Enhanced bioavailability and retinal accumulation of lutein from self-emulsifying phospholipid suspension (SEPS)

https://doi.org/10.1016/j.ijpharm.2011.04.015Get rights and content

Abstract

Ability of any formulation to keep the drug in solubilized form in vivo is essential for bioavailability (BA) enhancement rather than the solubility of drug in the formulation vehicle/matrix itself. Besides, utilization of an excess amount of surfactants/co-surfactants to solubilize the drug in the lipid formulation poses potential pharmaceutical as well as health problems. To address this problem, self-emulsifying phospholipid suspension (SEPS) consisting of high amount of phospholipid (an endogenous lipid with efficient in vivo emulsification capability) and relatively low amount of surfactant/co-surfactant has been proposed to enhance the bioavailability (BA) of lutein. In this study, the ability of SEPS formulation to enhance the BA of lutein was assessed from three SEPS formulations with various amounts of phospholipid (SEPS-0, SEPS-I, and SEPS-II with 0 mg, 250 mg, and 500 mg of Phosal® 53 MCT, respectively) in beagle dogs following a single oral administration of lutein equivalent to 100 mg, and were compared with commercial formulation (CF). In addition, the retinal accumulation of lutein in Sprague Dawley (SD) rats’ eyes from SEPS-II formulation (lutein dose of 100 mg/kg/day) was investigated following single daily oral administration for a period of 14 days. CF and placebo (vegetable oil without lutein) were also administered for the same period of time and were compared with the SEPS-II formulation. In the relative BA study in beagle dogs, no significant differences were observed between the pharmacokinetic (PK) parameters of formulation SEPS-O and CF. However, the Cmax in comparison to CF was 3.70 folds and 11.76 folds higher for SEPS-I and SEPS-II, respectively. Relative BA compared to CF was 178.88% and 473.13% for SEPS-I and SEPS-II, respectively. The retinal lutein accumulation was 0.91 ± 0.31 ng/g, 3.45 ± 1.63 ng/g, and 14.72 ± 2.02 ng/g for placebo, CF, and SEPS-II, respectively. This enhancement was about 16.1 folds and 4.27 folds compared to placebo and CF, respectively. The relative BA study in dogs and retinal accumulation study in rats demonstrated the excellent ability of SEPS to enhance the BA of lutein. For this reason, SEPS containing lutein could be a promising lipid based delivery system for the prevention of ocular diseases.

Introduction

Lutein (Fig. 1) is one among 600 carotenoids that has been gaining huge attention lately because of its ability to prevent ocular diseases including age-related macular degeneration (AMD) and cataracts (Hankinson et al., 1992, Brown et al., 1999, Chasan-Taber et al., 1999, Lyle et al., 1999, Berendschot et al., 2000, Gale et al., 2001, Bone et al., 2001, Bone et al., 2003). Although lutein is a vital macular component, it is not synthesized in the body and therefore dietary ingestion is the only source for the supplementation (Amar et al., 2003, Johnson, 2004). Bioavailability (BA) of lutein is extremely variable due to the inherently poor aqueous solubility (0.732 μg/ml) and also depends on the nature of vehicle (Handelman et al., 1999, Surai et al., 2000). Besides, lutein shows increased absorption in the presence of lipids and therefore is considered as a potential candidate for lipid based oral drug delivery system (LBODDS) (Chakraborty et al., 2009).

LBODDS, that utilizes lipids as a carrier for poorly water soluble compounds, is one of the promising methods for enhancing BA of highly lipophilic compounds through enhanced dissolution and selective lymphatic uptake (Pouton, 2006). One of the most popular and commercially viable formulation approaches among LBODDS is self emulsifying drug delivery systems (SEDDS) (Nazzal et al., 2002, Wang et al., 2009). Although traditional method of preparation of SEDDS involves solubilization of drugs in oils and surfactants/co-surfactants, some compounds impose solubility problems in both water as well as lipids and are difficult to solubilize even in lipid vehicles. Solubilization of such compounds requires huge amount of surfactants/co-surfactants and presents potential drawback of possible precipitation or recrystallization upon storage, and possible gastrointestinal (GI) irritation in vivo (Nazzal et al., 2002, Pouton, 2006, Chakraborty et al., 2009, Balakrishnan et al., 2009, Wang et al., 2009).

It has been reported that the ability of any lipid formulation to keep the drug in solubilized form after dilution in the GI tract is critical for BA enhancement rather than solubility of the drug in the formulation vehicle itself (Nazzal et al., 2002, Pouton, 2006, Chakraborty et al., 2009, Wang et al., 2009). Lipid excipients are able to solubilize hydrophobic drugs within the dosage form matrix, however their solubilization capacity might be lost due to three Ds viz., dispersion, dilution, and digestion in GI tract (Chakraborty et al., 2009). Therefore, necessity of new lipid vehicles that could withstand three Ds of GI tract for enhanced BA of highly lipophilic drugs such as lutein has been gaining much momentum lately.

Phosphatidylcholine (PC), a phospholipid primarily presents in bile secretion, undergoes natural process of digestion and is converted into lyso-phosphatidylcholine (LPC) by phospholipase in GI tract. Both PC and LPC are efficient emulsifiers and present the drug in solubilized form in GI tract, and eventually enhance the uptake of lutein by intestinal cells (Sugawara et al., 2001, Baskaran et al., 2003, Yonekura and Nagao, 2007). Besides, PCs enhance the BA through selective lymphatic delivery by assisting in chylomicron formation. Recent reports indicate that the BA of lutein from egg yolk is relatively higher than from other lutein-rich vegetable sources even though the amount of lutein is considerably less than other sources. This enhanced BA of lutein from egg yolk was apparently due to the presence of PC in egg yolk (egg contains high amount of PC and little amount of lutein) (Handelman et al., 1999, Surai et al., 2000). Eventually, self-emulsifying phospholipid suspension (SEPS) consisting of high amount of phospholipid and relatively low amount of surfactant/co-surfactant has been proposed to enhance the bioavailability (BA) of lutein.

In this study, the ability of SEPS to enhance the BA of lutein was assessed from three SEPS formulations with various amounts of phospholipid (SEPS-0, SEPS-I, and SEPS-II with 0 mg, 250 mg, and 500 mg of Phosal® 53 MCT, respectively) in beagle dogs following a single oral administration of lutein equivalent to 100 mg, and were compared with commercial formulation (CF). In addition, the retinal accumulation of lutein in Sprague Dawley (SD) rats’ eyes from SEPS-II formulation was investigated following a single daily oral administration of lutein equivalent to 100 mg/kg for a period of 14 days (Fig. 2). CF and placebo (vegetable oil without lutein) were also administered for the same period of time and were compared with the SEPS-II formulation.

Section snippets

Materials

The following materials were purchased from various companies and then used as received. Lutein 40% extract in sunflower oil (INABATA, Japan) was purchased and used without further purification. Phosal® 53 MCT was purchased from Phospholipid GmBH (Cologne, Germany). Propylene glycol monocaprylate (Capryol™ PGMC) was purchased from Gattefossé (Saint-Priest Cedex, France). Polysorbate 80 (Tween 80), ascorbic acid, glycerin, and d-α-tocopherol were obtained from Sigma Chemicals Co. Ltd. (St.

Results and discussion

One of the primary challenges to any oral formulation is maintaining drug solubility within the gastrointestinal tract (O’Driscoll and Griffin, 2008, Kohli et al., 2010). For poorly water soluble lipophilic compounds that exhibit dissolution-rate-limited absorption, SEDDS can offer an improvement in rate and extent of absorption. However, poorly water-soluble compounds, which are generally classified as lipophilic, behave differently in similar kind of vehicles and therefore, demanding the need

Conclusion

Proper selection of lipid excipients is critical to an efficient lipid based drug delivery formulations. In this study, we evaluated the feasibility of SEPS as a lipid delivery system to enhance the BA of lutein, and found that SEPS enhanced the lutein BA in dogs and accumulation in retina of the eyes in rats. Both relative BA and retinal accumulation of lutein from the phospholipid formulation, SEPS-II was more than 400% in comparison to commercial formulation (CF). It could be concluded that

Conflict of interest

Authors have no conflict of interest.

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