Vitamin E (Vit-E) s an antioxidant. It boosts the immune system against viruses and bacteria, it helps form red blood cells and widens blood vessels to keep blood from clotting inside them. It also helps the body to use vitamin K. The term vitamin E refers to a group of different antioxidant compounds. Tocopherols are phenolic compounds with vitamin E activity. Tocopherol comprises alpha-, beta-, gamma- and delta-Tocopherol. Vitamin E includes eight fat-soluble isoforms: α-, β-, γ-, and δ-Tocopherol and the related α-, β-, γ-, and δ-Tocotrienol.
D-α-Tocopheryl Polyethyl Glycol Succinate (TPGS) is a highly stabilized form of vitamin E. Some common synonyms for Vitamin E Polyethylene Glycol Succinate are Vitamin E-TPGS, TPGS and Tocophersolan.
D-α mixed Tocopherol has excellent antioxidant properties, which can protect unsaturated fatty acids from peroxides and other active substances, thereby maintaining the nutritional value of food. This contributes to the value of TPGS.
HOW IS VITAMIN E TPGS MADE?
Vitamin E Polyethylene Glycol Succinate is manufactured as a mixture by the esterification of D-alpha Tocopheryl Acid Succinate and Polyethylene Glycol (PEG 1000). The resulting ester mixture consists primarily of mono-esterified PEG and small quantities of di-esterified Polyethylene Glycol. It also contains a minimum of 25.0% D-alpha Tocopherol.
PROPERTIES OF VITAMIN E TPGS
Vitamin E TPGS usually exists in the form of a colorless to slightly yellow oily liquid or as a white to light brown waxy solid with a low melting point. It is a water-soluble derivative of natural vitamin E. At low temperatures, crystallization may occur. D-α mixed Tocopherol is easily soluble in organic solvents, such as Ethanol, Ether and Chloroform, and slightly soluble in water.
D-α mixed Tocopherol is relatively stable to heat, acid and alkali, but it is easily degraded in the presence of ultraviolet light or oxidants. It should therefore be protected from light and sealed during storage and transportation. Vitamin E is sensitive to oxidation by air in the presence of light and can undergo substantial photodegradation.
Vitamin E TPGS displays amphiphilic properties as it consists of polar hydrophilic (Polyethylene Glycol) and non-polar lipophilic (the phytyl chain of D-α-Tocopherol) moieties. As a waxy solid its melting point is 37–41 °C. It is extremely stable in the presence of oxygen, heat, light, or oxidizing agents, and unstable to alkali. Its Hydrophile Lipophile Balance (HLB) is 13. The HLB scale ranges from 0 to 20, with 0 being the least lipophilic and 20 being the most hydrophilic. The Vitamin E content of TPGS is 260 mg/g (387 IU/g). Vitamin E TPGS has a critical micelle concentration (CMC) of 0.02% w/w. TPGS has shown 67-times superior emulsification efficiency than the conventional polyvinyl alcohol emulsifier.
Modifications of the chromanol (head group) and phytyl (tail group) of vitamin E have led to many Alpha tocopheryl succinate (α-TOS) analogues which display improved biocompatibility and anticancer activity. Amongst such modified forms is TPGS (α-TOS conjugated to succinate PEG) prepared via the esterification of α-TOS succinate with the PEG.
TPGS is amphiphilic as it is composed of lipophilic α-TOS and hydrophilic PEG. TPGS is found to be safe and nongenotoxic. It is used as an excipient of choice (adjuvant) in an array of nanoformulations produced for tumor treatment owing to its significant anticancer potential when compared to plain α-TOS. Nanoformulations are formulations or drug combinations that utilize nanotechnology to enhance their therapeutic efficacy.
TPGS can be employed as a plasticizer in film preparation such as PLLA (Polylactic acid) and HPC (hydroxypropyl cellulose). It lowers the glass transition temperature and adhesion force of the films and improves the flexibility and elongation at flouting point through tensile testing. TPGS has improved the biocompatibility of hollow fiber membranes polysulfone for hemodialysis.
Vitamin E α-Tocopherol is an essential dietary vitamin. It is a fat-soluble, highly antioxidant vitamin with the ability to neutralize free radicals. It reduces cell damage and therefore reduces cell aging. Alpha-Tocopherol has a higher vitamin activity than the other forms of vitamin E. The vitamin activity for D-alpha Tocopherol is 100, while that of beta-Tocopherol is 40, gamma-Tocopherol is 20, and delta-Tocopherol is 1. The acetate form is a more stable ester that than the unesterified Tocopherols.
Vitamin E TPGS can function as a non-ionic surfactant and has a variety of other excipient functions for pharmaceutical and drug delivery applications. As an amphiphilic molecule it can encapsulate lipids and fats rendering them water soluble. This unique property, combined with its permeability glycoprotein inhibition, makes TPGS a highly effective emulsifier.
WHAT IS VITAMIN E TPGS USED FOR?
D-alpha Tocopherol acetate is a vitamin E product designed for the treatment and prevention of vitamin deficiencies. Alpha-Tocopherol is the primary form of vitamin E that is preferentially used by the human body to meet appropriate dietary requirements.
Tocophersolan has various commercial applications ranging from emulsifier in cosmetics to solubilizer in drugs and dietary supplements. It can also act as an absorption and permeation enhancer. Many industries benefit from the bioavailability and solubility of this agent including the following:
Pharmaceuticals
Nutritional Supplements
Personal Care
Beverages and Food
Animal Nutrition
Botanicals & Cannabidiol
Vitamin E TPGS is a multi-role excipient used extensively in nutraceutical and pharmaceutical applications. Vitamin E TPGS has shown proven and recognized properties to improve bioavailability of poorly absorbed drugs vitamins micro-nutrients acting as an absorption and permeability enhancer and as an emulsifier for Self Emulsifying Drug Delivery Systems (SEEDS) of poorly soluble drugs. As a water-soluble compound, Vitamin E TPGS is also used as an efficient source of natural Vitamin E, for both therapeutics purposes and nutrition. In addition, Vitamin E TPGS displays physical properties that render it a relevant plasticizer for innovative technologies in the pharmaceutical industry.
The natural isoforms of Vitamin E γ-Tocotrienol (γ-ΤΤ) and δ-Tocotrienol (δ-ΤΤ) and the synthetic derivative α-Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS) have promising anticancer potency. Clinical trials are examining the anti-tumor effectiveness of Tocotrienols (TTs) in combination with chemotherapeutic agents in patients suffering from breast, colon, non-small cell lung and ovarian cancers.
APPLICATIONS OF VITAMIN E TPGS
Bioavailability Enhancement: In the pharmaceutical arena usage of Vitamin E TPGS is proven to be a safe and effective method of improving the absorption and bioavailability of poorly soluble materials. TPGS has been widely used in producing nanodrugs or other formulations for many poorly water-soluble or permeable drugs, especially for drugs of the Biopharmaceutics Classification System (BCS) class Ⅱ and Ⅳ. The BCS classification system differentiates drugs on the basis of their solubility and permeability and is based on a United States Pharmacopoeia (USP) aperture. BSC class II drugs are generally characterized by low solubility and high permeability whereas BSC class IV drugs are characterized by low solubility and low permeability. Typical examples of the latter include Verapamil HCl, Papaverine, Propiverine HCl and Dipyridamole. These active pharmaceuticals are the most challenging for product and process development.
Improved drug bioavailability is achievable by formation of Vitamin E TPGS micelles and the modulation of the efflux pump through inhibition of P-glycoprotein (P-gp). This can block the action of P-gp to improve drug bioavailability and uptake in targeted organs. TPGS also facilitates the permeation of a variety of cellular membranes, including those in the gut, mouth, eyes and skin.
Drug Delivery: Vitamin E TPGS facilitates drug delivery. Since TPGS has been approved by the FDA as a safe pharmaceutical adjuvant, it has been extensively used in drug delivery systems as surfactant, solubilizer, stabilizer and P-gp inhibitor for enhancing bioavailability and reversing Multidrug Resistance (MDR). MDR lowers the efficacy of many substances, but TPGS can alleviate this by acting as a P-gp inhibitor, thereby significantly increasing the intracellular accumulation of co-formulated therapeutic agents. As a widely used adjuvant in drug deliveries, TPGS is one of the most potent, commercially available P-gp inhibitors.
Anticancer Agents: As noted, TPGS is known as a selective anticancer agent. It displays synergistic antitumor effects since it can induce apoptosis against many cancer types. TPGS can selectively induce apoptosis in tumor cells without being toxic to normal cells and tissues. It can target the mitochondria of cancer cells, resulting in the mitochondrial destabilization for activation of mitochondrial mediators of apoptosis. TPGS can be combined with chemotherapeutic drugs to reduce side effects and increase treatment efficiency. Thus, there is a significantly different response on normal immortalized breast cells and cancer cells after TPGS treatment. Some other examples of anticancer agents include:
- TPGS-Paclitaxel conjugate Paclitaxel (PTX) represents a BCS class Ⅳ drug. A redox-sensitive prodrug TPGS-SS-PTX has been reported that rapidly dissociated in intracellular redox environment to release PTX for cytotoxicity against tumors. The prodrug can self-assemble to stable micelles and realize a passive tumor targeting through an enhanced permeation and retention effect. Compared with non-responsive ester bond conjugated PTX prodrug TPGS-SS-PTX exhibited better stability and in vitro sustained drug release.
- TPGS-cisplatin conjugate: Cisplatin is widely used in various cancers. However, its clinical application is limited due to low solubility, nephrotoxicity, severe peripheral neurotoxicity, and inherent and acquired drug resistance. A TPGS-cisplatin prodrug was developed to improve Cisplatin’s water-solubility and reduce the neurotoxicity. TPGS-Cisplatin can self-assemble to micelles with high drug loading capability and exhibits higher cell uptake and cytotoxicity against HepG2 hepatocarcinoma cells compared with the free drug.
- Chitosan-TPGS polymer: To overcome P-gp induced MDR of cancer cells a Chitosan-g-TPGS (CT) polymer has been prepared. The resulting nanoparticles exhibited high encapsulation levels of Doxycycline (DOX), pH-responsive release behavior and significant cytotoxicity on human hepatocarcinoma cells. DOX-loaded CT nanoparticles also enhanced cytotoxicity and apoptosis against drug-resistant cells.
Drug Resistance: TPGS can be combined with mitochondrial targeting agents to overcome drug resistance. Multifunctional liposomes were for example prepared with the mitochondrial targeting molecule Dequalinium and TPGS. The liposomes can circumvent the intrinsic resistance by enhancing the delivery of cytotoxic agents across mitochondrial membrane and overcome the acquired resistance by inhibiting the activity of P-gp. The targeting liposomes were selectively accumulated in mitochondria and decreased the mitochondrial membrane potential.
Drug resistance of cancer cells can restrict the therapeutic efficacy in chemotherapeutic treatment. As the ATP dependent membrane transporter, P-gp is one of the primary causes for MDR. It can pump out the P-gp substrate drugs to decrease intracellular drug accumulation, thus reducing the cytotoxic effect of chemotherapeutic drugs in drug resistant cancer treatment.
TPGS Based Prodrugs
Prodrugs are agents with low or no pharmaceutical activity that can undergo in vivo biotransformation to generate parental drugs. Prodrugs are designed to optimize the pharmaceutical, pharmacokinetic and pharmacodynamic properties of drugs, such as by improving drug solubility, permeability, stability, bioavailability, treatment efficiency and decreasing the adverse effects.
The hydroxyl functions of PEG in TPGS are reactive and can be easily conjugated with therapeutic agents to form TPGS-based prodrugs, in which TPGS can serve as a drug carrier and P-gp inhibitor to overcome MDR in cancer treatment.
Oral Drug Delivery Vitamin E TPGS improves drug bioavailability as a surfactant, it enhances solubilization of poorly water-soluble drugs and solubilization of poorly permeable drugs that are water soluble. It enhances drug permeability by P-glycoprotein efflux inhibition.
Other Applications Vitamin E TPGS can act as emulsifier, vehicle for lipid-based formulations, plasticizer for hot melt extrusions, stabilizer for amorphous solid dispersion, source of Vitamin E and as an antioxidant.
TPGS REGULATORY STATUS
TPGS has GMP certification, a National Formulary (NF) monograph is in the United States Pharmacopeia/National Formulary (USP/NF) USP-NF 2024, Issue 1. D-ɑ-Tocopheryl Polyethylene Glycol Succinate is an FDA approved safe and biocompatible adjuvant and recognized in the pharmaceutical industry for its notable properties as solubilizer, absorption and permeation enhancer, emulsifier and stabilizer. TPGS is generally regarded as safe with an acute oral median lethal dose (LD50) of ≥7 g/kg. TPGS has been approved by the USFDA as a safe pharmaceutical additive.
MARKETED THERPEUTIC TPGS PRODUCTS
A large number of TPGS formulations have been developed commercially for many drugs and in various therapeutic areas. Examples include anti-virus (HIV & Hepatitis C), antihyperlipidemic, central nervous system diseases (e.g., acute migraine treatment) and orphan diseases. They have been approved by different drug agencies, such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMEA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA).
TPGS is commercially used in formulations, tablets, capsules, soft gels, solutions, creams via oral, mucosal (buccal, vaginal, nasal, parenteral, ophthalmic and dermal administration.
WHAT ARE THE SIDE EFFECTS OF TPGS?
Some drugs that may interact with TPGS are: anti-platelet drugs (such as aspirin, clopidogrel, ticlopidine), “blood thinners” (such as Warfarin), herbal products that can increase the risk of bleeding (such as garlic, gingko), fat-soluble supplements (such as vitamins A/D/E/K, coenzyme Q) and iron supplements. Vitamin E may also increase the risk of bleeding, especially if you are taking blood thinners, such as Warfarin (Coumadin), Aspirin, or Clopidogrel (Plavix).
Ask your doctor or pharmacist for more details and tell them about all the products you use (including prescription drugs, nonprescription drugs, and herbal products.
TPGS can be absorbed through the skin and lungs and may harm an unborn baby. Women who are pregnant or who may become pregnant should therefore not handle this medication or breathe the dust from the capsules.
CARBOMER, INC.’S D-α-TOCOPHERYL POLYETHYLENE GLYCOL SUCCINATE
CarboMer, Inc.’s offers D-α-Tocopheryl Polyethylene Glycol Succinate as a pharmaceutical grade that is manufactured under cGMP; it is EP and USP compliant. This product is compliant with USP/EP monographs.
CarboMer, Inc. adheres to strict guidelines set by the Food and Drug Administration (FDA), ensuring the safety and consistent quality of its Docusate products. Additionally, compliance with USP standards and those of other international regulatory bodies reflects CarboMer, Inc.’s commitment to providing the highest-quality Docusate products. Adherence to these regulatory standards guarantees that clients always receive reliable TPGS products of excellent quality.
SUMMARY
Features and Benefits of D-α-Tocopheryl Polyethylene Glycol Succinate:
It is a highly versatile, compendial excipient with a broad range of potential uses. It is also a highly effective solubilizing agent for use in the formulation of poorly soluble active pharmaceutical ingredients. It can be used in wet granulation, hot-melt extrusion, spheronization-extrusion and milling of poorly soluble compounds and as anionic surfactant and wetting agent in creams and gels.