Tocofersolan
[CAS# 9002-96-4]

Identification

• Classification: API >> Vitamins and minerals
• Name: Tocofersolan
• Synonyms: Vitamin E-TPGS; Tocopherosolan; D-alpha-Tocopheryl polyethylene glycol succinate; alpha-(4-((3,4-Dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)-1,4-dioxobutanol poly(ethylene glycol) succinate
• Molecular Formula: C₃₃H₅₄O₅^.(C₂H₄O)_n
• CAS Registry Number: 9002-96-4
• EC Number: 618-345-6
• SMILES: Cc1c(C)c2c(c(C)c1OC(=O)CCC(=O)OCCO)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2

Properties

• Melting point: >36 ºC (Expl.)

Discovory and Applicatios

Tocofersolan, also known as tocophersolan or polyethyleneglycolated vitamin E, is a water-soluble derivative of α-tocopherol, the most active form of vitamin E. Its discovery is rooted in the need to improve the solubility and bioavailability of fat-soluble vitamins, particularly in patients with malabsorption syndromes. Vitamin E was first identified in 1922 as an essential nutrient for reproduction in rats, and its antioxidant properties were later characterized. However, conventional α-tocopherol is lipophilic, limiting its absorption in individuals with impaired fat digestion. Tocofersolan was developed as a polyethylene glycol (PEG) conjugate of α-tocopherol to address these limitations, allowing water solubility while retaining the biological activity of vitamin E.

The chemical structure of tocofersolan consists of α-tocopherol esterified with a polyethylene glycol succinate moiety. This modification enhances solubility in aqueous media and facilitates absorption in the gastrointestinal tract without the need for bile salts. The polyethylene glycol chain also provides stability and protects the tocopherol moiety from oxidative degradation during formulation and storage. The design of tocofersolan reflects a broader trend in pharmaceutical chemistry to create prodrugs or derivatives of fat-soluble vitamins that overcome physiological barriers to bioavailability.

Tocofersolan has been primarily applied in clinical nutrition and therapeutic contexts. It is used to prevent or treat vitamin E deficiency in individuals with conditions such as cystic fibrosis, cholestatic liver disease, short bowel syndrome, and other disorders associated with impaired fat absorption. By providing a water-soluble form of vitamin E, tocofersolan enables effective systemic delivery, ensuring adequate antioxidant protection, maintenance of cellular membranes, and support of neurological and muscular functions that are dependent on vitamin E. Its ability to be formulated into oral solutions, enteral nutrition products, and parenteral preparations makes it versatile for clinical use.

Beyond its use in deficiency states, tocofersolan has been studied for its antioxidant properties. Vitamin E is known to inhibit lipid peroxidation, stabilize cell membranes, and modulate immune responses. The PEGylated form maintains these biological effects while allowing broader application in aqueous formulations. Research has investigated its role in reducing oxidative stress in various tissues, including liver, cardiovascular, and nervous systems, demonstrating the translational relevance of chemical modification to enhance pharmacological utility.

The development of tocofersolan exemplifies the integration of chemical modification and pharmaceutical formulation to address clinical challenges. By transforming a lipophilic vitamin into a water-soluble derivative, chemists and clinicians have expanded the therapeutic applications of vitamin E, particularly for populations with limited fat absorption capacity. The compound also illustrates the general strategy of PEGylation to improve solubility, stability, and bioavailability of hydrophobic bioactive molecules.

Overall, tocofersolan represents an important advancement in the delivery of essential nutrients. Its discovery and application demonstrate how chemical innovation can overcome physiological and formulation barriers, enabling the effective use of vitamins in clinical practice, enhancing patient outcomes, and supporting research into antioxidant therapies.

References

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DOI: 10.1021/acschembio.0c00343