The Four Rs of Skin Delivery

By: Johann W. Wiechers, PhD, JW Solutions

Posted: December 9, 2008

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Delivering the Right Chemical
The first of the four Rs looks at nanotechnology as a skin delivery system to ensure the Right chemical is being delivered. There are two ways in which the presence of the Right chemical in a skin delivery system can be influenced. On the one hand, active ingredients may degrade via oxidation and hydrolysis. On the other hand, precursors of active ingredients may rely on enzymes, such as esterases, on top of and within the skin to generate the active ingredients. In the first case, this constitutes a loss of activity whereas in the second case, this creates the activity. Encapsulation technology is the most frequently used technology in skin delivery systems to offer protection against oxidation and hydrolysis. Cyclodextrins, liposomes and microcapsules are examples of systems using such technology.

Cyclodextrins: Cyclodextrins typically protect the active by shielding it from the environment. This shielding enhances stability but the effect on the extent of delivery is often unknown. Linoleic acid, α- and γ-linolenic acid and arachidonic acid, for instance, are essential but highly unstable polyunsaturated fatty acids that are necessary for an optimal skin barrier formation; topical formulations containing these components are therefore warranted. Whereas the protective effects of such systems are well-demonstrated, information on the release of the incorporated and protected actives is often lacking. Regiert, for instance, describes how linoleic acid in 4/1 complexes of α-cyclodextrin/linoleic acid is significantly more stable, measured both chemically as well as by olfaction,³ but Regiert provides no information on whether the linoleic acid is ever liberated from the molecular encapsulation provided by the cyclodextrin. It should be noted that the van der Waals forces that keep the cyclodextrin and the linoleic acid together are only weak.³

But can one claim the use of cyclodextrin to be nanotechnology? This depends, of course, on the definition of nanotechnology. As with anything that has attracted the consumer’s attention, nanotechnology has become a catch-all term for techniques, materials and devices that operate at the nano-scale. The Royal Society and The Royal Academy of Engineering defined nanotechnologies in 2004 as the design, characterization, production and application of structures, devices and systems by controlling shape and size at the nano-scale.⁴ Most molecules also act on the nano-scale. The smallest molecule is H2, with an overall length of twice the bond length of 74 pm (picometer, 10^-12 meter). All other molecules are bigger and in the range of several Ångstroms (1 Å = 100 pm or 0.1 nm) and polymers like plastics and DNA can even have dimensions greater than nanometers. Nanoparticles are a subset of nanomaterials and were defined as single particles with a diameter below 100 nm,⁵ although their agglomerates may be larger. But to call molecular encapsulation like cyclodextrins nanotechnology would be a stretch of the imagination despite the fact that this application acts by controlling the shape and size. Regiert even mentions the existence of cyclodextrins with six, seven or eight glucose units, called α-, β-, and γ-cyclodextrin, respectively,³ which clearly reflects the fact that the size is controlled.

Liposomes: Liposomes are another application of encapsulation technology. They are hollow spheres that are enclosed by one (unilamellar) or more (multilamellar) membranes that consist of natural components such as, for example, phospholipids.⁶ They also offer a protection by shielding chemically labile molecules from oxygen or water that may cause oxidation and hydrolysis. But the main reason for using liposomes is their biocompatibility combined with their delivery benefits. They are used intravenously to protect the body from aggressive drugs such as anticancer agents that are then released via specific triggers at their site of action (the tumor) at high concentrations.⁷ In the cosmetic arena, where the chemicals used are not as aggressive as those used in cancer therapy, it is not necessary to use these skin delivery systems to protect the skin from contact with the active principles; instead, skin delivery systems are used to protect the active from aggressors such as oxygen and water in the environment. In contrast to the cyclodextrins, there is sufficient work available in both the cosmetic and the pharmaceutical industry to describe delivery benefits that relate to targeting and release, such as enhanced delivery⁶ or a trigger mechanism that only works in a tumor and not in normal tissue.⁷

But do liposomes belong to nanotechnology? Does size really matter in the deliverability of liposomes? Most liposomes are actually in the nanometer range, between 20 and 400 nm, and therefore they do fall within the definition of nanotechnology. Therefore, the skin penetration of these systems will be discussed in a future article (Part II).