Peptide skin permeability

The venoms of many kinds of bees, wasps, and hornets (the genera Vespa, Polistes, Vespula, Ropalidia, etc.) contain biogenic amines such as histamine (136), serotonin (141), and catecholamines in addition to polyamines such as putrescine (111), spermidine (110), and spermine (112) (Table VIII). The biogenic amines in the venoms act as the main pain-producing principles 46). The contents of these amines in the venom may affect the severity of pain production, edematous reaction of the skin, or increase in skin permeability by stings of these insects. Consequently these amines act as toxins for their defense, together with acetylcholine, enzymes, and peptides 47). 

Sanderson, J.E. Reil, S.D. Dixon, R. Iontophoretic delivery of non-peptide drugs formulation optimization from maximum skin permeability. J. Pharm. Sci. 1989, 78,361-364. 

A variety of chemical penetration enhancers with or without protease inhibitors or colloidal vehicles (liposomes) have been investigated for their potential to enhance the skin permeability of peptides and pro-teins, but these approaches have only been limited to animal models or in vitro or in vivo models of human skin and have not progressed to human clinical studies. A notable exception is the use of so-called Transferosomes , ultraflexible liposomes, containing a mixture of soybean phosphatidylcholine and sodium... 

It is widely accepted that the two most important physicochemical parameters that determine a molecule s skin permeability are a) its lipophilicity, with a log (octanol/water partition coefficient) value of 2 being quite favorable, and b) its molecular size— smaller compounds permeating better than big ones. " Thus, it is no surprise that the passive transdermal delivery of peptides and proteins, which are typically either very polar (or charged) and/or of high molecular weight (>1000 Da), is extremely inefficient and rarely results in fluxes, which would elicit significant therapeutic effect. 

Figure 4.1. Model of neurogenic inflammation. Stimulation at the skin initiates orthodromic impulses in sensory nerve receptors which elicit antidromic impulses in branching collaterals. The release of neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and somatostatin (SOM) from nerve terminals ensues and they in turn stimulate the release of histamine (H) and the generation of leukotrienes (LT) from nearby mast cells. These mediators then produce vasodilatation and an increase in vascular permeability. In addition, they act on the nerve terminal to produce further...

After IV application, peptides and proteins usually follow a biexponential plasma concentration-time profile that can best be described by a two-compart-ment pharmacokinetic model [13]. The central compartment in this model represents primarily the vascular space and the interstitial space of well-perfused organs with permeable capillary walls, especially fiver and kidneys, while the peripheral compartment comprises the interstitial space of poorly perfused tissues such as skin and (inactive) muscle [4]. 

The skin offers an even less naturally permeable boundary to macromolecules than the gastrointestinal tract. Thus, passive transdermal delivery of proteins and peptides using patch technology has not succeeded. Peptides and proteins can be shot through the skin into the body using high-pressure needle-less injection devices. The devices, which inject proteins like insulin, have been available for years, however they have failed to impress doctors or patients due to the associated discomfort and the potential for splash back to transmit blood-borne diseases such as AIDS or hepatitis. 

The penetration of CysA, incorporated into the same three formulations, into the SC and [E + D] was further evaluated using an in vivo mouse model [63]. Once more, the entrapment of CysA in the liquid crystaHine phases led to increased skin penetration of the peptide in vivo at 6 h post-application (Fig. 12.17). Even though the skin models used are different (mouse skin used in the in vivo experiment is more permeable than porcine skin), the results obtained in vivo confirmed the in vitro observation that monoolein-based delivery systems enhanced skin penetration of CysA. 

The applicability and efficiency of the Hn mesophase [43] and the corresponding hexosomes [76] as carriers for a transdermal delivery of desmopressin was also tested. In the case of bulk hexagonal mesophase, reduced values of steady-state flux of the drug and its permeability coefficients through the skin were obtained, and compared to water solution (Fig. 12.24). In other words, the peptide molecules penetrated more easily and freely through the skin from water solution than from hexagonal phase vehicles. Hence, a sustained release of desmopressin was obtained via the Hn mesophase. 

Cohen-Avrahami et al. examined the feasibility of a system based on Hn meso-phase loaded with a skin penetration enhancer and sodium diclofenac (Na-DFC) [44]. They used a penetration enhancer (RALA, a 16 amino-acid long peptide) belonging to a synthetic family of CPEs, based on GALA, amphipathic peptides. These peptides contain an alanine-leucine-alanine repeating unit that exhibited improved membrane permeability [104]. 

Duclohier H. Molle C, Spach G. Antimicrobial peptide magainin I from Xenopui skin forms anion-permeable channels in planar lipid bilayers. BiophysJ 1989 56 1017-1021. 

Similar results were obtained for calcitonin at a constant current density (0.5mA/cm for Ihr) in the presence or absence of a single exponential pulse of 500-V initial potential and 10-msec time constant applied at the onset of the iontophoresis. These results (data not shown) reveal an approximate 2-fold increase in calcitonin flux through human skin due to electrical pulsation. Furthermore, the high-permeability state induced by electroporation returned to pretreatment values within 24 hr. Finally, it should be noted that calcitonin concentration was determined using ELISA, which measures only intact peptide. 

The results presented here show that electrical pulsation causes reversible enhancement of peptide transport through human skin in vitro. In all cases, only intact peptide was measured. Moreover, the enhanced flux cannot be accounted for by increased current, and it is most likely due to increased ionic mobility of the peptide within the skin. Thus, electrical pulsation reversibly alters the ion-transport properties of skin. The rate-limiting barrier to skin transport of ionized compounds is the lipids of the stratum comeum. Alteration of stratum comeum lipids results in a significant increase in skin transport (Golden et al, 1987 Potts and Francoeur, 1990). For example, heating the skin to temperatures just above the stratum comeum lipid phase-transition temperature results in a 100-fold increase in sodium-ion conductivity. The sodium-ion conductivity returns to pretreatment values when the skin is cooled (Oh et al, 1993). Similarly, alteration of stratum comeum lipid stmcture with chemical perturbants such as oleic acid increases ion conductivity (Potts et al, 1992). The application of a transient electrical pulse to other lipid-based membranes creates a high-permeability state associated with the reversible formation of pores within the membrane (electroporation). Thus, it seems likely that electrical pulsation of human skin results in the formation of transient pores within stratum comeum lipids. 

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