Insights into various approaches of Phytosomes for Enhanced Therapeutic Potential of Bioactives

 

Rakesh Pahwa¹*, Chetna¹, Kamal Saroha¹, Bigul Yogeshver Bhardwaj¹,

Manish Kumar², Inderbir Singh³

¹Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra -136119, Haryana, India.

²M M College of Pharmacy, Maharishi Markandeshwar (Deemed to be University),

Mullana, Haryana, 133207 India.

³Chitkara College of Pharmacy, Chitkara University, Rajpura, Dist. Patiala, Punjab, 140401 India.

 

ABSTRACT:

Efficient delivery of phytoconstituents is almost challenging task for scientific community owing to predominantly imbalanced hydrophilicity and lipophilicity considerations. Phytoconstituents are mainly hydrophilic and reveal large molecular size which exhibit less absorption and poor bioavailability. Vesicular systems for instance phytosomes are recognized as unique and novel approach to enhance solubility and bioavailability of phytoconstituents and herbal extracts. These are complexed form of phytoconstituents and phospholipid molecules which are also called as phytophospholipid complex or herbosomes. Phytophospholipid complex has shown enhanced pharmacokinetic as well as pharmacodynamic properties in comparison to conventional dosage forms. Different methods have been utilized across the globe for phytosomes preparation such as solvent evaporation, anti-solvent precipitation, co-solvent lyophilization etc. The present review focuses on various approaches commonly employed in the preparation of phytosomes. Significant attributes, characterization aspects along with selection of dosage form for phytosomes have also been highlighted.

 

 

INTRODUCTION:

In recent years, usage of herbal actives or phytoactive compounds is challenging due to their less absorption and poor bioavailability¹. Phytoactive compounds shows poor absorption either because of their large multi-ring structure which restrict them to be absorbed by passive diffusion or owing to their hydrophilic properties which bound them from penetration through the outermost cell membrane of gastrointestinal tract. To conquer these constraints, vesicular drug delivery systems are considered as superior approach to deliver phytoactive compound at target site^2-4. Vesicular drug delivery system which incorporates standardized herbal extract or hydrophilic phyto-constituents in phospholipids to fabricate phyto-phospholipid complexes are called as phytophospholipid complex or phytosomes⁵.

 

Phospholipids are class of lipids that contain phosphate group; a hydrophilic head and lipophilic tail in their structures and their distinctive structural components are comparable to lipidic mammalian cell membranes which make them well-suited with physiological systems of human^6,7. Different phospholipids are commonly utilized in the development of phyto-phospholipid complex i.e. phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine etc. but phosphatidylcholine is generally used for its synergistic effect on liver and other therapeutic importance⁸. Phosphatidylcholine consist of the hydrophilic choline segment which is head (upper part) and the hydrophobic phosphatidyl segment is tail (lower part) of the compound. Therefore, choline section bound to the hydrophilic phytoconstituents, whereas lipid soluble phosphatidyl enclosed the choline bounded part^9-11. Phytosomes guard the valuable phytoconstituents from gut bacteria and digestive enzymes and also reveals improved absorption and better bioavailability^12,13. They also shows better pharmacokinetic as well as pharmacodynamic profiles in case of acute and chronic infection in liver^5,9,14. Ginkgo biloba, green tea, grape seed, milk thistle etc. are various herbal drugs that are integrated into phytosomes^10,15. Various significant attributes of phytophospholipid complexes are illustrated in the subsequent portion^4,5,9,16,17.

·       Phytosome increases the absorption of hydrophilic phytoconstituents via oral and topical route that depicts better bioavailability.

·       Enhances permeation of hydrophilic herbal constituent which allows greater absorption in the intestinal lumen.

·       Increased bioavailability of liver-protecting flavonoid and phosphatidylcholine provides a synergistic effect which helps in liver protection and shows hepatoprotective activity.

·       Chemical bond formation between the phospholipid molecule and herbal constituent shows enhanced stability profile.

·       Reduced dose requirement with improved absorption of phytoactive constituent provide satisfactory findings.

 

Components Utilized in the Formulation of Phytosomes:

Phospholipids, aprotic solvents, anti-solvents, alcohols, buffering agent etc. are mainly used in the formulation of phytosomes as shown in (Fig.1).

 

Fig. 1: Different Components Employed in Formulation of Phytosomes

 

Preparation Techniques:

Phytosomes are complex of phytoconstituent and phospholipid also known as phyto-phospholipid complex which can be fabricated by reacting one mole of phytoconstituent with 2-3 moles of phospholipid. The reaction can be carried out in organic solvents or utilizing aprotic solvents for example dioxane, methylene chloride, and phyto-phospholipid complex are separated by non-solvent precipitation technique or lyophilization process^9,16. General stages for preparation of phytosomes are shown in (Fig. 2).

 

 

Fig. 2: General Stages for Preparation of Phytosomes

 

Common techniques generally employed for the preparation of phytosomes are solvent evaporation method, anti-solvent precipitation and co-solvent lyophilization method as shown in (Fig. 3).

 

Solvent evaporation:

Phospholipids and phytoconstituents are mixed in an organic solvent such as ethanol in round bottom flask. Solution is subjected to magnetic stirring for few hours and evaporation of solvent takes place under vacuum condition at 40^oC using rotary evaporator. After solvent evaporation, formation of thin film occurs on the wall of flask. Thin film dispersed in distilled water, to obtain the phytosomal dispersion^18-21. Recently, Huang et al fabricated milk-phospholipid complex phytosome with vitamin C and E and characterized for complexing index, FTIR, DSC, UV spectra, in-vitro digestion and absorption and MIT assay. They revealed that milk phospholipid based phytosomes showed better in vitro digestion stability as compared to liposomes and therefore demonstrated superior prospective for developing as nutrients for functional foods¹⁸. Furthermore, Freag et al developed triterpine phytosomes utilizing above method and evaluated for enhanced delivery of triterpine compound through buccal mucosa by SEM, TEM, in-vitro drug release, ex vivo permeation along with in vivo pharmacokinetic study. They investigated triterpine delivery via buccal mucosa with enhanced bioavailability through triterpine phytosomes¹⁹. Moreover, Kalita et al developed resveratrol phytosomes using identical method and examined for efficient delivery of drug by SEM, stability study and pharmacokinetic study. Findings concluded increased permeability of resveratrol and enhanced anti-inflammatory activity²⁰. In another research, Gahandule et al utilized similar method for preparation of butea monosperma phytosomes and evaluated for solubility, entrapment efficiency, X-ray diffraction, DSC, in vitro dissolution and in vitro scavenging potential.  Results concluded that butea monosperma phytosomes showed extended release with enhanced free radical scavenging activity²¹. Furthermore, Yu et al formulated berberine phytosomes utilizing similar method and examined for DSC, X-ray diffraction, and FTIR. They demonstrated that the berberine phytosomes improved oral bioavailability and enhanced anti-diabetic efficacy²². In another endeavour, Kalita et al prepared resveratrol phytosomes for resveratrol delivery via skin to utilize its anti-inflammatory effect and evaluated them for particle size, drug entrapment, X-ray diffraction, DSC, FTIR, SEM, and permeation study. Results suggested that the resveratrol phytosomes shows increased skin permeation and prolonged anti-inflammatory effect²³.

 

Anti-solvent precipitation:

In round bottom flask of appropriate quantity, the standardized phytoconstituent as well as phospholipids are taken and then dissolved in an aprotic solvent such as dioxane, acetone etc. The solution is being refluxed and stirred for a night at a temperature not exceeding 60⁰C for complex formation. The complex formed is isolated by precipitation from non-solvent like n-hexane. The precipitate left to settle, filtered and dried under vacuum at 40⁰C temperature^24-26. Alhakamy et al formulated icariin phytosomes using anti-solvent precipitation method and evaluated phytosomes for vesicle size, TEM, FTIR, in vitro release and cytotoxic effects of optimized icariin phytosomes on ovarian cancer cells. Results concluded that icariin phytosomes considerably enhanced its cytotoxic activities against OVCAR-3 cells²⁴. Furthermore, Rajput S et al utilized similar method for preparation of lawsone phytosomes and characterized them for percentage yield, particle size, entrapment efficiency, drug content and scanning electron microscopy. Phytosomal gel was prepared by using lawsone phytosomes and evaluated for physical appearance, drug content, uniformity, pH measurement and spreadability. The lawsone phytosomes showed better antifungal activity, permeation rate activity and anti-inflammatory activity better than drug lawsone²⁵. In another research, Singh et al also used anti-solvent precipitation to prepare gingerol phytosomes by blending of gingerol with soya lecithin. Formulation of gingerol phytosomes was characterized for particle size, entrapment efficiency, FTIR, SEM, zeta potential, in vitro along with in vivo evaluation. They concluded that the prepared phytosomes provides sustained antibacterial and anti-inflammatory action through oral administration²⁶.

 

 

Fig. 3: Techniques Used for Preparation of Phytosomes

 

Co-solvent lyophilization:

The phytoconstituent and phospholipid are dissolved in different solvents separately. Further, both the solution mixed by continuous stirring or slow agitation till formation of clear mixture. Complex isolated by co-solvent lyophilization of clear mixture under a vacuum for few hours are collected and stored^27-29. Jain et al developed rutin-phospholipid complex by co-solvent lyophilization technique to improve the lipophilic properties of rutin and examined for UV, IR, X-ray diffraction and free radical scavenging potential. They investigated enhanced free radical scavenging property as well as improved rutin antioxidant activity²⁷. Moreover, Cui et al formulated insulin-phospholipid complex by utilizing the identical method and evaluated for IR, X-ray diffraction, in vitro release studies, hypoglycemic effect and relative bioavailability studies. They investigated enhanced solubility and intestinal absorption of insulin²⁹.Some of the investigators employed miscellaneous techniques for preparation of phytosomes as explained in (table 1).

 

Table 1: Phytosomes Preparation Using Varied Techniques

S. No.	Herbal drug	Methods utilized	Characterization techniques	Inferences	Author (s)	Year	Ref.
1.	Mangiferin	Solvent evaporation and nanoprecipitation method	DSC, TGA, FTIR, Powder-XRD, H1-NMR, solubility studies, in vitro dissolution, oral bioavailability, and in vivo antioxidant studies.	Enhanced biopharmaceutical and in vivo antioxidant potential	Telange et al	2020	30
2.	Rhein	Solvent evaporation, lyophilization and co-solvent evaporation method	FTIR, DSC, XRPD, solubility study, particle size, zeta-potential, TEM, in-vitro drug release, in-vivo characterization	Targeted different skin disorders through non-invasive topical application	Ebada et al	2020	31
3.	Naringenin	Solvent evaporation and freeze-drying method	SEM, TEM, particle size and zeta potential, XRD, DLS, DSC	Developed sustained release dry powder inhaler for acute lung injury	Yu et al	2020	32
4.	Glycine max (L.) Merrill	Solvent evaporation, cosolvency, salting out	Particle size, entrapment efficiency, zeta potential, drug release, FTIR	Investigated for anti-obesity action	Menshawe et al	2018	33
5.	Woodfordiafruticosa	Ethanol and reflux method	Percentage yield, entrapment efficiency, FTIR, particle size, zeta potential	Improved solubility and increased anti-oxidant activity	Rajashekhar et al	2015	34
6.	Sinigrin	Solvent evaporation and anti-solvent method	Particle size, zeta potential, complex efficiency, TEM, DSC, FTIR	Enhanced cytotoxic effect and wound healing efficacy	Mazumder et al	2015	35
7.	Diosmin	Solvent evaporation, salting out and lyophilization method	DSC, FTIR, drug content, solubility studies, TEM, in-vitro release studies, in vitro self-phytosomal stability, ex vivo intestinal permeation studies	Increased dissolution and permeation	Freag et al	2013	28
8.	Puerarin	Solvent evaporation and freeze-drying method	SEM, XRPD, DSC, IR, solubility and dissolution studies	Enhanced solubility and in vitro dissolution rate	Li et al	2008	36

 

Characterization and Spectroscopic Evaluation:

Phytosomes are generally evaluated for various physical attributes such as vesicle stability^20,36,37, vesicle size^28,38-44,drug content^28,41,42, zeta potential^28,37,41,42, transition temperature^45-48, entrapment efficiency^21-23,29,37as shown in (Fig. 4) and spectroscopic evaluation i.e. X-ray diffraction^21-23,38, FTIR^21-23,33-35, DSC^45-48, SEM^20,26,45, TEM^23,28,43,49, NMR^38,42,50, UV spectroscopy^27,48as shown in (Fig. 5).

 

Fig. 4: Characterization Techniques

 

Fig. 5: Spectroscopic Evaluation Techniques

Dosage Forms for Delivery of Phytosomes:

Appropriate dosage forms for phytosomes delivery can be chosen based on its capability to enhance the efficiency as well as effectiveness of phytoactive molecule¹⁶. Different considerations are needed to be taken for phytosomal formulations i.e. nature of herbal drug and other features of phytosomes for instance; permeability, degree of biodegradability, tonicity as well as drug release profile. Both oral and topical formulations can be developed for phytosome complexes and in order to enhance the bioavailability, optimal development methods must be selected. Oral formulations (soft gelatin capsules, hard gelatin capsules, tablets etc.) and topical dosage forms can be successfully fabricated for various phytosomes^14,15.

 

Therapeutic Applications:

Phytosomes confers various potential and beneficial therapeutic applications to overcome problems associated with phytoconstituents^{20,40,42,51-64}. These are systematically represented in (Fig. 6).

 

Fig. 6: Therapeutic Applications of Phytosomes

CONCLUSION:

This review is a cogent attempt to present a concise profile concerning phytosomes benefits, different preparation methods, characterization aspects and salient applications. Phytosomes have elicited improved absorption and enhanced bioavailability as compared to conventional plant extracts. Drug molecules which are incorporated in the structure of phytosomal complex provide more capacity for drug loading, protection against the gastric environment, increased permeation across skin and other biological membranes. Phytosomes also revealed better pharmacokinetic as well as pharmacodynamic properties in comparison to conventional dosage form. Phytosomes can be developed for different purposes like hepatoprotective, anti-inflammatory, immunomodulator, anticancer etc. This advanced frontier technology would surely represent a fruitful avenue for further resolving the queries of various plant based drugs.

 

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Accepted on 28.02.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(9):4277-4282.