1461-5347/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00317-5

▼ The skin is the largest organ of the body andacts as a protective barrier with sensory and im-munological functions. Although the skin is oneof the major sites for non-invasive delivery oftherapeutic agents into the body, this task can berelatively challenging owing to the imperme-ability of the skin.The penetration of small com-pounds into or through the skin has been inves-tigated widely and the factors that play a role inthe absorption of these molecules by the skin arewell understood. However, the transdermal de-livery approach for macromolecules is controver-sial, especially in light of the old dogma concern-ing the 500 rule, which states that compoundswith a molecular weight .500 Da cannot crossthe skin. Recent literature suggests that a revisionof this rule might be necessary owing to theavailability of novel methods that might improvethe transport of large molecular weight com-pounds into or through the skin1–6.

The nature of the topical vehicle is known toplay a major role in promoting drug absorptioninto and through the skin. Conventional topical

vehicles, such as ointments, creams or gels, pre-dominantly exert their effect by releasing thedrug onto the skin surface, and the drug mol-ecules then diffuse through the skin layers. Theextent and duration of diffusion depends on thephysicochemical properties of the drug itself. Ingeneral, the modification of drug absorption ki-netics by these vehicles is the result of their abil-ity to provide increased hydration by occlusionor some other mechanism. If the size and solu-bility properties of the drug are not amenable,only limited uptake by the skin will occur.

Significant efforts have been devoted to the de-velopment of various approaches to overcomethe permeability barrier of the skin. Success hasbeen limited, to date, particularly with the new‘biotechnology drugs’ such as proteins, oligonu-cleotides and polynucleotides. However, recentdevelopments might provide a method for tack-ling this problem.

Structure of the skin: its barrier propertiesHuman skin is, on average, 0.5 mm thick (rang-ing from 0.05 mm to 2 mm) and is composedof four main layers: the stratum corneum (SC),viable epidermis, dermis and subcutaneous tissue. A schematic cross-section of the skin ispresented in Fig. 1, with different layers identi-fied according to their role in influencing skinpermeability through various pathways.

Stratum corneumThe thick (10–20 mm) surface layer, the SC, ishighly hydrophobic and contains 10–15 layersof interdigitated corneocytes, which are con-stantly shed and renewed. Its organization can bedescribed by the ‘brick and mortar’ model7, inwhich extracellular lipid accounts for ~10% of

Non-invasive administration of drugsthrough the skin: challenges in delivery system designMarianna Foldvari

Marianna FoldvariCollege of Pharmacy and

NutritionUniversity of Saskatchewan

Saskatoon, SK S7N 5C9Canada

tel: +1 306 934 7471fax: +1 306 934 7453

e-mail: foldvari@duke.usask.caand

PharmaDerm LaboratoriesDowney Road

Saskatoon, SK S7N 4L8Canada

reviews research focus

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Vehicles designed to enhance drug delivery through the skin must

incorporate specific elements that improve the ability of the delivery

system to overcome the barrier posed by the stratum corneum. This

review discusses several chemical penetration enhancers that have

been investigated as potential tools to increase drug flux. In addition,

lipid-based delivery systems offer an attractive alternative to

traditional drug vehicles. The relationship between liposome

composition and drug permeation is discussed, in addition to the

possible mechanism of action of lipid vesicle-mediated drug delivery.

the dry weight of this layer, and 90% is intracellular protein(mainly keratin)8,9.The SC lacks phospholipids, but is enrichedin ceramides and neutral lipids (cholesterol, fatty acids, chol-esteryl esters) that are arranged in a bilayer format and form so-called ‘lipid channels’10. Interdigitated long-chain v-hydroxy-ceramides provide cohesion between corneocytes by formingtight lipid envelopes around the corneocyte protein compo-nent11. The barrier function of the skin is created by lamellargranules, which are synthesized in the granular layer and laterbecome organized into the intercellular lipid bilayer domainof the SC12. Barrier lipids are tightly controlled and any impair-ment to the skin results in active synthetic processes to restorethem.The skin’s barrier function appears to depend on the spe-cific ratio of various lipids; studies in which non-polar andrelatively polar lipids were selectively extracted with petroleumether and acetone, respectively, indicate that the relatively polarlipids are more crucial to skin barrier integrity13–15.

Because of its highly organized structure, the SC is the majorpermeability barrier to external materials, and is regarded asthe rate-limiting factor in the penetration of therapeutic agentsthrough the skin.The ability of various agents to interact withthe intercellular lipid therefore dictates the degree to whichabsorption is enhanced.

Viable epidermisThe viable epidermis consists ofmultiple layers of keratinocytes atvarious stages of differentiation.The basal layer contains activelydividing cells, which migrate up-wards to successively form thespinous, granular and clear layers.As part of this process, the cellsgradually lose their nuclei and undergo changes in composition.The role of the viable epidermis inskin barrier function is mainly re-lated to the intercellular lipidchannels and to several partition-ing phenomena. Depending ontheir solubility, drugs can partitionfrom layer to layer after diffusingthrough the SC.

Several other cells (e.g.melanocytes, Langerhans cells,dendritic T cells, epidermotropiclymphocytes and Merkel cells) arealso scattered throughout the vi-able epidermis, which also con-tains a variety of active catabolicenzymes (e.g. esterases, phos-

phatases, proteases, nucleotidases and lipases16,17). Lipid cata-bolic enzymes (such as acid lipase, phospholipase, sphin-gomyelinase, steroid sulfatase), although mainly concentratedin the SC and granulosum, have been demonstrated through-out the epidermal layers14. Although the basal and spinous lay-ers are rich in phospholipids, as the cells differentiate duringtheir migration to the surface, the phospholipid content de-creases and the sphingolipid (glucosylceramide and ceramide)and cholesterol content simultaneously increases.

Dermis and hypodermisThe dermis is largely acellular, but is rich in blood vessels, lym-phatic vessels and nerve endings. An extensive network of der-mal capillaries connects to the systemic circulation, with con-siderable horizontal branching from the arterioles and venulesin the papillary dermis to form plexuses and to supply capil-laries to hair follicles and glands. Dermal lymphatic vessels helpdrain excess extracellular fluid and clear antigenic materials.

The elasticity of the dermis is attributed to a network of pro-tein fibres, including collagen (type I and III) and elastin,which are embedded in an amorphous glycosaminoglycanground substance. The dermis also contains scattered fibro-blasts, macrophages, mast cells and leukocytes. Hair follicles,

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Figure 1. Pathways for skin absorption of drugs (a) and potential pathways achieved by various topical drugdelivery systems (b). Key: 1, intercellular pathway; 2, intracellular pathway; 3, appendageal pathway; 4, drugrelease from immobilized multilamellar liposomes with drug diffusion through skin, or, alternatively,penetration of intact liposome through skin; 5, drug delivery via biphasic lipid vesicle penetration and mixingwith skin lipids; and 6, drug delivery via transfersomes (small deformable lipid vesicles).

Pharmaceutical Science & Technology Today

1

4

3

2

5

6

Magnifiedview

Stratumcorneum

Epidermis

Drug partitioningDrug metabolism

(a) (b)

sebaceous glands and sweat glands are found in the dermis andsubcutis, and might serve as additional specific, albeit fairlylimited, pathways for drug absorption. In some cases, for ex-ample, hair follicles might act as target sites for drug delivery.

Percutaneous drug absorption and its modification by enhancers and pharmaceutical formulationsPercutaneous drug absorption is described by Fick’s first law ofdiffusion as in Eqn 1:

(1)

where dQ/dt is the amount of drug diffused per unit time (i.e.drug flux), Jss is the drug flux, Ks the partition coefficient, D thediffusion coefficient, h the diffusional path length (thicknessof SC), DCv the concentration gradient of drug and A is the skinsurface area treated.

Attempts can be made to manipulate any of these param-eters (Ks, D or DCv) in order to influence drug delivery (i.e.drug flux) through the skin. Earlier efforts concentrated on thechemical modification of drug molecules in order to increasedrug flux through the production of derivatives with optimumlipid solubilities.This concept is also applicable in the prodrugapproach, in which inactive but highly absorbable prodrugmolecules are subsequently activated within the skin. This ap-proach, however, is rarely possible with proteins and DNA.Theremaining and most feasible option might therefore involvemanipulation of the skin barrier.

In order to achieve enhanced drug delivery, structural alter-ations must be made within the skin by suitable agents or drugcarriers18. One or more of several pathways could be involvedin the process. To influence the transcellular route (a polarpathway), in which penetration is enhanced by swelling of theintracellular protein matrix, alteration of protein structurewithin the corneocytes is necessary. The passage of drug mol-ecules by the intercellular route could occur via the lipoidalpathway or the aqueous pathway. In the lipoidal pathway, pen-etration could be enhanced by altering the crystallinity of theintercellular lipid bilayer through an increase in hydration ofthe lipid polar head groups. Alternatively, the lipid hydro-phobic tails could be disordered to achieve the same effect.Increased drug partitioning could also be facilitated in theaqueous spaces between the lipid bilayers through a local en-richment of enhancer molecules. Finally, drug penetration canoccur through skin appendages such as hair follicles19.

Improvement of drug flux by chemical enhancersTo produce a systemic effect, transdermal drug delivery re-quires that suitable quantities of drug be transported through

the skin. This has proved to be a challenge, and has led to thedevelopment of a large repertoire of ‘penetration enhancer’compounds and physical techniques that, to different degrees,facilitate drug penetration across the skin20–22. Penetration en-hancers, in general, promote drug diffusion by disturbing thestructure of the SC and/or deeper layers. The specific mecha-nism can fall into one of three categories: (1) disruption of the highly ordered structure of intercellular lipid channels,(2) interaction with corneocyte intracellular protein com-ponents, and (3) enhanced partitioning of the drug in the presence or absence of the enhancer compound, which can bedescribed by the ‘lipid protein partitioning (LPP) theory’23.

SolventsMany harsh solvents and chemicals have been shown experi-mentally to compromise the epidermal barrier, resulting in en-hanced drug delivery.The application of organic solvents suchas acetone and ether mixtures for 20 min is known to causeextensive dryness, chapping and scaling of the SC24.This effectlasts for four days and is caused by the extraction of lipids fromthe SC. Studies have indicated that in vitro extraction of SC lipidsfrom human skin with a chloroform-methanol (2:1) mixtureincreases transepithelial water loss (TEWL) compared with ex-traction with a hexane-methanol (2:3) mixture or acetone, butnot to the extent that would be expected from the degree oflipid loss25.The authors suggest that there might be additionalmechanisms, such as protein binding, by which solvents com-promise skin barrier properties.The pre-treatment of skin withorganic solvents such as petroleum ether26 or a 2:1 mixture ofchloroform-methanol27 has been reported to increase the per-meability of topically applied lidocaine and ionized salicylicacid, respectively. However, the effect of these solvents on theintegrity of the skin barrier is too damaging for use in com-mercial preparations.

Pharmaceutically acceptable enhancersA selected group of pharmaceutically acceptable penetrationenhancers and their proposed mechanisms of action are shownin Table 1. In many cases, this enhancement promotes a local-ized effect by increasing the concentration of the drug withinthe skin. However, transdermal drug delivery requires trans-port through the dermal level of the skin into the systemic cir-culation. Only a few types of enhancers are powerful enoughto facilitate the delivery of therapeutic quantities of drugs, es-pecially macromolecules, into the blood.

Many current penetration enhancers influence the proper-ties of the various pathways by which drugs can cross the SC,including the lipoidal intercellular pathway, the inter- or intra-cellular polar pathways, and the appendageal pathways (Table 1).The actions of enhancers on intercellular lipid bilayers are

dQdt

= Jss = Ks × Dh

× DCv × A

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related to the disordering of the packing of the lipids.This canbe achieved through interactions with the polar lipid headgroups, such as in the case of water, DMSO and ethanol, orwith the hydrophobic lipid tails, such as in the case of oleicacid, Azone and terpenes.

Terpenes are naturally occurring constituents of plantvolatile oils.These molecules can be classified as hydrocarbons,alcohols, ketones or oxides, and have been shown to enhancethe penetration of several groups of drugs.The more lipophilicoxygen-containing terpenes, in particular, have been found to

increase the penetration of various drugs28–30. The permeationof ibuprofen across human skin, for example, was enhanced bythe formation of eutectic systems with terpenes such as thym-ol and menthol31. In addition, eugenol, menthone, and D-limonene have been shown to enhance the permeability oftamoxifen through porcine epidermis32.

Among the fatty acids, oleic acid has been investigated ex-tensively as a skin penetration enhancer for numerous com-pounds, including acyclovir, 5-fluorouracil, tetrahydro-cannabinol, mannitol and dihydroergotamine33,34. The

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Table 1. Selected skin-penetration enhancers

Class Representative compounds Mechanism of interaction with skin and enhancement of Refsdrug permeability

Water Hydrating and occlusive topical Hydrates the SC, evidence for increasing permeability of both 62–65preparations hydrophilic and lipophilic compounds, increases fluidity or

Occlusive dressings disorder of intercellular bilayers; occlusive dressings and vehicles prevent water loss from skin and provide full hydration

Organic solvents Alcohols (ethanol) Cotransports with the drug through the lipid channels, partial 66–68extraction of lipids

Polyols (PG) Replaces bound water in the intercellular space, enhances 38penetration of lipophilic drugs

Sulfoxides (DMSO) Partition into the corneocyte, binds keratin; at higher 69concentration increases lipid fluidity and disrupts lipid packing

Pyrrolidones Interacts with both the keratin and lipid component of the SC 70

Fatty acids Oleic acid Increases fluidity of the intercellular lipids: shorter chain 33(C10–12) and branched or unsaturated chain fatty acids are more effective than longer chain saturated fatty acids; the vehicle used (e.g. PG) might be synergistic

Terpenes Ascaridole Disrupts intercellular lipid order; increases electrical conductivity, 28–301,8-Cineole indicates the opening of polar pathways in SCL-MentholD-Limonene

Surfactants (nonionic, Polysorbates (Tween) Penetrates into skin, micellar solubilization of SC lipids 49cationic, anionic) Polyoxyethylene alkylphenols (Brij)

Dodecyltrimethyl ammonium bromide Penetrates into skin, extracts lipid from SC 49,50(DTA-B)

Sodium lauryl sulfate Binds to intracellular keratin in corneocytes, removes some 46–48of the intercellular lipid, increases TEWL, alters processing of epidermal lipids

Azone® 1-Dodecylhexahydro-2H-azepine-2-one Disrupts skin lipids in both the headgroup and tail regions 35–37and certain derivatives

Phospholipids Phosphatidylcholine from soybean or Diffuses into SC, perturbs intercellular lipids, enhances drug 57,71–76(liposomes) egg yolk partitioning into skin

Abbreviations: sc, stratum corneum; PG, propylene glycol; DMSO, dimethylsulfoxide; TEWL, transepidermal water loss.

magnitude of enhancement is affected by several factors, in-cluding fatty-acid chain length, the presence of double bondsand the solvent or vehicle in which the fatty acid is dissolved.

Extensive studies have also been conducted on the mecha-nism of action of Azone and its various derivatives35. Azone in-serts into the intercellular lipid layer of the skin and, throughhydrogen bonding to an adjacent ceramide head group, createsa ‘channel’ on the other side where hydrogen bonding to theother ceramide molecule is not possible36. The length of thealkyl chain of the Azone molecule also influences its locationwithin the lipids37. This disordering effect is responsible forenhancing drug permeation.

Propylene glycol (PG) alone is able to enhance the perme-ation of lipophilic drugs, probably because of a solvent drageffect38.The use of a combination of enhancers, such as Azoneand PG, might potentially enhance the absorption of lipophilicpenetrants in a synergistic manner39. An appropriate combi-nation of enhancers appears to be critical because the replace-ment of PG with other substances (dimethylisosorbide orpolyethylene glycol) does not produce the same effect40,41.Certain epidermal enzymes can also act as penetration en-hancers. Phospholipase C, for example, facilitates the absorp-tion of benzoic acid, mannitol and testosterone in vitro42.

From a pharmaceutical perspective, enhancement of drugflux should be safe, temporary and of sufficient magnitude toprovide a therapeutic benefit. To date, no enhancer has beenable to completely fulfill these requirements, and significantdrug absorption has been shown only with small molecules, asis evident from the limited number of commercially availableproducts. For example, ethanol has been shown to enhance thepermeation of estrogen and fentanyl, and is used in commer-cial transdermal preparations of these drugs [Estraderm™(Novartis, Basel, Switzerland) and Duragesic™ (Janssen,Beerse, Belgium)]. A novel agent, 2-N-nonyl-1,3-dioxolane, isused for the soft enhancement of percutaneous absorption(SEPA) method, and is present in formulations of low molecular weight compounds, such as prostaglandin-E1 and testosterone, which are currently undergoing clinical trials43.

The use of topical excipients to enhance drug penetrationinto the skinTopical formulations are designed to provide optimum treat-ment by taking two major factors into consideration: (1) skincondition, and (2) drug penetration. In a pharmaceutically ac-ceptable product, the ideal drug vehicle is compatible andcomplementary, able to promote drug absorption and to alleviatethe skin disorder by ‘cosmetic’ means. Increased skin hydrationhas been shown to result in increased drug absorption fromtopical formulations. For example, occlusion, a well-knowntechnique, enhances the absorption of many drugs, including

both hydrophobic and hydrophilic compounds, by increasingskin hydration (Table 1).

Surfactants have traditionally been used in topical pharmaceut-ical preparations, including hydrophilic ointments, absorptionbases and emulsion-type creams. Their usual role is to aid indrug solubilization and to attribute water washability to the ve-hicle for cosmetic appeal. More recently, surfactants have beenevaluated as components of transdermal sustained-release vehi-cles44 and specialized delivery systems (niosomes)45. Surfactantsinteract extensively with the skin, usually by penetrating into theskin and disrupting lipids or proteins (Table 1). One frequentlyused non-ionic surfactant, sodium lauryl sulfate (SLS), has beenshown to accumulate in the skin after topical treatment. After a 24 h treatment of hairless rats with a 1% SLS solution,0.4110 mmol of SLS per gram of tissue was detected deep in thedermis, indicating relatively widespread distribution in theskin46. SLS is capable of binding to keratin within the corneo-cytes, leading to irritancy47. Recent studies have demonstratedthat SLS has a detrimental effect on epidermal lipid processingand, consequently, the formation of the lipid barrier domain48.

Cationic and anionic surfactants have also been used to en-hance drug permeation through the skin. For example, DTA-B,a cationic surfactant, was reported to increase the permeationof methyl nicotinamide across human skin in vitro49. Othercationic surfactants have been associated with increased lido-caine flux across excised human skin50.These substances, how-ever, tend to be even more damaging to the skin than non-ionic surfactants and are unlikely to become accepted for usein pharmaceutical preparations.

Lipid-based delivery systems as topical and transdermalskin absorption enhancers.Traditionally, lipidic excipients have served as inert vehicles,providing only cosmetic appeal. In the past 20 years, lipid-based delivery systems have gained recognition as potentialparticulate carriers for topical drugs. The initial intent was todevelop new delivery systems for the topical application ofdrugs in order to improve bioavailability, increase residencetime of the drug within the skin, and decrease systemic andlocal toxicity. Following the first report by Mezei andGulasekharam in 1980 (Ref. 51), liposomal dosage forms havebeen extensively evaluated as vehicles for topical drugs.Numerous drugs have been encapsulated into liposomes andtested in vitro or in vivo to evaluate bioavailability and the degreeof penetration enhancement (Table 1). Several different lipidvesicle structures have been developed for use in topical drugdelivery.

An interesting aspect of topical liposomal delivery is thegreat diversity of potential liposome compositions and the de-pendence of successful drug delivery on this composition.

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Liposome-mediated skin delivery appears to be higher underconditions in which there is evidence for penetration of the liposome components into the skin. It has been shown that invitro tetracaine delivery into human skin was higher from a spe-cific multilamellar liposome formulation, which also increasedthe deposition of liposomal phospholipid within the skin lay-ers52. Two different formulations consisting of multilamellar liposomes labeled with 14C-dipalmitoyl phosphatidylcholine(14C-DPPC), but containing the same amount of tetracaine,were assessed for their ability to deliver tetracaine into humanskin. The first formulation consisted of 10% Phospholipon90H, 1.75% cholesterol and 0.7% stearic acid (pH 5.5),whereas the second formulation contained 10% Phospholipon90H, 1.75% cholesterol and 1.75% stearic acid (pH 8.5). Aftera 24 h in vitro treatment, 68.3 µg cm22 and 22.5 µg cm22 phos-pholipid was found in the skin following delivery from thesetwo formulations, respectively. This represents approximately0.2–0.7% of total applied lipids. Tetracaine delivery correlatedwith the amount of phospholipid deposited in the skin52.

Cevc and Blume1 constructed transfersomes, which are lipo-some-like vesicles of a specific composition (8.7 wt% soybeanphosphatidylcholine, with varying amounts of sodium cholateand ethanol).The lipid penetrating deep into the dermis repre-sented up to 10% of the total lipid (2.5 mg cm22) applied.Theuse of these transfersomes was associated with increased pene-tration of drug molecules. Further evidence of the fact that lipo-some composition plays a major role in the interaction with skinwas provided in a study using electron paramagnetic resonance(EPR) imaging53. In this study, only the liposome-encapsulatedform of a model compound was shown to be detectable withinthe skin; moreover, liposome size and lipid fluidity both influenced the diffusion coefficient of the entrapped compound.

Externally applied lecithin, in the form of liposomes madewith 400 mg ml21 lecithin, 30 mol% cholesterol, 1% hydro-cortisone and traces of tocopherol and labelled with 14C-egg-yolk phosphatidylcholine, has also been shown to penetrateinto the skin54. Evaluation of the lipid composition within theskin after liposome treatment indicated the presence of the externally applied lecithin in the SC (1013.6 6 467.67 mM),epidermis (3.5 6 0.41 mM) and dermis (0.91 6 0.35 mM).Although the dose applied to the human skin in vitro was fairlyhigh (4 mg lipid cm22), the amount of phospholipid penetrat-ing within 30 min should be considered significant54. Otherstudies have also indicated a liposome composition-dependentincrease in human skin phospholipid content after in vitrotopical treatment52. In vivo studies in hairless mice indicated the uptake of 20–40% of total applied lipids (both 3H-choles-terol and 14C-DPPC) into the deeper SC and ~3% of the lipids into the deeper skin strata2. Recent studies using EPRimaging suggest that multilamellar liposomes prepared from

phosphatidylcholine and 30–50mol% cholesterol interact andmix with deeper layers of the skin55.

Mechanism of delivery from lipid-based systemsThe studies described above support the theory that com-ponents of lipid vesicles migrate into the skin during drug delivery. The interaction of lipid vesicles with the skin and successful drug transport through the skin appear to be relatedto the ability of the liposomes to penetrate into the skin insome form.

Possibly because the definitive mechanism has yet to beidentified, few investigations report sufficient delivery oftherapeutic agents to allow a positive clinical outcome. Theconstruction of a suitable topical delivery system will be themost important factor in determining whether or not ther-apeutically significant quantities of a drug will be absorbed. Inaddition, the mechanism whereby drug delivery is achievedcan be specific to each case.

An extensive freeze-fracture electron microscopic study wascarried out to evaluate the interaction of phospholipid lipo-somes with the SC layer of excised abdominal skin56. Significantultrastructural changes were shown within the SC, with nu-merous intact vesicles accumulating in the intercellular lipidregions. Although other explanations are possible, it was sug-gested that the liposomal lipids might penetrate after disinte-gration (becoming ‘molecularly dispersed’) and, by interactingwith skin lipids, form new vesicular structures. Some corneo-cyte swelling was also observed after liposome treatment inthis study. Subsequent to the freeze-fracture studies, small-angle X-ray scattering measurements demonstrated definitechanges in the diffraction pattern of liposome-treated skin, in-dicating mixing of liposomal and skin lipids56.

Other studies have indicated that even multilamellar lipo-somes (MLV) can penetrate into skin in their intact form.WhenMLV were labeled with colloidal iron, an electron dense marker,then applied topically to guinea-pig skin, electron microscopyof thin sections of treated skin revealed the presence of intact liposomes in the dermis57.The penetration of intact liposomesinto the SC by fluoromicrography was also demonstrated58.

Transfersomes are vesicles that exhibit extreme deformabil-ity, and are able to pass through the skin intact, as demon-strated by the detection of intact transfersomes circulating inthe blood59. The mechanism of transfersome penetration ap-pears to be related to the ability of the vesicle to squeezethrough polar channels upon hydration gradients1.

Novel design for lipid-based delivery systemRecent work has indicated that enhanced dermal delivery ofsmall and large therapeutic compounds can be achieved usingbiphasic lipid vesicles. The composition of these vesicles

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was developed to produce a highly synergistic penetration-enhancing effect resulting from a combination of colloidal,thermodynamic and diffusivity considerations. Biphasic vesicles are multicompartmental lipid vesicles consisting ofconcentric mixed-lipid bilayers entrapping lipophilic, micellarand aqueous subunit compartments. The complex colloidal design allows the encapsulation of a variety of compounds,including proteins and DNA.This system has been shown to becapable of delivering therapeutic quantities of both small molecules (such as prostaglandin E60 and itraconazole61) andlarge molecules [such as insulin (M. King et al., unpublished),interferon alpha3, vaccine antigens4 and plasmid DNA (M. Kinget al., unpublished)] through the skin. This type of delivery system can produce a combination effect on skin propertiesand influence each of the three main permeation parameters(partition coefficient, diffusion coefficient and concentrationgradient).

PerspectivesThe skin, although an ideal site for drug administration, is alsoa major barrier to this process. Effective drug therapies musttherefore overcome the challenge of finding a technology toadminister, meter and deliver the required quantity of druginto or through the skin.

Through interactions with the skin, delivery vehicles provide a complementary action by which the skin can be ‘prepared’ to allow passage of the drug. Because active agentscan have widely different solubilities, sizes and structures,different agents would require different ‘preparation’ of the skin by appropriate delivery vehicles. Intense efforts are currently given over to the search for delivery vehicles suitablefor transporting macromolecules such as proteins, peptides,oligonucleotides and polynucleotides. Although some new delivery technologies show promise in this regard6, a significant amount of work is still required to develop newproducts.

AcknowledgementI would like to thank Deborah Black of D. Black Communications(Saskatoon, Canada) for the schematic diagram of the skin.

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PSTT Vol. 3, No. 12 December 2000 reviews research focus

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