Table 2.

Different classes of penetration enhancers, their commercial applications, and possible mechanisms of action. EDTA—ethylenediamine-N,N,N’,N’-tetraacetic acid; TAT—trans-activating transcriptional activator; FDA—Food and Drug Administration.

Class of Enhancers	Examples of Compounds	Commercial Applications in Drug Delivery	Possible Mechanism of Penetration Enhancement
Cyclodextrins	α-, β-, γ-cyclodextrins	Some cyclodextrins are already used in commercial ocular formulations, e.g., Vitaseptol eye drops (Novartis). They are often used as enhancers of drug solubility.	Extraction of cholesterol and lipids from ocular membranes [68].
Chelating agents	EDTA	Disodium-EDTA is commonly used in ocular formulations as a buffering agent [143].	Extraction of Ca2+ from tight junctions [17].
Crown ethers	12-crown-4, 15-crown-5, 18-crown-6	None of these are currently used in commercial formulations for drug delivery.	Extraction of Ca2+ from tight junctions [100].
Surfactants	Benzalkonium chloride	Around 74% of ophthalmic preparations have benzalkonium chloride as a preservative [144].	Morphological changes in the epithelium [145].
Bile acids and salts	Deoxycholate, glycocholate, taurodeoxycholate	None of these are currently used in commercial formulations for drug delivery.	Different mechanisms leading to modification of the integrity of the corneal epithelium [121].
Cell-penetrating peptides	TAT, penetratin, poly(arginine), and poly(serine)	None of these are currently used in commercial formulations for drug delivery.	Direct translocation and endocytosis [133].
Other amphiphilic compounds	Azone™	Designed and widely researched mostly as a skin penetration enhancer. No FDA-approved products containing AzoneTM on the market yet. It is recorded in Chinese Pharmacopoeia and widely used in China [146,147].	Changes in the structure and fluidity of biological membranes; facilitation of water influx leading to a more hydrated barrier [137].