Review on Phytosomal Gel for Enhanced Topical Drug Delivery

Figure 1: Structure of phytosome-loaded complex¹⁰

1.2 Components of phytosomes

There are three main components of phytosomes^11-12

1. Phospholipids
2. Active phytoconstituents
3. Solvents

1.2.1Phospholipids

Both cellular and sub-cellular membranes include phospholipids. Humans, animals, and plants all have them. A polar head and nonpolar acyl chains that are once more connected to alcohol make up phospholipids. There are many phospholipids present as a result of differences in hydrophilic groups, aliphatic chains, and alcohols. Examples of phospholipids found in eukaryotic cell membranes include phosphatidylcholine, cardiolipin, phosphatidylethanolamine, phosphatidylserine, sphingolipids, and phosphatidylinositol 7. Many various types of formulations use phospholipids, including natural, synthesized, and hydrogenated phospholipids such as soy lecithin components like phosphatidylcholine.

Relying on their backbone, phospholipids are classified as glycerophospholipids or sphingomyelins. Phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidic acid (PA), phosphatidylinositol (PI), and phosphatidylglycerol (PG) are all examples of glycerophospholipids (PG). The main phospholipids utilized to make complexes with a hydrophilic head group and two hydrophobic hydrocarbon chains are PC, PE, and PS. Phospholipid complexes are most often made with phosphatidylcholine, which is the most widespread phospholipid. The amphipathic features of phosphatidylcholine offer it moderate solubility in both water and lipid mediums, which is one of its advantages. Furthermore, because phosphatidylcholine is a necessary component of cell membranes, it has a high level of biocompatibility and is low in toxicity. Hepato-protective properties of phosphatidylcholine molecules have been observed in the remedy of liver-colored illnesses such as “hepatitis, fatty liver, and hepatocirrhosis”.

1.2.2 Active phytoconstituents

Flavonoids make up a large portion of phytomedicines’ bioactive components (e.g., milk bramble contains silymarin, bilberry has anthocyanidins, and green tea comprises catechins). The majority of flavonoids, however, are poorly absorbed. Phytosomes are generated from standardized plant extracts, primarily flavonoids. Flavonoids are chosen from a category that includes “quercetin, kaempferol, quercretin-3, rhamnoglucoside, quercetin-3-rhamnoside, hyperoside, vitexine, diosmine, 3-rhamnoside, (+) catechin, (-) epicatechin, apigenin-7-glucoside, luteolin, luteolinglucoside, ginkgetin, isogink”.

1.2.3 Solvents

In the preparation of phytosomes, the phospholipids are mixed with inorganic solvents; phytosomes are prepared by a one solvent or mixed solvent system. Though several publications have utilized mixed solvent systems in which the phospholipids are dissolved in a separate solvent than the drug/extract, for example, aprotic solvent tetrahydrofuran, dichloromethane, diethyl ether and chloroform, protic solvents ethanol, even though typical preparation procedures use a single solvent. More subsequently, protonic solvents including ethanol and methanol have been used to make phospholipid aggregates.

2. Formulation Strategies of Phytosomal Gel Systems

Formulation strategies for phytosomal gel systems focus on enhancing the solubility, stability, and skin penetration of phytoconstituents while ensuring patient acceptability and formulation stability. The development of an effective phytosomal gel involves two major steps: preparation of phytosomes and incorporation of phytosomes into a gel base.¹³

2.1 Selection of Phytoconstituent and Phospholipid

The first step involves selecting a suitable phytoconstituent such as flavonoids, polyphenols, or alkaloids with known therapeutic activity. Phosphatidylcholine is commonly used as the phospholipid due to its biocompatibility, amphiphilic nature, and ability to form stable complexes with phytoconstituents. The drug-to-phospholipid ratio plays a critical role in determining complex formation, entrapment efficiency, and skin permeation.¹⁴

2.2 Preparation of Phytosomal Complex

Phytosomes are prepared by dissolving the phytoconstituent and phospholipid in an appropriate organic solvent such as ethanol or dichloromethane. The solvent is then evaporated under controlled conditions to form a thin film or complex. The resulting phytosomal complex is further hydrated with aqueous medium to form vesicular structures. This step ensures molecular interaction between the phytoconstituent and phospholipid.¹⁵

2.3 Optimization of Process Variables

Process parameters such as temperature, solvent type, stirring speed, hydration time, and sonication affect the size, stability, and drug loading of phytosomes. Optimization of these variables is essential to achieve nanosized vesicles with uniform distribution and high stability. Design of Experiments (DoE) can be employed to systematically optimize formulation parameters.¹⁶

2.4 Incorporation into Gel Base

The optimized phytosomal dispersion is incorporated into a suitable gel base prepared using polymers such as carbopol, HPMC, or chitosan. Neutralizing agents like triethanolamine are added to adjust the pH and achieve desired viscosity. The gel base enhances spreadability, ease of application, and prolonged contact with the skin.¹⁷

2.5 Addition of Stabilizers and Permeation Enhancers

Stabilizers and preservatives are added to improve shelf-life and prevent microbial growth. Optional permeation enhancers may be included to further enhance skin penetration, provided they are safe and compatible.¹⁸

2.6 Evaluation and Stability Studies

The final phytosomal gel is evaluated for physicochemical properties such as pH, viscosity, drug content, vesicle size, and in vitro release. Stability studies are conducted to ensure long-term formulation integrity.¹⁹

3. Characteristics of phytosomes

3.1 Chemical properties

Phytocomplexes are prepared as a result of a reaction between substrate and polymer (phospholipids) generally in ratios 1:1 and 1:2 or based on the essential quantity of phospholipids and substrate. There is evidence of the establishment of hydrogen bonding during the time when both parties were in contact, in the polar regions of both phospholipids and substrate molecules. It is possible to investigate it using a spectroscopic apparatus. While phytosomes are linked to the phospholipids’ glacial surface, they can transform into a portion of the molecular film’s interior where OH bonds with the phenol hydroxyls of the flavone moiety can be formed. As long as the signals from the fatty sequence are largely unaffected, it is possible to make the NMR of the phytosomes more similar to that of the unaltered precursor, which would demonstrate the phytosomes’ accessibility through the evaluation of substance properties.

3.2 Biological properties

Phytosomes are the sophisticated as a natural world for herbal crops with the aim of these products making the superior absorption and consumption as improved domino effect over the entire predictable herbal drugs. It has been established as a result of in vitro and in vivo studies for better invention of herbs in living thing.

3.3 Advantages, limitations and challenges

Phytosomes show various advantages over poorly water-soluble drugs and protects phytoconstituents from degradation. Over their advantages some limitations and challenges are found which are summarized in Table 1.

Table 1: Advantages, limitations and challenges of Phytosomes²⁰

4. Application

Phytosomes have the following benefits over conventional medicinal herbs

1. 1. Enhancing bioavailability:

Evodiamine, a quinoline alkaloid from Evodia rutaecarpa, shows various pharmacological activities. Its phytosomal formulation enhances dissolution, absorption, and bioavailability with prolonged drug action. Phytosomes may also reduce first-pass metabolism by bypassing hepatic degradation. Compared to pure evodiamine, phytosomes significantly increased bioavailability (3787.24 vs. 1772.35 μg h⁻¹ L⁻¹) and half-life (2.07 vs. 1.33 hours).

4.2 Antimicrobial Application

Phytosomes improve the efficacy of antimicrobial phytoconstituents by enhancing their penetration into the skin. This helps in effectively targeting microbial infections at the site of action. Additionally, improved stability of phytoconstituents prevents degradation, thereby maintaining their activity. These properties make phytosomal gels useful in managing skin infections.

4.3 Cancer treatment:

Medicinal plant constituents such as flavonoids and catechins exhibit strong antioxidant and anticancer potential. Phytosomes enhance the solubility, permeability, and effectiveness of these compounds, making them more efficient therapeutic agents. They may also reduce the side effects associated with conventional cancer treatments. A study by Shalini et al. demonstrated that the phytosomal formulation of Terminalia arjuna showed greater antiproliferative activity on MCF-7 breast cancer cells compared to the extract alone. The IC₅₀ value of the phytosome (15 μg/ml) was significantly lower than that of the extract (25 μg/ml), indicating improved efficacy.²¹

4.4 Anti-inflammatory Application

Phytosomes enhance the delivery of anti-inflammatory phytoconstituents, leading to improved therapeutic outcomes. They reduce inflammation by increasing drug concentration at the target site. The lipid-based system also minimizes irritation commonly associated with conventional formulations. This makes phytosomal gels suitable for treating inflammatory skin conditions.

4.5 Wound healing:

Sinigrin, a glucosinolate from the Brassicaceae family, has shown significant wound healing potential when formulated as phytosomes. A study by Mazumder et al. demonstrated complete wound healing (100%) with sinigrin phytosomes compared to 71% with the free phytoconstituent. Additionally, sinigrin phytosomes exhibited enhanced anticancer activity against A-375 melanoma cells. These findings highlight the improved therapeutic efficacy of phytosomal formulations.^22-23

4.6 Antioxidant Delivery

Phytosomes enhance the stability and bioavailability of antioxidant phytoconstituents, protecting them from degradation. They facilitate deeper penetration into the skin, thereby improving their effectiveness against oxidative stress. This helps in preventing cellular damage caused by free radicals. As a result, phytosomal formulations improve overall skin health.

4.7 Transdermal application:

Phytosomes can overcome skin barriers, and are therefore effective carriers for herbal medicines. They are often made by mixing phospholipid molecules with phytoconstituent substances found in extracts from medicinal plants. By increasing the bioavailability and absorption of phytoconstituents like polyphenols, they have enhanced their clinical applications.²⁴

5. Reported Phytosomal Gel Formulations for Topical drug delivery

Phytoconstituent-based phytosomal gel formulations, highlighting the use of active compounds derived from different plant sources. Phytosome Technology enhances the incorporation of these compounds into gel dosage forms, improving skin penetration and bioavailability. For example, compounds like curcumin and quercetin exhibit antioxidant and anti-inflammatory properties.

Table 2:Reported Phytosomal Gel Formulations for Topical Drug Delivery^25-29

The market availability of various phytosome-based formulations, highlighting their phytoconstituents, dosage forms, and therapeutic applications. Phytosome Technology plays a key role in enhancing the bioavailability and effectiveness of herbal compounds such as silymarin, curcumin, and green tea extract. Most of the listed products are commercially available in capsule or tablet forms and are widely used for hepatoprotective, anti-inflammatory, antioxidant, and cardiovascular benefits. Additionally, some formulations like cosmetic creams and phytosomal gels are either limited in availability or still in the research stage. Overall, the growing market presence and therapeutic potential of phytosome-based products shows in Table 3.

Table 3.  Market Availability of Phytosome-Based Formulations^30-32