K. V. N. Naik S. P. Sanstha’s, Institute of Pharmaceutical Education & Research, Canada Corner, Nashik, 422002, Maharashtra, India
Quercetin, a polyphenolic flavonoid abundant in fruits and vegetables, exhibits strong antioxidant, anti-inflammatory, cardioprotective, anticancer, and neuroprotective effects. However, its therapeutic use is hindered by poor solubility, low absorption, rapid metabolism, and limited bioavailability. Conventional enhancement methods such as micronisation and cyclodextrin complexation offer only partial improvement. Phytosome technology provides an effective solution by forming molecular complexes between quercetin and phospholipids like phosphatidylcholine. This amphiphilic structure enhances lipophilicity, membrane permeability, and systemic retention, resulting in nanosized particles (100–300 nm), high entrapment efficiency (>80%), and up to fourfold higher bioavailability. Preclinical and early clinical studies confirm improved antioxidant, hepatoprotective, neuroprotective, and anti-inflammatory efficacy, with good safety and tolerance. Remaining challenges include large-scale production, stability, and cost. Future progress depends on green synthesis, polymer-coated or co-phytosome systems, and harmonised global regulations to ensure quality and safety.
Over the past few decades, there has been an increasing global interest in natural polyphenols due to their wide-ranging health benefits and therapeutic potential against chronic diseases such as cardiovascular disorders, neurodegenerative conditions, diabetes, and cancer. Among these bioactive compounds, quercetin has attracted significant attention because of its strong antioxidant, anti-inflammatory, and anticancer properties.[1,2] Quercetin is widely found in fruits, vegetables, and medicinal plants such as onions, apples, and tea, and is considered one of the most abundant flavonoids in the human diet. Despite its potent biological activities, its clinical use remains restricted, primarily because of its poor aqueous solubility, limited absorption, and rapid metabolic degradation after oral administration.[3] Quercetin’s therapeutic potential is hindered by its biopharmaceutical limitations. Being highly lipophilic, it dissolves poorly in water and therefore exhibits low gastrointestinal absorption. Once ingested, a large portion of quercetin undergoes enzymatic degradation and extensive first-pass metabolism in the liver and intestines, resulting in minimal systemic availability. Consequently, only a small fraction of the ingested dose reaches the target tissues in its active form. This challenge has prompted researchers to develop innovative formulation strategies aimed at improving the solubility, stability, and bioavailability of quercetin.[4] Several conventional approaches have been explored to enhance the absorption of poorly soluble compounds like quercetin. Micronisation and nanosizing have been employed to reduce particle size, thereby increasing surface area and dissolution rate. Other approaches, such as forming inclusion complexes with β-cyclodextrin or encapsulating quercetin within polymeric nanoparticles and liposomes, have shown moderate success in improving solubility and absorption. However, these methods often face challenges such as physical instability, low drug loading capacity, and complex production processes. Additionally, while liposomes and polymeric nanoparticles can enhance permeability, they sometimes fail to achieve sustained release or optimal interaction with biological membranes, limiting their overall efficiency.[5] To overcome these shortcomings, phytosome technology has emerged as a next-generation nanocarrier system designed to improve the pharmacokinetic performance of plant-derived compounds. Phytosomes are unique phospholipid complexes in which the bioactive phytoconstituent forms a molecular association with phosphatidylcholine or similar phospholipids. Unlike conventional liposomes, where the active compound is merely trapped inside the vesicle, phytosomes form a chemical bond, such as hydrogen bonding between the polar functional groups of the bioactive molecule and the polar head of the phospholipid. This interaction enhances the lipophilicity of the compound and enables better integration with biological membranes, facilitating more efficient absorption and systemic availability.[6] By mimicking the structure and behaviour of biological membranes, phytosomes offer several distinct advantages. They provide improved solubility and stability, protect the encapsulated compound from degradation, and promote efficient intestinal uptake. The lipid-compatible nature of phytosomes also allows the complex to pass more easily through the lipid-rich cell membranes of the gastrointestinal tract. This results in improved pharmacokinetic parameters such as higher peak plasma concentrations, prolonged circulation time, and enhanced therapeutic efficacy. For quercetin, phytosomal encapsulation has been shown to significantly increase its oral bioavailability compared to free quercetin or traditional delivery systems.[7] Given these benefits, the development of quercetin-loaded phytosomes represents a major advancement in natural compound delivery technology. This innovative approach bridges the gap between formulation science and therapeutic application, providing a viable strategy for translating quercetin’s promising biological activities into clinically effective outcomes.[8] The scope of this review is to provide a comprehensive overview of phytosomes as an emerging nanocarrier system for improving the bioavailability of quercetin. It will integrate insights from formulation design, mechanistic studies, pharmacokinetic evaluations, and clinical evidence to present a holistic understanding of how phytosome technology enhances quercetin’s therapeutic potential. Ultimately, this review aims to establish phytosomes as a powerful platform for the efficient delivery of natural polyphenols, paving the way for their broader application in chronic disease prevention and management.
Quercetin, chemically known as 3,3′,4′,5,7-pentahydroxyflavone, is a naturally occurring polyphenolic flavonol with the molecular formula C??H??O?. Structurally, it consists of a three-ring system (A, B, and C rings) characteristic of the flavonoid family, with five hydroxyl groups strategically positioned at the 3, 5, 7, 3′, and 4′ carbon atoms. This arrangement confers quercetin its strong antioxidant capacity by enabling efficient donation of hydrogen atoms or electrons to neutralize reactive oxygen species (ROS). The presence of conjugated double bonds and multiple hydroxyl substitutions enhances its radical-scavenging and metal-chelating properties, which are central to its biological activity.[9]
Natural Sources
Quercetin is one of the most abundant flavonoids found in the human diet and is widely distributed in various plant-based foods. Major dietary sources include onions, apples, berries, citrus fruits, cherries, grapes, kale, broccoli, and tea leaves. Its content varies depending on factors such as plant variety, cultivation conditions, and food processing methods. For example, onions and apples are particularly rich in quercetin glycosides, while berries and leafy vegetables contain both free and conjugated forms. Quercetin is usually present as glycosides, where sugar moieties such as glucose or rhamnose are attached to the hydroxyl groups, influencing its solubility and absorption profile.[10]
Pharmacological Activities
Quercetin exhibits a wide spectrum of pharmacological activities, making it a key compound in nutraceutical and therapeutic research.
These diverse activities underscore quercetin’s potential as a multifunctional therapeutic molecule for chronic disease prevention and treatment.[11,12]
Pharmacokinetic Limitations
Despite its remarkable pharmacological profile, quercetin’s therapeutic utility is limited by poor pharmacokinetics. Its aqueous solubility is extremely low, approximately 0.01 mg/mL, which leads to poor dissolution in gastrointestinal fluids and low intestinal permeability. Consequently, only a small fraction of orally administered quercetin is absorbed. Furthermore, once absorbed, quercetin undergoes extensive phase II metabolism, primarily through glucuronidation and sulfation in the intestinal mucosa and liver. These metabolic processes rapidly convert the active aglycone form into conjugated metabolites, which often have reduced biological activity.[13] In addition, quercetin exhibits a short biological half-life and rapid systemic clearance, resulting in limited plasma concentrations after oral administration. Its poor stability under physiological conditions further contributes to its degradation before reaching target tissues. These challenges collectively result in very low oral bioavailability, reported to be less than 20%, severely restricting its clinical applicability.[14]
Need for Bioavailability Enhancement
To unlock the full therapeutic potential of quercetin, it is essential to develop advanced delivery systems capable of overcoming these biopharmaceutical barriers. Strategies such as lipid-based carriers, polymeric nanoparticles, inclusion complexes, and phospholipid conjugates have been explored to improve solubility, permeability, and metabolic stability. Among these, phytosomes-phospholipid complexes that enhance lipophilicity and membrane compatibility, have demonstrated superior performance in enhancing quercetin’s absorption and bioavailability. These systems not only facilitate efficient transport across biological membranes but also protect quercetin from premature degradation, thereby maximizing its therapeutic efficacy.[15]
Table 1. Physicochemical and Pharmacological Properties of Quercetin
|
Property |
Description |
|
Chemical Name |
3,3′,4′,5,7-pentahydroxyflavone |
|
Molecular Formula |
C??H??O? |
|
Molecular Weight |
302.24 g/mol |
|
Solubility |
Poorly soluble in water (~0.01 mg/mL); soluble in ethanol, DMSO, and alkaline solutions |
|
Appearance |
Yellow crystalline powder |
|
Log P (Partition Coefficient) |
1.82–2.5 (moderately lipophilic) |
|
Melting Point |
316–317°C |
|
Primary Dietary Sources |
Onions, apples, berries, citrus fruits, broccoli, grapes, tea leaves |
|
Key Pharmacological Activities |
Antioxidant, anti-inflammatory, cardioprotective, anticancer, neuroprotective |
|
Metabolism |
Extensive phase II metabolism (glucuronidation, sulfation) |
|
Elimination Half-life |
Short (1–2 hours in plasma) |
|
Bioavailability |
Very low (<20%) |
|
Major Limitation |
Poor solubility and rapid metabolic degradation |
Over the last decade, phytosome technology has emerged as an innovative and highly efficient delivery system for enhancing the bioavailability of plant-derived bioactives such as polyphenols, flavonoids, and terpenoids. The term “phytosome” is derived from the Greek words phyto (plant) and soma (body), indicating a natural complex formed between a plant constituent and a phospholipid molecule. This system overcomes the inherent solubility and permeability challenges of many phytochemicals by transforming them into lipid-compatible complexes capable of interacting effectively with biological membranes.[16]
Concept and Definition
A phytosome is defined as a molecular complex formed between a polar phytoconstituent and a phospholipid, most commonly phosphatidylcholine, at a molar ratio of 1:1 or 1:2. Unlike conventional liposomes, where the active compound is merely encapsulated within the vesicular structure, phytosomes involve a chemical association, typically through hydrogen bonding between the hydroxyl groups of the phytoconstituent and the polar head (phosphate and choline moiety) of the phospholipid. This interaction imparts amphiphilic characteristics to the complex, rendering it both hydrophilic and lipophilic. Consequently, the complex becomes more compatible with lipid-rich biological membranes, significantly improving its absorption, transport, and bioavailability.[17] Phosphatidylcholine plays a central role in phytosome formation. It consists of a glycerol backbone linked to two fatty acid chains and a phosphoric acid attached to a choline group. The hydrophilic head of phosphatidylcholine interacts with the polar functional groups of the bioactive compound, while the nonpolar tail aligns with lipid environments. This dual nature allows the phytosome complex to seamlessly integrate into cellular membranes, facilitating passive diffusion across biological barriers such as the intestinal epithelium.[18]
Mechanism of Phytosome Formation and Action
The mechanism of phytosome formation involves the establishment of hydrogen bonds between the polar functional groups, typically hydroxyl or carbonyl of the phytoconstituent and the polar head group of the phospholipid. When quercetin, for example, interacts with phosphatidylcholine, its multiple hydroxyl groups form stable hydrogen bonds with the phosphate and ammonium groups of the lipid molecule. This results in the formation of a discrete, stable complex that is not merely a mixture but a distinct chemical entity.[19] Once administered, the lipid-compatible phytosome complex exhibits enhanced membrane permeability and solubility. Its amphiphilic structure allows it to dissolve readily in both aqueous and lipid environments, thereby improving its dispersion in gastrointestinal fluids and facilitating passive diffusion through the lipid bilayer of enterocytes. This enhanced permeability enables higher systemic absorption of quercetin, while the phospholipid matrix provides protection against enzymatic degradation and oxidative damage during transit. Moreover, because phosphatidylcholine is a natural component of biological membranes, phytosomes exhibit excellent biocompatibility and low toxicity, further supporting their suitability for therapeutic applications.[20]
Preparation Methods
Several techniques have been developed for the preparation of phytosomes, each offering distinct advantages in terms of yield, particle size control, and scalability:
In this widely used technique, the phytoconstituent and phospholipid are dissolved in an organic solvent such as dichloromethane or ethanol. The solvent is then evaporated under reduced pressure to form a thin film, which is subsequently hydrated to yield the phytosome complex.
The phytoconstituent and phospholipid are first dissolved in a common organic solvent. Upon addition of a non-solvent such as water or n-hexane, the complex precipitates out, which can then be filtered and dried to obtain the phytosome.
This method involves dissolving both components in a volatile organic solvent and evaporating the solvent under vacuum using a rotary evaporator. The resulting film is then collected and dried under nitrogen or in a desiccator.
The phytoconstituent and phospholipid are co-dissolved and spread into a thin layer on the walls of a flask. After solvent evaporation, hydration with an aqueous buffer under controlled agitation produces vesicular phytosomes.
This advanced, solvent-free technique uses supercritical carbon dioxide as a medium for complex formation. It offers superior control over particle size, eliminates residual solvents, and yields highly pure phytosome formulations suitable for pharmaceutical use. Each of these methods can be optimized by adjusting parameters such as molar ratio, temperature, solvent type, and reaction time to maximize complexation efficiency and stability.[21,22]
Phytosomes vs. Liposomes
Although phytosomes and liposomes may appear similar in structure, they differ fundamentally in their composition and mechanism of action. In liposomes, the bioactive compound is physically encapsulated within the aqueous or lipid compartment of the vesicle, while in phytosomes, the phytoconstituent forms a chemical complex with the phospholipid molecule. This distinction results in several key advantages for phytosomes, including higher stability, better drug loading efficiency, and improved bioavailability.[23]
Table 2. Comparison of Phytosomes with Other Nanocarriers
|
Feature |
Phytosomes |
Liposomes |
Polymeric Nanoparticles |
Solid Lipid Nanoparticles (SLNs) |
|
Drug Association |
Covalent or hydrogen bonding complexation |
Physical encapsulation |
Physical entrapment or adsorption |
Encapsulation in lipid matrix |
|
Main Component |
Phospholipid–phytoconstituent complex |
Phospholipid bilayer |
Biodegradable polymers (e.g., PLGA) |
Solid lipids and surfactants |
|
Solubility Enhancement |
Excellent (due to lipid compatibility) |
Moderate |
Variable |
Good |
|
Stability |
High (chemical complex is stable) |
Moderate (prone to leakage) |
High |
High |
|
Biocompatibility |
Excellent |
Excellent |
Good |
Good |
|
Entrapment Efficiency |
High |
Moderate |
High |
High |
|
Bioavailability Improvement |
Significant |
Moderate |
Variable |
Moderate |
|
Production Complexity |
Relatively simple |
Moderate |
High |
High |
Phytosome technology thus represents a transformative advancement in natural product formulation, combining the molecular precision of chemical complexation with the physiological compatibility of lipid-based carriers. Through its unique structure and mechanism, the phytosome system offers a practical and efficient strategy to enhance the delivery and bioavailability of quercetin and other poorly soluble phytochemicals, paving the way for their wider therapeutic application.[24]
Evaluation Parameters
Comprehensive evaluation of the prepared quercetin–phytosome complex involves analyzing several physicochemical and functional parameters to ensure reproducibility, stability, and efficacy.
Phytosome particles generally exhibit a mean size of 100–300 nm, suitable for enhancing intestinal absorption and tissue permeability. A PDI below 0.3 indicates uniform particle distribution and high formulation homogeneity, which is essential for consistent bioavailability.
The surface charge, typically ranging from –20 mV to –40 mV, reflects the electrostatic stability of the colloidal dispersion. Higher negative values help prevent aggregation due to repulsive forces between particles, thereby improving the shelf-life of the formulation.
Entrapment efficiency refers to the percentage of quercetin successfully incorporated into the phytosome complex relative to the initial amount used. Well-optimized formulations often achieve EE > 80%, indicating effective complexation and minimal drug loss during preparation.
Transmission or Scanning Electron Microscopy provides detailed insight into the surface topology and shape of phytosomal particles. Typically, quercetin–phytosomes appear as spherical or ellipsoidal vesicles with smooth surfaces and uniform distribution.
Differential Scanning Calorimetry (DSC) confirms complex formation through shifts in melting endotherms, while Fourier Transform Infrared (FTIR) spectroscopy identifies characteristic hydrogen-bonding interactions between quercetin and phosphatidylcholine.
Compared with pure quercetin, phytosomal formulations exhibit significantly enhanced dissolution rates, often several-fold higher due to increased wettability and lipid compatibility.[25,26]
One of the most compelling advantages of phytosome technology lies in its ability to markedly enhance the pharmacokinetic profile and bioavailability of poorly soluble phytoconstituents such as quercetin. The pharmacokinetic limitations of quercetin, namely its low aqueous solubility (~0.01 mg/mL), extensive phase II metabolism (glucuronidation and sulfation), and rapid systemic clearance, significantly restrict its therapeutic potential when administered orally. The development of quercetin-phytosome complexes has proven to be an effective solution to these challenges, demonstrating substantial improvements in absorption, plasma concentration, and half-life across preclinical and clinical studies.[27]
Mechanisms Underlying Enhanced Bioavailability
The improved pharmacokinetic performance of quercetin–phytosomes arises from multiple, complementary mechanisms that together facilitate more efficient absorption and systemic delivery:
The lipid-rich nature of phytosomes promotes absorption through the lymphatic system, bypassing hepatic first-pass metabolism, a major route of quercetin’s presystemic elimination. By entering systemic circulation via the lymphatic pathway, the quercetin–phytosome complex avoids extensive enzymatic conjugation, leading to higher plasma levels of the unmetabolized, bioactive form. Studies using radiolabelled formulations have confirmed enhanced lymphatic uptake and retention in intestinal lymph nodes.[28]
Free quercetin is highly susceptible to oxidative degradation and rapid enzymatic conjugation by UDP-glucuronosyltransferase and sulfotransferase enzymes. The phospholipid matrix of phytosomes shields quercetin from direct exposure to these enzymes and oxidative conditions, thereby improving its chemical stability and metabolic resistance. This encapsulation effect reduces premature degradation and allows more quercetin to reach systemic circulation in its active form. Together, these mechanisms contribute to a sustained and enhanced pharmacokinetic profile, which translates into improved pharmacodynamic performance and therapeutic efficacy.[29]
Comparative Analysis with Other Delivery Systems
To contextualize the advantages of the phytosome approach, it is valuable to compare it with other nanocarrier systems such as nanoemulsions, solid lipid nanoparticles (SLNs), and micellar systems that have also been explored for quercetin delivery.
Conventional quercetin suspensions suffer from poor dissolution and limited intestinal permeability, resulting in negligible plasma concentrations. Phytosome formulations, by contrast, enhance both solubility and membrane permeability, leading to 2-4× higher Cmax and AUC values in animal models. Additionally, the lipid-compatible nature of the complex promotes more consistent absorption, minimizing inter-individual variability.[30]
While nanoemulsions also enhance solubility, they often face stability issues such as droplet coalescence and phase separation. Phytosomes, being molecular complexes rather than physical mixtures, exhibit greater thermodynamic stability and resist degradation during storage. Furthermore, phytosomes provide a more predictable release profile, as drug release depends on the dissociation of the phospholipid complex rather than emulsion destabilization.[15]
SLNs encapsulate drugs within a solid lipid matrix, which can sometimes hinder release and absorption due to drug entrapment. Phytosomes, in contrast, facilitate direct interaction between the drug and biological membranes, leading to more efficient absorption and faster onset of action. The absence of surfactants and synthetic lipids in phytosomes also contributes to superior biocompatibility and reduced toxicity risk.[7]
Micelles can improve solubility but often require high concentrations of surfactants, which may cause gastrointestinal irritation or toxicity upon chronic use. Phytosomes avoid this issue by using naturally occurring phospholipids, ensuring better safety profiles and enhanced patient acceptability. Moreover, phytosomes display higher entrapment efficiency and longer circulation times compared to micellar systems.[31]
Future work aims to replace harmful organic solvents with green alternatives such as supercritical CO?, deep eutectic solvents, and bio-based systems. These sustainable methods minimise environmental impact and ease regulatory compliance.
Combining phytosomes with biodegradable polymers like chitosan, alginate, or PLGA can enhance stability and provide sustained, site-specific drug release, especially for oral and transdermal applications.
Co-phytosomes, containing multiple bioactives such as quercetin with curcumin or resveratrol, offer synergistic effects against complex diseases. They improve efficacy, simplify dosing, and enhance patient adherence.
Lack of unified global regulations hinders phytosome development. Establishing international standards for quality, safety, and efficacy similar to nano pharmaceutical guidelines will support approval and consumer confidence.[32,33]
CONCLUSION
Phytosomes provide an efficient, biocompatible delivery system that overcomes quercetin’s solubility and bioavailability issues. By forming stable lipid complexes, they enhance absorption and therapeutic performance across oxidative, inflammatory, and degenerative conditions. The integration of polyphenol pharmacology with lipid nanotechnology positions quercetin-phytosomes as promising candidates for nutraceutical and pharmaceutical formulations. Co-phytosome innovations further extend their potential in preventive and therapeutic health. To advance this field, standardised manufacturing, clinical validation, and regulatory alignment are crucial. With these developments, quercetin–phytosomes could become a model for next-generation natural bioenhancers, bridging traditional phototherapy and modern nutraceutical science.
REFERENCE
Anjali Kale*, Trupti Kadam, Phytosomes: An Emerging Nanocarrier System for Enhancing the Bioavailability of Quercetin, Int. J. Sci. R. Tech., 2026, 3 (3), 138-147. https://doi.org/10.5281/zenodo.18927730
10.5281/zenodo.18927730
