Phytosomes: Lipid-Based Nanocarriers for Enhanced Herbal Bioavailability

Gayatri Arun Pote¹, Riba Jakir Shaikh¹, Dr. Rutuja Kamble²*

1.        Research Scholar, Department of Pharmaceutical Chemistry & Quality Assurance, Indira University’s School of Pharmacy, Pune, Maharashtra, India.

2.        Department of Pharmaceutical Chemistry & Quality Assurance, Indira University’s School of Pharmacy, Pune, Maharashtra, India

*Correspondence: kamblerv23@gmail.com.

DOI: https://doi.org/10.71431/IJRPAS.2026.5501   

INTRODUCTION

Phytosomes are advanced lipid-based drug delivery systems developed to enhance the bioavailability of plant-derived phytoconstituents. They are formed by complexing bioactive plant molecules with phospholipids, primarily phosphatidylcholine, resulting in a molecular complex that exhibits both hydrophilic and lipophilic characteristics. This unique property enables phytosomes to efficiently cross biological membranes and improve the absorption of poorly bioavailable herbal compounds [1,2].

The term “phytosome” is derived from “phyto,” meaning plant, and “some,” meaning cell-like structure. Unlike conventional herbal extracts, phytosomes form a stable complex in which the polar functional groups of phytoconstituents interact with the polar head of phospholipids through hydrogen bonding. This interaction leads to the formation of a lipid-compatible structure that enhances membrane permeability and protects the active constituents from degradation in the gastrointestinal tract [3,4].

A major limitation of many phytoconstituents, such as flavonoids, terpenoids, and polyphenols, is their poor bioavailability. This is primarily due to their large molecular size, low lipid solubility, and limited ability to permeate biological membranes. As a result, their therapeutic potential is often not fully realized when administered in conventional forms [5,6]. Phytosome technology addresses these challenges by improving solubility, stability, and systemic absorption, thereby enhancing pharmacokinetic and pharmacodynamic profiles [7].

Figure 1. Structure of Phytosome

Over the past few decades, phytosomes have gained considerable attention in the field of novel drug delivery systems. Their improved absorption and therapeutic efficacy have led to their application in various conditions, including liver disorders, cardiovascular diseases, and inflammatory conditions [8]. This review aims to discuss the formulation, mechanism, characterization, advantages, and therapeutic applications of phytosomes as a promising approach in herbal drug delivery.

CONCEPT AND MECHANISM OF PHYTOSOMES

Phytosomes are molecular complexes formed through the interaction of bioactive phytoconstituents with phospholipids, most commonly phosphatidylcholine. Unlike conventional vesicular systems such as liposomes—where the drug is physically entrapped within the aqueous core or lipid bilayer—phytosomes involve the formation of a definite chemical complex between the phytoconstituent and the phospholipid. This distinction is critical, as it results in improved stability and enhanced bioavailability of the active compound [3,9].

The mechanism of phytosome formation is primarily governed by hydrogen bonding and other weak intermolecular interactions between the polar functional groups of phytoconstituents (such as hydroxyl, carboxyl, and phenolic groups) and the polar head of phosphatidylcholine. Phosphatidylcholine is an amphiphilic molecule composed of a hydrophilic choline-containing head and two lipophilic fatty acid tails. During complexation, the polar region of the phytoconstituent forms hydrogen bonds with the phosphate and ammonium groups of phosphatidylcholine, resulting in a stable molecular association [4,10].

Figure 2. Mechanism of Phytosome Formation

This interaction leads to the formation of a lipid-compatible complex in which the phytoconstituent becomes an integral part of the phospholipid structure rather than being merely encapsulated. The lipophilic fatty acid chains of phosphatidylcholine surround the bound phytoconstituent, creating a protective envelope that enhances its solubility in lipid environments. This structural arrangement significantly increases the partition coefficient of the phytoconstituent, thereby improving its ability to cross lipid-rich biological membranes [11,12].

The amphiphilic nature of phytosomes plays a crucial role in their enhanced absorption. Biological membranes, including those of enterocytes in the gastrointestinal tract, are composed predominantly of phospholipid bilayers. Due to structural similarity, phytosomes can readily merge with or diffuse across these membranes, facilitating efficient transport of the phytoconstituent into systemic circulation [5,13].

In contrast, many phytoconstituents in their free form exhibit poor absorption due to high polarity, large molecular size, and low lipid solubility. These factors limit their ability to permeate through the lipid-rich intestinal membrane via passive diffusion. Phytosome formation overcomes these barriers by increasing lipophilicity while preserving the pharmacological activity of the phytoconstituent [6,12].

Another important advantage of phytosomes is their ability to protect active phytoconstituents from degradation. In the gastrointestinal tract, many plant compounds are susceptible to enzymatic hydrolysis and chemical degradation. The phospholipid complex acts as a protective barrier, reducing premature metabolism and enhancing the stability of the active compound during absorption [7,13].

Furthermore, studies have demonstrated that phytosomes exhibit improved pharmacokinetic properties, including higher plasma concentration, increased area under the curve (AUC), and prolonged residence time compared to conventional extracts. This ultimately translates into enhanced pharmacodynamic effects and improved therapeutic efficacy [2,14].

Overall, the mechanism of phytosome formation and action is based on the creation of a stable, lipid-compatible molecular complex that enhances membrane permeability, protects against degradation, and significantly improves the bioavailability of phytoconstituents.

CONCEPT AND MECHANISM OF PHYTOSOMES

Phytosomes are molecular complexes formed through the interaction of bioactive phytoconstituents with phospholipids, most commonly phosphatidylcholine. Unlike conventional vesicular systems such as liposomes—where the drug is physically entrapped within the aqueous core or lipid bilayer—phytosomes involve the formation of a definite chemical complex between the phytoconstituent and the phospholipid. This distinction is critical, as it results in improved stability and enhanced bioavailability of the active compound [3,9].

The mechanism of phytosome formation is primarily governed by hydrogen bonding and other weak intermolecular interactions between the polar functional groups of phytoconstituents (such as hydroxyl, carboxyl, and phenolic groups) and the polar head of phosphatidylcholine. Phosphatidylcholine is an amphiphilic molecule composed of a hydrophilic choline-containing head and two lipophilic fatty acid tails. During complexation, the polar region of the phytoconstituent forms hydrogen bonds with the phosphate and ammonium groups of phosphatidylcholine, resulting in a stable molecular association [4,10].

This interaction leads to the formation of a lipid-compatible complex in which the phytoconstituent becomes an integral part of the phospholipid structure rather than being merely encapsulated. The lipophilic fatty acid chains of phosphatidylcholine surround the bound phytoconstituent, creating a protective envelope that enhances its solubility in lipid environments. This structural arrangement significantly increases the partition coefficient of the phytoconstituent, thereby improving its ability to cross lipid-rich biological membranes [11,12].

Figure 3. Mechanism of Enhanced Bioavailability

The amphiphilic nature of phytosomes plays a crucial role in their enhanced absorption. Biological membranes, including those of enterocytes in the gastrointestinal tract, are composed predominantly of phospholipid bilayers. Due to structural similarity, phytosomes can readily merge with or diffuse across these membranes, facilitating efficient transport of the phytoconstituent into systemic circulation [5,13].

In contrast, many phytoconstituents in their free form exhibit poor absorption due to high polarity, large molecular size, and low lipid solubility. These factors limit their ability to permeate through the lipid-rich intestinal membrane via passive diffusion. Phytosome formation overcomes these barriers by increasing lipophilicity while preserving the pharmacological activity of the phytoconstituent [6,12].

Another important advantage of phytosomes is their ability to protect active phytoconstituents from degradation. In the gastrointestinal tract, many plant compounds are susceptible to enzymatic hydrolysis and chemical degradation. The phospholipid complex acts as a protective barrier, reducing premature metabolism and enhancing the stability of the active compound during absorption [7,13].

Furthermore, studies have demonstrated that phytosomes exhibit improved pharmacokinetic properties, including higher plasma concentration, increased area under the curve (AUC), and prolonged residence time compared to conventional extracts. This ultimately translates into enhanced pharmacodynamic effects and improved therapeutic efficacy [2,14].

Overall, the mechanism of phytosome formation and action is based on the creation of a stable, lipid-compatible molecular complex that enhances membrane permeability, protects against degradation, and significantly improves the bioavailability of phytoconstituents.

PREPARATION METHODS OF PHYTOSOMES

Preparation methods play a critical role in determining the physicochemical properties, stability, entrapment efficiency, and therapeutic performance of phytosomes. Various formulation techniques have been developed to prepare phytosome complexes depending on the nature of the phytoconstituent, phospholipid, and desired formulation characteristics. The selection of an appropriate preparation method influences particle size, drug loading, bioavailability, and overall formulation stability.

1. SOLVENT EVAPORATION METHOD

The solvent evaporation method is one of the most commonly used techniques for phytosome preparation. In this method, the phytoconstituent and phospholipid are dissolved in an appropriate organic solvent such as ethanol, dichloromethane, or acetone in a specific molar ratio. The resulting solution is refluxed or stirred to facilitate complex formation between the phytoconstituent and phospholipid. The organic solvent is then removed under reduced pressure using a rotary evaporator, resulting in the formation of a thin film or precipitated phytosomal complex. The obtained complex is subsequently dried and collected for further characterization [15,16].

Figure 4. Solvent Evaporation Method

2. ANTI-SOLVENT PRECIPITATION METHOD

In the anti-solvent precipitation method, the phytoconstituent and phospholipid are first dissolved in a suitable organic solvent. This solution is then added slowly into a non-solvent (anti-solvent) such as n-hexane under continuous stirring. The sudden reduction in solubility causes precipitation of the phytophospholipid complex. The precipitate is filtered, dried, and stored appropriately. This method is simple, cost-effective, and suitable for large-scale preparation [17].

Figure 5. Antisolvent Precipitation Technique

3. THIN-FILM HYDRATION METHOD

The thin-film hydration method is widely employed for the preparation of vesicular systems including phytosomes. In this technique, phospholipids and phytoconstituents are dissolved in an organic solvent mixture and evaporated under reduced pressure to form a thin lipid film on the wall of a round-bottom flask. The dried film is then hydrated using distilled water or buffer solution with continuous agitation, resulting in the formation of phytosomal vesicles. Sonication or extrusion may be used to reduce particle size and obtain uniform vesicles [18].

Figure 6. Thin Film Hydration method

4. LYOPHILIZATION (FREEZE-DRYING) METHOD

Lyophilization is commonly used as a stabilization technique for phytosomal formulations. After preparation of the phytosomal suspension, the formulation is frozen and subjected to sublimation under vacuum conditions to remove water content. This process improves storage stability, prevents aggregation, and enhances shelf-life. Cryoprotectants such as mannitol or trehalose are often added to preserve vesicle integrity during freeze-drying [19].

5. SUPERCRITICAL FLUID TECHNIQUE

The supercritical fluid method is an advanced and environmentally friendly approach for phytosome preparation. Supercritical carbon dioxide is commonly used as a solvent or anti-solvent for complex formation. This technique offers several advantages including reduced solvent toxicity, improved particle uniformity, and enhanced control over particle size distribution. Additionally, it aligns with green chemistry principles and is increasingly explored for sustainable pharmaceutical manufacturing [20].

The method used for phytosome preparation significantly affects the quality and performance of the final formulation. Conventional methods such as solvent evaporation and thin-film hydration remain widely utilized due to their simplicity and effectiveness, while advanced techniques such as supercritical fluid processing provide opportunities for improved scalability, sustainability, and formulation precision [21]. Continuous advancements in preparation technologies are expected to further enhance the pharmaceutical potential of phytosomal drug delivery systems.

CHARACTERIZATION AND EVALUATION OF PHYTOSOMES

Characterization of phytosomes is a critical step in the development of an efficient drug delivery system, as it ensures the successful formation of the phytophospholipid complex and determines its physicochemical and biological performance. Various analytical techniques are employed to evaluate parameters such as particle size, morphology, surface charge, thermal behavior, and drug release characteristics. These parameters collectively influence the stability, bioavailability, and therapeutic efficacy of phytosomal formulations [22].

1. Particle size distribution and zeta potential

Particle size is a key determinant of the absorption and biodistribution of phytosomes. Nanosized particles provide a larger surface area, which enhances dissolution rate and facilitates better interaction with biological membranes. Particle size and size distribution are commonly measured using dynamic light scattering (DLS) or photon correlation spectroscopy (PCS) [23].

Zeta potential is an important indicator of surface charge and colloidal stability. A higher magnitude of zeta potential (either positive or negative) indicates strong repulsive forces between particles, thereby preventing aggregation and improving stability during storage. Generally, values above ±30 mV are considered stable for colloidal systems [24].

2. Morphological and surface characterization

The morphology, size, and surface characteristics of phytosomes are evaluated using advanced microscopic techniques such as scanning electron microscopy (SEM) and transmission electron microscopy (TEM). These techniques provide high-resolution images that help confirm the vesicular nature and uniformity of phytosomes. Typically, phytosomes exhibit spherical or near-spherical structures with smooth surfaces [25].

3. Spectroscopic analysis

Spectroscopic techniques play a crucial role in confirming the formation of phytosome complexes.

a. Fourier Transform Infrared Spectroscopy (FTIR)

FTIR analysis is used to identify functional groups and detect possible interactions between phytoconstituents and phospholipids. The formation of hydrogen bonds between the two components is indicated by shifts in characteristic absorption peaks, confirming successful complexation [26].

b. Nuclear Magnetic Resonance (NMR)

¹H-NMR and ¹³C-NMR spectroscopy provide detailed insights into molecular interactions. Changes in chemical shifts, peak broadening, or disappearance of signals indicate the formation of a phytophospholipid complex and help distinguish it from a simple physical mixture [27].

4. Thermal analysis (differential scanning calorimetry - dsc)

DSC is used to study the thermal behavior and phase transitions of phytosomal complexes. By comparing the thermograms of pure phytoconstituents, phospholipids, and the phytosome complex, it is possible to confirm the formation of a new molecular entity. The disappearance or shifting of melting peaks indicates successful complexation [28].

5. Solubility and partition coefficient

The solubility profile of phytosomes is evaluated in both aqueous and lipid media. Phytosomes generally exhibit enhanced solubility in lipid environments due to increased lipophilicity imparted by phospholipid complexation. The partition coefficient (log P) is measured using n-octanol/water systems to assess the drug’s ability to cross biological membranes. An increase in partition coefficient indicates improved membrane permeability [29].

6. Entrapment efficiency and drug content

Entrapment efficiency refers to the percentage of phytoconstituent successfully incorporated into the phytosomal complex. It is determined by separating free drug from the complex and quantifying it using analytical techniques such as UV spectroscopy or HPLC. High entrapment efficiency is desirable as it reflects effective complexation and improved drug delivery potential [30].

7. In vitro drug release studies

In vitro release studies are performed to evaluate the release behavior of phytoconstituents from the phytosome complex under simulated physiological conditions. These studies help determine whether the formulation provides immediate or sustained release and are essential for predicting in vivo performance. Release kinetics models may also be applied to understand the mechanism of drug release [31].

8. In vivo pharmacokinetic and pharmacodynamic studies

In vivo studies are conducted to evaluate the biological performance of phytosomes. Pharmacokinetic parameters such as maximum plasma concentration (Cmax), time to reach peak concentration (Tmax), and area under the curve (AUC) are measured. Phytosomes typically show higher Cmax and AUC values compared to conventional extracts, indicating enhanced bioavailability. Pharmacodynamic studies further confirm improved therapeutic efficacy [32].

9. Stability studies

Stability studies are carried out to assess the physical and chemical stability of phytosomes under different storage conditions, including variations in temperature, humidity, and light exposure. Parameters such as particle size, zeta potential, drug content, and appearance are monitored over time to determine shelf-life and storage requirements [22].

ADVANTAGES AND LIMITATIONS OF PHYTOSOMES

Phytosomes offer several advantages over conventional herbal formulations and other drug Phytosomes offer several advantages over conventional herbal formulations, making them a promising carrier system for enhancing the therapeutic performance of phytoconstituents. One of the most significant benefits of phytosomes is their ability to improve the bioavailability of poorly absorbed plant-derived active compounds. The complexation of phytoconstituents with phospholipids increases their lipophilic character, thereby facilitating better permeation across biological membranes and enhancing systemic absorption [33]. This property is particularly beneficial for phytoconstituents such as flavonoids, polyphenols, and terpenoids, which generally exhibit poor oral bioavailability due to limited membrane permeability and low solubility.

In addition to improved bioavailability, phytosomes exhibit enhanced absorption and permeability because of their structural resemblance to biological membranes. The phospholipid component of phytosomes allows the complex to integrate easily into the phospholipid bilayer of cell membranes, thereby promoting gastrointestinal absorption and improving systemic availability after oral administration [34]. For example, phytosomal formulations of curcumin and silybin have demonstrated superior absorption compared to their conventional extracts.

Another important advantage of phytosomes is their increased stability. Many phytoconstituents are susceptible to degradation in the gastrointestinal environment due to acidic pH, digestive enzymes, and exposure to environmental factors such as heat, moisture, and light. Encapsulation within a phospholipid complex protects these active compounds from such degradation, thereby improving their chemical and physical stability during storage and administration [35]. This stabilization is particularly important for sensitive compounds such as quercetin and epigallocatechin gallate.

Phytosomes also provide better therapeutic efficacy compared to conventional herbal preparations. Improved pharmacokinetic properties, including enhanced absorption, higher plasma concentration, and prolonged circulation time, contribute to superior pharmacological effects. For instance, phytosomal curcumin and resveratrol formulations have shown greater anti-inflammatory, antioxidant, and anticancer activities than non-phytosomal preparations [36]. Such improvements make phytosomes an attractive option for enhancing the clinical utility of herbal drugs.

Another major advantage is the reduced dose requirement. Since phytosomes improve the bioavailability of active constituents, lower doses are often sufficient to achieve the desired therapeutic effect. This reduction in dose may minimize the risk of adverse effects and improve safety profiles, especially for long-term treatment [37]. For example, phytosomal silybin formulations have demonstrated therapeutic efficacy at lower doses compared to conventional silymarin extracts.

Phytosomes are also highly versatile and can be incorporated into a wide range of dosage forms, including tablets, capsules, suspensions, topical gels, creams, and transdermal systems. This versatility makes them suitable for various routes of administration and broadens their pharmaceutical applications [33]. Commercial products such as Meriva® and Siliphos® are available in oral capsule forms, demonstrating the adaptability of this technology.

Improved patient compliance is another notable benefit of phytosomal formulations. Due to lower dosing frequency, enhanced therapeutic efficacy, and reduced side effects, patients are more likely to adhere to treatment regimens when compared with conventional herbal products [34]. This is particularly relevant in chronic diseases where long-term administration is required.

An additional unique feature of phytosomes is the dual function of phospholipids, particularly phosphatidylcholine. Besides acting as a carrier molecule, phosphatidylcholine itself possesses therapeutic properties, especially hepatoprotective activity. This synergistic contribution can further enhance the overall efficacy of the formulation, particularly in liver disorders where compounds such as silybin are used [38].

LIMITATIONS OF PHYTOSOMES

Despite the numerous advantages associated with phytosomal drug delivery systems, certain limitations restrict their widespread application and require further optimization. One of the major limitations is their limited stability under certain environmental conditions. Although phytosomes improve the stability of phytoconstituents compared to conventional herbal extracts, they may still undergo degradation, fusion, or aggregation when exposed to extreme temperatures, high humidity, or prolonged storage conditions [39]. Such instability may affect the physicochemical properties of the formulation and reduce its shelf life.

Another limitation is the possibility of drug leakage or dissociation of the phytoconstituent from the phospholipid complex. In some cases, the active compound may separate from the phospholipid during storage or after administration, leading to reduced drug content, compromised formulation integrity, and decreased therapeutic efficacy [40]. This issue is particularly relevant for unstable phytoconstituents with weak phospholipid-binding affinity.

High production cost is also considered a significant challenge in the commercialization of phytosomal formulations. The preparation of phytosomes often requires high-purity phospholipids such as phosphatidylcholine, specialized solvents, and advanced manufacturing techniques. These factors increase the overall cost of production compared to conventional herbal formulations, limiting their affordability and large-scale industrial application [33]. This may pose economic constraints for widespread use, particularly in low-cost herbal pharmaceutical markets.

Phytosomes also exhibit limited drug loading capacity, which restricts their application to specific categories of phytoconstituents. This delivery system is mainly suitable for compounds capable of forming molecular complexes with phospholipids. Not all plant-derived active compounds possess the required physicochemical characteristics for complex formation, thereby limiting the range of phytoconstituents that can be effectively incorporated into phytosomal systems [41]. For example, highly hydrophilic compounds may not efficiently interact with phospholipid molecules.

Scale-up challenges represent another important limitation. While phytosome preparation at laboratory scale is relatively simple and reproducible, scaling up the process for industrial manufacturing can be difficult. Maintaining uniform particle size, entrapment efficiency, and batch-to-batch consistency during large-scale production requires precise process control and specialized equipment [42]. These challenges may hinder the transition from laboratory research to commercial production.

Potential safety concerns have also been reported for certain phospholipid-based carriers. In some studies, phospholipids such as lecithin and phosphatidylcholine have shown the potential to influence cell membrane behavior and cellular proliferation under specific experimental conditions. Although phytosomes are generally regarded as safe, long-term safety studies are still necessary to evaluate their chronic toxicity and biological effects after repeated administration [43]. This is especially important for formulations intended for prolonged therapeutic use.

Despite these limitations, phytosomes remain a highly promising approach in herbal drug delivery due to their remarkable ability to enhance the bioavailability, absorption, and therapeutic efficacy of phytoconstituents. Continued advancements in formulation strategies, process optimization, and nanotechnology integration are expected to overcome current limitations and further expand the pharmaceutical and nutraceutical applications of phytosomal systems [34,36].

THERAPEUTIC APPLICATIONS OF PHYTOSOMES

Phytosomes have gained significant importance in modern pharmacotherapy due to their ability to enhance the bioavailability, absorption, and therapeutic efficacy of phytoconstituents. By improving membrane permeability and protecting active compounds from degradation, phytosomes have been successfully utilized in the management of a wide range of diseases, particularly where conventional herbal extracts show limited clinical effectiveness [44]. Their application spans hepatic disorders, cardiovascular diseases, inflammation, cancer, neurological disorders, dermatology, metabolic disorders, and infectious diseases.

One of the most well-established therapeutic applications of phytosomes is in hepatoprotection. Phytosomal formulations containing silybin, derived from Silybum marianum (milk thistle), have shown remarkable efficacy in the treatment of liver disorders. The improved bioavailability of silybin in phytosomal form enhances antioxidant activity, stabilizes hepatocyte membranes, and protects liver tissues against toxins such as alcohol, chemicals, and hepatotoxic drugs [45]. Clinical and preclinical studies have demonstrated that Siliphos® exhibits superior pharmacokinetic profiles compared to conventional silymarin extracts, resulting in improved liver function and reduced hepatic damage [38,45].

Phytosomes have also shown promising applications in cardiovascular protection. Phytosomal formulations of Ginkgo biloba phytosome improve blood circulation, reduce oxidative stress, and protect against myocardial injury. Ginkgo phytosomes are reported to enhance endogenous antioxidant defense systems and reduce lipid peroxidation, thereby contributing to cardioprotection [46]. Similarly, phytosomes containing grape seed extract, such as Leucoselect® Phytosome, exhibit strong antioxidant properties and help maintain vascular integrity, making them useful in cardiovascular disorders [44].

Another major therapeutic application is in anti-inflammatory and antioxidant therapy. Many phytoconstituents, including flavonoids and polyphenols, possess potent anti-inflammatory activity but suffer from poor oral absorption. Phytosome technology improves their absorption and therapeutic action. For instance, Meriva® has shown significantly improved anti-inflammatory activity compared to free curcumin. It inhibits inflammatory mediators, scavenges free radicals, and reduces oxidative stress, making it beneficial in conditions such as arthritis and chronic inflammatory disorders [47].

Phytosomes have also emerged as promising supportive systems in anticancer therapy. Curcumin phytosomes, quercetin phytosomes, and resveratrol phytosomes have demonstrated improved cytotoxicity against various cancer cells due to enhanced bioavailability and cellular uptake. Clinical studies suggest that phytosomal curcumin can be used as an adjunct to conventional chemotherapy to improve therapeutic outcomes and reduce adverse effects associated with anticancer drugs [48]. This highlights their potential role in integrative cancer management.

In neurological disorders, phytosomes are advantageous because of their enhanced ability to cross the blood-brain barrier. Phytosomal formulations of curcumin and ginkgo have demonstrated neuroprotective effects by reducing oxidative stress, inhibiting neuroinflammation, and improving cognitive function. These formulations are being investigated for use in disorders such as Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions [49].

Phytosomes are widely used in dermatology and cosmeceutical applications due to their enhanced penetration through the stratum corneum. Phytosomal formulations of green tea extract, grape seed extract, and other antioxidants are incorporated into topical preparations for anti-aging, skin protection, and treatment of inflammatory skin conditions. Their improved stability and deeper skin penetration make them more effective than conventional topical herbal formulations [50]. For example, green tea phytosomes are increasingly used in skincare products for photoprotection and anti-aging effects.

The antidiabetic potential of phytosomes has also been explored extensively. Phytosomes containing flavonoids, berberine, and polyphenols have demonstrated beneficial effects in diabetes management by improving glucose metabolism, reducing oxidative stress, and enhancing insulin sensitivity. The enhanced bioavailability of these phytoconstituents leads to improved glycemic control compared to conventional herbal preparations [44,51]. Berberine phytosomes, for example, have shown promising effects in reducing blood glucose levels and improving metabolic function.

Phytosomes also exhibit immunomodulatory activity. Certain formulations containing extracts of Echinacea have demonstrated the ability to stimulate immune cells, enhance immune responses, and improve resistance against infections. These properties make them useful as supportive agents in immune-related disorders and general health supplements [52].

In addition, phytosomes have been investigated for their antimicrobial properties. Enhanced penetration, sustained release, and improved absorption of phytoconstituents increase their effectiveness against microbial pathogens. For instance, phytosomal formulations of gingerol, curcumin, and other plant-derived antimicrobial compounds have demonstrated improved antibacterial and antifungal activity compared to free phytoconstituents [53]. Such formulations show potential in the treatment of infections caused by resistant microorganisms.

Figure 7. Therapeutic Applications overview of Phytosomes

COMPARISON OF PHYTOSOMES WITH OTHER DRUG DELIVERY SYSTEMS

Phytosomes represent a distinct class of lipid-based drug delivery systems that differ fundamentally from conventional vesicular carriers such as liposomes, niosomes, transferosomes, and ethosomes. While all these systems aim to enhance drug delivery and bioavailability, their structural organization, mechanism of drug incorporation, and functional performance vary significantly. A comparative understanding of these systems is essential to highlight the unique advantages of phytosomes in phytopharmaceutical applications [54].

1. PHYTOSOMES VS LIPOSOMES

Liposomes are spherical vesicles composed of one or more phospholipid bilayers surrounding an aqueous core. Drugs may be encapsulated either within the aqueous compartment or within the lipid bilayer. However, this encapsulation is purely physical, with no chemical bonding between the drug and lipid [55].

In contrast, phytosomes are formed through a specific molecular interaction between the phytoconstituent and phospholipid, typically via hydrogen bonding. This results in the formation of a well-defined complex in which the phytoconstituent becomes an integral part of the lipid structure rather than being merely entrapped [56].

This fundamental difference leads to several functional advantages:

• Higher stability
• Reduced drug leakage
• Improved bioavailability

However, liposomes offer broader applicability since they can accommodate both hydrophilic and lipophilic drugs [57].

Figure 8 Comparison of Phytosomes vs Liposomes

2. PHYTOSOMES VS NIOSOMES

Niosomes are vesicular systems formed using non-ionic surfactants and are considered more stable and cost-effective than liposomes [58].

However, they rely on physical entrapment, which may lead to:

• Drug leakage
• Lower entrapment efficiency

Phytosomes involve chemical complexation, resulting in stronger binding and enhanced bioavailability. However, niosomes may still be preferred for cost-effective large-scale production [59].

3. PHYTOSOMES VS TRANSFEROSOMES

Transferosomes are ultra-deformable vesicles designed primarily for transdermal drug delivery [60].

While they show excellent skin penetration:

• They are less stable
• Limited to topical applications

Phytosomes, in contrast, are more stable and suitable for both oral and topical delivery [61].

4. PHYTOSOMES VS ETHOSOMES

Ethosomes are lipid vesicles containing high concentrations of ethanol, which enhances skin permeability [62].

However:

• They may cause skin irritation
• Limited to transdermal use

Phytosomes offer better stability and broader application across different routes of administration [63].

Table 1 . Comparative Summary Table

Phytosomes offer a unique advantage due to their ability to form stable molecular complexes with phytoconstituents. This results in superior bioavailability and improved therapeutic efficacy compared to other vesicular systems. While systems like transferosomes and ethosomes are highly effective for transdermal delivery, phytosomes remain the most suitable carriers for enhancing the delivery of plant-based bioactive compounds [54,57,59].

Figure 9. Phytosome vs Liposome Comparison

RECENT ADVANCES AND FUTURE PROSPECTS OF PHYTOSOMES

Recent advancements in phytosome technology have significantly expanded its applications in modern drug delivery systems, particularly through the development of nanophytosomes and advanced nanoformulations. Nanophytosomes exhibit improved bioavailability, enhanced cellular uptake, and superior membrane permeability owing to their reduced particle size and increased surface area [64,65]. Several phytoconstituents have been successfully incorporated into nanophytosomal systems, resulting in improved pharmacological performance. For example, curcumin nanophytosomes have demonstrated enhanced anti-inflammatory and anticancer activity; quercetin nanophytosomes showed superior antioxidant and cytotoxic effects; silybin nanophytosomes improved hepatoprotective efficiency; resveratrol nanophytosomes exhibited enhanced cardiovascular and anti-aging properties; epigallocatechin gallate (EGCG) nanophytosomes improved antioxidant delivery; and berberine nanophytosomes showed enhanced antidiabetic activity [66,67].

Targeted drug delivery systems using phytosomes have also emerged as an important strategy to improve site-specific delivery and minimize systemic toxicity. For instance, folate-conjugated curcumin phytosomes have been developed for tumor targeting, transferrin-modified quercetin phytosomes have shown potential for brain-targeted delivery, hepatotropic silybin phytosomes are designed for liver-specific delivery, and ligand-attached resveratrol phytosomes improve cardiovascular targeting. Additionally, PEGylated phytosomes prolong systemic circulation time, while antibody-linked phytosomes provide selective targeting of cancer cells, thereby improving therapeutic efficacy [68–70].

Phytosomes have gained considerable attention in cancer therapy and clinical research due to their ability to improve the delivery and efficacy of anticancer phytoconstituents. For example, Meriva® (curcumin phytosome) has been investigated for anti-inflammatory and anticancer clinical applications. Quercetin phytosomes have shown enhanced tumor cell inhibition, andrographolide phytosomes induce apoptosis in cancer cells, resveratrol phytosomes demonstrate anti-proliferative effects, genistein phytosomes are being explored in hormone-dependent cancers such as breast and prostate cancer, and EGCG phytosomes have exhibited significant antitumor activity against various cancer cell lines [71–73].

The integration of phytosomes with advanced nanotechnology has further improved their stability, drug loading capacity, and controlled release properties. For example, polymeric curcumin phytosomes provide sustained drug release, solid lipid silymarin phytosomes enhance formulation stability, nanoemulsion-based green tea phytosomes improve dermal and transdermal delivery, chitosan-coated phytosomes increase mucoadhesion for oral and nasal administration, lipopolymer phytosomes ensure controlled release, and magnetic nanoparticle-loaded phytosomes enable targeted delivery under external magnetic guidance [74–76].

The successful commercialization of phytosome technology has resulted in several marketed products with proven clinical effectiveness. Commercially available formulations include Siliphos® for liver protection, Meriva® for anti-inflammatory applications, Greenselect® Phytosome for weight management, Leucoselect® Phytosome for cardiovascular support, Ginkgo phytosome formulations for cognitive enhancement, and Sabalselect® for prostate health [77].

Green and sustainable approaches are increasingly being adopted for phytosome preparation. For example, ethanol-water solvent systems are used as safer alternatives to toxic organic solvents, supercritical CO₂ extraction allows solvent-free preparation, microwave-assisted synthesis reduces energy consumption, ultrasound-assisted phytosome formation shortens processing time, enzyme-assisted extraction improves phytoconstituent yield, and green nanotechnology-based synthesis promotes sustainable production methods. These methods align with green chemistry principles and reduce environmental impact [78].

Future prospects indicate that phytosomes are evolving into next-generation multifunctional drug delivery systems. Emerging applications include gene delivery phytosomes for targeted genetic therapy, vaccine delivery phytosomes for improved immunogenicity, combination phytosomes such as curcumin–piperine phytosomes for synergistic therapeutic action, brain-targeted phytosomes for neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, glycyrrhizin-based antiviral phytosomes for viral infections, and personalized phytosomal formulations tailored to patient-specific therapies. These advancements suggest a broad future potential for phytosome technology in pharmaceutical research and clinical applications [79].

Table 2. Recent Advances in Phytosomes with Examples and Applications

CONCLUSION

Phytosomes have emerged as a promising lipid-based drug delivery system capable of overcoming key limitations associated with conventional herbal formulations, particularly poor bioavailability, low solubility, and limited membrane permeability. By forming stable complexes between phytoconstituents and phospholipids, phytosomes enhance pharmacokinetic performance and improve therapeutic outcomes across a wide range of disease conditions.

Recent advancements indicate a clear shift from conventional phytosomal formulations toward nano-engineered and hybrid systems with improved targeting efficiency, controlled release, and broader clinical applicability. The growing body of clinical evidence, particularly for compounds such as curcumin and silybin, further supports their potential in modern pharmacotherapy and nutraceutical development.

However, despite these advantages, several challenges remain. Issues related to large-scale manufacturing, formulation stability, cost, and the lack of standardized regulatory frameworks continue to limit widespread clinical translation. In addition, the need for well-designed, large-scale clinical trials is critical to establish long-term safety and efficacy.

Overall, phytosomes represent a versatile and evolving platform that bridges traditional herbal medicine with advanced drug delivery technologies. Future research should focus on optimizing formulation strategies, enhancing clinical validation, and addressing regulatory challenges to fully realize their potential in pharmaceutical and therapeutic applications.

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