Figure 2. Difference between phytosomes and liposomes

Difference Between Phytosomes and Liposomes^11,14-19

Both phytosomes and liposomes are novel approaches to increase the absorption and bioavailability of herbal extracts, however, they differ from each other as explained in Table no 1 and shown in Fig. 2.

Mechanism of phytosomes complex:

Phospholipids complexes by endocytosis can be absorbed from the gastrointestinal tract and the drugs are transported to the systemic circulation through the intestinal lymphatic system, which has a vast network throughout the body. Lymphatic transport has the benefit of bypassing the first-pass metabolism and can be used for targeted medication administration^20,21. The phyto-phospholipids complex is absorbed in the intestine are, via paracellular transport, endocytosis, drug efflux inhibition by blocking transporter proteins, chylomicron production, and lymphatic port entry. Various studies have proposed various methods, including Yeap et al suggestion by enterocytes²¹. Jain et al stated by endocytosis²². Phosphatidylcholine is transported paracellularly via lateral tight junctions, according to Stremmel et al²³

Figure 3. Mechanism of phospholipids complex

Different emerging nanotechnologies:

Properties of Phytosomes^35,36,29

1. Chemical properties:

Phytosomes are formed when stoichiometric amounts of phospholipids like soy lecithin compounds are used and phytoconstituients of plant extract are reacted with an inorganic solvent. The formation of the chemical bond between phytoconstituients and phospholipids takes place which is shown in various spectroscopic analysis shows that the phytoconstituents and phospholipids form a chemical bond with each other. The phospholipids and substrate form hydrogen bonds with each other. Preparation of phytosomes is done by treating phospholipids and substrate into inorganic solvent but, if it is treated with water it forms a micelle shape that resembles liposomes. In liposomes, the phytoconstituents are dispersed in phospholipids and no bond formation takes place in liposomes.

2. Biological properties:

Phytosomes technology is been widely used due to its ability to increase the bioavailability and absorption of herbal extracts as compared to the conventional dosage form. Pharmacokinetic investigations and pharmacodynamic testing in experimental animals and human subjects have been conducted due to the phytosome's increased bioavailability over non-complexed derivatives.

Figure 4. Phyto- phospholipid complex

Methods of preparation of phytosomes: ^37-44

Phytosomes are complexes prepared by the process in which, herbal extracts are mixed with natural or synthetic phospholipids like phosphotidylcholine, phosphotidylethanolamine, or phosphotidylserine and incorporated in aprotic organic solvent and then phytosomes are precipitated by using any anti-solvent and then dried.

1. Anti-solvent preparation method:

In this method the plant extract and phospholipids like soy lecithin are mixed with an organic solvent like dichloromethane in the round bottom flask and refluxed at fixed temperature and given experimental conditions then there is the addition of n-hexane as anti-solvent with continuous stirring which forms a precipitate of phytosomes which is then filtered and dried in desiccators

2. Rotary evaporation method:

In this method specific amount of plant extract and phospholipids like soy lecithin are mixed with a water-miscible organic solvent like acetone in the round bottom flask and is kept in a rota evaporator at fixed temperature with continuous stirring then thin film formed is treated with n-hexane to form a precipitate of phytosomes. The example, are quercetin phytosomes, phytosomes of lawsone, and phytosomes of Bael.

3. Solvent evaporation method:

In this method the plant extract and phospholipids are mixed with a suitable solvent like tetrahydrofuran placed in the round bottom flask (RBF) and refluxed at fixed temperature and then solvent evaporation is done under vacuum, and then it is concentrated and dried phytosomes is formed.

4. Co-Solvent lyophilization method:

In this method, plant extract or drug and phospholipids are mixed with a suitable solvent, and then it is free-dried under vacuum and stored in a closed airtight container. For example, rutin phytosomal preparation was prepared by the co-solvent lyophilization method.

Common stages in the preparation of phytosomes:

As we have seen above, phytosomes can are prepared using different methods, but the common stages in phytosomal preparation are given in Fig no5.

Fig. 5. Preparation of phytosomes

Commercial Phytosomal products:

Table 3. Phytosomal formulation in the market

Sr. No.	Phytosomal Product	Phytoconstituent	Natural Source	Pharmacological Activity	Ref.
1	Hawthron Phytosomes	Hyperin, Quercitin	Crateegus, Oxyacanthoids	Antihypertension, Cardioprotective	45
2	Ginseng Phytosomes	Ginsenosides	Panax Ginseng	Immunomodulator, Neutraceutical	45
3	Curcumin Phytosome	Curcumin	Curcuma Longa	Osteoarthritis, Anti-Inflammatory, Anticancer	46,47
4	Escin Β-Sitosterol Phytosome	Saponins	Aesculus Hippocastanum (Horse Chestnut Fruit)	Anti-Oedema	45
5	Green Tea Phytosome	Epigallocatechin, Catechin, Epicatechin-3-O-Gallate, Epigallocatechin-3-O-Gallate	Camellia Sinesis (Tea)	Neutraceutical, Systemic Antioxidant, Anticancer, Hepatoprotective, Anti-Inflammatory	45,48
6	VitaBlue Phytosome	Anthocyanosides tocotrienol complex, citrus bioflavonoid, alpha-lipoic acid	Vaccinium angustifolium (Blue berry)	Antioxidant, improve vision, memory enhancer	45
7	Glycyrrhetinic acid PhytosomeTM	Glycyrrhetinic acid	Glycyrrhiza glabra (Mulethi)	Anti-inflammatory, dermatitis	45
8	Silybin Phytosome	Silybin, Silycristin, isosilbin, Silydianin	Silybium maranium (Milk Thistle)	Hepatoprotective, Antioxidant for skin and liver	45,46,49
9	Mirtoselect Phytosome	Anthocyanosides	Vaccinum myrtillus (Bilberry)	Antioxidant, Improvement of Capillary Tone.	50,14
10	Ginkgo phytosome	24% Ginkgo flavon glycosides	Ginkgo biloba	Protect the brain and vascular lining, antiageing agent	45,14
11	Madeglucyl Phytosome	Tannins	Syzygium cumini Jamun	Antihyperglycemic, anti-inflammatory, antioxidant	45
12	Ximilene and Ximenoil Phytosome	Ximenynic acid, ethyl ximenynate	Santalum album (Sandal wood)	Improve microcirculation	45
13	Cucurbita PhytosomeTM	Tocopherols, steroids, Carotenoids	Cucurbita pepo Pumpkin	Anti-inflammatory, Benign prostatic hyperplasia	45
14	Soyselect PhytosomeTM	Genistein and daidzein	Glycine max (Soya)	Antiangiogenic, anticancer, cardioprotective, immunostimulatory and hypocholesterolemic	45

Characterization of phytosomes:

It is important to study the characteristics of phytosomes and their effects. Therefore, the characterization of phytosomes for physical attributes such as morphology, particle size distribution, drug entrapment efficiency, and chemical composition is important. The following are the techniques used for the characterization of phytosomes;

1. Entrapment efficiency:⁵¹

The drug entrapment efficiency of phytosomal preparation is measured by the ultracentrifugation technique. The drug phytosomal complex is centrifuged and the phytosomes are separated from non-entrapped drugs and the drug concentration is usually quantified by ultraviolet spectroscopy. Entrapment efficiency (%) is calculated by using the formula;

Weight of total drug – weight of free drug

Percentage = -------------------------------------------------------------- ×100

entrapment Weight of total drug

2. Zeta potential and particle analysis:^52,53,54,55

In phytosomes size and size, distribution is an important variable as they directly affect in absorption, bioavailability, and stability of the drug. The zeta potential is determined by using laser doppler velocimetry whereas zeta potential and particle analysis can be determined by various methods but the most commonly used method is by photon correlation spectroscopy and dynamic light scattering.

3. Spectroscopic properties:^56,57

The ¹³CNMR, ¹HNMR, and FT-IR are the spectroscopic techniques used to confirm the lipid compatible complex of phytosomes.

4. Transition Temperature:^58,59

The differential scanning calorimetry thermal analysis apparatus is used to measures the temperature variation of physical properties of a sample against time and this method is used to determine transition temperature.

5. Visualization of the morphology of phytosomes:⁶⁰

The size and shape of phytosomes and visual appearance are done by different microscopic techniques like scanning electron microscopy and transmission electron microscopy. Various factors affect and alter the size and shape of phytosomes like the shape and size of phytosomes can be affected by lipid purity grade.

6. Surface tension activity measurement:^61,62

The surface tension is measured using the ring method Du Nouy ring tensiometer

7. Crystallinity:⁶³

Crystalline properties of the phyto-phospholipid complex can be predicted by X-ray diffraction analysis. The peak obtained in the X-ray diffraction pattern specifies the product properties.

8. Vesicle stability:^12,64

Vesicle stability is determined by molecular size, polydispersity index (PDI) and zeta potential describe the vesicle stability. PDI value of phytosomes is determined and phytosomes with a PDI value of less than 0.5 are stable, while those with a zeta potential greater than 30 mV are considered stable complexes.

Recent research on phytosomes:

1. Vasaka phospholipid complex:

An overview on Adhatoda vasica:

Synonym: Vasaka, Malabar nut tree

Family: Acanthaceae

Genus: Justicia

Species: J. Adhatoda

Common name: Adulsa (Vasaka)

Medicinal Applications of Adhatoda vasica:

In Ayurveda, it is prescribed for various diseases like,

Bronchitis and Asthma:

It is used to treat acute bronchitis, potential bronchodilator and asthma’s it liquefies the sputum and reliefs many respiratory diseases.

Antitussive:

It is used to treat cough.

Antimicrobial:

Useful in the removal of parasites present in the intestine also help in treating diarrhea and dysentery. Other diseases treated by vasaka are malarial fever, skin diseases, fever, tuberculosis, chronic fever, intrinsic hemorrhage, leprosy.

Chemical constituents:

Important chemical constituents include pyrroloquinazoline alkaloids, vasicine, adhatonine, vasicinol, vasicinone, vasicol.^65,66

Phytosomal vasaka preparation:

The vasicine is an herbal extract that has many therapeutic benefits but there are restrictions for its use due to poor solubility, absorption, bioavailability, and stability. So, by using the thin layer hydration technique using quality by design approach the vasaka phytosomes can be prepared. So the bioavailability, absorption, and stability of Vasaka-loaded phytosomes were increased as compared to vasaka herbal extract as showed in fig no;6.⁶⁷

Fig. 6 graphs showing increased drug release of vasaka phytosomal extract

2. Quercetin Phytosomes:

Quercetin phytosomes in COVID-19:

Quercetin belongs to the flavonols class. Quercetin has various therapeutic benefits like cardiovascular protection, anticancer, anti-ulcer, anti-allergy, anti-inflammatory activity, anti-diabetic, gastroprotective effects, antihypertensive, and antiviral. In the outbreak of covid19 different compounds were screened for molecular docking studies to know about their anti-viral properties quercetin was identified as a reasonably potent inhibitor of 3-chymotrypsin-like protease, which is one of the durable targets of SARS-CoV-2[⁶⁸]. As quercetin has limitations due to its poor bioavailability to overcome these limitations the quercetin phytosomes are prepared by formulating quercetin and sunflower lecithin showed 20 times increase in bioavailability of quercetin. So, quercetin may have a well-defined role in the treatment of COVID-19. ^69,70,71

Quercetin phytosomes in fortification of food products with antioxidants:

The quercetin layer hydration method can be used for the preparation of quercetin phytosomes by mixing Quercetin, PC, and cholesterol, and the different characterization techniques of quercetin phytosomal preparation were studied like drug entrapment efficiency, thermal analysis, etc. As there are various therapeutic benefits of quercetin like the antioxidant property of quercetin but, due to poor bioavailability, the effect is limited. Quercetin-loaded nano phytosomes increase the bioavailability and stability which leads to an increase in the antioxidant property as compared to quercetin⁴².

3. Curcumin-cholesterol phytosomal complex:

Curcumin has various therapeutic benefits such as lowers bad cholesterol, immunity booster, relieves pain or inflammation, prevent Alzheimer's disease, and antioxidant. Despite these benefits limitations to attain the therapeutic effect arises due to lower absorption and faster elimination. To overcome these limitations it was incorporated with phytosomes reacting with cholesterol. After evaluation of all physicochemical properties, the Curcumin-cholesterol phytosomal complex shows increased solubility and bioavailability of curcumin⁷².

4. Phytosomes of green tea:

Green tea leaves have many therapeutic effects like antioxidant, antineoplastic, boost metabolism, prevent heart diseases, lowers bad cholesterol, etc. As it contains polyphenolic compound epiallocatechin 3-o gallate as the important constituent, but due to poor bioavailability of polyphenols from green tea extracts, so to overcome this the polyphenols of green tea herbal extract are complexed with phospholipids which increases the bioavailability of polyphenols¹.

5. Phytosomal extract of Allium sativum against breast cancer:

As phytosome technology is widely used to increase the solubility, bioavailability, absorption, and stability of herbal extracts. Phytosome prepared through the formation of a complex between phospholipids and methanolic substrate of herbal extract of allium sativum witch contains diallyl disulfide is effective than conventional herbal extract⁷³.

Applications of phytosomes:

1. Enhanced bioavailability:

The phytosomes technology is widely used to increase the bioavailability of phytoconstituients of herbal extracts, for example, Evodiamine, a quinoline alkaloid, (Evodia rutaecarpa) possess many therapeutic benefits such as anti-tumor, anti-inflammatory, anti-nociceptive, antiobesity, and thermoregulatory effects. The phytosomal Evodiamine preparation showed increased absorption and bioavailability as compared to evodiamine⁷⁴. another example is A European patent by 'Indena S.P.A.' Relates to the Oleaselect phytosomes shows improved bioavailability through the oral route as compared to normal olive fruits extract⁷⁵.

2. Wound healing:

The wound healing properties of sinigrin, which is major glucosinolates of the plant of the Brassicaceae family are found to be increased when it is prepared as sinigrin phytosomal preparation and antitumor activity of sinigrin was also increased⁷⁶. Another example is of wrightia arborea leaves the ethanolic extracts of this leaves when complexed with phytosomes it shows the increase in wound healing property and its phytosomes⁷⁷.

3. Transdermal application:

In transdermal drug delivery, phytosomes are used to increase the penetration of the herbal extract through the skin. Example rutin, which has many therapeutics benefits like capillary fragility, ultraviolet radiation-induced cutaneous oxidative stress, antiplatelet, etc. Rutin phytosomes have increased penetration in the skin as compared to rutin as when rutin is prepared in the form of phytosomes it penetrates through impermeable stratum corneum⁸.

4. Antioxidant property:

The antioxidant property is improved in phytosome technology. For example; quercetin phytosomal formulation shows improved stability and absorption which leads to an increase in its anti-oxidant activity such as it prevents the foodstuffs from oxidation⁴².

CONCLUSION:

Phytosomes are a novel approach to herbal drug extracts. This review is an attempt to present the benefits, chemical properties, biological properties, preparation technique, and uses of phytosomes. Several herbal extracts and phytoconstituients despite having various therapeutic benefits but limitations of their use arise due to ineffective in vivo actions owing to their low solubility, molecular size, resulting in poor absorption and poor bioavailability. Herbal extracts when complexed with phospholipids it forms a phyto-phospholipids complex which increases the solubility, bioavailability, absorption, and stability of herbal drugs. Phytomedicines are emerging formulation tool which is used widely in therapies such as antioxidant, antitumor, hepatoprotective. So, phytosome technology has major acceptance as it forms a connection between the general delivery system of phytoconstituents and novel drug delivery systems.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 20.07.2021 Modified on 03.12.2021

Asian J. Pharm. Ana. 2022; 12(1):61-69.

DOI: 10.52711/2231-5675.2022.00012

Sr. No.	Phytosomes	Liposomes
1	Phytosomes are prepared by the interaction between the polar or hydrophilic part (head) of phospholipids and water-soluble plant extract and form a complex by chemical (hydrogen) bonds.	Liposomes are prepared by mixing phospholipids in a water-soluble substance, but here no chemical bonds are formed.
2	In phytosomes the phospholipids and substrate complexes are formed in stoichiometric ratio, depending on the plant extract used.	In liposomes, thousands of phospholipids molecules are surrounded by the substance.
3	Using Phytosomes there is an increase in absorption of phytoconstituients and enhances the bioavailability of a substance	Using Liposomes the increase in absorption of phytoconstituients and bioavailability of substance is to a lesser extent than phytosomes
4	Phytosomes have greater stability than liposomes due to phyto-phospholipid complexes are formed in phytosomes.	Liposomes have less stability than phytosomes has there is the absence of chemical bonding no complex is formed.
5	The solvents used in phytosomes preparation are having reduced the dielectric constant.	In liposomes buffer solution or water is used as solvent.

Vesicular system	Description	Application	Reference
Aquasomes	It consists of core, coat, and drug which is self-assembled core is solid nanocrystalline particles(ceramic) coat is an oligomeric film and adsorbed with bioactive molecules	Specific targeting, molecular shielding	24
Virosomes	Virosomes show the viral envelope of glycoprotein. Liposomes spiked with virus glycoprotein’s, incorporated in the liposomal bilayer based on retrovirus based lipids	Immunological adjuvant	25,26
Ufasomes	Ufasomes are unsaturated fatty acids vesicles (oleic acid, linoleic acid)	Drug targeting	27
Emulsomes	Emulsomes consists of an internal core which is made up of fats like triglycerides and a phospholipid bilayer	Drug targeting, anti-neoplastic	28
Niosomes	Niosomes are bilayer structures and are formed by self-association of surface-active agents which are nonionic in vesicles and cholesterol in an aqueous phase.	Drug targeting, anti-neoplastic, carrier for hemoglobin	29,30
Pharmacosomes	Pharmacosomes are colloidal dispersions in which drug-lipid complex is formed such that drugs bound covalently with phospholipids	Absorption and penetration power of drugs is increased	28,31
Cubosomes	Cubosomes are microstructured bicontinuous and self-assembled liquid crystalline phase particles of surfactants with a specific ratio with water	Drug targeting	32
Ethosomes	Ethosomal systems are novel lipid vesicular carriers containing a relatively high percentage of ethanol and it contains phospholipids and water	Transdermal and intradermal delivery	33,34