Nanoparticulate System Based on Calcium-Crosslinked Carbomer Retards Percutaneous Drug Permeation: New Insight Into Skin Barrier Functions

Background: The stratum corneum poses a formidable barrier for dermal and transdermal delivery of drugs. Besides the stratum corneum barrier, the viable epidermis poses another challenge to pharmaceutical formulators. A drug is probably transdermally permeable if it rapidly crosses the epidermal secondary barrier, while stimulation of lamellar body secretion from granular cells and intracellular release of Ca⁺⁺ from endoplasmic reticulum (ER) result in retardation. Objective: To evaluate the skin permeability of lidocaine HCl loaded in nanoparticles made of carbomer calcified with calcium gluconate, while figuring out the physiological mechanism that regulates the Ca⁺⁺ related skin barrier function. Methods: Lidocaine hydrochloride was loaded in a nanoparticulate system based on calcified carbomer, fabricated by using a water-in-oil microemulsion as a precursor. In vitro release and percutaneous permeation testing were carried out to compare between calcified and non-calcified nanoparticles. In addition, comparison was also made between calcified nanoparticles using carbomer gels prepared at two pH values and at two different ratios of Ca⁺⁺/carbomer. Results: A unique structure of the calcified nanoparticles has been proposed, in which the carbomer nanoparticles are partially coated by gluconate ions through hydrogen bonding and partially through ionic interactions with calcium ions. Although the in vitro release data showed no difference between non-calcified and calcified carbomer nanoparticles, a calcium-related phenomenon of skin retardation has been revealed. Conclusions: It has been proposed that stimulation of lamellar body secretion from granular cells and Ca⁺⁺ release from ER, which is elicited by the calcium gluconate-coated nanoparticles, result in dermal retardation of lidocaine.