Research paper
Enhanced oral bioavailability of dexibuprofen by a novel solid Self-emulsifying drug delivery system (SEDDS)

https://doi.org/10.1016/j.ejpb.2009.03.001Get rights and content

Abstract

The main objective of this study was to prepare a solid form of lipid-based self-emulsifying drug delivery system (SEDDS) by spray drying liquid SEDDS with an inert solid carrier Aerosil 200 to improve the oral bioavailability of poorly water-soluble drug dexibuprofen. The liquid SEDDS was a system that consisted of dexibuprofen, Labrasol, Capryol 90 and Labrafil M 1944 CS. The particle size analysis revealed no difference in the z-average particle diameter of the reconstituted emulsion between liquid and solid SEDDS. The solid SEDDS was characterized by SEM, DSC and XRD studies. In vivo results of solid SEDDS and dexibuprofen powder in rats at the dose of 10 mg/kg showed that the initial plasma concentrations of drug in solid SEDDS were significantly higher than those of dexibuprofen powder (P < 0.05). The solid SEDDS gave significantly higher AUC and Cmax than did dexibuprofen powder (P < 0.05). In particular, the AUC of solid SEDDS was about twofold higher than that of dexibuprofen powder. Our results suggested that this solid SEDDS could be used as an effective oral solid dosage form to improve the bioavailability of poorly water-soluble drug dexibuprofen.

Introduction

Dexibuprofen, S(+)-ibuprofen is a pharmacologically active form and is more potent than ibuprofen, which has equal quantities of R(−)- and S(+)-enantiomers [1]. On the rationale basis that a fraction of the dose of R(−)-ibuprofen undergoes “metabolic inversion” to an extent of 57–69% to yield S(+)-ibuprofen, it has been argued that a dose of 1:0.75 (rac-ibuprofen vs. dexibuprofen) would be needed to obtain comparable pharmacodynamic effects [2]. Therefore, the use of pure dexibuprofen may show distinct advantages. The effectiveness of dexibuprofen as an anti-inflammatory and analgesic agent was discounted like ibuprofen, due to its poor water solubility and low bioavailability after oral administration [3]. However, there were no reported studies on the enhancement of solubility and bioavailability of dexibuprofen. Instead, numerous studies were reported on ibuprofen [4], [5], [6].

In recent years much attention has been focused on lipid-microemulsion formulations with particular emphasis on self-microemulsifying or self-emulsifying drug delivery systems to improve oral bioavailability of poorly water-soluble drugs [7]. It was reported that the percentage release of biphenyl dimethyl dicarboxylate from SMEDDS was >12-fold higher than that from the tablet containing the drug [8]. A few other studies have reported of an enhancement in the bioavailability of poorly soluble drugs when formulated as SEDDS [7], [9]. However, there exist a few limitations associated with this delivery system, including stability, manufacturing methods, interaction of the fill with the capsule shell, and storage temperature [10]. When the product is stored at a lower temperature, there may be some precipitation of the active ingredient and/or the excipients. The precipitated materials should therefore be dissolved again when warmed to room temperature; otherwise the drug will not be presented in a solution or as a fine emulsion droplet [11]. Moreover it has been suggested that the efficiency of the SEDDS or SMEDDS formulation is drug dependent in most instances [12]. Thus, the successful composition of the SEDDS or SMEDDS should be carefully explored.

Even though the researches focused on solid SEDDS area were increasing, very few publications were available for such attempts [13], [14], [15]. These solid SEDDS were almost prepared by extrusion/spheronization method or wet granulation in a high shear mixer. Recently, spray drying has been employed to prepare solid SMEDDS using dextran 40 as a water-soluble solid carrier by spray drying method [16]. However, in this study we intend to prepare solid SEDDS by spray drying liquid SEDDS with an inert solid carrier Aerosil 200. The objectives of the present study were therefore: (1) to develop a novel solid SEDDS of dexibuprofen by spray drying, using Aerosil 200 as an inert solid carrier. Reconstitution properties of the spray-dried powders were investigated and correlated to solid state characterization of the powders performed by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction; (2) to determine whether the powder SEDDS maintained the absorption characteristics, a comparative bioavailability study was performed in rats with the solid SEDDS and dexibuprofen powder. Composition of SEDDS was optimized using solubility, phase diagram, particle size and drug release studies.

Section snippets

Materials

Dexibuprofen was provided by Enzychem Co. (Seoul, South Korea). Polyglycolyzed glycerides (Capryol 90, Labrafac CC, Labrafac Lipophile WL 1349, Labrasol, Labrafil M 1944 CS, Labrafil M 2125 CS, Lauroglycol FCC, Peceol and Transcutol P) were obtained from Gattefosse (Saint-Priest Cedex, France). Castor oil, corn oil, cotton seed oil, sesame oil, soybean oil, sunflower oil and peanut oil were supplied by Sigma (St. Louis, USA). Span 20, Span 80, Tween 20 and Tween 80 were purchased from DC

Solubility study

The self-emulsifying formulations consisted of oil, surfactants, cosurfactants and drug should be a clear and monophasic liquid at ambient temperature when introduced to aqueous phase and should have good solvent properties to allow presentation of the drug in solution. The solubility of dexibuprofen in various vehicles is presented in Table 1. All the surfactants showed good solubility of the drug. Among the surfactants tested in this study, Labrasol, a medium-length alkyl chain surfactant

Conclusion

In this study, the solid SEDDS of dexibuprofen was prepared by spray drying, using water-insoluble Aerosil 200 as a solid carrier. The solid SEDDS consisted of well-separated particles with smooth surface and preserved the self-emulsification performance of the liquid SEDDS. Both DSC measurements and X-ray diffraction analysis suggested that dexibuprofen in the solid SEDDS may be in the molecular dispersion state. In vitro dissolution test showed that the solid SEDDS had a faster in vitro

Acknowledgements

This research was supported by the Grant No. RTI04-01-04 from the Regional Technology Innovation Program of the Ministry of Knowledge Economy (MKE) and was financially supported by the Ministry of Science and Technology (M10414030001-05N1403-00140) in South Korea.

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