Vitamin E TPGS and its applications in nutraceuticals
Introduction
Vitamin E TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate) is a water-soluble derivative of the naturally occurring d-α-tocopherol. Its polar hydrophilic head (polyethylene glycol 1000) and lipophilic tail (phytyl chain of d-α-tocopherol) provide amphiphilic properties. As an amphiphile, it is an emulsifier of lipids and helps solubilize poorly soluble compounds. In addition, it has been shown to form micelle-like particles and affect the absorption mechanism, resulting in increased absorption and bioavailability (Wu and Hopkins, 1999).
Vitamin E TPGS was initially used to overcome severe malabsorption and correct vitamin E deficiency in cholestatic children (Sokol et al., 1987). The observation that vitamin E TPGS increased the absorption of vitamin D in cholestatic children (Argao et al., 1992) provided impetus for further research on its role in increasing the solubility and absorption of lipophilic and poorly soluble compounds. Significant research and clinical evidence, including major multilocation human clinical trials, have evaluated its safety (Krasavage and Terhaar, 1977; NCI National Cancer Institute, 1994a,b; Zondlo Fiume, 2002; EFSA, 2007) and efficacy, leading to commercial applications. Its first application in pharmaceuticals was the formulation of cyclosporin (Sokol et al., 1991) and was followed by other drugs approved by the Food and Drug Administration (FDA), the European Medicines Agency, and other international regulatory agencies.
Vitamin E TPGS also has been used in the formulation of disease-specific nutritional products for conditions associated with malabsorption (Sokol et al., 1987; Traber et al., 1994; Socha et al., 1997; Papas et al., 2007, 2008; Sagel et al., 2011, 2018; Perin et al., 2018). There have been increasing interest and commercial applications of vitamin E TPGS in dietary supplements, food and beverage, personal care and cosmetics, and animal nutrition and health products. This chapter describes the properties, safety, and efficacy of vitamin E TPGS with a focus on its applications in nutraceuticals and the emerging field of cannabinoids.
Properties of vitamin E TPGS
Chemical properties
Vitamin E TPGS is the polyethylene glycol 1000 ester of d-α-tocopheryl succinate. It is produced by the esterification of crystalline d-α-tocopheryl succinate with polyethylene glycol 1000 (Wu and Hopkins, 1999; USP United States Pharmacopeia and National Formulary, 2016). Its chemical structure and properties are summarized in Table 59.1.
Physical properties
Vitamin E TPGS is a water-soluble waxy solid with a low melting point—the physical properties are summarized in Table 59.2.
Nutritional properties
Vitamin E TPGS is a water-soluble form of the naturally occurring d-α-tocopherol form of vitamin E (Table 59.3). Its enhanced absorption and bioavailability and role in malabsorption are discussed below.
Stability
The chemical structure of vitamin E TPGS, as ester of d-α-tocopherol, reduces oxidation due to air, light, and oxidizing agents. Its low melting temperature and high thermal degradation temperature and testing indicate good stability during storage at room temperature. TPGS it is stable during processing or formulation including sterilization, melt granulation, or hot-melt extrusion for solid dosage formulations such as tableting and encapsulation (Feiyan and Tatavarti, 2010; Pandey et al., 2013). The stability properties of vitamin E TPGS are summarized in Table 59.4.
Safety and regulatory status
The safety of vitamin E TPGS has been evaluated extensively, including studies by the National Cancer Institute and others supported by the National Institutes of Health (NIH), the Cystic Fibrosis Foundation, and research organizations (Krasavage and Terhaar, 1977; NCI National Cancer Institute, 1994a,b; Zondlo Fiume, 2002). These studies have evaluated the acute and chronic toxicity in two species, reproduction in rats, and developmental toxicity in rodents and rabbits. Major clinical studies in humans have confirmed its safe use in foods and beverages, dietary supplements, personal care, medical foods, and drug formulations. An extensive review is available in the Opinion of the Scientific Panel European Food Safety Authority (EFSA, 2007), which led to its approval for use in foods for special medical purposes. Table 59.5 summarizes the safety characteristics. The diverse functions and applications of vitamin E TPGS are reflected in its regulatory status as summarized in Table 59.6, which ranges from a nutrient form of vitamin E and inactive excipient to API (active pharmaceutical ingredient). It has been used in commercial products for over 20 years including pharmaceuticals, dietary supplements for babies and young children, and other products evaluated for safety in human clinical studies.
Functionality of vitamin E TPGS
Vitamin E TPGS has amphiphile properties with a polar hydrophilic head (polyethylene glycol 1000) and a lipophilic tail (phytyl chain of d-α-tocopherol). This amphiphilic characteristic leads to its self-association in
water when the concentration exceeds a threshold known as the critical micelle concentration (CMC). For surfactant molecules, the CMC value is a key parameter that characterizes their surface activity. Vitamin E TPGS
combines a low CMC with good hydrophile/lipophile balance and bulky lipophilic and hydrophilic portions surface areas. These characteristics, summarized in Table 59.7, make vitamin E TPGS a good emulsifier for wide range of lipophilic and wateroil immiscible systems (Wu and Hopkins, 1999; USP United States Pharmacopeia and National Formulary, 2016; Yang et al., 2018).
Digestion and absorption of lipids
A brief review will help understand the role of vitamin E TPGS. Water accounts for over 50% and up to 60% of the human body. The absorption, transport, and secretion systems are water based. The body has developed special mechanisms for the digestion, absorption, transport, and secretion of lipophilic and poorly soluble compounds. The key mechanism for absorption is the formation of micelles (Fig. 59.1), microsphere-shaped particles composed of a hydrophilic exterior encompassing a lipophilic or poorly water-soluble interior (Reboul, 2017; Papas, 1998, 1999). The reported sizes of micelles range from less than one to several microns. The formation of micelles requires two major components. Bile is produced in the liver and secreted into the duodenum, the upper part of the small intestine. Its main components, the bile salts and phospholipids, help emulsify the lipids in the diet and facilitate enzymatic hydrolysis. Bile also provides the key components for the outer layer of micelles. Bile plays a key role in removing byproducts of lipid digestion from the liver into the gut (Macierzanka et al., 2019).
Pancreatic juice is also secreted into the duodenum. This secretion includes pancreatic enzymes that have a critical role in the digestion and absorption of the major dietary components including proteins, carbohydrates, and lipids. Lipases and esterases in the pancreatic juice are key enzymes in the digestion and absorption of lipids (Keller and Layer, 2005).
Micelles are the key vehicle for absorption of lipids by entering the enterocytes of the intestinal wall. Further transport of lipids is facilitated by lipoproteins which include chylomicrons, very low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and highdensity lipoproteins (HDLs). Like the micelles, lipoproteins combine a hydrophilic exterior composed of phospholipids and cholesterol, and a hydrophobic interior, thus enabling the transport of lipids. In the intestinal wall, the micelle contents are formulated into chylomicrons and secreted into the lymph. Lipoprotein lipases catabolize chylomicrons rapidly forming chylomicron remnants. During this process, apolipoprotein E binds to chylomicron remnants. The liver, through specific apolipoprotein E receptors, retains and clears most of the chylomicron remnants. Contents of the remnants are secreted into VLDL and circulated through the plasma. VLDL is hydrolyzed by lipoprotein lipase to LDL, which carries the lipids and appears to exchange them readily with HDL (Fig. 59.2).
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Source: Antares, Ramesh C. Gupta, Rajiv Lall, Ajay Srivastava, brochure Nutraceuticals – Efficacy, Safety, And Toxicity
