Delivering On Time, In Full and On Target: Part II

Jun 1, 2008 | Contact Author | By: Johann W. Wiechers, PhD, JW Solutions; Jonathan Hadgraft, Barrie Finnin and Michael S. Roberts
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Title: Delivering On Time, In Full and On Target: Part II
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Editor’s note: This two-part article was originally written following a discussion among skin delivery experts on the technical aspects of topical formulations used in the cosmetic and pharmaceutical industries, with the aim to identify future trends in delivery. This second installment continues a discussion from Cosmetics & Toiletries magazine’s May 2008 issue and is also based on a chapter written for the book Skin Barrier: Chemistry of Skin Delivery Systems. Practical information for the cosmetic formulator regarding optimization of skin delivery has been added.

The first installment discussed the major developments in skin delivery in terms of formulation, in addition to special delivery considerations for the cosmetic formulator. This second installment discusses:

                 • What are the unsolved technical problems in skin delivery?

                 • What are the latest scientific developments that may influence the direction of skin                                delivery research?

                 • What areas of research should be focused upon to be ready for the next generation of                        cosmetic and pharmaceutical product forms?

After the complete discussion, it was generally concluded that although pharmaceutical and cosmetic formulations differ considerably because of regulatory and customer requirements, they share the same deficiencies with respect to skin delivery characteristics.

Unsolved Technical Problems in Skin Delivery


There are a few unsolved technical problems in skin delivery; however, a recent insight in dermatology will need to be discussed first. Skin conditions have changed over the last 30–40 years and more people are suffering from eczema as a result of environmental factors. For example, the incidence of atopic eczema in children rose from 5% in 1950 to more than 25% in 2000 and is still on the rise.2 This reduced skin barrier function as a consequence of diseases like atopic dermatitis also leads to an increased risk of allergen penetration.2

These factors require both industries to look carefully at the excipients included in topical formulations. Unfortunately, many chemicals that help to enhance the penetration of drugs through the skin also increase irritancy3 and these two effects are often linked.3,4 Therefore, new formulations being developed should take these environmental factors into account (see Excipients and Delivery). 

If the solution to enhancing skin penetration without irritation were to be found, the cosmetic industry would be more likely to incorporate it, whereas the pharmaceutical industry may not since its conservatism may prevent consideration of the solution. 

One of the outstanding technical issues in both the pharmaceutical and cosmetic industries is a lack of detailed knowledge on the effect of excipients on the thermodynamic activity (chemical potential) of the penetrating molecule in a formulation following application, as well as in the skin. Research in both these fields is, of course, ongoing. 

An excipient such as propylene glycol has been used extensively but knowledge of its effect on/in the skin is comparatively limited. Trottet et al. describe that the flux of loperamide hydrochloride is determined by the percentage of propylene glycol in a formulation.15 The propylene glycol penetrates into the skin where it helps to solubilize the drug in the stratum corneum, enhancing its penetration continually until it is depleted from the formulation. When more propylene glycol is included in the formulation, more loperamide hydrochloride penetrates the skin.15 Herkenne et al. found similar results for ibuprofen delivery that depended on the level of propylene glycol in the vehicle.16 In the cosmetic field, Rossi et al.17 found similar results for dimethyl isosorbide when delivering the self-tanning agent dihydroxyacetone.

Whereas some of these studies were performed on simple propylene glycol/water mixtures,16 others involved much more complex formulations.15,17 Both types of studies will be necessary to determine the influence of excipients on drug and active ingredient penetration into and through the skin. As a formulation strategy, a stepwise approach seems the best option: start off with relatively simple formulations and then make them pharmaceutically or cosmetically more acceptable, bearing in mind that this may alter the effectiveness of the delivery of the drug or active ingredient. A better understanding of the complex interactions of active ingredients and excipients with the skin may help to answer a major unsolved question of why the bioavailability of many topically applied compounds is only somewhere in the 1–10% range.18,19 

Another technical issue in translating the findings of studies into the mechanisms of skin delivery is that mechanistic studies are often performed with infinite doses, where the applied concentration of the drug is held constant for the duration of the experiment. In practice, the applied dose will be finite and the concentration of both active ingredient and excipient will change with time. As Trottet et al.15 and Cross et al.20 have already shown, results from infinite dose experiments can give different results from those with finite doses. Trottet et al. showed that it is very difficult, if not impossible, to dose in vitro at a clinically relevant amount (1–2 mg/cm2). 

Cross et al. reported that whereas increasing viscosity of a formulation may decrease skin penetration under infinite conditions, such effects were not seen with a finite dose. When formulations are applied to and rubbed into the skin, they undergo a metamorphosis.21 Apart from obvious changes such as the loss of water and other volatile components, changes in micellar structure are also possible. All of these changes have the potential to alter the delivery of active ingredients. Thus, it is important to understand the structure of the preparation applied to the skin and how it changes after application, as well as how this change is likely to impact the delivery of drugs and active ingredients.

A difference between the cosmetic and pharmaceutical industries is the preference of the former to include multiple active ingredients in a single formulation. This presents a formidable challenge, particularly for an industry without a record of formulating for delivery of active ingredients. Because each of the ingredients may differ widely in its physicochemical properties such as solubility and partition, for instance, vitamins C, D and E, an optimal formulation for one ingredient is not likely to be close to optimal for other ingredients. The formulation must also be optimized so that the penetration of excipients that are potential skin sensitizers (e.g., parabens) are minimized.22 Technologically, it is questionable whether each of these goals can be completely achieved in a single formulation.

On a positive note, it is now understood that it is possible to set target delivery profiles: how much active ingredient needs to be delivered, to where, and how quickly. With these targets, formulation approaches can be developed to try to match the desired profiles. 

The Influence of New Developments on Delivery Research

There is much interest of late in the genetic disposition of skin conditions. This is likely to become important for product use recommendations of the future. For instance, certain excipients in topical formulations may alter the skin etiology of some but not that of others. Individuals may also show differing reactivity to topically applied chemicals, depending on their genetic makeup. This could have a major impact. 

Cork et al. are examining genetic disposition in individuals predisposed to eczema,2 hypothesizing that there is an interaction between genetic diversity and environmental factors. Depending on what is found, recommendations could be made at the genetic level for which products are best for given skin types. For instance, if someone has one or two gene changes that hinder their desmosomes as less effective, they could be advised to use products that contain certain surfactants. As another example, if someone has a genetic disposition that could produce particularly allergic or irritant responses to, for instance, phenylenediamine,23 that individual would be advised not to become a hairdresser. Whereas pharmaceutical companies may be adopting this approach already, cosmetic companies are not thinking that way yet. 

Extrapolating from this genetic disposition, there seems to be a problem, particularly with surfactants. It is therefore advisable to begin thinking about formulations with either low surfactant levels or no surfactant levels. 

Another key scientific development affecting skin delivery is the increased emphasis on product safety with minimal animal study assessments.24 As a consequence, in silico predictions of efficacy, safety, formulation effects and skin penetration13,25,26 and a greater emphasis on human skin cultures24 are likely to become more pivotal in future skin delivery research developments. 

Focus on the Future: Next Generation of Cosmetics and Pharmaceuticals

Obviously one area in skin delivery research that scientists need to concentrate on is better identification or quantification of the desired targets; i.e., how much delivery is needed, what concentration is needed, where, and for how long. This knowledge is currently lacking in many cases, although some information is available from in vitro experiments. It is notable, however, that the large doses used in vitro may not provide an accurate descriptor of what happens in vivo. This knowledge is, in turn, useless unless one can actually measure the levels of drug or active ingredient at the target site. The resolution of most analytical techniques is insufficient at the moment to allow such measurements, in particular at the low levels one is likely to encounter following topical application.

At the same time, research into the mechanism of action of skin delivery systems needs to continue. It needs to be published in detail in peer-reviewed scientific journals and repeated by others to check the validity, in order to allow identification of essential requirements that may have been met only accidentally the first time. Therefore, companies that produce such new platform technologies—if confident—need to conduct external research that is unbiased in nature on these new technologies.

Conclusions

Summarizing this discussion, it can be concluded that both the pharmaceutical and cosmetic industries do not know enough about the basic principles of skin delivery, although some companies are realizing that delivery knowledge might give them a competitive edge. It is often possible to use far less active ingredient or drug to obtain the same clinical effect. Research in the next ten years should focus on improved development and eventual implementation of these concepts. New measurement technologies should be developed that can measure a drug or an active ingredient at the site of action in a noninvasive way. The effects of excipients should also be studied to allow for the development of products for people of different genetic dispositions. Finally, the benefit of delivery systems needs to be repeatable27 by other independent groups in order to gain credibility.

References:

1. Skin Barrier: Chemistry of Skin Delivery Systems, JW Wiechers, ed, Allured Publishing Corp, Carol Stream, IL (2008) 

2. MJ Cork, DA Robinson, Y Vasilopoulos, A Ferguson, M Moustafa, A MacGowan, GW Duff, SJ Ward and R Tazi-Ahnini, New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions, J Allergy Clin Immunol, 118 3–21 (2006)

3. RH Guy, Transdermal science and technology: an update, Drug Delivery System, 22 (4) 442–449 (2007)

4. JW Wiechers, Looking beyond the mechanisms of skin irritancy, skin penetration enhancement and preservation, J Cosmet Sci, 52 84–85 (2001)

5. JW Wiechers, CL Kelly, TG Blease and JC Dederen, “The influence of emulsifiers on the skin penetration from emulsions.” Science and Applications of Skin Delivery Systems, JW Wiechers, ed, Allured Publishing Corp, Carol Stream, IL 125–138 (2008)

6. N Kanikkannan, RJ Babu and M Singh, “Structure-activity relationship of chemical penetration enhancers.” Percutaneous Penetration Enhancers, 2nd Edition, EW Smith and HI Maibach, eds, CRC Taylor & Francis, Boca Raton, FL 17–33 (2006)

7. JW Wiechers, “The influence of emollients on skin penetration from emulsions.” Science and Applications of Skin Delivery Systems. JW Wiechers, ed, Allured Publishing Corp, Carol Stream, IL, 91–108 (2008)

8. JW Wiechers, CL Kelly, TG Blease and JC Dederen, Formulating for Efficacy, Int J Cosmet Sci, 26 173–182 (2004)

9. JW Wiechers and M Chandler, (Re)Formulating within REACH with formulating from first principles, Cosm & Toil, 122 (9) 63–72 (2007)

10. P Rossi, JW Wiechers and CL Kelly, Improved delivery and efficacy with dimethyl isosorbide, Cosm & Toil, 120 (3) 107–111 (2005)

11. JW Wiechers, A Judefeind, J du Plessis, CL Kelly, M Lane and J Hadgraft, “The effect of changing the polarity of the stratum corneum on the dermal and transdermal delivery of cosmetically active ingredients.” Science and Applications of Skin Delivery Systems, JW Wiechers, ed, Allured Publishing Corp, Carol Stream, IL, 109–123 (2008)

12. C Herkenne, A Naik, YN Kalia, J Hadgraft and RH Guy, Effect of propylene glycol on ibuprofen absorption into human skin in vivo, J Pharm Sci, 97 185–197 (2008)

13. BM Magnusson, YG Anissimov, SE Cross and MS Roberts, Molecular size as the main determinant of solute maximum flux across the skin, J Invest Dermatol, 122 993–999 (2004)

14. AC Lauer, LM Lieb, C Ramachandran, GL Flynn and ND Weiner, Transfollicular drug delivery, Pharm Res 12 179–186 (1995)

15. L Trottet, C Merly, M Mirza, J Hadgraft and AF Davis, Effect of finite doses of propylene glycol on enhancement of in vitro percutaneous permeation of loperamide hydrochloride, Int J Pharm, 274 213–219 (2004)

16. C Herkenne, A Naik, YN Kalia, J Hadgraft and RH Guy, Effect of propylene glycol on ibuprofen absorption into human skin in vivo, J Pharm Sci, 97 185–197 (2008)

17. P Rossi, JW Wiechers and CL Kelly, Improved delivery and efficacy with dimethyl isosorbide, Cosm & Toil, 120 (3) 107–111 (2005)

18. AF Davis, “How do we work out a topical dose? Dermal Delivery Downunder—Delivering the Dream,” ASCC 39th Annual Conference, Brisbane, QLD, Australia, March 2005

19. AF Davis, “Drug and dosage selection in topical dermatological treatment,” Skin and Formulation, 2nd Symposium, APGI, Versailles, France, Oct 2006, Proceedings pp 15–16. 

20. SE Cross, R Jiang, HAE Benson and MS Roberts, Can increasing the viscosity of formulations be used to reduce the human skin penetration of the sunscreen oxybenzone? J Invest Dermatol, 117 147–150 (2001)

       21. J Zhang, EW Smith and C Surber, “Galenic principles in skin protection.” Skin Protection, Practical Applications in the Occupational Setting, S Schliemann and P Elsner, eds, Karger, Basel, Switzerland 11–18 (2007)

22. SE Cross, and MS Roberts, The effect of occlusion on the epidermal penetration of parabens from a commercial allergy test ointment, acetone and ethanol vehicles, J Invest Dermatol, 115 914–918 (2000)

23. M Teixeira, L de Wachter, E Ronsyn and A Goossens, Contact allergy to para-phenylenediamine in a permanent eyelash dye, Contact Dermatitis, 55 92–94 (2006)

24. MS Roberts and KA Walters, Dermal Absorption and Toxicity Assessment, 2nd edn, Marcel Dekker, New York (2007)

25. MD Barratt, Quantitative structure-activity relationships for skin permeability, Toxicol In Vitro, 9 27–37 (1995)

26. RO Potts and RH Guy, Predicting skin permeability, Pharm Res, 9 663–669 (1992)

27. RP Chilcott, N Barai, AE Beezer, SI Brain, MB Brown, AL Bunge, SE Burgess, S Cross, CH Dalton, M Dias, A Farinha, BC Finnin, SJ Gallagher, DM Green, H Gunt, RL Gwyther, CM Heard, CA Jarvis, F Kamiyama, GB Kasting, EE Ley, ST Lim, GS McNaughton, A Morris, MH Nazemi, MA Pellett, J Du Plessis, YS Quan, SL Raghavan, M Roberts, W Romonchuk, CS Roper, D Schenk, L Simonsen, A Simpson, BD Traversa, L Trottet, A Watkinson, SC Wilkinson, FM Williams, A Yamamoto and J Hadgraft, Inter- and intralaboratory variation of in vitro diffusion cell measurements: an international multicenter study using quasi-standardized methods and materials, J Pharm Sci, 94 632–638 (2005)                         

 

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