Design principles of chemical penetration enhancers for transdermal drug delivery

Abstract

Chemical penetration enhancers (CPEs) are present in a large number of transdermal, dermatological, and cosmetic products to aid dermal absorption of curatives and aesthetics. This wide spectrum of use is based on only a handful of molecules, the majority of which belong to three to four typical chemical functionalities, sporadically introduced as CPEs in the last 50 years. Using >100 CPEs representing several chemical functionalities, we report on the fundamental mechanisms that determine the barrier disruption potential of CPEs and skin safety in their presence. Fourier transform infrared spectroscopy studies revealed that regardless of their chemical make-up, CPEs perturb the skin barrier via extraction or fluidization of lipid bilayers. Irritation response of CPEs, on the other hand, correlated with the denaturation of stratum corneum proteins, making it feasible to use protein conformation changes to map CPE safety in vitro. Most interestingly, the understanding of underlying molecular forces responsible for CPE safety and potency reveals inherent constraints that limit CPE performance. Reengineering this knowledge back into molecular structure, we designed >300 potential CPEs. These molecules were screened in silico and subsequently tested in vitro for molecular delivery. These molecules significantly broaden the repertoire of CPEs that can aid the design of optimized transdermal, dermatological, and cosmetic formulations in the future. stratum corneum ͉ spectroscopy ͉ skin irritation ͉ lipid C urrently, hypodermic needles are the only available mode for systemic delivery of macromolecular drugs into humans. Transdermal delivery offers an attractive alternative to needlebased drug administration. However, evolved to impede the flux of exogenous molecules, stratum corneum (SC), the topmost layer of the skin, provides a strong barrier to molecular delivery. This is especially problematic for relatively large drugs (molecular mass Ͼ 500 Da), which represent a large majority of active agents for therapeutic applications (1). Over 350 molecules, termed chemical penetration enhancers (CPEs), have been identified to perturb the SC barrier to facilitate molecular delivery. However, incorporation of CPEs into products has been mitigated by safety concerns related to the health of the skin membrane (2-4). Accordingly, overcoming the skin barrier in a safe and effective way still remains the bottleneck of transdermal and topical therapies.Identification of chemicals to increase skin permeability has been an area of high activity in the last three decades (5-7). After an initial rise in the number of CPEs in the 1980s, the active pool of CPEs has reached a plateau in the last decade. In an era where new chemical entities are being discovered at an exponential rate (as indicated by the entries in the Chemical Abstract Service), the plateau in the number of CPE molecules is rather surprising (only 1 in 100,000 known molecules represents a CPE). This anomaly originates from the slow rates of syntheses of CPEs when compar...

Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer

“…S2 E and F). Neither a change in the area of the symmetric CH 2 stretching peak nor a shift in center frequency was found indicating that the SPACE peptide did not induce extraction or fluidization of SC lipids (18). Consistent with the FTIR data, exposure to SPACE peptide did not induce a significant change in skin's electrical conductivity (Fig.…”

Transdermal Protein Delivery Using Choline and Geranate (CAGE) Deep Eutectic Solvent

“…Based on the FT-IR studies we postulate that CAGE improves permeability through SC lipid extraction/membrane fluidization, a quintessential chemical enhancer mechanism of action as seen for DMSO, alcohols, azones, and fatty acids among others. [20,70,71] However, additional studies using small and wide angle X-ray diffraction and other techniques are required to understand the exact mechanism of action of CAGE. [72] Application of neat CAGE to rats did not produce a significant drop in BGL, indicating no adverse blood glucose lowering effect of CAGE.…”

Enhancement of Percutaneous Absorption on Skin by Plasma Drug Delivery Method

“…The information tells us about several micrometres of surface; thus, it is also a useful method for analysing skin [45,46]. ATR-FTIR spectra can give us information about hydration of skin [47], structure of proteins [48] and lipids [49] and about their changes during skin treatment by chemical or other drug enhancers [50,51]. There are several vibrational bands associated with chemical functional groups.…”