Ren Et Al-2014-Journal of Pharmaceutical Sciences

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RESEARCH ARTICLE Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Passive and Iontophoretic Transport of Fluorides across EnamelIn Vitro

WEI REN,1 ARIF BAIG,2 S. KEVIN LI1

1Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio 45267

2Procter & Gamble Company, Mason, Ohio 45040

Received 21 January 2014; revised 10 March 2014; accepted 11 M arch 2014

Published online 8 April 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23961

ABSTRACT: Passive and iontophoretic transport of fluoride from three fluoride sources, NaF, sodium monofluorophosphate (MFP), andSnF2solutions, across bovine enamel was investigated to (1) determine the characteristics of the intrinsic barrier of enamel for ion transport,(2) examine the feasibility of iontophoretically enhanced transport of fluoride across enamel, and (3) identify the transport mechanismsinvolved in enamel iontophoresis. Conductivity experiments were performed with bovine enamel specimens in side-by-side diffusion cellsto evaluate the electrical and barrier properties of the enamel with electrolytes of different ion sizes and under different ion concentrationsand pH conditions in vitro. Transport experiments of the enamel were performed in the diffusion cells with the NaF, MFP, and SnF 2solutions. The conductivity results showed that the enamel specimens behaved as a neutral membrane or that of low pore charge density.

Cathodal iontophoresis significantly enhanced the delivery of fluoride ions across the enamel from the solutions over passive transport,consistent with NernstPlanck theory and the direct field effect (i.e., electrophoresis) as the dominant flux-enhancing mechanism. Theenamel demonstrated significant transport hindrance for the ions, and the effective pore radii of the transport pathways in the enamelwere found to be approximately 0.70.9 nm. C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci103:16921700, 2014Keywords: iontophoresis; enamel; diffusion; permeability; fluoride; dental; delivery; oral drug delivery; membrane conductance/resistance

INTRODUCTION

Approximately 2.4 billion people (36% of the population) suffer

from dental carries worldwide. The formation of a carious lesion

in the enamel involves the dynamic processes of the deminer-

alization and remineralization of hydroxyapatite.1 Fluoride ion

is one of the most important anticaries agents. The first fluo-ride compound used in dentifrice was stannous fluoride, which

was shown to be effective in treating dental caries.2,3 However,

because of the limited stability and poor formulation flexibility

of SnF2, monofluorophosphate (MFP) and NaF replaced SnF2as the active ingredient in most dentifrice products.4,5 Later,

by overcoming the major drawbacks of SnF2, this anticaries

agent has become the active ingredient in some recent denti-

frice products because of the additional antimicrobial and gin-

givitis control effects of SnF2 compared with the other fluoride

agents.68

Over the past decades, numerous efforts have been made to

overcome the intrinsic barrier of the enamel and the outward

flow of dentinal fluid.9 Ozawa et al.10 have successfully deliv-

ered lidocaine into the pulp in vivo by applying a pulpward

hydrostatic pressure against the outward flow through denti-

nal tubules. Another method is iontophoresis, which enhances

the transport of ionic and nonionic drugs by the assistance of

an external electric field11 and offers an alternative to facili-

tate the permeation of drugs through enamel. The mechanisms

of iontophoresis include electrophoresis, electroosmosis, and

electroporation.1216 Direct current (DC) iontophoresis of ionic

Correspondence to: S. Kevin Li (Telephone:+513-558-0977; Fax:+513-558-4372; E-mail: [email protected])

Journal of Pharmaceutical Sciences, Vol. 103, 16921700 (2014)C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

drugs metronidazole, sodium salicylate, and naproxen sodium

has been examined and found to provide enhanced delivery

of these drugs through intact and caries-affected dentine.17

Gupta et al.18 have shown that DC iontophoresis of 2% NaF

was more effective in reducing tooth sensitivity compared with

topical fluoride applications. Similar iontophoresis approaches

have been examined for treating tooth hypersensitivity and

desensitization.1921 Ikeda and Suda22 have investigated the

transport of lidocaine hydrochloride through human enamel

with alternating current iontophoresis.

Although it has been suggested that iontophoresis can be uti-

lized to control dental caries and dentine hypersensitivity, the

effect of fluoride iontophoresis on tooth remineralization was

found not to be superior to other fluoride application methods

such as acidulated phosphate fluoride gel and sodium fluoride

varnish.23,24 In addition, the conditions for dental iontophore-

sis (e.g., duration of application, formulation compositions, and

applied electric current density) were not optimized in most

studies. The barrier and electrical properties of enamel for ion-

tophoresis have not been well characterized. In spite of the con-siderations of iontophoresis in dental applications more than

four decades ago,25,26 the mechanisms of iontophoretic trans-

port of ions across enamel are not well understood. In order to

optimize dental iontophoresis and its development, the under-

standing of the barrier properties of enamel for ion transport

during iontophoresis is important. Also, previous passive and

iontophoresis studies were focused on sodium fluoride solution,

and MFP and SnF2 that are popular formulations in current

dentifrice have not been systematically studied.

The objectives of the present study were to (1) investigate the

physical characteristics of the intrinsic barrier of the enamel

for ion transport, (2) examine the feasibility of iontophoretically

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RESEARCH ARTICLE Pharmaceutics, Drug Delivery and Pharmaceutical Technology 1693

enhanced transport of fluoride from NaF, MFP, and SnF2 solu-

tions, and (3) identify the mechanisms involved in iontophoretic

transport of fluoride across the enamel. Bovine enamel was the

model tissue. Conductivity study was first performed to investi-

gate the electrical and barrier propertiesof the enamel.In addi-

tion to the barrier characterization study, conductivity was also

used to evaluate the reproducibility and stability of the enamel

specimens for the long duration experiments in the present

study. Transport study was conducted under passive and ion-tophoresis conditions to examine the effect of iontophoresis and

its mechanisms for fluoride delivery into and across the enamel.

EXPERIMENTAL

Materials

Phosphate buffered saline (PBS) tablet was purchased from

MP Biomedicals, LLC (Solon, Ohio). Sodium fluoride, MFP,

tin (II) fluoride (SnF2), 1, 2-diaminocyclohexanetetraacetic acid

(CDTA), and perchloric acid were purchased from Sigma

Aldrich (St. Louis, Missouri). Magnesium sulfate, potas-

sium chloride, sodium hydroxide, and sodium gluconate (SG)were purchased from Fisher Scientific (Rochester, New York).

Sodium chloride, sodium phosphate monobasic, and sodium

phosphate dibasic were purchased from Acros Organics (Morris

Plains, New Jersey).

Phosphate buffered saline of pH 7.4 (0.01 M phosphate

buffer, 0.0027 M potassium chloride, and 0.137 M sodium chlo-

ride) was prepared by dissolving PBS tablet in distilled, deion-

ized water (DI water). PBSof pH 5.7, 6.0, and 8.0 were prepared

by first mixing 0.2 M NaH2PO4 and 0.2 M Na2HPO4 stock so-

lutions at the ratio of 93.5 to 6.5, 87.7 to 12.3, and 5.3 to 94.7,

respectively, to obtain 100-mL solution, and then adding 8.0 g

NaCl, 0.2 g KCl, and distilled deionized water to the solution to

obtain final volume of 1 L. PBS of pH 5.0 and 9.0 were prepared

by adding concentrated HCl and NaOH into PBS of pH 5.7 and

8.0, respectively.

Fluoride Solution

NaF and MFP solutions were prepared by dissolving NaF and

MFP in DI water, respectively, to obtain equivalent fluoride

concentration of 1000 ppm. Stannous fluoride solution (SnF 2)

was prepared by dissolving SnF2 in 1% SG (w/w) in DI water

to produce equivalent fluoride concentration of 1000 ppm. The

conductivities and pH of PBS, NaF, MFP, and SnF 2 solutions

were measured with a pH/conductivity probe connected to a

pH/conductivity benchtop meter (Model PC 510; Oakton Instru-

ments, Vernon Hills, Illinois). The osmolarities of the solutions

were determined with an osmometer (Model 3300; AdvancedInstrument, Norwood, Massachusetts). The viscosities of the

solutions were measured using a capillary viscometer (Fisher

Scientific) with DI water as the reference.

Preparation of the Enamel Specimens

Eight enamel specimens (thickness between 0.45 and

0.66 mm) from bovine teeth were carefully examined microscop-

ically (10 magnification) to ensure that there was no crack onthe specimens before they were stored in moisture chambers

at 4C until use. Before the conductivity and transport experi-ments, all specimens were rinsed and equilibrated in DI water

for at least 30 min.

Figure 1. A schematic diagram of the order (steps) of the conductivity

experiments (protocols).

Conductivity Study

Conductivity experiments were performed with the enamel

specimens sandwiched in side-by-side diffusion cells under

well-stirred conditions in a circulating water bath at 37 1C.Conductivity (or conductance) is the reciprocal to electrical re-

sistivity (or resistance) and was used to characterize the barrier

properties of the enamel. Before the experiments, the enamel

specimen was mounted vertically between the two half cellsof a

side-by-side diffusion cell with the enamel side facing the donor.

Two rubber gaskets were used on both sides of the enamel to

prevent leakage at the junctions between the half cells and

enamel. The available diffusion area of the diffusion cells was

approximately 0.23 cm2. Both the donor and receptor cham-

bers contained 2 mL test solution. The electrical resistance of

the enamel was measured using a multimeter (Fluke 73III)and Ag/AgCl and Ag electrodes. The test solutions of 0.01, 0.04,

and 0.15 M NaCl, KCl, and MgSO4 were used to evaluate the

effects of ion size and concentration upon enamel conductivity,

and test solutions of PBS pH 5.0, 6.0, 8.0, and 9.0 were used

to investigate the effects of pH. The experiments (steps) of the

conductivity study for each enamel specimen are summarized

in Figure 1. The total duration of each conductivity experiment

(each step) was 48 h. In each conductivity experiment, the elec-

trical resistance across the enamel was measured every 12 h

and the average of the resistance values was calculated. Be-

tween each experiment, the enamel samples were rinsed by

replacing the donor and receptor chambers with fresh DI water

five times over 24 h. The resistance of enamel in pH 7.4 PBSwas used as the control. Control experiments were conducted

at the beginning, the end, and between each step.

Transport Study

Passive and iontophoretic transport experiments were per-

formed with the enamel specimens in the side-by-side diffusion

cells under well-stirred conditions at 37 1C. The volumes ofdonor and receptor solutions were 2 mL. PBS was the receptor

solution in all the transport experiments, and NaF, MFP, and

SnF2 solutions were the donor solutions. The durations of the

passive and iontophoretic transport experiments were 48 and

8 h, respectively. The long durations allowed ion transport to

reach steady state for mechanistic interpretation of the data. At

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1694 RESEARCH ARTICLE Pharmaceutics, Drug Delivery and Pharmaceutical Technology

predetermined time intervals (12 h for passive transport and

2 h for iontophoretic transport), 10 :L of the donor solution

and 1 mL of the receptor solution were withdrawn from the

diffusion cells for assay. Fresh PBS was added to the receptor

chamber to maintain a constant volume. To maintain the same

composition of the donor solution (NaF, MFP, or SnF2) over the

course of the iontophoresis experiments, the donor solution was

replaced with fresh donor solution every 2 h during iontophore-

sis. Cathodal iontophoresis experiments (cathode electrode inthe donor chamber) were performed by applying 0.1 mA con-

stant current across the enamel with an iontophoresis device

(Phoresor II Auto; Model PM 850; Iomed Inc., Salt Lake City,

Utah). Ag/AgCl (cathode) and Ag (anode) were the electrodes to

minimize electrolysis of water and pH changes in the solutions.

The electrical resistance of the enamel was monitored by the

voltage drop across the specimen during iontophoresis using

a multimeter (Fluke 73III). To evaluate reproducibility, in the

first set of experiments with NaF, passive and iontophoresis

experiments were alternately conducted three times for each

enamel specimen with half of enamel samples started with pas-

sive transport experiments first, whereas the other half began

with iontophoresis experiments. In the experiments with MFPand SnF2, passive experiments were conducted first and then

followed by iontophoresis experiments for each enamel spec-

imen. Before each transport experiment, the chambers were

thoroughly rinsed 46 times with DI water over 48 h, and flu-

oride concentration in the diffusion cells was found to be be-

low the detection limit of the fluoride assay after this rinsing

procedure.

Assay Method

The concentrations of fluoride ion in the samples were de-

termined with a fluoride selective electrode (Model WD-

35812-18, Oakton Instruments) coupled to a pH/conductivity

benchtop meter (Model PC 510; Oakton Instruments). Prior tofluoride concentration measurements, all samples were mixed

with equal volume of Total Ionic Strength Adjustment Buffer

I (TISAB I, 1 M acetic acid, 1 M NaCl, 0.011 M CDTA, and

0.938 M NaOH). For MFP, because MFP solutions only con-

tained about 3% (w/w) of free fluoride ions in aqueous solution,27

MFP was hydrolyzed before the assay. The MFP samples, which

had already been mixed with equal volume of TISAB I as de-

scribed above, were hydrolyzed with 1 M perchloric acid at

room temperature over 48 h. Then, the hydrolyzed samples was

neutralized with 4 M NaOH and diluted to the original ionic

strength with DI water. The concentration of fluoride in the

sample was determined and the equivalent MFP concentration

was calculated. For stannous fluoride, the samples were mixed

with TISAB II (1 M acetic acid, 1 M NaCl, 0.014 M ethylene-diaminetetraacetic acid, and 0.8 M NaOH). The final pH of all

samples was approximately 5.25. Standard solutions of NaF,

MFP, and SnF2 of equivalent fluoride concentration from 1 to

100 ppm were prepared as described in Fluoride Solution sec-

tion to construct the calibration curves in the assays. The MFP

and SnF2calibration curves overlapped with that of NaF when

compared at the same equivalent fluoride concentrations, vali-

dating the MFP and SnF2 assay methods.

Theory and Analysis

In the conductivity study, the electrical resistance of a solution

(R) or its conductance (G) is related to the resistivity () and

the dimensions of the solution:

R = 1G= l

A= 1

l

A (1)

where F is the conductivity, and l and A are the length and

cross-sectional area of the solution, respectively. For an elec-

trolyte solution ofz:z valence, the molar conductivity () can

be expressed as:

= Cion

= (zcc +zaa)F (2)

where Fis the Faraday constant, C ion is the electrolyte molar

concentration, c and a are the electrophoretic mobilities of

the cation and anion, and zc and za are the valence of charge

(in absolute value) of the cation and anion, respectively.

For a porous membrane, membrane conductivity (Fm) can be

expressed as:

m= (zcc,m +zaa,m)FCion,m (3)

where is combined porosity/tortuosity factor of the membrane,

Cion,mis the concentration of the ions in the membrane, and :c,mand:a,mare the effective electrophoretic mobilities of the cation

and anion in the membrane. Taking the ratio of membrane

conductivity to solution conductivity,

m

= (c,m + a,m)Cion,m

(c + a)Cion(4)

When the cation and anion have similar hydrated ion sizes,

the ratio of membrane conductivity to solution conductivity

becomes:

m

= eff (5)

whereeffis the effective porosity/tortuosity factor of the mem-

brane for the ions. In addition to describing membrane porosity

and tortuosity, effalso takes into account of hindered partition-

ing and transport of the ions across the membrane.

In the transport study, the cumulative amount of fluoride

ion transported across enamel (Q) was plotted against time (t).

The apparent flux (J) was calculated from the slope of the lin-

ear portion of the cumulative amount versus time plot (Q/t)

divided by the effective diffusion area (AD).

J= 1AD

Qt

(6)

The apparent permeability coefficient (P) was calculated by

dividing the flux by the concentration of the permeant in the

donor (CD).

P = 1CDAD

Q

t (7)

Permeability coefficients of passive diffusion are defined as:

P

=

Deff

h (8)

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RESEARCH ARTICLE Pharmaceutics, Drug Delivery and Pharmaceutical Technology 1695

whereh is the thickness of the membrane and Deffis the effec-

tive diffusion coefficient of the permeant across the membrane:

Deff= effD (9)

where D is the diffusion coefficient of the permeant. For ion-

tophoretic transport, the apparent permeability coefficient is

defined as the iontophoretic flux normalized by the donor

concentration.

The effective pore size of the transport pathway in the mem-

brane can be calculated using the ratio of the permeability

coefficients of the permeants obtained from the passive perme-

ation experiments with the assumptions of a single pore size

and cylindrical pore geometry and negligible chargecharge

interactions28:

Pi

Pj= Deff,i

Deff,j= HiDi

HjDj(10)

where the subscripts i and j represent permeants i and j, andHi

andHj are the hindered transport factors for these permeants,respectively. The hindrance factor can be expressed by:

H= 6B (1 8)2

Kt(11)

where8 is the ratio of permeant radius (rs) to pore radius (Rp)

andKt is a hydrodynamic coefficient29:

Kt=9

4B2

2 (1 8)5/2

1+

2n=1

an (1 8)n+

4n=0

an+38n (12)

wherea1=

1.217,a2=

1.534,a3=

22.51,a4=

5.612,a5=0.3363,a6= 1.216, anda7= 1.647.

The enhancement factor (E) of iontophoretic transport is de-

fined as the ratio of iontophoretic flux (Jiont) to passive flux

(Jpassive) with the same donor concentration:

E = JiontJpassive

(13)

For electrophoresis-dominant iontophoretic transport (i.e.,

negligible effect of electroosmosis), the enhancement factor

(E) can be predicted by the NernstPlanck equation:

E=zF

RgasT (14)

where z is the valence of charge, Rgasis the universal gas con-

stant,Tis absolute temperature, and is the voltage applied

across the specimens during iontophoresis.

RESULTS AND DISCUSSION

Conductivity Study: Effect of Ion Concentration

Figure 2 shows the relationships between the conductance of

the enamel versusthe conductance of solution at the same phys-

ical dimensions (0.23 cm2 0.56 mm) when the enamel wasequilibrated in 0.01, 0.04, and 0.15 M NaCl, KCl, and MgSO 4

Figure 2. Relationship between the conductance of enamel in NaCl

(diamonds), KCl (squares), and MgSO4 (triangles) solutions and the

conductance of the solutions of the same physical dimensions. Data

represent the mean and SD of the measurements with four enamel

specimens.

solutions. In the figure, enamel conductance was proportionalto solution conductance in NaCl, KCl, and MgSO4, giving lin-

ear least-squares slopes of 0.002, 0.002, and 0.008, respectively.

These enamel versus solution conductance slopes are related to

the effective porosity of the enamel specimens (Equation (5)).

For an uncharged porous membrane with pore size significantly

larger than the sizes of the electrolyte, the plots of membrane

conductance versus solution conductance should overlap for all

electrolyte solutions. The larger slopes of NaCl and KCl than

that of MgSO4 in the figure are consistent with the hydrated

radii of Mg2+ and SO42 being larger than those of Na+, K+,and Cl, this resulting in (1) differential partitioning of theions from the surrounding electrolyte solution into the pores of

the enamel because of the size-exclusion effect and/or (2) hin-

dered transport of these ions across the pores in the enamel forion conduction.

Because of the large sample-to-sample variability in

Figure 2, the results in the conductivity study were further an-

alyzed using the ratio of enamel conductivity in KCl or MgSO4to that in NaCl of an individual enamel sample. In this anal-

ysis, the ratio of enamel conductivity was divided by the ratio

of solution conductivity in the same experiments to provide the

ratio of the effective porosity for the conducting ions of a solu-

tion to that of NaCl (see Equation (5)):

eff,ion

eff,NaCl= m,ion

m,NaCl

ion

NaCl(15)

where the subscripts ion and NaCl represent the parameters

for the ion system (KCl or MgSO4) and NaCl, respectively.

Figure 3 shows the effective porosity ratio of KCl or MgSO 4 to

NaCl. It is evident from the figure that the effective porosity of

MgSO4was significantly lower than that of KCl and NaCl (p MFP > SnF2. This suggests the preference

of fluoride permeation from its free form in NaF solution and

significant transport hindrance (i.e., size selectivity) in ion de-

livery across the enamel. In addition, the low-effective porosity

of enamel (eff 0.0020.008) also contributes to the low perme-ability of enamel for the ions. The enamel is not permselective

for cation or anion transport (i.e., little or no charge selectivity)

as it behaves as a barrier without a net charge or of low-charge

density.

Iontophoresis offers an opportunity to enhance the delivery

of ions and drugs to their sites of action in oral care. In dentaliontophoresis, the electric current-driving electrode and drug

formulation can be in contact with either or both the gingiva

and tooth enamel in the oral cavity during application. Identi-

fying the principal mechanism of ion transport across enamel

and its characteristics during iontophoresis is essential for the

development of iontophoretic delivery of fluoride and drugs into

and across dental enamel. Similarly, the understanding of ion-

tophoretic transport properties of the gingiva tissue is neces-

sary for drug delivery in the treatment of periodontal diseases.

When iontophoresis is utilized for periodontal diseases, the

knowledge of iontophoretic transport across enamel can also

be useful because of the potential of electric current passage

to tooth enamel during iontophoresis application. Informationon the electrical properties of these barriers is important in

the development of an effective iontophoresis system for dental

applications. It should also be pointed out that iontophoresis

has been investigated for treating tooth sensitivity in human

in vivo,1821 and there was no report that iontophoresis would

lead to sensations that would prevent this technology to be used

in clinical settings.

For iontophoretic delivery to the tooth, although dental ion-

tophoresis treatment in practice has much shorter treatment

duration than those in the present study, the present steady-

state permeation data can provide insights into iontophoretic

delivery in practice. Particularly, the higher flux of fluoride

ion during iontophoresis observed in the present study implies

that a higher amount of fluoride can be delivered in the sametreatment time or the same fluoride delivery can be achieved

in a shorter duration of treatment. Under the condition of

0.43 mA/cm2 (0.63 V) across the enamel (0.450.66 mm thick),

iontophoresis can provide approximately 30100 times of flux

enhancement for small ions compared with passive delivery.

The flux enhancement can also lead to shorter transport lag

time during iontophoretic delivery compared with passive dif-

fusion. Electrophoresis is the major flux-enhancing mechanism

during enamel iontophoresis with minimal contributions from

electroosmosis and electroporation. This suggests that ion-

tophoresis would not be effective in enhancing the delivery of

neutral permeants into and across enamel because these per-

meants would not benefit from the mechanism electrophoresis.

ACKNOWLEDGMENTS

The authors thank Drs. Gerald B. Kasting and Donald J. White

for helpful discussion. The authors also thank Proctor and

Gamble (P&G, Cincinnati, Ohio) for kindly providing the bovine

enamel specimens used in the present study.

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Ren, Baig, and Li, JOURNAL OF PHARMACEUTICAL SCIENCES 103:16921700, 2014 DOI 10.1002/jps.23961

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Ren Et Al-2014-Journal of Pharmaceutical Sciences