Skin penetration enhancers

International Journal of Pharmaceutics 447 (2013) 12–21

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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Review

Skin penetration enhancers Majella E. Lane ∗ Department of Pharmaceutics, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1 N 1AX, United Kingdom

a r t i c l e

i n f o

Article history: Received 28 December 2012 Received in revised form 15 February 2013 Accepted 17 February 2013 Available online 24 February 2013 Keywords: Skin Chemical permeation enhancer Topical Transdermal Diffusion-Partition-Solubility theory

a b s t r a c t The skin has evolved to prevent excessive water loss from the internal organs and to limit the ability of xenobiotics and hazardous substances to enter the body. Notwithstanding this barrier function, a number of strategies have been developed by scientists to deliver drugs to and through the skin. The aim of this review is to consider the various types of chemical penetration enhancers (CPEs) which have been investigated in the scientific literature. Potential pathways for CPEs to exert their action are examined with reference to the physical chemistry of passive skin transport. The emphasis is on those studies which have focussed on human and porcine skin because of the limitations associated with skin permeation data collated from other species. Where known, the mechanisms of action of these compounds are also discussed. Examples of enhancers used in commercial topical and transdermal formulations are provided. It is proposed that overall the effects of CPEs on the skin barrier may best be explained by a DiffusionPartition-Solubility theory. Finally, some of the limitations of studies in the literature are considered and the importance of monitoring the fate of the penetration enhancer as well as the active is highlighted. © 2013 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The stratum corneum and the permeation process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The physical chemistry of skin penetration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical classification and mechanisms of action of CPEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Short chain alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Long chain alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Amides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. Azone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1. Alkyl esters – ethyl acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Benzoate esters – octyl salicylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.3. Fatty acid esters – isopropyl myristate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Glycols – propylene glycol (PG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Glycol ethers – Transcutol® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7. Pyrrolidones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8. Sulphoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9. Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.1. Anionic surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2. Cationic surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3. Non-ionic surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.10. Terpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Penetration enhancers in commercial formulations and the Diffusion-Partition-Solubility (DPS) theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Tel.: +44 207 7535821; fax: +44 870 1659275. E-mail address: [email protected] 0378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijpharm.2013.02.040

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M.E. Lane / International Journal of Pharmaceutics 447 (2013) 12–21

1. Introduction Drug delivery to and through the skin remains a challenging area for pharmaceutical and formulation scientists. This is largely because of the excellent barrier properties of this organ which has evolved to allow humans to survive in a dry environment. Although the skin is a multi-laminate tissue, it is the outermost layer, the stratum corneum (SC) which comprises the major barrier to drug permeation. This paper reviews the chemical permeation enhancement strategies which have been reported in the literature to overcome the SC in order to achieve dermal or transdermal delivery of drugs or actives. Attention will be focussed on porcine or human skin permeation data as results from other animal models should not be extrapolated to man, which has been known for many years. The mechanisms of action of representative compounds of the various chemical classes will be considered and examples of CPEs in practical use will be provided. Experimental design will be critically examined, specifically the relevance of infinite dose versus finite dose conditions for evaluation of CPEs. The application of advanced analytical techniques to elucidate the fate of the active and CPE in skin will be highlighted. This information will permit rational selection of CPEs and ultimately the development of safer and more efficacious formulations. 2. The stratum corneum and the permeation process Structurally the SC is a thin (∼15 ␮m) heterogeneous layer and it comprises layers of terminally differentiated and keratinised epidermal cells separated by an intercellular lipid domain (Menon et al., 2012). This arrangement of the corneocytes within the lipidprotein matrix has been compared to a brick wall (Fig. 1), with the corneocytes being the bricks and the lipid-protein matrix the mortar (Michaels et al., 1975). The dense overlapping dead cells (bricks) are ‘welded’ together by corneodesmosomes and are embedded in an intercellular matrix of a complex mixture of lipids (mortar). There are different routes by which a molecule can cross the SC. These are the intercellular, transcellular and appendageal (through either the eccrine – sweat glands or hair follicles) routes (Fig. 1). The appendageal route is not considered to be a significant pathway for drug permeation because sweat glands and hair follicles occupy only 0.1% of the total surface area of human skin (Tregear, 1966; Scheuplein, 1967). However, drug delivery via this route may be important for the permeation of slowly diffusing compounds and very high molecular weight substances, such as nanoparticles (Lademann et al., 2011). Nanoparticle delivery must result from a physical process as diffusion would be far too slow to be significant. It may also be important for the facilitated transport of charged molecules across the skin following application

of a small electric current (iontophoresis) (Edwards et al., 1995). Additionally, the transappendageal route may contribute to the rapid diffusion of compounds in the early stages of diffusion, before steady-state is achieved (Scheuplein, 1967). The transcellular route is another possible route of penetration but in experimental studies, the predominant route of penetration appears to be through the intercellular spaces. The diffusional pathlength has been found to be much longer than the thickness of the SC (20 ␮m) and has been estimated to be around 300–900 ␮m. The transport of molecules through this route involves sequential diffusion and partitioning between the polar head groups and the alkyl chains of the intercellular lipids (Albery and Hadgraft, 1979; Boddé et al., 1989). The processes which may occur after application of a topical formulation to the skin are illustrated in Fig. 2. Initially, the drug must be released from the vehicle followed by partitioning into the SC. Molecules will subsequently diffuse (as a result of a concentration gradient) through the SC before a further partitioning process into the viable epidermis, and further diffusion through the viable epidermis towards the dermis. The vasculature and lymphatic vessels in the dermis will clear the drug from the skin. This process is efficient and essentially produces a very low active concentration in the layers of the skin below the SC. A number of drugs may interact with the different skin layers in the course of percutaneous penetration, resulting in limited absorption. These interactions may be in the form of reversible/irreversible binding to several structures in the biological tissue, such as the SC keratin and/or specific sites in the skin to produce a physiological response (e.g. therapeutic activity or allergic reactions). Drug binding is distinct from drug accumulation or retention in the different compartments as the latter results from relatively high drug partition slow drug diffusivity or drug crystallisation. A further possibility is that both processes may contribute to the reservoir capacity of the skin for certain compounds, e.g. steroids (Vickers, 1963; Menczel et al., 1985). In addition drugs may undergo metabolism during the process of permeation (Pannatier et al., 1978). 3. The physical chemistry of skin penetration Diffusion is a passive kinetic process that takes place down a concentration gradient from a region of high concentration to a region of lower concentration. Steady-state diffusion can be described by Fick’s first law – Eq. (1). This equation describes the rate of transfer (or flux, J) of the diffusing substance through unit area A of the membrane as being proportional to the velocity of molecular movement through the diffusional medium (or diffusion coefficient, D) and to the concentration gradient measured across the membrane (dC/dx). J = −AD

Intercellular

Transcellular

Transappendageal

 dC  dx

(1)

The negative sign in Eq. (1) is because the diffusion process occurs in the opposite direction to increased concentration. Fick’s second law of diffusion, Eq. (2), can be derived from Eq. (1) to describe membrane transport under non-steady state conditions (Crank, 1975). This is a partial differential equation, relating the change in concentration with time to the rate of change in the concentration gradient: ∂C ∂2 C =D 2 ∂t ∂x

Fig. 1. Possible transport pathways through the stratum corneum.

13

(2)

An analytical solution of Eq. (2) may be used to describe the concentration profiles of a permeant across skin as they evolve with time, after application of a given formulation. Where the drug is applied to the membrane at a maximum fixed concentration in the donor compartment and maintaining sink conditions in the

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M.E. Lane / International Journal of Pharmaceutics 447 (2013) 12–21

Fig. 2. Schematic representation of the processes involved in drug transport into, and across, the skin from any topical or transdermal applied formulation.

receptor compartment, at steady state, Eq. (2) may be written as Eq. (3): J = AD

Cm h

(3) 4.1. Alcohols

where Cm is the concentration of the compound at the donor–membrane interface and h is the effective diffusional pathlength of the membrane. The vehicle-membrane partition coefficient (K) may be further defined as the ratio between the concentrations of the permeant in the membrane at the donor–membrane interface and the vehicle in which it is applied (Cv ). This term can be used to replace Cm in Eq. (3), leading to Eq. (4), a modified form of Fick’s first law of diffusion, descriptive of steady-state flux across membranes. Given the complex structure of the skin it is perhaps surprising that Fick’s laws work so well as a framework to understand transport through this membrane. Jss =

ADKCv h

(excluding patents). In this section, individual groups are examined in greater detail (examples are shown in Fig. 3) and their mechanisms of action, where known, will be discussed.

(4)

For passive drug permeation enhancement, inspection of Eq. (4) indicates that increased drug flux should be achieved by a change in D, K and C. Therefore compounds which are skin penetration enhancers may potentially change the solubility/partitioning behaviour of the drug into the SC and/or its diffusion properties. There is also the possibility of manipulating permeant flux by changing the thermodynamic activity of the drug in the formulation as noted by Higuchi (1960). Such approaches are not the focus of the current review as they do not typically result in an alteration in the skin barrier properties and have been discussed in detail elsewhere (Lane et al., 2012a). 4. Chemical classification and mechanisms of action of CPEs Table 1 provides examples of the most commonly cited classes of skin penetration enhancers in the technical literature

4.1.1. Short chain alcohols Ethanol and isopropyl alcohol are the two most common shortchain alcohols used in dermal and transdermal products. Ethanol was employed in the early “reservoir” transdermal patches such as EstradermTM as a co-solvent and penetration enhancer and it is still used in many transdermal and topical preparations. Various mechanisms have been proposed to explain the action of ethanol. The flux across skin was observed to be linearly related to ethanol flux for a number of actives (Berner et al., 1989a; Liu et al., 1991). Pershing et al. (1990) investigated the effects of ethanol on skin permeation of estradiol. Differences in in vivo flux and permeability coefficient (kp ) of tracer estradiol solutions in ethanol or ethanol solutions compared with a phosphate buffer vehicle reflected the difference in the apparent partition coefficients (K) of estradiol from the respective vehicles into isolated human stratum corneum. Neither the stratum corneum thickness nor the diffusion coefficient of estradiol was significantly different among the vehicles tested. Liu et al. (1991) investigated the estradiol/ethanol flux relationship using both symmetric and asymmetric physical model approaches. The asymmetric fluxes for both saturated estradiol and ethanol varied with ethanol donor concentration in a manner consistent with the ethanol gradient influencing both drug and ethanol transport. This was related to increased diffusion coefficient at ethanol concentrations <50% and decreased membrane activity coefficients at moderate concentrations (50–75%). In a later study, the same symmetric and asymmetric model was used to probe the effects of isopropanol and isopropyl myristate on estradiol permeation in human skin (Liu et al., 2009). IPA uptake correlated well with estradiol solubility in stratum corneum, both linearly

M.E. Lane / International Journal of Pharmaceutics 447 (2013) 12–21

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Table 1 Examples of penetration enhancers investigated in the technical literature. Chemical classification

Enhancer

Alcohols

Short chain alcohols Ethanol, Isopropyl alcohol Long chain alcohols Decanol, Hexanol, Lauryl alcohol, Myristyl alcohol, Octanol, Octyl dodecanol, Oleyl alcohol

Amides

Cyclic amides Azone

Esters

Alkyl esters Ethyl acetate Benzoic acid esters Octyl salicylate, Padimate O Fatty acid esters Ethyl oleate, Glyceryl monoleate, Glyceryl monocaprate, Glyceryl tricaprylate Isopropyl myristate, Isopropyl palmitate, Propylene glycol monolaurate, Propylene glycol monocaprylate

Ether alcohols

Transcutol®

Fatty acids

Lauric acid, Linoleic acid, Linolenic acid, Myristic acid, Oleic acid, Palmitic acid, Stearic acid, Isostearic acid

Glycols

Dipropylene glycol, Propylene glycol, 1,2-butylene glycol, 1,3- butylene glycol

Pyrrolidones

N-methyl-2-pyrrolidone, 2-pyrrolidone

Sulphoxides

Decylmethyl sulphoxide, Dimethyl sulphoxide

Surfactants

Anionic surfactants Sodium lauryl sulphate Cationic surfactants Alkyl dimethylbenzyl ammonium halides Alkyl trimethyl ammonium halides Alkyl pyridinium halides Non-ionic surfactants Brij 36T Tween 80

Terpenes

Monoterpenes Eugenol, d-Limonene, Menthol, Menthone Sesquiterpenes Farnesol, Neridol

increasing with increasing IPA. Based on DSC, wide angle and small angle X-ray diffraction studies of stratum corneum treated with IPA, Brinkmann and Muller-Goymann (2003) concluded that this molecule increases drug permeation by increasing lipid fluidity via disturbance of the intercellular lipid bilayer structure. The ability of ethanol or ethanol–water mixtures to modify the barrier function of the skin by a number of mechanisms has also been reported to include lipid fluidisation, lipid extraction and effects on lipid ordering (Kurihara-Bergstrom et al., 1990;

Bommannan et al., 1991; Goates and Knutson, 1994) as well as effects on keratin (Berner et al., 1989b; Kurihara-Bergstrom et al., 1990). Infinite dose studies on ibuprofen permeation from ethanol and ethanol–water mixtures reported by Watkinson et al. (2009a) reported increased flux from ethanol:water systems up to a limiting value of 75% ethanol. These authors suggested that ethanol increased drug permeation (Table 2) via increased solubility of ibuprofen in the skin. However, in finite dose studies the rapid evaporation of ethanol or isopropanol would be

Fig. 3. Examples of some of the skin penetration enhancers cited in the literature.

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Table 2 Steady-state fluxes and permeability coefficients for the permeation of ibuprofen from saturated formulations containing ethanol and water through human epidermis. Ethanol/water (v/v)

J (␮g/cm2 /h) ± SD

0/100 25/75 50/50 75/25 100/0a

24.4 48 273.8 293.3 59.8

± ± ± ± ±

2.69 19.34 32.71 23.63 23.93

O N

kp (cm/s) ± SD 6.38 × 10−5 ± 2.95 × 10−5 3.94 × 10−8 ± 1.55 × 10−8 1.46 × 10−7 ± 7.28 × 10−8 1.67 × 10−7 ± 1.32 × 10−8 1.04 × 10−7 ± 7.43 × 10−8

Data adapted from Watkinson et al. (2009a). Mean ± SD, n = 5. a Reagent grade ethanol was used.

expected to limit this contribution of ethanol to drug permeation enhancement. It is also important to note that the residence time of ethanol will influence its ability to act as a penetration enhancer. Once it has evaporated and/or passed through the skin it is no longer available to exert any effects on the transport of an active. For this reason, the early reservoir patches had a limited period of application – the DurogesicTM reservoir patch, for example, stopped working after 3 days because of ethanol exhaustion but there was still residual fentanyl in the patch (Lane, 2013). 4.1.2. Long chain alcohols Andega et al. (2001) investigated the effect of saturated fatty alcohols (octanol, nonanol, decanol, undecanol, lauryl alcohol, tridecanol, and myristyl alcohol) and unsaturated fatty alcohols (oleyl alcohol, linoleyl alcohol, and linolenyl alcohol) on melatonin permeation across porcine and human skin. A parabolic relationship between the carbon chain length of saturated fatty alcohols and permeation enhancement of melatonin was observed for both tissues. The maximum permeation of MT was observed when fatty alcohol carbon chain length was 10. In general, as the level of unsaturation increased from one to two double bonds, there was an increase in the permeation of MT both in porcine and human skin. A decrease in the permeation was observed with three double bonds. However, these studies were conducted using an ethanol:water vehicle containing 5% fatty alcohol under infinite dose conditions and the authors did not consider possible co-enhancement by ethanol. Dias et al. (2008) investigated the effects of hexanol, octanol and decanol in vivo in humans using a combination of ATR FTIR spectroscopy and tape stripping. Studies conducted using deuterated vehicles confirmed the lipid extraction effects of d-hexanol and doctanol, whereas d-decanol did not change skin lipid content. The uptake of d-decanol was higher than for the other vehicles. In general, solvent uptake was proportional to the induced shift in the C–H stretching frequency. Lipid disorder was induced by all vehicles studied in vivo and was proportional to the amount of vehicle present in the skin. 4.2. Amides 4.2.1. Azone Azone was the first compound to be specifically designed as a skin penetration enhancer (Stoughton and McClure, 1983) and was investigated extensively in the 1980s and 1990s (Wiechers et al., 1987; Harrison et al., 1996; Engblom et al., 1998; Degim et al., 1999). Structurally, the molecule comprises a polar headgroup (within a seven membered ring) attached to a C12 chain (Fig. 4). Using conventional Franz cell studies as well as ATR FTIR, Harrison et al. (1996) concluded that the penetration enhancement properties of Azone reflect the ability of this molecule to reduce the diffusional resistance of the skin. These authors also noted that the structural

H3C Fig. 4. Azone.

features of the molecule should allow it to interact directly with skin lipids and thus produce a more fluid environment. Despite considerable investigation and interest in the application of Azone as a CPE, this molecule has never been used commercially.

4.3. Esters 4.3.1. Alkyl esters – ethyl acetate Ethyl acetate has been investigated as a transdermal penetration enhancer by Friend and co-workers (Friend, 1991; Friend et al., 1991). Although the mechanism of action of this compound is not well understood, the use of the molecule in transdermal patches was associated with irritation and erythema in animal models.

4.3.2. Benzoate esters – octyl salicylate OSAL has traditionally been used as a chemical sunscreen and it is regarded as safe in concentrations up to 5% (v/v) (Funk et al., 1995). In transdermal drug delivery, OSAL has been used to enhance the permeation of testosterone (Morgan et al., 1998) and fentanyl through human skin in vitro using volatile formulations (Traversa, 2005; Santos et al., 2011, 2012). Similar enhancement properties have been observed in vitro for testosterone when OSAL was used as a pure solvent or in combination with PG, under occlusive conditions using porcine skin (Nicolazzo et al., 2005). There are limited data in the literature about the mechanism of permeation enhancement of OSAL. Nevertheless, ATR-FTIR studies conducted in vitro and in vivo suggested that OSAL may reduce the conformational order of the lipid bilayers located within SC surface layers (Traversa, 2005). After treatment with OSAL deposited as a thin film from a volatile solvent, the (CH2 ) frequencies, located at 2852 and 2920 cm, shifted to higher wavenumbers and proportionally to the concentration of OSAL applied. From the literature, these shifts are related to transitions of the SC lipid lamellae from a gel phase to a liquid phase (Casal and Mantsch, 1984; Potts and Francoeur, 1993). However, a non-deuterated solvent was used in this study and therefore the CH2 from OSAL may overlap the CH2 from the SC lipids thus leading to spurious conclusions. Santos et al. (2012) have recently reported enhanced fentanyl diffusivity when OSAL was used as a penetration enhancer but no effects on the SC lipids using DSC and ATR-FTIR. In addition, a relatively high volume of OSAL was taken up by the skin. Based on these observations the authors hypothesised that OSAL may enhance drug diffusion by creating “pools” of solvent within the gel lipid phase, rather than intercalating with the skin lipids i.e. OSAL exists as a separate phase in the lipid bilayers.

M.E. Lane / International Journal of Pharmaceutics 447 (2013) 12–21

4.3.3. Fatty acid esters – isopropyl myristate In the technical literature, isopropyl myristate is the most common fatty acid ester which has been investigated as a penetration enhancer in topical and transdermal formulations. DSC studies showed a decrease in enthalpy and a negative shift in the phase transition temperatures of SC lipids, indicating an integration of IPM within the lipid bilayer (Leopold and Lippold, 1995). These shifts are associated with an increase in the lipid fluidity (Hirvonen et al., 1995). However, opposing results were observed with Wide Angle X-Ray Diffraction (WAXD) and Small Angle X-Ray Diffraction (SAXD) techniques. These studies indicated that IPM slightly increases the short distance of the orthorhombic lipids, while decreasing the hexagonal lipids and keeping the inter-lamellar distance constant (Brinkmann and Muller-Goymann, 2003). The authors suggested that the pre-treatment of stratum corneum with IPM resulted in a more densely packed bilayer and a loss of the corneocyte-bonded lipids. In addition, it was suggested that IPM interacts with the lipids with an anchoring of the isopropyl group in the polar region of the layer (Brinkmann and Muller-Goymann, 2005). More recently, Santos et al. (2012) investigated the effects of a number of penetration enhancers on fentanyl permeation and suggested that IPM may act to promote drug solubility in the skin. A range of other fatty acid esters are found in commercial products (creams and patches), including ethyl oleate, glyceryl monolaurate, glyceryl mono-oleate, lauryl lactate, isopropyl palmitate, methyl oleate, oleyl oleate and sorbitan mono-oleate. 4.4. Glycols – propylene glycol (PG) The most commonly used glycol in topical and transdermal products is propylene glycol. Propylene glycol (propane-1,2-diol) has been used in skin preparations since 1932 either as a co-solvent for poorly soluble materials and/or to enhance drug permeation through skin from topical preparations (Barrett et al., 1965; Coldman et al., 1969; Hoelgaard and Mollgaard, 1985; Nicolazzo et al., 2005). The mechanism of action of PG in enhancing drug permeation is not clearly understood. From studies on fluocinolone acetonide permeability in human skin, Ostrenga et al. (1971) observed that pre-treatment of skin with pure propylene glycol caused the skin barrier to become less pliable and attributed this effect to dehydration. Occlusive exposure of intact human skin to propylene glycol for 48 h showed a low degree of irritation but did not reveal notable damage to skin on histological examination (Nater et al., 1977). Hoelgaard and Mollgaard (1985) examined the effects of propylene glycol on metronidazole flux enhancement in human skin and suggested a possible “carrier-solvent” effect. Aungst et al. (1990) reported an hourly flux of 0.8% and a lag time of 210 min for 14 C-radiolabelled propylene glycol applied under infinite dose conditions to dermatomed human cadaver skin. Bouwstra et al. (1989) investigated the effects of PG on skin using Differential Thermal Analysis. Their findings suggested that PG treatment decreased the hydration of skin. Later experiments by Bouwstra et al. (1991) indicated that PG is not intercalated in the lipid bilayers and the authors also suggested that PG might be incorporated in the head group regions of the lipids. Transmission electron microscopy studies on skin treated with PG also confirmed that it did not interfere with the lipid lamellar structure and that corneocytes did not appear to take up PG (Hoogstraate et al., 1991). Brinkmann and Muller-Goymann (2005) investigated the interaction of PG with the SC using DSC, small angle and wide angle X-ray diffraction techniques. PG was proposed to integrate into the hydrophilic regions of the packed lipids as PG pre-treatment of the SC increased the distance in the lamellar phase. Kasting et al. (1993) demonstrated significant permeation enhancement of triprolidine base from pure PG when compared

17

with oil vehicles in vitro in human skin (formulation dosed at 150 ␮l in cells of 0.79 cm2 ). These workers related this direct effect of PG on the membrane to solvent incorporation in the stratum corneum in a sufficient quantity to modify permeant solubility in the tissue. Trottet et al. (2004) investigated the in vitro percutaneous permeation of propylene glycol and loperamide hydrochloride in formulations containing propylene glycol under finite dose conditions; dose effects were also examined. The data showed a correlation between the amount of propylene glycol dosed on the skin and the amount of drug that had permeated. Similar findings were reported by Pudney et al. (2007) in an in vivo study conducted using advanced Confocal Raman analysis. The depth of penetration of retinol into the skin from PG/Ethanol formulations dosed at 70 ml over 16 cm2 was observed to be highly correlated with the depth of penetration of PG. More recently, Bonnist et al. (2011) used the same spectroscopic technique to examine the in vitro porcine skin penetration of cinnamaldehyde in propylene glycol. The results confirmed that the kinetic behaviour of both active and PG was broadly similar and that cinnamaldehyde penetration is directly related to propylene glycol penetration. Watkinson et al. (2009b) evaluated the effects of PG using infinite doses of PG and PG/water formulations in human skin in vitro. The permeation of ibuprofen from saturated propylene glycol–water mixtures increased with increasing volume fraction of propylene glycol. An analysis of the kinetic and thermodynamic parameters for experiments conducted on skin confirmed that the influence of PG in the simple PG/water systems was primarily on the solubility and partitioning behaviour of ibuprofen. As for the alcohols, the short residence time of PG in the skin will have a critical impact on its efficacy as a CPE for topical preparations. Once PG is cleared from the skin the possibility of stranding the drug in the SC and consequent drug crystallisation must be considered (Santos et al., 2011). Although the literature does not address mechanisms of action of 1,2-butylene glycol, 1,3-butylene glycol and dipropylene glycol it seems likely that their excellent co-solvent properties and skin uptake are also key to their application as CPEs. 4.5. Glycol ethers – Transcutol® Similarly to PG, Transcutol® , a monoethyl ether of diethylene glycol, is also reported to increase the solubility of drugs in the skin. Harrison et al. (1996) investigated the effects of Transcutol® on the diffusivity and solubility of a model permeant (4-cyanophenol) in human stratum corneum in vitro using Attenuated total reflectance Fourier transform infra-red (ATR-FTIR) spectroscopy. The data were also compared to the effects of the enhancers on flux as measured using Franz diffusion cells. A saturated solution of cyanophenol in Transcutol® /water was evaluated at a dose of 0.5 ml/cm2 . The ATR-FTIR data indicated that the enhancement of cyanophenol occurred as a result of changes in solubility rather than diffusion in the membrane. Although there are many reports in the literature demonstrating the ability of this molecule to enhance penetration, further mechanistic studies are required to elucidate its exact interaction with skin components. 4.6. Fatty acids Oleic acid is believed to act by increasing diffusivity of skin permeants because of a disordering effect on skin lipids. Using spectrometric and calorimetric measurements, Golden et al. (1987) demonstrated increased lipid fluidity in porcine skin after treatment of the stratum corneum with oleic acid; increased lipid fluidity was also associated with enhanced permeant flux. These workers also noted that only the cis form of oleic acid is effective as a penetration enhancer and the site of unsaturation in the molecule is also critical for its activity as a CPE. Ongpipattanakul

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M.E. Lane / International Journal of Pharmaceutics 447 (2013) 12–21

et al. (1991) demonstrated evidence that oleic acid exists as a separate phase within the lipid domains of porcine SC and suggested that the mechanism of enhancement of OA was mediated by the formation of permeable defects within the SC lipids. This probably results from the conformation of the cis double bond which favours oleic acid to condense with itself rather than distribute homogeneously in the skin lipids. This contrasts with Azone which does not have the cis double bond and which does distribute homogeneously (Harrison et al., 1996). This hypothesis was later confirmed in man by Naik et al. (1995) by ATR-FTIR measurements on human volunteers treated with per-deuterated oleic acid. Although both lauric and capric acid have been studied extensively (Aungst et al., 1990; Artusi et al., 2004) with demonstrable penetration enhancement effects, data are lacking on precisely how they achieve modulation of the skin barrier function. 4.7. Pyrrolidones 2-Pyrrolidone, N-methyl-2-pyrrolidone (NMP) and various pyrrolidone derivatives have been examined for their potential to enhance drug permeation in skin (Southwell and Barry, 1983; Franz, 1983; Rachakonda et al., 2008; Godavarthy et al., 2009). Both 2-pyrrolidone and NMP are used as solvents which may contribute to their penetration-enhancement properties. However, skin toxicity to NMP has been reported which suggests these compounds may not be promising for further development as penetration enhancers (Jungbauer et al., 2001). 4.8. Sulphoxides Dimethyl sulphoxide has been reported extensively in the literature as a co-solvent and penetration enhancer (Maibach and Feldmann, 1967; Coldman et al., 1971; Klamerus and Lee, 1992; Remane et al., 2006; Roth and Fuller, 2011). Stoughton (1965) demonstrated the induction of a “reservoir” of hydrocortisone or fluocinolone acetonide in vivo in humans when the drugs were applied in a 40% DMSO:60% ethanol vehicle under finite dose conditions. In addition to its co-solvent properties, a range of other mechanisms have been suggested for the skin penetration enhancement properties exhibited by DMSO including displacement of bound water from keratin (Rammler and Zaffaroni, 1967), extraction of skin lipids (Allenby et al., 1969), changes in keratin conformation and/or interaction with lipid alkyl chains in the SC (Anigbogu et al., 1995). Because of the relatively high amounts of DMSO which appear to be needed for penetration enhancement and associated issues of irritation and production of a malodourous metabolite in the breath this compound has had very limited use in commercial topical products. Recent work using molecular simulations has suggested that DMSO must be present in high concentrations in skin in order be efficacious as a CPE (Notman et al., 2008). Decyl methyl sulphoxide has also been investigated as a skin penetration enhancer but insight into its mechanism of action is lacking. 4.9. Surfactants Any application of surfactants in formulations must take account of the ability of these molecules to form micelles, solubilise the active and effectively lower its thermodynamic activity and ultimately its skin permeation. 4.9.1. Anionic surfactants Irritation and damage to the skin barrier is associated with sodium lauryl sulphate (van der Valk et al., 1985; Törmä et al., 2008). The likely causes for these observations are reported to be due to the interaction of SLS with lipids and keratin in the skin

(Robbins and Fernee, 1983; Dominguez et al., 1977) and effects on epidermal differentiation and desquamation (Denda, 2001; Ghosh and Blankschtein, 2007). 4.9.2. Cationic surfactants Kushla and Zatz (1991) investigated a range of cationic surfactants for their ability to act as CPEs for lidocaine. Maximum enhancement effects were seen at alkyl chain lengths of 12 or 14 carbon atoms. However, these compounds were not evaluated in vivo. As a number of cationic surfactants are reported to be skin irritants including benzalkonium chloride (Basketter et al., 2004) and cetylpyridinium chloride (Lin and Hemming, 1996) these compounds are not promising as candidates for topical and transdermal penetration enhancement. 4.9.3. Non-ionic surfactants Non-ionic surfactants are generally considered to be less irritating than ionic surfactants. The most extensively investigated compounds include the polyoxyethylene alkly ether (Brij) and polyoxyethylene sorbitan fatty acid ester (Tween) series. Unfortunately, most of the publications which have examined the skin penetration properties of these compounds report effects on rodent or murine skin rather than human skin. Ashton et al. (1986) investigated the influence of Brij 36T on time of erythema induced by nicotinates when formulated as simple gels. DSC studies indicated that the surfactant interacted with skin to destructure lipids and thus increase permeability; however the ability of the surfactant to influence skin permeation was dependent on the physicochemical properties of the permeant. Ryan and Mezei (1975) observed that the application of a preparation consisting of 10% Tween 85 in petrolatum to the forearm of human subjects appeared to increase epidermal permeability as reflected by increased water loss. 4.10. Terpenes The application of monoterpenes and sesquiterpenes in topical and transdermal drug delivery has been investigated extensively by Barry and co-workers (Williams and Barry, 1991; Cornwell and Barry, 1994; Yamane et al., 1995). Although these workers observed increased drug permeation for certain compounds compared with controls, terpenes have not emerged as promising penetration enhancers. This may be because of the relatively high amounts of these compounds investigated in the in vitro skin permeation studies conducted in these early reports; typically >100 ␮l of the neat monoterpene, sesquiterpene or final formulation was applied to an effective diffusional area of ∼0.13 cm2 . Even for menthol, the available literature does not provide substantial evidence that it is capable of enhancing topical or transdermal drug delivery in humans. 5. Penetration enhancers in commercial formulations and the Diffusion-Partition-Solubility (DPS) theory Tables 3 and 4 provide examples of penetration enhancers used in topical and transdermal preparations currently available on the market in the UK and USA. Clearly, the nature and purpose of the formulation will influence the selection of the enhancer. Topical formulations are intended for local action and target the drug to the outer layers of the skin whereas the objective of a transdermal formulation is to deliver the drug to the systemic circulation. Sprays and gels are more dynamic and less occlusive than patches, and penetration enhancers in the former will be expected to have a shorter contact time with the skin compared with the latter. It will be evident that the number and chemical diversity of enhancers employed in transdermal products is far greater than for topical formulations.

M.E. Lane / International Journal of Pharmaceutics 447 (2013) 12–21 Table 3 Examples of penetration enhancers used in commercial topical products.

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Table 4 Examples of penetration enhancers used in commercial transdermal products.

Active

Trade name

Enhancer

Active

Patch trade name

Enhancer

Adapalene Capsaicin Dapsone Diclofenac Isopropyl alcohol Diclofenac

Differin Gel Qutenza Patch Aczone Gel Mobigel

Propylene glycol Diethylene glycol monoethyl ether Diethylene glycol monoethyl ether Ethanol

Buprenorphine Estradiol Estradiol

BuTrans Alora Divigel

Estradiol

Elestrin

Propylene glycol

Diclofenac

Voltarol Emulgel

Estradiol Estradiol

Elleste Solo MX Esclim

Diclofenac

Voltarol Gel Patch

Idoxuridine Ketoprofen Propylene glycol

Herpid Feldene Lidoderm

Dimethyl sulphoxide Ethanol Propylene glycol Isopropyl alcohol Propylene glycol 1,3-Butylene glycol Propylene glycol Dimethyl sulphoxide Ethanol Propylene glycol

Estradiol Estradiol Estradiol

Estraderm Estraderm MX Estradot

Estradiol Estradiol Estradiol Estradiol

Evamist Fematrix Oestrogel Progynova

Estradiol

Sandrena

Estradiol

Vivelle-Dot

Ethinyl estradiol, norelgestromin Fentanyl Fentanyl Nitroglycerin

Evra

Oleyl oleate Sorbitan monoleate Ethanol Propylene glycol Diethylene glycol monoethyl ether Ethanol Propylene glycol Diethyltoluamide Dipropylene glycol Octyl dodecanol Ethanol Isopropyl palmitate Dipropylene glycol Oleyl alcohol Ethanol Octyl salicylate Diethyltoluamide Ethanol Ethyl oleate Glycerol monolaurate Isopropyl myristate Ethanol Propylene glycol Dipropylene glycol Oleyl alcohol Lauryl lactate

Oxybutynin

Anturol

Oxybutynin Testosterone

Kentera Androderm

Testosterone Testosterone

Androgel Axiron

Testosterone

Fortesta

Testosterone Testosterone

Intrinsa Testim

Testosterone Testosterone

Testoderm Testogel

Testosterone

Tostran

For transdermal patch delivery, there is a balance required between the partition coefficient of a drug and its inherent solubility and the patch provides an occlusive environment for the drug to move into the skin. In contrast for topical delivery using creams, gels, lotions and sprays the dose applied is not ‘infinite’ as the amount usually applied to the skin is ∼2 mg/cm2 . This is equivalent to a thickness of 20 ␮m, which is a volume which approximates that of the stratum corneum. This has implications for the role of solubility and partition as an ‘infinite dose’ is not applied. For such conditions, steady state diffusion is not obtained and the role of K and D in the formulation is no longer described by Eq. (4). As noted in earlier sections, the mechanism of action of a number of CPEs is linked to their ability to interact with skin lipids. Where this interaction allows the enhancer to increase drug solubility in the skin, knowledge of the drug solubility parameter may guide the selection of appropriate CPEs. However, the solubility parameter should not be considered in isolation for optimal formulation development. Recent work from our laboratory indicates that, for finite doses, the critical parameters for effective transdermal and topical delivery are (i) solubility of the active in the CPE and (ii) the residence time of the CPE in the skin (Santos et al., 2010; Lane et al., 2012b). We have also recently demonstrated the important effect of drug solubility in the vehicle on ultimate drug concentration in the skin in vivo (Lane et al., 2012b). Taken together with the available mechanistic data from the previous section a Diffusion-Partition-Solubility framework appears to best describe the mode of action of CPEs which are currently in use in topical and transdermal skin products (Fig. 5). Effects on diffusion through skin will be mediated by those compounds which intercalate with the lipid bilayers and disrupt them or fluidise them. Such effects will also be associated with those enhancers which are suggested to exist as discrete phases in the intercellular lipid domains (oleic acid and probably related compounds such as methyl oleate and sorbitan oleate). Improved partition of an active will be dictated by a more favourable environment for solubility. The latter will be mediated by those solvents which are well taken up into the skin and/or which are also

Cholesterol sulphate

Ceramide

Free fatty acid

Diffusion Lipidchain interaction or discrete phase formation

Partition & Solubility Lipid polar head groups

Fig. 5. Schematic of Diffusion-Partition-Solubility actions of skin penetration enhancers.

Fentalis Matrifen Minitran

Ethanol Dipropylene glycol Ethyl oleate Glyceryl monolaurate Diethylene glycol monoethyl ether Ethanol Propylene glycol Triacetin Ethanol Glycerol monoleate Methyl oleate Isopropyl myristate Octyl salicylate Ethanol Isopropyl alcohol Ethanol Oleic acid 2-Propanol Propylene glycol Sorbitan monooleate Ethanol Pentadecalactone Propylene glycol Ethanol Ethanol Isopropyl myristate Ethanol Isopropyl alcohol Oleic acid Propylene glycol

good solvents for the molecule of interest e.g. propylene glycol, Transcutol® . 6. Future developments The ideal skin penetration enhancer should be pharmacologically inert, non-toxic, non-irritating, non-allergenic and ideally should have a reversible action on the skin. In addition, the enhancer needs to be “matched” to the drug as if the permeation and/or skin residence time of the enhancer is very different from the drug it may not achieve effective permeation enhancement. In this respect, the solubility parameter is a useful starting point to identify CPEs for formulation design. As for the drug, the

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M.E. Lane / International Journal of Pharmaceutics 447 (2013) 12–21

penetration enhancer must be stable and aesthetically acceptable in the formulation. Finally, from a cost-of-goods aspect the enhancer should be relatively cheap and easy to source. But despite decades of investigation the number of penetration modifiers available to the formulation scientist which possess some or all of these desirable properties remains limited. Surprisingly little has been done to investigate the penetration rates and amounts of CPEs in the skin. A significant problem in the literature is the experimental design used to evaluate candidate CPEs. Human skin is the preferred membrane for evaluation and pre-formulation but porcine skin also appears to offer an acceptable surrogate for early developmental work. Finite dose conditions simulate better what is likely to occur in the clinical situation for creams, gels, lotions and sprays. However many studies have reported data for infinite dose conditions which will overestimate the likely utility of penetration enhancers when incorporated in such formulations. This is particularly the case where the residence time of the CPE in the skin may be short and crystallisation of the active is likely. Infinite dose studies may prove useful in the screening of enhancers for topical and transdermal patches but care still needs to be taken to ensure the actual dose applied is representative of the final formulation that the consumer or patient will use. Much scope remains for investigations into the actual mechanisms of many of the CPEs currently in use. The potential for synergistic enhancement arising from combining enhancers is also poorly understood. The distribution of the penetration enhancer after application to the skin should also be monitored where possible. Advances in analytical techniques should facilitate this and the application of Confocal Raman spectroscopy is beginning to provide some answers on how the role of the excipients and CPE is linked to the active. Although there is also scope to design new CPEs, the regulatory requirements associated with approval of such compounds are likely to be onerous. A further consideration is the fact that penetration enhancers exert their effects by being incorporated into the skin and changing the skin barrier function. Thus, irritation is a possible consequence of their action and in vitro studies are in no way predictive of the likely irritation of a formulation in use. Acknowledgement The author is grateful to Dr. G. Oliveira for expert technical assistance. References Albery, W.J., Hadgraft, J., 1979. Percutaneous absorption: in vivo experiments. J. Pharm. Pharmacol. 31, 140–147. Allenby, A.C., Fletcher, J., Schock, C., Tees, T.E.S., 1969. The effect of heat, pH and organic solvents on the electrical impedance and permeability of excised human skin. Br. J. Dermatol. 81 (Suppl. 4), 31–39. Andega, S., Kanikkannan, N., Singh, M., 2001. Comparison of the effect of fatty alcohols on the permeation of melatonin between porcine and human skin. J. Control. Release 77, 17–25. Anigbogu, A.N.C., Williams, A.C., Barry, B.W., Edwards, H.G.M., 1995. Fourier transform Raman spectroscopy of interactions between the penetration enhancer dimethyl sulfoxide and human stratum corneum. Int. J. Pharm. 125, 265–282. Artusi, M., Nicoli, S., Colombo, P., Bettini, R., Sacchi, A., Santi, P., 2004. Effect of chemical enhancers and iontophoresis on thiocolchicoside permeation across rabbit and human skin in vitro. J. Pharm. Sci. 93, 2431–2438. Ashton, P., Hadgraft, J., Stevens, J., 1986. Some effects of a non-ionic surfactant on topical availability. J. Pharm. Pharmacol. 38, 70. Aungst, B.J., Blake, J.A., Hussain, M.A., 1990. Contributions of drug solubilization, partitioning, barrier disruption, and solvent permeation to the enhancement of skin permeation of various compounds with fatty acids and amines. Pharm. Res. 7, 712–718. Barrett, C.W., Hadgraft, J.W., Caron, G.A., Sarkany, I., 1965. The effect of particle size on the percutaneous absorption of fluocinolone acetonide. Br. J. Dermatol. 77, 576–578. Basketter, D.A., Marriott, M., Gilmour, N.J., White, I.R., 2004. Strong irritants masquerading as skin allergens: the case of benzalkonium chloride. Contact Dermatitis 50, 213–217.

Berner, B., Mazzenga, G.C., Otte, J.H., Steffens, R.J., Juang, R.H., Ebert, C.D., 1989a. Ethanol:water mutually enhanced transdermal therapeutic system II: skin permeation of ethanol and nitroglycerin. J. Pharm. Sci. 78, 402–407. Berner, B., Juang, R.H., Mazzenga, G.C., 1989b. Ethanol and water sorption into stratum corneum and model systems. J. Pharm. Sci. 78, 472–476. Boddé, H.E., Kruithof, M.A., Brussee, J., Koerten, H.K., 1989. Visualisation of normal and enhanced HgCl2 transport through human skin in vitro. Int. J. Pharm. 53, 13–24. Bommannan, D., Potts, R.O., Guy, R.H., 1991. Examination of the effect of ethanol on human stratum corneum in vivo using infrared spectroscopy. J. Control. Release 16, 299–304. Bonnist, E.Y., Gorce, J.P., Mackay, C., Pendlington, R.U., Pudney, P.D., 2011. Measuring the penetration of a skin sensitizer and its delivery vehicles simultaneously with confocal Raman spectroscopy. Skin Pharmacol. Physiol. 24, 274–283. 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Coldman, M.F., Poulsen, B.J., Higuchi, T., 1969. Enhancement of percutaneous absorption by the use of volatile: nonvolatile systems as vehicles. J. Pharm. Sci. 58, 1098–1102. Coldman, M.F., Kalinovsky, T., Poulsen, B.J., 1971. The in vitro penetration of fluocinonide through human skin from different volumes of DMSO. Br. J. Dermatol. 85, 457–461. Cornwell, P.A., Barry, B.W., 1994. Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil. J. Pharm. Pharmacol. 46, 261–269. Crank, J., 1975. The diffusion equations. In: Crank, J. (Ed.), The Mathematics of Diffusion. , 2nd ed. Clareadon Press, Oxford, pp. 1–10. Degim, T., Uslu, A., Hadgraft, J., Atay, T., Akay, C., Cevheroglu, S., 1999. The effects of Azone and capsaicin on the permeation of naproxen through human skin. Int. J. Pharm. 179, 21–25. Denda, M., 2001. Epidermal proliferative response induced by sodium dodecyl sulphate varies with environmental humidity. Br. J. Dermatol. 145, 252–257. Dias, M., Naik, A., Guy, R.H., Hadgraft, J., Lane, M.E.M.E., 2008. In vivo infrared spectroscopy studies of alkanol effects on human skin. Eur. J. Pharm. Biopharm. 69, 1171–1175. Dominguez, J.G., Parra, J.L., Infante, M.R., Pelegero, C.M., Balaguer, F., Sastre, T., 1977. A new approach to the theory of adsorption and permeability of surfactants on keratinic proteins: the specific behaviour of certain Hydrophobie chains. J. Soc. Cosmet. Chem. 28, 165–182. Edwards, D.A., Prausnitz, M.R., Langer, R., Weaver, J.C., 1995. Analysis of enhanced transdermal transport by skin electroporation. J. Control. Release 34, 211–221. Engblom, J., Engström, S., Jönsson, B., 1998. Phase coexistence in cholesterol-fatty acid mixtures and the effect of the penetration enhancer Azone. J. Control. Release 52:, 271–280. Franz, T.J., 1983. On the bioavailability of topical formulations of clindamycin hydrochloride. J. Am. Acad. Dermatol. 9, 66–73. Friend, D.R., 1991. 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