N-Alkylmorpholines: Potent Dermal and Transdermal Skin Permeation Enhancers

Abstract

Transdermal drug delivery is an attractive non-invasive method offering numerous advantages over the conventional routes of administration. The main obstacle to drug transport is, however, the powerful skin barrier that needs to be modulated, for example, by transdermal permeation enhancers. Unfortunately, there are still only a few enhancers showing optimum properties including low toxicity and reversibility of enhancing effects. For this reason, we investigated a series of new N-alkylmorpholines with various side chains as potential enhancers in an in vitro permeation study, using three model permeants (theophylline, indomethacin, diclofenac). Moreover, electrical impedance, transepidermal water loss, cellular toxicity and infrared spectroscopy measurements were applied to assess the effect of enhancers on skin integrity, reversibility, toxicity and enhancers’ mode of action, respectively. Our results showed a bell-shaped relationship between the enhancing activity and the hydrocarbon chain length of the N-alkylmorpholines, with the most efficient derivatives having 10–14 carbons for both transdermal and dermal delivery. These structures were even more potent than the unsaturated oleyl derivative. The best results were obtained for indomethacin, where particularly the C10-14 derivatives showed significantly stronger effects than the traditional enhancer Azone. Further experiments revealed reversibility in the enhancing effect, acceptable toxicity and a mode of action based predominantly on interactions with stratum corneum lipids.

Natural Ingredients of Transdermal Drug Delivery Systems as Permeation Enhancers of Active Substances through the Stratum Corneum

“…Among chemical compounds that increase the permeability of the skin to drugs are those otherwise known as chemical penetration enhancers (CPEs) or sorption promoters: terpenes, terpenoids, sulfoxides, laurocapram (Azone), pyrrolidones, fatty acids, fatty alcohols, alcohols containing glycols, urea, and surfactants. , In 2021, 649 compounds classified as CPEs were collected in a database which included the following groups of chemicals: alcohols and polyols, lactams and their analogues (azepane, azone, caprolactam, morpholine, piperazine, piperidine, piperidone, pyrrolidine, pyrrolidone, and succinimide), esters and ethers, fatty acids, terpenes and steroids, and miscellaneous additives such as amino acids, aliphatic compounds, aromatic compounds, and inorganic compounds . However, some of the listed groups of compounds, primarily morpholine and morpholine derivatives and among them Azone, surfactants, aromatic compounds, and many others, carry the risk of causing skin irritation, permanent disorganization of the skin barrier, and toxic effects on skin cells. These effects may not be acceptable in the application of transdermal drug delivery systems to the skin.…”

The Contest of Nanoparticles: Searching for the Most Effective Topical Delivery of Corticosteroids

“…That can be due to the enhancing effect of ethanol in the formulation, which can disrupt the skin barrier more and thus enable the passage of API through the skin more effectively than other formulations. Although the reversal was not as fast and clear as for other formulations, the incorporation of ethanol in ethosomes showed lower effects on the barrier properties than even traditional and novel permeation enhancers [ 44 ]. LNC and PNP showed levels of alternation comparable to the PBS.…”

“…If it is the latter, one must find out how long it takes for the skin barrier to return to its original properties. Such reversibility measurements are well established in the evaluation of permeation enhancers [ 44 , 75 , 78 ]. Nanoformulations are also a type of enhancing system; therefore, we conducted a reversibility study, where we observed the TEWL of skin treated for 24 h by all three nanosystems (ETZ, PNP, and LNC) and hydrated by PBS as a control and then measured the same in set time intervals up to 24 h after the removal of the formulation.…”

“…For this purpose, the electrical impedance of each skin was measured, using a hand-held multimeter (LCR 4080, Voltcraft, Germany). The measurements were performed in the Franz diffusion cells according to established protocols [ 43 , 44 ]. After the initial hydration and equilibration, the donor compartments were filled with 500 μL of PBS.…”

Effect of Edge Activator Combinations in Transethosomal Formulations for Skin Delivery of Thymoquinone via Langmuir Technique

“…The effect of the formulation on skin integrity was investigated by conducting TEWL measurements before applying the formulation to the donor side and at the conclusion of the study, following established protocols [37].…”