Vitamin E TPGS Emerging Applications in Novel Parenteral Drug Delivery Systems

Abstract

d-α-Tocopheryl polyethene glycol 1000 succinate (TPGS) has long served as a safe, multifunctional excipient in oral drug delivery, where it acts as a solubiliser, emulsifier, absorption enhancer, and bioavailability promoter for poorly soluble compounds. Recent advances in parenteral formulation science have highlighted the value of TPGS in injectable emulsions, nanoemulsions, lipid nanoparticles, polymeric nanoparticles, and long-acting depot systems. Its amphiphilic architecture, efflux-pump inhibition, membrane-modulating effects, ability to stabilise pharmaceutical actives, and potential synergies to increase their efficacy and safety have expanded its utility to complex parenteral modalities, including oncology therapeutics and mRNA delivery platforms. This review summarises the physicochemical properties underlying TPGS function, its evolving role in parenteral systems, case studies of approved and investigational products, and emerging opportunities in nanoparticle-mediated and nucleic acid delivery. Collectively, the evidence suggests TPGS’s high potential to enhance the safety and efficacy of the next-generation parenteral therapeutics.

Introduction

For over sixty years, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) has been recognised as a safe and highly functional derivative of vitamin E. Its amphiphilic structure provides solubilisation, emulsification, membrane fluidisation, and permeability enhancement, contributing to improved oral bioavailability for poorly soluble APIs (1–3).

TPGS is incorporated in several commercial drug products, including VIEKIRA PAK ® , fenofibrate capsules, and ZEPATIER®, and is frequently employed in early-stage research formulations due to its ability to improve dissolution, stability, and absorption (4).

In recent years, TPGS has gained significant attention in parenteral drug delivery (5). Its hydrophobic tocopherol moiety facilitates encapsulation of lipophilic drugs, while its PEG-succinate segment provides aqueous dispersibility and steric stabilisation. Additionally, TPGS inhibits the multidrug resistance-contributing P-glycoprotein (P-gp), modulates membrane permeability, and contributes to nanoparticle stability—properties desirable in oncology, nucleic acid delivery, and long-acting injectables (6–9) (see Table 1). This review evaluates the emerging value of TPGS as an excipient for injectable formulations, supported by case studies and preclinical evidence.

Use of TPGS in parenteral products

Due to its favourable functionality, TPGS has been an ingredient in several marketed and experimental parenteral products. It has also received increased attention in formulation and delivery systems relevant to parenteral applications.

Solfredoc® (Docetaxel Injectable Emulsion)

Solfredoc (Sayre Therapeutics) is a ready-to-use docetaxel emulsion (20mg/mL) designed to eliminate polysorbate 80 and ethanol, excipients associated with hypersensitivity reactions and toxicity. TPGS serves

as a primary emulsifier, enabling an ethanol-free oil-in-water system that improves tolerability and simplifies administration.

It is currently marketed in India by Sayre Therapeutics for use in breast cancer, prostate cancer, gastric cancer, and head and neck cancer. This product demonstrates the feasibility of substituting TPGS for polysorbates in approved oncology products.

TOCOSOL ® Paclitaxel Nano-emulsion

The TOCOSOL® platform (Sonus Pharmaceuticals) represented a major effort to develop a Cremophor EL–free and ethanol-free paclitaxel formulation (10). The nano-emulsion included α-tocopherol, TPGS, and Poloxamer 407, producing ~100-nm droplets with high drug loading (10mg/mL). Although Phase III clinical studies did not meet their endpoints, early studies validated TPGS as a robust emulsifier capable of stabilising potent cytotoxic agents for parenteral use.

Emerging applications across conventional and nucleic-acid nanoparticle delivery systems

TPGS has a well-established role in conventional nanoparticle-based parenteral formulations for small-molecule and anticancer therapeutics, where it functions as a stabiliser, permeation enhancer, and pharmacokinetic modulator through its amphiphilic structure and PEG-mediated steric effects. In polymeric nanoparticles, liposomes, nanocapsules, and solid-lipid nanoparticles, these properties have been shown to improve colloidal stability, drug loading, and systemic exposure.

The formulation principles that govern the performance of conventional nanocarriers, namely protection of the payload from chemical and biological degradation, mitigation of aggregation, and optimisation of biodistribution, are directly applicable to nucleic acid–based therapeutics.

As a result, growing interest has focused on extending the use of TPGS from established small-molecule nanoparticle systems to emerging messenger RNA and RNA interference delivery platforms, where analogous stabilisation and stealth mechanisms may address key challenges in intracellular delivery and in vivo stability.

TPGS in conventional nanoparticle-based drug delivery systems

TPGS is widely used in polymeric nanoparticles, lipid nanoparticles (LNPs), solid-lipid nanoparticles, nanocapsules and other particle-based parenteral formulations due to its unique physicochemical attributes (11–15):

Reduced interfacial tension, promoting nanoparticle uniformity
Prevention of crystallisation of loaded lipophilic drugs
Improved aqueous dispersibility through PEG-mediated steric stabilisation
Enhanced drug loading facilitated by the tocopherol domain
Inhibition of P-gp efflux at the cellular membrane

Representative studies

TPGS-coated resveratrol liposomes: 5.7-fold increase in AUC and 6.7-fold extension of plasma half-life, with improved brain targeting (15).
W/O/W nano-capsules: improved vinorelbine encapsulation, stability, and hemocompatibility (11).

Solid-lipid nanoparticles: ~39-fold enhancement in anticancer activity versus free vinorelbine, outperforming poloxamer-based systems (14).

These findings confirm TPGS’s role as a multifunctional stabiliser, permeation enhancer, and performance booster in nanocarrier systems.

TPGS as a functional component of mRNA delivery systems

Messenger RNA (mRNA) has emerged as a powerful therapeutic modality, particularly in the development of vaccines and other parenteral products. Its appeal lies in its capacity to encode virtually any antigen and in the speed and scalability of its production via cell-free in vitro transcription, which circumvents the need for conventional cell-based manufacturing.

However, the clinical translation of mRNA vaccines critically depends on advanced delivery systems capable of protecting mRNA from degradation and facilitating efficient intracellular delivery. The physical and chemical properties of mRNA contribute to its inherent instability, with direct implications for formulation, delivery, efficacy, and safety. Hydrolytic cleavage represents a major pathway of chemical degradation, while oxidative damage mediated by reactive oxygen species has also been implicated.

For these reasons, nanoparticle-based delivery systems have been employed to facilitate effective mRNA delivery, including in mRNA-based Covid-19 vaccines (16, 17). Lipid nanoparticles protect mRNA from both chemical and enzymatic degradation and facilitate cytosolic delivery, where the mRNA is translated by ribosomes into the encoded protein.

Consequently, mRNA therapeutics require delivery platforms that ensure robust intracellular transport while minimising enzymatic and oxidative degradation (18). Incorporation of TPGS into nanoparticle and lipid nanoparticle (LNP) platforms is expected to confer PEG-mediated stealth properties, reducing opsonisation and reticuloendothelial clearance in a manner analogous to PEG-lipids used in LNPs for luciferase and therapeutic mRNA delivery.

These effects have been associated with prolonged plasma half-life, increased area under the concentration–time curve, reduced systemic clearance, improved biodistribution, enhanced colloidal stability, and mitigation of inflammatory responses (19). The antioxidant contribution, arising from residual tocopherol impurities in the mixture rather than TPGS itself, may further support mRNA performance by reducing reactive oxygen species, thereby limiting degradation into harmful byproducts and decreasing associated inflammation and toxicity.

In other applications, a novel biodegradable D-α-tocopheryl polyethene glycol 1000 succinate-b-poly (ε caprolactone-ran-glycolide) (TPGS-b-(PCL-ran-PGA)) nanoparticle (NP) was prepared as a delivery system for small interfering ribonucleic acid (siRNA) molecules targeting HIF-1α in nasopharyngeal carcinoma gene therapy. The results showed that the NPs could efficiently deliver siRNA into CNE-2 cells (20).

TPGS is an effective nanoparticle stabiliser assisting in the reduction of nanoparticle aggregation. Though TPGS is not an antioxidant, trace-free tocopherol impurities can scavenge reactive oxygen species and mitigate mRNA oxidative degradation.

TPGS-coated lipid nanoparticles are expected to reduce opsonisation and reticuloendothelial clearance through PEG-mediated stealth properties, analogous to PEG-lipids used in mRNA lipid nanoparticles. Consistent with this mechanism, TPGS-containing formulations have been associated with prolonged plasma half-life, increased area under the concentration–time curve (AUC), reduced systemic clearance, and improved biodistribution following intravenous administration (13).

The role of TPGS in overcoming major challenges in the development of parenteral therapeutics

Parenteral formulations must meet stringent requirements for sterility, solubility, physical and chemical stability, biocompatibility, and patient tolerability. APIs with low aqueous solubility, susceptibility to hydrolysis or oxidation, and poor physical stability pose a significant risk for precipitation, aggregation, or degradation during storage (21). Excipient-API interactions, container-closure compatibility, endotoxin control, and particulate minimisation are essential for patient safety (22, 23).

Particle size control is therefore critical, as larger particles are associated with increased risks of vascular irritation and embolic events. Parenteral formulations must accordingly maintain particle sizes sufficiently small to permit sterile filtration and minimise patient risk.

Stability of formulation

Long-term aqueous storage can pose both physical and chemical stability challenges in parenteral formulations. Physical instability may manifest as compromised emulsion stability, resulting in phase separation, particle aggregation and growth, or drug precipitation. In contrast, chemical instability arises from hydrolytic, oxidative, and other degradation pathways that structurally modify the drug substance and/or excipients.

Consequently, formulation composition is a critical determinant of overall stability. The functional properties of TPGS that support its use in parenteral products are illustrated in Table 2. With respect to excipient stability, the ester linkage in TPGS, connecting d-α-tocopherol to the succinate–polyethene glycol (PEG) moiety, remains largely stable under physiological conditions, with only limited hydrolysis observed under extreme pH conditions. These features demonstrate its suitability for a wide range of parenteral formulations.

Delivery/uptake (Formulation functionality and sterility considerations)

In nano-emulsions, lipid-carriers, and nanoparticle systems, formulators must balance drug loading, droplet size control, release kinetic profiles, and sterility considerations, especially when terminal sterilisation is not feasible. TPGS offers multiple functionalities that address these challenges, particularly its ability to stabilise emulsions, enhance solubility and loading, and form formulations acceptable for sterile filtration or terminal sterilisation. TPGS can successfully replace other functional ingredients in formulations due to its favourable properties, as illustrated in Table 3.

Metabolic products/toxicity

In addition to its functional utility, TPGS is supported by a robust safety knowledge base. A recent evaluation by the European Food Safety Authority (EFSA) confirmed its favourable toxicological profile. Following intravenous administration, TPGS distributes rapidly to highly perfused, reticuloendothelial system–rich organs and initially circulates in intact form before undergoing ester hydrolysis to polyethene glycol 1000 (PEG 1000), the principal detectable metabolite.

PEG 1000 reaches peak plasma concentrations within approximately ten minutes and is efficiently eliminated via urine and faeces, reducing the potential for tissue accumulation relative to intact TPGS. Systemic TPGS clearance therefore occurs primarily through tissue uptake followed by enzymatic conversion to PEG 1000 and subsequent renal and biliary elimination.

Consistent with this metabolic fate, toxicological studies in multiple animal species revealed no evidence of genotoxicity or treatment-related adverse effects at doses up to 1000mg/kg/day. Based on a margin-of-exposure approach, EFSA concluded that use of TPGS at proposed exposure levels poses no safety concern, supporting its suitability for food and pharmaceutical applications. (24)

Conclusion

TPGS is evolving from a traditional oral excipient into a sophisticated multifunctional component for advanced parenteral drug delivery. Its unique combination of solubilisation, steric stabilisation, P-gp inhibition, membrane interaction, and nanoparticle modulation enables formulators to address long-standing challenges in the delivery of hydrophobic drugs, cytotoxic compounds, and nucleic acids.

As the field moves toward increasingly complex injectable systems, including mRNA, lipid nanoparticles, nano-emulsions, and long-acting depots, TPGS is poised to play a transformative role in developing safe, stable, and high-performance parenteral therapeutics.

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Source: Clariant Health Care, MICHALIS NICOLAOU, PhD, ANDREAS M PAPAS, PhD

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Table 1. Potential Applications of TPGS in Parenteral Drug Delivery

Application	TPGS Function	Benefit
Nanoemulsions TPGS-W/O/W nanocapsules Example Vinorelbine	Emulsifier, droplet stabiliser, Stabilises double emulsions	Plasticiser, stabiliser, permeability enhancer
Lipid nanoparticles (LNPs) Examples: Resveratrol, Vinorelbine	Efflux inhibition; solubiliser	Enhanced circulation; reduced hepatic clearance 5.7× AUC increase; 6.7× half-life extension; targeted brain delivery~39× higher anticancer potency vs free drug
Polymer nanoparticles	Steric stabilisation, ROS reduction, stabiliser, reduces opsonisation, supports circulation time	Better encapsulation and cell uptake
Injectable depots	Amphiphilic co-solvent	Modulates release kinetics
Cytotoxic formulations	Efflux inhibition; solubiliser	Improved delivery of MDR-associated drugs
mRNA therapeutics: Experimental mRNA LNPs, e.g., Luc mRNA, therapeutic mRNA	Efflux inhibition; solubiliser	Improved stability and tolerability, improved biodistribution, reduced ROS and inflammatory signalling

Table 2. Key Functional Properties of TPGS Relevant to Parenteral Formulation

Property	Mechanism	Impact on Formulation
Solubilisation	Micelle formation	Increased drug loading
Steric Stabilisation	PEG-Chain	Reduced Aggregation
Permeability Enhancement	P-gp inhibition	Improved Cell uptake
Antioxidant impurity	Free-Tocopherol	ROS reduction

Table 3. Functional Advantages of TPGS vs Common Parenteral Excipients

Excipient	Limitations	Advantages of TPGS
Polysorbate 80	Hydrolysis, oxidation, hypersensitivity reactions	Ethanol-free emulsification; improved stability
Cremophor EL	Anaphylactic reactions; infusion reactions	Less immunogenic; improved tolerability
Poloxamer 188	Lower solubilising efficiency	Higher solubilisation capacity; efflux inhibition
PEG only	Lacks hydrophobic core	Amphiphilic structure improves drug encapsulation

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