`ELSEVIER
`
`International Journal of Pharmaceutics 184 (1999) 1-6
`
`
`
`international
`journal of
`pharmaceutics
`
`Mini review
`
`Passive enhancementstrategies in topical and transdermal
`drug delivery”
`
`Jonathan Hadgraft
`
`The Welsh School of Pharmacy, Cardiff University, King Edward VH Avenue, Cardiff CF10 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 topical bioavailability it
`employ enhancementstrategies. Optimization of the applied formulation can improverelease 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 twodistinct 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 ofsolvent 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; 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 1967, Feldmann and Maibach (1967) assessed
`
`:
`=
`.ac.uk (J. Hadgraft)
`E-mail address: hadgraft@cardi
`:
`e
`ee
`Based on a lecture given at a meeting of UKaps on 11th
`December 1998, London, on Current Regulatory Issues in
`Pharmaceutical Excipients.
`
`the bioavailability of hydrocortisone alcoholto be
`1.7%. Since then there has been a renewedinterest
`in using enhancementstrategies 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
`:
`:
`.
`:
`compromises will have to be made with appropri-
`2
`-
`:
`ate benefit to risk calculations. Water is perhaps
`the ideal enhancer, since hydrated skin is gener-
`
`0378-5173/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved.
`Noven Pharmaceuticals, Inc.
`PIT: $0378-5173(99)00095-2
`EX2005
`0001=Mylan Tech., Inc. v. Noven Pharma., Inc.
`IPR2018-00173
`
`
`
`2
`
`J. Hadgraft / International Journal of Pharmaceutics 184 (1999) 1-6
`
`Solvent
`
` modulators
`
`
`Chemical
`potential of
`drug
`
`ally more permeable (Roberts and Walker, 1993).
`However, it is not applicable to all permeants.
`PADDAAAM
`
`
`Considering an idealized representation of the
`REAR
`
`
`ODDSRROARA RR RABALLPAAA
`skin there are several different strategies that can
`
`
`SSSSESSERRRRREPREPLREA
`
`PONS RRRRRARERREDD
`
`
`
`be adopted to optimize dermaldelivery. These are
`OSSSOSSAAT RARRAARAARA
`
`RAAAAAAAAAAY) CRARRARADILA
`depicted in Fig. 1.
`SY, We
`
`
`Biochemical
`Vasoactive
`drugs
`
`
`
`
`Solvent
`effects
`
`
`
`
`
`
`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 70s.
`An excellent review article by Katz and Poulsen
`(1971)
`should
`be
`referred
`to
`for
`further
`information.
`The rate of delivery to the skin surface can be
`important, particularly in the case of transdermal
`systems. Whererate 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 alwaysresults 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 |
`Ideal characteristics of dermal permeation enhancers
`
`Pharmacologically inert
`Nontoxic
`Immediate in action
`Reversible in action
`Chemically and physically compatible
`Cosmetically acceptable
`
`0002
`
`1. 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 changesin 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., 1997). This
`is importantsince 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
`whenthe lipids are modified in this way, although
`the effect has been shown to be reversible. Some
`topical and transdermal products contain high
`
`
`
`J. Hadgraft / International Journal of Pharmaceutics 184 (1999) 1-6
`
`3
`
`that
`concentrations of solvents such as ethanol
`may be capable of altering the lipid content of the
`skin (Bommannanetal., 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 Ist
`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 (Gayet 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
`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 (Ci) to Cys
`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 (Ongpipattanakulet 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.
`
`HO
`
`HO.
`
`SS
`
`NH
`
`oO
`
`OH
`
`oO
`
`OH
`
`oO
`
`NH
`
`HO
`
`HO
`
`CH
`
`NNNNNN
`
`CH3
`
`CHg
`
`CH,
`
`Fig. 2. A diagrammatic representation of the interaction between Azone” and ceramides.
`
`0003
`
`
`
`NS
`
`H,C
`
`
`
`oO
`
`CHy
`
`CHWedi
`
`Oo
`
`weroLO:
`
`oO
`
`NH
`
`J. Hadgraft / International Journal of Pharmaceutics 184 (1999) 1-6
`
`
`
`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 ofthis 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 wayin 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,
`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 (0) 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 aneffect
`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, Watkinsonet al., 1991). The effect is
`also possible when supersaturation is combined
`with a ‘lipid fluidizer’, e.g. for flurbiprofen (in-
`creased degree of saturation plusoleic acid, Pellett
`et al., 1997).
`to distinguish between the
`It
`is often difficult
`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 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
`enhancers. Considering transdermal patches there
`are systems in which ethanol is present at high
`
`0004
`
`
`
`J. Hadgraft / International Journal of Pharmaceutics 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
`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 al., 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 (Ceveet al., 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.
`
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`
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`the most natural
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`0006
`
`