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Article Cite This: Mol. Pharmaceutics 2019, 16, 2808−2816
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Simultaneous Transdermal Delivery of Buprenorphine Hydrochloride and Naltrexone Hydrochloride by Iontophoresis Sarah F. Cordery, Stephen M. Husbands, Christopher P. Bailey, Richard H. Guy, and M. Begoña Delgado-Charro* Department of Pharmacy & Pharmacology, University of Bath, Bath BA2 7AY, U.K.
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S Supporting Information *
ABSTRACT: The opioids buprenorphine hydrochloride (BUP) and naltrexone hydrochloride (NTX) show promise as a combination treatment for addiction, but no means of delivering the two compounds in one medicine currently exist. In this paper, we report sufficient input rates of both these drugs from one iontophoretic transdermal drug delivery system. Experiments were performed using dermatomed pig skin mounted in glass side-bi-side cells. BUP and NTX were iontophoretically delivered together from the anode using direct constant current from Ag/AgCl electrodes. The transdermal drug fluxes and the masses of drugs in both the stratum corneum and the underlying epidermis/dermis were measured. The apparent electroosmotic flow was quantified using a neutral marker (acetaminophen). The effects of donor composition (drug concentration/molar fraction and pH), current density and profile, and the choice of receptor solution were assessed. Iontophoresis dramatically increased the flux of both drugs compared to passive control values. Target fluxes (calculated from literature clearance values and required therapeutic plasma concentrations) were greatly exceeded for NTX and were met for BUP. The latter accumulated in the skin and suppressed electroosmotic flow, inhibiting both its own flux and that of NTX. NTX, in turn, negatively influenced the flux of BUP via coion competition. Lowering current density by increasing the delivery area resulted in increased electroosmotic flow but did not significantly affect current-normalized drug fluxes. Delivering the drugs from both electrodes and reversing the polarity for every 2 h did not increase the flux of either compound. In summary, during iontophoresis, BUP and NTX inhibited each other’s flux by two distinct mechanisms. While the more complex behavior of BUP complicates the optimization of this drug combination, iontophoresis nevertheless appears to be a feasible approach for the controlled codelivery of NTX and BUP through the skin. KEYWORDS: transdermal, iontophoresis, naltrexone, buprenorphine, relapse prevention
1. INTRODUCTION A combination therapy comprising the opioids buprenorphine hydrochloride (BUP) and naltrexone hydrochloride (NTX) shows promise as an addiction treatment.1,2 Success of this therapy, however, is likely to depend on the ability to coformulate these two compounds in one medicine. This is not easily achieved with an oral formulation because, while BUP is bioavailable sublingually but not orally, NTX is bioavailable orally but not sublingually.3,4 Transdermal delivery may offer the opportunity to formulate these two drugs together in one single dosage form, as well as avoiding daily fluctuations in plasma concentration and reducing abuse liability (BUP incorporated in an adhesive matrix would be difficult to isolate for illicit intravenous injection, for example). Despite these advantages, no attempt has previously been made to codeliver NTX and BUP via the transdermal route. The target steady-state input fluxes for this application, calculated from systemic clearance rates5−9 and anticipated required therapeutic plasma concentrations,10−13 are about 15 μg cm−2 h−1 for NTX and 2 μg cm−2 h−1 for BUP, based on a 25 cm2 delivery area. The BUP target input rate is achievable by passive diffusion alone; indeed, passive transdermal patches © 2019 American Chemical Society
of the drug as the free base are currently on the market and indicated for analgesia. In contrast, NTX is not able to cross the intact skin at the target rate by passive diffusion.14 A key hypothesis of the research described in this paper, therefore, is that a sufficient delivery of NTX can be achieved by iontophoresis. Iontophoresis has previously been used to drive two or more compounds into the skin simultaneously either to provide polypharmacy15 or because the inclusion of a second active may increase the bioavailability of the primary therapeutic agent.16−18 The latter approach is elegantly demonstrated in the LidoSite iontophoretic device; the concurrent delivery of a vasoconstrictor (epinephrine) reduces the rate at which the drug (lidocaine) is cleared from the local targeted skin site.16 In a second example, the simultaneous delivery of an enzyme inhibitor was able to increase the bioavailability of therapeutic peptides administered for systemic activity.17,18 However, Received: Revised: Accepted: Published: 2808
March 22, 2019 May 2, 2019 May 9, 2019 May 9, 2019 DOI: 10.1021/acs.molpharmaceut.9b00337 Mol. Pharmaceutics 2019, 16, 2808−2816
a
current density reversing polarity
1 0.5
1 1 1a 1 0 0.5 2.5 0.5 0.5 1.0 1
[BUP] (mg/mL)
0.5 0.5 (in +/− chamber only)b
0
0.5
0.5
0.5
[ACM] (mg/mL)
donor solution
5 5
6
5
5 4 5 6 6 5
pH (donor background electrolyte)
5 7.4
7.4
7.4
5 4 5 6 6 5
pH (receptor electrolyte)
Data set is used for comparison in the later section. b+/− indicates chamber starting as anodal in reversing polarity (RP) experiments.
Part B Current effects
0.07 0.14 0.14 0 0.55 5.5 55 0.55 0.14 0.14
concentration of drug: physiologically relevant receptor
concentration of NTX
0.14
0.14
[NTX] (mg/mL)
concentration of BUP: symmetrical pH
Part A Formulation pH effects
parameter investigated
Table 1. Experimental Conditions for the Experiments Performed
8 each 3.5 each (3 compartments)
1.3 and 1.8
3.5 each
3.5 each
3.5 each
donor and receptor volumes (mL)
3.8 0.95
0.95
0.95
0.95
0.95
area (cm2)
0.38 0.38 0.38 0.38 0 0.285 0.285
0 0.285 0.285 0.285 0.285 0.285 0.285 0.285
current (mA)
6 8
6
6
6
6
duration (h)
Molecular Pharmaceutics Article
2809
DOI: 10.1021/acs.molpharmaceut.9b00337 Mol. Pharmaceutics 2019, 16, 2808−2816
Article
Molecular Pharmaceutics
the electrochemical reaction at the anode. Direct constant current was passed for 6 h, during which the receptor was sampled and replenished every hour for analysis by highperformance liquid chromatography (HPLC). During passive, control experiments, the receptor was sampled only at 3 and 6 h. Reversing polarity experiments (Table 1) used side-bi-side cells with three compartments (two outer electrode compartments sandwiching an inner receptor compartment). The volume of each of the three chambers was 3.5 mL; 0.95 cm2 of each of the two pieces of skin was exposed. The polarity of the electrodes was reversed every 2 h, and the experiments lasted for 8 h. The electrode compartment, which started as the anode, was denoted “+/−”; the other, which started as the cathode, was denoted “−/+”. BUP/NTX donor solution was placed in both electrode compartments, but only the +/− compartment contained ACM. A “standard iontophoresis” control was also performed, in which the electrodes’ polarities were not changed during the experiment and the BUP/NTX solution was placed at the anode only. 2.3. Determination of Drug in the Skin Tissue. At the end of selected experiments, cells were dismantled and excess donor solution was removed from the skin by gentle blotting with a tissue. Layers of stratum corneum were collected by tape-stripping (exposed area 0.79 cm2). Tapes (12) (3M Book Tape, The Consortium, Bournemouth, U.K.) were used per site, collecting an average of 7.3 ± 2.5 μm of stratum corneum (assessed by weight difference, Sartorius, Epsom, U.K.). The drug was extracted from each tape by shaking overnight with 1 mL of 33:67 acetonitrile: 0.03% trifluoroacetic acid. The drug was also extracted from the remainder of the skin that had been tape-stripped (i.e., an excised area of 0.79 cm2) with 4 mL of the same solvent in the same way. 2.4. HPLC Analysis. Samples were filtered (Millex-HV, Fisher, Loughborough, U.K. or Cronus nylon, Labhut, Gloucester, U.K.) and analyzed by HPLC (Dionex, Camberley, U.K.) with a 25 cm C18 column (HiQSil, Jasco, Essex, U.K.) at 25 °C, with UV detection at 220 nm for BUP and NTX, 254 nm for ACM. A gradient mobile phase (1 mL/min) was used: line A was 100% methanol, and line B was 5 parts acetonitrile and 95 parts 0.03% trifluoroacetic acid in water. For the analysis of receptor samples, the gradient changed from 7% line A to 55% line A from 5 to 17 min; retention times were 8, 15, and 21 min for ACM, NTX, and BUP, respectively. For the analysis of tape samples, the gradient changed from 7% line A to 55% line A from 0 to 15 min; retention times were 10 min for NTX and 20 min for BUP. Limits of quantitation were 0.03 μg/mL for ACM and 0.05 μg/mL for NTX and BUP. 2.5. Data Analysis and Statistics. The amount of drug permeated was calculated from the concentration of receptor samples and the volume of the receptor chamber, taking into account the drug removed at each sampling point. The flux (amount permeated per unit of time) for each compound, JACM, JNTX, and JBUP, was calculated for each sampling interval. The transport number was calculated as the number of moles of ions of each drug transported across the skin in 1 h, divided by the corresponding number of moles of electrons passed in the same period, in accordance with Faraday’s laws of electrolysis.29 The fraction of charge carried by ions other than BUP and NTX was determined by difference (i.e., 1 minus the sum of the transport numbers of BUP and NTX). Apparent EO solvent flow was calculated by dividing the flux of acetaminophen (JACM) by its concentration in the donor.30
while potentially attractive as a solution to a tricky problem, compounds formulated for delivery from the same electrode may negatively modify one another’s fluxes by known mechanisms identified in the iontophoresis literature. Specifically, during iontophoresis, molecules are driven across the skin by two distinct mechanisms: electrorepulsion (ER) and electroosmosis (EO). ER acts to drive cations away from the anode and anions away from the cathode.19 Not all ion species are transported by ER with the same efficiency, and smaller, more mobile species (such as buffer ions) will be transported preferentially.20 More abundant ion species will also be transported preferentially; consequently, a drug’s flux is generally proportional not to its nominal concentration in the delivery system but to its concentration relative to that of other co-ions.21,22 It follows that the delivery efficiency of one ionized drug must be reduced, to a certain extent, by the codelivery of a second ionized drug,15 and vice versa. EO is a current-induced, convective solvent flow that occurs at physiological pH and drags with it molecules in solution, ionized or otherwise.20,23 In physiological conditions, EO generally flows in the anode-to-cathode direction; hence, drug delivery from the anode is “helped” by this process. EO flow is a consequence of the net negative charge on the skin under normal conditions; it follows that any buildup of a cationic compound in the skin (due to its lipophilicity and/or electrostatic attraction to the barrier) can, at least partially, neutralize the negative charge and reduce EO flow.24−26 Hence, in anodal delivery, a cationic drug that accumulates in the skin and thereby suppresses EO flow might not only inhibit its own flux but also inhibit that of a simultaneously delivered drug. This work explored the feasibility of the transdermal codelivery of BUP and NTX using iontophoresis to meet the dual goals of increasing the flux of the latter to a therapeutically useful level and providing, for both compounds, greater control of their input rates23,27 to provide a novel treatment for addiction. Furthermore, an iontophoretic system may be superior to a passive system, in light of concerns over the amount of residual opioid in transdermal patches after use.28 To this end, formulation parameters (drug concentration/ molar fraction and pH), as well as current parameters (current density and reversing the direction of current), were examined.
2. MATERIALS AND METHODS 2.1. Materials. Buprenorphine hydrochloride (BUP) was from Reckitt Benckiser (Slough, U.K.). Naltrexone hydrochloride (NTX), acetaminophen (ACM), and trifluoroacetic acid were from Sigma-Aldrich (Poole, U.K.). High-performance liquid chromatography (HPLC)-grade methanol and acetonitrile were from Fisher (Loughborough, U.K.). Pig skin was collected from a local abattoir, dermatomed (Zimmer, Cleveland, OH), to a nominal thickness of 750 μm, frozen within 24 h of slaughter, and thawed before use. 2.2. Iontophoresis Studies. Table 1 details the specific conditions of the experiments performed. Unless otherwise stated, the experimental setup was as follows. Skin was placed across the aperture of a two-compartment side-bi-side cell. A power supply (Kepco, Guildford, U.K.) was connected to a silver/silver chloride anode and a cathode of the same composition, both prepared in-house (Supporting Information); drugs were delivered from the anode. The donor background electrolyte was 60 mM Tris−HCl for all experiments; Tris provided the source of chloride ions for 2810
DOI: 10.1021/acs.molpharmaceut.9b00337 Mol. Pharmaceutics 2019, 16, 2808−2816
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Molecular Pharmaceutics
quantified using acetaminophen (ACM), a neutral marker (not transported by ER) with negligible passive flux. It was also suspected that BUP could accumulate in the skin (given its lipophilicity and relatively high molecular weight), and the amount of this drug in the skin at the end of the experiment was therefore determined. 3.1. Part A: Formulation Effects. 3.1.1. A-1: pH. The pH of the iontophoretic vehicle has a critical influence on the transdermal flux. Ideally, the pH is chosen so that the majority of the drug is in the more soluble, ionized form and hence available for transport by ER.35 Also when attempting to deliver cationic drugs, the pH should ensure a net negative charge on the skin to further boost transport by EO.31,32 However, there is a conflict for basic drugs, such as BUP and NTX; in this case, a lower pH is desirable to maximize the fractions of the water-soluble, ionized form of the compounds, whereas EO is optimized at pH 6 and above.30 The effect of pH over the range 4−6 was therefore examined. To facilitate interpretation of the data, the pH was fixed at the same value in both the donor and receptor solutions in this first series of experiments, the results of which are shown in Figure 2. In the control (no current, pH 5) experiments, neither drug was quantifiable in the receptor. Application of an electric current dramatically increased the flux of both molecules even though the computation of transport numbers indicated that >99% of the charge was carried by TrisH+ from the buffer solution and subdermal chloride ions (transport numbers of NTX and BUP at pH 6 were 8.2 × 10−4 and 4.5 × 10−4, respectively). This was expected and consistent with previous findings.36,37 Importantly, the therapeutic target flux for BUP was achieved by iontophoresis. Figure 2 shows that BUP accumulated in the stratum corneum in a pH-dependent manner during iontophoretic experiments. This might be related to the lower aqueous solubility of BUP at pH 6 (1 mg/mL) compared to that at pH 4 (19 mg/mL),38 resulting in a lower partitioning of the drug from the stratum corneum into the viable tissue at the higher pH. Application of current increased this accumulation, as shown by the experiments at pH 5, where the recovery of the drug from the SC following iontophoresis (29.7 ± 7.3 μg/cm2) was more than 7-fold higher than that after passive delivery (4.1 ± 1.6 μg/cm2). Notably, the apparent EO was similar in the three symmetrical pH conditions tested (Figure 2). The lowerthan-anticipated value at pH 6 might be explained by the accumulation of the large, lipophilic BUP cation in the stratum corneum that neutralized, in part, the negative charge on the skin responsible for EO flow. This observation is consistent with the previous reports for other lipophilic, cationic drugs.24−26,30,39,40 To test this hypothesis, the pH 6 experiment was repeated with no BUP in the donor solution, and it was found (Figure 2) that the apparent EO flow was 1.6-fold higher (statistically significant difference, unpaired t-test) in this case. The reduced convective flow in the presence of BUP also impacted on the NTX flux, which was 21% lower when compared to the situation with no BUP (statistically significant difference, unpaired t-test). 3.1.2. A-2: Concentration of BUP: Symmetrical pH Experiments. Given the observed suppression of EO by BUP, and the potential impact on the iontophoretic transport of both drugs, it was important to determine how this effect depended on the concentration and molar fraction of BUP in the anode formulation (XBUP). A series of experiments at pH 5
Comparisons between different sets of data were made using either a two-tailed t-test (for 2 groups) or a one-way analysis of variance (ANOVA) (for > 2 groups) followed by Bonferroni post-tests. Statistical significance was set at p < 0.05. Values are reported throughout as mean ± standard deviation (SD). Fluxes are plotted at the end of the corresponding sampling interval.
3. RESULTS AND DISCUSSION The overall iontophoretic delivery of a drug depends on the contributions of both electrorepulsion and electroosmosis. The relative magnitude of these contributions depends on formulation factors (pH, ionic composition, and molar fraction of the drug), physiological factors (pH and endogenous ions), and drug-specific factors (mobility, solubility, and ionization).31,32 Figure 1 identifies the key parameters that can be
Figure 1. Schematic illustration of the factors influencing the iontophoretic flux of a monovalent basic drug from the positive electrode (anode). JER = electrorepulsive contribution to drug flux; JEO = electroosmotic contribution to drug flux; Jsolv a−c = electroosmotic solvent flow in the anode-to-cathode direction; t# = transport number; I = current.
manipulated in an iontophoretic system and shows how these may directly or indirectly influence the transdermal iontophoretic flux of a cationic drug. As Figure 1 shows, it is often the case that the modification of one formulation parameter impacts simultaneously on several flux predictors albeit not with the same (i.e., increase or decrease flux) outcomes. The situation is even more complicated when codelivering two compounds. In this work, some important physicochemical properties of the two drugs are quite distinct: specifically, the molecular weights of the hydrochloride salts of BUP and NTX are 504.10 and 377.86 Da, respectively, while the lipophilicities of the corresponding free bases, expressed in terms of log P, are 4.98 and 1.9.33,34 It was therefore anticipated that the relative importance of ER and EO would be different for the two drugs, reflecting their ability to carry charge in iontophoresis. For this reason, EO flow was 2811
DOI: 10.1021/acs.molpharmaceut.9b00337 Mol. Pharmaceutics 2019, 16, 2808−2816
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Molecular Pharmaceutics
Figure 2. Iontophoretic JACM, JNTX, and JBUP (left) and the amount of BUP recovered from tapes following 6 h of iontophoresis (right) as a function of pH. Donor solution contained 0.14 mg/mL NTX, 1.0 mg/mL BUP, and 0.5 mg/mL ACM. Background electrolyte in the donor and receptor was 60 mM Tris. All values correspond to the mean and standard deviations (n = 6); positive error bars (+SD) are shown except for “tapes 3−12” (right panel), where negative error bars (−SD) are shown. NTX was not quantifiable in the stratum corneum beyond tape 1.
Figure 3. Iontophoretic JNTX, JBUP, apparent EO, and amounts of BUP and NTX in the skin as a function of XBUP in the donor, anode solution (mean ± standard deviation; n = 4−6). The background electrolyte in both donor and receptor was 60 mM Tris pH 5. Donor contained 0.14 mg/ mL NTX, either 0.5, 1.0, or 2.5 mg/mL BUP (XNTX was 0.0060, 0.0059, and 0.0057; n = 4, 6, and 4, respectively), and 0.5 mg/mL ACM. One-way ANOVAs showed that JACM with 2.5 mg/mL BUP was different from the two other conditions; JNTX with 0.5 mg/mL BUP was different from that with 2.5 mg/mL BUP. T-Tests showed that the amount of BUP in the viable tissue was greater when delivered from a concentration of 2.5 mg/mL than that from 0.5 mg/mL, but the amount of NTX was not different. Lastly, the amount of BUP in the stratum corneum was different between 0.5 and 2.5 mg/mL and between 1.0 and 2.5 mg/mL (one-way ANOVA).
increase in XBUP in the donor, no change in JBUP was observed. With respect to NTX, the decrease in JNTX as BUP concentration increased cannot be explained simply by the greater co-ion competition because XNTX was essentially fixed (ranging from 0.0060 to 0.0057) and must therefore have been a consequence of EO suppression. In contrast to JACM, though, the fall in JNTX was not directly proportional to XBUP because the flux of naltrexone comprises contributions from ER and EO. While the iontophoretic “preloading” of the skin with cationic peptides has been shown to inhibit the flux of a
with a constant concentration of NTX and BUP of either 0.5, 1.0, or 2.5 mg/mL was therefore undertaken (Table 1). As well as the amounts of the drug in the receptor and in the stratum corneum, the quantity in the tissue underneath the stratum corneum was also measured (Figure 3). BUP inhibited EO in a concentration-dependent manner (Figure 3) consistent with a greater drug accumulation in the skin (stratum corneum and viable tissues) when delivered at a higher molar fraction. However, as a result, BUP flux was not proportional to its molar fraction; indeed, despite a 5-fold 2812
DOI: 10.1021/acs.molpharmaceut.9b00337 Mol. Pharmaceutics 2019, 16, 2808−2816
Article
Molecular Pharmaceutics Table 2. Iontophoretic JBUP and JNTX, Apparent EO Flow, and Amount of BUP and NTX Recovered from the Skina [NTX] (mg/mL) and XNTX
[BUP] (mg/mL) and XBUP
BUP flux 6 h (μg/h cm2)
NTX flux 6 h (μg/h cm2)
apparent EO 6 h (μL/h cm2)
BUP in SC (μg/cm2)
BUP in VT (μg/cm2)
NTX in VT (μg/cm2)
0.07, 0.0030 0.14, 0.0060 0.14, 0.0059
0.5, 0.0162 0.5, 0.0162 1.0, 0.0318
0.39 ± 0.21 0.64 ± 0.25a 0.20 ± 0.21a
1.60 ± 0.50b 3.55 ± 0.89b,c 2.10 ± 0.60c
1.98 ± 0.77 2.13 ± 0.63 1.33 ± 0.54
22.1 ± 16.9d 16.4 ± 5.76e 43.6 ± 20.8d,e
68.3 ± 19.6f 68.4 ± 35.9g 131 ± 7.34f,g
12.2 ± 7.11 13.9 ± 5.63 13.2 ± 1.62
a
Donor contained either 0.07 or 0.14 mg/mL NTX and 0.5 or 1.0 mg/mL BUP; all contained 0.5 mg/mL ACM in a background electrolyte of 60 mM Tris pH 5.0 (n = 3−9). Receptor solution was PBS pH 7.4. Values are mean ± standard deviation. Letters in the superscript indicate that pairs of values are significantly different. SC = stratum corneum; VT = viable tissue.
Table 3. Iontophoretic and Passive Fluxes (Mean ± Standard Deviation, n = 4−10) of NTX and BUP across Excised Pig Skin as a Function of NTX Concentration in the Donora NTX
BUP
NTX:BUP in the donor (mg/mL)
molar fraction
flux 6 h (μg/h cm2)
transport number
molar fraction
flux 6 h (μg/h cm2)
55:1 5.5:1 0.55:1 0:1 0.55:1 (passive)
0.702 0.191 0.023 n/a 0.023
286 ± 44 119 ± 45 25 ± 3 n/a 0.04 ± 0.04
0.0507 0.0211 0.0045 n/a n/a
0.0096 0.0259 0.0313 0.0321 0.0313
0.23 0.40 2.15 2.00 0.05
± ± ± ± ±
0.10 0.23 1.36 0.72 0.04
transport number 3.1 × 5.3 × 2.9 × 2.7 × n/a
10−5 10−5 10−4 10−4
% charge carried by ions other than BUP or NTX 94.9 97.9 99.5 100.0 n/a
a
Background electrolyte in the donor was 60 mM Tris buffer pH 6; receptor solution was PBS pH 7.4. Current intensity was 0.38 mA over an area of 0.95 cm2.
reduce and enhance their respective fluxes accordingly (Table 1). The strategy was successful (Table 3), and it proved possible to manipulate the molar fractions of the two drugs to achieve the targets JBUP and JNTX, as anticipated from the earlier work.22,43 The exercise demonstrates that the optimization of iontophoretic delivery is rarely achieved by the modification of a single experimental factor (Figure 1).44 Specifically, in this case, decreasing the concentration of NTX in the donor had the following simultaneous effects: (i) decreased XNTX, (ii) increased XBUP, and (iii) decreased ionic strength (range 62− 207 mM), which potentially increases EO.45 Of course, the key outcomes were that JNTX (and its transport number) decreased due to the increased co-ion competition, while the flux of BUP was elevated. Importantly, from a practical point of view, the target fluxes of both drugs were achieved simultaneously from one of the anode formulations tested (i.e., 0.55 mg/mL NTX and 1 mg/mL BUP, Table 3). 3.1.5. A−5: Receptor Solution. The data reported above suggested that the composition of the receptor solution influenced the magnitude of JBUP. Because the effects of receptor solution composition on iontophoretic flux are not fully understood, additional experiments were carried out (see the Supporting Information). The results confirmed that the manipulation of the receptor could have significant effects on JBUP and JNTX, emphasizing the care with which the results of in vitro experiments should be interpreted when the feasibility of a delivery option is being examined. It appears from these experiments that the routine measurement of the amount of drug in the viable tissue (tape-stripped epidermis + dermis) can enable a better estimation of the potential transdermal flux attainable in vivo. 3.2. Part B: Current Effects. 3.2.1. B-1: Current Density. While iontophoretic drug flux is directly proportional to the intensity of current passed between the electrodes, the magnitude of local side effects (such as itch, redness, tingling) is typically related to the current density (mA/cm2).46 At a fixed current intensity of 0.285 mA, therefore, the impact of decreasing the current density from 0.3 to 0.075 mA/cm2 and
second, subsequently iontophoresed drug,41,42 we believe that this is the first report of one drug altering the flux of a second via an effect on EO (rather than co-ion competition) during their simultaneous iontophoretic delivery. 3.1.3. A-3: Concentration of Drug: Physiologically Relevant Receptor. The previous experiments were conducted in a “symmetrical” fashion (background electrolyte in the receptor matched that of the donor). In this part of the work (Table 1), experiments were performed using a more physiologically relevant receptor solution (i.e., phosphatebuffered saline (PBS) at pH 7.4). The concentration of NTX was held constant first, while the concentration of BUP was varied; subsequently, the reverse was studied. The results are shown in Table 2. Use of a physiologically relevant receptor did not change the observation that JBUP was not proportional to its molar fraction. In fact, when the BUP donor concentration was doubled (0.5− 1.0 mg/L) at a fixed level of NTX, JBUP decreased (p < 0.05). Likewise, doubling the BUP donor concentration had a negative influence on JNTX (p < 0.05). The concurrent decrease in the apparent EO flow (from 2.13 ± 0.63 to 1.33 ± 0.54 μL/h/cm2) did not, however, reach statistical significance. Doubling the NTX concentration when that of BUP in the donor was fixed (thereby increasing XNTX) proportionally increased JNTX, while there was no impact on JBUP (XBUP having been reduced by
