Biochemical enhancement of transdermal delivery with magainin peptide: Modification of electrostatic interactions by changing pH

Abstract

Magainin is a naturally occurring, pore-forming peptide that has recently been shown to increase skin permeability. This study tested the hypothesis that electrostatic forces between magainin peptides and drugs mediate drug transport across the skin. Electrostatic interaction between positively charged magainin and a negatively charged model drug, fluorescein, was attractive at pH 7.4 and resulted in a 35 fold increase in delivery across human epidermis in vitro when formulated with 2% N-lauroylsarcosine in 50% ethanol. Increasing to pH 10 or 11 largely neutralized magainin's charge, which eliminated enhancement due to magainin. Shielding electrostatic interactions with 1-2 M NaCl solution similarly eliminated enhancement. Showing the opposite dependence on pH, electrostatic interaction between magainin and a positively charged anti-nausea drug, granisetron, was largely neutralized at pH 10 and resulted in a 59 fold increase in transdermal delivery. Decreasing to pH 5 increased magainin's positive charge, which repelled granisetron and progressively decreased transdermal flux. Circular dichroism analysis, multi-photon microscopy, and FTIR spectroscopy showed no significant pH effect on magainin secondary structure, magainin deposition in stratum corneum, or stratum corneum lipid order, respectively. We conclude that magainin increases transdermal delivery by a mechanism involving electrostatic interaction between magainin peptides and drugs.

Getting Drugs Across Biological Barriers

“…[165] A simple mixture of magainin and the small molecule CPE N-lauroylsarcosine achieved 35- to 92-fold increase in the delivery rate of fluorescein across human epidermis in vitro. [169–170] …”

Biomaterials as novel penetration enhancers for transdermal and dermal drug delivery systems

“…However, it is important to note that magainin's enhancement requires co-administration with a surfactant chemical enhancer, such as N-lauroyl sarcosine, because of its weak penetrating activity to the SC. Besides the interaction with SC lipids, electrostatic forces between magainin peptides and drugs could also mediate drug transport across the skin (Kim et al, 2008). To examine this effect, the study chose two model drugs including fluorescein and granisetron, which had similar molecular weight and opposite charges.…”

“…On the other hand, some peptide enhancers such as SPACE, chitosan and trypsin, have also been reported to alter the secondary structure of the keratin in SC to increase the permeability of the skin (He et al, 2009;Li et al, 2009;Hsu & Mitragotri, 2011). Furthermore, the complex interactions between the drug, enhancer and the component in SC are involved in the enhancing process, which could not be explained by mechanistic studies only focusing on the alteration of the SC (Kim et al, 2008).…”

Transportan in nanocarriers improves skin localization and antitumor activity of paclitaxel

“…Microemulsions (MEs) were selected as nanocarriers due to their simple preparation (since there is no special requirement in terms of energy supply), thermodynamic stability, and versatility of composition, which can reduce costs. 11,12 Considering that drug penetration can be enhanced when cationic lipids, protein transduction domains (PTDs), and pore-forming antimicrobial peptides are included in nanocarriers, [13][14][15][16] we evaluated the effects of adding three different types of PTDs on the microemulsion safety and penetration-enhancing ability.…”