Emerging Applications of Vitamin E TPGS in Drug Delivery

The author discusses some new applications of TPGS in the pharmaceutical field that should see this versatile excipient retain its place in the drug formulators toolbox.

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Emerging Applications of Vitamin E TPGS in Drug Delivery

Vitamin E TPGS, or d-α-tocopheryl polyethylene glycol 1000 succinate, was first developed more than 60 years ago as a water-soluble form of naturally occurring vitamin E. Originally used to treat vitamin E deficiency in cholestatic patients, TPGS quickly attracted attention as a versatile solubilizer due to its amphiphilic nature and surfactant properties. Further application of this molecule emerged in the 1990s, when TPGS was shown to improve epithelial absorption by modulating cellular efflux. Researchers have continued to find a variety of new and exciting applications of this molecule, and TPGS has become an important tool for drug delivery formulators. This report serves to summarize some of recent innovations using TPGS for improved delivery of bioactive materials.

History of TPGS

Vitamin E is a fat-soluble nutrient with important properties relating to vision, reproduction, and the general health of the skin, brain, and blood (1). Vitamin E occurs naturally in plant-based oils, nuts, and fruits, but low solubility in water limits its field of application, and in the case of malabsorbing patients, their ability to obtain adequate doses of this essential nutrient. This limitation led Eastman Kodak to develop TPGS (CAS 9002-96-4), or tocophersolan, in 1950 as a water-soluble form of vitamin E (2). The pharmaceutical field began to take a serious interest in TPGS in the 1990s, after Sokol demonstrated that Vitamin E TPGS overcame vitamin E deficiencies in cholestatic children with severe malabsorption (3). These patients were previously unresponsive to oral forms of vitamin E supplementation and were forced to rely on painful intramuscular injections.

In 1992, researchers at the University of Cincinnati reported that children with severe cholestasis exhibited enhanced absorption of vitamin D3 co-administered with TPGS (4). Sokol (5) then observed that TPGS enhanced the absorption of cyclosporin—an immunosuppressant drug required in huge doses to treat pediatric liver transplant patients—and several other groups reported similar findings (6,7). This early work provided the impetus for additional studies into the enhancement of solubility and absorption and many new and interesting properties began to emerge. In 1999, FDA approved the first drug using TPGS: Amprenavir, a protease inhibitor used in the treatment of HIV patients (8). Today, TPGS is a powerful tool for formulators in a wide variety of  industries and is used to improve the solubility and bioavailability of many lipophilic and poorly soluble bioactive materials.

Properties of TPGS

Vitamin E TPGS (Figure 1) is the mixed ester formed by the reaction of succinic anhydride with natural vitamin E and polyethylene glycol (PEG) 1000. This amphiphilic skeleton results in TPGS having significant solubility in water, approximately 200 g/L, which is around 100 times higher than that of the α-tocopherol (21 mg/L). TPGS has an average molecular weight of 1513 g/mol and with a melting range of 37–41 °C, it is a waxy solid at room temperature. TPGS delivers 387 IU/g of natural vitamin E when used as a nutritional supplement and is stable to most processing conditions including sterilization treatment. Its calculated hydrophilic/ lipophilic balance (HLB) number of 13.2 enables TPGS to act as an oil-in-water emulsifier, and while early applications have been focused on this property, TPGS can also function as a solubilizer, absorption enhancer, stabilizer, and permeation enhancer in a variety of biomedical and nutraceutical applications.

Delivery forms

TPGS is used to deliver products in a wide variety of industries including pharmaceuticals, dietary supplements, personal care and cosmetics, food and beverage, and animal nutrition and health. TPGS can be incorporated into product forms such as liquid formulations, capsules, chewable tablets, nutrition bars, gummies, drops, bottled beverages and sports drinks, sprays, and drops. In addition to these oral administration routes, TPGS can be used in topical, nasal, ophthalmic, and parenteral applications, as well as in a new generation of nanoparticles developed for targeted cell and tissue delivery.

TPGS safety and manufacturing status

The safety of TPGS has been evaluated thoroughly by several institutes, including the National Cancer Institute, the National Institutes of Health, the Cystic Fibrosis Foundation, and other research organizations (9–11). Major clinical studies in humans have ascertained its safety for use in foods and beverages, dietary supplements, personal care products, and medical food and drug formulations. An extensive review of the work that led to the approval of TPGS in foods for special medical purposes is available in the Opinion of the Scientific Panel European Food Safety Authority (12). A summary of TPGS’s safety characteristics is shown in Table I.

It is possible to purchase TPGS that is manufactured under current good manufacturing practices (CGMP) 21 Code of Federal Regulations (CFR) 210 and complies with the International Excipients Council (IPEC) and Pharmaceutical Quality Groups (PQG) manufacturing guidelines for pharmaceutical excipients. TPGS manufactured by Antares is available in both food grade (FG) and pharmaceutical grade (NF) and can also be purchased as a non-GMO material that is derived from sunflowers. All grades are provided in tamper evident containers of various sizes and is stored and distributed under IPEC Good Distribution Practices (IPEC-GDP).

BCS classification of new chemical entities

Pharmacokinetics—the branch of pharmacology concerned with the movement and disposition of drugs within the body—outlines four primary processes that are often summarized by the abbreviation ADME. These pharmacokinetic properties can strongly affect the therapeutic efficacy of a drug:

• Absorption: Orally administered drugs must enter the bloodstream through the mucus surfaces of the digestive tract before they can be taken up by the target cells. Many factors such as solubility, chemical stability, gastric emptying time, intestinal transit time, and the ability to permeate the intestinal wall can reduce the extent to which a drug is absorbed.
• Distribution: The drug’s journey through the bloodstream to various tissues of the body can be influenced by blood flow, lipophilicity, molecular size, and the interactions of the drug with components of the blood and anatomical barriers.
• Metabolism: Metabolism is the process that breaks down the drug. Most small-molecule drugs are metabolized and inactivated in the liver by cytochrome P450 enzymes. The metabolism process varies by patient and is affected by genetics, age, and interactions with other drugs.
• Excretion: By this process, drugs and their metabolites are removed from the body. If excretion is incomplete, drug substances can accumulate to problematic levels. The kidneys are the most common route for excretion, and their performance can be affected by age, renal function, and pathologies that affect renal blood flow.

Predicting and controlling the pharmacokinetic properties of a substance presents a major challenge for drug delivery innovators. To help with this challenge, the Biopharmaceutics Classification System (BCS) has been developed as a prognostic tool for assessing the absorption parameter of drugs using quantitative data on water solubility and membrane permeability. Drug formulators can use this to predict the rate-limiting step in the intestinal absorption process that follows oral administration. A drug substance is considered soluble when the highest clinical dose can be dissolved in 250 mL or less of an aqueous medium under specific pH and temperature conditions. A substance is highly permeable when 90% of an administered dose is absorbed. New chemical entities (NCEs) can be characterized as belonging to Class I-IV according to these properties, as shown in Figure 2 (13).

Because of its lower cost, simplicity, convenience, and patient compliance, oral administration is a strongly preferred dosage form. However, NCEs are being increasingly categorized as poorly soluble (Class II), poorly permeable (Class III), or both (Class IV), and this dramatically increases the probability that they will need to be delivered in non-oral form. As a result of these recent trends, developers are working to shift Class II-IV substances toward Class I by increasing solubility, decreasing particle size, and incorporating permeation enhancers.

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Source: Antares Health Products, PharmTech, Greg Paddon-Jones, PhD, Emerging Applications of Vitamin E TPGS in Drug Delivery, brochure Emerging Applications of Vitamin E TPGS in Drug Delivery

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