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Featured Application: Design and development of nanostructured lipid carriers containing tocopheryl acetate as liquid lipid to obtain a synergic effect with antioxidant drugs loaded into the nanocarriers. Several liquid lipids have been proposed to obtain nanostructured lipid carriers (NLC) with improved efficiency. An attractive strategy is the use of oils that could elicit a synergic effect with the loaded drug. In this work, different percentages (0–4% w/w) of tocopheryl acetate (TA), an oily antioxidant, were used as liquid lipid to prepare NLC loading idebenone (IDE), a synthetic antioxidant investigated for the treatment of neurodegenerative and topical diseases. The technological properties of such NLC were evaluated, as well as the interactions among lipid core components. Loading different percentages of IDE (1–4% w/w) into NLC containing TA up to 4% w/w, no significant change of mean size and polydispersity index was observed. IDE loading capacity was 4% w/w but NLC containing IDE percentages greater than 1.5% w/w showed poor stability during long-term storage. Differential scanning calorimetry analyses highlighted linear relationships between peak temperature and TA percentages, while the enthalpy variation and recrystallization index values showed that increasing the percentage of TA led to less crystalline structure of the NLC core. Therefore, NLC co-loading IDE and TA could be useful to design new delivery systems for the treatment of diseases that could benefit from the co-administration of these antioxidants. [ABSTRACT FROM AUTHOR]

Featured Application: Development of topical formulations based on lipid nanoparticles for the treatment of skin aging and diseases involving cutaneous dryness and scaling such as atopic and exfoliative dermatitis and psoriasis. Idebenone (IDE) is a strong antioxidant that has been proposed for the treatment of skin disorders, including skin ageing. Unfavorable physico-chemical properties make IDE a poor skin permeant where effectiveness could be improved by its loading into suitable delivery systems such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC). In this work, we designed novel IDE-loaded NLC containing tocopheryl acetate (VitE) as a liquid component to obtain a synergic effect between IDE and VitE. The resulting NLC showed small particle sizes (24–42 nm), low polydispersity indices (<0.300), good stability, and were assessed for their in vitro antioxidant activity and in vivo topical effects. IDE-loaded SLN and NLC showed a high antioxidant activity in in vitro assays (DPPH and reducing power method) and provided a similar and significant protection from oxidative stress of fibroblast cells, HS-68, exposed to UV light. After a two-week topical treatment of human volunteers with gels containing IDE-loaded SLN or NLC, a similar increase in skin hydration was observed, while IDE NLC reduced skin pigmentation to a greater extent than IDE SLN. These results suggest that co-loading IDE and VitE into NLC could be a promising strategy to obtain topical formulations with improved photo-protection. [ABSTRACT FROM AUTHOR]

The key role of antioxidants in treating and preventing many systemic and topical diseases is well recognized. One of the most potent antioxidants available for pharmaceutical and cosmetic use is Idebenone (IDE), a synthetic analogue of Coenzyme Q10. Unfortunately, IDE's unfavorable physicochemical properties such as poor water solubility and high lipophilicity impair its bioavailability after oral and topical administration and prevent its parenteral use. In recent decades, many strategies have been proposed to improve IDE effectiveness in the treatment of neurodegenerative diseases and skin disorders. After a brief description of IDE potential therapeutic applications and its pharmacokinetic and pharmacodynamic profile, this review will focus on the different approaches investigated to overcome IDE drawbacks, such as IDE incorporation into different types of delivery systems (liposomes, cyclodextrins, microemulsions, self-micro-emulsifying drug delivery systems, lipid-based nanoparticles, polymeric nanoparticles) and IDE chemical modification. The results of these studies will be illustrated with emphasis on the most innovative strategies and their future perspectives. [ABSTRACT FROM AUTHOR]

Idebenone (IDE) has been proposed for the treatment of neurodegenerative diseases involving mitochondria dysfunctions. Unfortunately, to date, IDE therapeutic treatments have not been as successful as expected. To improve IDE efficacy, in this work we describe a two-step approach: (1) synthesis of IDE ester derivatives by covalent linking IDE to other two antioxidants, trolox (IDETRL) and lipoic acid (IDELIP), to obtain a synergic effect; (2) loading of IDE, IDETRL, or IDELIP into solid lipid nanoparticles (SLN) to improve IDE and its esters' water solubility while increasing and prolonging their antioxidant activity. IDE and its derivatives loaded SLN showed good physico-chemical and technological properties (spherical shape, mean particle sizes 23-25 nm, single peak in the size distribution, ζ potential values -1.76/-2.89 mV, and good stability at room temperature). In vitro antioxidant activity of these SLN was evaluated in comparison with free drugs by means of oxygen radical absorbance capacity (ORAC) test. IDETRL and IDELIP showed a greater antioxidant activity than IDE and encapsulation of IDE and its derivatives into SLN was able to prolong their antioxidant activity. These results suggest that loading IDETRL and IDELIP into SLN could be a useful strategy to improve IDE efficacy. [ABSTRACT FROM AUTHOR]

Abstract: Idebenone (IDE), a synthetic derivative of ubiquinone, shows a potent antioxidant activity that could be beneficial in the treatment of skin oxidative damages. In this work, the feasibility of targeting IDE into the upper layers of the skin by topical application of IDE-loaded solid lipid nanoparticles (SLN) was evaluated. SLN loading different amounts of IDE were prepared by the phase inversion temperature method using cetyl palmitate as solid lipid and three different non-ionic surfactants: ceteth-20, isoceteth-20 and oleth-20. All IDE loaded SLN showed a mean particle size in the range of 30–49nm and a single peak in size distribution. In vitro permeation/penetration experiments were performed on pig skin using Franz-type diffusion cells. IDE penetration into the different skin layers depended on the type of SLN used while no IDE permeation occurred from all the SLN under investigation. The highest IDE content was found in the epidermis when SLN contained ceteth-20 or isoceteth-20 as surfactant while IDE distribution into the upper skin layers depended on the amount of IDE loaded when oleth-20 was used as surfactant. These results suggest that the SLN tested could be an interesting carrier for IDE targeting to the upper skin layers. [Copyright &y& Elsevier]

Lipid nanoparticles (LNPs) have been proposed as carriers for drug skin delivery and targeting. As LNPs effectiveness could be increased by the addition of chemical penetration enhancers (PE), in this work, the feasibility of incorporating PE into LNPs to improve idebenone (IDE) targeting to the skin was investigated. LNPs loading IDE 0.7% w/w were prepared using hydrophilic (propylene glycol, PG, 10% w/w or N-methylpyrrolidone, NMP, 10% w/w) and/or lipophilic PE (oleic acid, OA, 1% w/w; isopropyl myristate, IPM, 3.5% w/w; a mixture of 0.5% w/w OA and 2.5% w/w IPM). All LNPs showed small sizes (<60 nm), low polydispersity index and good stability. According to the obtained results, IDE release from LNPs was not the rate-limiting step in IDE skin penetration. No IDE permeation was observed through excised pigskin from all LNPs, while the greatest increase of IDE penetration into the different skin layers was obtained using the mixture OA/IPM. The antioxidant activity of IDE-loaded LNPs, determined by the oxygen radical absorbance capacity assay, was greater than that of free IDE. These results suggest that the use of suitable PE as LNPs components could be regarded as a promising strategy to improve drug targeting to the skin. [ABSTRACT FROM AUTHOR]

Idebenone (IDE), a strong antioxidant widely investigated for the treatment of neurodegenerative diseases and skin disorders, shows low oral and topical bioavailability due to its unfavorable physico-chemical properties. In this work, to improve IDE topical effectiveness, we explored a two-steps approach: (1) we synthesized an IDE ester (IDEPCA) with pyroglutamic acid, a molecule whose hydrating effects are well known; (2) we loaded IDEPCA into solid lipid nanocarriers (SLN). We evaluated in vitro antioxidant and anti-glycation activity and in vivo hydrating effects after topical application in human volunteers from gel vehicles of IDEPCA SLN in comparison to IDE SLN. All SLN showed good technological properties (mean particle size < 25 nm, polydispersity index < 0.300, good stability). The oxygen radical absorbance capacity assay showed that IDEPCA SLN and IDE SLN had similar antioxidant activity while IDEPCA SLN were more effective in the in vitro NO scavenging assay. Both IDEPCA and IDE SLN showed the same effectiveness in inhibiting the formation of advanced glycation end products. In vivo experiments pointed out a better hydrating effect of IDEPCA SLN in comparison to IDE SLN. These results suggest that the investigated approach could be a promising strategy to obtain topical formulations with increased hydrating effects. [ABSTRACT FROM AUTHOR]

Differential scanning calorimetry (DSC) has emerged as a helpful technique both to characterize drug delivery systems and to study their interactions with bio-membranes. In this work, we compared idebenone (IDE)-loaded solid lipid nanoparticle (SLN) interactions with bio-membranes assessed by DSC with previous in vitro skin penetration data to evaluate the feasibility of predicting IDE skin penetration using DSC analyses. In vitro interactions experiments were performed using multi-lamellar liposomes as a model of bio-membrane. Enthalpy changes (ΔH) and transition temperature (Tm) were assessed during nine repeated DSC scans to evaluate IDE-loaded SLN–bio-membrane interactions over time. Analyzing ΔH and Tm values for each scan, we observed that the difference of ΔH and Tm values between the first and the last scan seemed to be related to SLN ability to locate IDE in the epidermis and in the stratum corneum, respectively. Therefore, the results of this study suggest the possibility of qualitatively predicting in vitro IDE skin penetration from IDE-loaded SLN utilizing the calorimetric parameters obtained from interaction experiments between the carriers under investigation and a model of bio-membrane. [ABSTRACT FROM AUTHOR]

Abstract: In this study we prepared solid lipid nanoparticles (SLN), by the phase inversion temperature (PIT) method, using cetyl palmitate as solid lipid and three different non-ionic emulsifiers of the polyoxyethylene ethers family (ceteth-20, isoceteth-20, oleth-20). These SLN were loaded with different amount of idebenone (IDE), an antioxidant drug useful in the treatment of neurodegenerative diseases and skin oxidative damages. The differential scanning calorimetry (DSC) was employed to evaluate the effects of the different emulsifiers and the different amounts of drug loaded on the thermotropic behavior of SLN and to investigate how the drug was arranged into these nanoparticles. The IDE seemed to be located into different regions of the SLN depending on its concentration and on the surfactant used. The results of this study suggest that the calorimetric studies performed on SLN could provide valuable information to optimize SLN design and drug release from these carriers. [Copyright &y& Elsevier]