Penetration enhancers structure

Under normal conditions, the transcellular route is not considered as the preferred way of dermal invasion, the reason being the very low permeability through the corneocytes and the obligation to partition several times from the more hydrophilic corneocytes into the lipid intercellular layers in the stratum corneum and vice versa. The transcellular pathway can gain in importance when a penetration enhancer is used, for example, urea, which increases the permeability of the corneocytes by altering the keratin structure. 

Kanikkannan N, Kandimalla K, Lamba S, Singh M. Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery. Curr Med Chem 2000 7 593-608. 

In connection with studies on structure-property relationships with dermal penetration enhancers, substituted azepinone derivatives (e.g., 74, R = Me and 75, R = Me) were made by Kim et al. from the 3-aminoazepanone 71 via 72 and 73 using standard functional group manipulations (Scheme 8) <2001MI183>. 

FIGURE 12.1 Penetration enhancer activity, (a) Action at intercellular lipids. Some of the ways by which penetration enhancers attack and modify the well-organized intercellular lipid domain of the stratum comeum. (b) Action at desmosomes and protein structures. Such dramatic disruption by enhancers (particularly potent solvents) as they split the stratum corneum into additional squames and individual cells would be clinically unacceptable, (c) Action within comeocytes. Swelling, further keratin denaturation and vacuolation within individual horny layer cells would not be so drastic but would usually be cosmetically challenging (see Menon and Lee [69] for further details). (Reproduced from Barry, B.W., Nat. Biotechnol. 22, 165, 2004. With permission.)... 

A wide variety of long-chain fatty acids increase transdermal delivery the most popular is oleic acid. It is relevant that many penetration enhancers contain saturated or unsaturated hydrocarbon chains and some structure-activity relationships have been drawn from the extensive studies of Aungst et al. [22,23] who employed a range of fatty acids and alcohols, sulfoxides, surfactants, and amides as enhancers for naloxone. From these experiments, it appears that saturated alkyl chain lengths of around Cio to C12 attached to a polar head... 

Aungst, B.J. 1989. Structure-effects studies of fatty acid isomers as skin penetration enhancers and skin irritants. Pharm Res 6 244. 

Infrared microscopic imaging provides the significant advantages of direct spatially resolved concentration and molecular structure information for sample constituents. Raman microscopy (not further discussed in this chapter) possesses the additional benefit of confocal acquisition of this information and a 10-fold increase in spatial resolution at the expense of reduced signal-to-noise ratios compared with IR. The interested reader is urged to check the seminal studies of the Puppels group in Rotterdam,38 0 as well as our own initial efforts in this direction.41 The current section describes the initial applications of IR microspectroscopic imaging to monitor the permeation and tissue distribution of the dermal penetration enhancer, DMSO, in porcine skin as well as to track the extent of permeation of phospholipid vesicles. 

FIGURE 2.5 The stacked bilayers of the skin barrier are envisioned as composed of crystalline domains separated by fringes of lipids in the liquid crystalline state.38 The fringe zones may actually oscillate in a very small time scale between a liquid crystalline state and a crystalline (gel) state. Such a tentative idea would mean that the barrier is open just temporarily at a certain location since penetration must occur in the liquid crystalline areas. Thus, the action of a penetration enhancer would be to stabilize a liquid crystalline state or transform it into another type of structure, for example, a cubic phase. 

It must be realized that structural changes of these kinds are local phenomena. This reasoning implies that a penetration enhancer introduced into the lipid barrier is expected to diffuse in the liquid crystalline phase and exert its structure transformation effects more or less exclusively there. Within a relatively short time it will also be diluted through this diffusion process and then the bilayer structure will be restored and the normal barrier function will be regained. 

The principal routes of penetration are thus transcellular and intercellular. Currently there is considerable debate as to which of these predominates. Work with esters of nicotinic acid has shown that the intercellular channels are significant [5.] and considerable effort is being conducted to identify their exact nature and role. Microscopic examination shows that they contain structured lipids the chemical nature of which is complex [6J. Cholesterol esters, cerebrosides and sphingomyelins are present in association with other lipids in smaller concentrations. It is likely that the main barrier to skin penetration resides in the channels and that a diffusing drug molecule experiences a lipid environment which has considerable structure. Penetration enhancers may act by temporarily altering the nature of the structured lipids, perhaps by lowering their normal phase transition temperature which occurs around 38°C. 

However, as mentioned previously, a serious drawback associated with the use of penetration enhancers is their potential deleterious effect to the epithelial tissue, either directly, by damaging vital cell structures... 

Figure 8.9 Structures of selected chemical penetration enhancers...

To improve topical therapy, it is advantageous to use formulation additives (penetration enhancers) that will reversibly and safely modulate the barrier properties of the skin. Fick s first law of diffusion shows that two potential mechanisms are possible. The two constants that could be altered significantly are the diffusion coefficient in the stratum corneum and the concentration in the outer regions of the stratum corneum. Thus, one of mechanisms of action of an enhancer is for it to insert itself into the bilayer structures and disrupt the packing of the adjacent lipids, thereby, reducing the microviscosity. The diffusion coefficient of the permeant will increase This effect has been observed using ESR and fluorescence spectroscopy [16,17]. 

Niosomes In order to circumvent some of the limitations encountered with liposomes, such as their chemical instability, the cost and purity of the natural phospholipids, and oxidative degradation of the phospholipids, niosomes have been developed. Niosomes are nonionic surfactant vesicles which exhibit the same bilay-ered structures as liposomes. Their advantages over liposomes include improved chemical stability and low production costs. Moreover, niosomes are biocompatible, biodegradable, and nonimmunogenic [215], They were also shown to increase the ocular bioavailability of hydrophilic drugs significantly more than liposomes. This is due to the fact that the surfactants in the niosomes act as penetrations enhancers and remove the mucous layer from the ocular surface [209]. 

The primary goal of this chapter is to review comprehensively the x-ray diffraction literature concerned with normal, diseased, and penetration-enhancer-treated skin. Because diffraction methods have not been widely utilized in SC structural studies until rather recently, we begin the chapter with a review of the basic principles of diffraction not only as an aid to the reader but also to encourage others to consider the possibility of using x-ray diffraction as means of studying the stratum comeum and its lipids. 

---