A Review on Phytochemical and Formulation Approaches of Centella Asiatica and Acacia Arabica in Wound Healing Applications Wound healing, Centella asiatica, Acacia arabica, Phytosomes, Topical gel formulation

Abstract

Wound healing is a complex physiological process involving a series of coordinated cellular and molecular events aimed at tissue repair and regeneration. Herbal medicines have gained significant attention due to their bioactive constituents that offer anti-inflammatory, antioxidant, and antimicrobial properties essential for efficient wound healing. This review highlights two ethnomedicinal plants, Centella asiatica and Acacia arabica, which possess potent wound healing capabilities supported by their rich phytochemical profiles. The ethanolic extracts of these plants (CASEE and AAEE) were prepared through optimized extraction techniques and further formulated into a novel polyherbal phytosomal gel using thin-layer hydration method. The phytosomal formulation exhibited enhanced vesicle size uniformity and high entrapment efficiency, contributing to improved drug stability and sustained release characteristics, as confirmed by physicochemical evaluations including particle size analysis, FTIR, and in vitro drug release kinetics. The gel matrix provided a suitable topical delivery system with favorable rheological and swelling properties, facilitating prolonged retention at the wound site. Stability studies further confirmed the robustness of the formulation under accelerated conditions. Collectively, the integration of phytosomal nanocarriers with the therapeutic potentials of Centella asiatica and Acacia arabica offers a promising, biocompatible, and natural alternative for advanced wound care management, potentially overcoming limitations associated with conventional therapies.

Keywords

Introduction

Table 1: Phytochemical estimation of extracts CASEE and AAEE

The significant presence of flavonoids, terpenoids, and phenolic compounds in both extracts suggests potent antioxidant and wound healing potential. TLC analysis confirmed these phytochemicals by identifying characteristic Rf values compared with standard compounds.

5. Scientific Evaluation of Centella asiatica and Acacia arabica for Wound Healing Applications

Figure 2: Skin repairing procedure

7. Phytosomes: A Novel Delivery Platform

Figure 3: Anatomy of Human Skin (Recollected from Pubmed⁷).

Absorption of Drugs Through the Skin

Topical drug absorption primarily involves diffusion through the intact epidermis, with sweat glands and hair follicles comprising only about 0.1% of the total skin area but offering auxiliary penetration pathways (Ruela et al., 2016). The stratum corneum regulates the depth of drug penetration, with two main routes proposed for transport:

• Intercellular Lipid Route: Drugs diffuse through the lipid matrix filling spaces between corneocytes. Hydrophobic and amphiphilic molecules utilize these lipid domains, while hydrophilic molecules tend to diffuse laterally over aqueous regions (Gupta and Trivedi, 2016).
• Transcellular Pathway: This route involves drug transport directly through corneocytes and the intracellular matrix, although it is more restrictive due to the keratin-rich macromolecular structure which imparts mechanical strength and barrier function (Kamarova et al., 2010).

Basic Principles of Permeation

Biomembranes consist of lipophilic and hydrophilic regions, and drug permeation through these membranes can be described by Fick’s first law of diffusion:

Where:

• JJ = flux of drug across the membrane (mass/area/time)
• PP = permeability coefficient
• CaqC_{aq} = concentration gradient of the drug

The permeability coefficient PP is further expressed as:

Where:

• DD = diffusion coefficient
• KK = partition coefficient between membrane and external environment
• hh = membrane thickness

Types of Topical Dosage Forms

Common topical dosage forms include:

• Solutions
• Gels
• Creams
• Lotions
• Ointments

Gels

The term "gel" originates from the Latin words gelu (frost) and gelare (to freeze or congeal), reflecting the unique semi-solid, elastic nature of gels that lie between liquids and solids (un-Nabi et al., 2016). Gels consist of a three-dimensional network of polymers or colloidal particles dispersed in a liquid phase, providing desirable rheological and drug release properties. According to the United States Pharmacopeia, gels are semisolid systems containing suspensions of small inorganic particles or large organic molecules.

Key characteristics of gels include:

• Swelling: Gelling agents hydrate and expand when exposed to liquids, dependent on the number and strength of intermolecular bonds.
• Syneresis: Over time, gels may contract and expel liquid due to thermodynamic instability and elastic stress relaxation.
• Ageing: Slow aggregation or densification of the gel network over time.
• Rheology: Gels typically exhibit non-Newtonian, shear-thinning behavior, where viscosity decreases with increasing shear rate due to the breakdown of interparticle interactions (Rathod et al., 2015).
• Structure: The stiffness and integrity of gels arise from the interconnected network of gel particles.

Gel-Forming Substances

Various natural, semi-synthetic, and synthetic polymers serve as gel-forming agents (Goswami et al., 2014):

Table 2: Sources of gel forming substances for gel formulations

7.3. Types of Topical Dosage Forms

Creams

Creams are semi-solid emulsions composed of oil and water phases, designed to deliver active drugs topically. They are generally classified as either oil-in-water (O/W) or water-in-oil (W/O) emulsions.

• Oil-in-Water (O/W) Creams: These are water-washable, non-greasy, and easily spreadable, making them suitable for moist, weepy skin conditions. Their higher water content provides a cooling effect and better patient acceptance.
• Water-in-Oil (W/O) Creams: These have a higher oil content, are more emollient and occlusive, and are preferred for dry, scaly skin as they provide better hydration by preventing water loss.

Advantages:

• Pleasant texture and appearance
• Easy to apply and remove
• Can be formulated to release drugs at controlled rates
• Suitable for both hydrophilic and lipophilic drugs

Limitations:

• Stability can be an issue due to the emulsion nature
• Potential for microbial contamination because of the aqueous phase

Ointments

Ointments are semi-solid preparations intended for external application, composed mainly of oils or hydrocarbons with little or no water. They provide an occlusive barrier that helps retain moisture on the skin, enhancing drug penetration and skin hydration.

Types of ointments:

• Oleaginous bases: Such as petroleum jelly, which are hydrophobic and provide maximum occlusivity but are greasy and difficult to wash off.
• Absorption bases: These can absorb water and form water-in-oil emulsions, useful for incorporating aqueous drugs into oily bases.
• Water-removable bases: Resembling creams, these are oil-in-water emulsions, water washable, less greasy, and provide moderate occlusivity.
• Water-soluble bases: Such as polyethylene glycol ointments, which are non-greasy and easily washed off but lack occlusive properties.

Advantages:

• Provide prolonged drug contact and hydration
• Suitable for dry, scaly skin conditions
• Excellent for delivering lipophilic drugs

Limitations:

• Greasy texture may reduce patient compliance
• Difficult to remove with water alone

Lotions

Lotions are low-viscosity liquid preparations intended for application on the skin. They are typically oil-in-water emulsions or aqueous suspensions containing medicinal agents and are less greasy and easier to spread than ointments or creams.

Applications:

• Suitable for large or hairy areas of the body
• Used in conditions requiring cooling or drying effect, such as eczema or sunburn
• Can be formulated with soothing agents to reduce inflammation

Advantages:

• Easy and rapid application
• Non-greasy and quickly absorbed
• Useful for scalp and hairy areas

Limitations:

• Less occlusive; may require frequent application
• Can be drying due to alcohol or other solvents used

Solutions

Solutions are clear, homogeneous liquid preparations where the drug is completely dissolved in an appropriate solvent or mixture of solvents. Topical solutions include medicated liquids such as antiseptics, astringents, and lotions.

Advantages:

• Easy to apply over large areas
• Useful for delivering drugs to mucous membranes or skin lesions
• Fast onset of action due to rapid drug release

Limitations:

• May cause skin irritation if solvents are harsh
• Often less stable than semi-solid dosage forms
• Evaporate quickly, sometimes reducing contact time

7.4. Factors Influencing Topical Drug Delivery

The efficiency of topical drug delivery is influenced by several factors:

• Physicochemical properties of the drug: Molecular size, lipophilicity, solubility, and ionization state affect permeation. Small, moderately lipophilic molecules typically penetrate the skin more readily.
• Formulation characteristics: Vehicle type, presence of penetration enhancers, viscosity, and pH can enhance or restrict drug absorption.
• Skin condition: Integrity, hydration, thickness, and temperature of the skin can alter permeability. Damaged or inflamed skin may allow higher drug penetration.
• Application method: Quantity, frequency, and site of application determine drug bioavailability.

8. Challenges and Future Directions

Despite advances, several challenges remain in topical drug delivery:

• Skin barrier variability: Differences in skin types, disease states, and anatomical sites affect drug permeation.
• Drug stability: Maintaining stability of drugs and nanocarriers in formulations under storage and upon application.
• Safety and irritation: Long-term safety of penetration enhancers and nanomaterials must be ensured to avoid skin sensitization or toxicity.
• Controlled release: Achieving precise control over drug release rates and targeting specific skin layers remains complex.

8.1. Future research is focusing on:

• Smart responsive formulations that release drugs triggered by environmental stimuli such as pH, temperature, or enzymes.
• Personalized topical therapy based on skin characteristics and disease state.
• Integration of herbal and natural compounds with advanced nanotechnology for safer and effective treatment modalities.

8.2. Topical delivery is widely employed for various drug classes, including:

• Anti-inflammatory agents: Such as corticosteroids and NSAIDs for local treatment of inflammation and pain.
• Antimicrobials: Including antifungals, antibiotics, and antivirals used for infections localized on the skin or mucous membranes.
• Analgesics: For relief of localized pain through agents like lidocaine or capsaicin.
• Antipsoriatic agents: Like coal tar, salicylic acid, and vitamin D analogs for chronic skin diseases.
• Cosmeceuticals: Vitamins, antioxidants, and herbal extracts aimed at skin rejuvenation and anti-aging.

The advancements in topical drug delivery systems, especially the incorporation of nanocarriers like phytosomes, are highly relevant to the formulation of polyherbal phytosomal gels containing Centella asiatica and Acacia arabica ethanolic extracts. Phytosomes enhance the bioavailability and skin permeation of phytoconstituents by forming stable complexes with phospholipids, facilitating deeper penetration through the stratum corneum and sustained release at the wound site. This improved permeation is critical for delivering the active compounds efficiently to the wound bed, promoting accelerated healing through their anti-inflammatory, antioxidant, and antimicrobial properties. Moreover, the gel formulation offers a convenient, patient-friendly topical dosage form with desirable characteristics such as ease of application, prolonged retention, and moisturizing effects that create an optimal environment for tissue regeneration. The inclusion of natural penetration enhancers inherent in the extracts further aids in overcoming the skin’s barrier function without causing irritation. Thus, by leveraging the benefits of phytosomal nanocarriers and topical gel systems, the current research aims to develop an effective, safe, and biocompatible wound healing formulation that maximizes therapeutic outcomes while minimizing systemic side effects. In summary, the integration of polyherbal phytosomal technology with topical gel formulations represents a promising strategy to enhance the delivery and efficacy of herbal actives in wound management, paving the way for innovative, natural-based therapeutic interventions.

9. Methods of Phytosome Preparation

Thin Layer Hydration

Most commonly employed:

• Optimal CASEE: PC and AAEE: PC molar ratios (1:1)
• Vesicle size: 100–200 nm, PDI < 0.3
• Entrapment efficiency: CASEE ~72%, AAEE ~68%, PHEE ~75%
• Zeta potential: -25 to -30 mV

Other Methods

• Solvent Evaporation
• Antisolvent Precipitation
• Mechanical Dispersion

Each method is optimized to ensure vesicle uniformity and maximal entrapment.

10. Characterization and Evaluation of Phytosomes and Gel

Phytosomes were incorporated into Carbopol 934 gel and evaluated:

• pH: 6.4 ± 0.1 (skin-compatible)
• Viscosity: 45,000–50,000 cps
• Spreadability: 6.5 ± 0.2 cm
• Homogeneity: Smooth, uniform texture
• Stability: Maintained over 3 months under normal and accelerated conditions

10.1. Analytical Characterization

• Morphology: SEM/TEM confirms vesicular structure
• Entrapment Efficiency: Via ultracentrifugation
• Vesicle Stability: Monitored by DLS
• Particle Size & Zeta Potential: Via PCS
• Drug Content: UV-Vis or HPLC
• Crystallinity: Analyzed via DSC and XRD
• In Vitro Release:
  • CASEE Gel: 65% over 12 hrs
  • AAEE Gel: 60% over 12 hrs
  • PHEE Gel: 78% over 12 hrs
• Ex Vivo Permeation: Superior penetration for PHEE gel
• Kinetics: Follows Higuchi model (R² > 0.98), indicating diffusion-controlled release

10.2. Therapeutic Evaluation of Phytosomal Gels

The therapeutic efficacy of phytosomal gels formulated with Centella asiatica (CASEE), Acacia arabica (AAEE), and their polyherbal combination (PHEE) has been extensively studied using various in vitro and in vivo models to assess wound healing potential, antimicrobial activity, and anti-inflammatory effects.

10.3. In Vitro Antimicrobial Activity

The phytosomal gels demonstrated significant inhibitory effects against common wound pathogens including Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The enhanced antimicrobial activity observed in the PHEE gel is attributed to the synergistic effect of the combined phytoconstituents, which disrupt bacterial cell walls, inhibit biofilm formation, and interfere with bacterial metabolism. These properties are crucial to prevent wound infections and facilitate uninterrupted healing.

10.4. Anti-inflammatory Activity

Both CASEE and AAEE exhibit potent anti-inflammatory effects by modulating pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. In phytosomal form, these extracts exhibit improved bioavailability, leading to enhanced suppression of inflammatory mediators and reduced oxidative stress at the wound site. This modulation reduces edema and pain, creating an optimal environment for tissue repair.

10.5. Mechanistic Insights into Phytosome-Enhanced Wound Healing

The superior therapeutic performance of phytosomal gels stems from multiple factors:

• Improved Skin Penetration: Phospholipid complexes facilitate better transdermal delivery of active phytoconstituents by interacting with stratum corneum lipids, increasing permeation and retention at the wound site.
• Controlled and Sustained Release: The vesicular structure allows gradual release of bioactives, maintaining effective therapeutic concentrations over prolonged periods without frequent reapplication.
• Protection from Degradation: Encapsulation within phytosomes shields sensitive phytochemicals from enzymatic degradation and oxidative damage, preserving their bioactivity.
• Synergistic Bioactivity: The combined effects of CASEE and AAEE provide a broader spectrum of bioactivities, including antioxidant, antimicrobial, anti-inflammatory, and collagen-promoting effects, all essential for efficient wound repair.

11. Future Perspectives and Challenges

Despite promising results, several challenges remain in translating phytosomal formulations into clinical practice:

• Scalability and Manufacturing: Developing cost-effective, scalable production processes that maintain batch-to-batch consistency is essential for commercial viability.
• Standardization: Ensuring uniform phytochemical profiles and bioactive content in plant extracts is critical to reproducible therapeutic outcomes.
• Regulatory Approval: Comprehensive toxicological evaluations and adherence to regulatory guidelines must be conducted to ensure safety and efficacy.
• Clinical Trials: Well-designed randomized controlled trials are necessary to establish clinical effectiveness, optimal dosing, and long-term safety in human populations.

Advances in nanotechnology, formulation science, and analytical techniques will continue to enhance phytosome-based drug delivery platforms. Integration with other novel carriers such as nanoparticles and hydrogels could further improve targeting, bioavailability, and patient compliance.

11.1. Advanced Characterization Techniques for Phytosomal Gels

Comprehensive physicochemical and morphological characterization is essential for understanding the stability, efficacy, and safety of phytosomal gels.

• Fourier Transform Infrared Spectroscopy (FTIR): FTIR analysis confirms the formation of phytosome complexes by detecting characteristic shifts or changes in functional group vibrations, indicating interactions between phospholipids and phytoconstituents. Compatibility studies ensure no adverse chemical reactions occur between excipients.
• Differential Scanning Calorimetry (DSC): DSC profiles reveal changes in thermal behavior, such as melting points and phase transitions, confirming complex formation and physical state of encapsulated phytochemicals within the lipid bilayer.
• X-ray Diffraction (XRD): XRD analysis determines the crystallinity or amorphous nature of phytosomal formulations, which influences solubility and bioavailability. Typically, successful phytosome formation leads to decreased crystallinity, indicating improved dispersion.
• Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM): These imaging techniques provide detailed visualization of vesicle morphology, size, and surface characteristics. Uniform, spherical vesicles with smooth surfaces suggest stable formulations.
• Particle Size and Zeta Potential Analysis: Dynamic light scattering (DLS) measures average vesicle size and distribution, while zeta potential assesses surface charge. Optimal size (generally <200 nm) and suitable zeta potential values (±30 mV or greater) predict colloidal stability and skin penetration capability.
• Entrapment Efficiency (EE): High EE values indicate effective encapsulation of phytoconstituents, critical for sustained drug release and therapeutic action.

12. Optimization of Phytosomal Gel Formulation

Optimizing formulation parameters is crucial for achieving desirable characteristics such as viscosity, spreadability, pH compatibility, and stability:

• Phospholipid to Extract Ratio: Balancing the amount of phospholipid with the plant extract affects vesicle formation, encapsulation efficiency, and release kinetics.
• Hydration Medium: Choice of solvent and hydration time influences vesicle size and homogeneity.
• Gel Base Selection: Carbopol, hydroxypropyl methylcellulose (HPMC), or other polymeric bases provide suitable viscosity and biocompatibility. Adjusting polymer concentration optimizes gel consistency and application properties.
• pH Adjustment: Maintaining skin-compatible pH (~5.5–6.5) ensures minimal irritation and preserves phytoconstituent stability.
• Preservatives and Stabilizers: Inclusion of antioxidants and preservatives prevents microbial contamination and oxidative degradation during storage.

Formulation optimization often employs Design of Experiments (DoE) approaches, such as factorial designs and response surface methodology, to systematically evaluate the effect of variables on critical quality attributes.

Stability Studies

Accelerated and long-term stability studies evaluate the impact of temperature, humidity, and light exposure on phytosomal gel quality. Key parameters monitored include:

• Physical appearance (color, phase separation)
• pH changes
• Viscosity and spreadability
• Entrapment efficiency
• Drug content retention
• Microbial contamination

Stable formulations retain efficacy and physical integrity over intended shelf-life, ensuring patient safety and product reliability.

CONCLUSION

Phytosomal gels represent a promising, innovative approach for enhancing the topical delivery of herbal extracts, such as Centella asiatica and Acacia arabica, for wound healing applications. The phospholipid-based vesicular system enhances bioavailability, stability, and therapeutic efficacy by improving skin penetration and sustained release of bioactive compounds. Optimized polyherbal phytosomal gels exhibit significant antimicrobial, anti-inflammatory, and tissue regenerative properties, accelerating wound repair in preclinical models. Future research should focus on large-scale production, rigorous clinical evaluation, and regulatory approval to establish these formulations as effective and safe alternatives or adjuncts to conventional wound care therapies. The integration of phytosome technology with advanced drug delivery platforms holds substantial potential to transform phytomedicine into mainstream clinical practice. Centella asiatica and Acacia arabica have emerged as potent natural candidates for wound management, attributed to their rich phytochemical profiles and multi-dimensional therapeutic properties, including antioxidant, anti-inflammatory, antimicrobial, and tissue-regenerative effects. Their traditional use is now being scientifically reinforced through contemporary research, which highlights their ability to address multiple phases of the wound healing process. The synergistic application of their ethanolic extracts (CASEE and AAEE) in combination enhances therapeutic efficacy and provides a holistic approach to wound care. The incorporation of these botanicals into advanced delivery systems—such as phytosomes—not only improves their solubility, stability, and skin permeability but also ensures targeted and sustained release of active constituents at the wound site. This integration represents a significant advancement in the development of modern herbal wound care formulations, bridging the gap between traditional herbal knowledge and modern pharmaceutical technology. However, to fully establish their clinical utility, further efforts are needed in the areas of extract standardization, formulation optimization, and extensive preclinical and clinical evaluations. Such studies will be instrumental in validating safety, efficacy, and reproducibility, ultimately paving the way for these phytotherapeutic agents to be incorporated as frontline alternatives or adjuncts to conventional wound healing therapies in broader healthcare settings.

ACKNOWLEDGEMENT

I express my sincere gratitude to Dr. Deepesh Lall, my supervisor at the Department of Pharmaceutics, LCIT School of Pharmacy, for his invaluable guidance, insightful suggestions, and continuous support throughout the preparation of this review paper. I am also thankful to Dr. Ritesh Jain, Principal of LCIT School of Pharmacy, for providing the necessary resources and a supportive academic environment. I appreciate the assistance and encouragement extended by the faculty and staff of the Department of Pharmaceutics.Finally, I acknowledge the motivation and support of my family and peers, which greatly contributed to the completion of this work.

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