Phyto-phospholipid Complex Vesicles:A Revolutionary Approach for Enhancing Bioavailability and Optimizing Therapeutic Potential in Herbal Medicine

Ruchika Chandrakar¹, Amber Vyas², Narendra Kumar³, Umakant Sahu⁴, Vishal Jain^5*

^1,2,3,4,5University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G), India-492010

Abstract:

The medicinal potential of phytoconstituents obtained from plants is widely recognized. Whole-plant extracts or isolated phytoconstituents have been shown through experiments to exhibit a variety of medicinal potentials, including antibacterial, neurologically protective, liver-protective properties, an antioxidant and skin-protective properties. Although these phytoconstituents offer potential therapeutic effects, their usage is restricted due to inadequate bioavailability, persistence in physiological fluids, and authenticity problems. These remain unresolved issues that impact the use of these priceless traditional herbal remedies in the efficient management and treatment of a range of medical ailments. Phytoconstituents’ loading in phospholipid-based vesicular systems may be a way to tackle these challenging issues. The goal of this review is to summarize phyto-phospholipid vesicles and some of their relevant uses in drug delivery systems, as well as to emphasize the relationship between properties and applications, as well as the effect of phospholipid species on drug delivery efficiency. Based on the findings of various research investigations, this literature review attempts to investigate why Phyto-phospholipid vesicles are considered as the best nanotechnology in delivery systems for drugs. Optimal absorption and utilization of nutraceuticals and herbal medications can be enhanced by the process of Phyto phospholipid complexation.

Keywords: Phyto-phospholipid complexation, Vesicles, Drug delivery system, Herbal drug, Bioavailability, Therapeutic effects.

Introduction

Phyto-phospholipid phytovesicles, commonly known as phyto-phospholipid complex vesicles, are a novel drug delivery system that enhances the bioavailability of plant-derived bioactive compounds. Indena (Milan, Italy) created the first Phytovesicles in the late 1980s to improve medicine bioavailability by combining them with phospholipid (Mandeep and Gagandeep n.d.). They are formed by complexing natural phospholipids, such as phosphatidylcholine, with phytoconstituents, leading to the formation of lipid-compatible molecular complexes. These are plant-derived compounds, often with potent health benefits, but their clinical efficacy can be limited by poor absorption and rapid elimination from the body (Bhogam et al. 2023). Phyto-phospholipid complex vesicles technology addresses these challenges by creating a lipid-compatible molecular complex, improving the bioavailability and therapeutic potential of these compounds.

Phyto-phospholipid phytovesicles are designed to improve the delivery and efficacy of botanical extracts. By embedding phytoconstituents within a phospholipid bilayer, these vesicles facilitate better integration with cell membranes, enhancing the absorption and stability of the active compounds (Dutt et al. 2023). The phospholipid typically used in phyto phospholipid vesicles formulations is Phosphatidylcholine, Phosphatidylethanolamine (PE), Phosphatidylinositol (PI), Phosphatidylserine (PS), and others. This technology addresses common challenges associated with plant-based therapeutics, such as poor solubility and low bioavailability, making phytophospholipid complex vesicles a valuable tool in the fields of pharmaceuticals and nutraceuticals. Through this approach, the therapeutic potential of plant-derived compounds can be maximized, leading to more effective treatments and health supplements (Singh et al. 2011).  (Table N0. 01 and 02)

Mechanism of phytophospholipid complex vesicles

Phyto-phospholipid complex vesicles are formed by complexing phytoconstituents with phospholipids. This complexation enhances the solubility and absorption of the phytoconstituents. Phosphatidylcholine, a major component of cell membranes, is commonly used in phyto-phospholipid complex vesicles formulations. The phytoconstituent-phospholipid complex mimics the molecular environment of cell membranes, facilitating easier passage into the bloodstream and enhancing systemic bioavailability (Sawant and Yadav 2020).

Background and significance’s

Phytochemicals, the bioactive compounds derived from plants, have long been recognized for their significant health benefits and therapeutic properties. These compounds, found in herbs, fruits, vegetables, and other plants, have been used in traditional medicine for centuries (Dodle et al. 2023). Modern scientific research continues to validate the efficacy of phytochemicals in preventing and treating various health conditions, including chronic diseases like cancer, cardiovascular diseases, and neurodegenerative disorders. However, despite their potential, the clinical application of many phytochemicals is often limited by poor bioavailability. This refers to the extent and rate at which the active ingredients are absorbed and become available at the site of action (Dodle et al. 2023).

The bioavailability of phytochemicals is typically hampered by several factors, including poor solubility in water, instability in the digestive tract, rapid metabolism, and elimination from the body. These limitations can result in insufficient therapeutic concentrations of the active compounds in the bloodstream, reducing their efficacy (Poudyal et al. 2022). Therefore, there is a growing need for innovative delivery systems that can enhance the absorption and bioavailability of these beneficial compounds.

Method of preparations of complex vesicles

To create a drug-phosphatidylcholine complex, an equimolar concentration of drug was combined with phosphatidylcholine. Equimolar drug concentrations were combined in a 100 ml round bottom flask with 25 ml dichloromethane for 3 hours in a closed conical flask. To precipitate the complex, add 30 ml of phosphate buffer to the solution at a concentration of 10-15 ml, or 1/3 of the volume, and then filter. Additionally, it can be used to make phyto-phospholipid complex vesicles (Gaurav et al. 2021). (Figure 01 and 02)

v Solvent Evaporation thin film hydration technique of phyto-phospholipid complex vesicles

·       This method involves dissolving both the phytoconstituent and phospholipid in a suitable aprotic solvent, followed by solvent evaporation to form a thin film containing the phyto-phospholipid complex vesicles.

·       Dissolve 10 mg of the phytoconstituent and equimolar ratio of the phospholipid in 20 ml of the organic solvent, Transfer the solution to a round-bottom flask. Attach the flask to a rotary evaporator.

·       Set the water bath temperature of the rotary evaporator to 40-60°C (choose a temperature that ensures solvent evaporation without degrading the phytoconstituent).

·       Evaporate the solvent under reduced pressure until a thin film is formed on the inner walls of the round bottom flask.

·       Further dry the thin film under vacuum in a desiccator to remove any residual solvent. Drying time typically 12-24 hours, depending on the solvent and conditions.

·       Hydrate the thin film with a small amount of water or buffer to form a suspension if a liquid formulation is desired.

·       Sonicate the suspension if necessary to reduce particle size. keep the temperature below 30°C during sonication to prevent degradation.

·       Store the resultant phyto-phospholipid complex vesicles complex in an airtight container, preferably under refrigerated conditions to maintain stability(Saputra, Dzakwan, and Dewi 2020).

v Thin film formation technique of phyto-phospholipid complex vesicles complex

·        Weigh out the phytoconstituent and phospholipid. Dissolve both in a mixture of organic solventsin a 2:1 ratio).

·        Transfer the solution to a round-bottom flask; attach the flask to a rotary evaporator.

·        Evaporate the solvent under reduced pressure to form a thin film on the inner wall of the flask, set the rotary evaporator to operate at a temperature of 40-60°C.

·        Rotate at 150-200 rpm for efficient solvent removal (Gaikwad et al. 2021).

·        Once the solvent has evaporated and a thin film is formed, remove the flask from the evaporator.

·        Add a hydration medium (e.g., water or a suitable buffer) to the flask to hydrate the thin film.

·        Typical hydration volume: 10 mL for the given amount of phytoconstituent and phospholipid maintain the hydration temperature at 25-40°C, Swirl or gently shake the flask to ensure even hydration of the film.

·        Sonicate the hydrated mixture using a bath sonicator or probe sonicator to reduce the size of phyto-phospholipid complex vesicles and ensure homogeneity, Keep the temperature below 30°C during sonication to prevent degradation of the phytoconstituent.

·        After hydration and sonication, a uniform suspension of phyto-phospholipid complex vesicles is formed.

·        Collect the phyto-phospholipid complex vesicles suspension, If a dry phyto-phospholipid complex vesicles powder is desired, further process the suspension. Freeze-dry or vacuum-dry the suspension to obtain the phyto-phospholipid complex vesicles complex in powder form.

·        Store the prepared phyto-phospholipid complex vesicles in an airtight amber container,Protect from light and moisture and store at a cool temperature (preferably 4-8°C) (Saputra, Dzakwan, and Dewi 2020).

v Reflux technique of phyto-phospholipid complex vesicles complexation

• Measure the desired quantities of phytoconstituent and phospholipid according to the desired ratio. Typical ratios range from 1:1 to 1:2 (phytoconstituent), but this can vary depending on the specific compounds and desired properties.
• Dissolve the phytoconstituent and phospholipid in anaprotic solvent in a round-bottom flask. The volume of the solvent can vary based on the solubility of the compounds.
• Set up the reflux apparatus with a condenser attached to the round-bottom flask containing the solution.
• Heat the solution under reflux conditions, typically at the 40°Cor slightly higher for 3 hours. Refluxing allows for thorough mixing and incorporation of the phytoconstituent into the phospholipid bilayer.
• After the reflux period, allow the solution to cool to room temperature.If necessary, isolate the phyto-phospholipid complex vesicles complex by evaporating off the solvent under reduced pressure or by other means such as filtration or centrifugation.
• Dry the isolated phyto-phospholipid complex vesicles complex under vacuum or by other suitable methods such as freeze-drying (lyophilization).
• Store the dried phyto-phospholipid complex vesicles complex in a amber colour container under appropriate conditions to prevent degradation. (R. P. Singh, Gangadharappa, and Mruthunjaya 2018)

v Cosolvent technique of phyto-phospholipid complex vesicles complexation

• Dissolve the phytoconstituent and phospholipid in a suitable solvent. Add a predetermined amount of cosolvent (glycerol, propylene glycol) to the solvent mixture.
• Typical cosolvent ratio: 10-50% (v/v) of the total solvent volume, Example: Add 1-5 mL of cosolvent to 10 mL of solvent mixture.
• Stir the solution to ensure uniform mixing. Optionally, perform sonication to further enhance solubility and mixing.
• Evaporate the solvent mixture using a rotary evaporator under reduced pressure.
• Further dry the residue under vacuum to remove any residual solvent.
• Store the resultant complex in an airtight container (Vaishnavi et al. 2021).

v Antisolvent precipitation technique

·       Dissolve the phytoconstituent and phospholipid in a suitable organic solvent, Typical ratio: 1:1. For example: 100 mg of each in 10 mL of ethanol.

·       Add the solution dropwise to water (anti-solvent) with constant stirring. At room temperature to 25°C.

·       Volume of anti-solvent: 100 mL (10 times the solvent volume).

·       Collect the precipitated phyto-phospholipid complex vesicles by filtration or centrifugation, Centrifuge at 4°C if needed (Rani, Kumar, and Khar 2022).

v Mechanical dispersion technique of phyto-phospholipid complex vesicles complexation

·        The mechanical dispersion method is a technique used for the preparation of phyto-phospholipid complex vesicles, where the active phytoconstituents are dispersed in a phospholipid solution under mechanical agitation. Here's a simplified procedure along with typical ratios:

·        Dissolve the phytoconstituent and phospholipid in an organic solvent. Typical ratio: 1:1 or as desired. Mix the solution thoroughly to ensure uniform dispersion.

·        Use a mechanical disruptor such as a homogenizer, ultrasonicator or magnetic stirrer.

·        Apply mechanical force to disrupt the lipid bilayers and disperse the phytoconstituents within the phospholipid matrix.

·        Duration and intensity of homogenization can vary depending on the equipment used and the desired particle size. typically at room temperature or below to avoid degradation of sensitive components (Zhang et al. 2018).

·        If necessary, remove the solvent under reduced pressure or by evaporation.

·        If residual solvent is present after removal, further dry the phyto-phospholipid complex vesicle dispersion under vacuum or by gentle heating. Mild heating up to 40-50°C can be applied if necessary.

Advantages of Phytosomes

§ Enhanced Bioavailability: One of the main advantages of Phyto-phospholipid complex vesicles complexes is their ability to improve the bioavailability of herbal active constituents. Phyto-phospholipid complex vesicles can encapsulate poorly soluble phytochemicals, such as flavonoids, terpenoids, and polyphenols, within phospholipid bilayers(Nanavati 2017). This enhances their solubility and absorption in the gastrointestinal tract, and outer surface of body leading to higher plasma levels of the active compounds.

§ Stability Enhancement: Phyto-phospholipid complex vesicles technology can improve the stability of herbal extracts by protecting them from degradation, oxidation, or other chemical reactions. This ensures the preservation of the therapeutic properties of the active compounds over time (Telange et al. 2017).

§ Standardization of Herbal Extracts: Phyto-phospholipid complex vesicles technology enables the standardization of herbal extracts based on their bioactive content rather than just their raw plant material. By encapsulating specific phytochemicals within Phytophospholipid complex vesicles complexes (Molaveisi, Shahidi,Noghabi and Naji Tabasi 2020).

§ Targeted Drug Delivery: Phytophospholipid complex vesicles can be designed to facilitate targeted drug delivery to specific tissues or organs within the body. By modifying the surface properties of Phyto-phospholipid complex vesicles complexes or incorporating targeting ligands, herbal active constituents can be delivered selectively to sites of action, minimizing off-target effects and improving therapeutic outcomes (Shriram et al. 2022).

§ Combination Therapy: Phyto-phospholipid complex vesicles technology allows for the formulation of combination therapies where multiple herbal active constituents or conventional drugs are co-encapsulated within Phyto-phospholipid complex vesicles complexes. This synergistic approach can enhance the therapeutic efficacy by targeting multiple pathways involved in disease pathogenesis or by potentiating the effects of individual components (Chen et al. 2024).

§ Clinical Applications: Phyto-phospholipid complex vesicles formulations have been investigated and utilized in the treatment of various health conditions, including liver disorders, cardiovascular diseases, metabolic syndrome, inflammation, and oxidative stress-related disorders.

§ Improved Bioavailability: Phyto-phospholipid complexation significantly enhance the absorption of phytoconstituents compared to conventional herbal extracts. Studies have shown increased plasma levels of active compounds, leading to improved efficacy.

§ Enhanced Therapeutic Effects: With better absorption, the therapeutic effects of phytochemicals are more pronounced. This can lead to lower required doses and reduced side effects.

§ Sustained Release: Phyto-phospholipid complexation formulations can provide a controlled release of the active compounds, maintaining therapeutic levels in the blood over an extended period (Palachai et al. 2020).

§ Better Stability: The complexation with phospholipids can protect phytochemicals from degradation by digestive enzymes and harsh pH conditions in the gastrointestinal tract.

§ Enhanced Skin Penetration: Phyto-phospholipid complex vesicles complexes improve the skin penetration of herbal active constituents by encapsulating them within phospholipid bilayers. This enhanced penetration allows the bioactive compounds to reach deeper layers of the skin where inflammation may be localized (Allaw et al. 2022).

§ Reduced Irritation: Transdermal delivery of herbal extracts can sometimes cause skin irritation. Phyto-phospholipid complex vesicles complexes help mitigate this issue by encapsulating the active constituents, thereby reducing direct contact with the skin surface and minimizing irritation while maintaining therapeutic efficacy (Allaw et al. 2022).

§ Weight Management: Certain plant extracts, when complexed with phospholipids in phytosomes, may assist in weight management by enhancing the absorption of bioactive compounds that promote fat metabolism and appetite control.

§ Nutraceuticals: Phyto-phospholipid complex vesicles are utilized in the development of nutraceutical products, where they enhance the bioavailability of phytochemicals present in dietary supplements. This improves the effectiveness of the supplements in delivering health benefits (El-Menshawe et al. 2018).

§ Formulation Flexibility: Phyto-phospholipid complex vesicles offer flexibility in formulation design, allowing for the development of various dosage forms such as tablets, capsules, liquid formulations, and topical preparations.

§ Cosmaceuticals: Phyto-phospholipid complex vesicles technology is also employed in the formulation of cosmeceutical products, such as skincare creams and serums. By increasing the absorption of herbal extracts, it enhances the skin's ability to utilize the active ingredients for various skincare benefits(Hendawy et al. 2023).(Table No. 03 and 04)

Future Perspectives and Conclusion

In conclusion, phyto-phospholipid complex vesicles offer a promising approach to enhance the bioavailability, efficacy, and targeted delivery of phytoconstituents in clinical applications. Clinical evidence supports their ability to improve absorption, enhance therapeutic effects, and provide targeted delivery to specific tissues or organs. Phyto-phospholipid complex vesicles formulations have demonstrated efficacy in managing various health conditions, including chronic diseases, metabolic disorders, inflammatory conditions, and skin health. Furthermore, their favourable safety profile and tolerability make them attractive candidates for long-term use. However, further research is warranted to fully understand their mechanisms of action, optimize formulations, and explore their potential applications in diverse clinical settings. Overall, phyto-phospholipid complex vesicles represent a valuable strategy to harness the therapeutic potential of plant-based compounds for improved health outcomes. Phyto-phospholipid complex vesicles technology represents a significant advancement in the delivery of phytochemicals, overcoming traditional barriers of poor absorption and rapid metabolism. By enhancing the bioavailability and therapeutic efficacy of plant-based compounds, phytophospholipid complex vesicles hold great promise in the development of more effective and safer herbal medicines. As research progresses, we can expect to see more innovative applications and formulations, further expanding the potential of this revolutionary drug delivery system.

 References:

Agarwal, A., Wahajuddin, M., Chaturvedi, S., Singh, S. K., Rashid, M., Garg, R Chauhan, D; Sultana, N., Gayen, J. R. (2024). Formulation and Characterization of Phytosomes as Drug Delivery System of Formononetin: An Effective Anti-Osteoporotic Agent. Current Drug Delivery, 21(2): 261-270.

Allaw, M., Manca, M. L., Castangia, I. and Manconi, M. (2022). From plants to phospholipid vesicles: A comprehensive review on the incorporation of phytochemicals into phospholipid vesicles designed for skin applications with special focus on scalability and in vitro and in vivo efficacy. Journal of Drug Delivery Science and Technology, 67: 103049.

Amjadi, S., Shahnaz, F., Shokouhi, B., Azarmi, Y., Siahi-Shadbad, M., Ghanbarzadeh, S., ... & Hamishehkar, H. (2021). Nanophytosomes for enhancement of rutin efficacy in oral administration for diabetes treatment in streptozotocin-induced diabetic rats. International journal of pharmaceutics, 610: 121208..

Andishmand, H., Yousefi, M., Jafari, N., Azadmard-Damirchi, S., Homayouni-Rad, A., Torbati, M. and  Hamishehkar, H. (2024). Designing and fabrication of colloidal nano-phytosomes with gamma-oryzanol and phosphatidylcholine for encapsulation and delivery of polyphenol-rich extract from pomegranate peel. International Journal of Biological Macromolecules, 256: 128501.

List of Figures

Figure No. 1: Schematic Representation of Preparation of Complex of Phytophospholipid complex vescicle

Figure No.  2: preparation of Phytophospholipid complex vesicles with hand shaking method

List of Tables

Table No. 01 - Materials Used for phytophospholipid Complex formulation (Pierro et al. 2021, Poudyal et al. 2022, Pasala et al. 2022)

Table No. 02. System for characterization of Phytophospholipid vesicles parameter (El-Batal et al. 2018, Agarwal et al. 2024)

Table No. 03. An overview of current research on phytophospholipid complex vesicles, methods of preparations used, solvents used, and values.

Table No. 04. Commercialized phytophospholipid complex vesicles with Phytochemicals.