Interactions between Sodium Cholate or Sodium Deoxycholate and

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Interactions between Sodium Cholate or Sodium Deoxycholate and Nonionic Surfactant (Tween 20 or Tween 60) in Aqueous Solution Dejan M. Ć irin,* Mihalj M. Poša, and Veljko S. Krstonošić Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia ABSTRACT: Knowledge of physicochemical parameters of mixed micelles is important in order to develop drug delivery systems with required characteristics. Investigated bile salts and Tweens are relatively nontoxic surfactants, extensively studied as biocompatible colloidal drug carriers. The micellization behavior of binary anionic−nonionic surfactant mixtures built of sodium cholate or sodium deoxycholate and one of two Tweens (Tween 20 or Tween 60) was investigated by conductivity and surface tension measurements. The results of the study have been analyzed using Clint’s, Rubingh’s, and Motomura’s theories for mixed binary systems. The determined physicochemical properties, particularly the negative values of the interaction parameter, indicate synergism between the individual surfactants in the mixed micelles. It was noticed that Tween with a longer hydrophobic tail shows stronger interactions with selected bile salts. However, it was found that the more hydrophilic bile salt (sodium cholate) generates the stronger synergism with investigated Tweens.

1. INTRODUCTION Surfactant mixtures usually show different characteristics than their individual components.1−4 Therefore, the properties and functionality of mixed micelles can be fine tuned by composition variation. The micellization behavior of anionic− nonionic surfactant mixtures has been particularly studied since these binary systems can provide better performances in many technological fields of application than the individual surfactants.1−12 In the pharmaceutical area, anionic−nonionic surfactant mixtures have been investigated due to their ability to improve solubilization of poorly soluble drugs13−19 and enhance bioavailability of different active ingredients.14,17 Tweens are nonionic surfactants and derivatives of polyethoxylated sorbitan esters of fatty acids. Investigated Tweens are homologus polysorbates having different lengths of the alkyl tail (laurate in Tween 20 and stearate in Tween 60). Tween 20 and Tween 60 are stable, biocompatible nonionic surfactants, widely used as inert vehicles in many pharmaceutical formulations.20,21 Furthermore, it is found that Tween 20 and Tween 60 are capable of enhancing drug transport across biological membranes.22 Tweens are emerging as a special class of pharmaceutical excipients capable if inhibiting P-glycoprotein (P-gp) mediated drug efflux, thus improving oral bioavailability of certain drugs.23,24 Bile salts are steroid anionic amphiphiles, which form micelles above the critical micelle concentration (cmc).25,26 Sodium cholate (NaC) and sodium deoxycholate (NaDC) have the same steroidal skeleton, but NaDC lacks a 7-hydroxyl group. Micelles of bile salts are used in pharmaceutical formulations where they solubilize poorly soluble molecules.27,28 Several studies have found that NaC and NaDC can improve the permeation of various drugs across biological membranes.29,30 Therefore, it is assumed that the bile salt− Tween binary systems would be interesting in the pharmaceutical research area for development of novel, more effective formulations. In addition, the desired qualities of colloidal drug © 2012 American Chemical Society

carriers could be tuned by combining the individual surfactants (Tweens and bile salts). NaDC−Tween 80 mixed micelles have been characterized in two studies.31,32 However, to the best of our knowledge, there are no reports investigating the effect of the hydrophobic tail length of Tweens on the micellar properties of bile salt−Tween binary systems. To our knowledge, the influence of different bile salt structures on interactions with Tweens in the mixtures has not been described in the literature. In this study, four different anionic−nonionic binary systems were analyzed using conductivity and surface tension measurements. As the anionic cosurfactant, sodium cholate (NaC) or sodium deoxycholate (NaDC) was used. Tween 20 or Tween 60 was used as the nonionic cosurfactant. Therefore, we investigated four anionic−nonionic binary pairs: NaC−Tween 20, NaC−Tween 60, NaDC−Tween 20, and NaDC−Tween 60. The interactions in the binary systems were studied by determining physicochemical parameters of the mixed micelles: the experimental cmc values of the individual surfactants, the experimental cmc values of the mixed micelles, the cmc values of ideal mixed micelles, the mole fraction of the more hydrophobic cosurfactant in the real mixed micelles, the mole fraction of the more hydrophobic cosurfactant in the ideal mixed micelles, and the interaction parameter (β) of the surfactant mixture. The physicochemical properties have been determined using Clint’s, Rubingh’s, and Motomura’s theories for mixed micellar systems.33−35 The first aim of our study was to provide more information on how elongation of the Tweens hydrophobic tail affects the interactions and stability of the bile salt−nonionic mixed systems. Hence, two homologous nonionic polyoxyethylene Received: Revised: Accepted: Published: 3670

October 15, 2011 January 31, 2012 February 1, 2012 February 1, 2012 dx.doi.org/10.1021/ie202373z | Ind. Eng. Chem. Res. 2012, 51, 3670−3676

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and below the cmc. The straight line above the cmc value was determined by linear regression starting at the highest concentration, while the straight line below the cmc value was obtained by linear regression beginning at the lowest concentration of investigated individual surfactant or binary surfactant mixture. The regression diagnostic was repeatedly performed after addition of each subsequent experimental point. If an experimental point was identified as an outlier, by measuring Cook’s distance,36 the regression would be stopped and the straight line would be formed using previously added experimental points (Figures 1 and 2).

(20) sorbitan ester surfactants having a laurate (Tween 20) or stearate (Tween 60) hydrophobic tail have been investigated. The second goal was to find how structural differences between two different bile salts (sodium cholate and sodium deoxycholate) can impact the interactions with selected nonionic cosurfactants.

2. MATERIALS AND METHODS 2.1. Materials. Sodium cholate and sodium deoxycholate were purchased from Sigma-Aldrich (Germany). The degree of purity is >99%. Nonionic surfactants, polyoxyethylene (20) sorbitan monolaurate (Tween 20) and polyoxyethylene (20) sorbitan monostearate (Tween 60), were obtained from J. T. Baker (Holland). The degree of purity is >99%. Surfactant solutions were prepared by dissolving accurately weighed quantities of surfactants in requisite volumes of deionized water. Deionized water (conductivity < 1 μS cm−1, at 25 °C) was used for all purposes. 2.2. Critical Micelle Concentration Determination. The cmc values of pure NaC and NaDC were acquired through conductivity and surface tension measurements. The critical micelle concentrations of the NaC−Tween and NaDC−Tween binary mixtures were determined by means of conductivity and surface tension studies as well. The cmc values of Tweens were obtained through surface tension measurements since these amphiphiles do not have an influence on electric conductance. 2.3. Conductivity Measurements. Conductivity measurements were carried out on aqueous solutions of pure NaC and NaDC. Aqueous solutions of mixtures of NaC or NaDC and one of two nonionic surfactants (Tween 20 or Tween 60) were also analyzed by measuring conductivities. The cmc values of the binary systems were obtained for different molar ratios of the components. Conductivities were measured by gradual dilution of surfactant solutions with the deionized water. Data were acquired using a Consort C 860 conductometer. The cell containing solutions was immersed in a water bath, controlling the temperature variation at ±0.1 °C. The temperature was kept constant at 25 °C. Trials were repeated three times for reproducibility. The cmc determination error did not exceed 4%. 2.4. Surface Tension Measurements. Surface tension measurements were carried out on aqueous solutions of two different nonionic surfactants (Tween 20 and Tween 60) in order to determine their individual cmc. The cmc values of mixtures of NaC or NaDC and one of two nonionic surfactants (Tween 20 or Tween 60) were also determined through surface tension studies. Surface tension measurements were carried out on a Sigma 703D tensiometer (Finland) using the du Nouy ring method. All measurements were repeated three times. In all measurements the temperature was kept constant at 25 ± 0.1 °C. The cmc determination error did not exceed 4%.

Figure 1. Dependence of the specific conductivity, κ in μS cm−1, on concentration of mixed NaC−Tween 20 (α = 0.1) micellar solution at 25 °C. (●) Experimental points. Straight lines are determined by linear regression. Discontinuous line represents the Gaussian curve, and arrow denotes the cmc.

Figure 2. Dependance of the specific conductivity, κ in μS cm−1, on concentration of mixed NaDC−Tween 20 (α = 0.1) micellar solution at 25 °C. (●) Experimental points. Straight lines are determined by linear regression. Discontinuous line represents the Gaussian curve, and arrow denotes the cmc.

For the NaC−Tween and NaDC−Tween binary mixtures one intersection point in the conductivity against surfactant concentration plot was noticed for all investigated mole fractions of nonionic cosurfactant (α). Figures 1 and 2 show the intersection points. However, this method can be applied for determination of cmc values only if there is an abrupt change in conductivity. Since the change in conductivity for the investigated individual surfactants and mixed binary systems does not show an abrupt alteration, the uncertainty in determination of cmc values using this method is increased. In order to determine the cmc values more reliably, Phillips’ method37 was used. In this method, the cmc is considered as the concentration at which the maximun

3. RESULTS AND DISCUSSION The cmc values of individual bile salts (NaC and NaDC) were acquired using conductivity and surface tension studies. The cmc values of the binary mixtures were studied by means of conductivity and surface tension measurements at different mole fractions of a nonionic cosurfactant (α). Prepared mixtures consisted of 0.1, 0.2, 0.3, 0.4, or 0.5 mol fractions of Tween 20 or Tween 60 (α). The cmc values acquired in the conductivity measurements were obtained from the intersection of the straight lines above 3671

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change in a physical property of the solution, ϕ, versus concentration curve occurs.

the standard deviation was calculated for conductivity and surface tension studies and is presented in Tables 1−3. The

(d3φ /dc 3)c = 0; c = cmc

Table 1. Experimentally Obtained Critical Micelle Concentrations of the Individual Surfactants (cmcex) As Determined by (a) Conductivity and (b) Surface Tension Measurements Compared to Literature Values (cmclit)a

Phillips’ method was employed as proposed by Mosquera et al.38 The Runge−Kutta integration was applied, and a leastsquares fitting method, according to Levenberg−Maquardt, was used. Use of Phillips’ method for determination of cmc values has been reported in previous studies as well.39,40 Figures 1 and 2 show the application of Phillips’ method in determination of the cmc values of NaC−Tween 20 (α = 0.1) and NaDC−Tween 20 (α = 0.1) binary systems. The linear regression and Phillips’ method were used together to determine the cmc values. The linear regression was used to estimate the region were cmc occurs, while Phillips’ method was used to determine the cmc values more reliably. The cmc values of all individual surfactants and investigated binary systems were obtained from surface tension studies as well, where a plot of surface tension (γ) versus concentration of individual surfactant or binary mixture was obtained. The plots of surface tension, γ, against the surfactant concentration show one break. Figures 3 and 4 show the break points.

cmcex (mM) surfactant

a

NaC NaDC Tween 20 Tween 60

12.90 ± 0.13 4.35 ± 0.06

cmclit (mM)

b 12.73 4.25 0.050 0.0220

± ± ± ±

0.15 0.05 0.001 0.0001

12.8 4.16 0.049 0.021

cmcex represents the mean value ± the standard deviation of three determinations.

a

Table 2. Comparison of the Experimentally Obtained Critical Micelle Concentrations of the Binary Mixtures (cmcex) for the NaC−Tween Binary Systems As Determined by (A) Conductivity and (B) Surface Tension Measurementsa cmcex (mM) α [Tween]

a

Tween 20 0 0.1 0.2 0.3 0.4 0.5 Tween 60 0 0.1 0.2 0.3 0.4 0.5

Figure 3. Dependence of surface tension, γ in mN m−1, on concentration of mixed NaC−Tween 20 (α = 0.1) micellar solution at 25 °C. Arrow denotes the cmc.

b

12.90 0.207 0.135 0.102 0.084 0.072

± ± ± ± ± ±

0.13 0.003 0.003 0.002 0.002 0.002

12.73 0.212 0.138 0.104 0.083 0.071

± ± ± ± ± ±

0.15 0.004 0.002 0.002 0.002 0.001

12.90 0.093 0.056 0.042 0.032 0.028

± ± ± ± ± ±

0.13 0.002 0.002 0.001 0.001 0.001

12.73 0.091 0.055 0.043 0.031 0.029

± ± ± ± ± ±

0.15 0.002 0.002 0.001 0.001 0.001

cmcex represents the mean value ± the standard deviation of three determinations.

a

experimentally obtained cmc values for individual surfactants, with standard deviations of three determinations, are presented in Table 1 and compared to literature values.41,42 The experimentally determined cmc values for the NaC−Tween and NaDC−Tween binary sytems, with standard deviations of three determinations, are presented in Tables 2 and 3. As seen in Tables 1−3 the cmc values determined by conductivity and surface tension measurements are in good agreement. Since there is no statistically significant difference between the cmc values obtained by means of the two methods, the cmc values determined through conductivity measurements were used in further calculations. In order to study the influence of the structure of Tweens on formation of mixed micelles with NaC and NaDC, the physicochemical parameters of the micellar systems were obtained (Tables 4 and 5). The determined physicochemical parameters are the critical micelle concentration of ideal mixtures (cmcid), the mole fraction of the more hydrophobic surfactant in the ideal mixed micelle (xid), the mole fraction of the more hydrophobic surfactant in the real mixed micelle (x1), and the β parameter.

Figure 4. Dependence of surface tension, γ in mN m−1, on concentration of mixed NaDC−Tween 20 (α = 0.1) micellar solution at 25 °C. Arrow denotes the cmc.

In order to evaluate the reproducibility of the used methods, all conductivity and surface tension measurements were repeated three times. The cmc determination error did not exceed 4%. Extended t test (p < 0.05) shows that the mean cmc values determined using conductivity and surface tension measurements belong to the same population. Additionally, 3672

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Table 3. Comparison of the Experimentally Obtained Critical Micelle Concentrations of the Binary Mixtures (cmcex) for the NaDC−Tween Binary Systems As Determined by (A) Conductivity and (B) Surface Tension Measurementsa

Table 5. Comparison of Experimental Parameters Determined by Conductivity Measurements (cmcex and x1) with Ideal Parameters (cmcid and xid) and Interaction Parameter (β) for the NaDC−Tween Binary Systems α [Tween]

ex

cmc (mM) α [Tween]

a

Tween 20 0 0.1 0.2 0.3 0.4 0.5 Tween 60 0 0.1 0.2 0.3 0.4 0.5

Tween 20 0 0.1 0.2 0.3 0.4 0.5 Tween 60 0 0.1 0.2 0.3 0.4 0.5

b

4.35 0.236 0.148 0.117 0.091 0.077

± ± ± ± ± ±

0.06 0.003 0.003 0.003 0.002 0.002

4.25 0.239 0.144 0.113 0.089 0.076

± ± ± ± ± ±

0.05 0.003 0.004 0.002 0.002 0.001

4.35 0.094 0.065 0.046 0.037 0.032

± ± ± ± ± ±

0.06 0.002 0.002 0.001 0.001 0.001

4.25 0.096 0.063 0.045 0.038 0.031

± ± ± ± ± ±

0.05 0.002 0.001 0.001 0.001 0.001

ex

Table 4. Comparison of Experimental Parameters Determined by Conductivity Measurements (cmcex and x1) with Ideal Parameters (cmcid and xid) and Interaction Parameter (β) for the NaC−Tween Binary Systems α [Tween]

cmcex (mM)

cmcid (mM)

x1

xid

β

12.90 0.207 0.135 0.102 0.084 0.072

0.483 0.246 0.165 0.124 0.099

0.704 0.759 0.790 0.816 0.838

0.966 0.985 0.991 0.994 0.996

−6.06 −5.86 −5.79 −5.73 −5.78

Tween 20 0 0.1 0.2 0.3 0.4 0.5 Tween 60 0 0.1 0.2 0.3 0.4 0.5

12.90 0.093 0.056 0.042 0.032 0.028

0.217 0.109 0.073 0.055 0.044

0.725 0.763 0.790 0.798 0.818

0.985 0.993 0.996 0.997 0.998

cmc id

=

∑ i

αi cmci

x1

xid

β

4.35 0.236 0.148 0.117 0.091 0.077

0.453 0.239 0.162 0.123 0.099

0.689 0.752 0.805 0.822 0.846

0.905 0.955 0.973 0.983 0.988

−3.91 −3.89 −3.60 −3.91 −3.97

4.35 0.094 0.065 0.046 0.037 0.032

0.21 0.108 0.0725 0.0546 0.0438

0.701 0.770 0.791 0.813 0.838

0.956 0.98 0.988 0.992 0.995

−5.54 −5.00 −5.31 −5.42 −5.40

where cmc1 is the experimentally obtained cmc of the more hydrophobic surfactant (Tween), cmc2 is the cmc of NaC or NaDC, and α is the mole fraction of the more hydrophobic surfactant in the solution (Tween). The xid values were used to calculate the mole fraction of the more hydrophobic surfactant in the real mixed micelle (x1) following the relation proposed by Rubingh34 x12 ln(cmcex α /cmc1x1) (1 − x1)2 ln[cmcex (1 − α)/cmc2(1 − x1)]

=1 (3)

Equation 3 was solved iteratively to obtain the value of x1. The xid and x1 values related to the mixed micelles are presented in Tables 4 and 5. The difference between xid and x1 also indicates nonideal behavior of the mixtures. The x1 value was used to determine the β interaction parameter by employing the equation according to Rubingh’s model34

−7.13 −7.2 −7.29 −7.74 −7.58

β=

It is important to explain the procedure for obtaining the physicochemical parameters shown in Tables 4 and 5. The values for the critical micelle concentrations of ideal mixtures (cmcid) were calculated using the following equation proposed by Clint33 1

cmcid (mM)

The mole fractions of the more hydrophobic surfactant in the ideal mixed micelle (xid), according to Motomurás model,35 were calculated using the relation cmc2α x id = cmc2α + cmc1(1 − α) (2)

cmc represents the mean value ± the standard deviation of three determinations.

a

cmcex (mM)

ln(cmcex α /cmc1x1) (1 − x1)2

(4)

The more negative value of the β interaction parameter indicates the stronger synergism between the components. From Tables 4 and 5 it can be observed that values of the β parameter are negative at all molar ratios of the mixtures. These values correspond to the deviation between the experimentally obtained (cmcex) and the calculated (cmcid) cmc values and indicate synegism in all investigated bile salt−Tween mixtures. In Table 6, the average values of the interaction parameter (βav) for analyzed binary systems are presented in order to make the results easily comparable. The first goal of this study was to find how elongation of the hydrophobic tail of Tween affects interactions with selected bile salts. By analyzing Table 4 it is clear that the components of the NaC−Tween 60 binary system showed stronger synergism than NaC−Tween 20. Building units of NaDC−Tween 60 mixed micelles also formed stronger interactions than the

(1)

where αi is the mole fraction in the solution of component i and cmci is the experimentally obtained cmc of component i. The cmcid values are presented and compared to the experimental cmc (cmcex) in Tables 4 and 5. The deviation of the cmcex values from those calculated according to Clint’s theory indicates nonideal behavior of examined mixtures and the existence of mutual interactions of the components in the micelles. 3673

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We assume that in studied aggregates the β side of the steroid skeleton of the bile salts is oriented toward the hydrophobic core of the micelles, while polar heads of Tweens are located at the surface of the aggregates, as presented in Figure 5. The median plain of Tweens is perpendicular to the hydrophobic surface of the micelles as well as the axial αhydroxyl groups of the bile salts. This probably enables formation of the hydrogen bonds between the proton acceptor ethoxy groups of the polar head of investigated Tweens and the α-axial hydroxyl groups. Both effects, hydrophobic interactions and formation of the hydrogen bonds, make micellar systems more stable. Consequently, the cmc values of NaC−Tween 20, NaC− Tween 60, NaDC−Tween 20, and NaDC−Tween 60 mixed micelles are lower than those predicted by Clint’s theory of ideal mixtures.

Table 6. Average β Interaction Parameters (βav) for Analyzed Mixed Binary Systems (NaC−Tween 20, NaC−Tween 60, NaDC−Tween 20, and NaDC−Tween 60) βav surfactant

NaC

βav

Tween 20 Tween 60

−5.84 −7.39

−3.86 −5.33

components of NaDC−Tween 20 micelles. These results suggest that Tween with a longer hydrophobic tail (Tween 60) generates stronger synergism. It is evident that elongation of the hydrophobic tail of nonionic cosurfactant induces stronger hydrophobic interactions with the β side of the steroid skeleton of investigated bile salts. The second aim was to investigate the effect of structural differences between sodium cholate and sodium deoxycholate on interactions with the nonionic cosurfactants. On the basis of previous studies of conventional surfactants,1−12 it was expected that a more hydrophobic bile salt (NaDC) will generate stronger synergism with the nonionic cosurfactants due to stronger hydrophobic interactions. However, if the interaction parameters of the NaC−Tween and NaDC−Tween binary systems are compared (Table 6), it is evident that a more hydrophilic bile salt (NaC) creates stronger interactions with investigated Tweens. The stronger synergistic effect of sodium cholate compared to sodium deoxycholate can be explained by the fact that NaC contains two α-axial hydroxyl groups at the C7 and C12 positions, while NaDC has only one α-axial hydroxyl group at C12. Obviously, the number of the αaxial hydroxyl groups is important for the stability of the micelles.

4. CONCLUSIONS We studied four anionic−nonionic binary pairs by means of conductometry: NaC−Tween 20, NaC−Tween 60, NaDC− Tween 20, and NaDC−Tween 60. The critical micelle concentration of the ideal mixed micelle, the mole fraction of the more hydrophobic surfactant in the ideal mixed micelle, the mole fraction of the more hydrophobic surfactant in the real mixed micelle, and the β interaction parameter of the mixed micelles were calculated using experimental data. On the basis of the calculated values of the β parameter we concluded that investigated bile salts (sodium cholate and sodium deoxycholate) generate stronger interactions with Tween 60 than with Tween 20. It is evident that the longer lipophilic part of the nonionic cosurfactant creates stronger

Figure 5. Hydrogen bonds between the axial hydroxyl groups of sodium cholate (1) or sodium deoxycholate (2) and the polar head of the Tween molecule (Tween 20 or Tween 60). Bile salts are represented by Newman projections. Since sodium deoxycholate lacks an axial hydroxyl group at C7, it probably creates only one hydrogen bond with the polar head of Tween. 3674

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(13) Bhattacharjee, J.; Verma, G.; Aswal, V. K.; Date, A. A.; Nagarsenker, M. S.; Hassan, P. A. Tween 80-Sodium Deoxycholate Mixed Micelles: Structural Characterization and Application in Doxorubicin Delivery. J. Phys. Chem. B 2010, 114, 16414. (14) Yu, J. N.; Zhu, Y.; Wang, L.; Peng, M.; Tong, S. S.; Cao, X.; Qiu, H.; Xu, X. M. Enhancement of Oral Bioavailability of the Poorly Water-Soluble Drug Silybin by Sodium Cholate/Phospholipid-Mixed Micelles. Acta Pharmacol. Sin. 2010, 31, 759. (15) Sznitowska, M.; Klunder, M.; Placzek, M. Paclitaxel Solubility in Aqueous Dispersions and Mixed Micellar Solutions of Lecithin. Chem. Pharm. Bull. 2008, 56, 70. (16) Liu, J.; Gong, T.; Wang, C.; Zhong, Z.; Zhang, Z. Solid Lipid Nanoparticles Loaded with Insulin by Sodium Cholate-Posphatidylcholine-Based Mixed Micelles: Preparation and Characterization. Int. J. Pharm. 2007, 340, 153. (17) Guo, J.; Wu, T.; Ping, Q.; Chen, Y.; Shen, J.; Jiang, G. Solubilization and Pharmacokinetic Behaviors of Sodium Cholate/ Lecithin-Mixed Micelles Containing Cyclosporine A. Drug Delivery 2005, 12, 35. (18) De Castro, B.; Gameiro, P.; Guimarães, C.; Lima, J. L.; Reis, S. Partition Coefficients of Beta-Blockers in Bile Salt/Lecithin Micelles as a Tool to Assess the Role of Mixed Micelles in Gastrointestinal Absorption. Biophys. Chem. 2001, 90, 31. (19) Hammad, M. A.; Müller, B. W. Increasing Drug Solubility by Means of Bile Salt-Phosphatidylcholine-Based Mixed Micelles. Eur. J. Pharm. Biopharm. 1998, 46, 361. (20) Myers, D. Surfactant Science and Technology; VCH: New York, 1988. (21) Artman, N. R. Safety of Emulsifiers in Fats and Oils. J. Am. Oil Chem. Soc. 1975, 2, 49. (22) Dimitijevic, D.; Shaw, J. A.; Florence, A. T. Effects of Some Non-Ionic Surfactants on Transepithelial Permeability in Caco-2 Cells. J. Pharm. Pharmacol. 2000, 52, 157. (23) Li, M.; Si, L.; Pan, H.; Rabba, A. K.; Yan, F.; Qiu, J.; Li, G. Excipients Enhance Intestinal Absorption of Ganciclovir by P-gp Inhibition: Assessed in Vitro by Everted Gut Sac and in Situ by Improved Intestinal Perfusion. Int. J. Pharm. 2011, 403, 37. (24) Yamagata, T.; Kusuhara, H.; Morishita, M.; Takayama, K; Benameur, H.; Sugiyama., Y. Effect of Excipients on Breast Cancer Resistance Protein Substrate Uptake Activity. J. Controlled Release 2007, 124, 1. (25) Calabresi, M.; Andreozzi, P.; Mesa, C. L. Supra-Molecular Association and Polymorphic Behaviour in Systems Containing Bile Acid Salts. Molecules 2007, 12, 1731. (26) Subudhi, U.; Mishra, A. K. Micellization of Bile Salts in Aqueous Medium: a Fluorescence Study. Colloids Surf. B 2007, 57, 102. (27) Camile, W. The Practice of Medicinal Chemistry; Academic Press: Oxford, 2003. (28) De Castro, B.; Gameiro, P.; Guimaraes, C.; Lima, J. L. F. C.; Reis, S. Study of Partition of Nitrazepam in Bile Salt Micelles and the Role of Lecithin. J. Pharm. Biomed. Anal. 2001, 24, 595. (29) Bowe, C.; Mokhtarzadeh, L.; Venkatesen, P.; Babu, S.; Axelrod, H.; Sofia, M. J.; Kakarla, R.; Chan, T. Y.; Kim, J. S.; Lee, H. J.; Amidon, G. L.; Choe, S. Y.; Walker, S.; Kahne, D. Design of Compounds That Increase the Absorption of Polar Molecules. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 12218. (30) Gordon, G. S.; Moses, A. C.; Silver, R. D.; Flier, J. R.; Carey, M. C. Nasal Absorption of Insulin: Enhancement by Hydrophobic Bile Salts. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 7419. (31) Haque, M. E.; Das, A. R.; Moulik, S. P. Mixed Micelles of Sodium Deoxycholate and Polyoxyethylene Sorbitan Monooleate (Tween 80). J. Colloid Interface Sci. 1999, 217, 1. (32) Bhattacharjee, J.; Verma, G.; Aswal, V. K.; Date, A. A.; Nagarsenker, M. S.; Hassan, P. A. Tween 80-Sodium Deoxycholate Mixed Micelles: Structural Characterization and Application in Doxorubicin Delivery. J. Phys. Chem. B. 2010, 114, 16414. (33) Clint, J. H. Micellization of Mixed Nonionic Surface Active Agents. J. Chem. Soc., Faraday Trans. I 1975, 71, 1327.

hydrophobic interactions with the steroid ring of investigated bile salts, thus increasing the synergistic effect. We also noticed that the more hydrophilic bile salt, sodium cholate, generates stronger synergism with investigated Tweens. We assume that this is the consequence of the hydrogen bonds which are probably created between α-axial hydroxyl groups of sodium cholate and proton acceptor ethoxy groups of the polar head of selected nonionic cosurfactants. Since NaC consists of more axial hydroxyl groups it showed stronger synergism than NaDC.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the Provincial Secretariat for Science and Technological Development, AP Vojvodina, Republic of Serbia, Grant No. 114-451-2113/201101. The Hungary-Serbia IPA Cross-border Co-operation programme HUSRB/1002/214/193, Bile Acid Nanosystems as Molecule Carriers in Pharmaceutical Applications (BANAMOCA), is thanked as well.

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REFERENCES

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