Improved Dermal Delivery of Cyclosporine A Loaded in Solid Lipid Nanoparticles

Abstract

Cyclosporine A (CsA) is an immunosuppressant frequently used in the therapy of autoimmune disorders, including skin-related diseases. Aiming towards topical delivery, CsA was successfully incorporated into lipid nanoparticles of Lipocire DM and Pluronic F-127 using the hot homogenization method. Two different nanocarriers were optimized: solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) where oleic acid was the liquid lipid. The developed nanoparticles showed mean sizes around 200 nm, a negative surface charge, and drug entrapment efficiencies around 85% and 70% for SLNs and NLCs, respectively. The spherical CsA-loaded lipid nanoparticles were stable for 9 weeks when stored at room temperature, and exhibited in vitro pH-dependent release under skin mimetic conditions, following the Peppas–Korsmeyer model. CsA, when loaded in SLNs, was safe to be used up to 140 μg mL−1 in fibroblasts and keratinocytes, while CsA-loaded NLCs and free drug exhibited IC50 values of 55 and 95 μg mL−1 (fibroblasts) and 28 and 30 μg mL−1 (keratinocytes), respectively. The developed SLNs were able to retain the drug in pork skin with a reduced permeation rate in relation to NLCs. These findings suggest that SLNs are a potential alternative to produce stable and safe CsA nanocarriers for topical administration.

New Nanoparticle Formulation for Cyclosporin A: In Vitro Assessment

“…As a result of its immunosuppressive capabilities, this peptide was initially approved to prevent graft rejection in organ transplantation [ 6 , 7 ], but other clinical applications are now employed, such as in psoriasis or in atopic dermatitis treatment. In addition, clinical trials for the treatment of other types of diseases such as rheumatoid arthritis, ulcerative colitis, or ophthalmic applications are currently under investigation [ 8 , 9 , 10 , 11 , 12 ]. CsA was initially marketed as an oil-based formulation for oral administration (Sandimmune Neoral ® from Novartis); however, nowadays, other commercial formulations of CsA are available on the market.…”

Freeze-Dried Softisan® 649-Based Lipid Nanoparticles for Enhanced Skin Delivery of Cyclosporine A

“…Analyzing Figure 5, it is possible to observe biocompatibility and safety of SLNs up to concentrations of 6 mg mL −1 in lipid for both cell lines, corresponding to a CsA concentration of approximately 0.6 mg mL −1 . In previous studies performed by the group, free CsA was toxic for L929 when using concentrations higher than 35 µg mL −1 and for HaCaT using concentrations higher than 17.5 µg mL −1 [38]. For the higher tested lipid concentrations (8 and 10 mg mL −1 ) containing 0.8 and 1 mg mL −1 in CsA, respectively, cell viability decreased to values below 70%, indicating a cytotoxic effect that was more evident in keratinocytes ( Figure 5B) than in fibroblasts ( Figure 5A), when compared to the control cells.…”

“…The mean size, polydispersity index (PDI) and zeta potential of the formulations were determined using a ZetaPALS zeta potential analyzer (Brookhaven Instruments Corporation; Holtsville, NY, USA) [38]. Samples where diluted in double deionized water (1:100), which is the same aqueous phase used to prepare the nanoparticles prior each determination.…”

“…Recent topical strategies for CsA delivery focus on the design of PLGA-based nanocapsules to treat severe atopic dermatitis [36] and the preparation of liposomal carriers as ultraflexible systems to assist the topical absorption of CsA [37]. Recently, our research group disclosed the potential of SLN in improved dermal delivery of CsA in relation to nanostructured lipid carriers [38]. SLN of Lipocire DM/ Pluronic F-127 retained CsA in the skin layers with reduced permeation to avoid systemic side effects.…”

Nanostructured Lipid Carriers for the Formulation of Topical Anti-Inflammatory Nanomedicines Based on Natural Substances

“…Yet, an in vivo experiment showed that cytokines levels of IL-4 and IL-5, normally overexpressed in atopic dermatitis, decreased by 40% in both cases [ 138 ]. Topical CyA delivery was also achieved by Silva and colleagues (2020) [ 140 ], Essaghraoui and co-workers (2019) [ 139 ], and Trombino and collaborators (2020) [ 141 ]. Efficient permeation was observed with reduced transdermal permeation.…”