iontophoresis successfully delivers dexamethasone sodium phosphate to dermis as measured by...

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Iontophoresis Successfully Delivers Dexamethasone SodiumPhosphate to Dermis as Measured by Microdialysis

ABHAY JOSHI,1 GRAZIA STAGNI,1 ANN CLEARY,2 KOMAL PATEL,1 DAVID S. WEISS,3 MARSHALL HAGINS4

1Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, Brooklyn,New York 112012School of Nursing, Long Island University Brooklyn, New York 112013Department of Orthopaedic Surgery, New York University School of Medicine, New York City, New York 100164Department of Physical Therapy, Long Island University, Brooklyn, New York 11201

Received 12 August 2013; revised 29 September 2013; accepted 14 October 2013

Published online 6 November 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23771

ABSTRACT: Despite its widespread and long term use, the effectiveness of iontophoresis to increase the delivery of dexamethasone sodiumphosphate (DSP) remains controversial. The goal of this study was to quantitatively compare the DSP concentrations in dermis’ dialysatesin two delivery scenarios: with and without iontophoresis. Interstitial fluid concentrations were measured by cutaneous microdialysis.Passive and active iontophoresis were applied simultaneously on the skin of the forearm in eight healthy adult participants using eachparticipant as his/her own control. The iontophoresis apparatus and procedures were identical to those used in common clinical practice.Iontophoresis electrodes were loaded with 2 mL of 4.4 mg/mL of preservative-free DSP solution. Electric current (4 mA) was applied for 20min. Dialysate samples were collected for 2 h and analyzed for DSP and its active metabolite dexamethasone (DXM). Seven out of eightiontophoresis sites contained quantifiable levels of DSP and DXM, whereas none of the samples collected at the passive site containedeither form of the drug. In conclusion, this study demonstrates that iontophoresis significantly (p < 0.0001) increases delivery of DSP tothe dermis compared with passive delivery of the same, and that microdialysis can be used to monitor DSP delivery and DXM formationin skin. C© 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:191–196, 2014Keywords: microdialysis; iontophoresis; transdermal drug delivery; bioavailability; passive diffusion/transport; percutaneous; skin

INTRODUCTION

Painful musculoskeletal conditions are a major public healthconcern.1 The steroidal and nonsteroidal drugs commonly usedto alleviate pain in these conditions may have significant ad-verse effects related to the invasive nature of the drug deliv-ery (e.g., injections into joints) or unintended side effects (e.g.,stomach ulcers) when administered orally. Consequently, thelocal noninvasive delivery of drugs to areas of musculoskele-tal pain using transdermal methods has been an ongoing areaof interest.2 Iontophoresis has been used clinically for over 50years to deliver medications transdermally to localized areasof inflammation.3 Iontophoresis uses a mild electrical currentto “push” ionic compounds through the skin4 and usually in-creases the rate and extent of absorption compared with passivetreatments like the application of creams, gels, or ointments. Itis therefore preferable for the treatment of pain.

The most common drug used clinically for musculoskeletalpain delivered by iontophoresis is dexamethasone sodium phos-phate (DSP). DSP is a phosphate ester prodrug of dexametha-sone (DXM) that transforms the highly lipophilic dexametha-sone (log P: 1.83)5 in a water-soluble molecule suitable for in-jection (log P: 1.64)6 (Fig. 1). DSP is water soluble and hastwo ionizable groups (pKa 1.89 and 6.18) that make it an idealsubstrate for transdermal iontophoresis.7

Correspondence to: Grazia Stagni (Telephone: +1-718-488-1231; Fax: +1-718-780-4586; E-mail: [email protected])

Ann Cleary’s present address is VNSNY.

Journal of Pharmaceutical Sciences, Vol. 103, 191–196 (2014)C© 2013 Wiley Periodicals, Inc. and the American Pharmacists Association

Figure 1. Molecular structure of dexamethasone sodium phosphateand its metabolite dexamethasone.

Despite its widespread and long term use, the effectivenessof DSP delivered by iontophoresis remains controversial.8 Somestudies have reported benefit with the use of iontophoresisfor musculoskeletal conditions using outcomes such as self-reported pain and function,9–15 whereas other studies havefound no benefits.16–18 Consequently, further study to determineif iontophoresis can successfully deliver DSP transdermally inhumans is needed.

Joshi et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:191–196, 2014 191

192 RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Microdialysis is a minimally invasive sampling techniquethat allows collecting soluble and unbound molecules present inthe interstitial fluid.19 Cutaneous microdialysis is becoming amethod of choice in the assessment of dermal and transdermaldelivery of topically applied drug products20–22 for moleculesthat are suitable for microdialysis recovery, for example, wa-ter soluble at physiological pH, low protein bound, and witha molecular weight less than 1000.23 Indeed, once in dermis,drug molecules (1) are uptake by dermal capillaries into thesystemic circulation from where they will distribute to the dis-eased areas, and/or (2) diffuse further into the underneath mus-cle and joints. Which of the two mechanisms is predominant isstill controversial. However, both of them require that the drugmolecules reach the dermis. Therefore, the presence of drug indermis is a meaningful precursor of therapeutic effectiveness.Further, because the conversion of DSP to DXM also occurs exvivo in plasma, the use of microdialysis has the advantage, overconventional blood sampling, that (1) dialysate samples do notcontain esterase so DSP cannot convert to DXM during storage,and (2) samples are injected directly in the high-performanceliquid chromatography (HPLC) without extraction and there-fore it lowers the possibility of degradation during sample han-dling procedures.

Comparison of DSP concentration in dermis following pas-sive and active iontophoresis would clearly answer the questionof whether iontophoresis effectively enhance the bioavailabil-ity of DSP in skin compared with passive delivery. Given theabove, the purpose of the current study was to compare theiontophoretic delivery of DSP with passive delivery, measur-ing DSP and its active metabolite DXM in the skin of healthyhuman volunteers under standard clinical procedures.

MATERIALS AND METHODS

Chemicals

Dexamethasone sodium phosphate USP (98.7%) was purchasedfrom Lecto Medical (Decature, Alabama) and DXM was pur-chased from Enzo Life Sciences (Farmingdale, New York). Lac-tated ringer’s Injection USP was from Hospira, Inc. (Lake For-est, Illinois). HPLC grade methanol was purchased from FisherScientific (Fair Lawn, New Jersey). Tetrabutylammonium hy-drogen sulfate was purchased from J.T. Baker (Philipsburg,New Jersey). HPLC grade water was purchased from EM Sci-ence, (Gibbstown, New Jersey). Sodium hydroxide was fromRicca Chemical Company (Arlington, Texas).

Analytical Method

Dexamethasone sodium phosphate and DXM concentrationswere determined by reversed-phase chromatography per-formed at room temperature (25◦C). The analytical procedurewas modified from Samtani and Jusko.24 The HPLC equip-ment consisted of a Waters 717 plus Auto sampler, HitachiL-4250 UV–VIS Detector, Hitachi L-2130 Pump, Perkin ElmerNelson 900 Series Interface, and the Perkin Elmer softwareTurbochrom Navigator (Perkin Elmer Nelson-Version 6.5) datahandling system. Detection wavelength was 240 nm. For rab-bit and in vitro studies, samples were injected onto a C18 col-umn (SS EXSIL ODS C18; 3 :m, 4.6 × 100 mm2). Flow ratewas 1.5 mL/min; the mobile phase consisted of methanol:water(53:47) containing 10 mM tetra-butylammonium hydrogen sul-fate and adjusted to pH 3 with sodium hydroxide. The injection

volume was 10 :L. Retention times for DSP and DXM weretypically 5.4 and 4.3 min, respectively. No endogenous sourcesof interference were observed at the retention time of DSP orDXM. The assay was linear over the range 50–10,000 ng/mL forboth DSP and DXM. Limit of quantification [coefficient of vari-ation (CV%) and percentage error (E%) < 20] was 100 ng/mLfor DSP and 50 ng/mL DXM. For human studies, the LLOQ ofDSP was improved to 50 ng/mL by increasing the percentageof methanol in the mobile phase to 61:39 methanol:water andusing a longer column (Agilent Eclipse Plus ODS C18; 3 :m,4.6 x 150 mm2). Typical retention times were 6.8 and 5.3 min,respectively.

Microdialysis Apparatus

The microdialysis apparatus consisted of a Harvard PHD2000- Programmable pump (Harvard Apparatus, Inc., Hollis-ton, Massachusetts) used for in vitro and rabbit studies andof a Fusion 400 Touch – Syringe Pump Systems (Chemyx Inc.,Stafford, Texas) for studies in humans. Both pumps used sterile3 mL plastic syringe, (Becton Dickinson, Franklin Lakes, NewJersey). The disposable, linear probes were made in our labora-tory as previously described.21 They consisted of two 7 cm armsof polyamide tubing and a semi-permeable hollow membraneof polyacrylonitrile with a molecular weight cutoff of 50 kDa(AN69 HF; Gambro Industries, Meyzieu, France). The hollowmembrane was 1 cm long for all the in vitro and rabbits stud-ies but it was increased to 2 cm for the human study. LactatedRinger solution was used as perfusing solution in all experi-ments.

Iontophoresis: Studies in Human Participants

A total of eight healthy volunteers 18–70 years of age (twomales, six females, mean age 23.9 yrs, +/− 2.7 yrs) were en-rolled in the study approved by the Institutional Review Boardat Long Island University, Brooklyn, New York. All procedureswere in accordance with the principles enunciated in the Decla-ration of Helsinki (6th revision, Seoul, 2008). Written informedconsent was obtained from all participants before the study.Health screening was conducted by a clinician on all subjectsto ensure eligibility for the study.

Two microdialysis probes were inserted by a registered nursein the volar area of the nondominant arm of participants. Be-fore probe insertion, the probe and the skin were wiped withsterile Alcohol Prep Pads (Dynarex, Orangeburg, New Jersey).Local anesthesia was achieved with ice packs applied to theskin. The site of insertion was labeled A or B as depicted in Fig-ure 2. The skin perforations were covered with surgical tape toavoid drug penetration through them. After at least 45 min25 toallow recovery from the insertion trauma, a medium butterfly(size: 7.6 × 8.6 cm2; active area: 2 × 5 cm2) Dupel R© B.L.U.E.buffered electrode (Empi, St. Paul, Minnesota) loaded with 2mL (4.4 mg/mL) preservative free DSP solution was placed ontop of each microdialysis probe with the shortest side of the ac-tive pad (2 cm) carefully centered between the inlet and outletof the MD probe (approximately 3 cm; Fig. 2). One of the patcheswas then connected to the negative end of a constant currentsource Empi Dupel R© iontophoresis instrument (Model199437–001; Empi) and the other was used as control (passive delivery).Electrical assisted delivery or passive delivery was applied tosites A and B (Fig. 2) according to a cross-over design. A dis-persive pad was then placed on a proximal part of the skin

Joshi et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:191–196, 2014 DOI 10.1002/jps.23771

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology 193

Figure 2. Schematic representation of iontophoresis patches locationon the participant arm: location A and B represent the sites wherethe dexamethasone sodium phosphate patches were applied. Electri-cal current was applied to A or B according to a crossover design. Thedispersive pad was always applied to location C. The insert shows theDupel R© B.L.U.E. buffered electrode and the inlet and outlet of the mi-crodialysis probe.

and connected to the positive electrode. To replicate commonclinical practice,26 an 80 mA dose (0.496 mA/cm2) was usedwith the current set at 4 mA/min with the total treatmenttime being 20 min. The DSP solution (4.4 mg/mL), equivalentto 4.0 mg/mL of DXM, was prepared according to physicianprescription by Long Island University Pharmacy (Brooklyn,New York) the day before each experiment; this solution waspreservative free; however, no substantial formation of DXMwas observed for at least 48 h when stored at 1◦C–4◦C. Probeswere perfused with ringers’ solution at a constant flow rate of 1:L/min. Microdialysis samples were collected manually every20 min for a period of 120 min and stored in an ice box untilanalysis by HPLC. Calibrator standards for HPLC were freshlyprepared on the morning of the experiments. Standards wereinjected before and after the dialysate samples to detect possi-ble degradation during the permanence in the auto sampler. Nosignificant difference was detected between the two calibrationcurves.

DXM Formation

Before this study in humans, we performed a preliminary studyin rabbits27 to optimize the experimental procedures. Duringthat study, we performed retrodialysis19 to calculate the in vivocorrection factor for computing the actual interstitial fluid con-centration from the dialysate concentration. In retrodialysis,a solution of known concentration of the analyte is perfusedthrough the probe inserted in the subject skin. During theseexperiments, we observed the presence of substantial concen-trations of DXM in the dialysates whose origin was ambiguous.To better estimate the source of this conversion, we performedthe following additional studies before the primary study on hu-mans: A standard DSP solution was perfused through probes(i) implanted in rabbit skin, (ii) placed in a stirred isotonic solu-tion at body temperature (37◦C), or (iii) placed in a paperboardbox where the dialysis membrane was kept in contact with aironly.

In Vivo (Rabbit)

The institutional Animal Care and Use Committee (IACUC) atLong Island University (LIU), Brooklyn, New York, approvedall the animal procedures. The experiments were performed onthree female, pathogen-free New Zealand albino rabbits. Theday before the experiment, the back of the rabbits were shavedcarefully with an electrical animal hair clipper. On the day ofthe experiment, the rabbits were tranquilized with 1 mg/kgIM acetopromazine maleate injection (ACE) (Boehringer In-gelheim Vetmedica, St. Joseph, Missouri) and allowed at least30 min period for the tranquilization to take place. Three mi-crodialysis probes were implanted in the dorsum of each rabbitaccording to the technique described by Stagni et al.28 as su-perficially as possible, using a 25-gauge needle as a guide. Inthese conditions, the depth of the probe is not greater thanapproximately 2 mm that corresponds to the deep dermis. Afourth probe was inserted in a hollow paperboard box (5 × 11× 22 cm3) covered with aluminum foil to protect from light.After approximately 45 min, which allowed the skin to recoverfrom the insertion trauma, the four probes were connected tothe pump via Teflon tubing (Valco Instruments Company, Inc.,Houston, Texas) and perfused with known concentrations ofDSP (5.0 or 2.5 :g/mL) in ringer’s solution at a constant flowrate of 1 :L/min. Microdialysis samples were collected every20 min for a period of 240 min and analyzed for DSP and DXMconcentrations. The solution in the syringe was analyzed forDSP and DXM content at the beginning and at the end of theexperiment.

In Vitro

The microdialysis probe was inserted into custom made glasscell21 (total capacity of 2 mL) in such a fashion that the micro-dialysis semipermeable membrane was positioned exactly inthe center of a glass cell. The cell contained 2 mL of blankringer’s solution that was continuously stirred with a star-headed magnetic stirrer. The glass syringe of the microdialysispump was filled with the DSP solution (5.0 and 2.5 :g/mL) thatwas perfused throughout the probe at 1 :L/min flow rate. Sam-ples were collected manually every 20 min for 4 h The temper-ature of the circulating water in the cell jacket was maintainedat 37◦C to mimic the skin temperature by a circulator (BF-41;Yamato Scientific Company, Ltd., Tokyo, Japan). Another probewas inserted in the hollow paperboard box protected from lightwith aluminum foil and perfused under the same conditions asthe other probes. The solution in the syringe was analyzed forDSP and DXM content before and at the end of the experiment.

Data Analysis

Means, standard deviations, CV%, E%, and calibration curvesof DSP and DXM concentrations were obtained using MicrosoftExcel 2010 (Microsoft, Seattle, Washington). Independent ttests (Microsoft Excel 2010) were used to determine whetheriontophoretic delivery was affected by patch location on thearm (Fig. 2). The nonparametric Mann–Whitney U test wasused to compare iontophoretic delivery versus passive deliveryand a two-way analysis of variance (ANOVA) was performedto assess the effect of time and of the surrounding environ-ment (air, isotonic solution, and skin) on the formation of DXMfrom DSP using the statistical software “R: A Language andEnvironment for Statistical Computing” (Vienna, Austria).29 Apost hoc Tukey test was performed to determine significant

DOI 10.1002/jps.23771 Joshi et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:191–196, 2014


Figure 3. Average dexamethasone concentration detected in dialysate samples when a 5 :g/mL solution of dexamethasone sodium phosphatewas perfused through a microdialysis probe inserted in (i) rabbit skin (n = 9), (ii) isotonic solution (n = 3), or (iii) hollow box (n = 5). Error barsrepresent standard error.

differences among time points in the presence of significantmain findings.

RESULTS

Iontophoresis Studies in Human Subjects

All eight participants tolerated the iontophoresis treatmentswell and no sign of irritation or erythema was observed on theskin at the time when the patches were removed. In addition,no infection or any reaction was observed due to the presenceor removal of the microdialysis probes at the time of dismissal.None of the participants reported any problems in the days fol-lowing the experiments due to either the microdialysis probe orthe iontophoresis treatment, although they were encouraged todo so when signing the consent. Dialysates samples collectedat the iontophoresis sites in seven out of eight participantscontained level of DSP and DXM above the LLOQ (50 ng/mL),whereas none of the samples collected at the passive site con-tained a quantifiable amount of either form of the drug. Specifi-cally, of the 48 dialysis samples (six per subject) collected at theiontophoresis sites, 29 contained quantifiable concentrations ofDSP. Figure 4 shows the time course profiles of DSP and DXMmeasured at the iontophoresis sites; samples containing DSPor DXM concentrations below the LLOQ were not included inthe average. The nonparametric Mann–Whitney U test usedto compare iontophoresis and passive sites confirmed that ion-tophoresis significantly increases the delivery of DSP to dermis(p < 0.0001) compared with passive application of DSP. Addi-tionally, given the cross-over design related to probe location, apaired t-test was performed and demonstrated that there wasno statistically significant difference (p > 0.05) between theresults due to the location of the probe (site A versus B; Fig. 2).

DXM Formation: In Vivo (Rabbit) and In Vitro

Our preliminary studies attempted to understand if the produc-tion of DXM was generated in vivo due to dermis metabolism of

Figure 4. Average dexamethasone sodium phosphate (DSP) and dex-amethasone (DXM) concentrations detected in skin dialysate following20 min iontophoresis in human participants. At the passive site DSPand DXM concentration were always below the limit of quantification(50 ng/mL).

DSP and then collected by the microdialysis probe, or if it wasthe product of degradation occurring during the retrodialysisprocess. The concentration of DXM within the syringe beforethe start of the experiment was compared with all subsequentsamples over the 4-h period of the experiment. The ANOVA in-dicated a significant effect of time on the formation of DXM fromDSP during the 4-h retrodialysis experiments (F value(DF = 12)

= 5.48, p < 0.05); however, a post hoc Tukey test showed thatthere was no significant difference between any two sequentialconcentrations, suggesting that for a period of time less than20 min the formation of DXM is negligible. The ANOVA alsoindicated that the environment surrounding the probe had aninsignificant effect on the formation of DXM; rather, the DXMobserved in the dialysate is produced mostly in the probe it-self and it is not produced in vivo. To evaluate the possibilitythat DSP converts to DXM when still in the syringe due toa potential instability of DSP in the lactated ringer solution,the concentration of DXM in the last dialysate samples were


RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology 195

compared with the concentration in the syringe at the end of theexperiments. DXM was expressed as percentage of the concen-tration of DSP in the same sample. A paired t test showed thatDXM concentration was significantly higher in the dialysatecompared to that in the syringe. In summary, the results of thisstudy showed a large variability in the formation of DXM dur-ing the retrodialysis procedure, hence we decided to not performretrodialysis in human studies.

DISCUSSION

This study demonstrated that cathodal iontophoresis deliverssignificantly more quantifiable amounts of DSP across humanskin in vivo compared with passive delivery. It also demon-strated the feasibility of microdialysis to collect successfullyDSP from dermis interstitial fluids.

Mechanistic studies such as this which attempt to support ef-ficacy of the use of iontophoresis to deliver DSP across the skinhave used a large variety of technical approaches for estimationof the amount of DSP delivered to the tissues (e.g., observationof cutaneous vasoconstriction,30 analysis of blood plasma,7,31

mass spectrometry assay of extracted connective tissue,32 andFranz diffusion cells).7 The current study is the first to use mi-crodialysis to determine dermal concentration levels of DSP.There are only three existing studies that have examined ion-tophoretic delivery of DSP using in vivo human tissue. Smutoket al.31 did not find DSP within the blood plasma taken prox-imally to the site of iontophoresis application. These resultsmay be due to analytical limitation because the small amountof DSP delivered by iontophoresis dilutes in the large plasmavolume. Results from a study by Anderson et al.30 suggest thatDSP was successfully delivered transdermally; however, theseresults are limited by the failure to control for passive diffusioneffects and from a method of measurement, which is exception-ally indirect—vasoconstriction as determined by observationand differential infrared surface temperature measurement. Ina more rigorous, but more invasive study, Gurney and Wasche33

examined 29 participants previously scheduled for surgery. Be-fore surgery, 16 participants received iontophoresis with DSPover the semitendinosis tendon, whereas a control group (n =13) received passive iontophoresis. During surgery, the tendonwas extracted and HPLC was used to determine tissue con-centration. Eight of the 16 iontophoretic treatments achieved adetectable level of DSP, whereas only one of the control groupachieved a detectable level of DSP.

Comparison between the current study and the study per-formed by Gurney and Wascher33 is difficult for several reasons.First, the findings demonstrated a 50% failure to detect DSP af-ter iontophoresis (eight of 16 participants). As the authors rec-ognized, there are many factors that may have contributed tothis varying effect including errors in procedures or individualdifferences in anatomy or metabolism. Regardless, the currentstudy’s examined concentrations dermally rather than in thedeeper connective tissue of a tendon and direct comparisons arenot appropriate. We speculate that dermal measurements (e.g.,approximately 2 mm in depth) achieved through microdialy-sis would minimize variation due to metabolism (if any) as themeasure occurs close to the delivery site and is congruent withthe time of delivery. However, even within the current study,we observed a large interindividual variation and there wasa failure to detect DSP/DXM in one of the eight participants,suggesting that measurement of detectable levels of DSP/DXM

may be limited by technical issues and/or individual differencesin skin permeability.

As this is the first study to use microdialysis to examine ion-tophoretic transdermal delivery of DSP there are no studies forcomparison regarding the relative magnitude of concentrationfound within the skin. The single existing in vivo human studydescribed above33 that used appropriate quantitative methodssacrificed tissue and provided results using HPLC in units ofng/g of tissue. Microdialysis also uses HPLC to quantify theconcentration of the drug but measures instead perfusing solu-tion that has been in contact with the interstitial compartmentproducing units of ng/mL. The concentration in the dialysateis proportional but less than the actual concentration in thedermis interstitial fluid. Typically a calibration method likeretrodialysis19 is applied to calculate skin concentration. In thepresent study, we did not perform retrodialysis because someDSP converts spontaneously to DXM during the procedure witha large interexperiment variability. Instead, we performed pas-sive and iontophoretic delivery on the same subject at the sametime as the overall purpose of the study was the comparisonof delivery performance not the determination of the actualskin concentration. This experimental design also has the ad-vantage that it requires only a one-day commitment loweringparticipant burden. The in vitro studies demonstrated that theDSP collected in the dialysate does not convert substantiallyto DXM during the brief transit time (approximately 1 min)required to travel from the skin to the collecting tube and nosubstantial degradation was observed during storage in lac-tated ringer solution from collection to analysis. Further, theDXM concentrations detected in the human dialysate keep in-creasing, whereas the concentrations of DSP decrease (Fig. 4).We interpret the sum of these findings as suggesting that theDXM measured in the dialysate (Fig. 4) likely reflects the DXMformed by dermis metabolism. However, this hypothesis needsto be confirmed in future studies.

It should be noted that in preliminary studies we used thecommercially available DSP USP injection solution for place-ment in the iontophoresis electrodes, as is the common clinicalpractice. However, results were very variable and in most ofthe participants DSP was not detected at the iontophoresissite. This prompted us to: (1) improve the LLOQ of the ana-lytical assay, (2) double the length of the dialysis membrane to2 cm to increase the probe recovery,19 and (3) use a DSP so-lution compounded in our pharmacy in distilled water insteadof the commercial IV-injection solution. Indeed, the commer-cially available formulation contains preservatives and bufferssuch as citric acid, sodium citrate, edetate disodium, sodiumsulfite, sodium metabisulfite, and benzyl alcohol, depending onthe manufacturer. Concentrations of these substances may beas high as 10 mg/mL. The negative citrate, sulfite, and edetateions may compete with DSP to carry negative charges acrossthe skin and lower the overall efficiency of the iontophoreticdelivery of DSP. Sylvestre et al.34 observed a decrease in DSPtransport across pig skin in vitro when 0.44% DSP was dis-solved in 40 mM potassium citrate. We believe that the use ofthe specially compounded preservative-free DSP solution wasthe major determinant of the positive results finally obtainedin this study.

In any event, all existing studies, including this one, haveno data on which to determine what magnitudes of concentra-tion, whether subdermally, or within deeper tissue, are associ-ated with clinical outcomes relative to musculoskeletal injury.

DOI 10.1002/jps.23771 Joshi et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:191–196, 2014


Consequently, the results from this study are limited in thatthey only represent support for the underlying mechanism ofiontophoretic delivery of DSP but do not provide informationabout effective therapeutic levels.

CONCLUSIONS

The current study found that cathodal iontophoresis deliverssignificantly more quantifiable amounts of preservative-freeDSP solution across in vivo human skin compared with passivedelivery of the same suggesting that positive clinical outcomesare likely validly related to an increase in drug delivery. Thisstudy also demonstrated the feasibility of microdialysis to suc-cessfully assess iontophoretic delivery of DSP. Future studiesmay benefit from this relatively noninvasive technique to ac-quire direct measures of DSP delivery using different types ofiontophoresis approaches.

ACKNOWLEDGMENT

The authors thank Dr. Thierry Crost (Gambro Industries,France) for the donation of the dialysis membranes.

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iontophoresis successfully delivers dexamethasone sodium phosphate to dermis as measured by...

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