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2003; 83:161-170.PHYS THER.Peter C Panus and Walter L SembrowichCarter R Anderson, Russell L Morris, Stephen D Boeh,Localized Drug RetentionDuration on Dexamethasone Deposition andEffects of Iontophoresis Current Magnitude and

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Effects of Iontophoresis Current

Magnitude and Duration onDexamethasone Deposition and

Localized Drug Retention

Background and Purpose. Iontophoresis is a process that uses bipolarelectric fields to propel molecules across intact skin and into underly-ing tissue. The purpose of this study was to describe and experimen-tally examine an iontophoresis drug delivery model. Subjects and

Methods. A mechanistic model describing delivery was studied in vitrousing agarose gels and was further tested in vivo by evaluation ofcutaneous vasoconstriction following iontophoresis in human volun-teers. Results. In vitro cathodic iontophoresis at 4 mA and 0.1 mA eachdelivered dexamethasone/dexamethasone phosphate (DEX/DEX-P)from a 4-mg/mL donor solution to a depth of 12 mm following a 40mAminute stimulation dosage. Delivery of DEX/DEX-P to at least thedepths of the vasculature in humans was confirmed by observation ofcutaneous vasoconstriction. This cutaneous vasoconstriction waslonger lasting and greater in magnitude when using low-current,long-duration (0.1 mA) iontophoresis compared with equivalentdosages delivered by higher-current, shorter-duration (1.54.0 mA)iontophoresis. Discussion and Conclusion. From data gathered with thegel model, the authors developed a model of a potential mechanism ofdrug depot formation following iontophoresis. The authors believethis drug depot formation to be due to exchange of drug ions forchloride ions as the ionic current carriers. Furthermore, diffusion, notmagnitude of current, appears to govern the depth of drug penetra-tion. Although the authors did not address the efficacy of the drugdelivered, the results of human experiments suggest that currentmagnitude and duration should be considered as factors in treatingmusculoskeletal dysfunctions with iontophoresis using DEX/DEX-P ata concentration of 4 mg/mL. [Anderson CR, Morris RL, Boeh SD,

et al. Effects of iontophoresis current magnitude and duration ondexamethasone deposition and localized drug retention. Phys Ther.2003;83:161170.]

Key Words: Cutaneous administration, Dexamethasone phosphate, Iontophoresis, Transdermal drug

delivery.

Carter R Anderson, Russell L Morris, Stephen D Boeh, Peter C Panus, Walter L Sembrowich

Physical Therapy . Volume 83 . Number 2 . February 2003 161

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Iontophoresis is used as a means of delivering drugsacross the skin for the management of a variety ofmedical conditions, most often, we believe, forlocalized inflammation and pain.13 There are

reports indicating that this mode of drug delivery can beuseful, and iontophoresis with dexamethasone phos-phate (DEX-P), sodium diclofenac, and acetic acid

appears to be effective in treating inflammations inseveral areas of the body.411 Unfortunately, we believe,the general lack of a strong theoretical foundation forthe practice of iontophoresis has hampered its wide-spread acceptance among all medical professionals.There is, however, literature that we contend can beused to guide the construction and testing of a modelthat could be useful in understanding the scientific basisfor use of iontophoresis. In this article, we address issuesaffecting the delivery of dexamethasone/dexametha-sone phosphate (DEX/DEX-P). Further studies on theefficacy of delivered drugs will be necessary in the future.

After evaluating tissue under the delivery electrodefollowing iontophoresis of dexamethasone (DEX), pred-nisolone, lidocaine, or salicylic acid, several research-ers1215 have described a depot of drug that is found inthe area of the epidermis. This intracutaneous depotrepresents the highest concentration of the drugsdetected. The mechanism of the formation of the depothas not been established. An objective of our study wasto determine whether the magnitude of iontophoresiscurrent may influence the proportion and depth ofDEX-P delivered. Using an in vitro agarose gel model,depth of penetration following high-current, short-

duration (HCSD) delivery (4 mA 10 minutes) iscompared with an equal dosage from low-current, long-duration (LCLD) delivery (0.1 mA 400 minutes).

The corticosteroid DEX/DEX-P (4 mg/mL) is com-monly administered by iontophoresis for the manage-ment of local inflammation.1 Because DEX is unchargedand has a poor solubility in aqueous solutions, thewater-soluble DEX-P is generally used in iontophoreticapplications. At neutral pH, DEX-P is a negativelycharged prodrug that is dephosphorylated into the

active form of DEX once it is in the body.2

Glass and colleagues12 found that DEX/DEX-P penetra-tion into tissue of a rhesus monkey following ionto-phoresis was up to 17 mm and included joint capsules.More recently, however, researchers have been unable tofind DEX/DEX-P in equine tibiotarsal joints16 or inhuman blood extracted from a vein proximal to thetreatment area17 following iontophoresis. Other objec-tives of our study were to verify that DEX/DEX-P actuallypenetrates into human skin at least to the approximatedepth of the vasculature underlying the skin and todetermine how long the drug is retained locally. In thispart of the study, we used a noninvasive vasoconstrictorassay.18,19 When introduced topically onto the flexoraspect of a forearm, corticosteroids such as DEX/DEX-Pinduce a cutaneous vasoconstriction that can be seen asa blanching of the skin.18 This vasoconstriction effect hasbeen used to measure the relative potency of percutane-ously absorbed steroids.1922 Transdermal penetration ofDEX/DEX-P was evaluated qualitatively, through visualobservation of blanching, and quantitatively, using infra-red temperature measurements as an indirect measureof cutaneous blood flow.23,24 Equal dosages from HCSDiontophoresis (1.5 4.0 mA) and LCLD iontophoresis

(0.1 mA) were compared.

CR Anderson, MS, is President and Chief Technology Officer, Birch Point Medical Inc, Oakdale, Minn.

RL Morris, PhD, Vice President of Operations, Birch Point Medical Inc.

SD Boeh, MS, is Vice President of Clinical and Regulatory Affairs, Birch Point Medical Inc.

PC Panus, PT, PhD, is Associate Professor, Department of Physical Therapy, College of Public and Allied Health, East Tennessee State University,

Johnson City, Tenn.

WL Sembrowich, PhD, is Chairman and CEO, Birch Point Medical Inc, 473 Hayward Ave N, Oakdale, MN 55128 (USA) ([email protected]).

Address all correspondence to Dr Sembrowich.

Mr Anderson and Dr Sembrowich provided concept/idea/research design. Mr Anderson, Dr Panus, and Dr Sembrowich provided writing. Mr

Anderson provided data collection, and Mr Boeh and Dr Sembrowich provided data analysis. Mr Anderson provided project management, and

Dr Panus and Dr Sembrowich provided subjects. Dr Morris, Mr Boeh, Dr Panus, and Dr Sembrowich provided consultation (including review of

manuscript before submission).

The Institutional Review Board at East Tennessee State University/Veterans Administration approved the study.

This research was supported by Birch Point Medical Inc.

This article was submitted March 29, 2002, and was accepted August 23, 2002.

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Materials and Methods

Human SubjectsSubjects were excluded from the study if they had at anytime during the 3 months preceding the study any of thefollowing self-reported conditions: systemic fungal infec-tions; hypersensitivity to sulfites; demand-type cardiacpacemakers; metallic surgical implants in the area of theiontophoretic treatment; skin, liver, kidney, pituitary,pancreatic, or adrenal disorders; any wounds; surgery;fractures; shinsplints or stress fractures; and use ofanti-inflammatory medications containing glucocorti-coids. These conditions were chosen based on contra-indications for DEX/DEX-P described in the 2002 Phy-

sicians Desk Reference.25Additionally, due to the unknowneffects of externally administered weak electromagneticfields or glucocorticoids, women who were pregnantwere excluded from participation in this investigation.The subjects tested were 5 Caucasian men, ranging inage from 34 to 58 years, who reported no impairments orpathologies. All subjects gave written informed consent.

In Vitro Depot Formation StudiesExperiments were performed to quantify the depth ofpenetration and depot formation of DEX/DEX-Pachieved during iontophoresis. The iontophoresis test

apparatus is illustrated in Figure 1. Hydrogels wereprepared with agarose (SeaKem Gold*) at 1% wt/vol in1% saline to approximate normal tissue water concen-trations of sodium and chloride. The salt-containinghydrogel was formed into a cylinder of 4 cm height and1.5 cm diameter by heating the solution to near boilingand then allowing it to cool in a mold. A silver-silverchloride electrode served as the cathode, with the silverwire anode positioned distally against the hydrogel. We

have found (unpublished data) that DEX-P is deliveredmore effectively from the negative electrode if the donorsolution is free of competing ions.26 An absorbent padsaturated with 1.5 mL of 4 mg/mL DEX/DEX-P, pH7.02, was used as the drug reservoir. To restrict passivedrug flow, a cellulose ultrafiltration membrane with anominal molecular weight limit of 1,000 served to sepa-

rate the donor drug solution reservoir from the hydrogelmatrix. Because the molecular weight of DEX/DEX-P isapproximately 500, this represents a restrictivemembrane.

The fixed direct current source was the Iontophoriontophoretic drug delivery instrument (model6111PM/DX). The DEX/DEX-P was iontophoreticallyadministered from the cathode into the hydrogels usingthe following experimental protocols: (1) iontophoresisof 4 mA for 10 minutes, followed by immediate sam-pling; (2) iontophoresis of 4 mA for 10 minutes, fol-lowed by sampling 400 minutes after iontophoresis, and(3) sampling immediately after iontophoresis of 0.1 mAfor 400 minutes. At the conclusion of each iontophoresisapplication, hydrogels were immediately separated fromthe donor solution. At the time of sampling, each gel wassliced into equal 2-mm-thick slices cut parallel to theelectrode surface and transverse to the hydrogel speci-men, and DEX/DEX-P was extracted into 10 mL ofdistilled water overnight.

Extraction solution aliquots were measured using ultra-violet/visible spectrophotometry# at a wavelength of243.5 nm, and drug delivery (in milligrams) was deter-

mined by comparison of absorbance with referencestandards. Net iontophoretic delivery was determined byrunning a passive system side-by-side, then subtractingthe amount of drug delivered passively from the amountof drug delivered as a result of iontophoresis.

Human DEX/DEX-P Iontophoresis ExperimentsTo ascertain whether DEX/DEX-P could be delivered tolocal tissue and vasculature and to measure its localretention as a function of time, experiments were con-ducted on 5 human volunteers. The iontophoreticdevice used in HCSD testing was a Life-Tec model 6111

PM/DX.

The current level was set at the maximumamount tolerable to the volunteer and averaged (aver-age2.97 mA, SD0.81, range1.5 4.0). For LCLDdelivery, the IontoPatch, a wearable self-powered dis-posable patch that delivers medication at a current ofapproximately 0.05 to 0.16 mA was used. The IontoPatchis voltage controlled; thus, the actual current levels will

* FMC Corp, 191 Thomaston St, Rockland, ME 04841. Birch Point Medical Inc, 473 Hayward Ave N, Oakdale, MN 55128.

Sigma Chemical Co, PO Box 14508, St Louis, MO 63178. Millipore Corp, 80 Ashby Rd, Bedford, MA 01730. Life-Tec, 4235 Greenbriar Dr, Stafford, TX 77477.# Cecil Instruments Ltd, Milton Technical Centre, Cambridge, England CB4

6AZ.

Figure 1.Depth of penetration test apparatus for iontophoretic delivery of dexa-methasone/dexamethasone phosphate (DEX/DEX-P).

Physical Therapy . Volume 83 . Number 2 . February 2003 Anderson et al . 163



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vary according to skin resistance. Thus, for LCLD ionto-phoresis, a wear time of 12 hours was used, which isenough time to discharge at least 90% of the 40-mAminlabeled dosage.

The iontophoretic dosage for both the Life-Tec ionto-phoretic device and the IontoPatch was 40 mAmin, and

each device was used in accordance with manufacturerrecommendations. The cathodic (negative) deliveryelectrodes of both devices were loaded with 1.5 mL of4 mg/mL DEX/DEX-P, and either 1% sodium chloride(IontoPatch) or conductive gel (Life-Tec device) servedas the return electrode ion source. Before each treat-ment, skin sites were cleaned with an isopropyl alcohol(70% by volume) swab, in accordance with electrodemanufacturer recommendations. Iontophoresis elec-trodes were placed on the ventral surface of the forearm.A placebo-controlled, repeated-measures experimentaldesign was used to separate drug effects from currenteffects. As a placebo, separate iontophoretic applicationswere repeated on each subject using a buffered salinesolution in the cathodic delivery chambers. Each of the5 volunteers received both HCSD and LCLD ionto-phoretic administrations of DEX/DEX-P and saline atcontralateral locations on the upper extremity. A mini-mum of 48 hours elapsed between iontophoresisapplications.

After completion of the iontophoresis and removal ofthe electrodes, DEX/DEX-P delivery and its retention inlocal tissue was monitored by observing evidence oflocalized cutaneous vasoconstriction under the delivery

site. This vasoconstriction was monitored quantitativelyby a differential infrared surface temperature measure-ment. The differential determinations were made bycomparing skin surface temperature under the deliveryelectrode site with that of the immediately adjacent skin.A K-type infrared thermocouple,** calibrated to 37C,served as the means of measuring surface temperature.The probe is designed to automatically compensate forambient temperature-related variations associated withemissivity and reflected radiation.

Temperature measurements were made by positioning

the probe perpendicular to the skin, using a custom-built fixture to reproducibly position the probe 6 mmfrom the skin surface and shield it from stray light. Eachskin temperature measurement was completed inapproximately 1 minute. Temperature measurementswere made periodically until thermographic evidence ofvasoconstriction had ceased. A minimum of 7 measure-ments were made in the first 315 minutes followingcompletion of iontophoresis. Cutaneous vasoconstric-tion was evaluated qualitatively by visual observation of

the skin under the delivery site, with researchers lookingfor skin blanching, or lightening of skin tone,18,19withinthe area of the delivery electrode. If blanching wasevident, its time of onset and duration were recorded.

Data AnalysisAll data are presented as means and standard deviations.

Significance between 2 groups was determined by apaired ttest. Our main interest was in the comparison ofplacebo and DEX/DEX-P treatments and in the compar-ison of LCLD and HCSD treatments. A priori level ofsignificance between 2 groups was established as P.05.

ResultsThe quantity of DEX/DEX-P measured as a function ofthe depth in the agarose gel penetration studies isdepicted in Figure 2. These results showed that followinga 40-mAmin dosage delivered at 4 mA for 10 minutes,DEX/DEX-P was found nearly exclusively in the toplayer of the gel (Fig. 2A). A 10-minute delivery of a40-mAmin dosage followed by removal of the deliverypatch and 400 minutes of passive diffusion resulted inpenetration of DEX/DEX-P into the hydrogel to a depthof approximately 12 mm (Fig. 2B). A 40-mAmin ionto-phoretic dosage of DEX/DEX-P delivered at 0.1 mA for400 minutes also resulted in penetration of DEX/DEX-Pinto the hydrogel to a depth of approximately 12 mm(Fig. 2C). Total drug delivery was higher and morevariable with the 0.1-mA delivery method. This variabilityin DEX/DEX-P delivery may be due to the increasedcontact period between the electrode reservoir and thehydrogel matrix.

The results from our use of in vitro investigation tech-niques were followed by confirmation of cathodic ionto-phoresis of DEX/DEX-P in humans. Figure 3 illustratesdifferential temperature measurements of cutaneousvasoconstriction as a function of time following HCSDiontophoresis. After HCSD placebo iontophoresis, rela-tive skin temperature was elevated, and slowly cooled tonormal over the course of approximately 3 hours. AfterHCSD iontophoresis of DEX/DEX-P, relative skin tem-perature was initially elevated, rapidly dropped to nor-mal temperatures over the next 2 hours, then became

relatively cooler than adjacent skin from approximatelyhours 2 to 5 after iontophoresis. Figure 4 illustratesdifferential temperature measurements of the cutaneousvasoconstriction as a function of time following ionto-phoresis at the lower rates of current flow. After LCLDiontophoresis of DEX/DEX-P, skin temperature wascooler than adjacent skin and warmed to normal skintemperature over the next 5 hours. After iontophoresisof placebo at low currents, skin temperature did notdeviate from that of adjacent skin.

** Omega Engineering Inc, PO Box 2349, Stamford, CT 06906.



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The maximum degree of cutaneousvasoconstriction, as measured by aver-aging the lowest differential tempera-tures found after application of a40-mAmin DEX/DEX-P dose, was

approximately 1.86C (SD0.47C,range2.44C to 1.27C) afterLCLD iontophoresis and 0.35C(SD0.23C, range0.56C to0.22C) after HCSD iontophoresis(Fig. 5A). These results suggest that theLCLD delivery rate causes greater cuta-neous vasoconstriction when comparedwith an equal dosage applied at theHCSD delivery rate (P.003).

Results based on observation correlated

with the quantitative findings. Immedi-ately after completion of HCSD ionto-phoresis, whether using DEX/DEX-Por placebo, the erythemous skin underthe delivery electrode was red ratherthan blanched. With iontophoresis ofDEX/DEX-P at the higher currents, ablanched skin appearance became evi-dent between 165 and 195 minutesfollowing iontophoresis and lasted anaverage of 415 minutes (SD187,range210 708). This cutaneous vaso-constriction was not evident in any sub-ject following placebo iontophoresis.The skin under the delivery electrodesite was blanched in all cases immedi-ately following LCLD iontophoresiswith DEX/DEX-P. The blanchedappearance lasted for an average of 984minutes (SD508, range380 1,500).No blanching at the application site wasnoted following placebo iontophoresis.Figure 5B illustrates the comparativeduration of cutaneous vasoconstrictionfollowing LCLD and HCSD ionto-

Figure 2.Permeation of 4-mg/mL dexamethasone/dexa-methasone phosphate (DEX/DEX-P) into agarosegel. The graphs represent the experimental condi-tions and time points under which DEX/DEX-P wasmeasured: (1) immediately after iontophoresis at4.0 mA for 10 minutes (panel A), (2) 400 minutesafter iontophoresis at 4.0 mA for 10 minutes(panel B), and (3) immediately after iontophoresis

at 0.1 mA for 400 minutes (panel C). Total andpassive drug delivery measured for 4.0-mA ionto-phoresis were 0.420.05 mg and 0.040.03mg, respectively. Total and passive drug deliverymeasured for 0.1-mA iontophoresis were0.750.40 mg and 0.510.35 mg, respectively(n3).




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phoresis with DEX/DEX-P as determined by observa-tion. Duration of the skin blanching was approximatelytwo-fold greater following LCLD application than it waswith an equivalent HCSD dosage.

DiscussionStudies designed to evaluate the depth of penetration ofthe drugs (DEX, prednisolone, salicylate, and lidocaine)

into local tissue following iontophoresis have demon-strated that a depot is formed in the area of theepidermis.1215 This depot formation appears in contra-diction to the general impression that the current flowinduced by iontophoresis extends by field lines unabatedinto tissue well below the epidermis and ultimately to thecounter electrode. One objective of our investigation

was to construct and study a mechanistic model todetermine how drug depot formation may occur duringiontophoresis. We hypothesized that once any drug isdelivered into tissue, it contacts an environment with aproportionately higher concentration of smaller ions oflike charge (ie, competing ions). In the case of DEX/DEX-P iontophoresis, the drug will be introduced intothe tissue water, which contains many more, and muchsmaller, chloride ions. Therefore, we expected thatcurrent flow into deep tissue would be dominated bymovement of the smaller competing ion.

Based on the results of our research using in vitroagarose gels, we found support for the delivery modelthat we studied. The active transport process of ionto-phoresis with DEX/DEX-P does not appear to deliverdrug ions deeper than 2 mm in the gels, despite currentflow that extended through the entire 40-mm length ofthe gels. By the second millimeter, the DEX/DEX-Pappeared to be immediately overwhelmed by the dilu-tion effects of competing chloride ions. The data suggestthat the drug is essentially dropped off as soon as itencounters the aqueous saline environment. Deeperpenetration of the drug apparently occurs not fromiontophoretic current, but from passive diffusion. Pas-

sive diffusion is a slower, mass transfer process comparedwith iontophoresis. Thus, for equivalent iontophoreticdosages, it is time, not current magnitude, that dictatesthe ultimate local depth of penetration. In living tissue,however, other factors such as local blood flow willdetermine the ultimate depth of local penetration.

The results of our study also are supported by otherpublished investigations. James et al13 measured pred-nisolone levels following iontophoresis across palmar,abdominal, or arm skin of human subjects. Prednisolonewas found in the epidermis for up to 4 days following

application and was released to the blood for 15 daysfollowing application. With other pharmacologic agentssuch as ketoprofen,27,28 fentanyl,29,30 and lidocaine,14

there is also a depot effect in the skin. Published studiesdocument the formation of an intracutaneous reservoiror depot for a variety of pharmacologic agents followingiontophoresis.13,14,2730

The cutaneous vasoconstriction (blanching) and mea-surable reduction in surface skin temperature that wefound suggest that iontophoresis successfully transportsDEX/DEX-P across the epidermis in humans, using

Figure 3.Cutaneous temperature in humans following iontophoresis of 4-mg/mLdexamethasone/dexamethasone phosphate (DEX/DEX-P) and placeboat higher currents. Iontophoresis was as follows: 1.5 to 4.0 mA for a40-mAmin dose, with current level set to the highest level tolerable to thevolunteer. Cutaneous temperature under the delivery electrode wasmeasured by thermography and was reported as the difference com-

pared with the cutaneous temperature of adjacent untreated skin.Significance (denoted by asterisk) was determined by a paired t test ateach time point, comparing DEX/DEX-P iontophoresis with placeboiontophoresis (N5 per group).

Figure 4.Cutaneous temperature in humans following iontophoresis of 4-mg/mLdexamethasone/dexamethasone phosphate (DEX/DEX-P) and placeboat lower currents. Iontophoresis was as follows: 0.1 mA for a40-mAmin dose. Cutaneous temperature under the delivery electrodewas measured by thermography and was reported as the differencecompared with the cutaneous temperature of adjacent untreated skin.

Significance (denoted by asterisk) was determined by a paired t test ateach time point, comparing DEX/DEX-P iontophoresis with placeboiontophoresis (N5 per group).



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both LCLD and HCSD administration. In a previousreport,20 a general relationship between a vasoconstric-tive blanching effect and cutaneous anti-inflammatoryaction was shown. The presence of DEX/DEX-Pinduced vasoconstriction, however, does not in itselfguarantee any clinical benefits of subcutaneous applica-tions. The iontophoresis of DEX/DEX-P at high current,1.5 to 4.0 mA for a 40-mAmin dosage, resulted inerythema lasting for approximately 2 hours followingapplication. Galvanic current-induced cutaneous ery-thema is well documented,26,30,31 and this erythemiceffect can be seen even after HCSD iontophoresis with

the systemic vasoconstrictor NG-mono-methyl-L-arginine acetate.31 In con-trast, iontophoresis at low current,0.1 mA for a 40-mAmin dosage, dem-onstrates cutaneous vasoconstrictionimmediately following completion ofthe iontophoresis, without the vasodila-

tion phase. These results are consistentwith our in vitro results and the datafrom the theoretical model, in thattime, not magnitude of current flow,dictates the physiologic effect of glu-cocorticoids on this local vasculature.For equivalent doses, low currentappears more efficient than high cur-rent in the creation of a localized phys-iologic effect, based on the magnitudeand duration of cutaneous vasocon-striction. A possible explanation forthis effect is that a greater degree oferythema induced by the HCSD ionto-phoresis reduces the local drug concen-tration via loss to the systemic vascula-ture during the vasodilation phaseprior to the vasoconstriction phase.Further studies of DEX/DEX-P deliv-ered under these conditions also arewarranted.

Our findings may provide insight intothe results obtained in previous studiesof DEX/DEX-P iontophoresis. Glass

and colleagues12 reported that DEX/DEX-P could reach deep tissues andjoint capsules after iontophoresis,based on their findings using anodaliontophoresis of DEX-P at 5 mA for20 minutes (current density0.94 mA/cm2) on a rhesus monkey. Consistentwith the depot concept, the highestconcentrations of the drug were foundin the skin. Although Glass et al12 dem-onstrated the ability of iontophoresis todeliver DEX/DEX-P locally to depths

and in concentrations that may have some benefit, theystudied only one animal and they did not use clinicallyrelevant iontophoresis. Recently, Smutok et al17

reported that they were unable to find DEX/DEX-P inthe effluent venous blood of human volunteers whounderwent cathodic iontophoresis of DEX/DEX-P at4 mA for 10 or 20 minutes. Blood samples were takenprior to, during, and at 5 time points up to 120 minutesafter iontophoresis. The results of our investigation mayprovide a potential explanation for the negative resultsobserved by Smutok et al. First, following 1.5- to 4.0-mAcathodic iontophoresis, a cutaneous erythema devel-

Figure 5.Comparison of magnitude (panel A), and duration (panel B) of apparent vasoconstrictionfollowing equivalent dexamethasone/dexamethasone phosphate (DEX/DEX-P) dosagesapplied using low-current, long-duration (LCLD) and high-current, short-duration (HCSD) ionto-phoresis. Significance (denoted by asterisk) was determined by a paired t test, comparingHCSD iontophoresis of DEX/DEX-P with LCLD iontophoresis of DEX/DEX-P (N5 per group).




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oped and persisted for approximately 2 hours beforevasoconstriction was observed. These results suggest thatduring the 2 hours immediately following HCSD ionto-phoresis, the absorption of DEX/DEX-P by the vascula-ture in the tissue during erythema was sufficient to dilutethe effluent blood concentrations of DEX/DEX-P belowthe level of detection for the high-performance liquid

chromatography protocol.

The lack of detectable DEX/DEX-P concentrations inthe equine tibiotarsal joint, when compared with thedetection of 21 g/mL in the monkey elbow joint, alsomay be related to different settings used during ionto-phoresis.12,16 The current density used by Glass et al12

was 0.94 mA/cm2 , whereas the current density in theequine investigation16 was 0.11 mA/cm2. The currentdensity of 0.94 mA/cm2 used by Glass et al12 exceeds thenormal maximum clinical value of 0.50 mA/cm2 , asreported by Banga and Panus1 and Riviere et al,32 andmay cause local tissue damage, decreasing blood flow. Alack of local blood flow may artifactually increase boththe drug concentrations in local tissue and the depth ofdrug penetration at the iontophoretic application site.

An important area of investigation has been the mech-anisms that influence the subcutaneous penetration ofdrug ions such as salicylate and lidocaine from theintracutaneous depot during and following iontophore-sis. As the drug diffuses away from the depot and intodeeper tissues, it encounters the vascular capillary bedsthat can move the drug away from the immediateapplication area. The importance of this vascular clear-

ance has been documented by Singh and Roberts33using animals. Iontophoresis of salicylic acid and lido-caine across intact skin and into the tissues was com-pared with passive delivery into the tissues after removalof the epidermis. Under both conditions, the penetra-tion of salicylic acid and lidocaine were the same. Thus,once a drug transits the epidermis, the forces thatdistribute it away from the depot are the same. Drugsstudied were found in concentrations above those seenin the plasma to a depth of about 4 mm. Drugs also werefound as deep as 12 mm but in concentrations belowthose of the plasma, suggesting delivery to these deeper

tissues is the result of circulation.

The effects of local cutaneous vasoconstriction andvasodilation on penetration of iontophoretically andpassively delivered drugs into tissue also have beenexamined. Compared with vasodilation, concentrationsof transcutaneously delivered drugs in tissue are greaterin the presence of local vasoconstriction.14,33 Addition-ally, during local cutaneous vasoconstriction, the pene-tration of drugs into tissue approached 8 mm. Thisdepth of penetration has the potential to reach subcu-taneous muscular and tendinous sites, depending on the

anatomic location. When these forms of transcutaneousdrug delivery were used in freshly euthanized animals,drug concentrations were even higher at any given tissuedepth when compared with those of live animals. Theseexperiments suggest that the cutaneous vasculature isthe main modulator of diffusion of drugs into tissueduring and following trancutaneous delivery. We believe

that our observations of sustained local tissue vasocon-striction following LCLD suggest that the kinetics ofDEX/DEX-P in tissue are similar to the characterizationsof other drugs in the literature. Verification of theseeffects across a wider spectrum of drugs is needed.

Proposed Model of Iontophoretic Delivery and DepotFormationBased on our results and the literature, we propose ageneral model to explain the mechanism of cutaneousand subcutaneous tissue penetration by drug ions as aresult of the iontophoresis of drugs across the skin. Thefirst step involves current flow. Voltage applied to theskin under the proper conditions with a donor electrodefilled with ionized drug and a return electrode will causean ionic current to flow, with the current being carried,in part, by the drug ions. The drug apparently will betransported into the stratum corneum by the current.

The second step involves penetration. The drug pene-trates the stratum corneum at a rate proportional to themagnitude of the current. The third step involves depotformation within the epidermis, at the avascular basalepithelial cell layers where drug ions will encounter anaqueous environment dominated by sodium and chlo-

ride ions. In the aqueous environment, the drug mole-cules face competition from the more numerous andmore mobile like-charged ions. In the case of DEX/DEX-P iontophoresis, the negatively charged ion, chlo-ride, would be the competing ion. The current is carriedby chloride ions leaving the drug molecules behind. Dueto this effect, we believe, a reservoir or depot of drugbegins to accumulate in the avascular epidermal layerjust under the donor electrode. An assumption is thatthe drug delivery rate exceeds the systemic vascularabsorption rate.

The final step is deeper tissue penetration. Drug absorp-tion from the depot and into the surrounding tissuesoccurs by diffusion. As the drug diffuses into the dermis,it encounters the capillaries of the microcirculation.Drug molecules are distributed from the local tissuesunder the donor electrode by the blood, decreasing thegradient for deeper penetration. Some drug is returnedto the deeper tissues by the circulation, but in relativelylow concentrations. The status of the cutaneous micro-vasculature bed (ie, vasoconstriction or vasodilation) willhave the greatest effect on drug penetration into localtissue. Generally, drug penetration will be deeper when



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the local cutaneous capillary beds are vasoconstricted,and penetration will be less when the local cutaneouscapillary beds are vasodilated. Other factors also appearto operate in the tissues to modulate clearance.34 Theyinclude metabolism of the drug by the tissues andprotein binding, each of which would reduce the freedrug concentration gradient to the deeper tissue below

the donor site.

ConclusionIontophoresis, theoretically, may facilitate the penetra-tion of drugs such as DEX/DEX-P up to 8 to 10 mm intolocal tissues at pharmacologic concentrations. Thus, anyconditions managed with DEX/DEX-P for control ofinflammation should be within these known depth lim-its. In addition, because DEX/DEX-P is a cutaneousvasoconstrictor, this may promote deeper penetrationthan other vasoneutral or vasodilatory drugs. Finally, wehave provided evidence to suggest that comparableiontophoretic doses delivered at low currents over sev-eral hours are more effective than those delivered byhigher currents over 10 to 30 minutes in the creation ofa localized physiologic effect for DEX/DEX-P, based onthe magnitude and duration of local cutaneous vasocon-striction. Additional investigations will be needed todetermine whether iontophoresis delivers therapeuticconcentrations of DEX/DEX-P into the local subcutane-ous tissue for effective local anti-inflammatory action.

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2003; 83:161-170.PHYS THER.Peter C Panus and Walter L SembrowichCarter R Anderson, Russell L Morris, Stephen D Boeh,Localized Drug RetentionDuration on Dexamethasone Deposition andEffects of Iontophoresis Current Magnitude and

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