Penetration enhancement principles

Karande, P., et al. 2005. Design principles of chemical penetration enhancers for transdermal drug delivery. PNAS 102 4688. 

The objective of this chapter is to show how the concepts of chemical kinetics can be applied to the passage of molecules across the skin. The barrier function of the skin is still not totally understood but application of kinetic principles has allowed us to gain a better understanding of the barrier and how penetration enhancers may modulate it. The application of kinetics has allowed a mechanistic interpretation and therefore the development of predictive models. These can assist in the identification and design of novel transdermal drugs, and in the optimal design of topical formulations. 

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. 

Karande, P. Jain, A. Ergun, K. Kispersky, V. Mitragotri, S. Design principles of chemical penetration enhancers for transdermal drug dehvery. Proc. Natl. Acad. Sci. USA 2005, 102, 4688 693. 

Barry. B. W, (1991). The LPP theory of skin penetration enhancement, In In Vitro Percutaneous Absorption Principles, Fundamentals, and Applications (R. L. Bronough and H. 1. Maibach, Eds.), pp. 165-185. CRC Press, Boca Raton, FL. 

Blankschtein et al. have concluded that micelle size is a major factor in surfactant induced irritation.37 As the micelle size increases, penetration of the surfactant into deeper layers decreases and therefore increasing the micelle size is an approach to enhancing mildness. In principle, factors that reduce the micelle charge will increase the micelle size and therefore have the potential to reduce swelling and penetration under cleansing conditions. Note, however, that the inherent tendency of the molecule to cause an irritation response may be related to the charge density of the molecule rather than the micelle size. 

Mechanism of Proteolioid Vesicle Penetration into Monolayers. The principle conclusion from the penetration studies at the air-water and oil-water interfaces is that intrinsic membrane protein in vesicles greatly facilitates the transfer of material into monolayers. In marked contrast lipid vesicles do not penetrate monolayers to any appreciable extent although some exchange of lipid between a monolayer and the outer lipid layer of a liposome can occur (48.49). It is established that both glycophorin (50) and the anion transporter (51) increase the rate of "flip-flop" when incorporated into bilayers. Thus in the initial encounter between the proteolipid vesicles and the monolayer the protein-enhanced rate of "flip-flop" between the inner and outer halves of the vesicle bilayer would facilitate lipid transfer to the monolayer. The process of redistribution of lipid between vesicle and monolayer would bring the protein into intimate contact with the monolayer leading to penetration. 

The principle of the Eu-release cytotoxicity assay using the penetrating fluorescence enhancing ligand. 

The evanescent wave depends on the angle of incidence and the incident wavelength. This phenomenon has been widely exploited to construct different types of optical sensors for biomedical applications. Because of the short penetration depth and the exponential decay of the intensity, the evanescent wave is absorbed mainly by absorbing compounds very close to the surface. In the case of particularly weak absorbing analytes, sensitivity can be enhanced by combining the evanescent wave principle with multiple internal reflections along the sides of an unclad portion of a fiber optic tip. 

In PLE, the increased pressure (up to 20 MPa) helps to keep extraction solvents in a liquid state at temperatures above their atmospheric boiling points, taking advantage of their enhanced solvation power and lower viscosities and hence higher diffusion coefficients. Based on a similar principle, supercritical fluid extraction (SFE) employs even more penetrative and solvating supercritical fluids. CO2 is most... 

For NR nanocomposite filled with silica, it has always been known that the hydrophilicity-hydrophobicity issue is a challenge since silica is hydrophilic and NR is hydrophobic. The usual method to overcome this issue is by adding coupling agent. In 1987 Wu and coworkers introduced admicellar polymerization where a thin polymeric film will be formed on the silica s surface. This process yields a thin film of polymer on the silica which can further enhance the adhesion between the surfaces of silica and rubber. The steps involved in admicellar polymerization are outlined in Scheme 7.7. In principle, a bilayer of surfactant, i.e. the admicelle, is first formed on the surface of the silica. Monomer will then penetrate the admicelle, i.e. the adsolubilization of monomer. Upon addition of initiator to the reaction system, in situ polymerization occurs in the admicelles. Finally, the surfactant is removed by washing with water and an ultrathin polymer layer is formed on the surface of the silica. The polymerization of the monomer in the admicelles can be induced by thermal process, chemical initiators or radiation. ... 

Ever since the introduction of membrane-based suppressor systems, attempts have been made to support the ion transport through the ion-exchange membranes with an electric field, thus utilizing the principle of electrodialysis. The basic idea behind this is to enhance suppression by applying an electric field that will impel the ions involved in the suppression reaction to penetrate the ion-exchange membranes. 

This section will summarise the basic principles involved in the preparation of microemulsions and the origin of their thermodynamic stability (see Chapter 10 for more details). A sub-section is devoted to emulsifier selection for both O/W and W/0 microemulsions. Physical methods that may be applied for characterization of microemulsions will be briefly described. Finally a sub-section is devoted to the possible enhancement of biological efficacy using microemulsions. The role of microemulsions in enhancing wetting, spreading and penetration will be discussed. Solubilization is also another factor that may enhance the penetration and uptake of an insoluble agrochemical. 

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