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Iontophoretic delivery of propranolol hydrochloride through human epidermis
The passive and iontophoretic transport of propranolol hydrochloride (PHCl) has been studied through human epidermis by varying the pH of the donor solution and the current density. The steadystate flux during passive transport of PHCI was maximal at pH I I and minimal at pH 7.4. The transport was enhanced during iontophoresis in comparison to the passive diffusion at all pHs. The cathodal iontophoretic flux was greater than anodal and was maximal at pH 1 I. The llux was also found to be proportional to the current density. One of the most important applications of this study is the possibility of enhancing and controlling the transdermal delivery of PHCI by iontophoresis. Keywords: Transdermal: density
Transport;
Iontophoresis:
Introduction
The transport of ionic and polar solutes across human skin is not favoured by passive diffusion. One promising technique for increasing the transdermal delivery of ionic solutes is iontophoresis. It enhances the penetration of solutes into tissues by applying electric current [ 1,2]. It was first used for the introduction of strychnine and cyanide ions into rabbits [ 31 and siuce then it has been used with success for local delivery of drugs [4-71. More recently, this technique has been explored for transdermal delivery of drugs for systemic effects [&IS]. Tbe factors affecting iontophoretic transport of
Fhtx: Propranolol
hydrochloride;
pH; Current
solutes across human epidermis have been discussed [ I I ?I2 1. The transport of drugs through skin during iontopboresis has been shown to be dependent on the pH ofthe donor solution [ 12161 and the current density [ 14.15 I. The purpose of this study was to investigate the effect of pH and current density on the transport of propranolol hydrochloride (PHCI ), an non selective P-blocker antihypertensive drug. PHCi has a pKa value of 9.4 which permits protonation and deprotonation in the PH range of 7.4 to I I. It undergoes extensive first pass metabolism and only 30-60% of the oral dose is systematically available [ 171. It also has a short elimination half life (14) of about 3 h [18], which makes it a suitable candidate to be delivered transdermally at a controlled rate by iontophoresis. However, the basicity makes potential skin irritation aconcern.
Materials and Methods
Propranolol hydrochloride was obtained from CIPLA, Bombay. Benzyl alcohol, trisodittm citrate, disodium hydrogen phospbate anhydrous and glycine were obtained respectively from Ranbaxy Laboratories, Delhi, Glaxo Laboratories, Bombay, E. Merck Pvt. Ltd., Bombay and Glaxo Laboratories, Bombay. All other reagents were ofanalytical grade. Prcpnration
of buffers
The donor solution buffer was prepared by mining equal proportions of 30 mM each of trisodium citrate, dihydrogenorthophosphate and glycine. The pH of the buffer was adjusted by adding I M NaCH or I M HCl. The same buffer
t=,g. 2. Plo,
of mean
e”m”lallYC
anlO”“,
pemlemd
Yerw6
tnne for propranolol hydrochloridein different pH during cathodalmntophorcGs al 0.21 mAlcm’ wrrent density.Only hm0rk smdard dcvmimnbar is shownforclarity. 0: pH 7.4: a: p” 9.4: 0: pH I1.0.
90 mM concentration was used to vary the pH of the donor solution to minimize changes in the transport efficiency. The receptor was phosphate buffer (pH 7.4). In vitro transport
passived0Tuusxon. Only half of the standardd&ion shownrorclarity. 0: pH 7.4: A: pH 9.4: 0: pH
b.xrii
Il.0
studies
Glass diffusion cells fabricated in our laboratory were used tn all the transport studies. The maximum volume of each compartment of the cell was 4 ml. Working electrodes were made from platinum wire (99% purity, 0.5 mm diameter). The constant current source, fabricated at our University Science Instrumentation Centro, was used for supplyiog the required cure~t. Samples of skin of 2 I-50years old Caucasian cadavers of either sex, including the suhcutaneo’ls fat, approkiaately 25 cm by 6 cm were re-
167
Effect of pH on the fractron mnned and fmcdan change in IbC nun ofpropranolol by*mcblor,dc PH
7.4 34 11.0
Frrction Lonlled~
099 0.50 0.02
*Fraction ofpropranolol c&led
7.4 9.4 Il.0 __-
5.00~2.66 10.40i 1.05 11.75i2.33
11.0+4.60 14.00+0.80 t7.75+ 1.66 ____~
Frxlion
change m Jssb
C-athodal
Anodal
0.55 0.29 0.34
0.18 0.06
lhydrachlonde mmzed has been cat-
by the Henderson-Hasselbalchequation.
12.65~1.10 12 50t0.07
mowd from the mid-abdominal region within 24 h of death and storzd at -20°C. The subcutaneous
fat was trimmed
and
Kligman
and
[ 19 ] was adopted
of to remove the epidermis. Then, the epidermis was washed with water, dried overnight at room temChristophers
the method
current densities. Only half of the standsrd deviation bar is shown for clarity. 0: 0.14 mA/cm’: 0.28 mA/cm2; 0: 0.53 mAfcm’.
168 this technique the pH was kept to within 20.2 unit of the desired DH as determined at the end ofthe experiment. Samples were withdrawn at regular intervals from the receptor compartment (0.5 ml) for analyses of the drug concentration and the same volume was replaced by fresh receptor fluid. At the start and end of the experiment, 0. I ml of the donor solution was also sampled for analysis. The samples were diluted as desired with phosphate buffer (pH 7.4) and the absorbance was measured at 290 nm on a Beckman Model 24 Spectrophotometer. The absorbance at 290 nm showed no interference from water soluble cxtm;ts of the skin. At the end of each experiment, integrity of the skin was examined by quantifying the permeation of 0.59’6benzyl alcohol for an hour. All the in vitro transport experiments were carried out in triplicate. pemture
andstoredat -20°C [ZO].Theepidermis was allowed to thaw overnight at room temperature and rehydrated by immersing in water for 1h [Z I ] before being placed in the pemxation cell with dermal side towards receptor compartment. It was supported in this position by wire mesh. A thin film of silicone grease was spread on the lapped glass surfaces of the cell to provide a wat‘:r-tight seal. The cells were clamped and immersed in a water bath at 37 +OS”C. The media of the diffusion cell were stirred at the rate of 48 rwminusing magnetic star fleas. The donor and receiver compartments contained 3 ml of PHCI solution in buffer of the desired pH and phosphate buffer (pH 7.41, respectively. The surface arca of the epidermis exposed to the solution was 2.83 cm’. Cathodal ionthophoresis wetsperformed by inserting the anode in the donor compartment and the cathode in the receiver compartment. Anodal iontophoresis was done by reversing the polarity. The effect of the pH of the donor solution on the drug transport was studied at 0.21 mA/ cm2 current density. The current density was also varied between 0.14 to 0.53 mA/cm’ to observe its effect on the transporl of PHCI. Changes in pH during iontophoresis were monitored and corrected for bv the addition of microliter amounts ol’ i M tkl or I RI NaOH solutions. By
RCSPltS The cumulative amounts of PHCI transported at different pH during passive diffusion are shown in Fig. I The passive transport was increased as the pH of the donor solution was increased from 7.4 to 9.4. Figs. 2 and 3 show the cumulative amounts of drug transported versus time during cathodal and anodal iontophoresis, respectively. The transport was found to be more during cathcdal than anodal ionthophoresis. The steady state flux. the slope of the linear portion of the plot of cumulative amount permeated against time is given in Table I. The steady state flux during cathodal ionthophoresis is found to be greater than the corresponding passive thtx at all pH. The flux is statistically greater (P
lion change in flux is observed at pH 7.4 during cathodal iontoohoresis where a 0.99 fraction of PHCI is protonated in the bulk solution. The effect ofcurrent density on the transport of PHCI has been measured only at pH 7.4 because this pH does not allow irreversible structural and impedance changes in the skin. The results have been shown in Fig. 4. The transport was increased with increasing current density. The flux at current densities 0 and 0.53 mA/cm’ was 5 and 20.5 flgcg/cm’/h, respectively. Therefore, in,. creasing the rmrznt densities from 0 to 0.53 mA/ cm2 have enhanced the flux fourfold. A linear relationship (r=0.9954) was also observed bctween the flux and current density with slope (30.1 I /Ig/mA/h) and intercept (5.1 flgjcm’jb j (Fig. 5).
Discussion The results show an increase in the steady state flux as the oH is increased from 7.4 to I1 durine passive diffusion. This may kx in accordance wit; the pH-partition hypothesis according to which the transport of unionized moiety of the drug is. favoured through lipophilic biologic membranes [22,23]. Water diffusion through excised hairless mouse skin has been consistent in the pH range 4 to 10. However, an increase in water diffusion [241 and decrease in skin impedance 1251 have been noted at pH> 10. The greater flux of PHCI at pH 1 I can also be attributed to lesser impedance of the epidermis at this PH. The steady state flux of the drug was enhanced at each pH during iontophoresis. At pH 7.4, the drug is mostly in the ionized fortn and with application of current the ionic mobility increases and the transport of the drug as such incrcdses. It is known that the steady state Run depends on the charge of the solute molecule, ionic mobility and electrical potential applied as well as the solute concentration. But our findings suggest that even at pH 11, the transport of unionized form of PHCI has been affected by current density. This can be explained on the basis of the work of Rein [ 281who has shown an increase in the current induced convective flow of water across ex-
cised human skin with increasing pH of the donor solution The hiahest flux at oH I1 during passive transport and iontophoresis can also refleets damage to skin due to soluhility of keratin at this pH. The higher flux of PHCI with increasing pH of the donor solution can also be explained on the basis of the permselective nature of the epidermis. The epidermis above its isoelectric point would be negatively charged (pH 7.4-l I ). As the pH increases, the negative Bxed charge density in the pores increases resulting in an increase in the fixed pore ccunter ions concentration. The mcreas~d counter ions concentration would result in an increase in the convective flow in the direction of counter ion transfer. This is the reason of the greater transport of PHCI with increasing pH of the donor solution during iontophoresis [ 151. At pH 7.4, PHCI is 99% protonated in the bulk solution. We assume that PHCl remains charged as it passes through the epidermis, then the observed flux can be attributed to the electrical and convective transport terms. The fraction change in flux during cathodal iontophoresis is greater at PH 7.4 than 9.4 showing the contributton of electrical transport term. However, the change in flux again increases at pH I I where PHCI is 98% unprotonated. The applied electric field can only influence the flow of charged pertueants. The convective solvent flow due to electro-osmosis [27] can affect the flux ofaay permeant, whether charged or uncharged. Therefore, electro-osmosis appears to be a predominant contributing factor to increase the cathodal iontophoretic flux at pH I I. Since the skin acts as a permselective membrane the convective flow in the direction
of counter ion transfer is facilitated to a greater extent during catbodz! :bro anodal iontophoresis. The linear relationship between flux and current density can well be validated with the help of the work of Bumette and Marrero I. I5 -1. In conclusion, ionthophoresis has enhanced the transport of PHCI through human epidermis. The resulting steady state flux is found to he proportional to the applied current density. These findings suggest the possibility of delivering
170
PHCl ttansdcrmatly io a controlled manner by iontophoresis with the potcntiar caveat of skin irritation.
R. Hams.
Therapeulic
electricity
and ultraviolet
mlia-
“on. S. Lmtv Ied.) 2nd edition, WaverlyPressInc., Batlimo% Maryland, Chapter 4, 1967. L P. Gangarosa.N.H. Park, CA. Wi&sa”dJ.M. HdI, Incrczed penetnlion ofnoneleetmlytesinto mouseski” dunng ioniophorelic wafer transport (iontahydrakinesis). J. Phamucol. Exp. Ther.. 212 (1980) 377-381. S. Ledac. Electricions and their usesin medicine.Reb. man. London. ,908. M. Comcau. R.B. Drumme” and I. Vernon. Locai anoesthesiao? the car by iontophoreris,Arch. O~olsryngol.,Ps (1973) 114-120. A.H. Gordon and M.V. Weinntcin. Sodnlm salicylatc lomophsrnis in Ihe lrealmcnl of ptamar wans. Phys. Thcr.. 49 J. Rusw. A. Lipman. ‘I’. Cornstock,B. pageand R. Slephen. Lidocalne anesthesia:Comparisonoi iontopkoTCIIS.i”Jeclwn snd swabbing,Am. J. Hosp. Phann., 37 (198ot 843-847. P. Harris, lontophoresis:CXnical researchin muscaloskclelalintlammatarycon&lions 1. OnhopaedicSpa%. Pkys.Tker.. 4 (19S2) 109-l 12. K. Sapkc”.T. Perelmzand S. Jacobsen, PotemiSlcowl mrlhodr :or inrufin ad.dmini,lralion.I. lontophoras. Biomed.Bioehim. Acla. 43 (19R4) 553-558. K. Okabe. H. Yamaguchl and Y. Kai,ai, New iontophorel~ctnnsdermalBdminiStmlionoftke~ela blocker meloprolol. J. COnlrD”CdRelea;e,4 ( 1986) i9-85. 0. Siddiqui. Y. Sun. J.C. Liu and Y.W. Chic”, Pacilitated trnnsdcmmlua”sp”rt of insulin, I. Pbann. Sci.. 76fl987)341-345. J.S;“&& MS. Roberts,Tra”sdem~?ldelive~ofdrugs by io.tophoreri% a review. Drug Derign Ddivcry. 4 (1989) L-12. MS. Roberts.I. Sindl. N. Yoskidaend K.I. Currie, tonlophorctictnnspo~o~selccled solulesthroughhuman epidermis. In: Predicrion ol Perwlane~w Absmplion R.C. Scott.J. Hadgr3fl ad R. Guy (edst, 1BC Tech+ cal ServicesLtd.. 1990pp. 231-241. 0. Siddiqui. MS. Raberls and A.E. Polack.The efFcct of ioniaokoresisandvekide “i-t 0” the in-villa oermealion ofk&nocvine rkmugh human srralum comcum,1. Phsrm.Pkarmacoi.,37 (1985, 732-735.
, ,969) 869-870.
14
16
17
18 I9
20
21
22
23
24
25
26
27
rests.1. Evaba~tmnof an in-vitro systemand transpo~ ofmodel compounds.Inl. J. Pkarm.. 30 (1986) 63-72. R.R. Bumele and D. Marwo, Comparisonbetweenthe iontophoreticand passwe imnspon OF thymwopin mleasinghammnc acrossexcisednude mouse skin. J. Pharm.Set.. 75 ( 1986) 738-743. I. Sin& Effect of pH on ionmphorelic and passive lrn”spa~ of p-amino bcnz.,~cacid tkrou&hfdullthicknessranski”, Pharnwie, 45 (I%@) 634. SC. Harvey, AdrenergicBlockingDrugs. Reminglon’s Phamweutical Sciences,161kedition. Mack Publirhi”” Comoanv.1980.cm.846. Dh. Sk;“d;&u&$y: propra”&,l.N. En& 1. Med., 293(1975)1110-284. A.M. Kligmm and E. Chrirtopkerr, Preparationof laled skeetsof humanstrawm comeurn,Arch. Dernm IOL, 88 (1963) 702-705. 0. Siddiqui, M.S. R&ens and AX. Polack. Topical absorption of methotrexote:role of dcrmal transport.Int. 1. Pkam.27 (1985) 193-203. J. Swabrick. G. Lee and I. Brom, Drug pemwaliiln dwoughhuman skin. 1. EtTcclofaorage conditionsof ski”. 1. Inven. Derm., 78 ( ,982) 63-66. E. Menzel and S. Goldberg. pH ellect 0” Ihc pcreotanco~!j.pmetmlion orlignocainehydrochloride,Demmtolog,ica,156 (1978) S-14. J. Swarhrick. 0. Lee. J. Bmm and W.P. Genrman~el. Drug permealio” throughhuman ski” 11.Permeability of ionizable compound?., J. Phann. Sci., 73 (1984) 1352-1355. AC. ALnby, I. “ewhcr, C. Schockand T.P.S. Trees, The e&c, of heat, pH and organicsoI”cnts0” the elecwicat impedanceand pemxability of excisedhuman &in. Br. I. Dcm~.,81, Suppl. 4 (1969) 31-39. A.G. Matoksy, A.M. DownerandT.M.Sweeny,Studies aftke eoidermelwax barrier. Pan II. lnvesliedtio”of thechemical“aweof Ike water harrier. J. Ives;. Dam., SO(1968) 19-26. H. Rein, Expaimenkdly Studie” Uber Elektrwxdosmose““!.a iebendcrMenschlichcr,HauL Z. Biol., 81 (1924) 125-140. V. Srinivzsanand W.I. Higuchi, A model Wr iontophorcsisinca~orati”glkee~ectofco”vectiverolve”tflow, In,. J. Pharnx.60 (1990) 133-138.
is"-
Transport;
Iontophoresis:
Introduction
The transport of ionic and polar solutes across human skin is not favoured by passive diffusion. One promising technique for increasing the transdermal delivery of ionic solutes is iontophoresis. It enhances the penetration of solutes into tissues by applying electric current [ 1,2]. It was first used for the introduction of strychnine and cyanide ions into rabbits [ 31 and siuce then it has been used with success for local delivery of drugs [4-71. More recently, this technique has been explored for transdermal delivery of drugs for systemic effects [&IS]. Tbe factors affecting iontophoretic transport of
Fhtx: Propranolol
hydrochloride;
pH; Current
solutes across human epidermis have been discussed [ I I ?I2 1. The transport of drugs through skin during iontopboresis has been shown to be dependent on the pH ofthe donor solution [ 12161 and the current density [ 14.15 I. The purpose of this study was to investigate the effect of pH and current density on the transport of propranolol hydrochloride (PHCI ), an non selective P-blocker antihypertensive drug. PHCi has a pKa value of 9.4 which permits protonation and deprotonation in the PH range of 7.4 to I I. It undergoes extensive first pass metabolism and only 30-60% of the oral dose is systematically available [ 171. It also has a short elimination half life (14) of about 3 h [18], which makes it a suitable candidate to be delivered transdermally at a controlled rate by iontophoresis. However, the basicity makes potential skin irritation aconcern.
Materials and Methods
Propranolol hydrochloride was obtained from CIPLA, Bombay. Benzyl alcohol, trisodittm citrate, disodium hydrogen phospbate anhydrous and glycine were obtained respectively from Ranbaxy Laboratories, Delhi, Glaxo Laboratories, Bombay, E. Merck Pvt. Ltd., Bombay and Glaxo Laboratories, Bombay. All other reagents were ofanalytical grade. Prcpnration
of buffers
The donor solution buffer was prepared by mining equal proportions of 30 mM each of trisodium citrate, dihydrogenorthophosphate and glycine. The pH of the buffer was adjusted by adding I M NaCH or I M HCl. The same buffer
t=,g. 2. Plo,
of mean
e”m”lallYC
anlO”“,
pemlemd
Yerw6
tnne for propranolol hydrochloridein different pH during cathodalmntophorcGs al 0.21 mAlcm’ wrrent density.Only hm0rk smdard dcvmimnbar is shownforclarity. 0: pH 7.4: a: p” 9.4: 0: pH I1.0.
90 mM concentration was used to vary the pH of the donor solution to minimize changes in the transport efficiency. The receptor was phosphate buffer (pH 7.4). In vitro transport
passived0Tuusxon. Only half of the standardd&ion shownrorclarity. 0: pH 7.4: A: pH 9.4: 0: pH
b.xrii
Il.0
studies
Glass diffusion cells fabricated in our laboratory were used tn all the transport studies. The maximum volume of each compartment of the cell was 4 ml. Working electrodes were made from platinum wire (99% purity, 0.5 mm diameter). The constant current source, fabricated at our University Science Instrumentation Centro, was used for supplyiog the required cure~t. Samples of skin of 2 I-50years old Caucasian cadavers of either sex, including the suhcutaneo’ls fat, approkiaately 25 cm by 6 cm were re-
167
Effect of pH on the fractron mnned and fmcdan change in IbC nun ofpropranolol by*mcblor,dc PH
7.4 34 11.0
Frrction Lonlled~
099 0.50 0.02
*Fraction ofpropranolol c&led
7.4 9.4 Il.0 __-
5.00~2.66 10.40i 1.05 11.75i2.33
11.0+4.60 14.00+0.80 t7.75+ 1.66 ____~
Frxlion
change m Jssb
C-athodal
Anodal
0.55 0.29 0.34
0.18 0.06
lhydrachlonde mmzed has been cat-
by the Henderson-Hasselbalchequation.
12.65~1.10 12 50t0.07
mowd from the mid-abdominal region within 24 h of death and storzd at -20°C. The subcutaneous
fat was trimmed
and
Kligman
and
[ 19 ] was adopted
of to remove the epidermis. Then, the epidermis was washed with water, dried overnight at room temChristophers
the method
current densities. Only half of the standsrd deviation bar is shown for clarity. 0: 0.14 mA/cm’: 0.28 mA/cm2; 0: 0.53 mAfcm’.
168 this technique the pH was kept to within 20.2 unit of the desired DH as determined at the end ofthe experiment. Samples were withdrawn at regular intervals from the receptor compartment (0.5 ml) for analyses of the drug concentration and the same volume was replaced by fresh receptor fluid. At the start and end of the experiment, 0. I ml of the donor solution was also sampled for analysis. The samples were diluted as desired with phosphate buffer (pH 7.4) and the absorbance was measured at 290 nm on a Beckman Model 24 Spectrophotometer. The absorbance at 290 nm showed no interference from water soluble cxtm;ts of the skin. At the end of each experiment, integrity of the skin was examined by quantifying the permeation of 0.59’6benzyl alcohol for an hour. All the in vitro transport experiments were carried out in triplicate. pemture
andstoredat -20°C [ZO].Theepidermis was allowed to thaw overnight at room temperature and rehydrated by immersing in water for 1h [Z I ] before being placed in the pemxation cell with dermal side towards receptor compartment. It was supported in this position by wire mesh. A thin film of silicone grease was spread on the lapped glass surfaces of the cell to provide a wat‘:r-tight seal. The cells were clamped and immersed in a water bath at 37 +OS”C. The media of the diffusion cell were stirred at the rate of 48 rwminusing magnetic star fleas. The donor and receiver compartments contained 3 ml of PHCI solution in buffer of the desired pH and phosphate buffer (pH 7.41, respectively. The surface arca of the epidermis exposed to the solution was 2.83 cm’. Cathodal ionthophoresis wetsperformed by inserting the anode in the donor compartment and the cathode in the receiver compartment. Anodal iontophoresis was done by reversing the polarity. The effect of the pH of the donor solution on the drug transport was studied at 0.21 mA/ cm2 current density. The current density was also varied between 0.14 to 0.53 mA/cm’ to observe its effect on the transporl of PHCI. Changes in pH during iontophoresis were monitored and corrected for bv the addition of microliter amounts ol’ i M tkl or I RI NaOH solutions. By
RCSPltS The cumulative amounts of PHCI transported at different pH during passive diffusion are shown in Fig. I The passive transport was increased as the pH of the donor solution was increased from 7.4 to 9.4. Figs. 2 and 3 show the cumulative amounts of drug transported versus time during cathodal and anodal iontophoresis, respectively. The transport was found to be more during cathcdal than anodal ionthophoresis. The steady state flux. the slope of the linear portion of the plot of cumulative amount permeated against time is given in Table I. The steady state flux during cathodal ionthophoresis is found to be greater than the corresponding passive thtx at all pH. The flux is statistically greater (P
lion change in flux is observed at pH 7.4 during cathodal iontoohoresis where a 0.99 fraction of PHCI is protonated in the bulk solution. The effect ofcurrent density on the transport of PHCI has been measured only at pH 7.4 because this pH does not allow irreversible structural and impedance changes in the skin. The results have been shown in Fig. 4. The transport was increased with increasing current density. The flux at current densities 0 and 0.53 mA/cm’ was 5 and 20.5 flgcg/cm’/h, respectively. Therefore, in,. creasing the rmrznt densities from 0 to 0.53 mA/ cm2 have enhanced the flux fourfold. A linear relationship (r=0.9954) was also observed bctween the flux and current density with slope (30.1 I /Ig/mA/h) and intercept (5.1 flgjcm’jb j (Fig. 5).
Discussion The results show an increase in the steady state flux as the oH is increased from 7.4 to I1 durine passive diffusion. This may kx in accordance wit; the pH-partition hypothesis according to which the transport of unionized moiety of the drug is. favoured through lipophilic biologic membranes [22,23]. Water diffusion through excised hairless mouse skin has been consistent in the pH range 4 to 10. However, an increase in water diffusion [241 and decrease in skin impedance 1251 have been noted at pH> 10. The greater flux of PHCI at pH 1 I can also be attributed to lesser impedance of the epidermis at this PH. The steady state flux of the drug was enhanced at each pH during iontophoresis. At pH 7.4, the drug is mostly in the ionized fortn and with application of current the ionic mobility increases and the transport of the drug as such incrcdses. It is known that the steady state Run depends on the charge of the solute molecule, ionic mobility and electrical potential applied as well as the solute concentration. But our findings suggest that even at pH 11, the transport of unionized form of PHCI has been affected by current density. This can be explained on the basis of the work of Rein [ 281who has shown an increase in the current induced convective flow of water across ex-
cised human skin with increasing pH of the donor solution The hiahest flux at oH I1 during passive transport and iontophoresis can also refleets damage to skin due to soluhility of keratin at this pH. The higher flux of PHCI with increasing pH of the donor solution can also be explained on the basis of the permselective nature of the epidermis. The epidermis above its isoelectric point would be negatively charged (pH 7.4-l I ). As the pH increases, the negative Bxed charge density in the pores increases resulting in an increase in the fixed pore ccunter ions concentration. The mcreas~d counter ions concentration would result in an increase in the convective flow in the direction of counter ion transfer. This is the reason of the greater transport of PHCI with increasing pH of the donor solution during iontophoresis [ 151. At pH 7.4, PHCI is 99% protonated in the bulk solution. We assume that PHCl remains charged as it passes through the epidermis, then the observed flux can be attributed to the electrical and convective transport terms. The fraction change in flux during cathodal iontophoresis is greater at PH 7.4 than 9.4 showing the contributton of electrical transport term. However, the change in flux again increases at pH I I where PHCI is 98% unprotonated. The applied electric field can only influence the flow of charged pertueants. The convective solvent flow due to electro-osmosis [27] can affect the flux ofaay permeant, whether charged or uncharged. Therefore, electro-osmosis appears to be a predominant contributing factor to increase the cathodal iontophoretic flux at pH I I. Since the skin acts as a permselective membrane the convective flow in the direction
of counter ion transfer is facilitated to a greater extent during catbodz! :bro anodal iontophoresis. The linear relationship between flux and current density can well be validated with the help of the work of Bumette and Marrero I. I5 -1. In conclusion, ionthophoresis has enhanced the transport of PHCI through human epidermis. The resulting steady state flux is found to he proportional to the applied current density. These findings suggest the possibility of delivering
170
PHCl ttansdcrmatly io a controlled manner by iontophoresis with the potcntiar caveat of skin irritation.
R. Hams.
Therapeulic
electricity
and ultraviolet
mlia-
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