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Langmuir 1998, 14, 6840-6845
Hydrophilic Model Drug Delivery from Concentrated Reverse Emulsions S. Rocca,*,† M. J. Garcı´a-Celma,‡ G. Caldero´,‡ R. Pons,‡ C. Solans,‡ and M. J. Ste´be´† Laboratoire de Physico-Chimie des Colloı¨des, UMR 7565 CNRS/Universite´ Henri Poincare´ Nancy1, Faculte´ des Sciences, BP 239, 54506 Vandoeuvre-le` s-Nancy Cedex, France, and Departamento de Tecnologı´a de Tensioactivos, Centro de Investigacio´ n y Desarollo (CSIC), c/Jordi Girona, 18-26, 08034 Barcelona, Spain Received January 22, 1998. In Final Form: April 24, 1998 Highly concentrated water-in-oil gel-emulsions have been prepared from five components: fluorocarbon, hydrocarbon, fluorinated and hydrogenated surfactants, and water. Whatever the ratio of fluorinated to hydrogenated compounds, the stability of these mixed emulsions allows them to be used for the transport of drugs. A series of model molecules solubilized in water have been chosen because of the modulation of the hydrophobicity of the probe molecule by varying the alkyl substitute length: methyl, ethyl, and propyl paraben. The release of these molecules has been studied with an automatic setup. The experiments take about 48 h to reach equilibrium regardless of the emulsion composition. Nevertheless some variations have been observed with respect to either the chosen probe molecule or the amount of hydrogenated and fluorinated compounds in the gel emulsion. In light of the results, diffusion takes place in two possible steps: (i) transfer from big droplets to the continuous micellar phase and (ii) transfer from the continuous oily phase to the aqueous receptor solution. The influence of these two steps is related to the molecular structure of the model drug on one hand and to its solubility both in the micellar oily phase and in the aqueous phase constituting the gel emulsion in the other hand.
Introduction Concentrated reverse water in either hydrogenated or fluorinated oil emulsions, stabilized by nonionic hydrogenated or fluorinated surfactants, can contain up to 99% (w/w) of water.1-4 Because of their foamlike structure they present a highly viscoelastic behavior that prompted the use of the gel-emulsion term to designate these systems.5-8 Gel-emulsions are quite stable despite their low surfactant and oil content, especially some fluorinated emulsions which can be stored for several months without any measurable change in their properties. Phase behavior studies showed that gel-emulsions separate into two isotropic liquid phases at equilibrium:4 one phase is a submicellar surfactant solution in water and the other phase is a swollen reverse micellar solution (or waterin-oil (W/O) microemulsion). Optical microscopy of gelemulsions with water volume fractions near unity revealed a close-packed structure of droplets with polyhedral shape. The structure of these emulsions resembles that of foams: the water droplets are covered by a very thin layer of * To whom correspondence should be addressed. E-mail:
[email protected]. † Laboratoire de Physico-Chimie des Colloı¨des, UMR 7565 CNRS/ Universite´ Henri Poincare´ Nancy1. ‡ Departamento de Tecnologı´a de Tensioactivos, Centro de Investigacio´n y Desarollo (CSIC). (1) Kunieda, H.; Solans, C.; Shida, N.; Parra, J. L. Colloids Surf. 1987, 24, 225-237. (2) Kunieda, H.; Yano, N.; Solans, C. Colloids Surf. 1989, 36, 313. (3) Ravey, J. C.; Ste´be´, M. J. Physica B 1989, 394, 156-157. (4) Ravey, J. C.; Ste´be´, M. J. Prog. Colloid Polym. Sci. 1990, 82, 218-228. (5) Pons, R.; Erra, P.; Solans, C.; Ravey, J. C.; Ste´be´, M. J. J. Phys. Chem. 1993, 97, 2320-2324. (6) Ravey, J. C.; Ste´be´, M. J.; Sauvage, S. J. Chim. Phys. 1994, 91, 259-292. (7) Ravey, J. C.; Ste´be´, M. J.; Sauvage S. Colloids Surf. 1994, 91, 237-257. (8) Pons, R.; Carrera, I.; Erra, P.; Kunieda, H.; Solans, C. Colloids Surf., A 1994, 91, 259.
continuous phase. The interfacial area is very large although the volume of the continuous phase is very small. The natures of the continuous and dispersed phases, a microemulsion of the water-in-oil type and water, respectively, were assessed by means of phase behavior studies. At low values of oil-to-surfactant ratio, gelemulsions either are very unstable or they do not form, while at high oil-to-surfactant ratios, when the continuous phase is a W/O microemulsion, the stability is maximum.4,6,7 Therefore the structure of the continuous phase has a drastic influence on the formation and stability of gel-emulsions. Small angle X-ray and neutron scattering of gel-emulsions, as a function water volume fraction, oilto-surfactant ratio, and temperature confirmed that the structure of such a system is a water emulsion in a waterin-oil microemulsion.4,9 The high stability of these emulsions may be due to the contribution of the microemulsion which acts as a reservoir of surfactant molecules. Moreover the simultaneous presence of big water droplets and water-swollen micelles could be one of the reasons for favorable interactions and such a great stability. This concept has not been interpreted yet, from a theoretical point of view, but has to be developed. These emulsions display a compartmentalized structure: the micellar phase disjoining the big water droplets of the dispersed phase (Figure 1). This divided structure allows them to be new drug delivery systems to slow and control the release of molecules entrapped in the water droplets of the emulsion.10-13 The influence of several (9) Pons, R.; Ravey, J. C.; Sauvage, S.; Ste´be´, M. J.; Erra, P.; Solans, C. Colloids Surf. 1993, 76, 171-177. (10) Kreuter, J. In Colloidal drug delivery systems. Drugs and the Pharmaceutical Sciences; M. Dekker: New York, 1994; Vol. 66. (11) Pons, R.; Caldero´, G.; Garcia-Celma, M. J.; Azemar, N.; Carrera, I.; Solans, C. Prog. Colloid Polym. Sci. 1996, 100, 132-136. (12) Caldero´, G.; Garcia-Celma, M. J.; Solans, C.; Plaza, M.; Pons, R. Langmuir 1997, 13, 385-390. (13) Caldero´, G.; Garcia-Celma, M. J.; Solans, C.; Ravey, J. C.; Rocca, S.; Ste´be´, M. J.; Pons, R. Langmuir 1998, 14, 1580-1585.
10.1021/la9800856 CCC: $15.00 © 1998 American Chemical Society Published on Web 10/24/1998
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follow the diffusion of model drugs by automatic UV spectrophotometric analysis on three samples simultaneously. Results of these diffusion experiments are correlated with the solubilization of these model drugs in the two phases present in the emulsion: the aqueous dispersed phase and the oily micellar continuous phase. Moreover, the behavior of either mixed systems or single fluorinated and hydrogenated emulsions was studied with time. Therefore, emulsion stability has been also determined to assess its influence on the diffusion coefficients. Experimental Section
Figure 1. Schematic description of the gel-emulsions, water emulsion in a water-in-oil microemulsion.
variables on release rates of a hydrophilic molecule is shown in these papers. These emulsions would act as reservoir of active principles in pharmaceutical preparations and cosmetics. In addition the high water content and the low content in oil and surfactant of these peculiar emulsions make them attractive for economical and toxicological reasons. In our previous article, release of mandelic acid from fluorinated and hydrogenated gel emulsions has been described.13 The release rate was strongly system dependent and was found to be higher for hydrogenated than for fluorinated gel-emulsions. Because of this different behavior, mixed systems have been prepared by combining these two kinds of emulsion (hydrogenated and fluorinated one). Despite the two antagonistic behaviors of fluorocarbons and hydrocarbons, some of these mixtures are stable for about 1 week. A previous study has shown that symmetrical hydrogenated and fluorinated surfactants (i.e., with related hydrophilic and lipophilic chains) lead to the formation of mixed micelles or mixed liquids crystals. These studies were made for relatively concentrated systems despite the repulsive interactions of the fluorocarbon and hydrocarbon tails of the surfactants.14,15 Other results show that for mixtures of fluorinated and hydrogenated surfactants in liposomes, bilayers, and micelles16-18 phase separation or partial miscibility can occur. In our present study, mixtures are more complex because of the simultaneous presence of water with a high content, both hydrogenated and fluorinated surfactants, but also hydrocarbon and fluorocarbon. Such mixtures with five components have not been investigated yet. Studies about the structure of these mixed emulsions are in progress to determine if the continuous phase is a mixed homogeneous micellar phase or if segregation between hydrogenated and fluorinated domains occurs. For the purpose of studying systematically the release from gel emulsions, methyl, ethyl, and propyl paraben were selected as probe molecules. These molecules are used in cosmetics as preservatives.19 An automatic experimental setup has been developed that allows us to (14) Ravey, J. C.; Gherbi, A.; Ste´be´, M. J. Prog. Colloid Polym. Sci. 1989, 79, 272-278. (15) Ravey, J. C.; Gherbi, A.; Ste´be´, M. J. Prog. Colloid Polym. Sci. 1991, 84, 95-98. (16) Mukerjee, P.; Yang, A. Y. S. J. Phys. Chem. 1976, 80, 1388. (17) Elbert, R.; Folda, T.; Ringsdorf, H. J. Am. Chem. Soc. 1984, 106, 7687. (18) Kunitake, T. Angew. Chem., Int. Ed. Engl. 1994, 31, 709. (19) Wallhauser, K. H. In Surfactants in Cosmetics, Rieger, M. M., Ed; Surfactant Science Series; M. Dekker: 1985; Vol. 16, p 211.
1. Materials. Methyl, ethyl, and propyl paraben (F-hydroxybenzoic acid n-alkyl ester) were purchased from Sigma. Decane (purity >99%) was purchased from Sigma. Perfluorodecalin was supplied by Interchim. The hydrogenated surfactant (tetraethylene glycol mono-n-hexadecyl ether, C16E4) was supplied from Nikko Chemicals Co. Ltd (Japan). 1,2-Propanediol was purchased from Aldrich. The fluorinated surfactant was CmF2m+1C2H4SC2H4(OC2H4)2OH. It was synthesized by IRCHA (France) according to a method described by Cambon.20 The length of the fluorinated chain varies from m ) 6 to 10. A measurement of the molecular weight by tonometry gives an average value of 597 g‚mol-1, which corresponds to a hydrophobic tail with m ) 8. 2. Gel-Emulsion Preparation. Hydrogenated and fluorinated emulsions are prepared using the same procedure. Water is gently incorporated into the micellar oily continuous phase under stirring. These emulsions present a gel appearance. Their optical properties vary from white to colorless. The fluorinated emulsions can be translucent for a selected oil/surfactant ratio (O/S). Fluorocarbons present a refractive index lower than that of water. As the fluorinated surfactant refractive index is higher, a certain O/S ratio matches the water refractive index; in this situation the emulsion is transparent.6 These emulsions can be prepared using an oil/surfactant ratio between 0.5 and 200. In this work, the O/S ratio is 1.5 (60/40 w/w) for hydrogenated emulsion and 2.33 (70/30 w/w) for the fluorinated one, which corresponds to the transparent emulsion. Methyl, ethyl, and propyl paraben have been chosen as probe molecules. To enhance their solubility in water, 1,2-propandiol has been added to water (1/9 v/v propandiol/water). The addition of propandiol has no influence on the stability of the gel emulsions either hydrogenated or fluorinated. The solution of paraben used, in the mixture propandiol/water was 0.025% w/w. This constitutes the dispersed phase and represents 95% of the emulsion weight. We studied hydrogenated emulsion (H 100), fluorinated emulsion (F 100), and three mixed emulsions with variable proportions of hydrogenated and fluorinated gels: 75% hydrogenated, 25% fluorinated (H 75); 50% hydrogenated, 50% fluorinated (H 50); 75% fluorinated, 25% hydrogenated (H 25). Mixed emulsions have been prepared using two different methods. In the first method all components of the continuous phase (fluorinated, hydrogenated oils, and surfactants) are mixed together and then the aqueous phase is gently dispersed into the micellar oily phase under mechanical stirring (vortex). The second preparation involves each type of emulsion prepared separately and then the fluorinated emulsion is added to the hydrogenated one. The mixing of the two emulsions is provided by stirring. In both cases, the mixtures are easily prepared in any proportion. By visual or microscopic observations, no differences have been observed in the emulsion properties between the two methods. 3. Partition Coefficient Determination. Drug partition coefficients were determined by measuring the concentration of n-alkyl paraben in the dispersed phase of the emulsions by UV spectrophotometry. First, gel-emulsion was prepared according to the procedure explained above; the model drug is partitioned between the aqueous phase and the oily continuous phase of the emulsion. Then, the emulsion is destabilized by decreasing temperature to approach the phase inversion temperature (PIT). (20) Cambon, A.; Delpuech, J. J.; Matos, L.; Serratrice, G.; Szonyi, F. Bull. Soc. Chim. 1986, 6, 965.
6842 Langmuir, Vol. 14, No. 24, 1998 As a matter of fact, the stability of this kind of emulsions is related to the PIT: If temperature is close to the PIT, the formation of gel-emulsions is made uneasy.1 Finally, by centrifugation we obtain two fully separated phases. In the case of the mixed gel emulsions three separated phases are obtained: the dispersed aqueous phase, and two micellar phases, the upper rich in hydrogenated compounds and the lower rich in fluorinated compounds. Absorbency intensity of the paraben, solubilized in the aqueous phase, is measured at 257 nm (absorption UV coefficients (1cm%) for methyl, ethyl, and propyl paraben in water are respectively 1087, 920, and 840). So we obtain the paraben concentration in the aqueous phase and infer the concentration in the oily micellar continuous phase. K, the partition coefficient, is then determined as the ratio of the paraben concentration in the oily micellar phase to that in the aqueous phase: K ) Cmicellar phase/Caqueous phase. 4. Diffusion Experiments. A new experimental setup has been developed to study the release of model drug entrapped in the gel-emulsions. Release experiments can go on from one to several days with these unusual emulsions. Thus a fully automated setup collects the data during all the experiment without any intervention of the operator. The assembling is made of three identical diffusion cells. A diffusion cell consists of a cylindrical double side thermostated glass vessel of about 10 cm height and 5 cm diameter. A small Teflon cup of 0.5 cm height and 2 cm diameter is filled with 1.5 g of gel-emulsion, loaded with the drug molecule to study. This cup is placed at the bottom of the diffusion cell. The cup is overlaid by 35 mL of a receptor solution (mixture of propandiol and water 1/9 v/v) in the diffusion cell. The release of the model molecule takes place from the gel-emulsion to the receptor solution, as soon as the emulsion is put in contact with the receptor solution. Homogeneity of the receptor solution is ensured by agitation with a glass paddle rotated by a motor with adjustable rotation speed. Three diffusion cells are used in parallel to check the reproducibility. More, two sets of experiments were performed for each kind of gel emulsion studied: six release profiles are hence obtained. A peristaltic pump allows a small amount of the receptor solution to circulate, from the diffusion cell to a UV spectrophotometer, in a closed circuit, to measure its absorbency intensity. The circulation of the receptor solution is continuous, but absorbency measurements are performed now and then. Time periods of absorbency measurements are a function of the release rate of the probe molecule. At the beginning of the experiment the release is fast, and so frequency of the measurements is high (every 2 or 3 min). When the experiment progresses, the release is slower: measurement frequency is lower (every 30 min or more). All data are collected by a computer, and after an easy calculation, the amount of model drug released is obtained as a function of time. 5. Stability. Gel-emulsions loaded with methyl, ethyl, and propyl paraben are prepared and allowed to evolve with time. Three grams of emulsion is placed in a 1 cm diameter tube. These samples are observed for a few days. Droplet size is measured by optical microscopy observation. The amount of paraben solution that is spontaneously released by the emulsion is removed from the tube and weighed. We report the evolution of the released amount with time.
Results Diffusion curves of paraben from gel-emulsions present the same evolution: in the first part of the curve, drug release is fast, then the diffusion slows down until equilibrium is reached (Figure 2). Release curves are dependent on the mixture composition. They vary between totally hydrogenated, totally fluorinated, or mixed emulsions. The more fluorinated the emulsion, the faster the diffusion (Figures 2 and 3). The two ways of preparing gel-emulsion do not influence the drug release experiments. The small differences from one experiment to another are not meaningful. Therefore, gel-emulsions are systematically prepared by mixing all components of the continuous phase and then adding the dispersed phase. It appears clearly that ethyl and propyl paraben release
Rocca et al.
Figure 2. Diffusion curve from hydrogenated (H 100) and fluorinated emulsion (F 100). The amount of methyl paraben released is plotted as a function of time (hours).
Figure 3. Diffusion curve from mixed gel emulsions: amount of ethyl paraben as a function of time, influence of the composition of the emulsion.
Figure 4. Amount of methyl, ethyl, and propyl paraben released from fluorinated gel-emulsions, influence of the length of the alkyl chain.
curves lie below that of methyl paraben (Figure 4). Moreover, the effect of the proportion of added fluorinated emulsion is an acceleration of the diffusion. A problem of reproducibility with the more lipophilic paraben (propyl) has been noted, but the same trend is observed. Despite the use of the same initial concentration for methyl, ethyl, and propyl paraben solution in the gel-emulsion, the amount of probe molecule released is bigger from methyl to propyl when equilibrium is reached (9.5 × 10-3 mg/mL for methyl paraben released by fluorinated emulsion versus 4 × 10-3 mg/mL for propyl paraben released by fluorinated emulsion). To explain the different release rates and released amounts, the partition coefficients (Κ) were determined to learn the probe molecule distribution between water dispersed and micellar continuous phases. The results
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Table 1. Partition Coefficient of Alkyl Paraben between Oily Continuous and Aqueous Dispersed Phase of the Studied Gel Emulsions gelemulsion
methyl paraben
ethyl paraben
propyl paraben
H 100 H 75 H 50 H 25 F 100
34 40 34 34 18
61 88 78 90 45
136 245 167 178 152
Table 2. Diffusion Coefficients of Alkyl Paraben (10-10 m2 s-1) gelemulsion
methyl paraben
ethyl paraben
propyl paraben
H 100 H 75 H 50 H 25 F 100
1.7 2.2 2.2 2.7 1.9
1.0 1.0 1.3 1.6 1.9
1.1 0.9 1.5 1.3 1.9
for the fluorinated, the hydrogenated, and the mixed emulsions are summarized in Table 1. In any case, the solubilization of paraben is better in the continuous micellar phase than in the aqueous dispersed phase. It can be observed that partition coefficients of mixed emulsions are slightly higher compared to single fluorinated and hydrogenated systems, the more fluorinated the emulsion the smaller the partition coefficient. Affinity for the micellar continuous phase is greater for propyl than for ethyl and methyl, regardless of the hydrogenated/fluorinated ratio. Partition of model drugs in the different phases of the emulsion is one of the major factors which can influence diffusion. To compare and to explain these experimental results, diffusion coefficients were determined by fitting experimental diffusion curves, obtained from the amount of drug released as a function of time, to simulated curves, obtained by using classical Fick’s diffusion law.11,21 Diffusion coefficients reported take into account the different partition coefficient values for each type of emulsion. As a matter of fact, as the partition coefficient K is different from one molecule to another, the final amount of drug released varies. Therefore, a factor of proportionality is used to free experimental results of the variation of the final concentrations of the probe molecule. In Table 2, the mean values of diffusion coefficients calculated from all the diffusion experiments are summarized. Diffusion coefficient values vary from about 1.0 to 3.0 × 10-10 m2 s-1. Hydrogenated emulsions display the smallest values of diffusion coefficients, while release rate from fluorinated ones is faster for all the probe molecules considered here. In the case of mixed emulsions one can notice that an increase in the fluorinated proportion of the emulsions leads to larger diffusion coefficients and therefore faster release rates. An ANOVA test with a 95% confidence shows that the variation of the diffusion coefficients is significant, despite their close values. For mixed hydrogenated and fluorinated emulsions, one can observe a roughly linear trend of the diffusion coefficients as a function of the amount of hydrogenated compounds in the emulsion (Figure 5) except for the fluorinated methyl paraben emulsion. To check for the possible influence of coalescence on the diffusion coefficients, the stability has been evaluated. Measurement of paraben aqueous solution spontaneously released by gel emulsions allows us to assess stability of (21) Cussler, E. L. Diffusion, Mass transfer in fluid systems; Cambridge University Press: 1984.
Figure 5. Diffusion coefficients as a function of the amount of hydrogenated compounds in the gel-emulsion, result of an ANOVA test with 95% confidence.
Figure 6. Percentage of paraben aqueous solution spontaneously released from gel-emulsions as a function of time, an assessment of the stability of the different kinds of emulsion. Table 3. Stability Evaluation, Percentage of Water Released after 70 h from Gel Emulsions gel emulsion
methyl paraben
ethyl paraben
propyl paraben
H 100 H 75 H 50 H 25 F 100
9.7 1.4 3.5 4.4 0.8
5.5 2.9 3.6 5.9 1.4
10.1 1.9 5.2 4.9 1.5
emulsions, in particular to compare the different compositions (Figure 6 and Table 3). Stability of fluorinated emulsions is the greatest: Only 1% of paraben solution is released. For hydrogenated emulsions the amount of water released is about 10%, showing that hydrogenated emulsion is the less stable. Mixtures have intermediate stability between hydrogenated and fluorinated gel emulsions. However, their stability is quite surprising because the higher the content in hydrogenated emulsion, the more stable the mixture. Discussion The diffusion experiments carried out from gel-emulsion (hydrogenated, fluorinated or mixtures of both kinds of emulsions) loaded with methyl, ethyl, and propyl paraben show significant variations in the release rates. Emulsion composition and molecular structure of the probe molecule are the two main parameters to consider. Concerning variations with the composition of the emulsions, the differences are not large with paraben compared to the dependence found as a function of fluorinated-to-hydrogenated ratio in the case of an other probe molecule,
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Table 4. Partition Coefficients and Diffusion Coefficients for Mandelic Acid (10-10 m2 s-1) gel emulsion
K
D
H 100 H 75 H 50 H 25 F 100
2.1 1.0 0.7 0.7 0.8
1.9 0.8 0.7 0.5 0.2
mandelic acid.13 About the molecular structure, with increasing lipophilic character with the addition of a methylene group to the molecule, the release rate is clearly reduced: the more lipophilic the molecule, the slower the diffusion. All partition coefficients for this family of molecules are much higher than unity. According to the partition coefficients, the fraction of probe molecule in the continuous phase increases from methyl to propyl (0.5-0.88 for fluorinated emulsions and 0.7-0.95 for hydrogenated ones). This implies that the transfer from the interior of the big water droplets to the continuous phase would not be the rate-limiting process. This result is in contrast with our previous study13 with a more hydrophilic molecule (mandelic acid), which has a small partition coefficient of the order of unity (see Table 4) and only a small proportion of the molecule is present in the continuous phase (a fraction lower than 0.1). Solubility of the paraben molecules in the two phases of the emulsion (micellar oily continuous phase and aqueous dispersed phase) varies from methyl to propyl paraben. Increasing lipophilicity of the probe molecule increases the partition coefficient. Following linear saturated hydrocarbons solubility in water, solubility of paraben in water/propandiol follows an exponential law according to the number of carbons of the hydrogenated chain.22 However, the contribution of a CH2 group to solubility is about half for paraben in this mixture what is for classical hydrocarbons in water (200 kJ/mol compared to 400 kJ/mol for classical Tanford’s law22). This trend is the same regardless of the type of the emulsion (hydrogenated, fluorinated, or mixed). The similar behavior could be due to the fact that the aromatic ring interacts favorably with the ethylene oxide group23,24 of the polar heads of both surfactants, and therefore, the probe molecule solubilization follows a similar process for all systems. About emulsion stability, there is no noticeable difference with or without paraben. The most stable system is the fluorinated one, while the most unstable is the hydrogenated one. Intermediate stability is obtained for the mixtures. However the stability does not change smoothly from one extreme to the other. Surprisingly the order of stability of the mixtures is reversed from what can be expected from the relative content of hydrogenated and fluorinated emulsions. This phenomenon has been observed both for mixtures prepared with preformed hydrogenated and fluorinated gel emulsions and for mixtures formed from fluorinated and hydrogenated continuous phase mixtures. The trends obtained for stability are roughly similar to what had been deduced from conductivity measurements performed on gel-emulsions incorporating mandelic acid.13 Fluorinated emulsions are definitively the most stable. The occurring (22) Tanford, C. The hydrophobic effect; Wiley: New York, 1980. (23) Podzimek, M.; Friberg, S. E. J. Dispersion Sci. Technol. 1980, 1, 341-359. (24) Ravey, J. C. In nonionics surfactants in microemulsion; Friberg, S. E., Bothorel, P., Eds.; CRC Press: Cleveland, OH, 1987; pp 93-117.
coalescence is negligible. Stability of hydrogenated and mixed emulsions are on the same order. The lack of linear trend with the amount of hydrogenated compounds in the emulsion could be the result of a modification in the structure of the mixed gel emulsion when the fluorinated compounds are in majority (H 25). Some investigations are in progress to confirm this assertion. If coalescence occurs, some collective movement of matter can result and some direct contact between the water phase and the receptor phase is possible. Nevertheless, slow and reduced coalescence would be expected to occur progressively, being small for short times of diffusion and larger for longer times without changing the structure of the emulsion. As a resume, coalescence effects can be neglected to analyze the behavior of all kinds of gel emulsions toward molecular diffusion. Let us consider, methyl paraben, the molecule with the shortest alkyl chain. Fluorinated emulsions loaded with this molecule are very stable (only 1% of aqueous paraben solution released), and the partition coefficient is rather small (K ) 18). Diffusion of the released molecule, from big water droplets to microemulsion, is limited by its poor affinity for the micellar continuous phase, and since there is almost no coalescence of big droplets during the experiment, methyl paraben stays in the big droplets of the fluorinated emulsion and D is weak (1.7 × 10-10 m2 s-1). Hydrogenated emulsions present a smaller stability (10% of paraben aqueous solution released), and therefore coalescence of the big droplets is in this case more important. In addition the partition coefficient is larger, the affinity of the methyl paraben for the oily micellar continuous phase is enhanced. This can be explained at least in part by favorable interactions between C16E4 and methyl paraben. The diffusion coefficient is small, 1.6 × 10-10 m2 s-1; methyl paraben stays entrapped in the micellar oily phase of the hydrogenated emulsion. Rheological experiments have measured the linear domain of these emulsions: it is characteristic of the reversibility of the system after applying a deformation and gives an idea of the interfacial film resistance. The linear domain is about 10% (% strain) for both kinds of emulsions,25 and thus, differences in the release rates between hydrogenated and fluorinated systems are probably not related to interfacial film mechanical properties. Otherwise molecular interactions between the probe molecule and surfactant are expected. If we consider big droplets covered with surfactant molecules, an easy calculation shows that there is about one molecule of paraben solubilized in water for every two molecules of surfactant, where the surface per polar head is 38 Å2 for hydrogenated surfactants and 28 Å2 for fluorinated surfactants. Therefore interaction effects have to be taken into account. For mixed emulsions, if we consider that the continuous phase is constituted from mixed micelles (similar polar heads for both surfactants14,15), one can assume that paraben molecules act as a cosurfactant adsorbing at the interfaces both of the emulsion and of the microemulsion, and so favor interactions between fluorinated and hydrogenated tails. The more hydrogenated the emulsion, the stronger the interactions between hydrogenated surfactant and released molecule. Hence transfer through the interfaces would be limited. This increase of the favorable interactions is in agreement with the decrease of the diffusion coefficients from H 25 to H 75 (from 2.7 × 10-10 m2 s-1 for H 25 to 2.2 × 10-10 m2 s-1 for H 75). (25) Langenfeld, A.; Lequeux, F.; Ste´be´, M. J.; Schmitt, V. Langmuir, in press.
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molecule). When K is small (especially lower than unity), the first phenomenon is the bottleneck for diffusion. However, if K values are big, the second phenomenon controls the diffusion rate. Release rates to the receptor are then fixed by the transfer between dispersed aqueous phase and external oily micellar phase.
Figure 7. Two possible steps of the diffusion of a model molecule through the gel-emulsion (a) and (b). See text.
Concerning experiments with ethyl and propyl paraben, diffusion coefficients given by the experimental curves decrease when the proportion of the hydrogenated emulsion in the gel increases. With increase of the hydrogenated tail from methyl to propyl, the amphiphilic behavior is enhanced. The molecule acts as a cosurfactant as in the case of methyl but more efficiently. The release rate is reduced (D ) 1.1 × 10-10 and 1.0 × 10-10 m2 s-1 for ethyl and propyl compared to 1.7 × 10-10 m2 s-1 for methyl); the probe molecules stay entrapped in the interfacial film. Diffusion experiments obtained with emulsions loaded with mandelic acid13 show that partition coefficient is one of the major factors. This thermodynamic parameter sets the proportions of the molecule in the two phases of the emulsions and fixes the initial and final equilibrium states. For high partition coefficient (paraben) the rate of diffusion would be mainly governed by the diffusion coefficient in the micellar continuous phase. However, for small K values, and particularly K < 1 (fluorinated emulsion loaded with mandelic acid), a large amount of the probe molecule is in big droplets and stays entrapped, diffusing slowly through the interfaces. As a summary diffusion through these gel-emulsions involves two different steps as depicted in Figure 7: (i) The first step is transfer of the probe molecule from the big water droplets to the microemulsion. Big droplets act as a reservoir of releasing molecule (Figure 7a). (ii) The next step is transfer from microemulsion to the receptor phase (Figure 7b). This process is controlled by interactions between the active molecule and the surfactant; it varies for each system (amount of hydrogenated and fluorinated surfactant, molecular structure of the probe
Conclusion From our results it has been shown that reverse highly concentrated water in oil emulsions prepared from hydrogenated and/or fluorinated compounds could be new drug delivery systems. The partition coefficient of a probe molecule has a major influence on its release from gelemulsions. Low partition coefficients allow the probe molecules to be enclosed in the big water droplets, and their diffusion is then controlled both by the pass through the interfaces as well as by the transport through the continuous phase of the emulsion. A high partition coefficient implies a high presence of the probe molecule in the continuous phase of the emulsion. In this situation the interfaces of the big droplets play a secondary role and the main contribution seems to be the transport through the continuous phase of the gel-emulsion. The stability of mixtures of hydrogenated and fluorinated emulsions is intermediate between that of the fluorinated and hydrogenated systems, depending on interactions between the hydrocarbon/fluorocarbon and the probe molecule. We have shown that the stability of these peculiar systems does not play a major role in the molecular diffusion. The probe molecule could act in some cases as a cosurfactant and thus reduce the unfavorable fluorocarbon/hydrocarbon interactions. Mixed emulsions are very promising from a practical point of view. These gel-emulsions, with high water content, can entrap model drugs which are dissolved in water. With different ratios of fluorinated and hydrogenated compounds, it seems possible to modify release rates and thus to control release of drugs. These experimental results have to be complemented by structural studies to get an insight of the continuous phase of these mixed emulsions. Are fluorocarbons and hydrocarbons solubilized by hydrogenated and fluorinated mixed micelles? Once the structure of these mixed systems is learned, the mechanism of the drug release will be easier to explain and the control of the release rate will certainly be improved. Acknowledgment. We thank Claude Selve and Ste´phane Muller for the helpful discussions about the probe molecules and the determination of the diffusion coefficients, respectively. LA9800856
