Recent Advances in Vitamin E TPGS-Based Organic Nanocarriers for Enhancing the Oral Bioavailability of Active Compounds: A Systematic Review
Abstract
Background: D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), an amphiphilic derivative of natural vitamin E, functions as both a drug efflux inhibitor and a protector against enzymatic degradation and has been widely incorporated into nano-formulations for drug design and delivery.
Objective: This systematic review evaluates TPGS-based organic nanocarriers, emphasizing their potential to enhance bioavailability of active compounds which include drugs and phytochemicals, improve pharmacokinetic profiles, and optimize therapeutic outcomes, eventually overcoming the limitations of conventional oral active compounds delivery.
Search strategy: Data collection was carried out by entering key terms (TPGS) AND (Micelle OR Liposome OR Nanoparticle OR Nanotube OR Dendrimer OR Niosome OR Nanosuspension OR Nanomicelle OR Nanocrystal OR Nanosphere OR Nanocapsule) AND (Oral Bioavailability) into the Scopus database.
Inclusion criteria: Full-text articles published in English and relevant to TPGS, which featured organic materials, utilized an oral administration route, and included pharmacokinetic study, were included to the final review.
Data extraction and analysis: Data selection was conducted by two review authors and subsequently approved by all other authors through a consensus process. The outcomes of the included studies were reviewed and categorized based on the types of nanocarriers.
Results: An initial search of the database yielded 173 records. After screening by title and abstract, 52 full-text articles were analyzed. A total of 21 papers were excluded while 31 papers were used in this review.
Conclusions: This review concludes that TPGS-based organic nanocarriers are able to enhance the bioavailability of various active compounds, including several phytochemicals, leveraging TPGS’s amphiphilic nature, inhibition of efflux transporters, protection against degradation, and stabilization properties. Despite using the same excipient, variability in particle size, zeta potential, and encapsulation efficiency among nanocarriers indicates the need for tailored formulations. A comprehensive approach involving the development and standardized comparison of diverse TPGS-incorporated active compound formulations is essential to identify the optimal TPGS-based nanocarrier for improving a particular active compound’s bioavailability.
Introduction
Oral drug administration remains the most preferred route due to its numerous advantages. It is convenient, non-invasive, and enhances patient compliance, especially for long-term therapies. Oral formulations are also cost-effective to manufacture, store, and distribute, with versatile dosage forms such as tablets, capsules, and suspensions allowing for a flexible and controlled drug release. Nevertheless, the primary challenge in oral drug delivery is poor bioavailability, largely attributed to the first-pass metabolism, which significantly reduces the amount of the active compound reaching systemic circulation. Additionally, factors such as enzymatic degradation in the gastrointestinal tract, low solubility, and limited permeability further hinder effective drug absorption [1].
In addition to these challenges, many active compounds are chemically unstable and are prone to degradation when exposed to factors like light, heat, moisture, or gastrointestinal fluids, leading to reduced efficacy and shelf life [2]. Poor water solubility further limits an active compound’s ability to dissolve in the gastrointestinal fluids, a critical step for effective intestinal absorption [3]. Collectively, these issues contribute to diminished bioavailability, which may be further compromised by poor permeability across the intestinal lining or extensive first-pass metabolism in the liver.
Nanocarriers have been explored for oral drug formulation since the late 20th century, with significant advancements occurring in the early 2000s. The concept of nanoscale drug delivery systems, including liposomes and polymeric nanoparticles, was introduced in the 1970s–1980s. However, their application in oral formulations gained momentum in the 1990s with the development of solid lipid nanoparticles (SLNs) and polymer-based nanocarriers [4]. Over the past two decades, innovations in nanotechnology, such as self-emulsifying drug delivery systems (SEDDSs) and micelles, have further improved the bioavailability of poorly soluble drugs, making nanocarriers a crucial tool in modern oral drug delivery [5,6,7]. A nanocarrier is a nanoscale delivery system designed to encapsulate, protect, and transport active compounds, such as drugs, peptides, or bioactive molecules, to enhance their stability, solubility, and bioavailability. These carriers typically range in size from 1 to 1000 nm and are engineered to improve drug absorption, control the release, and target specific sites in the body [8,9]. Table 1 provides a comparative overview of various nanocarriers, categorized into polymer-based and lipid-based systems, as well as nanocrystals and nanosuspensions [10,11,12].
Table 1. Comparison of nanocarrier types: structure, drug loading, and stability.
| Type of Nanocarrier | Characteristics | ||
| Structure | Drug Loading | Stability | |
| Polymer-based | |||
| Micelle | Amphiphilic block copolymer self-assembled into a core–shell structure | Hydrophobic drug loaded into the core | Sensitive to dilution and environmental changes |
| Polymersome | Vesicle composed of amphiphilic block copolymers | Can entrap both hydrophilic and hydrophobic drugs | Enhanced stability compared to liposome |
| Amorphous solid dispersion | Drug dispersed in a polymer matrix in an amorphous state | Improve solubility of poorly water-soluble drugs | Thermodynamic instable and may crystallize over time |
| Lipid-based | |||
| Liposome | Phospholipid bilayer surrounding an aqueous core | Hydrophilic drug in core, hydrophobic drug in bilayer | Prone to fusion and leakage |
| Polymer lipid hybrid nanoparticle | Polymer core with a lipid shell | Can load both hydrophilic and hydrophobic drugs | Stable as it inherits advantages from both parental carriers |
| Niosome | Non-ionic surfactant vesicle with a bilayer structure | Hydrophilic drug within the core and hydrophobic drug between the bilayer | More stable than liposome |
| Solid lipid nanoparticle | Solid lipid core stabilized by surfactants | Can load both hydrophilic and hydrophobic drugs | Susceptible to lipid polymorphism-induced drug leakage |
| Lipid nanocapsule | Oily liquid core enclosed by a solid lipid-based shell | Lipophilic drug within the core | Highly stable |
| Self-emulsifying drug delivery system | Oil in water emulsion comprising a mixture of active compound, liquid oil, surfactant, and co-surfactant | Able to incorporate both hydrophilic and hydrophobic drugs | Thermodynamically stable |
| Nanocrystal | |||
| Nanocrystal | Crystalline drug particles, stabilized by surfactants | Incorporate hydrophobic drug | Require stabilizer to enhance stability |
| Nanosuspension | |||
| Nanosuspension | Nanodrug particles dispersed within aqueous or organic medium | Improve solubility of hydrophobic drug | Thermodynamically unstable |
Among these, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) formulations have emerged as a promising solution. TPGS not only improves solubility and permeability but also enables sustained drug release, ultimately optimizing therapeutic efficacy and overcoming the inherent limitations of oral drug delivery [13,14]. TPGS is an amphiphilic derivative of natural vitamin E. synthesized through an esterification reaction between vitamin E succinate and polyethylene glycol (PEG) 1000. Its chemical structure consists of four key components: a chromanol ring, a phytyl tail, a succinate group, and a polyethylene glycol chain (Figure 1). The chromanol ring and phytyl tail form the foundational structure akin to that of vitamin E. Through an esterification process, the succinate group binds this structure to the PEG chain. TPGS is classified as a polymer derivative of vitamin E, having a molecular weight of approximately 1513 Da (with the PEG portion contributing around 1000 Da). It is typically a waxy solid at room temperature (25 °C) and liquefies upon slight heating (37 °C). This unique composition makes it particularly valuable in pharmaceutical and nutraceutical applications as an active compound carrier or excipient (Table 2).
Figure 1. Chemical structure of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). TPGS is a polymeric derivative of vitamin E, consisting of D-α-tocopheryl succinate conjugated with polyethylene glycol (PEG 1000). Its molecular weight is approximately 1513 Da, accounting for both the PEG 1000 segment and the tocopheryl succinate moiety.
Table 2. Challenges in oral active compound formulation and the roles of TPGS.
| Challenges in Oral Active Compound Formulation | Potential of TPGS as an Oral Active Compound Bioavailability Enhancer |
|---|---|
| Solubility: Many active compounds have poor water solubility, leading to low bioavailability when administered orally. | The amphiphilic nature of TPGS enables it to form hydrogen bonding with hydrophilic active compounds and engage in hydrophobic interaction with lipophilic active compounds, allowing it to effectively dissolve both types of active compounds, making it a potent solubility enhancer. |
| Stability: Active compounds can degrade due to factors such as moisture, heat, light, and pH variations in the gastrointestinal tract. | Encapsulation of active compound within TPGS coating effectively forms a protective shield around the active compound, blocking the access of degradative enzymes to the active pharmaceutical compound. |
| First-pass metabolism: The liver metabolizes many active compounds before they reach systemic circulation, significantly reducing their bioavailability. | TPGS-containing formulation strategies such as proactive compounds, enzyme inhibitors, etc., are used to bypass or reduce first-pass metabolism. |
| Permeability: Some active compounds have low permeability across the gastrointestinal membrane. | TPGS enhances active compound permeability by inhibiting P-gp through modulation of membrane fluidity and P-gp ATPase inhibition. |
| Bioavailability: The fraction of the administered active compound that reaches the systemic circulation in an active form can be very low for some active compounds. | Enhancing solubility, using permeation enhancers, and employing active compound delivery systems like nanoparticles can improve bioavailability. |
ATPase: Adenosine triphosphatase; etc: et cetera; P-gp: P-glycoprotein; TPGS: D-α-tocopheryl polyethylene glycol 1000 succinate.
The amphiphilic nature of TPGS, stemming from incorporating both hydrophilic polar heads and lipophilic alkyl tails, enables it to form hydrogen bonds with hydrophilic active compounds and engage in hydrophobic interaction with lipophilic active compounds. This dual interaction capability allows TPGS to effectively enhance the solubility and absorption of both hydrophilic and lipophilic drugs [15,16]. The increasing use of TPGS as an absorption enhancer is attributed to its unique combination of properties that overcome key limitations associated with other enhancers (Table 3) [17,18]. Unlike chitosan, which is limited by pH sensitivity and becomes less effective in the neutral to alkaline conditions of the intestine, TPGS remains effective across a broader pH range (4.5–7.5), fully adapting the intestinal environment. Compared to chelating agents, which may interfere with calcium-dependent processes and formulation stability, TPGS does not chelate essential ions, preserving physiological balance. In contrast to fatty acid derivatives, which are mainly effective for hydrophilic drugs and may cause irritation, TPGS is versatile, enhancing the absorption of both hydrophilic and lipophilic compounds due to its amphiphilic property. Moreover, TPGS is biodegradable, surfactant-like, and stabilizes nanoparticle formulations, offering protection to drugs against degradation while minimizing safety concerns. Although TPGS may face challenges, such as non-specific P-gp inhibition, this can be mitigated by incorporating specific ligands to enhance targeted delivery. This broad-spectrum capability, combined with its safety profile, positions TPGS as an outstanding and more versatile absorption enhancer in drug delivery systems.
Table 3. Mechanism of action, advantages, and disadvantages of several common absorption enhancers.
| Common Absorption Enhancer | Mechanism of Action | Advantage(s) | Disadvantage(s) |
|---|---|---|---|
| TPGS | Solubilizes drug and inhibit P-gp efflux | Tailorable chemical modifications to meet the specific needs of drug delivery systems | Non-specific P-gp inhibition |
| Chitosan | Increases permeability of intestinal wall | Non-toxic and biodegradable | pH-sensitive |
| Bile salt | Reduces surface tension and increases drug solubility | Biocompatible and readily metabolized by the body | High concentration can cause significant membrane damage and local irritation |
| Chelating agent such as ethylene glycol tetraacetic acid and ethylene diamine tetraacetic acid | Bind to calcium ions, disrupting cell–cell contacts | Synergistic with other enhancers |
|
| Fatty acid and derivatives such as sodium caprate and salcaprozate sodium | Disrupt cellular tight junctions | Biocompatible and protects drug against degradation | Dose-dependent irritation and less useful for lipophilic drugs |
P-gp: P-glycoprotein; TPGS: D-α-tocopheryl polyethylene glycol 1000 succinate.
Moreover, TPGS has been shown to disrupt the optimal functioning of P-glycoprotein (P-gp), a drug efflux transporter, by modulating membrane fluidity [19] and inhibiting P-gp adenosine triphosphatase (ATPase) activity [20]. Through these mechanisms, TPGS enhances the intracellular concentration and bioavailability of P-gp substrates. While TPGS has been widely recognized for its ability to enhance intracellular drug accumulation by inhibiting P-gp, it is crucial to acknowledge that indiscriminate P-gp inhibition in healthy tissues may lead to adverse effects. P-gp serves a protective role in physiological barriers such as the blood–brain barrier and intestinal epithelium, preventing the entry of xenobiotics and potentially harmful compounds. Uncontrolled inhibition could result in unintended toxicity and drug accumulation in non-targeted tissues [21]. To mitigate these risks, incorporating active targeting ligands into TPGS-based nanocarriers presents a promising approach to enhance their specificity toward diseased tissues, thereby improving therapeutic efficacy and reducing off-target effects. For instance, folic acid (FA) conjugation exploits the overexpression of folate receptors on certain cancer cells, facilitating receptor-mediated endocytosis of the drug-loaded nanocarriers. A study demonstrates that FA-modified TPGS micelles effectively deliver nitidine chloride to Huh7 human hepatocellular carcinoma cells, resulting in increased apoptosis compared to non-targeted formulations [22]. By enabling selective accumulation in pathological sites, such as tumor tissues, TPGS-based nanocarriers can effectively modulate P-gp activity where needed while minimizing systemic toxicity [23]. This targeted strategy not only enhances therapeutic efficacy but also reduces the potential risks associated with widespread P-gp inhibition.
Additionally, TPGS serves as a safeguard against enzymatic degradation for active compounds. Encapsulation of active compounds within TPGS coating effectively forms a protective shield around the active compound, blocking the access of degradative enzymes to the active pharmaceutical compound [24]. Consequently, this shielding effect minimizes interactions between active compounds and external biomolecules, thereby averting undesired chemical reactions. Additionally, storage-induced oxidative degradation could be eliminated by TPGS antioxidant capability, thereby stabilizing active compounds and preserving therapeutic effects [25].
TPGS is approved by the Food and Drug Administration (FDA) and the Japanese regulatory authorities as a pharmaceutical excipient, with the FDA allowing a maximum potency of 300 mg per unit dose [26,27]. In Europe and Canada, TPGS is approved for different applications; Europe permits its use in foods for special medical purposes at a maximum level of 58 mg per 100 g of product, while Canada recognizes it as a form of Vitamin E with a tolerable upper intake level of 1000 mg per day for adults [26,28,29]. TPGS can be incorporated into various product forms, including liquid formulations, capsules, and tablets administered via the oral route [14]. It is also used in topical, nasal, ophthalmic, and parenteral applications, providing versatility across different routes of administration [25].
TPGS has been approved for use in several specialized products in various countries, which includes the United States and in Europe. Notable examples include Ibuprofen (Boots, Nottingham, UK), Aptivus® (Boehringer Ingelheim, Ingelheim, Germany), Agenerase® (GlaxoSmithKline, London, UK), Viekira Pak™ (Abbvie, Chicago, IL, USA), Technivie™ (Abbvie, Chicago, IL, USA), Zepatier™ (Merck Sharp & Dohme, Rahway, NJ, USA), Fenofibrate (Abbott, Chicago, IL, USA), and Mavyret™ (Abbvie, Chicago, IL, USA), which incorporate TPGS in their formulations as a major inactive ingredient, serving as a solubilizer, surfactant, and therapeutic effect enhancer [14,30,31]. In contrast, Vedrop® (Recordati Rare Diseases Ltd., London, UK) utilizes TPGS as an active ingredient for treating vitamin E deficiency caused by digestive disorders or conditions that impair fat absorption, particularly in children with malabsorption syndromes [32]. In addition to its role in active compound delivery, various studies have demonstrated that TPGS is a potent free-radical scavenger, which can be beneficial in combating oxidative stress [33]. This antioxidant feature makes TPGS particularly valuable in pharmaceutical and nutraceutical applications, serving not only as an active compound carrier or excipient but also as an adjunctive molecule that enhances therapeutic outcomes.
Various TPGS-based nanocarriers, each with unique structures and compositions, have been extensively explored for encapsulating a wide range of synthetic active compounds and molecules derived from natural sources. While inorganic nanocarriers offer excellent stability and controlled drug release, their potential for bioaccumulation raises safety concerns [34]. In contrast, organic nanocarriers are preferred for oral drug formulations due to their superior biocompatibility, biodegradability, and ability to enhance biocompatibility while minimizing toxicity risks [35]. Therefore, this review focuses on the role of TPGS-based organic nanocarriers as bioavailability enhancers, emphasizing their potential to improve the pharmacokinetic profiles and therapeutic outcomes of orally administered active compounds.
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Wong, C.N.; Lee, S.-K.; Lim, Y.M.; Yang, S.-B.; Chew, Y.-L.; Chua, A.-L.; Liew, K.B. Recent Advances in Vitamin E TPGS-Based Organic Nanocarriers for Enhancing the Oral Bioavailability of Active Compounds: A Systematic Review. Pharmaceutics 2025, 17, 485. https://doi.org/10.3390/pharmaceutics17040485
See also the interesting video on Vitamin E TPGS below and read more: here