer gel developing semi-solid formulations. Rheological properties, porosity and extensibility of TH dispersed in carbomer as well as phosphatidylcholine-TH-NLCs were assessed demonstrating suitable properties for dermal applications. Moreover, both formulations were applied in healthy volunteers demonstrating that gel-phosphatidylcholine-TH-NLCs were able to increase in skin hydration, decrease water loss and reduce skin sebum. Therefore, gel-phosphatidylcholine-TH-NLCs proved to be a suitable system for skin pathologies linked with high sebum generation, loss of hydration and high oxidation, such as acne vulgaris.

Gel-Dispersed Nanostructured Lipid Carriers Loading Thymol Designed for Dermal Pathologies.

Purpose: Acne vulgaris is one of the most prevalent dermal disorders affecting skin health and appearance. To date, there is no effective cure for this pathology, and the majority of marketed formulations eliminate both healthy and pathological microbiota. Therefore, hereby we propose the encapsulation of an antimicrobial natural compound (thymol) loaded into lipid nanostructured systems to be topically used against acne. Methods: To address this issue, nanostructured lipid carriers (NLC) capable of encapsulating thymol, a natural compound used for the treatment of acne vulgaris, were developed either using ultrasonication probe or high-pressure homogenization and optimized using 22-star factorial design by analyzing the effect of NLC composition on their physicochemical parameters. These NLC were optimized using a design of experiments approach and were characterized using different physicochemical techniques. Moreover, short-term stability and cell viability using HaCat cells were assessed. Antimicrobial efficacy of the developed NLC was assessed in vitro and ex vivo. Results: NLC encapsulating thymol were developed and optimized and demonstrated a prolonged thymol release. The formulation was dispersed in gels and a screening of several gels was carried out by studying their rheological properties and their skin retention abilities. From them, carbomer demonstrated the capacity to be highly retained in skin tissues, specifically in the epidermis and dermis layers. Moreover, antimicrobial assays against healthy and pathological skin pathogens demonstrated the therapeutic efficacy of thymol-loaded NLC gelling systems since NLC are more efficient in slowly reducing C. acnes viability, but they possess lower antimicrobial activity against S. epidermidis, compared to free thymol. Conclusion: Thymol was successfully loaded into NLC and dispersed in gelling systems, demonstrating that it is a suitable candidate for topical administration against acne vulgaris by eradicating pathogenic bacteria while preserving the healthy skin microbiome.

Nanostructured lipid carriers loaded with Halobetasol propionate for topical treatment of inflammation: Development, characterization, biopharmaceutical behavior and therapeutic efficacy of gel dosage forms.

The aim of this research was the development and characterization of three gel dosage forms of Halobetasol propionate loaded lipid nanoparticles (HB-NLC) for the treatment of inflammatory skin diseases. A Pluronic gel (Pl-HB-NLC), a Carbopol gel (Cb-HB-NLC) and a Cremigel (Cg-HB-NLC), were characterized for stability, swelling, degradation, porosity and rheology. The biopharmaceutical behavior of in vitro release and ex vivo permeation, along with microbiological stability were also evaluated. Tolerance and therapeutic efficacy were determined in vivo. The gels proved to have eudermic pH and to be effective to improve HB-NLC stability for more than 6 months. In vitro drug release profiles were adjusted to a first order (Pl-HB-NLC, Cg-HB-NLC) and hyperbola (Cb-HB-NLC) kinetic models, revealing sustained drug release. Ex vivo biopharmaceutical behavior showed slow drug penetration through skin, delaying the drug entrance into systemic circulation. The formulations were effective in reducing inflammation with a lower drug dose in comparison with existing treatments, obtaining the fastest effect when using Pl-HB-NLC. After application of the formulations in volunteers, no irritation, redness or edema reactions were detected, plus, an enhancement of the biomechanical properties of the skin was evidenciated. Therefore, the results indicate that these formulations are a suitable alternative to current treatments.

In-situ forming gels containing fluorometholone-loaded polymeric nanoparticles for ocular inflammatory conditions.

Thermosensitive gels have been developed and optimized in such a way that they become gels at corneal temperature and with a viscosity that allows the adequate release of the Fluorometholone (FMT)-loaded PLGA nanoparticles (NPs) in order to improve ocular anti-inflammatory efficacy against a commercial formulation. It has been shown that gels avoid burst release of the drug in the first hours with a slow and increasing profile after administration. NPs have maintained their average size and spherical shape within the gels as confirmed by transmission electron microscopy (TEM). In turn, the in-situ gelling of the formulations allows the administration in eye drops dosage form due to its state of sol at temperatures below 25 °C. Ocular tolerance studies have shown that no formulation causes eye irritation. The administration of the developed formulations has improved the precorneal residence time reflected in the ocular bioavailability, where deep tissues as aqueous humour and crystalline were reached. In conclusion, the use of thermosensitive gels for the topical application of NPs has demonstrated their effectiveness in the acute and preventive treatment of ocular inflammatory conditions.

Efecto modulador de los glucocorticoides sobre la angiogénesis mediada porPI3K/Akt activada por α7-nAChR: Una revisión narrativa

Introducción: los glucocorticoides (GC) han sido ampliamente utilizados en el tratamiento de patologías oculares debido a sus efectos antiinflamatorios y anti-angiogénicos. Se ha sugerido que el mecanismo de acción anti-angiogénico de los GC puede estar relacionado con la enzima fosfatidilinositol-3-cinasa (PI3K), la cual desempeña un papel crucial en la angiogénesis mediada por el receptor de acetilcolina nicotínico alfa 7 (α7-nAChR). La PI3K es una enzima lipoproteica heterodimérica compuesta por las subunidades; reguladora (p85) y catalítica (p110). Objetivo: esta revisión examina la evidencia de cómo los GC modulan la vía de señalización de PI3K activada por α7-nAChR en el proceso de angiogénesis in vitro. Metodología: se realizó una revisión bibliográfica utilizando los motores de búsqueda PubMed y Web of Science, relacionando los conceptos "endothelial cell", "α7-nAChR", "PI3K" y "glucocorticoid". Resultados: se seleccionaron 30 artículos que informaron sobre la expresión de α7-nAChR y PI3K en células endoteliales humanas. Además, del efecto de dexametasona sobre las subunidades de PI3K y Akt (proteína cinasa B) en modelos humano, murino y porcino. A partir de estos hallazgos, se propuso un mecanismo mediante el cual los GC ejercen su efecto anti-angiogénico a través de la modulación en la expresión de la subunidad inhibitoria p85 de PI3K activada por α7-nAChR en células endoteliales humanas. Conclusión: los antecedentes evidencian que dexametasona, ejerce su mecanismo de acción anti-angiogénico mediante el incremento de la expresión de la subunidad inhibitoria p85 de PI3K activada por α7-nAChR.

Introduction: glucocorticoids (GC) have been widely used in the treatment of ocular pathologies due to their anti-inflammatory and anti-angiogenic effects. It has been suggested that the anti-angiogenic mechanism of GC may be related to the enzyme phosphatidylinositol-3-kinase (PI3K), which plays a crucial role in angiogenesis mediated by the alpha 7 nicotinic acetylcholine receptor (α7-nAChR). PI3K is a heterodimeric lipoprotein enzyme composed of regulatory (p85) and catalytic (p110) subunits. Objective: this review examines the evidence of how the GC modulate the PI3K signaling pathway activated by α7-nAChR in the process of in vitro angiogenesis. Methodology: a literature search was conducted using the PubMed and Web of Science search engines, relating the concepts of "endothelial cell," "α7-nAChR," "PI3K," and "glucocorticoid." Results: thirty-two articles were selected that reported on the expression of α7-nAChR and PI3K in human endothelial cells. Furthermore, the effect of dexamethasone on PI3K and Akt (protein kinase B) subunits was documented in human, murine, and porcine models. Based on these findings, a mechanism was proposed whereby GC exert their anti-angiogenic effect through modulation of the expression of the inhibitory p85 subunit of PI3K activated by α7-nAChR in human endothelial cells. Conclusion: background evidence suggests that dexamethasone exerts its anti-angiogenic mechanism of action by increasing the expression of the α7-nAChR-activated PI3K inhibitory subunit p85