Invasomes in the Era of Smart Transdermal Therapeutics:
From Molecular Design to Clinical Translation
Vinod K. Matole, Pranita Kokare, Vaishnavi S. Vhatte
Shivai Charitable Trust’s College of Pharmacy, Koregaonwadi Tq. Omerga, Dist. Dharashiv 413606,
Maharashtra, India.
*Corresponding Author E-mail: matole7414@gmail.com
Abstract:
Invasomes are soft nanovesicles made of phospholipids, ethanol, and terpenes. These components help the vesicles penetrate the skin effectively and deliver drugs into deeper skin layers. One of the major advantages of invasomes is their ability to enhance drug permeation through the skin while reducing drug absorption into the bloodstream. This helps to increase the local therapeutic effect and minimize systemic side effects. Due to these properties, invasomes have emerged as a promising carrier system for transdermal and dermal drug delivery. This review discusses their structure, penetration mechanism, characterization methods, applications, and advantages in skin drug delivery. It emphasizes their ability to overcome biological barriers, improve drug bioavailability, and enhance therapeutic efficacy. With further research and development, invasomes hold great promise as an innovative drug delivery system, offering numerous opportunities for advancements in medical treatments and patient care.
KEYWORDS: Invasomes, Transdermal Drug Delivery System (TDDS), Nanovesicles, Liposome, Invasome, Terpene, Nanocarrier.
INTRODUCTION:
The transdermal route involves delivering medicines through the skin to produce either local effects at the application site or systemic effects throughout the body. However, the outermost layer of the skin, called the stratum corneum, acts as a strong barrier and prevents many drugs from penetrating effectively. To overcome this challenge, several techniques have been developed, such as ultrasound, electroporation, and iontophoresis, which temporarily increase skin permeability. In addition, special drug carriers and nanotechnology-based systems are used to improve drug penetration through the skin. Recently, various types of nanocarriers have been developed to enhance both dermal and transdermal delivery of medications, making treatment more effective and patient-friendly.
Liposomal vesicular systems can incorporate both lipophilic and hydrophilic drugs to assist in the penetration of the incorporated agents. However, conventional liposomes are not approved as appropriate systems for transdermal delivery of drugs as they are unable to permeate the inner layers of skin and, therefore, their effects remain limited to the upper layers. Novel elastic vesicles containing penetration enhancers are superior to conventional liposomes due to their improved interactions with skin and better drug penetration.
Invasomes are novel and flexible vesicles containing a mixture of soy phosphatidylcholine (PC), terpenes, lyso PC, and ethanol with improved skin penetration in comparison with liposomes. Furthermore, invasomes have the same structural constituents as liposomes but contain terpene in their structure. Terpenes are hydrocarbon compounds and are known to be the primary constituents of essential oils from many plants. Addition of terpenes creates deformable vesicles, which can increase the fluidity of the lipid bilayers of the skin.
Structure of Invasomes:
Invasomes, classified as soft liposomal vesicles, serve as promising carriers designed to enhance skin penetration capabilities. They are formulated with minute quantities of ethanol and terpenes, either individually or as blends 13. These specialized lipid vesicles consist of water, terpenes (such as citral, cineole, limonene, and eugenol, typically ranging from 1% to 5% v/v), low concentrations of ethanol (usually within the range of 3% to 3.3% v/v), and phospholipids (which may include phosphatidylcholine, phosphatidylserine, soya phospholipids, and egg lecithin).
Structure of Invasomes:
Terpenes, characterized by the general chemical formula (C5H8) n, play a pivotal role in enhancing the percutaneous absorption of both hydrophilic and hydrophobic drugs. These natural components, derived from essential oils, are widely recognized as effective penetration enhancers. Notably, terpenes offer the additional advantage of being non-irritating to the skin when used in low concentrations. Furthermore, they are generally considered safe for use, a designation upheld by the FDA, as corroborated in scholarly literature.
Composition and Molecular Design of Invasomes:
Invasomes typically consist of:
1. Phospholipids
2. Ethanol (5–20%)
3. Terpenes (0.5–5%)
4. Aqueous phase
5. Drug molecule
Each component contributes to the overall performance of the vesicular system. Phospholipids form the bilayer structure, ethanol imparts flexibility and enhances lipid fluidity, while terpenes disrupt the ordered arrangement of stratum corneum lipids, facilitating drug permeation.
Advantages of Invasomes:
1. Non-invasive technique of drug delivery.
2. Enhanced permeation of drug through the skin for transdermal drug delivery.
3. Delivery of hydrophilic and lipophilic drug is possible.
4. Contains non-toxic raw material in formulation.
Disadvantages of Invasomes:
1. It requires a high cost for production
2. Chance of leakage and fusion of encapsulated active.
3. The phospholipid present may undergo hydrolysis/oxidation, thus affecting stability of Invasomes.
Comparison:
|
Parameter |
Invasomes |
Liposomes |
|
Composition |
Phospholipids, ethanol, and terpenes |
Phospholipids and cholesterol |
|
Vesicle Flexibility |
Highly flexible and deformable |
Less flexible |
|
Skin Penetration |
Excellent transdermal penetration |
Limited skin penetration |
|
Permeation Enhancers |
Contains ethanol and terpenes |
No permeation enhancers |
|
Drug Delivery |
Suitable for deep skin and transdermal delivery |
Mainly for topical and systemic delivery |
|
Entrapment Efficiency |
Generally higher |
Moderate |
|
Stability |
Less stable due to ethanol content |
More stable |
|
Cost |
Relatively higher |
Relatively lower |
Mechanism of Skin Penetration of Invasomes:
The enhanced skin penetration ability of invasomes is attributed to the combined action of phospholipids, ethanol, and terpenes. These components work synergistically to overcome the barrier function of the stratum corneum and improve drug delivery into deeper skin layers.
1. Lipid Disruption by Terpenes:
Terpenes act as effective penetration enhancers by interacting with the lipid bilayers of the stratum corneum. They disrupt the highly ordered lipid arrangement, increasing lipid fluidity and creating temporary pathways for drug diffusion through the skin (Dragicevic-Curic et al., 2008).
2. Ethanol-Mediated Fluidization:
Ethanol increases the flexibility of invasomal vesicles and fluidizes the lipids of the stratum corneum. This reduces the barrier resistance of the skin and facilitates deeper penetration of both the vesicles and the encapsulated drug molecules (Verma and Fahr, 2004).
3. Vesicle Deformability:
The presence of ethanol and terpenes imparts elasticity to invasomes, enabling them to deform and pass through narrow intercellular spaces that are smaller than their own diameter. This property allows efficient transport of drugs across the skin barrier (Elsayed et al., 2007).
4. Intercellular and Intracellular Transport:
Invasomes primarily penetrate through the intercellular lipid pathway of the stratum corneum. Some vesicles may also interact with skin cells and facilitate intracellular drug transport, thereby increasing drug accumulation within deeper skin layers (Dragicevic-Curic et al., 2008).
5. Controlled Drug Release:
After penetrating the skin, invasomes gradually release the encapsulated drug into the epidermis and dermis, resulting in enhanced local or systemic therapeutic effects and prolonged drug action.
Preparation of Invasomes:
1. Mechanical dispersion technique:
In this process, the drug and terpenes are mixed with ethanolic phospholipid solution. Then the mixture is sonicated and vortexed for 5min so that the solution becomes clear. Phosphate Buffer Solution (PBS) of pH 7.3 is added by continuous vortexing. To extrude the multilamellar vesicles, polycarbonate membranes with varying pore diameters are used. Invasome dispersions repeatedly perforate polycarbonate membranes.
2. Film hydration technique:
The preparation of invasomes through the traditional film hydration method involves a systematic procedure. Initially, a mixture of ethanol and chloroform in a 2:1 v/v ratio is dissolved in a solution containing phospholipids. Subsequently, this mixture is subjected to a controlled drying process using a Rotary Flask Evaporator maintained at 50°C, while gradually reducing the pressure from 500 to 1 mbar. This results in the formation of a thin film layer along the inner surface of the flask.
The formed film is then subjected to a two-hour vacuum treatment at room temperature (1 mbar), followed by a nitrogen flush to ensure optimal conditions. To create invasomes from this film, either a combination of PBS with a pH of 7.4 and terpenes/ethanol mixture or a single terpene is introduced. After this, the system is allowed to cool to room temperature, and a hydration process of 30 minutes takes place. To achieve the desired vesicle size, the hydrated mixture is subsequently subjected to multiple rounds of extrusion through polycarbonate membranes with various pore sizes. This is achieved by utilizing a combination of vortex mixing and ultrasonication techniques.
Effect of Composition on the Physicochemical Characteristics of Invasomes:
Effect of Ethanol:
The addition of ethanol in the formulation of lipid nanovesicles is an effective strategy to increase the fluidity of the lipid bilayer of the skin [39,40]. The interaction of ethanol with the lipid elements in the polar group area of the SC leads to alterations in the structure of the keratinized or lipophilic domains, decreased transition temperature of lipids, and consequently fluidization and disruption of the tightly packed SC lipids [40,41]. Ethanol-based nanocarriers can fluidize and disturb the SC lipids. The presence of ethanol increases the flexibility of the intercellular lipid matrix due to the rotating freedom of the lipid acyl chains. Thus, ethanol increases the fluidity of lipids in the vesicle structure, resulting in a structure that has softer and less rigid properties than conventional liposomes. In addition to enhanced penetration ability, ethanol creates a net negative surface charge and limited vesicle aggregation due to electrostatic repulsion, leading to increased stability of invasomes under storage conditions.
Effect of Terpenes on Invasomes:
Terpenes are important penetration enhancers in invasomes that significantly improve the transdermal delivery of drugs. They interact with the lipid components of the stratum corneum, disrupting their highly ordered structure and thereby increasing skin permeability. Terpenes also enhance the fluidity and deformability of the vesicular membrane, allowing invasomes to penetrate deeper into the skin layers. The type and concentration of terpene used influence vesicle size, entrapment efficiency, stability, and drug permeation. Common terpenes such as limonene, cineole, and citral have been shown to increase drug transport across the skin. However, excessively high terpene concentrations may destabilize the vesicles, leading to aggregation or leakage of the encapsulated drug.
Therapeutic Applications of Invasomes:
Invasomes have emerged as promising nanovesicular carriers for transdermal and dermal drug delivery due to their superior skin penetration ability. Their unique composition enables the efficient delivery of various therapeutic agents for both local and systemic treatment.
1. Anti-inflammatory Drug Delivery:
Invasomes have been extensively investigated for the delivery of anti-inflammatory drugs such as diclofenac and curcumin. Enhanced skin penetration improves drug accumulation at the site of inflammation, resulting in prolonged therapeutic effects and reduced systemic side effects.
2. Antifungal Therapy:
Invasomal formulations of antifungal agents such as clotrimazole and terbinafine have demonstrated enhanced permeation through the skin, leading to improved treatment of fungal infections including candidiasis and dermatophytosis.
3. Antiviral Drug Delivery:
Invasomes have shown significant potential in the transdermal delivery of antiviral drugs, particularly acyclovir for the treatment of herpes simplex infections. Enhanced skin penetration increases drug concentration at the infected site and improves therapeutic efficacy.
4. Anticancer Therapy:
The delivery of anticancer agents through invasomes has gained considerable attention. Temoporfin-loaded invasomes have demonstrated improved skin penetration and targeted delivery for photodynamic therapy of skin cancers, reducing damage to healthy tissues.
5. Hormonal Therapy:
Invasomes are effective carriers for hormones such as estradiol and testosterone. Their enhanced permeation properties facilitate controlled transdermal delivery, thereby improving bioavailability and patient compliance.
6. Cardiovascular Drug Delivery:
Transdermal administration of cardiovascular drugs using invasomes can provide sustained drug release and maintain therapeutic plasma concentrations, reducing the frequency of dosing and improving treatment outcomes.
Challenges and Future Perspectives:
Recent advances in invasomal technology include the development of stimuli-responsive invasomes, hydrogel-based invasomal systems, and the delivery of peptides, vaccines, and herbal drugs. These innovations have improved drug stability, skin penetration, and controlled drug release. Although invasomes have shown promising results in preclinical studies, their clinical translation is still limited due to challenges related to large-scale manufacturing, stability, regulatory approval, and commercialization. However, ongoing research suggests that invasomes have significant potential as next-generation carriers for smart transdermal therapeutics.
Challenges of Invasomes:
1. Poor long-term stability due to vesicle aggregation and leakage of entrapped drug.
2. High production cost compared to conventional formulations.
3. Difficulty in large-scale manufacturing while maintaining uniform quality.
4. Limited shelf life and sensitivity to storage conditions.
5. Variability in vesicle size and entrapment efficiency during formulation.
6. Potential skin irritation caused by high concentrations of ethanol and terpenes.
7. Limited clinical studies available to confirm long-term safety and efficacy.
8. Regulatory challenges for approval and commercialization
Future Perspectives of Invasomes
1. Development of stimuli-responsive invasomes for targeted drug release.
2. Integration with microneedles and hydrogel systems for enhanced transdermal delivery.
3. Application in vaccine, peptide, and protein delivery.
4. Use in personalized medicine and targeted therapy.
5. Improvement of formulation stability through advanced lipid technologies.
6. Development of cost-effective large-scale production methods.
7. More preclinical and clinical studies to establish safety and efficacy.
8. Expansion of applications in smart transdermal therapeutics and nanomedicine.
CONCLUSION:
Invasomes represent an advanced vesicular carrier system capable of overcoming the limitations of conventional transdermal drug delivery. Their unique composition, enhanced deformability, and superior skin penetration properties make them highly suitable for the delivery of various therapeutic agents. Continued research and clinical investigations are expected to establish invasomes as a key platform in the next generation of smart transdermal therapeutics.
REFERENCE:
1. Paudel, K.S.; Milewski, M.; Swadley, C.L.; Brogden, N.K.; Ghosh, P.; Stinchcomb, A.L. Challenges and opportunities in dermal/transdermal delivery. Ther. Deliv. 2010; 1: 109–131.
2. Ashtikar, M.; Langelüddecke, L.; Fahr, A.; Deckert, V. Tip-enhanced Raman scattering for tracking of invasomes in the stratum corneum. Biochim. Et Biophys. Acta (Bba)-Gen. Dragicevic-Curic, N., Gräfe, S., Gitter, B., Winter, S., and Fahr, A. Surface charged temoporfin-loaded flexible vesicles: In vitro skin penetration studies and stability. International Journal of Pharmaceutics. 2008; 359(1–2): 15–22.
3. Verma, D. D., and Fahr, A. Synergistic penetration effect of ethanol and phospholipids on the topical delivery of cyclosporin A. Journal of Controlled Release. 2004; 97(1): 55–66.
4. Elsayed, M. M., Abdallah, O. Y., Naggar, V. F., and Khalafallah, N. M. Deformable liposomes and ethosomes as carriers for skin delivery of ketotifen. Pharmazie. 2007; 62(2): 133–137.
5. Dragicevic-Curic, N., Scheglmann, D., Albrecht, V., and Fahr, A. Temoporfin-loaded invasomes: Development, characterization and in vitro skin penetration studies. Journal of Controlled Release. 2008; 127(1): 59–69. Subj. 2017, 1861, 2630–2639.
6. Dragicevic-Curic N, Winter S, Stupar M, Milic J, Krajišnik D, Fahr A. Development of temoporfin-loaded invasomes for dermal delivery. International Journal of Pharmaceutics. 2009; 384(1–2): 100–108.
7. Hope MJ, Bally MB, Webb G, Cullis PR. Production of large unilamellar vesicles by rapid extrusion. Biochimica et Biophysica Acta. 1985; 812(1): 55–65.
8. Gupta A, Prajapati SK, Balamurugan M, Singh M, Bhatia D. Design and development of invasomal systems for transdermal drug delivery: A review. Journal of Drug Delivery Science and Technology. 2021; 61: 102316.
9. Abdallah MH. Invasomes as a novel vesicular carrier for transdermal drug delivery: Recent advances and future perspectives. Drug Delivery and Translational Research. 2020; 10(6): 1821–1838.
10. S. Babaie, A.R.D. Bakhshayesh, J.W. Ha, H. Hamishehkar, KH. Kim, Invasome: a novel nanocarrier for transdermal drug delivery, Nanomaterials. 2020; 10(2): 341, https://doi.org/10.3390/nano10020341.
11. M. Kamran, A. Ahad, M. Aqil, S.S. Imam, Y. Sultana, A. Ali, Design, formulation and optimization ofnovel soft nano-carriers for transdermal olmesartan medoxomil delivery: in vitro characterization and invivo pharmacokinetic assessment, Int. J. Pharm. 2016; 505(1-2): 147–158, https://doi.org/10.1016/j. ijpharm.2016.03.030.
|
Received on 12.06.2026 Revised on 26.06.2026 Accepted on 08.07.2026 Published on 14.07.2026 Available online from July 25, 2026 Research J. Science and Tech. 2026; 18(3):299-304. DOI: 10.52711/2349-2988.2026.00042
|
|
|
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License. |
|