Our research aims to explore the possibility of incorporating atorvastatin calcium (ATC) in ultraflexible nanovesicles (UFNVs) to avoid the hepatic first metabolism and enhance its effectiveness as a potential alternative to oral treatment. ATC nanovesicles were developed utilizing the rotary evaporation‐sonication method and assessed in vitro concerning their vesicle diameter, zeta potential (ZP), entrapment efficiency (EE), as well as in vitro release studies. The chosen formulation of ATC‐UFNVs was integrated into a different gel base that was evaluated for content uniformity, pH, spreading ability, viscosity, and rheological behavior. The skin permeation of the prepared nanovesicles was assessed using an ex vivo permeation and confocal laser microscopy images (CLSM). In vitro evaluation of the ATC‐loaded UFNVs showed that the mean diameter of the nanovesicles ranging between 60.84 ± 0.53 nm and 91.68 ± 2.11 nm, the Zeta potential values ranged from of –15.8 ± 0.31 to –25.1 ± 0.81 mV, the EE% were between 84.33 ± 1.94 and 86.53 ± 2.02%, and the ATC release from the formulations was 75.25–90.89%. All release patterns were analyzed kinetically following Higuchi's diffusion approach. Carbapol 934 gel bases containing ATC‐UF exhibited non‐Newtonian pseudo‐plastic flow with thixotropy equal to 2.013 cm2. Ex vivo data showed that ATC‐UFNVs had better penetration compared to free AC. CLSM revealed that the UF‐nanovesicle exhibited stronger and deeper fluorescence signals up to 90 µm depth of permeation in skin versus the rhodamine B‐free solution (50 µm). The transdermal ability of the ATC‐UFNVs gel formulation has been conclusively demonstrated by our research.Practical Applications: The successful development of atorvastatin calcium‐loaded ultraflexible nanovesicles (ATC‐UFNVs) in this study offers promising applications for researchers and healthcare professionals. The ability of these nanovesicles to bypass hepatic first‐pass metabolism and enhance drug delivery to the skin presents a potential alternative to oral administration, which can be associated with gastrointestinal side effects and variable absorption. The findings of this research can be applied in the development of novel transdermal drug delivery systems for the treatment of various cardiovascular conditions. ATC‐UFNVs may be incorporated into topical formulations for the management of hypercholesterolemia, reducing the need for systemic medication. Additionally, the insights gained from this study could be utilized to explore the feasibility of using nanovesicles for the delivery of other lipophilic drugs, expanding their potential therapeutic applications.
