The effect of internal structure of selected water–Tween 40®–Imwitor 308®–IPM microemulsions on ketoprofene release

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Abstract

Microemulsions are a promising vehicle for administrating drugs. In order to lay the basis for predicting drug release under in vivo conditions, where the microemulsion composition is continuously varying, we have studied the release of ketoprofene as a model drug, from microemulsions on a dilution line containing, initially, 20 wt.% of isopropyl miristate (IPM) and 80 wt.% of the surfactant (Tween 40®)/co-surfactant (Imwitor 308®), 1:1 wt.% mixture. Mixture compositions corresponding to the different types and structure of microemulsion were identified by measuring density, surface tension, electric conductivity, pH and differential scanning calorimetry. Ketoprofene release was then measured for each type and structure. The main factor influencing ketoprofene release was shown to be the strength of the interactions between microemulsion components. Strong interactions prevented rapid ketoprofene release in the water-in oil region, although the release was not dependent on the degree of percolation. Release kinetics in all cases follow zero order kinetics, indicating that the release rate is dependent on the diffusion of ketoprofene inside the microemulsion carrier. Combining different methods to obtain the physical and structural properties of microemulsions can be thus used to predict the release of ketoprofen from a microemulsion.

Introduction

Colloidal drug delivery systems are important as a means of improving the bioavailability of drugs. Microemulsions are dispersions of oil and water stabilized with a surface active film composed of surfactant and cosurfactant, and are of special interest in this context because of their spontaneous formation, thermodynamic stability and optical transparency (Tenjarla, 1999, Bagwe et al., 2001).

In contrast to the easy preparation of microemulsions, however, it is a far from trivial matter to characterize their microstructure. Due to the low interfacial tension between oil and water, a wide range of microemulsion structures is possible. At low water content elongated, rod-like micelles are observed, but water in oil (W/O) spherical droplets, as in classical emulsions but smaller, are also present. In the water rich region, O/W droplets are the most frequent form. In microemulsions with more similar contents of water and oil, bicontinuous structures are formed. Droplets begin to interconnect with several “bridges”, described as the percolation phenomenon. When large amounts of surfactants are present, lamellar phases are sometimes observed, which substantially increase the viscosity of the microemulsion. Microemulsions are thermodynamically stable, however their microstructure in the bicontinuous region is continuously changing, complicating structure determination. Using a number of different methods however, such as differential scanning calorimetry (DSC), electric conductivity, density and surface tension, it is possible to characterise the internal structure of the microemulsion (Podlogar et al., 2004). Authors also report that DSC enables the state of water in microemulsion systems to be determined (Garti et al., 1996, Garti et al., 2000, Garti, 2001, Schulz, 1998, Erzahi et al., 2001). Information about the phenomenon of percolation in the system can be obtained by measuring transport and volumetric properties (Eicke et al., 1989, Boned et al., 1993, D’Aprano et al., 1993, Camett et al., 1995, Giustini et al., 1996, Meier, 1996, Sheu, 1996, Weigert et al., 1997, Testard and Zemb, 2000). We showed (Podlogar et al., 2004) that, by comparing these experimental methods it is possible to determine the type and internal structure of the microemulsion, although it is best if we compare results from different samples relatively.

When a microemulsion is introduced into a physiological environment it sooner or later becomes diluted with aqueous medium, resulting in changes in the structure of the microemulsion. It is therefore reasonable to characterise microemulsion samples on the same dilution line. This is most useful if the microemulsion is intended for peroral use. If a microemulsion is intended for topical use, dilution is lower, however, determining the microstructure could enable the release rate of a drug to be predicted. The variety of possible structures means that microemulsions would be expected to release a drug at different rates. In O/W microemulsion, hydrophobic drugs, solubilized mainly in the oil droplets, exhibit hindered diffusion and are therefore released rather slowly. The diffusion of water-soluble drugs, on the other hand, is less restrained. The reverse behaviour is expected in W/O microemulsions. However, diffusion also depends strongly on the oil/water partitioning of the drug and on the pH of the water phase. If pH of the water phase lowers the partitioning coefficient, hydrophobic drugs could be released rapidly from O/W microemulsions. Therefore, the relation between composition, internal microstructure and pH of the water phase of the microemulsion is essential to predict drug release rate from microemulsions.

In order to lay the basis for predicting drug release under in vivo conditions, where the microemulsion composition is continuously varying, we have studied the release of ketoprofene from microemulsions of various compositions on a dilution line with constant ratio of surfactant mixture and IPM to 4:1, whose structures have been determined by physical techniques. Correlations have then been sought between structure and drug release.

Section snippets

Materials

Isopropyl myristate (IPM) was obtained from Fluka Chemie GmbH, Switzerland, and was used as the lipophilic phase. Tween 40® (TW40)—polyoxyethylene (20) sorbitan monopalmitate (Fluka chemie GmbH, Switzerland) was used as surfactant and Imwitor® 308 (IMW)—glyceryl caprylate (Condea Chemie GmbH, Germany) as cosurfactant. Twice distilled water was used as the hydrophilic phase. Ketoprofene was obtained from Lek d.d., Slovenia.

Preparation of the microemulsion carrier system

The surfactant and cosurfactant were blended in a 1:1 mass ratio to give

Results and discussion

In our previous work the disadvantages of microemulsions for pharmaceutical use that contain large amounts of surfactants was discussed shortly (Podlogar et al., 2004). However, often there is no other way to obtain stable microemulsion systems, especially when a broad quantitative composition range should be under investigation. In this study a dilution line was chosen starting with 20 wt.% of isopropyl miristate (IPM) and 80 wt.% of the 1:1 surfactant (Tween 40®)/co-surfactant (Imwitor 308®)

Conclusion

At the selected dilution line we can conclude that a microemulsion containing less than ∼20 wt.% water is expected to be oil continuous; however, surfactants, because of their large amount, are also present in the continuous phase. A microemulsion containing between 20 and 40 wt.% water will be water as well as oil continuous–bicontinuous microemulsions. Finally, a microemulsion containing more than 40 wt.% water is expected to be O/W. When more than 45 wt.% water is present in the system the

Acknowledgements

The authors thank Prof. Werner Kunz and Dr. Didier Touraud from the Institute of Physical and Theoretical Chemistry, University of Regensburg, Germany, for their helpful suggestions and valuable discussion.

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