Nanostructured Lipid Carriers (NLC) as Vehicles for Topical Administration of Sesamol: In Vitro Percutaneous Absorption Study and Evaluation of Antioxidant Activity.

Sesamol is a natural phenolic compound extracted from Sesamum indicum seed oil. Sesamol is endowed with several beneficial effects, but its use as a topical agent is strongly compromised by unfavorable chemical-physical properties. Therefore, to improve its characteristics, the aim of the present work was the formulation of nanostructured lipid carriers as drug delivery systems for topical administration of sesamol.Two different nanostructured lipid carrier systems have been produced based on the same solid lipid (Compritol® 888 ATO) but in a mixture with two different kinds of oil phase such as Miglyol® 812 (nanostructured lipid carrier-M) and sesame oil (nanostructured lipid carrier-PLUS). Morphology and dimensional distribution of nanostructured lipid carriers have been characterized by differential scanning calorimetry and photon correlation spectroscopy, respectively. The release pattern of sesamol from nanostructured lipid carriers was evaluated in vitro determining drug percutaneous absorption through excised human skin. Furthermore, an oxygen radical absorbance capacity assay was used to determine their antioxidant activity.From the results obtained, the method used to formulate nanostructured lipid carriers led to a homogeneous dispersion of particles in a nanometric range. Sesamol has been encapsulated efficiently in both nanostructured lipid carriers, with higher encapsulation efficiency values (> 90 %) when sesame oil was used as the oil phase (nanostructured lipid carrier-PLUS). In vitro evidences show that nanostructured lipid carrier dispersions were able to control the rate of sesamol diffusion through the skin, with respect to the reference formulations.Furthermore, the oxygen radical absorbance capacity assay pointed out an interesting and prolonged antioxidant activity of sesamol, especially when vehiculated by nanostructured lipid carrier-PLUS.

Nanoparticles prolong N-palmitoylethanolamide anti-inflammatory and analgesic effects in vivo.

N-Palmitoylethanolamide showed great therapeutic potential in the treatment of inflammation and pain but its unfavourable pharmacokinetics properties will hinder its use in the clinical practice. A nanotechnology-based formulation was developed to enhance the probability of N-palmitoylethanolamide therapeutic success, especially in skin disease management. Lipid nanoparticles were produced and characterized to evaluate their mean size, ζ-potential, thermal behaviour, and morphology. The ability of N-palmitoylethanolamide to diffuse across the epidermis as well as anti-inflammatory and analgesic effects were investigated. Particles had a mean size of about 150 nm and a ζ-potential of -40 mV. DSC data confirmed the solid state of the matrix and the embedding of N-palmitoylethanolamide while electron microscopy have evidenced a peculiar internal structure (i.e., low-electrondense spherical objects within the matrix) that can be reliably ascribed to the presence of oil nanocompartments. Lipid nanoparticles increased N-palmitoylethanolamide percutaneous diffusion and prolonged the anti-inflammatory and analgesic effects in vivo. Lipid nanoparticles seem a good nanotechnology-based strategy to bring N-palmitoylethanolamide to clinics.

In vitro Percutaneous Absorption of Niacinamide and Phytosterols and in vivo Evaluation of their Effect on Skin Barrier Recovery.

In this study, we evaluated different strategies to optimize the percutaneous absorption of niacinamide (NA) and soy phytosterols (FITO) by making use of solid lipid nanoparticles (SLN) and penetration enhancers, such as the hydrogenated lecithin. The evaluation of the skin permeation of NA and FITO has been effected in vitro using excised human skin (i.e., stratum corneum-epidermis or SCE). Furthermore, we evaluated the in vivo effect that NA and FITO has on skin barrier recovery after the topical application; using the extent of methyl nicotinate (MN)-induced erythema in damaged skin as a parameter to determine the rate of stratum corneum recovery. Results pointed out the importance of these strategies as valid tools for NA and FITO topical delivery. In fact, soy lecithin based formulations were able to increase the percutaneous absorption of the two active ingredients, while SLN guaranteed an interesting delayed and sustained release of FITO. In vivo evaluation showed clearly that the formulation containing both the actives (NA and FITO) is able to recover about 95% of skin barrier integrity eight days after tape stripping. This effect is probably due to the "synergistic effect" of NA and FITO.

Design of solid lipid nanoparticles for caffeine topical administration.

CONTEXT: Solid lipid nanoparticles (SLN) are drug carriers possessing numerous features useful for topical application. A copious scientific literature outlined their ability as potential delivery systems for lipophilic drugs, while the entrapment of a hydrophilic drug inside the hydrophobic matrix of SLN is often difficult to obtain. OBJECTIVE: To develop SLN intended for loading caffeine (SLN-CAF) and to evaluate the permeation profile of this substance through the skin once released from the lipid nanocarriers. Caffeine is an interesting compound showing anticancer and protective effects upon topical administration, although its penetration through the skin is compromised by its hydrophilicity. MATERIALS AND METHODS: SLN-CAF were formulated by using a modification of the quasi-emulsion solvent diffusion technique (QESD) and characterized by PCS and DSC analyses. In vitro percutaneous absorption studies were effected using excised human skin membranes (i.e. Stratum Corneum Epidermis or SCE). RESULTS: SLN-CAF were in a nanometric range (182.6 ± 8.4 nm) and showed an interesting payload value (75% ± 1.1). DSC studies suggest the presence of a well-defined system and the successful drug incorporation. Furthermore, SLN-CAF generated a significantly faster permeation than a control formulation over 24 h of monitoring. DISCUSSION AND CONCLUSIONS: SLN-CAF were characterized by valid dimensions and a good encapsulation efficiency, although the active to incorporate showed a hydrophilic character. This result confirms the suitability of the formulation strategy employed in the present work. Furthermore, the in vitro evidence outline the key role of lipid nanoparticles in enhancing caffeine permeation through the skin.

Ophthalmic applications of lipid-based drug nanocarriers: an update of research and patenting activity.

Ophthalmic diseases collect great attention by researchers and pharmaceutical technologists, since they can dramatically worsen the quality of life. Because of the limited duration of action on the eye surface, and anatomical/physiological barriers to drug penetration from it into the inner eye structures, conventional ocular formulations are generally unable to perform at their best. Nanotechnology approaches can represent a solution to improve the therapeutic efficiency, compliance and safety of ocular drugs. In this respect, lipid-based nanocarriers are among the most interesting systems. Their composition and production methods make them highly biocompatible and safe formulations. This review illustrates the developments achieved in ocular drug delivery using lipid-based nanocarriers, with a critical revision of recent scientific articles and filed patents.

A comparative study on the possible cytotoxic effects of different nanostructured lipid carrier (NLC) compositions in human dermal fibroblasts.

Nanostructured lipid carriers (NLC) are widely used for topical delivery of active ingredients into the skin for both local and systemic treatment. But concerns have been raised regarding their potential nanotoxicity. To understand the role of NLC composition in terms of cytotoxicity and pro-oxidant effects, we investigated cell viability and intracellular levels of ROS (reactive oxygen species) production in human dermal fibroblasts (HDF) incubated with five NLC formulations differing in their solid lipid composition. HDF and NLC were also exposed to UVA irradiation in order to evaluate the behavior of NLC under realistic environmental conditions which might promote their instability. Using the Guava via-count assay, all nanoparticles, except for those formulated with Compritol 888 ATO, showed a significant decrease in live cells and a parallel increase in apoptotic or dead cells compared to the control, either before and/or after UVA irradiation (18 J/cm(2)). NLC formulated with Geleol™ Mono Diglycerides resulted the most cytotoxic. A similar trend was also observed when intracellular ROS levels were measured in HDF incubated with NLC: there was increased ROS content compared to the control, further exacerbated following UVA. NLC formulated with Dynasan 118 were particularly susceptible to UVA exposure. The results indicate which could be the most suitable candidates for formulating NLC that are biocompatible and non-cytotoxic even when exposed to UVA and hence help direct future choices during the formulation strategies of these delivery systems. Of those tested, Compritol 888 ATO appears to be the best choice.

Lipid nanocarriers (LNC) and their applications in ocular drug delivery.

The peculiar physio-anatomical structure of the eye and the poor physico-chemical properties of many drug molecules are often responsible for the inefficient treatment of ocular diseases by conventional dosage forms, and justify the development of innovative ocular drug delivery systems. Lipid-based nanocarriers (LNC) are among the newer and interesting colloidal drug delivery systems; they show the capability to improve the local bioavailability of drugs administered by various ocular routes and, therefore, their therapeutic efficacy. Furthermore, their extreme biodegradability and biocompatible chemical nature have secured them the title of 'nanosafe carriers.' This review treats the main features of LNC [namely, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and lipid-drug conjugates (LDC)]; examples and advantages of the application of these colloidal carrier systems for the ophthalmic administration of drugs are presented.

Protective effect of red orange extract supplementation against UV-induced skin damages: photoaging and solar lentigines.

BACKGROUND: Exposure of the skin to solar ultraviolet (UV) radiations causes important oxidative damages that result in clinical and hystopathological changes, contributing to premature skin aging. Hyperpigmented lesions, also known as age spots, are one of the most visible alterations in skin photoaging. Skin is naturally equipped with antioxidant systems against UV-induced ROS generation; however, these antioxidant defenses are not completely efficient during exposure to sunlight. Oral antioxidants are able to counteract the harmful effects of UV radiation and to strengthen the physiological skin antioxidant defenses. AIMS: The present study was performed to evaluate the in vivo skin photo-protecting and anti-aging effects of a red orange (Citrus sinensis varieties Moro, Tarocco and Sanguinello) extract supplementation. Previous studies showed that red orange extracts possess strong in vitro free radical scavenging/antioxidant activity and photo-protective effects on human skin. MATERIALS/METHODS: The photo-protective effects of red orange extract intake against UV-induced skin erythema and melanin production in solar lentigo was evaluated on healthy volunteers by an objective instrumental method (reflectance spectrophotometry). RESULTS: Data obtained from in vivo studies showed that supplementation of red orange extract (100 mg/daily) for 15 days brought a significant reduction in the UV-induced skin erythema degree. Moreover, skin age spots pigmentation (melanin content) decreased from 27% to 7% when subjects were exposed to solar lamp during red orange extract supplementation. CONCLUSIONS: Red orange extract intake can strengthen physiological antioxidant skin defenses, protecting skin from the damaging processes involved in photo-aging and leading to an improvement in skin appearance and pigmentation.

Evaluation of nanostructured lipid carriers (NLC) and nanoemulsions as carriers for UV-filters: characterization, in vitro penetration and photostability studies.

The increased awareness of protection against UV radiation damages has led to a rise in the use of topically applied chemical sunscreen agents and to an increased need of innovative carriers designed to achieve the highest protective effect and reduce the toxicological risk resulting from the percutaneous absorption of these substances. In this paper, nanostructured lipid carriers (NLC) and nanoemulsions (NE) were formulated to optimize the topical application of different and widespread UVA or UVB sun filters (ethyl hexyltriazone (EHT), diethylamino hydroxybenzoyl hexyl benzoate (DHHB), bemotrizinol (Tinosorb S), octylmethoxycinnamate (OMC) and avobenzone (AVO)). The preparation and stability parameters of these nanocarriers have been investigated concerning particle size and zeta potential. The release pattern of the sunscreens from NLC and NE was evaluated in vitro, determining their percutaneous absorption through excised human skin. Additional in vitro studies were performed in order to evaluate, after UVA radiation treatment, the spectral stability of the sunfilters once formulated in NLC or NE. From the results obtained, when incorporated in NLC, the skin permeation abilities of the sun filter were drastically reduced, remaining mainly on the surface of the skin. The photostability studies showed that EHT, DHHB and Tinosorb S still retain their photostability when incorporated in these carriers, while OMC and AVO were not photostable as expected. However, no significant differences in terms of photoprotective efficacy between the two carriers were observed.

Optimization of curcumin loaded lipid nanoparticles formulated using high shear homogenization (HSH) and ultrasonication (US) methods.

Lipid nanoparticles (LN) are drug carriers possessing advantages with respect to stability, drug release profile, and biocompatibility. There are several production methods for lipid nanoparticles. Recently high shear homogenization (HSH) and ultrasound (US) techniques have been used to produce these systems in a cheaper and easier way. The objective of the present study was to evaluate the effect of same important instrumental parameters, such as homogenization time (HT) and ultrasonication time (UT), on particle size (MD) and polydispersity index (PDI) of LNs obtained by HSH-US techniques. Curcumin was used as a model drug to be incapsulated in the LNs. LN were prepared by HSH-US technique using tripalmitin (Dynasan 116) and poloxamer 188 (Lutrol F68) as solid lipid and surfactant, respectively. The preparations were characterized and then evaluated using a factorial design study. From the results obtained, LNs produced by HSH-US method were characterized by nanodimension, high homogeneity and encapsulation efficiency. US technology plays an important role in controlling the final dimension of LN dispersion, while longer times of HSH seem mainly to exert a positive effect on the final homogeneity of particle dispersion. Additional studies are in progress to evaluate drug release profile from LNs, for further in vitro/in vivo correlation studies.

Formulation strategies to modulate the topical delivery of anti-inflammatory compounds.

The aim of this study was to assess the ability of some vehicles (emulsion and emulgel), containing hydrogenated lecithin as penetration enhancer, in increasing the percutaneous absorption of the two model compounds dipotassium glycyrrhizinate (DG) and stearyl glycyrrhetinate (SG). Furthermore SG-loaded solid lipid nanoparticles (SLNs) were prepared and the effect of this vehicle on SG permeation profile was evaluated as well. Percutaneous absorption has been studied in vitro, using excised human skin membranes (i.e., stratum corneum epidermis or [SCE]), and in vivo, determining their anti-inflammatory activity. From the results obtained, the use of both penetration enhancers and SLNs resulted in being valid tools to optimize the topical delivery of DG and SG. Soy lecithin guaranteed an increase in the percutaneous absorption of the two activities and a rapid anti-inflammatory effect in in vivo experiments, whereas SLNs produced an interesting delayed and sustained release of SG.

Nanostructured lipid carriers loaded with CoQ10: effect on human dermal fibroblasts under normal and UVA-mediated oxidative conditions.

Nanostructured lipid carriers (NLC) represent an emerging tool for drug delivery and are characterized by important features which promote increased bioavailability and epithelial penetration of lipophilic compounds. However, despite these advantages, their potential cytotoxicity should not be underestimated, especially under in vivo usage conditions. Here we analyzed the viability, intracellular reactive oxygen species (ROS), oxidative DNA damage and mitochondrial functionality in human dermal fibroblasts (HDF) in the presence of NLC either empty or loaded with the reduced or oxidized form of Coenzyme Q10. Experiments were carried out under standard culture conditions and under oxidative stress induced by UVA irradiation, where the latter treatment significantly affected all the endpoints tested above compared to the non-UVA condition. The data show that NLC alone, whether exposed or not exposed to UVA, produce a slight, though significant decrease in cell viability associated with enhanced oxidative stress, which did not however lead to oxidative DNA damage nor mitochondrial impairment. Reduced CoQ10-NLC, differently from oxidized CoQ10-NLC, were able to efficiently counteract UVA-associated mitochondrial depolarization suggesting a potential role of this molecule in antiageing cosmetological formulations. In conclusion, our results suggest that interactions of NLC with cells and biomolecules should be routinely assessed for understanding their compatibility and toxicity, not only under normal conditions, but also under any chemical or physical stress which these delivery systems might be subjected to during their employment.

Evaluation of monooleine aqueous dispersions as tools for topical administration of curcumin: characterization, in vitro and ex-vivo studies.

Curcumin (CUR) is a well-known natural compound showing antioxidant, anti-inflammatory, and antitumor abilities but characterized by poor bioavailability and chemical instability, which drastically reduce its application in the treatment of chronic diseases such as osteoarthritis. The aim of the present study is the design and evaluation of monooleine aqueous dispersion (MAD) as novel carriers for the topical administration of CUR. CUR-loaded MAD was formulated using two different emulsifier systems, namely poloxamer 407 (MAD-A) and sodium cholate-sodium caseinate (MAD-B). These vehicles were characterized, and their influence on in vitro percutaneous absorption of CUR was also evaluated. Furthermore, an oxygen radical absorbance capacity assay was used to determine their antioxidant activity, and a Western blot analysis was performed to evaluate the inhibitory effect of the formulations on inducible nitric oxide synthase and cyclooxygenase 2 expressions. From the obtained results, CUR encapsulation efficiency was higher than 98% for MAD-A and 82% for MAD-B. Shelf-life studies showed that MAD-A maintains CUR stability better than MAD-B, and both vehicles demonstrated, in vitro, control of drug diffusion through the skin. Finally, MAD-A and MAD-B were able to extend the antioxidant/anti-inflammatory effects of CUR, also confirming the protective effect toward CUR chemical stability.