Design and Characterization of Ethosomes for Transdermal Delivery of Caffeic Acid

Abstract

The present investigation describes a formulative study aimed at designing ethosomes for caffeic acid transdermal administration. Since caffeic acid is characterized by antioxidant potential but also high instability, its encapsulation appears to be an interesting strategy. Ethosomes were produced by adding water into a phosphatidylcholine ethanol solution under magnetic stirring. Size distribution and morphology of ethosome were investigated by photon correlation spectroscopy, small-angle X-ray spectroscopy, and cryogenic transmission electron microscopy, while the entrapment capacity of caffeic acid was evaluated by high-performance liquid chromatography. Caffeic acid stability in ethosome was compared to the stability of the molecule in water, determined by mass spectrometry. Ethosome dispersion was thickened by poloxamer 407, obtaining an ethosomal gel that was characterized for rheological behavior and deformability. Caffeic acid diffusion kinetics were determined by Franz cells, while its penetration through skin, as well as its antioxidant activity, were evaluated using a porcine skin membrane–covered biosensor based on oxygen electrode. Ethosome mean diameter was ≈200 nm and almost stable within three months. The entrapment of caffeic acid in ethosome dramatically prolonged drug stability with respect to the aqueous solution, being 77% w/w in ethosome after six months, while in water, an almost complete degradation occurred within one month. The addition of poloxamer slightly modified vesicle structure and size, while it decreased the vesicle deformability. Caffeic acid diffusion coefficients from ethosome and ethosome gel were, respectively, 137- and 33-fold lower with respect to the aqueous solution. At last, the caffeic acid permeation and antioxidant power of ethosome were more intense with respect to the simple solution.

The Potential of Caffeic Acid Lipid Nanoparticulate Systems for Skin Application: In Vitro Assays to Assess Delivery and Antioxidant Effect

“…To prepare ethosome (ETHO), firstly, PC was solubilized in ethanol (3% w / v ); afterwards, bidistilled water was added dropwise to the ethanol phase up to a final 70:30 ( v / v ) ratio [ 11 ]. The dispersion has been magnetically stirred at 750 rpm (IKA RCT basic, IKA ® -Werke GmbH & Co. KG, Staufen, Germany) for 30 min at room temperature.…”

“…For Cryo-TEM analyses, SLN and ETHO samples have been firstly vitrified following a method previously described [ 10 , 11 ]. The vitrified species have been placed into a Zeiss EM922 Omega transmission electron microscope (Carl Zeiss Microscopy, GmbH, Munich, Germany) for imaging using a cryoholder (CT3500, Gatan, Pleasanton, CA, USA).…”

“…The encapsulation efficiency (EE) and loading capacity (LC) of CA in SLN and ETHO was determined by ultracentrifugation and HPLC [ 10 , 11 ]. Briefly, 500 μL aliquots of SLN-CA or ETHO-CA were poured into a centrifugal filter (Microcon centrifugal filter unit YM-10 membrane, NMWCO 3 kDa, Sigma-Aldrich, St. Louis, MO, USA) and centrifuged (Spectrafuge™ 24D Digital Microcentrifuge, Woodbridge, NJ, USA) for 20 min at 8000 rpm.…”

“…Thanks to this potential, CA can be employed in the treatment of UVB-induced photoaging and in the chemoprevention of malignant melanoma [ 7 , 8 , 9 ]. However, the poor water solubility and chemical stability of CA makes necessary the use of specialized delivery systems suitable for its solubilization, protection from degradation, and the maintenance of antioxidative power [ 10 , 11 , 12 , 13 ]. Recently, researchers have proposed nanoparticulate systems for antioxidant molecules encapsulation in order to preserve them from degradation and ensure a prolonged action [ 14 , 15 ].…”

“…The ethanol presence (30–45% v / v ) confers to ETHO vesicles a soft consistency, enabling their interaction with physiological membranes. Due to their potential, ETHO have been investigated as cutaneous delivery systems of many drugs, including phenolic compounds [ 11 , 26 , 27 ]. The cutaneous application of lipid nanosystems gives the opportunity to treat many dermatological disorders and pathologies.…”