It
`
`- \
`ELS EVlER
`
`international
`journal of
`pharmaceutles
`International Journal of Pharmaceutics 184 (1999) 1—6 =
`
`
`
`Mini review
`
`Passive enhancement strategies in topical and transdermal
`drug delivery‘i"
`
`Jonathan Hadgraft
`
`The Welsh School' of Pharmacy. Cardiff University. King Edward VII Aware. Cordifl' CF10 3XF. UK
`
`Received 22 January 1999; accepted 26 February 1999
`
`
`
`Abstract
`
`The skin has an extremely good barrier function and to improve tepieal bioavailability it is usually necessary to
`employ enhancement strategies. Optimization of the applied formulation can improve release to the skin and the use
`of supersaturation achieves this objective. However, supersaturated states are inherently unstable. High solvent
`concentrations in the formulation may remove skin lipids reducing the barrier function of the stratum corneum.
`Alternatively formulation components can diffuse into the barrier function where they can have two distinct effects.
`They may intercalate into the structured lipids of the bilayer, decreasing their diffusional resistance. Alternatively they
`can modify the solubility parameter of the skin lipids; the diffusing drug may then have an enhanced solubility in the
`skin. If the two effects can be combined Synergy is observed. Deeper permeation of solvent into the viable tissue may
`also result in increased drug concentrations in this layer of the epidermis. The viable layer is metabolically very active
`and perturbation of the enzyme systems responsible for the formation of the stratum corneum lipids can reduce the
`barrier function. Finally a diffusing drug will encounter the blood supply. If vasoactive drugs modulate the blood flow
`rate. absorption can be influenced. © 1999 Elsevier Science B.V. All rights reserved.
`
`Keywords: Skin penetration; Enhancers; Transdcrmal delivery
`
`1. Introduction
`
`Over the past decades there has been a general
`realization that the bioavailability of topically ap-
`
`plied drugs is very low. For example, as long ago
`as 196?, Feldmann and Maibach (196'?) assessed
`
`_
`—
`E-mar’l address: hadgraft@card1 .ac.uk (J. Hadgraft)
`.
`.
`Based on a lecture glven at a meetlng of UKaps on 11th
`December 1998, London, on Current Regulatory Issues in
`Pharmaceutical Excipients.
`
`the bioavailability of hydrocortisone alcohol to be
`1.?" 0. Since then there has been a renewed interest
`
`in using enhancement strategies with the general
`
`recognition that any chemical enhancer should
`possess certain characteristics. These are summa-
`rized in Table 1. It is unlikely that any enhancer
`will be found that has all of these properties and
`.
`.
`.
`.
`compromlses Will have to be made WIth approprl-
`.
`.
`,
`ate benefit to “5k calcmatlons- Water 15 perhaps
`the ideal enhancer, since hydrated skin is gener—
`
`OHS-5173,3995 - see front matter © 1999 Elsevier Science B.V. All rights reserved.
`pn: SO378-51?3(99)00095-2
`
`Noven Pharmaceuticals, Inc.
`EX2005
`0001 Mylan Tech., Inc. v. Noven Pharma., Inc.
`IPR2018—00‘l74
`
`

`

`2
`
`J. HadgrtgfiInternational Jam-rm! of Phai'rirm'emim 184 (I999) l —6
`
`ally more permeable (Roberts and Walker, 1993).
`
`However, it is not applicable to all permeants.
`Considering an idealized representation of the
`skin there are several different strategies that can
`be adopted to optimize dermal delivery. These are
`depicted in Fig. 1.
`
`2. Formulation effects
`
`Release from
`formulatlon
`
`Lipid
`fluidizallon
`
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`
`\‘fifififlfl-‘
`Biochemical
`Vasoactive
`
`modulators
`
`drugs
`
`
`Removal of
`lipids
`
`Chemical
`
`polenti al of
`
`drug
`
`The simple way in which the solubility and
`partition coefficient of the diffusing drug can im-
`pact on formulation strategies is often ignored but
`has been systematically studied in the 60s and 705.
`An excellent review article by Katz and Poulsen
`
`l. A schematic representation of the skin and the way
`Fig.
`various enhancement strategies can be envisaged.
`
`varied over two orders of magnitude. Despite this,
`the flux was the same for all 11 solvent systems
`
`be
`
`referred
`
`to
`
`for
`
`further
`
`tested. This is to be expected provided the solvent
`
`should
`(197'1)
`information.
`
`The rate of delivery to the skin surface can be
`
`important, particularly in the case of transdermal
`
`systems. Where rate control is required, the diffu-
`sion through the polymeric matrix of the delivery
`system should be significantly slower than that
`through the stratum corneum. In general, diffu-
`sion through topical preparations, after they have
`been rubbed into the skin, does not control the
`
`absorption process. It is a common misconception
`that an increase in the applied concentration of a
`drug always results in an increase of drug flux. If
`the drug is presented as a suspension, the flux will
`
`be invariant with applied concentration. The driv-
`
`ing force for diffusion through the skin is the
`
`chemical potential gradient. Twist and Zatz
`(1988) showed the significance of this in a diffu-
`sion study of parabens through a silicone mem-
`brane. The diffusant was presented to the
`membrane in a variety of solvents but in each of
`the solvents it was saturated. Due to the different
`
`solubilities
`
`in the
`
`solvents
`
`the concentration
`
`Table 1
`
`Ideal characteristics of dermal permeation enhancers
`
`Pharmacologically inert
`Non toxic
`Immediate in action
`Reversible in action
`
`Chemically and physically compatible
`Cosmetically acceptable
`
`0002
`
`does not alter the properties of the membrane.
`
`In order to improve absorption it is possible to
`use supersaturated solutions which have chemical
`potentials greater than that of a saturated solu-
`tion. They are, however, inherently unstable. It is
`
`possible that some changes in efficacy of transder-
`mal systems after storage is due to their being
`supersaturated at manufacture with subsequent
`crystallization on extended storage. Changes in
`delivery rates have been observed for transdermal
`patches when the expiry date has been exceeded
`(Brain et al., 1993). Stabilization of supersatu-
`rated topical preparations can be achieved over
`limited periods using anti-nucleant polymers (Pel-
`lett et al., 1994) and enhanced absorption through
`skin achieved. There appears to be an almost
`linear
`increase in drug flux with degree of
`supersaturation.
`In a further investigation, the absolute concen-
`trations found in the different strata of the skin
`
`were also in direct proportion to the degree of
`saturation of piroxicam (Pellett et al., 199?). This
`is important since it is the ratio of the concentra-
`tion of the drug at
`the site of action to that
`applied which needs to be as high as possible for
`optimal bioavailability.
`
`Some solvents can remove lipids from the stra-
`tum corneum. The barrier function is reduced
`
`when the lipids are modified in this way, although
`the effect has been shown to be reversible. Some
`
`topical and transdermal products contain high
`
`

`

`J. HadgrtgfiInmmaffomd Jam-mt! of Pharrnarcutim [84 (I999) l —6
`
`3
`
`concentrations of solvents such as ethanol
`
`that
`
`may be capable of altering the lipid content of the
`skin (Bommannan et al., 1991). Little systematic
`studies have been conducted on the effect of lipid
`extraction.
`
`3. Effects on the stratum corneum
`
`law of diffusion
`An inspection of Fick’s lst
`shows that two major effects can be obtained if a
`formulation excipient permeates into the stratum
`corneum. It may intercalatc into the structured
`lipids of the skin where it can disrupt the packing.
`The effect may render them more ‘fluid’ thereby
`increasing the diffusion coefficient of the perme-
`
`ant. This has been demonstrated using differential
`scanning calorimetry (DSC) and measuring the
`effect on phase transition temperature (Cornwell
`et al., 1996), ESR studies [Gay et al., 1989), FTIR
`(and Raman) investigations (Golden ct al., 1986;
`Barry et al., 1992), and fluorescence spectroscopy
`(Garrison ct al., 1994).
`
`on
`relationships
`activity
`structure
`Recent
`Azone® and its analogues (Hadgraft et al., 1996)
`have indicated that hydrogen bonding between
`
`the polar head group in Azone may be important
`
`and that it probably interacts in a manner de-
`picted in Fig. 2.
`typifies an
`The molecular characteristic that
`enhancer which disrupts the skin lipids is a polar
`head group with a long alkyl chain (Cm to C14
`appear optimal, Bouwstra et al., 1989). Com-
`pounds such as the non-ionic surfactants have
`such properties and Brij 36T has been shown to
`
`be an effective enhancer (Walters et al., 1988).
`
`Olcic acid also acts by disrupting the skin lipids
`but appears to form pools in the lipids rather than
`distribute homogeneously (Ongpipattanakul ct al.,
`1991).
`
`One of the problems of such structural features
`is that this type of molecule also tends to have
`irritant properties. When more is known about
`structure activity relationships for both enhance-
`ment and skin irritancy it should be possible to
`design molecules that have ideal properties.
`
`CH3
`
`CH3
`
`CH3
`
`NWCHS
`
`CH3
`
`HO
`
`Ho
`
`\
`
`NH
`
`0
`
`OH
`
`0 O
`
`H
`
`0
`
`NH
`
`Ho
`
`Ho /
`
`Fig. 2. A diagrammatic representation of the interaction between Azone‘“J and ceramides.
`
`0003
`
`

`

`4
`
`J. Hadgrtgfifinmmaffonaf Journal of Pharmaceutics [84 (I999) I —6
`
`
`
`Fig. 3. Structures of commercial skin penetration enhancers, from top, of SEPA 009 (ex Macrochem); NexAct 88 (ex NexMed} and
`SR38 (ex Pharmetrix). The 3D images were energy minimized using ACD software (Toronto, Canada).
`
`A number of commercial enhancers of this type
`have been developed and are depicted in Fig. 3.
`Structural
`similarities are obvious and it
`is
`
`thought that these compounds have minimal skin
`
`tOXiCity.
`
`It is possible that some structures with similar
`molecular features will stabilize the skin lipids,
`
`reducing permeability (Hadgraft et al., 1996).
`Such compounds would have utility in formula-
`tions where systemic absorption needs to be mini-
`
`mized, e.g. UV filters, insect repellents.
`The second way in which exeipients can modify
`skin permeability is to shift the solubility parame-
`ter of the skin in the direction of that of the
`
`permeant. The solubility of the permeant in the
`outer layers of the skin will be increased and this,
`
`in turn,
`
`improves the flux. Simple solvent
`
`type
`
`such as propylene glycol, ethanol,
`molecules,
`Transcutol®,
`and N—methyl
`pyrollidone
`are
`thought to act in this way. For example, it is well
`known that propylene glycol permeates the skin,
`it
`therefore must be distributed in the stratum
`
`corneum (Potts et al., 1991). The inherent solubil-
`ity parameter (5) of the skin lipids is thought to
`be about 10 (Liron and Cohen, 1984). The pres-
`ence of propylene glycol will
`increase
`this.
`Metronidazole (estimated 6 = 13.5) has an en-
`
`is interesting to note that Fiek’s laws of
`It
`diffusion show that if enhancement strategies in-
`clude both an effect on diffusion (D) and an effect
`on the solubility, a multiplicative result
`is ex-
`
`pected. Synergy between these approaches has
`
`been shown for numerous
`systems
`including
`metronidazole
`(Azone plus propylene glycol,
`Wotton et al., 1985), prostaglandin (Azone plus
`
`Transeutol, Watkinson et al., 199]). The effect is
`
`also possible when supersaturation is combined
`
`with a ‘lipid fluidizer’, e.g. for flurbiprofen (in-
`creased degree of saturation plus oleic acid, Pellett
`et al., 199?).
`
`It is often difficult to distinguish between the
`
`effects on D and solubility, however, a recent
`technique involving ATR-F'TIR has allowed the
`deconvolution of the effects of Azone and Tran-
`
`scutol on the skin.
`
`In this instance the model
`
`permeant was cyanophenol and the results indi-
`cated the two discrete mechanisms for the two
`
`different enhancer types with Azone improving D
`by a factor of 3 and Transcutol having a similar
`
`effect on solubility in the stratum corneum (Har-
`
`rison et al., 1996).
`A number of formulation excipients have been
`
`incorporated into topical and transdermal systems
`
`that may be anticipated to act as permeation
`
`hanced permeability if skin is pretreated with
`propylene glycol (Wotton et al., 1985).
`
`enhancers. Considering transdermal patches there
`are systems in which ethanol is present at high
`
`0004
`
`

`

`J. HadgrtgfiInmmaffomd Journal of Plimvuar'eutim 184 (1999) 1—6
`
`5
`
`concentrations. Other solvents include: propylene
`
`glycol, 1,3 butylene glycol, dipropylene glycol.
`Long alkyl chain (plus polar head group) excipi-
`
`ents include isopropyl palmitate (and myristate),
`
`glyceryl mono-laurate (and oleate), methyl
`rate, oleie acid.
`
`lau-
`
`4. Effects in the viable tissue
`
`For very lipophilic permeants there could be a
`problem of poor solubility in the aqueous envi-
`ronment of the viable tissue. The presence of
`solvents such as propylene glycol
`in this region
`could be advantageous for permeability. How-
`ever, there have been very few systematic studies
`to demonstrate the significance of solubility ef-
`fects in the deeper tissues of the skin. This region
`is biochemically very active and enzyme systems
`present are responsible for controlling the synthe-
`sis of the lipids that maintain the barrier function
`of the stratum corneum. Use of fatty acid and
`cholesterol synthesis inhibitors have been shown
`to enhance the permeability of murine skin. A
`combination of the two inhibitors appears to
`provide a synergistic effect (Tsai et al., 1996). It is
`
`unclear how regulatory authorities will react to
`
`biochemical
`this
`modulation.
`
`approach
`
`to
`
`permeability
`
`5. Blood supply
`
`Vasoactivc drugs will have an effect on the
`local removal of the permeant. However,
`it
`is
`generally thought that the process of elimination
`is efficient and that
`there is little that can be
`
`achieved in improving permeability using this
`mechanism. If vasoconstrictor drugs are used the
`removal rate will be impaired which may lead to
`
`enhanced local concentrations of the permeant in
`
`the viable epidermis and dermis.
`
`6. Miscellaneous
`
`There are reports that large molecular entities
`such as DNA can be absorbed into deeper layers
`
`of the skin using eomplexation with DOTAP. The
`resultant DNA lipid complex will have a size of
`several hundreds of nanometers and it is unclear
`
`what mechanism of penetration is involved. How-
`ever, gene expression in murine epidermis, dermis
`and hair follicles indicates that
`the complex is
`capable of penetration (Alexander and Akhurst,
`1995). Similar work in our laboratories has confi-
`
`rmed these findings. Similar sized entities (Trans-
`fersomes) have been reported to deliver insulin
`(and other large drugs) through rat and human
`skin in vivo (Ceve et al., 1993). In this instance it
`may be the hydration energy of the polar head
`groups of the highly deformable vesicles that is
`
`important.
`
`7. Conclusions
`
`The last decade has shown a huge growth in the
`application of sophisticated biophysical
`tech-
`niques to monitor skin permeability. The under-
`standing of the mechanisms of absorption and
`enhancement has improved and the different de-
`terminants at a molecular level are beginning to
`be understood. This knowledge can be used in the
`design
`of
`better
`dermal
`and
`transdermal
`medicines and associated permeation enhancers.
`
`With these it
`
`should be possible to achieve
`
`bioavailabilities comparable to those expected as
`the norm in oral drug delivery. With this possibil-
`ity developing safe and effective dermal and trans-
`dermal delivery systems
`should be far more
`successful.
`
`References
`
`Alexander, M.Y., Akhurst, R.J._. 1995. Liposome-mediated
`gene-transfer and expression via the skin. Human Molec.
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`1992.
`Barry. B.W., Edwards, H.G.M., Williams, A.C.,
`Fourier-transform Raman and infrared vibrational study
`of human skin-assignment of spectral bands.
`.1. Raman
`Speet. 23, 641—645.
`Bommannan, 13.. Potts, R.O., Guy, R.H., 1991. Examination
`of the effect of ethanol on human stratum corneum in vivo
`
`using infra red spectroscopy. J. Control. Rel. 16. 299—304.
`Bouwstra, J.A.. Peschier, L.J.C., Brussee, J., Bodde, H.E.,
`1989. Effect of N-a1kyl-azocycloheptan-Z-ones including
`
`0005
`
`

`

`6
`
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`
`thermal behavior of human stratum
`Azone on the
`corneum. Int. J. Pharm. 52, 4T—54.
`Brain, K.R., Hadgraft, J., James, V.J., Shah, V.P., Walters,
`K.A., Watkinson, A.C., I993. In vitro assessment of skin
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`Cevc. G., Gebauer. D., Stieber, J., Schatzlein, A., Blume, G.,
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`Int. J.
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`I.W.,
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`
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`M.L.,
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`
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`
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`
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`In: Walters, K.A., Hadgraft,
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`I. Effect of lipid synthesis in-
`hibitors. J. Pharm. Sci. 85, 643—648.
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`
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`
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`
`0006
`
`