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International Journal of Pharmaceutical Sciences and Nanotechnology
Volume 3 Issue 1April – June 2010
Research Paper
In vitro Passive and Iontophoretically Assisted Transport of Salbutamol sulphate
through Hairless Mice Skin

Abdul Faruk*, Gurpreet Singh and Mohan Paul Singh Ishar
Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India. ABSTRACT: Investigations were carried out to ascertain the relative importance of the described mechanism in
iontophoretic transport using an ionizable drug salbutamol sulphate, which has two pKa values 9.3 (for amino group) and
10.3 (for phenolic group). Ionization of salbutamol sulphate varies with pH, hence the rate and extent of transport across the
skin can be enhanced, controlled and manipulated by the application of factors like anodal and cathodal current at varied
pH of donor solution and current densities. To determine these parameters, experiments were performed and data was
collected at 7.4, 9.3, 10.3 and 11 pH using 4mg/ml drug concentration and 0.3mA/cm2 current density for 6 hours. After
establishing the pH for optimum transport of drug, effect of current density (0.1, 0.2, 0.3 and 0.4 mA/cm2) on the transport of
drug (keeping drug concentration constant) were investigated. Passive diffusion of salbutamol sulphate was maximal at pH
10.3 and 9.3, when unionized form of drug was 50%. Anodal iontophoresis at pH 7.4 was most effective (significant result,
p < 0.05) in transport of drug across skin as compared to cathodal iontophoresis at pH 11. The effect of current density on
steady state flux by salbutamol sulphate during anodal iontophoresis at 7.4 pH showed 2.26 and 28.05µg/cm2/h at 0.0 i.e.,
passive diffusion and 0.4 mA/cm2, respectively. Thus, flux was enhanced nearly 12 times during anodal iontophoresis.
KEYWORDS: Iontophoresis; transport; steady state flux; current density; salbutamol sulphate
Introduction
flux induced by iontophoresis may be controlled by manipulating the current density and applied concentration The skin has been identified as a route of drug of drug in the delivery system (Pillai et al., 2004, Artusi et administration for decades. Several drug delivery system has been developed for utilizing this route and the ultimate goal is to ensure that compounds are delivered preferably In this study, we investigated in-vitro passive and at a specific rate to the systemic circulation. Topical drug iontophoretic delivery of salbutamol sulphate in hairless delivery system has some limitations, arising mainly from mice skin. Investigations were aimed at understanding: (i) excellent barrier properties of stratum corneum. how pH of the donor solution affects the permeation of Iontophoresis has potential to overcome many barriers drug during passive diffusion and iontophoretic transport, associated with transdermal delivery of drugs and it and to what extent the transport of the drug was enhanced broadens the spectrum of drugs that can be delivered via by iontophoresis? It has been reported that ionization rate skin, increases systemic treatment efficacy, therefore, this of drugs plays an important role in permeability through method of transport is in high demand for increasing skin (Kamath et al., 1995, Kochhar et al., 2004). The permeation (Droog et al., 2003, De Graaff et al., 2003, effect of pH of the aqueous vehicle on the rate and extent through human stratum corneum has been investigated for Iontophoresis uses a small electrical current to enhance a number of drugs such as lidocaine (Siddiqui et al., 1985), the transport of both ionic and nonionic molecules across thyrotropin releasing hormone, (Bumette et al., 1986), the skin in controlled and programmable manner (Nair et amphotericin, (Roberts et al., 1989), gonadotropin al., 2003, Kalia et al., 2004). The enhancement of drug due releasing hormone (Miller et al., 1990), certain alkanols to this method results from a number of possible and alkanoic acids (DelTerzo et al., 1989), verapamil mechanisms including the ion-electric field interaction (Wearly et al., 1990), calcitonin (Morimoto et al., 1992), (electrorepulsion) (Kalia et al., 2004), convective flow leuprolide (Kochhar et al., 2004), buprenorphine (Bose et (electro-osmosis) (Wang et al., 2005) and current-induced al., 2001), Glibenclamide (Takahashi et al., 2001), (Pillai et al., 2004) increase in skin permeability. The drug pilocarpine (Huang et al., 1995). The rate of penetration was greatest at the pH where drug exists mainly in ionized form. The importance of pH in the enhancement of solute * For correspondence: Abdul Faruk, transport by iontophoresis has also been proven for other solutes. The pH changes become particularly significant 812 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 1 April - June 2010
for protein and peptide drugs since the pH of the solution Materials and Methods
determines the charge on these molecules. For example, insulin has been shown to have greater skin permeability at Materials
a pH below its isoelectric pH than at a pH above its The constant current source (0-4 mA, at a resistive load of isoelectric point (Siddiqui et al., 1987). 5 Kilo ohm) was designed by University Instrumentation in-vitro passive and electrically assisted Science Centre (USIC), Guru Nanak Dev University, transport of salbutamol sulphate was investigated to study Amritsar, India and was assembled by M/S B. S. the various parameters affecting the permeation of drug Electronics, Amritsar, India. Two different electrodes of across different synthetic membranes (Bayon et al, 1993). platinum wire (99 % pure, 0.5 mm dia) were connected to Later in 1998, Tuncer et al., had stressed the role of ion the load points of constant current device. Generous gift complexant on the iontophoretic transport of salbutamol sample of salbutamol sulphate was obtained from CIPLA, (Tuncer et al, 1998). These reported studies were aimed to Mumbai, India and analytical grade chemicals such as investigate and to determine for their possible application disodium hydrogen phosphate, sodium acid phosphate, in transdermal drug delivery system. The present work sodium hydroxide, potassium hydrogen orthophosphate relates to the determination of the effect of iontophoretic were procured from Qualigens fine chemicals, Mumbai. parameters in the permeation of salbutamol sulphate across Preparation of Buffers
animal skin. Since salbutamol sulphate has ampoteric properties (Ijzerman et al., 1984), it can exist as cation, Donor buffer: Phosphate buffer was prepared by placing
anion and uncharged molecule in proportions that depend 50 ml of 0.2 M monobasic potassium phosphate in a 200 on the pH of the solution. Therefore, significant role of ml volumetric flask. The specified volumes of 65.1, 75.2 different ionization behavior of the drug at different pH and 88.2 ml of 0.2 M sodium hydroxide was added to it and quantitative effect of the size of the iontophoretic and volumes were made up to 200 ml in each case with current in passive and electrically modulated transport deionized water for the preparation of solution of pH 9.3, were investigated for the development of iontophoretic induced drug delivery of salbutamol sulphate for Receptor buffer: The buffer used for receptor solution (pH
therapeutic benefit.
7.4) was prepared by dissolving 2.1 g of sodium acid phosphate and 4.4 g of sodium chloride in deionized water. Since different pH conditions are involved in the experimental protocol it is, therefore, very important to In vivo transport studies
verify the stability of salbutamol sulphate. Malkki et al., studied the decomposition of salbutamol sulphate in aq. Skin diffusion experiments were carried out on full- Solution (Malkki et al., 1990). The result showed that rate thickness skin from hairless mice (7-19 week old, supplied of decomposition of salbutamol obeyed apparent 1st order from animal house of Guru Nanak Dev University, kinetics w.r.t salbutamol sulphate. The reaction rate Amritsar). The experiments using animal were carried out increased with increasing initial concentration and elevated as per the ethical guidelines and housed at appropriate temperature. Another study by Malkki et al., in 1995 conditions of temperature 25 ± 2oC, relative humidity 50 ± revealed that decomposition of salbutamol sulphate was 5 %, 12 hour light and 12 hour dark side (CPCSEA No 226) (Care, 2003). Mice were sacrificed by cervical less in phosphate buffer even at higher temperature (85 oC) dislocation. The abdominal skin was excised and whole (Malkki et al in 1995). It is because of this reason donor thickness of skin was removed; excess adipose tissue was buffer of sufficient strength and high initial drug removed by gentle scraping and was immediately mounted concentration (4mg/ml) was chosen in the present between donor and receptor half cells horizontally with the stratum corneum facing the donor half cell (dermal side The studies were conducted at different pH conditions down) on franz diffusion cells (Leboulanger et al., 2004). A thin film of silicone gelly was spread on the lapped glass which affect both nature and degree of ionization of surface of cell to provide a watertight seal. The cells were salbutamol sulphate and which in turn, will affect the clamped and immersed in water bath at 35 ± 0.5 0C, placed permeation. (i) The study tried to ascertain how do current on the magnetic stirrers (Charro MB, 2008). The maximum densities affect the efficiency of drug transport and capacity of each of the donor and receiver compartments (ii) how delivery rate can be manipulated and controlled by was 5.0 ml and the surface area of skin exposed to the varying pH and current densities? With these twin solution was 2.855 cm2. The medium of the diffusion cell was stirred at the rate of 25 rpm using small magnetic objectives in mind, salbutamol sulphate was chosen as a beads. To see the effect of pH on the transport of model drug to understand in-depth the parameters affecting salbutamol sulphate four different pH i.e., 7.4, 9.3, 10.3 the permeation as this molecule having two pKa values 9.3 and 11 were selected using 4.0 mg/ml drug concentration and 10.3 corresponding to amino group and phenolic and 0.3 mA/cm2 current density for 6 hours. After Abdul Faruk et al. : In Vitro Passive and Iontophoretically Assisted Transport of…
obtaining the optimum transport of drug at particular pH, All statistical analysis of the data was done by ANOVA effect of current density (0.1, 0.2, 0.3, and 0.4 mA/cm2) and student’s paired t-test as appropriate. The level of was then observed on the transport of drug. For passive diffusion, this assembly was used as such i.e., without
applying current. Iontophoresis was carried out by Results
inserting platinum wire electrodes. Anodal iontophoresis
was carried out by inserting anode in the donor Effect of pH
compartment and cathode in receiver compartment. Table 1 shows that the steady state flux during
Cathodal iontophoresis was done by reversing the polarity. iontophoresis is greater than the corresponding passive diffusion at all pH i.e., 7.4, 9.3, 10.3 and 11. The anodal Parameters evaluated
iontophoretic flux was significantly higher (Student ‘t’ test, Sample analysis was done at 276 nm (λmax) using p < 0.05) at pH 7.4, 9.3 and 10.3 than passive diffusion of Shimadzu UV-VIS spectrophotometer (model-1601, drug at corresponding pH. At pH 11 anodal iontophoretic Japan) for measuring the drug concentration (Faruk et al., flux was not significantly different (p > 0.05) from passive diffusion. The flux obtained at cathodal iontophoresis was The drug concentration was corrected for sampling significantly higher (p < 0.05) at pH 11, 10.3 and 9.3 but effects according to the equation-I described by Hayton was insignificant at pH 7.4 (p > 0.05) than corresponding passive flux at same pH. Anodal iontophoretic flux was significantly higher compared to corresponding cathodal C´n = Cn (Vt / Vt-Vs) (C´n-1 / C n-1) ….(1) flux at pH 7.4 and pH 9.3, but at pH 10.3 and 11 cathodal iontophoretic flux was significantly higher than n is the corrected concentration of the nth corresponding anodal flux. The permeability coefficient of n is the measured concentration of drug in the nth salbutamol sulphate at different pH during passive n-1 is the corrected concentration of (n-1)th diffusion and iontophoresis, shown in table 2, indicates n-1 is the measured concentration of drug in the that permeability coefficient of drug increased during t is the total volume of the donor solution iontophoresis (anodal and cathodal) at all pH compared to s is the volume of the sample withdrawn. The cumulative amount of drug permeated per unit area is the corresponding values for passive diffusion. Increase in plotted against time (all experiments were performed thrice the pH of the donor solution from 7.4 to 11, there was and results were expressed as mean ± S.D) and the slope of decrease in the permeability coefficient of drug during the linear portion of the plot gives the steady state flux anodal iontophoresis, while during cathodal iontophoresis (µg/cm2/h). (Julraht et al., 1995). The permeability permeability coefficient of drug was increased. coeficient (K Enhancement in flux (Table 3) due to anodal iontophoresis p) was calculated as Kp = Jss/Cv. Where, Jss is (E1) was maximum at pH 7.4 (11 folds) and it decreases drug (unionized and ionized) in donor half cell. with increase of pH from 7.4 to 11. The cathodal Enhancement factor was calculated as E = J iontophoretic flux enhancement (E2) was maximum at pH is the flux of the drug during iontophoresis, and J 11 (4 folds) and it decreased with the decrease of pH from flux of drug during passive diffusion (Williams et al., 11 to 7.4 (Fig. 1). The relationship between fraction of 1994). Fraction change in flux is determined by deducting ionized drug and fraction change in flux is shown in the passive flux from iontophoretic flux and then divided table 4. The highest fraction change in flux was observed at pH 7.4 during anodal iontophoresis, where 99% of salbutamol sulphate existed in cationic form. Despite the Fraction ionized (degree of ionization) was calculated fact that there is 99% ionization at pH 11, fraction change on the basis of Henderson Hasselbalch equation (Martin et in flux was minimal during cathodal iontophoresis, where 99% of salbutamol sulphate existed as anionic form. Table 1 Effect of pH on steady state flux of salbutamol sulphate through hair less mice skin during passive
diffusion and iontophoresis at 0.3mA/cm2 current density. Steady state flux (µg/cm2/h)
Passive* Anodal* Cathodal*
*All values are expressed as mean ± S.D; n = 3 814 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 1 April - June 2010
Table 2 Permeability coefficient of salbutamol sulphate at different pHs during passive diffusion and
Permeability coefficient, Kp.(cm/h) 10-2
Passive Anodal
Cathodal
Table 3 Enhancement factor for salbutamol sulphate at different pH.
Enhancement factor
E1 (Anodal) E2 (Cathodal)
Where, E 1= Ja / Jp and E 2 = Jc / Jp Ja, Jc and Jp are the steady state flux during anodal, cathodal iontophoresis and passive diffusion, respectively Table 4 Effect of pHs on the fraction of ionized and fraction change in the flux of salbutamol sulphate.
Fraction ionized
Fraction change in flux
Anodal Cathodal
Effect of current density
For passive diffusion, the results show an increase in Fig. 2 shows a linear relationship between the steady state the steady state flux with the increase in the pH from 7.4 to flux and current density for anodal iontophoresis at pH 7.4 10.3 and there is decrease of flux at pH 11. Salbutamol and cathodal iontophoresis at pH 11 respectively. It is sulphate has two pKa values 9.3 and 10.3, corresponding to evident that increase in current density resulted in amino and phenolic group, respectively. Hence the drug increased transport of the drug. The respective flux at 0.0 would be 99%, 50%, 50% and 99% ionized at pH 7.4, and 0.4 mA/cm2 current densities was 2.26 and 28.05 9.3, 10.3 and 11 respectively. The ionization behaviors of µg/cm2/h during anodal iontophoresis at pH 7.4, where as amino group and phenolic group of salbutamol sulphate for cathodal iontophoresis at pH 11 steady state flux was are entirely different at varied pH. At pH 7.4 and 9.3 6.69 and 37.94 µg/cm2/h (Table 5). This, enhanced the flux amino group is ionized (cationic form), while at pH 10.3 nearly 12 and 6 times during anodal and cathodal and 11 phenolic group is ionized (anionic form). At pH 10.3 and 9.3, 50 % of the drug would be in unionized form Discussion
(Table 4). Steady state flux at pH 9.3 and 10.3 was not significantly different (p > 0.05) but at pH 7.4 and 11 Commonly observed electrochemical decomposition of steady state flux was significantly different (p < 0.05) for water with the production of H+ and OH- at the anode and passive diffusion. It means that transport of drug across cathode respectively takes place with platinum wire as animal skin occurs even at 50% of salbutamol drug is in electrode which causes the pH of the donor compartment to increase during cathodal iontophoresis, therefore, ionic unionized form may be through lipophilic biological strength of the donor medium kept high to give sufficient membrane. The result complied with the pH partition buffering capacity (Davis et al., 2002). Abdul Faruk et al. : In Vitro Passive and Iontophoretically Assisted Transport of…
Table 5 Effect of current densities on the steady state flux of salbutamol sulphate.
S.No Current
Steady state flux (µg/cm2/h)
(mA/cm2)
Anodal (pH 7.4)* Cathodal
*All values are expressed as mean ± S.D; n=3 Enhanced iontophoretic transport of drug at pH 7.4 and Long term application of current leads to the 11 may be due to increased ionic mobility caused by 99% dissipation of heat which in turn increase lipid fluidity and ionization of salbutamol at these pH (Table 4). Nernst- thus changes in the integrity of the skin structure (Burnette Plank equation verifies this phenomenon (Swarbrick et al., et al., 1988), with the result permeability of the skin is 1984) and therefore, maximum flux obtained at pH 7.4 altered (Hamann et al., 2006, Delgado-Charro et al., 2001) during anodal iontophoresis at pH 11 during cathodal This may be the reason for increased permeability coefficient of drug during iontophoresis (anodal and cathodal) at all pH compared to the corresponding values When the pH of the donor solution is decreased from pH 11 to 7.4, it results in a higher anodal iontophoretic flux i.e., greater transport of drug at pH 7.4 of donor solution. The results of the effect of pH on the steady state flux The reason for this may be explained on the basis of is shown in Fig. 1. It is clear that both the form of drug permselective nature of the skin. The epidermis of the skin species i.e., unionized and ionized can permeate through above pH 4.2 (isoelectric point) acquire negative fixed rat epidermis may be through intracellular (Marro et al., 2001) and intercellular routes (Siddiqui et al., 1985a). charge density in the pore, there by causing accumulation of positive ion concentration (counter ions) in the pores. The data in table 2 and 5 indicate that at higher pH This leads to the movement of cations from the donor (pH 11) and higher current density, the membrane damage solution in the direction of counter ions transfer is greater than at lower pH (pH 7.4) and lower current (convective flow) facilitating anodal iontophoretic flux and density. The results of the effect of current densities on the impeding cathodal iontophoretic flux. Therefore, combined transport of salbutamol sulphate both during anodal and effect of electrical and convective transport was observed cathodal iontophoresis suggest a direct relationship between flux and current density for which values of R2 is 0.9746 and 0.9859 respectively. This relationship can well Theoretically it was assumed that anodal iontophoretic be validated with the help of Nernst-Plank equation flux at pH 11 and cathodal iontophoresis at pH 7.4 would be negligible due to respective attraction of cations and anions by the electrode, but it demonstrated significant The enhancement in the cathodal flux at pH 11 is value. The transport of drug under these circumstances can predominantly due to convective solvent flow. The be understood by the fundamental principle of electroosmotic volume flow increases with an increase in electroosmosis (Roberts et al., 1997). current density (Mudry et al., 2007), which leads to Another reason for the maximum iontophoretic flux increase in the flux of the drug. By increasing current enhancement and fraction change in flux at pH 7.4 are density the electrical resistance decreases with time better explained from the view of model proposed by Sims (Mudry et al., 2007, Pikal et al., 1990), therefore, flux and Higuchi (Sims et al., 1990), wherein transport of during later stage is more. The steady state reaches quickly ionized and non ionized drug moiety occurs from aqueous (Fig. 2) at higher current densities than at low current pore pathways and through the parallel lipoidal phase of densities. At pH 11, the rate of increase in the flux with the stratum corneum by the process of diffusion and current is more during cathodal iontophoresis. This is also partition respectively. Therefore, in general term it is stated supported by greater delivery efficiency of salbutamol at that when pore pathways dominate (due to iontophoretic pH 11 than pH 7.4 during cathodal and anodal treatment), the difference between passive flux and iontophoresis, respectively. The results indicate that by iontophoretic flux become larger (Santi et al., 1996). The proper selection of donor solution, pH and type of result comply with the paper published previously iontophoresis (cathodal or anodal), the efficiency of drug (Srinivasan et al., 1990, Pikal et al., 2001). delivery can be increased. Appropriate drug counter ion 816 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 1 April - June 2010
can minimize generation of the electro-chemicals and Bayon Rodriguez AM, Corish J, Corrigan OI. In vitro passive and extraneous ions in the donor reservoir during iontophoresis iontophoretically assisted transport of salbutamol sulphate and hence increase the efficiency of drug delivery across synthetic membranes. Drug Dev Ind Pharm. 1993; Bose S, Ravis WR, Lin YJ, Zhang L, Hofmann GA, Banga AK. Conclusion
Electrically-assisted transdermal delivery of buprenorphine. J In summary, the delivery of ionizable drug (salbutamol sulphate) using iontophoresis can be manipulated, Bumette RR, Marrero D. Comparison between the iontophoretic controlled and optimized, considering the following points: and passive transport of thyrotropin releasing hormone across 1. Iontophoresis (anodal and cathodal) enhances the excised nude mouse skin. J Pharm Sci. 1986; 75: 738-743. transport of salbutamol sulphate through hairless Burnette RR, Orgipattanakal B. Characterization of pore transport mice skin as compared to passive diffusion. properties and tissue alteration of excised human skin during 2. Passive diffusion of salbutamol sulphate was iontophores. J Pharm Sci.1988; 77: 132-137. Care V. CPCSEA Guidelines for laboratory animal facility. Indn 3. Anodal iontophoresis at pH 7.4 was more effective in transport of salbutamol sulphate across skin as compared to cathodal iontophoresis at pH 11. Charro MB, In vitro optimization of dexamethasone phosphate delivery by iontophoresis. Phys Ther. 2008; 88: 1177–1185. 4. The transport steady state flux and permeability coefficient of drug were increased with increase in Davis KA, Anseth KS. Controlled release from cross linked current densities (for both anodal and cathodal degradable networks, Crit Rev Ther Drug Carr Syst. 2002; iontophoresis). The flux of the drug showed linear De Graaff AM, Li GL, van Aelst AC, Bouwstra JA. Combined The investigation has probed a number of aspects chemical and electrical enhancement modulates stratum pertinent to salbutamol sulphate delivery across the skin. corneum structure. J Cont Rel. 2003; 90: 49-58. The ability to enhance transport of drug is established Delgado-Charro MB, Guy RH. Transdermal iontophoresis for using different variables, and the patterns of behaviour controlled drug delivery and non-invasive monitoring. STP observed are found to be reasonably consistent. The findings of the present investigation could be further DelTerzo S, Behl CR, Nash RA. Iontophoretic transport of a utilized for better optimization in the process of homologous series of ionized and nonionized model development of complete iontophoretic drug delivery compounds: influence of hydrophobicity and mechanistic interpretation. Pharm Res.1989; 6:85-90. Acknowledgement
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