`
`.,
`
`rel
`ELS EVI E
`
`
`
`international
`journal of
`pharmaceutlcs
`| —6 =
`
`International Journal of Pharmaceutics 184 {1999)
`
`Mini review
`
`Passive enhancement strategies in topical and transdermal
`drug delivery’i"
`
`Jonathan Hadgraft
`
`The Welsh Selma! ofPl'iarmrrcr. Cardiff University. King Edward VII Arcane. Cardiff CFIO 3XF. UK
`
`Received 22 January 1999: accepted 26 February 1999
`
`
`
`Abstract
`
`is usually necessary to
`The skin has an extremely good barrier function and to improve t0pica1 bioavailability it
`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.
`
`Kellni-‘ords: Skin penetration; Enhancers; Transdermal 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 (1967) assessed
`
`‘
`_
`—
`.ac.uk {.1. Hadgratt)
`E-mnd address: hadgraft@cardl
`.
`.
`.
`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 hydroeortisonc alcohol to be
`1.75%. 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 w111 have to be made w1th appropri-
`_
`_
`_
`ate benefit to “Sk calcmallons- Water 15 perhaps
`the ideal enhancer, since hydrated skin is gener—
`
`0378-5173_.-"99,-'$ - see front matter © 1999 Elsevier Science B.V. All rights reserved.
`pn: 80378-5] 73(99)00095-2
`
`Noven Pharmaceuticals, Inc.
`EX2005
`0001 Mylan Tech., Inc. v. Noven Pharma, Inc.
`1PR2018—00173
`
`
`
`2
`
`J. Hridgrtgfi_:1nrcrnafhmrd Journal of Phw‘nmc'twrim 1'84 U999) 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.
`l.
`
`2. Formulation effects
`
`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
`
`should
`(l9?l)
`information.
`
`be
`
`referred
`
`to
`
`for
`
`further
`
`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
`
`I.....'.‘.\
`
`
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`
`_____ mamas
`Biochemical
`Vasoactlve
`Chemical
`
`
`
`modulators
`
`drugs
`
`potential of
`
`
`drug
`
`
`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
`tested. This is to be expected provided the solvent
`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
`
`0002
`
`
`
`J. Hridgrqfihim-national? Jom‘imf of Phammc'rwrim 184 (1999) 1—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 intercalate 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 et al., 1986;
`Barry et al., 1992), and fluorescence spectroscopy
`(Garrison et al., 1994).
`
`on
`relationships
`activity
`structure
`Recent
`rfllaone‘La 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 CI4
`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).
`Oleic acid also acts by disrupting the skin lipids
`but appears to form pools in the lipids rather than
`distribute homogeneously (Ongpipattanakul et 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
`
`OH:
`
`CH3
`
`NWCHS
`
`CH3
`
`HO
`
`HO
`
`\
`
`NH
`
`0
`
`OH
`
`O O
`
`H
`
`0
`
`NH
`
`HO
`
`HO
`
`Fig. 2. A diagrammatic representation of the interaction between Azone'w and ceramides.
`
`0003
`
`
`
`J. Hmfgrqfi lmernafirmaf JtJIH'i'ItJ'f of Phummc'wnim [84 (£999) l —6
`
`
`
`Fig. 3. Structures of commercial skin penetration enhancers. from top, of SEPA 009 (ex Macrochem); Neert 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 excipients 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
`molecules,
`such as propylene glycol, ethanol,
`Transcutolf“,
`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 (6) 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-
`hanced permeability if skin is pretreated with
`propylene glycol (Wotton et al., 1985).
`
`is interesting to note that Fick’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
`
`Transcutol, Watkinson et al., 1991). 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., 1997).
`
`It
`
`is often difficult
`
`to distinguish between the
`
`effects on D and solubility, however, a recent
`technique involving ATR-FTIR 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 Transeutol having a similar
`effect on solubility in the stratum corneum (Har-
`
`rison et al., 1996).
`A number of formulation exeipients have been
`
`incorporated into topical and transdermal systems
`that may be anticipated to act as permeation
`enhancers. Considering transdermal patches there
`are systems in which ethanol is present at high
`
`0004
`
`
`
`J. Hridgrrgfi_:'hircrriarfrmaf Journal of Phammc'wrrics 1'84 (1999) 1—6
`
`5
`
`concentrations. Other solvents include: propylene
`glycol.
`1,3 butylene glycol. dipropylene glycol.
`Long alkyl chain (plus polar head group) exeipi-
`ents include isopropyl palmitate (and myristate),
`glyceryl mono-laurate (and oleate), methyl
`lau-
`rate, oleic acid.
`
`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 a1., 1996). It is
`unclear how regulatory authorities will react
`to
`this
`biochemical
`approach
`to
`permeability
`modulation.
`
`5. Blood supply
`
`Vasoactive 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 complexation 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 (Cevc et a1., 1998). 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. KL. 1995. Liposome-medialed
`gene-transfer and expression via the skin. Human Melee.
`Genet. 4. 2279—2285.
`I992.
`Barry, B.W.. Edwards. H.G.M., Williams. A.C.,
`Fourier-transform Raman and infrared vibrational study
`of human skin-assignment of spectral bands. J. Raman
`Spect. 23. 641—645.
`Bomrnannan. D., Potts. 12.0., Guy. R.H.. 1991. Examination
`of the effect of ethanol on human stratum corneum in vivo
`
`using infra red spectroscopy. .1. Control. Rel. 16. 299—304.
`Bouwstra. 1A., Peschier, L..I.C.. Brussee,
`.l.. Bodde, 1-1.E.,
`1989. Effect of N-alkyl-azoeyeloheptan-E-ones including
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`K.A., Watkinson, A.C., 1993. In vitro assessment of skin
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`Cornwell, P.A.. Barry. B.W., Bouwstra.
`.1.A.. Gooris. G.S..
`I996. Modes of action of terpene penetration enhancers in
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`Liron, 2., Cohen, S., 1984. Percutaneous absorption of alka-
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`the most natural
`Roberts, M.R.. Walker. M.. 1993. Water:
`penetration enhancer.
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`
`Wotton, P.K., Mollgaard. B.. Hadgraft. J., Hoelgaard, A.,
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`
`0006
`
`