Clotrimazole-Loaded Mediterranean Essential Oils NLC: A Synergic Treatment of Candida Skin Infections

Abstract

The increasing development of resistance of Candida species to traditional drugs represents a great challenge to the medical field for the treatment of skin infections. Essential oils were recently proposed to increase drug effectiveness. Herein, we developed and optimized (23 full factorial design) Mediterranean essential oil (Rosmarinus officinalis, Lavandula x intermedia “Sumian”, Origanum vulgare subsp. hirtum) lipid nanoparticles for clotrimazole delivery, exploring the potential synergistic effects against Candida spp. Small sized nanoparticles (<100 nm) with a very broad size distribution (PDI < 0.15) and long-term stability were successfully prepared. Results of the in vitro biosafety on HaCaT (normal cell line) and A431 (tumoral cell line), allowed us to select Lavandula and Rosmarinus as anti-proliferative agents with the potential to be used as co-adjuvants in the treatment of non-tumoral proliferative dermal diseases. Results of calorimetric studies on biomembrane models, confirmed the potential antimicrobial activity of the selected oils due to their interaction with membrane permeabilization. Nanoparticles provided a prolonged in vitro release of clotrimazole. In vitro studies against Candida albicans, Candida krusei and Candida parapsilosis, showed an increase of the antifungal activity of clotrimazole-loaded nanoparticles prepared with Lavandula or Rosmarinus, thus confirming nanostructured lipid carriers (NLC) containing Mediterranean essential oils represent a promising strategy to improve drug effectiveness against topical candidiasis.

Sucupira Oil-Loaded Nanostructured Lipid Carriers (NLC): Lipid Screening, Factorial Design, Release Profile, and Cytotoxicity

“…Since a mixture of a solid lipid (fat) with a liquid lipid (oil) form the lipid phase of the NLC emulsion, a lipid screening assay was firstly performed to select the best solid lipid for the production of NLC. For a successful NLC production, the selection of a proper lipid blend is very important, especially to ensure particle's chemical stability to limit the risk of phase separation over storage time [7,30,54]. Thus, a suitable lipid blend requires (i) the solubility of the active compound (oil) in lipid matrix (solid lipid) to attempt lipid incorporation into lipid nanoparticles, ensuring proper drug loading capacity and encapsulation efficiency; (ii) a major spatial incompatibility of liquid and solid lipids molecules, wherein the oil molecules have no active participation in the solid crystalline matrix of the solid lipid and solid lipid crystals, in turn, are not dissolved in the oil; (iii) stability of lipid phase to chemical degradation; (iv) biodegradable lipids, also capable to produce nanometric particles; and (v) an acceptable toxicological profile, with no production of toxic residues along NLC production process [36,39].…”

“…To overcome the above-mentioned issues and to benefit from their biological activities, nanoparticles have been proposed to load EOs for therapeutic use [7,9,30]. Nanoparticles have the advantages of site-specific targeted delivery of bioactive molecules, improving their bioavailability with minimal toxicological events [29,31].…”

Nanomaterials for Skin Delivery of Cosmeceuticals and Pharmaceuticals

“…Cell viability, anti-inflammatory, and anti-oxidant activities have been evaluated in vitro, confirming that NLC formulations can be fine-tuned for dermocosmetic applications. These Mediterranean oils can also be used to dissolve drugs in order to increase the loading capacity of NLC [15]. An antifungal NLC formulation, composed of clotrimazole and Lavandula or Rosmarinus as anti-proliferative agents, has been developed with the potential to be used as co-adjuvants in the treatment of non-tumoral proliferative dermal diseases [15].…”

“…These Mediterranean oils can also be used to dissolve drugs in order to increase the loading capacity of NLC [15]. An antifungal NLC formulation, composed of clotrimazole and Lavandula or Rosmarinus as anti-proliferative agents, has been developed with the potential to be used as co-adjuvants in the treatment of non-tumoral proliferative dermal diseases [15]. A prolonged in vitro release of clotrimazole could be achieved while in vitro studies against Candida albicans, Candida krusei, and Candida parapsilosis confirmed the increased antifungal effect when using Lavandula or Rosmarinus oils in comparison to the non-loaded oil formulations.…”

“…Since then, several other types of biocompatible nanomaterials have been proposed, being nanoemulsions, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) of special interest due to their lipid composition. Besides, lipid nanoparticles also improve skin hydration because of the formation of a thin lipidic film onto the surface of the skin, retaining its moisture for longer time [15][16][17]).…”