Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment

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Abstract

The goals of our investigations are to develop and characterize self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10 (CoQ10), using polyglycolyzed glycerides (PGG) as emulsifiers and to evaluate their bioavailability in dogs. Solubility of CoQ10 was determined in various oils and surfactants. SEDDS consisted of oil, a surfactant and a cosurfactant. Four types of self-emulsifying formulations were prepared using two oils (Myvacet 9-45 and Captex-200), two emulsifiers (Labrafac CM-10 and Labrasol) and a cosurfactant (lauroglycol). In all the formulations, the level of CoQ10 was fixed at 5.66% w/w of the vehicle. The in vitro self-emulsification properties and droplet size analysis of these formulations upon their addition to water under mild agitation conditions were studied. Pseudo-ternary phase diagrams were constructed identifying the efficient self-emulsification region. From these studies, an optimized formulation was selected and its bioavailability was compared with a powder formulation in dogs. Medium chain oils and Myvacet 9-45 provided higher solubility than long chain oils. Efficient and better self-emulsification processes were observed for the systems containing Labrafac CM-10 than formulations containing Labrasol. Addition of a cosurfactant improved the spontaneity of self-emulsification. From these studies, an optimized formulation consisting of Myvacet 9-45 (40%), Labrasol (50%) and lauroglycol (10%) was selected for its bioavailability assessment. A two-fold increase in the bioavailability was observed for the self-emulsifying system compared to a powder formulation. SEDDS have improved the bioavailability of CoQ10 significantly. The data suggest the potential use of SEDDS to provide an efficient way of improving oral absorption of lipophilic drugs.

Introduction

Approximately 40% of new drug candidates have poor water solubility and the oral delivery of such drugs is frequently associated with implications of low bioavailability, high intra- and inter subject variability, and lack of dose proportionality (Robinson, 1996). To overcome these problems, various formulation strategies are reported in the literature including the use of surfactants, cyclodextrins, nanoparticles, solid dispersions, micronization, lipids, and permeation enhancers (Aungst, 1993, Robinson, 1996). These approaches are successful in selected cases. In recent years much attention has been focused on lipid-based formulations (Humberstone and Charman, 1997) with particular emphasis on self-emulsifying drug delivery systems (SEDDS) to improve oral bioavailability of lipophilic drugs (Constantinides, 1985, Pouton, 1997). SEDDS are isotropic mixtures of an oil, surfactant, cosurfactant and drug. They form fine oil-in-water emulsions when introduced into aqueous media under mild agitation. The digestive motility of the stomach and intestine provide the agitation necessary for self-emulsification in vivo (Shah et al., 1994). Factors controlling the in vivo performance of SEDDS include their ability to form small droplets of oil (<5μ) and the polarity of the oil droplets to promote faster drug release into aqueous phase (Shah et al., 1994). The smaller oil droplets provide a large interfacial area for pancreatic lipase to hydrolyze triglycerides and thereby promote the rapid release of the drug and/or formation of mixed micelles of the bile salts containing the drug (Tarr and Yalkowsky, 1989). The surfactants used in these formulations are known to improve the bioavailability by various mechanisms including: (a) improved drug dissolution (Constantinides, 1985); (b) increased intestinal epithelial permeability (Swenson and Curatolo, 1992); (c) increased tight junction permeability (Lindmark et al., 1995); and (d) decreased/inhibited p-glycoprotein drug efflux (Nerurkar et al., 1996, Nerurkar et al., 1997, Lo et al., 1998, Yu et al., 1999). Recently Shah et al. (1994) have reported a three-fold increase in the bioavailability of a poorly soluble compound when formulated as SEDDS. A marketed formulation of cyclosporine (Sandimmune Neoral®), a microemulsion preconcentrate with self-emulsifying properties, is reported to improve oral bioavailability and reduce inter- and intra subject variability in cyclosporine pharmacokinetics (Friman and Backman, 1996). A few other studies have reported enhancement in the bioavailability of poorly soluble drugs when formulated as SEDDS (Lin et al., 1991, Charman et al., 1992, Klem et al., 1993, Matuszewska et al., 1996, Hauss et al., 1998).

Coenzyme Q10 (CoQ10) also known as ubidecarenone (Fig. 1) is a lipid soluble compound that inhabits the inside of the inner mitochondrial membrane, where it functions as an integral part of electron transport of oxidative phosphorylation (Folkers et al., 1986). It is used as an antioxidant and also in the treatment of cardiovascular disorders such as angina pectoris, hypertension, and congestive heart failure (Greenberg and Fishman, 1990). CoQ10, a yellow colored crystalline powder with a melting point of 48°C, is practically insoluble in water and poorly absorbed from the gastrointestinal tract. The slow absorption of CoQ10 (Tmax 5–10 h) from the gastrointestinal tract was attributed to its high molecular weight and poor water solubility (Greenberg and Fishman, 1990). Oil based and powder filled capsule formulations are currently available on the market as nutritional supplements. However, oral bioavailability of these formulations differs widely (Kishi et al., 1984). Recently, we have reported that a simple oil-based formulation of CoQ10 did not significantly enhance bioavailability when compared to that of powder filled capsule formulation (Kommuru et al., 1999). SEDDS are sought to enhance the oral delivery of CoQ10. For selecting a suitable self-emulsifying vehicle, it is important to assess: (a) the drug solubility in various components; (b) the area of self-emulsifying region in the phase diagram; and (c) droplet size distribution following self-emulsification. The objectives of the present study were to develop and characterize SEDDS of CoQ10 using polyglycolyzed glycerides as surfactants and to assess their bioavailability in coonhounds.

Section snippets

Materials

CoQ10 and triglyceride oils (peanut, soybean and corn) were purchased from Spectrum Chemicals (Gardena, CA). Polyglycolyzed glycerides (Labrafac CM-10 CM-10, Labrasol, Labrafill M -1944CS, Plurol olique and Lauroglycol) were obtained from Gattefosse (Westwood, NJ). Captex-200 was obtained from Abitec Corp. (Columbus, OH) and Neobee M-5 was obtained from Stepan Co (Maywood, NJ). The internal standard CoQ9 was kindly supplied by Eisai Co. (Tokyo, Japan). Sep-Pak silica (100 mg) solid phase

Solubility studies

The self-emulsifying formulations consisted of one or more surfactants and drug dissolved in oil. The mixture should be a clear, monophasic liquid at ambient temperature, and should have good solvent properties to allow presentation of the drug in solution. The solubilities of CoQ10 in various surfactants and oils are presented in Table 3. These components are soluble in each other and form homogenous liquids. Medium chain fatty acid glycerides and Myvacet 9-45 provided higher solubility than

Discussion

Lipid based formulations including self-emulsifying formulations offer the potential for enhancing the absorption of poorly soluble and/or poorly permeable compounds. In addition to several patents (Hauer et al., 1994, Lacy and Embleton, 1997, Cho et al., 1998, Al-Razzak et al., 1999), there are a few commercial examples of these formulations, which include cyclosporine, ritonavir saquinavir and amprenavir (Roman, 1999). However, there exist a few limitations associated with these formulations,

Acknowledgements

The authors would like to thank Laurie Waczula at Eurand America, Inc. for her help in droplet size analysis.

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    Present address: Eurand America, Inc., Research & Development, 845 Center Drive, Vandalia, OH-45377, USA.

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