Transdermal Drug Delivery: Penetration Enhancement Techniques
`
`Current Drug Delivery, 2005, 2, 23-33
`
`23
`
`Heather A.E. Benson*
`
`Western Australian Biomedical Research Institute, School of Pharmacy, Curtin University of Technology, GPO Box
`U1987, Perth, Western Australia 6845
`
`Abstract: There is considerable interest in the skin as a site of drug application both for local and systemic effect.
`However, the skin, in particular the stratum corneum, poses a formidable barrier to drug penetration thereby limiting
`topical and transdermal bioavailability. Skin penetration enhancement techniques have been developed to improve
`bioavailability and increase the range of drugs for which topical and transdermal delivery is a viable option. This review
`describes enhancement techniques based on drug/vehicle optimisation such as drug selection, prodrugs and ion-pairs,
`supersaturated drug solutions, eutectic systems, complexation, liposomes, vesicles and particles. Enhancement via
`modification of the stratum corneum by hydration, chemical enhancers acting on the structure of the stratum corneum
`lipids and keratin, partitioning and solubility effects are also discussed. The mechanism of action of penetration enhancers
`and retarders and their potential for clinical application is described.
`
`Keywords: Transdermal delivery, skin penetration, enhancer, retarder.
`
`INTRODUCTION
`Transdermal delivery of drugs through the skin to the
`systemic circulation provides a convenient
`route of
`administration
`for a variety of clinical
`indications.
`Transdermal delivery systems are currently available
`containing scopolamine (hyoscine) for motion sickness,
`clonidine and nitroglycerin for cardiovascular disease,
`fentanyl for chronic pain, nicotine to aid smoking cessation,
`oestradiol (alone or in combination with levonorgestrel or
`norethisterone) for hormone replacement and testosterone for
`hypogonadism. Despite the small number of drugs currently
`delivered via this route, it is estimated that worldwide market
`revenues for transdermal products are US$3B, shared
`between the USA at 56%, Europe at 32% and Japan at 7%.
`In a recent market report it was suggested that the growth
`rate for transdermal delivery systems will increase 12%
`annually through to 2007 [1]. Transdermal products for
`cardiovascular disease, Parkinson’s disease, Alzheimer’s
`disease, depression, anxiety, attention deficit hyperactivity
`disorder (ADHD), skin cancer, female sexual disfunction,
`post-menopausal bone loss, and urinary incontinence are at
`various stages of formulation and clinical development. The
`application of transdermal delivery to a wider range of drugs
`is limited due to the significant barrier to penetration across
`the skin which is associated primarily with the outermost
`stratum corneum layer of the epidermis. Consequently the
`daily dose of drug that can be delivered from a transdermal
`patch
`is 5-10 mg, effectively
`limiting
`this route of
`administration to potent drugs. Significant effort has been
`devoted
`to developing
`strategies
`to overcome
`the
`impermeability of intact human skin. These strategies
`include passive and active penetration enhancement and
`
`*Address correspondence to this author at the Western Australian
`Biomedical Research Institute, School of Pharmacy, Curtin University of
`Technology, GPO Box U1987, Perth, Western Australia 6845; Tel: +618
`9266 2338; Fax: +618 9266 2769; E-mail: h.benson@curtin.edu.au
`
`technologies to bypass the stratum corneum. This review
`describes the routes of penetration, how drug properties
`influence penetration and the techniques that have been used
`to enhance penetration across human skin. Physical
`enhancement
`technologies
`such
`as
`iontophoresis,
`electroporation, phonophoresis, microneedles and
`jet-
`injectors are reviewed in a separate article in this journal by
`Cross and Roberts [2] and in other recent review articles [3,
`4].
`
`DRUG DELIVERY ROUTES ACROSS HUMAN SKIN
`Drug molecules in contact with the skin surface can
`penetrate by three potential pathways: through the sweat
`ducts, via
`the hair
`follicles and sebaceous glands
`(collectively called the shunt or appendageal route), or
`directly across the stratum corneum (Fig. 1). The relative
`importance of the shunt or appendageal route versus
`transport across the stratum corneum has been debated by
`scientists over
`the years (eg. [5-7]) and
`is further
`complicated by the lack of a suitable experimental model to
`permit separation of the three pathways. In vitro experiments
`tend to involve the use of hydrated skin or epidermal
`membranes so that appendages are closed by the swelling
`associated with hydration. Scheuplein and colleagues [8, 9]
`proposed that a follicular shunt route was responsible for the
`presteady-state permeation of polar molecules and flux of
`large polar molecules or ions that have difficulty diffusing
`across the intact stratum corneum. However it is generally
`accepted that as the appendages comprise a fractional area
`for permeation of approximately 0.1%
`[10],
`their
`contribution to steady state flux of most drugs is minimal.
`This assumption has resulted in the majority of skin
`penetration enhancement
`techniques being focused on
`increasing transport across the stratum corneum rather than
`via the appendages. Exceptions are iontophoretic drug
`delivery which uses an electrical charge to drive molecules
`into the skin primarily via the shunt routes as they provide
`less electrical resistance, and vesicular delivery.
`
` 1567-2018/05 $50.00+.00
`
`© 2005 Bentham Science Publishers Ltd.
`
`MYLAN - EXHIBIT 1039
`
`

`

`24 Current Drug Delivery, 2005, Vol. 2, No. 1
`
`Heather A. E. Benson
`
`Fig. (1). Simplified representation of skin showing routes of penetration: 1. through the sweat ducts; 2. directly across the stratum corneum;
`3. via the hair follicles.
`
`Considerable research effort has been directed towards
`gaining a better understanding of the structure and barrier
`properties of the stratum corneum. A recent review by
`Menon provides a valuable resource [11]. The stratum
`corneum consists of 10-15 layers of corneocytes and varies
`in thickness from approximately 10-15 µm in the dry state to
`40 µm when hydrated [12-14]. It comprises a multi-layered
`“brick and mortar” like structure of keratin-rich corneocytes
`(bricks)
`in an
`intercellular matrix (mortar) composed
`primarily of
`long chain ceramides, free fatty acids,
`triglycerides, cholesterol, cholesterol sulfate and sterol/wax
`esters [15]. However it is important to view this model in the
`context that the corneocytes are not brick shaped but are
`polygonal, elongated and flat (0.2-1.5 µm thick, 34-46 µm in
`diameter). The intercellular lipid matrix is generated by
`keratinocytes in the mid to upper part of the stratum
`granulosum discharging their lamellar contents into the
`intercellular space. In the initial layers of the stratum
`corneum this extruded material rearranges to form broad
`intercellular lipid lamellae [16], which then associate into
`lipid bilayers [17, 18], with the hydrocarbon chains aligned
`and polar head groups dissolved in an aqueous layer (Fig. 2).
`As a result of the stratum corneum lipid composition, the
`lipid phase behaviour is different from that of other
`biological membranes. The hydrocarbon chains are arranged
`into regions of crystalline, lamellar gel and lamellar liquid
`crystal phases thereby creating various domains within the
`lipid bilayers [19]. The presence of intrinsic and extrinsic
`proteins, such as enzymes, may also affect the lamellar
`structure of the stratum corneum. Water is an essential
`component of the stratum corneum, which acts as a
`plasticizer to prevent cracking of the stratum corneum and is
`also involved in the generation of natural moisturizing factor
`(NMF), which helps to maintain suppleness.
`
`the physicochemical
`to understand how
`In order
`properties of the diffusing drug and vehicle influence
`permeation across the stratum corneum and thereby optimise
`delivery, it is essential to determine the predominant route of
`drug permeation within the stratum corneum. Traditionally it
`was thought that hydrophilic chemicals diffuse within the
`aqueous regions near the outer surface of intracellular keratin
`filaments
`(intracellular or
`transcellular
`route) whilst
`lipophilic chemicals diffuse through the lipid matrix between
`the filaments (intercellular route) [9] (see Fig. 2). However,
`this is an oversimplification of the situation as each route
`cannot be viewed in isolation. A molecule traversing via the
`transcellular route must partition into and diffuse through the
`keratinocyte, but in order to move to the next keratinocyte,
`the molecule must partition into and diffuse through the
`estimated 4-20 lipid lamellae between each keratinocyte.
`This series of partitioning into and diffusing across multiple
`hydrophilic and hydrophobic domains is unfavourable for
`most drugs. Consequently, based on more recent data (for
`example [16, 20-23])
`the
`intercellular route
`is now
`considered to be the major pathway for permeation of most
`drugs across the stratum corneum. As a result, the majority
`of techniques to optimise permeation of drugs across the skin
`are directed towards manipulation of solubility in the lipid
`domain or alteration of the ordered structure of this region
`(Fig. 3).
`
`PENETRATION ENHANCEMENT THROUGH OPTI-
`MISATION OF DRUG AND VEHICLE PROPERTIES
`
`Drug permeation across the stratum corneum obeys
`Fick’s first law (equation 1) where steady-state flux (J) is
`related to the diffusion coefficient (D) of the drug in the
`stratum corneum over a diffusional path length or membrane
`thickness (h), the partition coefficient (P) between the
`
`

`

`Transdermal Drug Delivery
`
`Current Drug Delivery, 2005, Vol. 2, No. 1 25
`
`Fig. (2). Diagrammatic representation of the stratum corneum and the intercellular and transcellular routes of penetration (adapted from [3]).
`
`Fig. (3). Techniques to optimise drug permeation across the skin.
`
`stratum corneum and the vehicle, and the applied drug
`concentration (C0) which is assumed to be constant:
`
`and partition coefficient of a drug on diffusion across the
`stratum corneum has been extensively studied and an
`excellent review of the work was published by Katz and
`Poulsen [24]. Molecules showing intermediate partition
`coefficients (log Poctanol/water of 1-3) have adequate solubility
`within the lipid domains of the stratum corneum to permit
`diffusion through this domain whilst still having sufficient
`hydrophilic nature to allow partitioning into the viable
`tissues of
`the epidermis. For example a parabolic
`
`=
`
`J
`
`PDC
`dm
`0
`dt
`h
`Equation 1 aids in identifying the ideal parameters for
`drug diffusion across the skin. The influence of solubility
`
`=
`
` (1)
`
`

`

`26 Current Drug Delivery, 2005, Vol. 2, No. 1
`
`relationship was obtained between skin permeability and
`partition coefficient for a series of salicylates and non-
`steroidal anti-inflammatory drugs [25]. The maximum
`permeability measurement being attained at log P value 2.5,
`which is typical of these types of experiments. Optimal
`permeability has been shown to be related to low molecular
`size [7] (ideally less than 500 Da [26]) as this affects
`diffusion coefficient, and low melting point which is related
`to
`solubility. When a drug possesses
`these
`ideal
`characteristics (as in the case of nicotine and nitroglycerin),
`transdermal delivery is feasible. However, where a drug does
`not possess ideal physicochemical properties, manipulation
`of the drug or vehicle to enhance diffusion, becomes
`necessary. The approaches that have been investigated are
`summarised in (Fig. 3) and discussed below.
`
`1. Prodrugs and Ion-Pairs
`
`The prodrug approach has been investigated to enhance
`dermal and transdermal delivery of drugs with unfavourable
`partition coefficients [27, 28]. The prodrug design strategy
`generally involves addition of a promoiety to increase
`partition coefficient and hence solubility and transport of the
`parent drug in the stratum corneum. Upon reaching the
`viable epidermis, esterases release the parent drug by
`hydrolysis thereby optimising solubility in the aqueous
`epidermis. The intrinsic poor permeability of the very polar
`6-mercaptopurine was increased up to 240 times using S6-
`acyloxymethyl and 9-dialkylaminomethyl promoieties [29]
`and that of 5-fluorouracil, a polar drug with reasonable skin
`permeability was increased up to 25 times by forming N-acyl
`derivatives [30-34]. The prodrug approach has also been
`investigated for increasing skin permeability of non-steroidal
`anti-inflammatory
`drugs
`[35-39],
`naltrexone
`[40],
`nalbuphine [41, 42], buprenorphine [43, 44], b -blockers [45]
`and other drugs
`[27]. Well established commercial
`preparations using this approach include steroid esters (e.g.
`betamethasone-17-valerate), which provide greater topical
`anti-inflammatory activity than the parent steroids.
`Charged drug molecules do not readily partition into or
`permeate through human skin. Formation of lipophilic ion-
`pairs has been investigated to increase stratum corneum
`penetration of charged species. This strategy involves adding
`an oppositely charged species to the charged drug, forming
`an ion-pair in which the charges are neutralised so that the
`complex can partition into and permeate through the stratum
`corneum. The ion-pair then dissociates in the aqueous viable
`epidermis releasing the parent charged drug which can
`diffuse within the epidermal and dermal tissues [46-48]. In
`general permeability increases of only two to three-fold have
`been obtained although Sarveiya et al. [49] recently reported
`a 16-fold increase in the steady-state flux of ibuprofen ion-
`pairs across a lipophilic membrane.
`
`2. Chemical Potential of Drug in Vehicle – Saturated and
`Supersaturated Solutions
`
`The maximum skin penetration rate is obtained when a
`drug is at its highest thermodynamic activity as is the case in
`a supersaturated solution. This can be demonstrated based on
`Equation 1 rewritten in terms of thermodynamic activities
`[50]:
`
`Heather A. E. Benson
`
` (2)
`
`=
`
`dm
`dt
`
`aD
`h
`
`Where a
` is the thermodynamic activity of the permeant
`in its vehicle and g is the effective activity coefficient in the
`membrane. This dependence on thermodynamic activity
`rather than concentration was elegantly demonstrated by
`Twist and Zatz [51]. The diffusion through a silicone
`membrane of saturated solutions of parabens in eleven
`different solvents was determined. Due to the different
`solubility of the parabens in the various solvents, the
`concentration varied over
`two orders of magnitude.
`However, paraben flux was the same from all solvents, as the
`thermodynamic activity remained constant because saturated
`conditions were maintained throughout the experiment.
`Supersaturated solutions can occur due to evaporation of
`solvent or by mixing of cosolvents. Clinically, the most
`common mechanism is evaporation of solvent from the
`warm skin surface which probably occurs in many topically
`applied formulations. In addition, if water is imbibed from
`the skin into the vehicle and acts as an antisolvent, the
`thermodynamic activity of the permeant would increase [52].
`Increases in drug flux of five- to ten-fold have been reported
`from supersaturated solutions of a number of drugs [52-58].
`These systems are inherently unstable and require the
`incorporation of antinucleating agents to improve stability.
`Magreb et al [59] reported that the flux of oestradiol from an
`18-times saturation system was increased 18-fold across
`human membrane but only 13-fold in silastic membrane.
`They suggested that the complex mixture of fatty acids,
`cholesterol, ceramides, etc. in the stratum corneum may
`provide an antinucleating effect thereby stabilizing the
`supersaturated system.
`
`3. Eutectic Systems
`As previously described, the melting point of a drug
`influences solubility and hence skin penetration. According
`to regular solution theory, the lower the melting point, the
`greater the solubility of a material in a given solvent,
`including skin lipids. The melting point of a drug delivery
`system can be lowered by formation of a eutectic mixture: a
`mixture of two components which, at a certain ratio, inhibit
`the crystalline process of each other, such that the melting
`point of the two components in the mixture is less than that
`of each component alone. EMLA cream, a formulation
`consisting of a eutectic mixture of lignocaine and prilocaine
`applied under an occlusive film, provides effective local
`anaesthesia for pain-free venepuncture and other procedures
`[60]. The 1:1 eutectic mixture (m.p. 18°C) is an oil which is
`formulated as an oil-in-water emulsion thereby maximizing
`the thermodynamic activity of the local anaesthetics. A
`number of eutectic systems containing a penetration
`enhancer as the second component have been reported, for
`example: ibuprofen with terpenes [61], menthol [62] and
`methyl nicotinate [63]; propranolol with fatty acids [64]; and
`lignocaine with menthol [65]. In all cases, the melting point
`of the drug was depressed to around or below skin
`temperature thereby enhancing drug solubility. However, it
`is also likely that the interaction of the penetration enhancer
`with stratum corneum lipids also contributed to the increased
`drug flux.
`
`g
`

`

`Transdermal Drug Delivery
`
`4. Complexes
`
`Complexation of drugs with cyclodextrins has been used
`to enhance aqueous
`solubility and drug
`stability.
`Cyclodextrins of pharmaceutical relevance contain 6, 7 or 8
`dextrose molecules (a -, b -, g -cyclodextrin) bound in a 1,4-
`configuration to form rings of various diameters. The ring
`has a hydrophilic exterior and lipophilic core in which
`appropriately sized organic molecules can form non-covalent
`inclusion complexes resulting in increased aqueous solubility
`and chemical stability [66]. Derivatives of b -cyclodextrin
`increased water solubility (e.g. hydroxypropyl-b -
`with
`cyclodextrin HP-b -CD) are most commonly used
`in
`pharmaceutical formulation. Cyclodextrin complexes have
`been shown to increase the stability, wettability and
`dissolution of the lipophilic insect repellent N,N-diethyl-m-
`toluamide (DEET) [67] and the stability and photostability of
`sunscreens [68, 69]. Cyclodextrins are large molecules, with
`molecular weights greater than 1000 Da, therefore it would
`be expected that they would not readily permeate the skin.
`Complexation with cyclodextrins has been variously
`reported to both increase [70, 71] and decrease skin
`penetration [66, 72-74]. In a recent review of the available
`data, Loftsson and Masson concluded that the effect on skin
`penetration may be related to cyclodextrin concentration,
`with reduced flux generally observed at relatively high
`cyclodextrin concentrations, whilst
`low cyclodextrin
`concentrations resulting in increased flux [75]. As flux is
`proportional to the free drug concentration, where the
`cyclodextrin concentration is sufficient to complex only the
`drug which is in excess of its solubility, an increase in flux
`might be expected. However, at higher cyclodextrin
`concentrations, the excess cyclodextrin would be expected to
`complex free drug and hence reduce flux. Skin penetration
`enhancement has also been attributed to extraction of stratum
`corneum lipids by cyclodextrins [76]. Given that most
`experiments that have reported cyclodextrin mediated flux
`enhancement have used rodent model membranes in which
`lipid extraction is considerably easier than human skin [77],
`the penetration enhancement of cyclodextrin complexation
`may be an overestimate. Shaker and colleagues recently
`concluded that complexation with HP-b -CD had no effect on
`the flux of cortisone through hairless mouse skin by either of
`the proposed mechanisms [78]. This remains a controversial
`area.
`
`5. Liposomes and Vesicles
`
`There are many examples of cosmetic products in which
`the active ingredients are encapsulated in vesicles. These
`include humectants such as glycerol and urea, sunscreening
`and tanning agents, enzymes, etc. Although there are few
`commercial topical products containing encapsulated drugs,
`there is a considerable body of research in the topic. A
`variety of encapsulating systems have been evaluated
`including liposomes, deformable liposomes or transfer-
`somes, ethosomes and niosomes.
`Liposomes are colloidal particles formed as concentric
`biomolecular layers that are capable of encapsulating drugs.
`Their potential for delivering drugs to the skin was first
`reported by Mezei and Gulasekharam in 1980 who showed
`that the skin delivery of triamcinolone acetonide was four to
`
`Current Drug Delivery, 2005, Vol. 2, No. 1 27
`
`five times greater from a liposomal lotion than an ointment
`containing
`the
`same
`drug
`concentration
`[79].
`Phosphatidylcholine from soybean or egg yolk is the most
`common composition although many other potential
`ingredients have been evaluated [80]. Cholesterol added to
`the composition tends to stabilize the structure thereby
`generating more rigid liposomes. Recent studies have tended
`to be focused on delivery of macromolecules such as
`interferon [81], gene delivery [82] and cutaneous vaccination
`[83], in some cases combining the liposomal delivery system
`with other physical enhancement
`techniques such as
`electroporation [84]. Their delivery mechanism is reported to
`be associated with accumulation of the liposomes and
`associated drug in the stratum corneum and upper skin
`layers, with minimal drug penetrating to the deeper tissues
`and systemic circulation (eg. [79, 85-88]. The mechanism of
`enhanced drug uptake into the stratum corneum is unclear. It
`is possible that the liposomes either penetrate the stratum
`corneum to some extent then interact with the skin lipids to
`release their drug or that only their components enter the
`stratum corneum. It is interesting that the most effective
`liposomes are reported to be those composed of lipids
`similar to stratum corneum lipids [81], which are likely to
`most readily enter stratum corneum lipid lamellae and fuse
`with endogenous lipids.
`Transfersomes are vesicles composed of phospholipids as
`their main ingredient with 10-25% surfactant (such as
`sodium cholate) and 3-10% ethanol. The surfactant
`molecules
`act
`as
`“edge
`activators”,
`conferring
`ultradeformability on the transfersomes, which reportedly
`allows them to squeeze through channels in the stratum
`corneum that are less than one-tenth the diameter of the
`transfersome [89]. According to their inventors, where
`liposomes are too large to pass through pores of less than 50
`nm in size, transfersomes up to 500 nm can squeeze through
`to penetrate the stratum corneum barrier spontaneously [90-
`93]. They suggest that the driving force for penetration into
`the skin is the “transdermal gradient” caused by the
`difference in water content between the relatively dehydrated
`skin surface (approximately 20% water) and the aqueous
`viable epidermis (close to 100%). A lipid suspension placed
`on a non-occluded skin surface is subject to evaporation, and
`to avoid dehydration transfersomes must penetrate to deeper
`tissues. Conventional liposomes remain near the skin
`surface, dehydrate and fuse, whilst deformable transfersomes
`penetrate via the pores in the stratum corneum and follow the
`hydration gradient. Extraordinary claims are made for the
`penetration enhancement ability of transfersomes, such as
`skin
`transport of 50-80% of
`the applied dose of
`transferosome-associated insulin [94]. More recently Guo et
`al. also demonstrated
`that flexible
`lecithin
`liposomes
`containing
`insulin
`applied
`to mouse
`skin
`caused
`hypoglycaemia, whilst conventional liposomes and insulin
`solution had no hypoglycaemic effect [95]. Other researchers
`who have evaluated transfersomes have also shown that
`ultradeformable liposomes are superior to rigid liposomes.
`For example, in a series of studies the skin penetration of
`estradiol was enhanced more by ultradeformable liposomal
`formulation (17-fold) than by traditional liposomes (9-fold)
`[96-98, 99]. Pretreatment of the skin membranes with empty
`vesicles had minimal effect on drug flux and the size of the
`
`

`

`28 Current Drug Delivery, 2005, Vol. 2, No. 1
`
`Heather A. E. Benson
`
`vesicles did not influence the enhancement effect. This group
`also confirmed that hydration gradient was the main driving
`force for transport of highly deformable liposomes as the 17-
`fold increase in oestradiol flux reduced to a six to nine-fold
`increase under occlusion [99]. Evidence of vesicles between
`the corneocytes in the outer layers of the stratum corneum
`has been demonstrated by electron and fluorescence
`microscopy [100]. Whilst the mechanism and degree of
`enhancement of deformable liposomes remains controversial
`it is likely that this formulation approach will receive further
`attention.
`Ethosomes are liposomes with a high alcohol content
`capable of enhancing penetration to deep tissues and the
`systemic circulation [101-104]. It is proposed that the
`alcohol fluidises the ethosomal lipids and stratum corneum
`bilayer lipids thus allowing the soft, malleable ethosomes to
`penetrate. Niosomes are vesicles composed of nonionic
`surfactants that have been evaluated as carriers for a number
`of drug and cosmetic applications [105-110]. This area
`continues to develop with further evaluation of current
`formulations and reports of other vesicle forming materials.
`
`6. Solid lipid Nanoparticles
`
`Solid lipid nanoparticles (SLN) have recently been
`investigated as carriers for enhanced skin delivery of
`sunscreens, vitamins A and E, triptolide and glucocorticoids
`[111-118]. It is thought their enhanced skin penetration is
`primarily due to an increase in skin hydration caused by the
`occlusive film formed on the skin surface by the SLN. A
`31% increase in skin hydration has been reported following
`4 weeks application of SLN-enriched cream [119].
`
`PENETRATION ENHANCEMENT BY STRATUM
`CORNEUM MODIFICATION
`There is extensive literature, including many excellent
`reviews (e.g. [3, 120-122]), describing chemicals and
`methods to reduce the barrier capability of the stratum
`corneum in order to promote skin penetration. The enhancer
`activity of many classes of chemicals has been tested
`including water, surfactants, essential oils and terpenes,
`alcohols, dimethyl sulfoxide (DMSO), Azone analogues. In
`addition some chemicals have been identified as penetration
`retarders. The activity of penetration enhancers may be
`expressed in terms of an enhancement ratio (ER):
`
`ER = Drug permeability coefficient after enhancer treatment
`Drug permeability coefficient before enhancer treatment
`
`Barry and coworkers [123-125] devised the lipid-protein-
`partitioning (LPP) theory to describe the mechanisms by
`which enhancers effect skin permeability:
`• Disruption of the intercellular bilayer lipid structure
`•
`Interaction with the intracellular proteins of the stratum
`corneum
`Improvement of partitioning of a drug, coenhancer, or
`cosolvent into the stratum corneum
`
`•
`
`1. Hydration
`Water is the most widely used and safest method to
`increase skin penetration of both hydrophilic [126] and
`
`lipophilic permeants [127]. The water content of the stratum
`corneum is around 15 to 20% of the dry weight but can vary
`according
`to humidity of
`the external environment.
`Additional water within the stratum corneum could alter
`permeant solubility and thereby modify partitioning from the
`vehicle into the membrane. In addition, increased skin
`hydration may swell and open the structure of the stratum
`corneum leading to an increase in penetration, although this
`has yet to be demonstrated experimentally. For example,
`Scheuplein and Blank showed that the diffusion coefficients
`of alcohols in hydrated skin were ten times that observed in
`dry skin [9, 128]. Hydration can be increased by occlusion
`with plastic films; paraffins, oils, waxes as components of
`ointments
`and water-in-oil
`emulsions
`that prevent
`transepidermal water loss; and oil-in-water emulsions that
`donate water. Of these, occlusive films of plastic or oily
`vehicle have the most profound effect on hydration and
`penetration rate [129, 130]. A commercial example of this is
`the use of an occlusive dressing to enhance skin penetration
`of lignocaine and prilocane from EMLA cream in order to
`provide sufficient local anaesthesia within about 1 hour.
`Also drug delivery from many transdermal patches benefits
`from occlusion.
`
`2. Lipid Disruption/Fluidisation by Chemical Penetration
`Enhancers
`
`Many enhancers, such as Azone, DMSO, alcohols, fatty
`acids and terpenes, have been shown to increase permeability
`by disordering or ‘fluidising’ the lipid structure of the
`stratum corneum. The diffusion coefficient (D in Eq. 1) of a
`drug
`is
`increased as
`the enhancer molecules
`form
`microcavities within the lipid bilayers hence increasing the
`free volume fraction. In some cases the enhancers penetrate
`into and mix homogeneously with the lipids. However,
`others such as oleic acid and terpenes, particularly at high
`concentration, pool within the lipid domains to create
`permeable ‘pores’ that provide less resistance for polar
`molecules. These effects have been demonstrated using
`differential scanning calorimetry (DSC) to measure the phase
`transition temperature [131-133], electron spin resonance
`(ESR) studies [134, 135], fourier transform infrared (FTIR)
`[136], Raman spectroscopy [137] and x-ray diffractometry
`[19]. These enhancer compounds consist of a polar head
`group with a long alkyl chain [138] and are more effective
`for hydrophilic permeants, although increased delivery of
`lipophilic permeants has also been reported.
`It has been hypothesised that the enhancement effect of
`Azone is related to its ability to exist in a ‘bent spoon’
`conformation with
`the ring at a right angle
`to
`the
`hydrocarbon chain [139, 140]. Permeability enhancement
`would result from its ability to intercalate between stratum
`corneum ceramides to create spatial disruption. However,
`Hadgraft and coworkers [141] suggested that intercalation
`into a lipid bilayer structure of packed ceramides would
`provide additional resistance to the existence of this high
`energy ‘bent spoon’ conformation. They suggested an
`alternative mechanism based on hydrogen bonding from data
`obtained
`from
`their examination of
`the effect on
`metronidazole permeation across excised human stratum
`corneum and the mechanism of action of Azone and five
`analogues (Table 1). The sulphur analogue (N-0721) had a
`
`

`

`Transdermal Drug Delivery
`
`Current Drug Delivery, 2005, Vol. 2, No. 1 29
`
`have been considered (eg. [138, 143-145]). Optimal
`penetration enhancement was obtained with saturated alkyl
`chain lengths of C 10 to C 12 attached to a polar head group, or
`C18 for unsaturated alkyl chains [138, 143].
`Some solvents, such as DMSO and alcohols, may also
`extract lipids thereby forming aqueous channels within the
`stratum
`corneum
`that
`increase permeability
`[146].
`Unfortunately many of the skin penetration enhancers that
`act on lipid bilayers also cause skin irritation thereby
`limiting their clinical application [147].
`
`3. Interaction with Keratin
`
`In addition to their effect on stratum corneum lipids,
`chemicals such as DMSO, decylmethylsulphoxide, urea and
`surfactants also interact with keratin in the corneocytes
`[148]. It has been suggested that penetration of a surfactant
`into the intracellular matrix of the stratum corneum,
`followed by interaction and binding with the keratin
`filaments, may result in a disruption of order within the
`corneocyte. This causes an increase in diffusion coefficient,
`and hence increases permeability. However in many studies
`of surfactants, a close relationship between permeation
`enhancement and lipid bilayer fluidisation has been observed
`suggesting that the lipid lamellae of the stratum corneum
`rather than the keratin of the corneocytes is the main site of
`action (eg. [149]). Barry [124] suggested
`that
`these
`molecules may also modify peptide/protein material in the
`lipid bilayer domain to enhance permeability. Again, there
`are problems with skin irritancy associated with many of
`these chemicals.
`
`4. Increased Partitioning and Solubility in Stratum
`Corneum
`
`A number of solvents (such as ethanol, propylene glycol,
`Transcutol(cid:210) and N-methyl pyrrolidone) increase permeant
`partitioning into and solubility within the stratum corneum,
`hence increasing P in Fick’s equation (Eqn. 1). Indeed,
`ethanol was
`the
`first penetration enhancer-cosolvent
`incorporated into transdermal systems [150]. It has been
`shown that a solvent capable of shifting the solubility
`parameter (d ) of the skin closer to that of the permeant will
`increase permeant solubility in the stratum corneum and
`hence flux [151]. The inherent solubility parameter of skin
`lipids (d
`s) is about 10 (cal/cm3)1/2 [152] therefore if a
`permeant has a solubility parameter (d
`i) signi