drug delivery systems. 6. transdermal drug delivery

DRUG DELIVERY SYSTEMS

J Cbbn Pharmacol 1991;31:401-418 401

Drug Delivery Systems. 6. TransdermalDrug Delivery

Vasant V. Ranade, PhD

Transdermal drug delivery system has been in existence for a long time. In the past, themost commonly applied systems were topically applied creams and ointments for derma-tological disorders. The occurrence of systemic side-effects with some of these formula-tions is indicative of absorption through the skin. A number of drugs have been applied tothe skin for systemic treatment. In a broad sense, the term transdermal delivery systemincludes all topically administered drug formulations intended to deliver the active in-gredient into the general circulation. Transdermal therapeutic systems have been de-signed to provide controlled continuous delivery of drugs via the skin to the systemiccirculation. The relative impermeability of skin is well known, and this is associated withits functions as a dual protective barrier against invasion by micro-organisms and theprevention of the loss of physiologically essential substances such as water. Elucidation offactors that contribute to this impermeability has made the use of skin as a route forcontrolled systemic drug delivery possible. Basically, four systems are available thatallow for effective absorption of drugs across the skin. The microsealed system isa parti-tion-controlled delivery system that contains a drug reservoir with a saturated suspensionof drug in a water-miscible solvent homogeneously dispersed in a silicone elastomermatrix. A second system is the matrix-diffusion controlled system. The third and mostwidely used system for transdermal drug delivery is the membrane-permeation con-trolled system. A fourth system, recently made available, is the gradient-charged system.Additionally, advanced transdermal carriers include systems such as iontophoretic andsonophoretic systems, thermosetting gels, prodrugs, and liposomes. Many drugs havebeen formulated in transdermal systems, and others are being examined for the feasibil-ity of their delivery in this manner (e.g., nicotine antihistamines, beta-blockers, calciumchannel blockers, non-steroidal anti-inflammatory drugs, contraceptives, anti-arrhyth-mic drugs, insulin, antivirals, hormones, alpha-interferon, and cancer chemotherapeuticagents). Research also continues on various chemical penetration enhancers that mayallow delivery of therapeutic substances. For example, penetration enhancers such asAzone may allow delivery of larger-sized molecules such as proteins and polypeptides.

A lthough some drugs have inherent side effectsthat cannot be eliminated in any dosage form,

many drugs exhibit undesirable behaviors that arespecifically related to a particular route of adminis-tration. One recent effort at eliminating some of theproblems of traditional dosage forms is the transder-mal delivery system. Oral administration of drugsinitially through powders extracts and liquids hasbeen practiced since before recorded history, andmore recently, through tablets and capsules. Inject-ables came into being about 130 years ago, but have

From the Action Medical Marketing Co. Libertyville, Illinois. Address forreprints: Vasant V. Ranade, PhD, 1219 Deer Trail, Libertyville, IL60048. For reprint requests, please send a self-addressed stampedenvelope.

only been acceptable since the development of a bet-ter understanding of sterility. Topical applicationhas been used for centuries mostly in the treatmentof localized skin diseases. Local treatment requiresonly that the drug permeate the outer layers of skinto treat the diseased state and it is hoped this occurswith little or no systemic accumulation.1

Transdermal delivery systems, on the other hand,are specifically designed to obtain systemic blood lev-

els and have been used in the U.S. since the 1950s;only recently have these systems been refined.Transdermal permeation or percutaneous absorp-tion can be defined as the passage of a substance,such as a drug, from the outside of the skin throughits various layers into the bloodstream. Any timethere is systemic accumulation of a drug, unwanted

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side effects or toxic effects can occur. Certainly, eachdosage form has its unique place in medicine, butsome attributes of the transdermal delivery systemprovide distinct advantages over the traditionalmethods of attaining systemic levels of drugs. Clearyhas listed important advantages and disadvantages ofthe transdermal delivery systems. The advantagesare that the system 1) avoids chemically hostile GIenvironment, 2) does not have GI distress or other

physiologic contraindications of oral route, 3) pro-vides adequate absorption of drugs with some oralabsorption promptly, 4) increases patient compli-ance, 5) avoids first-pass effect, 6) allows effectiveuse of drugs with short biological half-lives, 7) allowsadministration of drugs with narrow therapeuticwindow, 8) provides controlled plasma levels of po-tent drugs, and 9) interrupts drug input promptlywhen toxicities occur. Disadvantages of this systeminclude 1) drugs that require high-blood levels can-not be administered, 2) adhesive may not adherewell to all types of skin, 3) drug or drug formulationmay cause skin irritation or sensitization, 4)it is un-

comfortable to wear, and 5) system may not be eco-nomical.1’2

In the development of transdermal delivery sys-tems, a series of interrelated elements must be takeninto consideration. These factors can be classifiedinto five basic areas: bioactivity of the drug, skincharacteristics formulation, adhesion, and systemdesign. The transport of drugs through the skin iscomplex since many factors influence their perme-

ation. To simplify it somewhat, one can look at 1)skin structure and its properties, 2) the penetratingmolecule and its physical-chemical relationship toskin and the delivery platform, 3) the platform ordelivery system carrying the penetrant, and 4) thecombination of skin, the penetrant, and the deliverysystems as a whole. This article discusses each ofthese factors, their complexities, and their interde-pendencies in the development of transdermal deliv-ery systems.3’4

STRUCTURE OF HUMAN SKIN

Human skin consists of two distinct layers, the strati-fied avascular cellular epidermis and an underlyingdermis of connective tissue. A fatty subcutaneouslayer resides beneath the dermis. Hairy skin de-velops hair follicles and sebaceous glands, and thehighly vascularized dermis supports the apocrineand eccrine sweat glands, which pass through poresin the epidermis to reach the skin surface. In respectof drug permeation, the most important tissue in thiscomplex membrane is the stratum corneum or horny

layer, which usually provides the rate-limiting orslowest step in the penetration process.5

The transport mechanisms by which drugs crossthe intact skin are still not elucidated despite manyyears of investigation. The possible macro routescomprise the transepidermal pathway (across thehorny layer either intracellularly or intercellularly)or via the hair follicles and sweat glands (the append-ageal way).

The appendages may be important at short diffu-sional times and for large polar molecules. For drugsthat penetrate directly across the intact stratum cor-neum, entry may be transcellular or intercellular.For many years, for polar molecules, the probableway was through the hydrated keratin of the corneo-

cyte. However, it now seems more likely that thedominant path is the polar region of the intercellularlipid, with the lipid chains providing the nonpolar

routes (Figure 1).b0

The relative importance of these alternatives de-pends on many factors that include the time-scale of

permeation (steady-state vs. transient diffusion), thephysicochemical properties of the penetrant (for ex-ample, its pKa, molecular size, stability and bindingaffinity, and its solubility and partition coefficient),integrity and thickness of the stratum corneum, den-sity of sweat glands and follicles, skin hydration, me-

tabolism, and vehicle effects.In developing a topical system, a stable prepara-

tion of controlled-chemical potential, with thecorrect partition coefficient relative to the drug reser-voir, and any device membrane and the skin layers isneeded. In particular, for the type of transdermal de-livery device that incorporates a rate-controllingmembrane, the flux across this barrier should be lowenough so that the underlying skin acts as a sink.This is a severe restriction because of the generalimpermeability of the stratum corneum. If the hornylayer is not made as a sink, the skin of the patient will

control drug input and variable consequences willfollow due to the significant biological variabilitythat exists among people and from skin site to skinsite. In the future, new penetration enhancers willhave to be designed and manufactured and their de-livery should be dovetailed with that of the drug sothat they precede medicament entry. In this way, theresistance of the horny layer could be reduced sothat the tissue does perform as a sink. Many pharma-cologically active drugs have the incorrect physio-

chemical properties to partition into the skin, and animportant effort in the future will be devoted to syn-thesizing suitable prodrugs to optimize the partitioncoefficient, stratum corneum: vehicle. In developingnew drug entities, more attention should be paid to

IA:

Stratum Cornettn

Viable Epidermis

papillary

layer

Dermis

reticularlayer

Subcutaneous

Connective Tissue

TRANSDERMAL DRUG DEL IVERY

DRUG DELIVERY SYSTEMS 403

Figure 1. Basic diagram of skin structure (reprinted with permission from CRC Press Inc., Boca Raton Fl, from Medical Applications of

Controlled Release, Vol 1 Longer and Wise (eds.) 1984; 207.)

producing chemicals with low melting points (prefer-ably liquids at biological temperatures) and to in-clude penetration-enhancer groups in the active mol-ecule.

Light, oxygen, and bacteria degrade the microen-vironment of the skin surface. For example, skin mi-croflora can degrade nitroglycerine and steroid es-ters. Predictably, occlusive systems such as thetransdermal delivery devices, when applied for sev-eral days, will cause problems with changes in skinflora, with maceration and irritation of the skin sinceprolonged application can shut down the sweatglands.16

In transversing the skin, the drug must partitioninto the stratum corneum and diffuse through thisimpermeable barrier. The molecules will interactwith many potential binding sites, possibly forming areservoir operating for days or even weeks. Free drugeventually reaches the interface between the stra-tum corneum and the viable epidermis, where themedicament must partition into this water-rich tis-sue. There is a potential problem in that a drug or aprodrug that is designed to partition from a vehicleinto the horny layer may have difficulty leaving thestratum corneum to enter the epidermis. For very

lipid-soluble drugs, clearance from the viable tissuemay replace diffusion through the stratum corneumas the rate-limiting step.15

Living skin is a storehouse of enzymes that mayhave catalytic activities of 80-90% as efficient asthose formed in the liver. Hydrolytic, oxidative, re-ductive, and conjugative reactions can all take place.One reason why the activities approach those in theliver is the extreme dilution at which moleculescross the viable epidermis. The process positionsthem open to attack, although this is counterbal-anced by the much greater permeation rates com-pared with those operating within the stratum cor-neum. Metabolism may alter permeation pharmaco-kinetics, activating prodrugs and destroying activedrug while generating active and inactive metabo-lites. A future possibility would be to incorporate en-zyme inhibitors into the devices to protect the drugs.In epidermis, the drug meets pharmacologic recep-tors as it permeates to the epidermal/dermal bound-ary where it partitions into the dermis. Since bothviable tissues consist mainly of water, it is preferablethat the partition coefficient be approximately one,provided that there are no different binding sites inclose proximity on either side of the interface. The

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sensitization reactions will probably always occur intime to a fraction of the patient population when anychemical is delivered via an unusual route, i.e., oneto which the body is not accustomed. This phenome-non of sensitization has been observed with cloni-dine, and it may occur with other drugs, enhancersenzyme inhibitors, adhesives, and vehicle compo-nents in general.17’18

After the penetrant partitions into the dermis, ad-ditional receptor, metabolic, and depot sites may in-tervene as the drug moves to a blood capillary, parti-tions into the wall, exits into the blood. The lymphsystem may also aid in drug elimination. A portion ofthe penetrant may even partition into the subcutane-ous fat and the underlying muscle to form furtherdepots, even though this would appear unlikelybased on theoretic considerations.19’2#{176}

The aforementioned scheme is complex althoughit has been simplified by representing the process asone of simple unidirectional transport; in practice,the sequence is more complicated. Factors playingtheir part include the inhomogeneity of the stratifiedtissues, the interruption of the stratum corneum byhair follicles and sweat glands, and the division ofbasal cells - their transport through the horny layerand their loss from the surface. Additionally, drugspenetrate the skin under dynamic conditions. Thus,the medicament, vehicle components, and occlusivehydration effects may progressively change the skinbarrier. Sweat, sebum, and cellular debris may enterthe product, changing its physico-chemical charac-teristics. Volatile solvents may evaporate and emul-sions can crack or invert when rubbed into the skin.Such processes will alter the chemical potential ofthe drug and may even develop supersaturated solu-tions.

Theoretical Advantages of the Transdermal Route

It is usual to contrast the percutaneous route withoral delivery as the latter regime provides the mostpopular way for delivering medicaments in general.Transdermal input of a drug would eliminate severalvariables that make gastrointestinal absorption aproblem. These factors include the dramatic changesin pH as the molecule moves from gastric acid with apH as low as 1 to the intestine with a pH of up to 8.Other variables that may be obviated include gastricemptying, intestinal motilities and transit times, theoperation of human and bacterial enzymes, and theinfluence of food on drug absorption.

Via skin, the drug enters the systematic circula-tion without first passing into the portal system andtraversing the liver. The route therefore avoids the

‘first-pass’ phenomenon by which the liver can sig-nificantly reduce the amount of intact agent thatpasses into the systemic circulation. Additionally,the medicament avoids the enzymes that are presentin the gut wall. However, as emphasized earlier, theskin itself possesses a metabolic capability.

For a correctly formulated product, the percutane-ous input of a drug can control administration andthus limit pharmacologic action; indeed the corre-sponding oral or injectable formulation may wellelicit several effects that include toxic reactions. Pa-tient compliance may be helped by the continuity ofinput of drugs with short half-lives. (Figure 2)

Transdermal administration under suitable ratecontrol could minimize pulse entry into the blood-stream - undesirable side-effects being particularlyassociated with peak plasma levels. However, a moredifficult matter is to deliberately provide a con-trolled on/off action because intact skin membranesare intrinsically slow-response systems with pro-longed lag times, at least when shunt diffusion viathe appendages is neglible. Percutaneous administra-tion can be valuable for drugs with low therapeutic

indices - those for which the toxic concentration inthe plasma is near the clinical level.

Some investigators claim that it would be easy toterminate therapy by simple removal of a topical de-vice so as to interrupt medicament delivery. How-ever, the stratum corneum would continue to de-liver molecules to the viable tissues for some timeafter device removal, at a declining rate as governedby the properties of the drug reservoir. This is an-other consequence of the long response times ofhorny layer membranes.

Figure 2. Process of transdermal permeation (reprinted with per-

mission from S. Krager AG Basel, Switzerland, from Higuchi T,Design of Chemical Structure for optimal dermal delivery, Curr

Prob Dermatol 1978; 7:121.)

TRANSDERMAL DRUG DELIVERY


Optimization of Percutaneous Absorption

When formulators develop dermatologic prepara-tions for optimum bioavailability, they employ twomain methods of approach either singly or com-bined. The first scheme formulates the vehicle ordevice so that the drug has the maximum tendencyto leave the base and to partition into the skin. Theformulator does not intend that the vehicle compo-nents should affect the physicochemical propertiesof the stratum corneum. Thus, the vehicle designpromotes drug release by simply optimizing chemi-cal potential of the medicament. However, even themost innocuous of vehicles tends to change the na-ture of the stratum corneum if only by hydrating it.The alternative strategy incorporates materialsknown as penetration enhancers into the formula-tion. These are chemicals that enter the skin, dynam-ically and reversibly altering it to promote the pene-tration of drug. The desirable attributes of such en-hancers have been listed by Barry5 and they includethe following: 1) they should be pharmacologicallyinert, interacting with no receptors in the skin or inthe body generally, 2) the enhancer should be nei-ther toxic, irritating nor allergenic, 3) the onset ofenhancer activity and the duration of effect shouldbe predictable, controllable, and suitable, 4) the skinshould show an immediate and full recovery for itsnormal barrier property when the enhancer leavesthe tissue, 5) the accelerant should promote penetra-tion into the skin without developing significantproblems of loss of body fluids, electrolytes or otherendogeneous materials, 6) the chemical should becompatible with a wide range of drugs and pharma-ceutical adjuvants, 7) where appropriate, the sub-stance should be a suitable solvent for the drugs, 8)for traditional formulations, the material shouldspread well on the skin and it should have a suitableskin ‘feel’, 9) the chemical should formulate intocreams, ointments, gels, lotions, suspensions, aero-sols, skin adhesives, and delivery devices, 10) itshould be odorless, tasteless, colorless, and relativelyinexpensive.21

Theory for Penetration-Enhancer Activity

It seems that in most situations the crucial eventsoccur in the intercellular spaces within the stratumcorneum and the main sites associated with the bi-layer lipid structure. Many penetration enhancerswill interact with the polar head groups of the lipidvia hydrogen bonding and ionic interactions. Theconsequent disturbance of the hydration spheres ofthe lipids and alterations in head group interactionswill upset the packing at the head region. This dis-

turbance may decrease the retarding action that thisdomain imposes on the diffusion of polar penetrants.A second response may be to increase the volume ofthe aqueous layer so that more water enters the tis-sue. This swelling provides a greater cross-sectionalarea for polar diffusion and a larger fractional vol-ume of ‘free’ water as distinct from the structuredwater at the lipid interface.

This modification may also happen with simplehydration - water itself is a good penetration en-hancer. The disturbance of the interfacial structurewill tend to alter the packing of the lipid tails suchthat the lipid hydrophobic route becomes more dis-ordered and more easily traversed by a lipid-likepenetrant.

In addition to any effect a penetration enhancerhas on the aqueous region by increasing its watercontent, there can be a direct action whereby thedomain temporally changes its bulk chemical consti-tution. Thus, with high concentration of solventssuch as dimethylsulfoxide, propylene glycol, or eth-anol in a vehicle or device, so much may penetrateinto the aqueous region of the tissue that it becomesa better solvent for molecules such as hydrocortisoneand estradiol. In other words, the operational parti-tion coefficient now favors an elevated drug concen-tration in the skin. The solvent diffuses out into thedermis followed by the drug diffusing down its con-centration gradient.22

Penetration enhancers can insert between the hy-drophobic tails of the bilayer, upsetting their packingand following easier diffusion for lipid penetrants.This alteration in lipid packing can reflect back toprovide an element of disorder at the polar-headgroup region of the intercellular domain, promotingpolar route permeation.

An important feature of the activity of certain pen-etration enhancers is the correct choice of a cosol-vent for materials such as Azone and cis-unsaturatedoleic acid. For these enhancers to reach the polarsurface of the lipid bilayer in relatively largeamounts, they may need a material such as propyl-ene glycol. This alters the polarity of the aqueousregion and increases its solubilizing ability for lipid-like materials; the cosolvent may also change headgroup packing. Then, the polar heads of the oleicacid and Azone insert between the head groups ofthe lipid and the enhancer tails flip over to insertbetween the hydrophobic groups of the membranelipids, thus increasing the fluidity of the lipid do-main. Azone is so water insoluble that under ex-treme conditions it may move fully into the internalregion of the lipid to provide maximum disordering.This cooperation between the elements of cosolventsystems operates particularly with azone/propylene

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glycol mixtures. Not only does propylene glycol aidthe penetration of Azone into the stratum corneum,but Azone also increases the flux of propylene glycolthrough the skin, which further increases theamount of Azone in the tissue.

When dramatic effects occur such that the resis-tance of the horny layer reduces to that of an equiva-lent thickness of viable tissue, even more drastic dis-order in the intercellular domain may be suspected.It is believed that the biomolecular structure com-pletely breaks down, and the components from glob-ular micelles are dispersed in a relatively extensivecontinuous phase rich in polar or aprotic solvent.This situation would permit drug penetration atrates that are several orders of magnitude greaterthan those operating in the unaffected horny layer.The final stage in this process would be the dissolu-tion of the lipid to form a homogeneous phase withlittle resistance to molecular diffusion. This extremedisruption would occur only in the presence of highconcentrations of molecules with good solvent prop-erties for lipid components.

If, for a particular penetrant, the intracellularroute provided a significant permeation pathway,the enhancer could interact with whatever lipid re-mains within the corneocyte.

With regard to keratin fibrils, there is a need toconsider the typical spread of interactions which ma-terials such as the aprotic solvents (e.g., dimethylsul-foxide) and surfactants undergo with proteins. Thesemechanisms include interactions with polar groups,relaxation of binding forces, and alterations in helixconformations. Pore routes may form through thistissue. Most investigators no longer accept the factthat the transcellular route presents a significantpathway for molecular diffusion through the stratumcorneum, though presumably the corneocyte maysequester and retain certain molecules within itsstructure.

The aforementioned theory is not exclusive andhas concentrated on agents that are delivered inamounts that alter the permeability of the stratumcorneum without producing frank damage. How-ever, aprotic solvents such as dimethylsufoxide athigh concentrations may damage the skin or producegross structural changes in it, whereas the high os-motic activity of the sulfoxide may induce channelsin the stratum corneum and so form a continuousnetwork throughout the tissue. Incidentally, humanskin shows great variation in permeability and in re-spect of its modification by enhancers. The humanpopulation may be divided into a minimum of twosubgroups - one is susceptible to enhancer activityand the other much less so. Within each subset,there is the usual biologic variability. A large-scale

investigation to find such a biomodal distribution ofpermeabilities would be informative.5

DEVELOPMENT OF THE TRANSDERMALTHERAPEUTIC SYSTEM

Transdermal Penetration of Drugs

In the last 45 years or so, many terms have been usedto describe one of the objectives of a transdermaldelivery system, i.e., penetration of a substance from

the outside of skin through the skin and into thebloodstream. Rothman described this as percutane-ous absorption.1 Others have used different termssuch as sorption, persorption, permeation, and pene-tration. All of these relate to passively driven masstransfer; some terms such as sorption, have otherconflicting meanings. No matter how it is referred to,absorption through the skin involves passive diffu-sion through the outer and middle structure of theskin until the systemic circulation is attained.2325

The skin is stratified histologically into the stra-tum corneum, epidermis, dermis, and subcutaneoustissue, and as such it can be considered as a laminateof barriers. This laminate consists of the stratum cor-neum, the viable epidermis, and a portion of the der-mis. For most purposes, the subcutaneous tissue canbe considered not to be involved in percutaneousabsorption, or it may act as a potential depot. Perme-ation can occur dy diffusion via: 1) transcellular pen-etration, through the stratum corneum, 2) intercel-lular penetration, through the stratum corneum, and3) transappendageal penetration, especially includ-ing the sebaceous pathway of the pilosebaceous appa-ratus and the aqueous pathway of the salty sweatglands. The first two mechanisms require furtherdiffusion through the rest of the epidermis and der-mis. The third mechanism allows diffusional leakageinto the epidermis and direct permeation into thedermis.263#{176}

Formulation

The formulation of the transdermal systems is essen-tial for providing suitable delivery rates of drugs. Thecomponents of the system impact on the rate thedrug is released to the skin and on the adherence ofthe device to the skin, and thus on the design of thefinal product.

The drug must be incorporated into some type ofphysical structure that serves as a reservoir andwhich provides for diffusive “communication” ofthe drug with the surface of the skin. This physicalstructure or laminar construction serves as a “plat-form” for the drug. The platform could consist of 1) a



liquid, 2) a semisolid, 3) a nonflowing (three dimen-sional stable) material, or 4) a combination of any ofthese. A liquid by itself is rather impractical for anyextended wearing. However, if well-contained, itcould be made useful. The semisolid platform, ex-emplified by the traditional ointment or semisolidgel material, with containment, is truly acceptablefor wearing on the skin. Even without containment,such materials are ideal for spreading over irregularsurfaces. A three-dimensionally stable material(such as a polymeric film or rubbery gel) has a dis-crete size and shape and can be easily held in hand.This type can be called “solid-state” platform. The“solid-state” delivery system is more amenable forwearing and removing from the skin. On the otherhand, it may not as easily conform to the applicationarea, and complete system-to-skin contact is less cer-tain.

Platforms thus consist of materials that are eitherliquid, semisolid, or solid state. Some investigatorshave referred to these platforms as either monoliths,slabs, reservoirs, vehicles, films, polymer matrixes,or just matrixes. A matrix can be totally amorphousand of varying viscosities, or crystalline, or some ofthe both. If a barrier or some material is placed in thepath of the diffusing molecule so that it controls therate of flux of the drug, it will be referred to as amembrane or film. Hwang and Kammermeyer38have classified membranes in terms of their nature,structure, application, or mechanism of action. Thenature of a membrane can be said to be either natu-ral (such as skin or intestinal walls) or synthetic,(such as polymeric films). Defining membranes struc-turally, they can be either porous (such as micropo-rous polymeric films, filters etc.) or nonporous (suchas films of polyethylene, vinyl, or other polymerscommonly used in packaging).

The analysis of data on matrix- or film-diffusioncan be presented in several formats. The most com-mon methods are to observe either the cumulativeamount of a drug that permeates or by the rate that itdiffuses out of or through a matrix or membrane.Depending on the system selected, the drug willhave a particular release rate profile curve. Mathe-matical diffusion models have been reviewed exten-sively and are useful references.3137

Adhesion

The modern transdermal product is a unique deliv-ery system in that it is worn on the skin. This re-quires good skin contact over the total area of appli-cation, and ease of applying and removing the trans-dermal patch. Also, if the transdermal deliverysystem is made of two or more laminating structures,

good bonding between these layers must take place.Other parts of the system must not adhere well, suchas the release liner (peel-away strip that is removed).If the drug is to be formulated into the adhesive itself,care must be taken to see that the drug or any adhe-sives do not influence the adhesive properties of theadhesive. Along with an understanding of the effectof the formulation on drug release, one has to con-sider tradeoffs with optimized adhesive properties. Agood understanding of adhesion, adhesive proper-ties, and adhesive materials, particularly in relationto pressure-sensitive adhesives, is helpful when deal-ing with these materials. Although the literatureprovides little specific information on pressure-sen-sitive adhesives, there are some reviews on the prac-tical aspects, and others on the theoretical aspects ofadhesives. Generally, the adhesive-cohesive proper-ties, peel strength, tack, and creep qualities of adhe-sives are basic properties used in formulating suit-able pressure-sensitive adhesives. The basic con-struction of pressure-sensitive tapes has beenreviewed in the literature. The facestock or backingcan be a material that is occlusive (serves as abarrier, such as vinyl, polyethylene, polyester films,etc.) or nonocclusive (allows water and gases toreadily flow through, such as nonwoven or porousfilms). The backing serves as a platform or carrier forthe adhesive and is essential for application to andremoval from the skin.39’40

The adhesive layer is pressure sensitive and theanchor of the system. The American Society forTesting and Materials (ASTM) definition of a pres-sure-sensitive adhesive is a viscoelastic materialthat, in solvent-free form, remains permanentlytacky.43 Such material will adhere instantaneouslyto most solid surfaces with the application of veryslight pressure. The adhesive can be removed from asurface such as the skin or release liner withoutleaving a residue. The pressure-sensitive adhesives(called adhesive mass) commonly used in medicalapplications are based on natural or synthetic rub-bers, polyacrylates, or silicone. The release liner(also called release paper or peel-away strip) is asheet that serves as a protectant and/or carrier for anadhesive film or mass, which is easily removed fromthe adhesive mass before use. The release liner con-sists of either paper, polystyrene, polyethylene, poly-ester, or other polymeric films with a light coating ofsuch compounds as silicones, long chain-branchedpolymers, chromium complexes, fluoro chemicals,or various hard polymers.41-42

Bioactivity

Other dosage forms that are intended to deliverdrugs to the systemic regions of the body often pro-

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vide highly fluctuating levels in the blood and tis-sues, especially after repeated dosing. The transder-mal method offers an alternative where such prob-lems do not exist. To determine if the transdermalroute is indeed a workable alternative, one must askwhat problems exist with the current dosage formsof a particular drug. In most cases, the therapeuticeffect of a drug is related to drug concentration.There is an upper and lower limit of a drug that willestablish a “therapeutic window.” In this range, thediseased state can be treated with minimal side ef-fects. Some drugs may have nominal inherent sideeffects in this window but reach toxic proportionswhen higher levels are achieved. When levels go be-low the therapeutic threshold, the drug essentiallybecomes ineffective (e.g., at a subtherapeutic level).Ideally, a drug delivery system should provide druglevels within the limits of the therapeutic window.

To achieve systemic levels from a transdermal de-livery system, the drug must first dissolve in the ma-trix and migrate from the matrix through the skinand into the capillary plexus. Pharmacokinetictreatment of percutaneous absorption in the litera-ture concentrates largely on drugs that permeateinto rather than through the skin. However, Beckettet al.45 compared the transdermal route with the oralroute of four ephedrine derivatives. They showedthat metabolites were formed in lesser amounts andthat the combination of unchanged drug plus its me-tabolites was less using the percutaneous route. Rie-gelman also showed the skin is rate limiting and in-dicated that by adjusting the drug loading, vehiclecomponents, and surface area, prolonged steady-state blood levels can be sustained.81

The use of pharmacokinetic parameters provides auseful tool for the development of transdermal sys-tems. It can allow one to establish what steady-statefluxes of the drug are needed to reach a therapeuticlevel systematically (therapeutic window). Pharma-cokinetic parameters are also important from thebiopharmaceutics point of view as part of the U.S.Food and Drug Administration review for market ap-proval to support drug labeling. Further, the systemmust show reproducibility of plasma levels and thatthese levels are within the therapeutic limits of astandard dosage form.

EXAMPLES OF TRANSDERMAL APPLICATIONS

Transdermal systems such as Nitrodur and Nitrodiscare referred to as monolithic systems because theycontain the drug as a semisolid solution or disper-sion. With these systems, the drug reservoir is manu-factured by dissolution of all components, includingthe polymer that serves as the matrix, with subse-

quent casting and drying. In some cases, the solventmay form the continuous phase of the matrix, andprocessing may involve mixing high-viscosity fluidat elevated temperature before forming the gelledmatrix either in sheet form or as a solid cylinder. Theindividual units must then be punched from thesheet or sliced cylinder.46

Once the drug reservoir that has the specified sur-face area is obtained, it must be assembled togetherwith the system backing, peripheral adhesive, andprotective liner. This process is the most labor inten-sive, and consequently, the most expensive part ofthe manufacturing process. Undoubtedly, in the fu-ture, monolithic systems will be manufactured bymore continuous processes such as extrusion, injec-tion molding, and laminating lines.8285

Transderm-Nitro (Summit, Div. of CIBA, Summit,NJ) and Transderm-Scop (CIBA, Summit, NJ) are ex-amples of membrane-controlled transdermal sys-tems. Their methods of manufacture are somewhatdifferent, however, in that the former is a product oftechnologies that originated in the packaging in-dustry, referred to as form-fill seal, whereas the lat-ter system derives purely from lamination processes.The technologies for both processes are well estab-lished, having been applied for some time in the foodand cosmetics industry. Hence, these processesmake it possible to produce pharmaceutical productsunder GMP regulations (Figure 3).

In the case of form-fill seal systems, the formula-tion of the drug reservoir can be accomplished bytechniques that are used in the pharmaceutical in-dustry. With the processes of lamination, however,dosing of the drug reservoir and heat sealing must berefined and adapted somewhat before the overallmanufacturing process becomes general and routine.Nevertheless, this technology may be closer to find-ing a place in pharmaceutical production than thosetechnologies needed for efficient production ofmonolithic systems.

Hormones. The female reproductive hormones, es-tradiol and progesterone or synthetic gestagens areobvious choices for transdermal delivery. Estradiolis particularly promising because its oral administra-tion causes a large fraction of the dose to be con-verted in the liver to the less active metabolite, es-trone. Transdermal administration avoids most he-patic metabolism and results in therapeutic bloodlevels of estradiol at total doses much lower thanthose required by oral administration.

Cardiovascular drugs. Diseases of the cardiovascularsystem lend themselves readily to transdermal ad-ministration of drugs because of the nature of the

Adhesive Device

Backing

1:. . :l’s- Drug-Containing

Adhesive

Monolithic Device

Backing

.- Rate-Controlling MatrixContaining Drug

‘s-Adhesive

Reservoir Device

Backing

4- -Drug-ContainingReservoir

Rate-ControllingMembrane

“Adhesive



Figure 3. Types of transdermal delivery devices (reprinted with

permission from Pharmaceutical Technology magazine. The Lat-

est Developments in Drug Delivery Systems-I 987 Conference Pro-

ceedings, p. 27.)

diseases. Drug treatment of hypertension and angina

is generally a protracted process, often requiring con-tinuous use for several years. As such, compliancewith the established regimen is important and can bea problem-particularly with hypertension becausethe disease is often asymptomatic giving the patientno incentive to take their medication on time. Thetwo beta blockers, timolol and propranolol, havebeen studied in their free-base forms in skin perme-ation models and have been shown to provide suffi-cient skin permeability to obtain significant bloodlevels. Both of these compounds are used in oral formto treat hypertension and angina. Neither of these iscardioselective, and several of the hepatic metabo-lites of propranolol are active beta-adrenergic antago-nists. Timolol has been introduced in an ocular for-mulation for the treatment of ocular hypertension(glaucoma). It has a potential advantage in this appli-cation because it lacks a membrane-stabilizing effectthat produces local anesthesia. It is not yet knownwhat significance local anesthesia at the site of appli-cation may have on the acceptance of a transdermal

system. It seems likely, however, that both timolol

and propranolol administered transdermally would

have some efficacy in reducing the blood pres-sure.47’

Analgesics. Compounds used to control pain con-

tinue to be of interest to many folks in the medicaland pharmaceutical communities. It is important,however, to understand when a transdermal deliv-ery system, or any controlled delivery system for

that matter, is an advantage in the control of pain.Clearly the amelioration of acute pain requires fastonset of action and probably is not an appropriate use

of transdermal therapy. Still, control of chronic painmay well lend itself to transdermal therapy. At least

one group has studied transdermal delivery of salicy-lates. It appears, however, that dosing requirementsmay prove too great for common nonnarcotic analge-

sics. At the same time, many fundamental questions

regarding the development of tolerance during con-tinuous dosing must be answered before any trans-dermal analgesics can become a reality.49

Antihistamines. There may be a need for continuousdelivery of both over-the-counter (OTC) and pre-scription antihistamines, particularly in the treat-ment of certain allergies. At least one firm is develop-ing a transdermal delivery system for chlorphenira-

mine. The primary advantage’ of continuous

transdermal delivery of antihistamines is the possi-bility of maintaining histamine-receptor antagonismwhile reducing the occurrence of CNS side effects

such as drowsiness. Because chiorpheniramine has arelatively long half-life, it is believed that its trans-dermal administration may not provide major ad-vantages in dosing the interval, unless the systemcan be designed to last more than 1 day. Substantialbenefit in minimizing the side effects, however, maywell overcome modest benefits in duration of effect.The primary drawback to transdermal administra-tion of anti-histamines, particularly the tertiaryamines, is the possibility of skin irritation and/orhypersensitization. These problems must be ad-dressed early in the development phase.

Central nervous system drugs. In a paper that de-scribed skin permeability of physostigmine, a cho-linesterase inhibitor, the authors studied a transder-mal system that delivered the drug at a sufficientrate through pig skin, in vivo, to inhibit the break-down of acetylcholine by 30% to 40% over 4 days.This mode of treatment could have far-reaching ef-fects for certain dementias involving central acetyl-choline deficit, including Alzheimer’s disease. Onemust, however, be cautious, because physostigmine

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is not specific to the CNS and peripheral side effectsmust be carefully controlled. Nonetheless, this sys-tem provides a convenient means of delivering phy-sostigmine at a controlled rate to the systemic circu-lation - bypassing hepatic metabolism - over along period. It should prove useful in studying thetreatment of these diseases and their responses tocholinestrase inhibition. Table I contains a partiallist of transdermal controlled-release products anddevices.

Iontophoresis. An alternate way to drive drugsthrough the skin that seems to be enjoying a revivalof interest is iontophoresis. In this method, a battery

is connected to two electrodes on the skin. If ionized

drug is placed in contact with one electrode, it willmigrate under the influence of the voltage gradientthrough the skin and enter the systemic circulation.Very large enhancements can be obtained in thisway (Figure 4).

The earliest patents describing the essential fea-tures of iontophoresis date back to the 1890s, al-though apparently their objective was to shock theirsubjects rather than drug them. The first modern de-vice appeared in 1972, and advances since then haveenabled smaller and smaller devices to be built. Thenewest devices, from Drug Delivery Systems, have abuilt-in battery layer and are comparable in size to a

TABLE I

Partial List of Transdermal Controlled-Release Products and Devices

Drug Trade Name Type of Device Indication

Scopolamine (Hyoscine) Transderm-Scop Reservoir Motion sicknessKimite Patch

Nitroglycerine* Transderm-Nitro Reservoir AnginaDeponit Mixed monolithic Angina

reservoirNitro-Dur Monolithic AnginaNitrodisc Monolithic AnginaNTS Monolithic Angina

lsosorbide-Dinitrate Frandol Tape Monolithic AnginaClonidine Catapress-TTS Reservoir HypertensionEstradiol Estraderm Reservoir and ethanol Hormone treatment

enhancerEstradiol esters - t Hormone treatmentTestosterone - t Hormone treatmentTimolol - t CardiovascularPropranolol - t CardiovascularFentanyl Duragesic - Opioid AnalgesicGlycol Salicylate - t AnalgesicMethyl Salicylate

Chlorpheniramine - t AntihistamineDiphenhydramine Zenol - AntihistaminePhysostigmine - f Cholinergic

Insulin - t DiabetesNicotine - t Aid to Smoking

CessationAlbuterol - I’ BronchodilatorPiroxicam - t ArthritisKetorolac (Toradol) - t Non-narcotic

analgesicFlurbiprofen Zepolas - Anti-inflammatoryIndomethacin Indomethin - Anti-inflammatoryBufuralol - I Angina, hypertensionBupranolol - t Angina, hypertension,

antiglaucoma agent

* Other trade names are Diafusor, Minit ran, Nitriderm, Nitrol Patch, Nitrocine,Deponit, Millistrol Tape, and Herzer.

t In research and development.

Battery

111111

Solution of SaltCithode Solution

4\ A’ lNa

Skin

Current



Figure 4. Schematic diagram illustrating the principles of ionto-

phoresis (reprinted with permission from Pharmaceutical Technol-

ogy magazine. The Latest Developments in Drug Delivery Systems-1987 Conference Proceedings, p. 31.)

normal transdermal patch. The patents in this areaso far deal with device design and do not specify par-ticular drugs. There is considerable potential for in-novative work in this specialized area.5#{176}

The iontophoretic system currently marketed(Phoresor, Motion Control Inc., Salt Lake City, UT)uses a continuous, waveless, unidirectional currentof low voltage (DC). All ions are either positive ornegative. For a drug to be phoresed, it must be ioniz-able, and its polarity must be determined. The drugis then injected into a reservoir in the active pole(electrode). This electrode is smaller than the inac-tive or indifferent electrode to concentrate the ef-fects of the drug. When the pads are placed, theyshould be as directly opposite each other as possible(that is, on either side of the elbow). When the sys-tem is activated, the drug is driven out of the activepole toward the inactive pole. The inactive pole, be-ing the opposite polarity of the drug, will thereforeattract, allowing the drug to be distributed to the tis-sues between the two electrodes.

Human skin has a limited tolerance for flow ofelectric current, therefore the unit must be turnedon and off slowly to avoid muscle stimulation. Turn-ing the unit on or off suddenly, changing the elec-trode placement, or changing the polarity while theunit is running may cause the patient to receive ashock. When lower voltages are used, the patientwill have less sensation of penetration, but the levelof drug penetration will also be lower. The amount ofdrug that is delivered is equal to the current that isapplied times duration of treatment. The recom-mended treatment time is 20 minutes, and the recom-mended maximum current is 4 mA. Therefore, the

amount of drug that is delivered would be 80 mA/mm. lontophoresis is currently used for treatment ofacute musculoskeletal and neuromuscular inflam-matory problems, using a mixture of lidocaine anddexamethasone or dexamethasone alone. Lidocainealone is also used for local anesthesia. Many drugsare being studied for the feasibility of their deliveryvia iontophoresis. They are listed in Table II.

Other Transdermal Systems. Lectec Corporation(Eden Prairie, MN) has developed a solid state, hydro-philic reservoir system that uses body heat and hu-midity to hydrate the skin and allows the diffusion ofdrug through the skin for systemic absorption.

Health-C hem Corporation (New York, NY) has de-veloped a transdermal laminar system that releasesdrug by using different polymers in the reservoir andprotective layers. The Zetachron Company has de-veloped its own transdermal system that can slowdown skin permeation of drugs that are highly per-meable. This is very useful in transdermally deliver-ing low-dose, potent drugs such as antihypertensiveand antianginal agents. Its transdermal systems arebelieved to be easier to manufacture than conven-tional transdermal patches.

The Elan Company (Ireland) has developed twotransdermal systems, Dermaflex and Panoderm.Both of these systems are to be worn like bracelets.The active ingredients are absorbed from the brace-let by electrical impulses.

The Moleculon Biotech Company (Cambridge,MA) has developed a poroplastic membrane system.This system is a molecular sponge that can holdwithin its pores a large quantity of solid solubilizedcompounds. This membrane system is very flexible.

TABLE II

Drug Use

Lidocaine AnesthesiaDexamethasone ArthritisHydrocortisone ArthritisAcetic acid Calcified tendinitisIodine Scar tissue removalPenicillin BurnsSalicylates Arthritis, myalgiasHistamine Peripheral vascular diseaseHyaluronidase EdemaLithium Gouty arthritisMagnesium ArthritisCalcium MyospasmCopper Fungal infectionsZinc Scars, adhesionsAcetate Calcifications

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It can alter release rate by adding various com-pounds to deliver drugs from a few hours to months.

Finally, some examples of skin applications are: 1)

pressure-sensitive adhesive compositions containingchlorhexidine or PVP-1 and iodine as antimicrobialagents and for administering Tretinoin for acne,86 2)

topical treatments for dermatologic conditions, e.g.,tricyclic antidepressants such as imipramine, ami-tryptyline, and doxepin for pruritis and anthracen-one derivatives for psoriasis, and87 3) antiphiogisticanalgesic adhesive that contains indomethacin forarthritis.88

RECENT ADVANCES

1. Transdermal drug absorption can be enhanced

to a degree by various chemical and physical meth-ods. Chemical enhancers exert their influence on lip-ids in the stratum corneum as well as on lower der-

mal layers and possibly capillary beds. Physical en-hancers seem to promote the penetration of thestratum corneum, whereas diffusional permeationseems to be important in the lower layers of the skin.In addition, the effect that the chemical enhancersmight have on the activity of the drug in the deliverydevice must always be considered. Further, a meansof enhancement that can provide reproducibletransdermal delivery through a variety of skinsunder various conditions in needed. lontophoresishas an advantage over chemical methods because it

apparently offers better control of transdermal drugdelivery. However, it requires a device separate fromand in addition to the drug delivery reservoir andtherefore often is considered cumbersome to use anduncertain from a regulatory standpoint. This is animportant consideration for companies that attemptto commercialize such a product. Rolf in this discus-sion, has also described some examples of ampho-teric enhancers such as sodium lauryl sulfate, laurylamine oxide, Azone, (Laurocapram, Nelson Re-search Corp., Irvine, CA.) decylmethyl sulfoxide,lauryl ethoxylate and octanol.51

2. Using the cell or the cylinder method, Aiache etal. have evaluated the rate of release and dissolutionof trinitrine from a membrane reservoir transdermicdelivery system. Both methods yielded the same re-sults in terms of the quantity of drug released perunit area per hour and thus ensure a satisfactoryquality control of the system. Regardless of themethod used, the drug release is zero-order at 1 hourafter diffusion and thereafter. The authors concludethat the method proposed by the supplier (the cylin-der method) is validated against that described bythe pharmacopoeia.52

3. Despite the great need for effective transdermalpermeation enhancers, the search is still largely em-

pirical. Very few studies have involved systematic

evaluation of enhancer congeners. The enhancercongeners that have been evaluated by Chow andHseih include surfactants of alkyl sulfates, saturatedfatty acids, fatty alcohols with different numbers ofdouble bonds, unsaturated fatty acids with equalnumbers of double bonds at different positions or

with different configurations, and cyclic compoundswith various carbon numbers and sizes.53

4. Pressure-sensitive adhesives (PSAs) are neces-

sary components in transdermal systems becausethey ensure intimate contact of the device with theskin. PSAs are used in many system designs that canbe configured using an adhesive overlay face adhe-sive, adhesive matrix, and multilaminated PSA ma-trix. The science and engineering involved in theselection, formulation, and optimization of PSA prop-erties is critical to the successful development oftransdermal systems. Adverse interactions between

the drug, excipients, cosolvents, and permeation en-hancers in reservoir or matrix-type systems cancompromise the performance of the adhesive, result-ing in system failure.54

5. The skin is a vital metabolic and immunocom-

petent organ that serves as the first line of defense of

the body against environmental attack. Certainchemicals, however, are capable of producing imme-diate and delayed hypersensitivity reactions withinthe skin by interacting directly or indirectly with via-ble cells in the epidermis and dermis. These cellsalso contain receptors for many autocoids and cyto-kines, which makes the cells susceptible to appro-priate concentrations of drugs and other structurallyanalogous xenobodies. For these reasons, the deliv-ery of drugs through the skin might produce adversereactions by affecting responsive cells. Dunn has dis-

cussed work regarding the biologic response ofwhole skin and isolated epidermal keratinocytes tophorbol esters, potent drugs, irritants, and mito-gens.55

6. The article by Pfister illustrates how siliconepressure-sensitive adhesives (PSA5) can be custom-ized to accommodate specific drug, material, andcoating requirements of transdermal delivery sys-

tems. Physicochemical properties of silicone PSAsand their end-use properties such as tack, adhesion,and cohesive strength are characterized. The articlealso describes how these properties can be variedeither chemically - by altering silanol functionally,resin-to-polymer ratio, or choice of solvent - orphysically - by adjusting coating thickness. Finally,relationships between silicone PSAs and drug re-lease kinetics are addressed and methods of develop-ing formulations to optimize system performance aresuggested.56



7. Because of the side effects that are associatedwith the oral administration of tetra-hydrocanna-binol (THC), Touitou et al. tested the use of the skinas a noninvasive portal for the sustained delivery ofthe drug. Rat skin was found to be approximately 13

times more permeable than human skin. Autoradio-graphs showed that after 24 hours, the drug was con-centrated in the stratum corneum, in the upper epi-dermis, and around the hair follicles, which suggeststhat THC penetrates through the lipophilic path-ways.57

8. Touitou et al. tested the permeation enhance-ment properties of n-decyl methyl sulfoxide (decylMSO) in the presence of water and propylene glycolin vitro through hairless mouse skin. 5-Fluorouraciland idoxuridine were used as test drugs because oftheir respective hydrophilic and hydrophobic prop-erties. Results showed that the enhancement of per-meation of decylMSO occurred only in an aqueousmedium and only at concentrations greater than thecritical micelle concentrations.58

9. Ashton et al. investigated the influence of so-dium lauryl sulfate (SLS) and Brij 36T on the thermo-dynamic activity of methyl nicotinate in aqueousgels. The permeability of skin in vivo was assessed bymeasuring the time required for nicotine esters andhexyl nicotinate in aqueous gels. The time requiredfor SLS gels to cause erythema correlates with the invitro release rates. Because SLS is considered to be apowerful penetration enhancer, the results of thisstudy indicate that these two surfactants exert theirinfluences in different ways.59

10. Key Pharmaceuticals (Miami, FL) has receivedapproval to market Nitro-Dur II (nitroglycerine)Transdermal Infusion System for prevention of se-vere angina pectoris. Applied once a day to the chestor upper arm, it delivers nitro-glycerine for a full 24hours.

11. Cygnus Research, (Redwood City, CA) in col-laboration with Family Health International, is devel-oping a weekly contraceptive patch. Patches wouldbe replaced weekly for 3 weeks, and a drug-freepatch worn on week 4.

12. Forest Laboratories (St. Louis, MO) has formu-lated nitroglycerine in a transdermal polymer gel.The gel, which Forest will market itself, is applied inliquid form to the skin where it quickly dries and isabsorbed.

13. A transdermal formulation of ketoprofen fororthopaedic use is being developed by Hisamatsu forthe treatment of osteoarthritis, tenditis, and bursitis.The formulation comprises a flexible pad and adhe-sive layer that contains the water-based drug.

14. MacroChem has filed a patent application forenhancing the transdermal delivery of minoxidil.

This technology will be employed in the Dermelecproduct of the company - a transdermal device tobe worn and adjusted by patients to control the rateand amount of dosage.

15. Beiersdorf is developing a transdermal patchthat contains moxonidine for the chronic treatmentof hypertension. The patch is designed to liberate atherapeutic 24-hour dose of moxonidine for a dura-tion of 7 days.

16. Transdermal delivery of glibenclamide fromthe polymeric matrices of Eudragit, ethylcellulose,hydroxypropylmethyl cellulose, polyvinyl pyrroli-done carboxymethyl cellulose, and polyvinyl ace-tate with plasticizers was studied. It was observedthat the permeation rate was enhanced dependingon the type and the concentration of the enhancers.The advantage of using enhancer combination wasalso observed.60

17. Occlusion of skin under a transdermal patchmay facilitate the occurrence of adverse dermal reac-tions. To minimize such reactions, the authors havedeveloped a novel system that is ultrathin, breath-able (oxygen and moisture permeable), and has ex-cellent conformability to the skin. This system is ide-ally suited for topical application of medications,such as anti-inefective, anti-inflammatory, and anti-fungal agents, and for transdermal delivery of rela-tively nontoxic and nonvolatile drugs. They investi-gated a patch construction incorporating chlorhexi-dine diacetate for use as an antiseptic dressing forwound and other applications.61

18. During the course of work on the developmentof a transdermal levonorgestrel (LN) delivery system,the authors investigated a number of permeation en-hancers that could be used in conjunction with eth-anol to achieve therapeutically effective fluxes of LNthrough the intact stratum corneum. The effective-ness of this enhancer for 5-fluorouracil, estradiol,and hydrocortisone was also studied.62

19. The article by Bodde et al63 focuses on twoaspects of transdermal peptide delivery: transepider-mal penetration and intra(epi)dermal biotransforma-tion, taking the example of desenkephalin endor-phin, a highly potent neuropeptide. In vitro studieswith this peptide using both intact human skin sam-ples and cultured human skin cells, showed trans-dermal fluxes (without enhancers). From these re-sults, it is anticipated that the transdermal deliveryof small peptides, even hydrophilic ones, is a distinctpossibility.

20. Based on the long-term physical and chemicalstability results, a transdermal contraceptive (TCS)formulation was selected. Extensive effort was de-voted to the development of process and equipmentfor the scale-up manufacturing of TCS patches. A

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continuous operation-type fabrication machine(SFM) was designed. The patches so fabricated wereevaluated by measuring their weight variation, con-tent uniformity as well as the release and skin perme-ation rates of levonorgestrel and estradiol against thepatches prepared by hand-operated, compression-coated (HCC) process, which was used in the formu-lation development phase.

21. A transdermal delivery system for verapamilwas developed and applied for a 24-hour period onthe chest skin of eight healthy male volunteers. Theplasma concentration was monitored during 48hours after the onset of system application. Not onlyverapamil, but its active metabolite (norverapamil)also were detected in the plasma. The plasma con-centration reached a steady-state within about 10hours after the system application. The clinical datawas found to be predictable from the in vitro pene-tration study using hairless mouse skin by the help ofcomputer simulation technique.65

22. A transdermal polymeric delivery system forhydromorphone was developed. Various penetrationenhancers such as isopropylmyristate, 1-dodecylaza-cycloheptan-2-one (Azone), hexamethylene palmi-tamide, hexamethylene lauramide, aliphatic acids,alcohols, and esters were incorporated in the poly-mer matrix. The rate of drug penetration across hair-less mouse skin increased and the time-lag de-creased as the enhancer concentration increased.Hexamethyl lauramide improved the penetration ofhydromorphone most significantly among the en-hancers that were investigated.

23. The transdermal route offers several advan-tages over other routes of administration. However, akey problem is the low permeability of skin to mostdrugs. Low-skin permeabilities require impracti-cally large devices if useful drug delivery rates are tobe achieved. Potent drugs that are effective at lowdosage rates, and hence, do not demand large de-vices, are promising candidates for the transdermaldelivery route. Levonorgestrel (LN) is one such drugand is capable of suppressing ovulation.67

24. A multilaminate-type transdermal drug deliv-ery (mTDD) system was recently developed for con-trolled administration of various drugs. The skin per-meation rates of progestins and other drugs werefound substantially enhanced, to varying degrees, byreleasing different types of skin permeation en-hancers from the surface adhesive layers to modifythe skin permeability of drug.

25. BIOTEK (Burlington, VT) has developed a Uni-versal Transdermal Delivery System, which ishighly versatile and adaptable to a wide variety ofdrugs and dosing requirements. Its unique featuresinclude a macroporous non-rate controlling mem-brane, a viscous liquid base as a solvent for the drug,

and suspended drug microparticles as reservoirs.After application, the system maintains a thin film ofdrug solution in direct contact with the skin, provid-ing for skin occlusion. The system is compatible withenhancers and additives, and its delivery rate andduration are controllable by formulation variables.The system has been evaluated in vitro and in vivo

for the simultaneous delivery of estradiol and levon-orgestrel.69

26. Polydimethylsiloxane (PDMS) pressure sensi-tive adhesives (PSAs) are used in transdermal drugdelivery systems, in part because of the excellent bio-compatibility and the high permeability of this classof materials. BIO-PSA(R) 355 silicone pressure sensi-tive adhesive is well suited as a contact adhesive inreservoir type delivery systems. Its properties aresomewhat compromised, however, when co-formu-lated with amine-functional agents. BIO-PSA(R) Q7-2920 was developed to exhibit amine-resistance.PSA either functions as contact adhesive or may po-tentially act as a drug-loaded adhesive matrix, a con-ceptually simple, yet technologically complex drugdelivery system. Preliminary suitability of BIO-PSA(R) Q7-2920 as a drug-loaded matrix was deter-mined by characterizing the release kinetics of nitro-glycerine, indomethacin, estradiol, progesterone,propranolol and testosterone from the PSA, and test-ing the adhesive tape properties (release, adhesionand tack) of the drug-loaded matrices as a function oftime.7#{176}

27. Since the adhesive matrix material can de-crease the release rate of the active ingredient, it wasbelieved to be non-adhesive diffusion matrix systemby use of its improved delivery characteristics, whileat the same time, maintaining direct contact with theskin. There are already transdermal systems on themarket where the non-adhesive diffusion matrix isplaced directly on the skin and held in place, i.e., bysurrounding adhesive stripe. However, since it isknown that in several cases the area of the non-ad-hesive matrix is large to maintain this type of matrixin an intimate contact with the skin, it was decidedintentionally to develop transdermal systems show-ing, besides the improved delivery characteristics,especially a significantly better skin contact. Atransdermal drug delivery system containing textilefabrics was developed.71

28. Actibase (Schering Corp., Kenilworth, NJ) is anoptimized vehicle of propylene glycol, propyleneglycol stearate, white wax, and white petrolatumused in the topical formulation of betamethasone di-propionate.93

29. Erythromycin that was formulated with a hy-droalcoholic solution composed of ethanol and pro-pylene glycol seems to be effective, as does tetracy-cline, (e.g., Topicycline, Proctor & Gamble, Cincin-



nati, OH) formulated with the enhancer decylmethyl sulfoxide.93

30. Actiderm (Bristol Myers Squibb, Princeton,NJ), a patch that does not contain any drug, was re-cently introduced for use as an occlusive dressing.The patch is placed over topically applied corticoste-roids to enhance their efficacy by promoting hydra-tion of the stratum corneum. This treatment leads toenhanced percutaneous absorption and prolonged ac-tivity, thus minimizing the need for high-potency ste-roidsY4

31. Hercon has developed the laminated reservoirsystem for the controlled-release transdermal deliv-ery of agents to the systemic circulation, achievingsteady-state blood levels for extended periods whileminimizing side-effects. The system is thin and flex-ible and consists of 2 to 4 layers including a backingmembrane, the drug reservoir, a rate-controllingmembrane and an adhesive that holds the system tothe skin. The system is suited to compounds that re-quire 1-day or 7-day frequency of delivery. Herconhas signed agreements with several pharmaceuticalcompanies to develop and/or market its polymerictransdermal system for selected products that in-clude antiarthritics, antiemetics, antihistamines,beta-blockers, antihypertensives, antiasthmatics,antiaddictives, calcium antagonists, tranquilizers,and hormonal agents.

CONCLUSION

There are many factors to be considered in designinga delivery system for a drug to be applied to the skin.Certain aspects such as drug stability, physical stabil-ity of the formulation, irritation and sensitizationproperties, preservation, and aesthetic acceptabilityare all critical parameters. None of these consider-ations can be neglected in developing a new drug fortransdermal delivery. There is little doubt that thevehicle can grossly affect drug bioavailability, andthus, influence the clinical efficacy of the drug. Un-fortunately, there is no blueprint that can be fol-lowed to ensure development of an optimal product.Much depends on the specific pharmacologic proper-ties of the drug, its physical-chemical properties, andits clinical function. In addition, there can be no as-surance that maximizing drug penetration into theskin is, in every case, synonymous with optimizingdrug delivery. Topical products are applied to theskin that has been completely stripped of its barrierproperties and also to skin that is anatomically intactand enormously resistant to drug diffusion. Thesetwo situations only define the extremes as far as thediffusional resistance of skin is concerned. It shouldbe recognized that the same topical product cannot

be ideal, in terms of drug bioavailability, for everytype of skin disease or for every patient.7274

There is no doubt that the physicochemical proper-ties of the drug determine the ease or difficulty withwhich it passes through the skin barrier. However, inview of recent evidence, the vehicle must be re-garded as something more than an elegant diluent inwhich the drug is placed to ensure its uniform con-tact with the skin surface. If the intent is to manipu-late the diffusion rate of a drug across the skin, thereare two general mechanisms by which this might beaccomplished. One is to change the degree of inter-action between drug and vehicle, i.e., affect the ther-modynamic activity of the drug. The other is to pro-duce changes in the stratum corneum that will affectits diffusional resistance. In general terms, one candescribe these two approaches as involving eitherdrug-vehicle interactions or vehicle-barrier inter-actions. Both effects are generally involved, and dis-tinction of the specific mechanism may be difficult.Careful characterization of the physical properties ofthe delivery system and the solubility and the parti-tioning properties of the drug in this system will aidconsiderably in analyzing subsequent in vitro and invivo penetration data that involves human skin.

There seems to be little question that the skinowes its principal barrier properties to the thin layerof keratinized, epithelial cells that comprise the“dead” surface layer of the epidermis. This layer offlattened, closely packed cells is known as the stra-tum corneum or the horny layer. For the great major-ity of substances, diffusion through the stratum cor-neum represents the rate-limiting step in percutane-ous absorption. Almost all substances that are usedas drugs can be expected to penetrate even intactskin to some degree. Even particles of more than mac-romolecular size appear to pass through skin, al-though the rates are infinitesimally small. Charac-teristically, the penetration rate of most drugs will besmall and only a fraction of the total dose that isapplied to the skin will reach the systemic circula-tion and be excreted. Obviously if a finite rate ofabsorption occurs, the drug will ultimately be com-pletely absorbed if it remains on the skin surface. Inpractice, much of the drug, along with the debris ofthe vehicle in which it was applied, will be removedby contact with dressings, clothing, and other objectsor simply be washed off by the patient. Because theskin is a complex, biological barrier that is not yetfully understood, generalizations about its relativepermeability to different types of compounds mustbe made with considerable caution.

Transdermal therapy appears to be on the brink ofa rapid expansion for the rate-controlled administra-tion of potent, non-allergenic agents with suitablephysicochemical properties, where current methods

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of administration cause problems. One unreasonablyoptimistic estimate is that by the midl99Os, 70% ormore of all drugs will be delivered by the transder-mal patch system. However, because of the con-straints that arise from drug potency, skin permeabil-ity, or topic reaction, transdermal administrationmay not become the preferred dosage route for ahigh percentage of drugs. There are additional prob-lems with, for example, cutaneous metabolism andthe fact that a small volume of the skin has to sufferthe entire body load of a drug. Possibilities for thefuture include making more use of prodrugs, pene-tration enhancers, and specific non-toxic enzyme in-hibitors to diminish drug degradation. There is a defi-nite need for a significant expansion in researchwork on the fundamentals of skin metabolism as iteffects drug destruction and prodrug activation.7578

A challenge for drug therapy in the future is toefficiently deliver the peptide drugs that arise fromthe biotechnology revolution. At present, simple ap-plication to the skin of a peptide in a vehicle wouldproduce suitable clinical effects. One possible ap-proach would be to develop delivery devices thatwould synchronize the insertion of a suitable pene-tration enhancer into the stratum corneum togetherwith the peptide. Another possibility would be toemploy iontophoresis, a technique that has beenused for a number of ionic drugs, and possibly com-bine it with the use of suitable penetration en-hancers.79’80’89’9#{176}

Alternately, drug molecules could be redesignedto achieve higher skin penetration. Most drugs in themarket today were not only structured to elicit a par-ticular pharmacologic response, but also designed tohave suitable solubilities, particularly with respectto oral and parenteral dosage forms. More lipid solu-ble molecules (prodrugs) could be made fromcurrently approved drugs to provide a more favor-able prognosis for the transdermal approach in casesin which the drugs do not have the requisite physico-chemical attributes.91’92’95

The author thanks Dr. Jacob J. Plattner for his helpful com-ments, Mr. Bipin K. Shah for his support, and Usha Ranade for herhelp in the preparation of the manuscript.

REFERENCES

1. Cleary CW: Transdermal controlled release systems, in, RSLanger, DL Wise,(eds.) Medical Applications of Controlled Release.Vol. I, Boca Raton, FL: CRC Press Inc., 1984; 203-251.

2. Kydonieus AF: Controlled Release Technologies: Methods,Theory and Applications. Vol 1 & II. Boca Raton FL: CRC Press Inc.1987; 213.

3. Juliano RL (ed.): Biological approaches to the controlled deliv-ery of drugs. Ann NY Acod Sci 1987;507: 364.

4. Chien YW, (ed): Transdermal Controlled Medications. NewYork: Marcel Dekker Inc., 1987; 440.

5. Barry BW: Johnson P, Lloyd-Jones JG,(eds.) Transdermal DrugDelivery in Drug Delivery Systems: Fundamentals and Tech-niques. Chichester, England: Ellis Horwood Publishers, 1987; 200-223.

6. Idson B: Percutaneous absorption in topics in medicinal chem-istry, in, Rabinowitz, Myerson RM (eds.) Absorption PhenomenaNew York: Wiley (Interscience),1976;4: 181.

7. Katz M: Design of topical drug products: Pharmaceutics, in,Ariens EJ (ed.) Drug Design New York: Academic PressInc.,1973;IV: 93-148.

8. Katz M, Poulsen BJ: Absorption of drugs through the skin, in,Brodie BB, Gillette J, (eds.) Handbook of Experimental Pharmacol-ogy New York: Springer-Verlag, 1971;28: 103.

9. Poulsen BJ: Design of topical drug products: Biopharmaceutics,in, Ariens EJ (ed.) Drug Design New York: Academic Press1973;IV:149-192.

10. Higuchi T: Pro-drug, molecular structure and percutaneousdelivery, in, Roche B (ed) Design of Biopharmaceutical PropertiesThrough Prodrugs and Analogs Washington, DC: American Phar-maceutical Association, 1977;409-421.

11. Scheuplein RJ: The skin as a barrier, skin permeation, sitevariation in diffusion and permeability, in, Jarret A (ed.) The Physi-ology and Pathophysiology of the Skin, London: Academic PressNew York, 1978; 1669, 1693, 1731.

12. Flynn GL: Topical drug absorption and topical pharmaceuti-cal systems, in, Banker CS, Rhodes CT (eds.) Modern Pharmaceu-tics, New York & Basel: Dekker, 1979; 263.

13. Chien YW: Novel Drug Delivery Systems. New York& Basel:Dekker, 1982; 149.

14. Schafer H, Zesch A, Stuttgen C: Skin Permeability, New York:Springer-Verlag, 1982.

15. Bronaugh RL, Maibach HI teds.): Percutaneous Absorption,

New York & Basel: Dekker.

16. Denyer SP, Guy RH, Hadgraft J, Hugo WB: The microbial deg-radation of topically applied drugs. J Pharm Pharmacol 1985;37:89.

17. Wester RC, Noonan PK: Relevance of animal models for percu-taneous absorption mt j Pharm 1980;7: 99.

18. Noonan PK, Wester RK: Cutaneous metabolism of xenobio-tics, in, Bronaugh RL, Maibach HI (eds.) Percutaneous Absorption.New York & Basel: Dekker, 1985; 65.

19. Guy RH, Hadgraft J: Pharmacokinetics of percutaneous ab-

sorption and concurrent metabolism. mt j Pharm 1984;20: 43.

20. Marty JP, Guy RH, Maibach HI: Percutaneous penetration as amethod of delivery to muscle and other tissues, in, Bronaugh RL,Maibach HI (eds.) Percutaneous Absorption. New York & Basel:Dekker, 1985.

21. Woodford R, Barry BW: Penetration enhancers and the percu-taneous absorption of drugs: An update. J Toxicol Cut Ocular Toxi-col 1986; 5: 165.

22. Southwell D, Barry BW, Woodford R: Variations in permeabil-ity in human skin within and between specimens. mt j Pharm1984;18: 19.

23. Schuplein RJ, Blank IH: Permeability of the skin. Physiol Rev1971;51: 702-747.

24. Schuplein RJ: Molecular structure and diffusional processesacross intact epidermis, Report #7, Maryland: Edgewood Arsenal,1966.

25. Ebling FJ: Dermototoxicology and Pharmacology, MarzulliFN, Maibach HI,(eds.) New York: John Wiley & Sons 1977; 56.



26. Barr M: Percutaneous absorption. I Pharm Sci 1962;51: 395-409.

27. Katz M, Paulsen BJ: Corticoid, vehicle and skin interaction inpercutaneous absorption. I Cosmetol Chem 1972;23: 565.

28. Shaw JE, Taskovich L, Chandrasekaran SK: Properties of skinin relation to drug absorption in vitro, and in vivo, in, Drill VA(ed.) Current Concepts in Cutaneous Toxicity. NY: AcademicPress 1980; 127.

29. Elias PM: Epidermal lipids, membranes, and keratization. IntlDermatol 1981;20:1-19.

30. Wepierre J, Martz JP: Percutaneous absorption of drugs.Trends Pharm Sci 1979;1: 23.

31. Crank J: The Mathematics of Diffusion. London: Oxford Uni-versity Press, 1956.

32. Higuchi WI: Diffusional models useful in biopharmaceutics. JPharm Sci 1967;56: 315-324.

33. Baker RW, Lonsdale HK: Controlled release mechanism andrates, in, Tanquary TC, Lacy RE (eds.) Controlled Release of Biolog-

ically Active Agents, NY: Plenum Press Inc., 1974; 15.

34. Crank J, Park CS (eds.): Diffusion in Polymers. London: Aca-demic Press, 1968.

35. Flynn GL, Yalkowski SH, Roseman TJ: Mass transport phe-nomena and models: Theoretical concepts. I Pharm Sci 1974;63:479-510.

36. Flynn CL: Influence of physico-chemical properties of drugand system on release of drugs from inert matrices, in, TanquaryTC, Lacy RE (eds.) Controlled Release of Biologically Active AgentsNY: Plenum Press, 1974; 72.

37. Langer R: Polymer delivery systems for controlled drug re-lease. Chem Eng Commun 1980; 6.

38. Hwang S, Kammermeyer K: Membranes in separations, in,Weissberger A (ads.) Techniques of Chemistry. NY: Wiley-Inter-science 1975; 3.

39. Kaeble DH: Physical Chemistry of Adhesion. NY: John Wiley &Sons, 1971.

40. Wake WC: Theories of adhesion and uses of adhesives, a re-view. Polymer 1978;19: 219.

41. Fukuzawa K, Satas D: Packaging tapes, in, Satas D (ed.) Hand-book of Pressure Sensitive Adhesive Technology. NY: Von Nos-trand Reinhold, 1982; 426.

42. Adair WH: Pressure sensitive fastening systems. Adhes Age1975;18: 31.

43. ASTM Designation D 907: 74 Stanford Definitions of TermsRelating to Adhesives. Philadelphia: American Society for Testingand Materials, 1974.

44. Higuchi T: Design of chemical structure for optimal dermaldelivery. Curr Prob Dermatol 1978;7: 121.

45. Beckett AH, Gorrod JW, Taylor DC: Comparison of oral andpercutaneous routes in man for the systemic administration ofephedrines. Pharm Pharmacol 1972;24: 65P.

46. Good WR: Transdermal drug delivery systems, in, The LatestDevelopments in Drug Delivery Systems Conference Proceedings.Pharm Tech 1985;40-48.

47. Vlasses PH, Ribeiro L, Rotmensch H, et aI: Initial evaluation oftransdermal timolol: Serum concentrations and beta blockade. JCardiovasc Pharmacol 1985;7: 245-250.

48. Nagai T, Yoshiaki S, Nambu N, Machida Y: Percutaneous ab-sorption of propranolol from gel ointment in rabbits. J Control Rel1985;1: 239.

49. Rabinowitz IL: Absorption of labeled triethanolamine salicy-late, in, Proceedings of the 12th International Symposium on Con-trolled Release of Bioactive Materials, July 8-12, 1985. Control Rel

Soc 1985;347.

50. Baker RW, Farrant J: Patents in transdermal drug delivery, in,The Latest Developments in Drug Delivery Systems. Pharm Tech1987; 26-31.

51. RoIf D: Chemical and physical methods of enhancing trans-dermal drug delivery. Pharm Tech 1988;12: 130-140.

52. Aiche JM, Cardot JM, Aiche S: mt J Pharm 1989;55: 147-155.

53. Chow DSL, Hsieh D: Structure-activity relationship of perme-ation enhancers and their possible mechanisms. Pharm Tech1989;13: 37.

54. Pfister B: Compatibility of permeation enhancers with pres-sure-sensitive adhesives used in transdermal systems. PharmTech 1989;13: 37.

55. Dunn JA: Safety and toxicity considerations in the design oftopical drug delivery systems. Pharm Tech 1987;11: 47.

56. Pfister WR: Customizing silicone adhesives for transdermaldrug delivery systems. Pharm Tech 1989;13: 126-138.

57. Touitou E, Fabin B, Dany 5, Almog 5: Transdermal delivery oftetrahydrocannabinol. Int I Pharm 1988;43: 9-15.

58. Touitou E: Skin permeation enhancement by n-decyl methylsulfoxide: Effect of solvent systems and insights on mechanism ofaction. Int J Pharm 1988;43: 1-7.

59. Ashton P, Hadgraft J, Brain KR, Miller TA, Walter KA: Surfac-tant effects in topical drug delivery. mt j Pharm 1988;41: 189-195.

60. Das SK, Chattraj SC, Gupta BK: Transdermal delivery of gli-benclamide for blood glucose control in diabetic rabbits. Program& Abstracts of the 15h International Symposium on ControlledRelease Bioactive Materials, Basel, August 15-19, 1988.

61. Shah KR, Apostolopoulos DV, Franz TJ, Sochan T, KydonieusAF: Novel transdermal drug delivery system, ibid.

62. Friend DR, Catz P, Heller J, Baker R: Transdermal permeationenhancers for levonorgestrel and other drugs, ibid.

63. Bodde HE, VerhoffJ, Ponec M: Transdermal peptide delivery,ibid.

64. Chien YW, Chien T, Huang YC: Transdermal fertility regula-tion in female (II): Scaleup process development and in vivo clini-cal evaluation, ibid.

65. Tojo K, Shah HS, Chien YW, Huang YC: In vivo/in vitro corre-lation for transdermal verapamil delivery, ibid.

66. Tojo K, Chiang CC, Chien YW, Huang YC: Development oftransdermal delivery system for hydromorphone: Effect of en-hancers, ibid.

67. Friend DR. Catz P, Heller J, Reid J, Baker RW: Transdermaldelivery of levonorgestrel, Proceed Int Symp Control Rel BioactMater 1987;14:135.

68. Lee CS, Chien YW: Transdermal controlled delivery of pro-gesterone: Enhancement in skin permeation rate by alkanoicacids and their derivatives, ibid, 1987;219-220.

69. Tsuk AC, Nuwayser ES, Cay MH: A new system for transder-mal drug delivery, ibid, 1987;227-228.

70. Marinan DS, Noel RA, Pfister WR, Swarthout DE, Watters DE,Walters PA: Evaluation of release kinetics of selected therapeuticagents and physical properties of silicone adhesive transdermalmatrices, ibid, 1987;265-266.

71. Wolter KME:A transdermal delivery system containing tex-tile fabrics, ibid, 1987;273-274.

72. van Ham GS, Herzog WP: The design of suncreen prepara-tions,in, Ariens EJ (ed.) Drug Design. 1973;IV: 193-235.

73. Baker R: Controlled Release of Biologically Active Agents.New York: John Wiley, 1987.

74. Shaw JE, Chandrasekaran SK: Controlled topical delivery ofdrugs for systemic action. Drug Metab Rev 1978;8: 223-233.

75. Hymes AC: Transdermal drug delivery from a solid state by-drophilic reservoir system in recent advances, in, JM Anderson,

RANADE

418 #{149}J Clin Pharmacol 1991;31:401-418

SW Kim (ads.) Drug Delivery Systems. New York & London: Ple-num Press, 1984; 309-313.

76. Karim A: Transdermal delivery systems, in, McCloskey J (ed.)Drug Delivery Systems. Springfield. OR: Aster, 1983; 28.

77. Lenaerts VM, Curny R, (eds.): Bioadhesive Drug Delivery Sys-tems. Boca Raton, FL: CRC Press Inc,

78. Nimmo WS: The promise of transdermal drug delivery. Br JAnaesth 1989;64: 7.

79. Lelawongs P. Liu JC, Siddiqui 0, Chien YW: Transdermal ion-tophoretic delivery of arginine-vasopressin 1. Physicochemicalconsiderations. mt j Pharm 1989;56: 13.

80. Williams AC, Barry BW: Urea analogs in propylene glycol aspenetration enhancers in human skin. Int J Pharm 1989;56: 43.

81. Riegelman S: Pharmacokinetic factors affecting epidermalpenetration and percutaneous absorption. Clin Pharmacol Ther1974;16: 873-883.

82. Schwenkenbecker A: Studies on skin absorption. Arch AnalPhysiol 1904;28: 121.

83. Blank IH: Factors which influence the water content of thestratum corneum. J Invest Derm 1952;18: 433-440.

84. Hadgraft J, Somers CE: Percutaneous absorption. I Pharm

Pharmocol 1956;8: 625-634.

85. Scheuplein RJ: Mechanism of percutaneous absorption,routes of penetration and influence of solubility. J Invest Derm1965;45:334-346.

86. Marvel JR, Mezick IA: U.S. Patent 4,073,291, February 14,1978.

87. Bernstein JE: U.S. Patent 4,395,420, July 26, 1983.

88. Nagai H, Wada Y, Kobayashi I, Tamada M, Ushiyama K, Ya-mamoto T: U.S. Patent 4,390,520, June 28, 1983.

89. Transdermal and related drug delivery systems, DA Jones(ed.) Noyes Data Corporation, New Jersey, 1984.

90. Hoelgaard A, Mollgaard B: Dermal drug delivery- Improve-ment by choice of vehicle or drug derivative, in, Anderson JM,Kim SW (eds.) Advances in Drug Delivery Systems. Amsterdam:Elsevier,1986; 111.

91. Rosoff M (ed.): Controlled Release of Drugs: Polymers and Ag-gregate Systems. NY: VCH and Weinheim, 1989; 315.

92. Buyukyaylaci 5, Joshi YM, Peck GE, Banker GS: Polymericpseudolatex dispersions as a new topical drug delivery system, in,Anderson JM, Kim SW (ads.) Recent Advances in Drug DeliverySystems. NY & London: Plenum Press, 1984; 291-307.

93. Pflster WR, Hsieh DST: Permeation enhancers compatiblewith transdermal drug delivery systems: Part I, selection and for-mulation considerations. Pharm Tech 1990;14: 132-140.

94. Queen D, et al: Assessment of the potential of a new hydrocol-laid dermatological (Actiderm) in the treatment of steroid-respon-sive dermatoses. mt j Pharm 1988;44: 25-30.

95. Pflster WR, Hsieh DST: Permeation enhancers compatiblewith transdermal drug delivery systems: Part II system design con-siderations. Pharm Tech 1990;14: 54-60.

drug delivery systems. 6. transdermal drug delivery

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