The Four Rs of Skin Delivery

Dec 9, 2008 | Contact Author | By: Johann W. Wiechers, PhD, JW Solutions
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Title: The Four Rs of Skin Delivery
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"Unknown, unloved" is a well-known expression that applies everywhere and for everything, especially if you cannot see it, because invisibility makes things almost per definition unknown. Take radioactivity, for instance. You cannot see it but it does kill people. The nuclear physicists Marie and Pierre Curie were among the first victims of their own discoveries. But since their pioneering days, we became familiar with the nature of radioactivity and have identified how we can now work safely with radioactive materials. Instead of being classified only as a ruthless killer, radioactivity is now also used in nuclear medicine where it can help save human lives.

A similar situation arises for nanotechnology. We’ve all heard about it but we don’t know what it really entails and we can’t see it, so we classify it as dangerous. Evolution programmed us to fear the unknown in order to survive. This review aims to explain what the implications of nanotechnology in cosmetic science and products are, to eliminate the "unknown" aspect. The review will be in two parts and will focus on the skin delivery aspects of nanotechnology much more than on the principles of nanotechnology and its reputed benefits, although some of them, in particular in sun care, will be mentioned.

Part I, presented here, describes the role of nanotechnology in skin delivery systems in terms of what I call the four Rs of skin delivery. Part II will appear in print in the January 2009 issue of Cosmetics & Toiletries magazine. Part II addresses the fear issue by evaluating experimental skin penetration data on nanomaterials used in cosmetics. Part II also presents a summary and a brief look at the benefits of using nano-sized materials in general and in cosmetics in particular. This knowledge should allow the cosmetic scientist to make a well-informed decision on whether or not to use nanotechnology in his or her products.

Part I begins here with my definition of skin delivery. The definition does not change in the context of nanotechnology and skin delivery. It is: to transport the Right chemical, to the Right site in the skin, at the Right concentration for the corRect period of time.1 In fact, all skin delivery systems do have an influence on one or more of these four Rs. They may, for instance, affect the right chemical by protecting it and thereby ensure that it will not be an ineffective degradation product that reaches the site of action. They could also impinge on the right site in the skin by targeting the delivery to the site of action of the active ingredient. They could also enhance the skin delivery, thereby ensuring that the right concentration is being used. And finally, they might prolong skin delivery, thereby ensuring that the active ingredient is delivered for a sufficiently long period of time. Please note that I am not saying that all four of these benefits apply for every skin delivery system but if nanotechnology would have any skin delivery benefit, it should influence at least one or more of these four Rs of skin delivery.

Many skin delivery systems actually do use nanotechnology. Dozens of them are listed in the table of contents in Meyer Rosen’s recent book2 on delivery systems for personal care and cosmetic products. One could cite liposomes, nanospheres, penetration enhancers, microcapsules, microspheres, stable multiple emulsions, cationic silicone complexes, enzymatically activated encapsulation techniques and many others from Rosen’s seemingly endless list! When I attempted to order such a range of skin delivery systems and functionalities, I finally realized that the functionality of a delivery system is actually following my own definition of the four R’s of a cosmetic delivery system. That is why I will subdivide skin delivery systems as those that affect the Right chemical, the Right site, the Right concentration and the corRect period of time in the following discussion of how nanotechnology fits in with each of these functions of skin delivery systems.

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).

Microcapsules: Although microcapsules do provide a protective functionality, the main reason for their use as a skin delivery system is their controlled release characteristic, which will be discussed later in this article.

Delivering to the Right Site
The second of the four Rs looks at nanotechnology as a skin delivery system to ensure the right chemical is being delivered to the right site. Of the four Rs that can be affected in cosmetic skin delivery, ensuring the right chemical is being delivered to the right site is technically by far the most difficult one. Targeting can be created by either getting a system to accumulate in a specific subsection of the skin or—in case of an encapsulating system—by ensuring that the release of the content happens exclusively at the target site. The first mechanism depends on predominantly physical grounds such as size exclusion whereas the second mechanism relies on much more biochemical principles such as the presence of specific enzymes in cancerous tissue which—if the presence of such an enzyme triggers the release—allows a high tumor-to-normal tissue drug ratio.

In cosmetics, one is dealing with healthy skin and therefore the opportunities to use targeting via the biochemical route are very limited. This actually leaves only the physical route such as size exclusion and the only sites in the skin where this can be used are the holes in the skin: the sebaceous glands, the sweat glands and the infundibulum (the orifice around the hair follicle). This principle was already described in the mid-1990s by Rolland et al.8 who described that fluorescent particles with a diameter between 3 μm and 10 μm penetrated almost exclusively via the sebaceous glands and the transfollicular orifice, whereas particles smaller than 3 μm penetrated generally into the skin and those greater than 10 μm did not penetrate the stratum corneum at all (see Figure 1, modified from Reference 8).

More than 10 years passed before the next paper emerged. Ossadnik et al. described that particles in the range of 300 nm penetrated more efficiently into the orifice around the hair follicle than the same chemical solubilized in non-particle-containing emulsions,9 but this will be discussed more in detail in a future article (Part II) when dealing with particle penetration. Considering the size of these particles (typically below 100 nm), the use of such particles to improve skin delivery definitely belongs to the skin delivery applications of nanotechnology.

Delivering at the Right Concentration
The third of the four Rs examines nanotechnology as a skin delivery system to ensure the right chemical is being delivered to the right site at the right concentration. Many of the skin delivery systems or parts thereof contribute to the third R of delivery: to ensure that the Right concentration is being delivered. Penetration enhancers, liposomes, transfersomes, niosomes, ethosomes, volatile silicones, liquid crystals and emulsions (both emollients and emulsifiers) all play a role in achieving this Right concentration. They all have the capability to enhance skin penetration, but—as always—they can do this in different ways. According to the well-known Fick’s First Law of Diffusion, the flux, J, of a chemical through the skin equals to Equation 1 in which kp is the permeability coefficient, ΔC the concentration difference between the concentrations at the top and bottom of the stratum corneum, D the diffusion coefficient, K the partitioning coefficient and L the length of the pathway of diffusion. As long as we do not use microneedles (a future and upcoming cosmetic delivery system, described in the November 2008 Cosmetics & Toiletries magazine), there will be no change in L. This means that at the same loading of active ingredient in the formulation (ΔC), there will be only two possibilities for skin delivery systems to increase the input of chemicals into the stratum corneum: by increasing the D or by increasing the K.

The two ways of enhancing skin delivery are, however, fundamentally different. When the partition coefficient K (defined as the concentration at equilibrium of the penetrant in the stratum corneum divided by that in the formulation) is increased, a larger fraction of what is present in the formulation will end up in the stratum corneum at equilibrium. When the diffusion coefficient D is increased, the speed of transport through the stratum corneum will be enhanced. K therefore describes the ratio between two quantities at equilibrium whereas D describes the speed with which chemicals transverse through the stratum corneum. The question arises: Which of the skin delivery systems or parts thereof influence K and which affect D? The diffusivity is influenced by penetration enhancers, liposomes, transfersomes, ethosomes, niosomes, liquid crystals and emulsifiers within emulsions, because of their interaction with the skin lipid packing structure. Liposomes, volatile silicones, adjuvants and solubilizers like propylene glycol, dimethyl isosorbide and diethylene glycol monoethyl ether and emollients within emulsions affect the partition coefficient because they change the polarity of either the stratum corneum or the formulation or both.

Please note that this list is not complete. Occlusion, for instance, results in more water in the skin, which changes its polarity (the ingress of hydrophilic materials will be facilitated) but also affects the skin diffusivity because water has also been described as a skin penetration enhancer.10

When a cosmetic formulator is considering using a system, it is appropriate to identify whether the system affects the K or the D. First, consider whether the selected system is affecting the D because in order to obtain higher levels in the stratum corneum, the speed of transport through the stratum corneum should not be enhanced. Thereafter, consider the effect of the proposed system on K. If more active into the skin is better, then a system that increases K should be used. But for organic sun filters that need to stay on top of the skin rather than be within the stratum corneum, the use of K-enlarging skin delivery systems is not recommended. Table 1 summarizes this information and gives practical examples of which system to use for what type of application. 

But the same question needs to be addressed as before: Is all this nanotechnology or not? Simply based on size, the liposomes, the transfersomes, the niosomes and the ethosomes clearly belong to nanotechnology, where it should be noted that the latter three are special types of liposomes, made from elastic membranes, non-ionic surfactants and prepared with high levels of ethanol, respectively. In short, this means that liposomes and the derivatives thereof are applications of nanotechnology and their effect on skin delivery will therefore be discussed in this series of articles.

Delivering for the Correct Period of Time
The last of the four Rs looks at nanotechnology as a skin delivery system to ensure the right chemical is being delivered to the right site at the right concentration for the corRect period of time. Assuming that the period of time during which an active is available at the site of action needs correction, this time can be either shortened or lengthened. Shortening is often very easy. Remove the formulation or the delivery device and skin delivery will cease.

To prolong the time of delivery, a plethora of controlled release systems has been invented, which is, in my opinion, predominantly marketing hype because in most cases the skin delivery of an active ingredient needs to be enhanced in order to result in a clinical effect. If the effect is insufficient because insufficient material reaches the site of action to lift the levels of the active above the minimal effective concentration, controlled release is not going to help to increase these levels. Worse, the use of such systems controls the amount of active that reaches the skin to penetrate and compared to no system, it can only go down! Of course, there are some very specific cases where skin penetration might be too quick, or when an activity is only needed under specific conditions (e.g., release of a sweat-controlling active only when you sweat), but it would be better to call such systems "triggered release" or if you really want ,"controlled triggered release" systems. When someone offers you a controlled release system to be used in cosmetics, ask yourself the question whether the speed of active getting into the skin is really the problem with your application.

Technologically, the answer to controlled release in skin delivery is a particulate system like a microparticle or a nanoparticle that often combines stability and release characteristics. Almost without exception they belong to applications of nanotechnology. Particles can be either filled (solid) or open (hollow). A solid core provides more flexibility in controlling release (slower degradation) and has advantages for the stability of the active ingredient (see Figure 2).

When dealing with solid particles, two types can be differentiated: solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). Because the names are rather non-descriptive (both are solid, both contain lipids, both are nanostructured and both are carriers), it takes quite a while to understand the real difference but Souto and Müller explain it very well in Reference 16. The difference between SLNs and NLCs is in the composition of the lipid matrix. The matrix consists of highly pure lipids for SLNs and a mixture of solid and liquid lipids for NLCs. The pure, solid lipids of the SLNs with their relatively perfect lipid crystals provide only little space where solubilized molecules can be inserted into the lipid crystal structure; SLN’s therefore have a limited loading capability. NLCs, on the other hand, are a mixture of solid and liquid lipids which yields crystal structures with many imperfections; NLCs therefore have a high loading capability. The typical particle size of such colloidal carriers is below 1 μm; that is at the high end of nanotechnology that typically deals with sizes from 20 to 200 nm, in particular from 20 to 100 nm.

The variety in these skin delivery systems comes from their release mechanisms, which can involve fracture, passive diffusion, fusion, enzymatic degradation and pH.17 When studying the scientific literature it quickly becomes apparent that the majority of papers describing these systems deal with either the stability of the encapsulated chemically labile molecule18 or the release and release mechanism of encapsulated molecules or both,19 whereas reports on enhanced skin delivery (i.e., larger amounts being delivered into skin) from micro- and nanoparticles are difficult to find. This suggests that these particles are used almost exclusively to enhance the stability of chemically labile molecules (the first R) and/or to optimize the time profile of skin delivery (the fourth R). But there is something else going on with micro- and nanoparticles. They accumulate in furrows and ridges on the skin surface where they act as a reservoir, and that leads to a discussion of whether particles and in particular nanoparticles can penetrate skin! That is the topic in Part II, appearing in the January 2009 issue of Cosmetics & Toiletries magazine.

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1. JW Wiechers, Skin delivery: What it is and why we need it, In Science and Applications of Skin Delivery Systems, JW Wiechers, ed, Carol Stream, Illinois, USA: Allured Publishing (2008) Chapter 1, pp 1–21
2. Delivery System Handbook for the Personal Care and Cosmetic Products. Technology, Applications, and Formulations, MR Rosen, ed, Norwich, New York, USA: William Andrew, Inc (2005)
3. M Regiert, Delivering chemically labile molecules into the stratum corneum: An example of stabilizing linoleic acid with α-cyclodextrin, In Science and Applications of Skin Delivery Systems, JW Wiechers, ed, Carol Stream, Illinois, USA: Allured Publishing (2008) Chapter 19, pp 353–364
4. The Royal Society and The Royal Academy of Engineering, Nanoscience and Nanotechnologies: Opportunities and Uncertainties, London: The Royal Society and The Royal Academy of Engineering (2004) available at: (Accessed Sep 21, 2008)
5. AD Maynard, Nanotechnology: The next big thing, or much ado about nothing? Ann Occup Hyg 51 1–12 (2007)
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7. TL Andresen, SS Jensen and K Jørgensen, Advanced strategies in liposomal cancer therapy: Problems and prospects of active and tumor specific drug release, Progress in Lipid Research 44 68–97 (2005)
8. A Rolland, N Wagner, A Chatelus, B Shroot and H Schaefer, Site-specific drug delivery to pilosebaceous structures using polymeric microspheres, Pharm Res 10 1738–1744 (1993)
9. M Ossadnik, H Richter, A Teichmann, S Koch, U Schäfer, R Wepf, W Sterry and J Lademann, Investigation of differences in follicular penetration of particle- and nonparticle-containing emulsions by laser scanning microscopy, Laser Physics 16 747–750 (2006)
10. J Zhang, CH Purdon, EW Smith, HI Maibach and C Surber, Penetration enhancement by skin hydration, In Percutaneous Penetration Enhancers, 2nd Edition, EW Smith and HI Maibach, eds, Boca Raton, Florida, USA: CRC Press (2006) Chapter 5, pp 67–71
11. G Cevc, Non-invasive transdermal delivery of drugs, The Drug Delivery Companies Report 2001/02, (Accessed Sep 4, 2009)
12. E Touitou and B Godlin, Enhanced skin permeation using ethosomes, In Percutaneous Penetration Enhancers, 2nd Edition, EW Smith and HI Maibach, eds, Boca Raton, Florida, USA: CRC Press (2006) Chapter 8, pp 95–108
13. I Effendy and HI Maibach, Surfactants and experimental irritant contact dermatitis, Contact Derm 33 217–225 (1995)
14. JW Wiechers, C Kelly, TG Blease and JC Dederen, Formulating for fast efficacy: Influence of liquid crystalline emulsion structure on the skin delivery of active ingredients, IFSCC Magazine 9 15–21 (2006)
15. JW Wiechers, CL Kelly, TG Blease and JC Dederen, Formulating for efficacy, Int J Cosmet Sci 26 173–182 (2004)
16. EB Souto and RH Müller, Challenging cosmetics–Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), In Science and Applications of Skin Delivery Systems, JW Wiechers, ed, Carol Stream, Illinois, USA: Allured Publishing (2008) Chapter 13, pp 227–250
17. D Fairhurst and A Loxley, Micro- and nano-encapsulation of water- and oil-soluble actives for cosmetic and pharmaceutical applications, In Science and Applications of Skin Delivery Systems, JW Wiechers, ed, Carol Stream, Illinois, USA: Allured Publishing (2008) Chapter 17, pp 313–336
18. J-P Jee, S-J Lim, J-S Park and C-K Kim, Stabilization of all-trans retinol by loading lipophilic antioxidants in solid lipid nanoparticles, Eur J Pharm Biopharm 63 134–139 (2006)
19. K Vivek, H Reddy and RSR Murthy, Investigations of the effect of the lipid matrix on drug entrapment, in vitro release, and physical stability of olanzapine-loaded solid lipid nanoparticles, AAPS Pharm Sci Tech 8 16–24 (2007)



Table 1. The Effects of Skin Delivery Systems

Table 1
Summary of the effects skin delivery systems may have on the partition coefficient K and the diffusion coefficient D and for what target site and type of applications such systems will be most applicable depending on the polarity of the active ingredient. Abbreviations used: sc = stratum corneum; ve = viable epidermis; d = dermis.

Figure 1. Schematic overview of targeted delivery of polystyrene beads of varying sizes

Figure 1
Schematic overview of targeted delivery of polystyrene beads of varying sizes. Beads with diameters greater than 10 microns do not penetrate the stratum corneum (left), whereas beads smaller than 3 microns penetrate the skin by both the intercellular spaces between the corneocytes as well as via the infundibulum (right). When beads are between 3 and 10 microns in diameter, targeted delivery to the sebaceous gland and the follicular unit can be achieved. (Figure modified from Reference 8.)

Figure 2. Schematic representation of microcapsules and solid lipid nanoparticles

Figure 2
Figure 2. Schematic representation of microcapsules (top) and solid lipid nanoparticles. (Reproduced from Reference 17 with permission.)

Equation 1.

Equation 1
According to the well-known Fick’s First Law of Diffusion, the flux, J, of a chemical through the skin equals to Equation 1 in which kp is the permeability coefficient, ΔC the concentration difference between the concentrations at the top and bottom of the stratum corneum, D the diffusion coefficient, K the partitioning coefficient and L the length of the pathway of diffusion.

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