Article

Transdermal delivery of the tetrapeptide Hisetal (melanotropin (6-9)) and amino acids: their contribution to the elucidation of the existence of an 'aqueous pore' pathway

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Abstract

In order to address the problem of the elucidation of overall valid transdermal transport mechanisms, the permeation data on 20 amino acids and on the tetrapeptide hisetal as well as other literature data about skin permeation were analyzed in the present study. In addition, the iontophoretic as well as passive transport of the tetrapeptide hisetal across human skin was studied using Franz cells. The anode was placed in the side of the diffusion cell facing the epidermis and the cathode in the acceptor compartment. Current densities of 0.5 and 1 mA were applied. After 12 h of passive permeation maximally 1.2 μg hisetal was found in the acceptor compartment. After 2 h of iontophoretic delivery applying a constant current of 0.5 mA, 18.8 μg hisetal was detected while the application of a constant current of 1 mA for 2 h resulted in 28.7 μg hisetal in the acceptor compartment. Consequently, iontophoretic treatment increased the permeation rate of hisetal by a factor of 30. In comparison to the use of enhancers, iontophoretic treatment is much more effective. Facilitated permeation by enhancer treatment increased the permeation rate of hisetal across human skin maximally by a factor of 6. The results of the analysis of literature data, of our previous work on amino acids and the tetrapeptide hisetal, and of the present iontophoretic study show that the skin does not act as a simple lipoid barrier. The observation that increasing hydrophobicity did not correlate with increasing permeability of these amino acids as well as the finding that no relationship between the molecular weights of the amino acids and the peptide was observable led to the conclusion that amino acids and peptides appear to use another pathway through the skin. These findings and the fact that iontophoretic treatment is much more effective than enhancer treatment clearly seem to indicate that amino acids and the peptide permeate the skin mainly through water filled pores.

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Chapter
This chapter provides an overview of the transdermal, topical, uterine, and rectal routes for protein and peptide delivery. These routes are used for possible protein and peptide delivery, taking into account various aspects like local biological environment, use of various formulation excipients like absorption promoters, advantages and disadvantages of each route, and inherent properties of the proteins or peptides. The transdermal route has less proteolytic activity compared to the mucosal route. The transdermal route has the potential to hydrolyze peptides. Protease inhibitors are used to avoid or reduce the enzymatic barrier of the skin. The development of a transdermal delivery technique for the controlled administration of proteins and peptides could provide biomedical benefits such as less variation in absorption and metabolism, avoidance of risks and inconveniences, and rapid termination of the medication. For the topical delivery of proteins and peptides, the drug must reach local site skin ailments. The chapter also presents numerous examples of effective delivery of peptide and protein drugs using the rectal route of administration. The rectal route has many advantages over oral and parenteral routes for protein and peptide delivery and has emerged as a possible alternative for administering drugs.
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Transdermal delivery of the tetrapeptide hisetal (melanotropin (6–9)): II. Effect of various penetration enhancers. In vitro study across human skin
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Advancing quantitative and mechanistic studies in animals and humans
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