Pharmaceutical NanotechnologyPhysicochemical and pharmacological characterization of α-tocopherol-loaded nano-emulsion system
Introduction
Vitamin E is an essential nutrient derived from various crops, such as barley, wheat, and soybean (Hakkarainen et al., 1984, Hall and Laidman, 1968, Ito et al., 2007). Vitamin E has several isomers, including α-, β-, γ-, and δ-tocopherols (Leth and Sondergaard, 1977), the activity and bioavailability of which vary depending on their structures and physicochemical properties. Among these isomers, d-α-tocopherol (α-TC) has the highest bioactivity, and its oral bioavailability is also higher than other vitamin E series (Hidiroglou and Karpinski, 1988). The α-TC prevents oxidative damage and lipid peroxidation in central and peripheral nervous systems (Scholz et al., 1997, Teranishi et al., 2001, Terrasa et al., 2009). Because of its promising therapeutic potential and safety, α-TC has been widely used as a functional food, in food additives, and cosmetics, as well as drugs (Biesalski, 2009, Jialal and Devaraj, 2005, Krol et al., 2000). However, the bioavailability of α-TC is not high enough and is sometimes affected by factors such as food consumption, lipid digestion, and micelle formation (Lodge et al., 2004, Sokol et al., 1989). Lower endogenous antioxidants with elevated lipid peroxidation levels have been identified as significant risk factors for oxidative stress-related diseases and diabetic complications (Baynes, 1991, Doi et al., 2001, Giugliano et al., 1996). Therefore, the development of α-TC formulations with improved bioavailability and pharmacodynamics might be a key consideration for the treatment of systemic oxidative stress.
Recently, attention has been drawn to nanoencapsulated systems (Mora-Huertas et al., 2010), showing high intracellular uptake, and improved stability and solubility of active substances. In particular, liquid nano-emulsion (NE) formulations have been used for the solubilization of poorly water-soluble drugs (Mora-Huertas et al., 2010, Shakeel and Faisal, 2010). NE strategies are often applied to lipophilic drugs, such as paclitaxel (Khandavilli and Panchagnula, 2007), primaquine (Singh and Vingkar, 2008), and saquinavir (Vyas et al., 2008). In addition to pharmaceutical substances, nano-emulsification of highly lipophilic neutraceuticals has been attempted in the production of beverages and liquid/gel foods (Boon et al., 2008, McClements et al., 2007). Previously, our group also developed a novel NE formulation of coenzyme Q10 using high-pressure homogenization (Hatanaka et al., 2008), and the NE formulation exhibited rapid and stable dispersion in water and improved oral bioavailability in rats. Thus, emulsifying techniques have been applied to a number of neutraceuticals, and the NE formulation approach might also be a promising delivery option for α-TC, possibly leading to improved clinical outcomes.
The main purpose of the present study was to develop a novel nano-emulsified formulation of α-TC with the aim of increasing pharmacokinetic and pharmacodynamics. In the present study, several liquid formulations of α-TC were prepared by a mechanochemical method. The physicochemical properties of the novel formulations were characterized with a focus on droplet size, zeta-potential, stability, and morphology. Pharmacokinetic profiling of α-TC after oral administration of NE formulation of α-TC or α-TC suspension in rats was carried out for comparison. In addition, experimental diabetic rats were prepared by intravenous administration of streptozotocin, and the anti-oxidative properties of newly developed NE formulation were evaluated in the diabetic rats.
Section snippets
Chemicals
α-Tocopherol was purchased from MP Biomedicals (Solon, USA), medium chain triglyceride (MCT) was from Kao Corporation (Tokyo, Japan), decaglyceryl monooleate were from Taiyo Kagaku Co., Ltd. (Mie, Japan), soybean lecithin was from Kyowa Hakko Kogyo Co., Ltd. (Tokyo, Japan), glycerol was from Sakamoto Yakuhin Kogyo Co., Ltd. (Osaka, Japan), and storeptozotosin (STZ) was from Sigma Chemical Company (St. Louis, MO, USA).
Preparation of α-TC-loaded NE formulations
NE formulations, NE-1–3, listed in Table 1, were prepared using a
Preparation and characterization of α-TC-loaded NE formulations
In the present study, α-TC-loaded NE formulations were prepared by a mechanochemical method using a homomixer and microfluidizer. These NE formulations were composed of decaglyceryl monooleate and soybean lecithin as an emulsifier, MCT as an oil medium, and glycerol and water as aqueous media (NE-1–3; Table 1). NE formulations, containing 10% (w/w) and 30% (w/w) of α-TC, could be processed by a microfluidizer with ease. In contrast, NE-3, containing 50% (w/w) of α-TC, could be emulsified by
Conclusion
In the present study, NE formulations, loading 10–50% of α-TC (w/w), were prepared using a mechanochemical method, and they were easily dispersed into water, forming nano-sized emulsion with a diameter of ca 80–400 nm. A stability study demonstrated that water-dispersed NE-1, containing 10% of α-TC, was the most stable in these formulations. After oral administration of NE-1 in rats, there appeared to be a 2.6-fold increase of systemic exposure of α-TC compared with the control mixture, an oil
Acknowledgements
The authors are grateful to Ms. Miki Kikuchi, Mr. Hirokazu Wakuda, and Ms. Yukiko Shinme, University of Shizuoka, for their excellent assistance throughout the work.
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