Table 1- Comparison between Transferosomes, Ethosomes and Transethosomes

Parameters
Sr.no	UDV system	Composition	Entrapment efficiency	Flux Rate	Skin Permeation	Reference
1	Transferosomes	Water, phospholipid, edge activator	Higher than ethosomes	More or equal to ethosomes	Deformation of vesicles	3, 7, 12
2	Ethosomes	Water, phospholipid, ethanol	Higher than liposomes	More than liposomes	Lipid perturbation	14,15,4
3	Transethosomes	Water, phospholipid, ethanol, edge activator	Higher than ethosomes and transferosomes	Higher flux rate	Ultra deformation of vesicles	1,5,6,8

Table-2 Excipients and Methods used in formulation of Nanotransethosomes

Sr.No	List of Phospholipid	List of Edge activator	Methods used	Author	Reference
1	Lipoid S100	Sodium cholate	Box Behnken	Thasleem Moolakhhadath	9
2	PL90G	Cholestrol	Edge activators with different HLB values and SDC were employed to prepare vesicles using thin film hydration technique	Sajeev Kumar	11
3	Soy Lecithin S100	Sodium deoxycholate, tween 80	In this the Transethosomes were prepared by ultrasound guided injection method	Hui Song	13
4	Lipoid S 100	Tween 80	Transethosomes are prepared by the mechanical dispersion technique and the hot and cold method	Mudassir Farooq	20
5	L-αphosphatidylcholine from egg yolk	Span 20, Span 60, Sodium deoxycholate	Vesicles were prepared by adopting thin-film hydration method	Rofida Albash	21
6	Lipoid S100	Oleic acid	Transethosomes vesicles were prepared by Homogenization method	Lalit Kumar	22
7	Phospholipon 90 G	Sodium cholate	Transethosomes vesicles were prepared by cold method. This method is easy to scale up and can be used for both thermolabile and thermostable drugs.	Jessy Shaji	23
8	Soya Lecithin	Cholesterol, Tween 80	For the preparation of Transethosomes cold method were used.	Akshaykumar Verma	24
9	Soya phosphatidylcholine 70	Span 80	In this the thin film hydration method is used for the preparation of transethosomal vesicles.	Varun Garg	18
10	Soyaphosphatidyl choline	Tween 80	The thin film hydration method was used for the preparation of the vesicles.	Gadad AP	25

Adaptability and flexibility are the most important properties of ethanol for the formulation of nano-vesicular systems, which can easily permit them to perforate inside the stratum corneum through very small openings due to the process of fluidization.¹⁰When the edge activator and ethanol are combined then it causes the transposition of the lipid bilayer which can also cause a more deformation structure, which can easily penetrate the deeper skin layer. Different excipients used in the formulation of nano sized transethosomes can be depicted in the table 2.

Methods of Preparation of Transethosomes:

The vesicular nano-transethosomal systems can be easily prepared and also it is very easy to formulate without any involvement of any high-tech machines.¹² There are different methods are there by which we can easily prepare our nanotransethosomal vesicular system which can easily incorporate into a gel form, creams, or in patch form to increase penetrability into the skin.¹³ The following are commonly used methods for the preparation of the vesicular system.¹⁴

Cold Method:

In this method of preparation, Transethosomes phospholipids were added to ethanol and properly mixed, and heated to 30⁰C (Organic Phase). In the second step in a separate container the edge activator, drug and water are all combined and heated up to 30⁰C (Aqueous phase).¹⁵Then an aqueous phase is added to the alcoholic phase with constant stirring for 5 to 10 mins and the temperature is maintained at 30⁰C throughout the procedure.¹⁵Now the above mixture is sonicated in a sonicator.¹⁶

Reverse phase evaporation method:

For the preparation of nanotransethosomes, this method can also be preferred. In this particular method firstly, the phospholipids can be dissolved in the organic solvent and the drug and edge activator dissolved in an aqueous solvent.¹⁷ Now aqueous phase is added to the organic phase the mixture is placed in an ultrasonic bath at 0⁰C till the two-phase separation.¹⁸Now the organic phase is removed, and under the low-pressure gel, formation occurs. After continuous agitation, the lipid layer is incorporated in the aqueous layer now the sample is filtered.¹⁹

Advantages of Nanotransethosomes:

The flexibility of nanotransethosomes is very high and it also has a very high skin permeation rate and high flux rate as compared to other vesicular systems.²⁰ The main advantage of nanotransethosomes is that they can easily deform and easily move through narrow obstructions.^21,22Biocompatible and biodegradable nanotransethosomes can be easily formulated help of natural phospholipids.²³ It is much more stable than another vesicular system. It has very high entrapment efficiency, the drug can be easily incorporated and also protected from metabolic degradation. The preparation method of nanotransethosomes is easy and it has high penetration power.

Disadvantages of Nanotransethosomes²⁴:

In the preparation of nanotransethosomes ethanol is used which can irritate the skin. So, to overcome this problem nanotransethosomal patch can be prepared. Agglomeration of nanotransethosomes takes place if it is not prepared in the proper method.

Characterization of Nanotransethosomes:

· Morphological characteristics of nanotransethosomes

· Zeta potential of nanotransethosomes and their particle size

· Loading capacity and entrapment efficiency of nanotransethosomes

· Phase transition temperature

· In vitro drug release study

· Vesicular stability study

· In vitro skin permeation

· Ex vivo skin permeation

· Determination of pH

Morphological characteristics of nanotransethosomes

Transmission Electron Microscopy and Scanning Electron Microscopy studies can be easily used to determine the morphological characteristics of nanotransethosomes.²⁴

Zeta potential of nanotransethosomes and their particle size

To determine the exact particle size of nanotransethosomes two methods are used

Dynamic light scattering (DLS)

Photon correlation spectroscopy (PCS).

Entrapment Efficiency:

By doing entrapment efficiency we can easily determine the actual amount of drug entrapped in the nanotransethosomes.^25,26It can be done by ultracentrifugation technique also known as the column centrifugation technique. In this analysis, the drug is first loaded in nanotransethosomes and then placed into a column and then the column is centrifuged.^27,28,29 Speed and temperature can be easily controlled in the ultracentrifugation method. After the completion of the centrifugation process, the upper layer is developed and separated from the vesicles.^30,31 Then these vesicles are treated with solvents like triton-X-2 propanol, and methanol and set lysed. Then the drug content can be analyzed by UV visible spectrophotometry. The amount of drug entrapped in the vesicular system can be calculated by using the formula-

% Drug Entrapment = Amount of entrapped drug/Total amount of drug*100

Phase Transition Temperature:

The phase transition temperature of Transethosomes can be easily determined by DSC. In DSC the sample can be easily analyzed at a range of temperatures under a constant nitrogen stream.³²

In-vitro drug release study:

The quantity of drug release from the nanotransethosomes can be easily determined by an in-vitro study by using the Dialysis bag method.

Vesicular stability study:

The vesicular stability study of nanotransethosomal vesicles can be done by depositing them at different temperatures 25±2⁰C, 37±2⁰C, and 45±2⁰C. DLS and TEM can be used to determine the size and morphology of nanotransethosomes.³³

In vitro skin permeation study:

Franz diffusion cell can be used to determine the in-vitro skin permeability study of nanotransethosomes.³⁴ In this method, the capability of nanotransethosomes to penetrate deeper into the skin for targeted drug delivery can be done by using CLSM. The instrument temperature should be maintained at 32⁰C±1⁰C.³⁵ There is a receptor compartment cell that contains 10ml of PBS. The skin on which the permeation study can be determined is placed in between the donor compartment and receptor compartment.³⁶Now the nanotransethosomal vesicles are applied to the outermost surface of the skin. After a particular time, interval, the samples can be withdrawn such as 1, 2, 3, 4, 8, 12, 16, 20, 24hours. The samples which are withdrawn at a particular time interval can be analyzed by using HPLC.³⁷

Determination of pH:

The pH of Nanotransethosomal formulation can be determined by using a digital pH meter.³⁸

Applications of Nanotransethosomal vesicular system:

Delivery of Anticancer Drugs:

Formulations for fisetin-loaded transethosomes were improved utilizing the Box-Behnken method. For the cutaneous administration of fisetin, the optimized formulation demonstrated vesicle sizes in the nano range and high entrapment efficiency with moderate flux. Rhodamine B loaded fisetin transethosomes have been shown to penetrate rat skin more effectively than control solution in confocal research.^39,40 Further dermatokinetic research showed that fisetin transethosomes gel penetrated the skin more effectively than fisetin conventional gel. The current findings show that the transethosomes formulation was created as a suitable medication carrier for fisetin cutaneous administration.⁴¹

Delivery of Antiarthritic Drug:

Sajeev et al performed an experiment in which Naproxen-Sulphapyridine transethosomal vesicle was developed and evaluated for transdermal delivery of drugs in the management of Rheumatoid Arthritis. In this, the ethosomal hydrogel has been combined and loaded with NAP-SULF (NSAID, DMARD) which could reduce the pain and inflammation. In the present study, NAP-SULF EH was developed by modifying the thin film hydration technique.

Song et al conducted research on Rheumatoid Arthritis. In Sinomenine hydrochloride loaded ascorbic acid (Antioxidant) transethosomes were decorated using ascorbyl palmitate as an antioxidant and transethosomes as a basic transdermal carrier. AS-TE can be transdermally delivered to inflamed joints of CFA rats with similar therapeutic efficacy to that of gastric administration of Sinomenine hydrochloride.⁴²

Garg et al conducted an experiment with piroxicam-loaded transethosomal hydrogel for the treatment of Rheumatoid Arthritis. In the present study, the Nanotransethosomal hydrogel has been prepared by using lipid, ethanol, and edge activator and their characterization also have been done. It can be easily concluded that the formulated piroxicam Nanotransethosomal hydrogel has the ability to penetrate deeper into the skin with targeted drug delivery.⁴³

Delivery of Antihypertensive drugs:

Albash et al performed an experiment in which transethosomes were formulated as a transdermal delivery system for Olmesartan medoxomil. The result has concluded that transethosomes could be considered as a promising transdermal delivery system for OLM as they can avoid extensive first-pass metabolism of OLM.⁴⁴

Lalit et al conducted an experiment in which nanotransethosomes loaded with propranolol hydrochloride showed better skin in-vitro permeation with highly controlled release of the drugs.⁴⁵ Based on the recent research work it can be concluded that the nanotransethosomal vesicles can be easily prepared for antihypertensive drugs.

Verma et al performed an experiment in which Irbesartan loaded with transethosomes has been formulated. Irbesartan loaded with transethosome formulations was successively prepared using the cold method. Characterization of transethosome as vesicle shape, vesicle size, PDI, zeta potential, entrapment efficiency, a calibration curve of UV, % drug release, FTIR, and SEM as responses.

Delivery of Antifungal Drug:

The creation of transethosomes of VRC and its inclusion into a gel for antifungal and antileishmanial applications are elaborated on by Farooq et al. Zeta potential, entrapment effectiveness, particle size, PDI, optical microscopy, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), drug release studies, and stability assessments were used to characterize transethosomes. The developed VTEG was further evaluated for a number of physicochemical properties, drug release studies, molecular docking, antifungal, and antileishmanial activity. results showed that the antifungal activity against susceptible strains was greatly increased by VTEG.

Future Prospects:

In the current scenario, the nanotransethosomal vesicular system has attracted the attention of scientists and researchers. Due to its ultra-deformable characteristics, it is in high demand for deeper skin penetration and for targeted drug delivery through the transdermal route its nano-size particles, and deformable system. Edge activator has been shown better permeation and penetration properties than Ethosomes and Transferosomes, Liposomes and Phytosomes. It is also suitable for both hydrophilic and hydrophobic drugs and high and low-molecular-weight drugs. It is a recent vesicular system which is in high demand in present and on future. Scientists and Researchers are doing research on Nanoparticles (Nanotransethosomes) so currently, there is no marketed formulation is available. Nanotransethosomes can also be loaded into novel drug delivery systems such as cream, gel, emulgel, and in patch form. Thus, the Nanotransethosomal vesicular system has a lot of potentials to use as the carrier for transdermal drug delivery.

CONCLUSION:

The transdermal route has been the most used drug delivery method in recent years. It solved numerous oral drug delivery method drawbacks, including first-pass metabolism. Transdermal drug delivery has been developed to address this constraint, although few drug molecules can easily pass through the stratum corneum. Our scientists and researchers created the extremely deformable vesicle technology to solve this problem. This technique incorporates synthetic or herbal medicinal molecules into vesicles that can penetrate deeper into the skin for targeted medication delivery. Transethosomes are a new type of transferosome and ethosome that could improve transdermal drug delivery. Nanotransethosomes penetrate due to ethanol, edge activator, and phospholipids. Nanotransethosomes can be developed via hot, cold, transmembrane pH gradient, ethanol injection, and thin film hydration procedures. UDV systems can transdermally deliver anti-arthritic, analgesic, anticancer, antibiotic, and antiviral medicines. Besides synthetic medications, herbal drugs, proteins, and peptides can be delivered transdermally in vesicles. Novel drug delivery systems like cream, gel, emulgel, and patches can also contain nanotransethosomes. Thus, the Nanotransethosomal vesicular system has many potential uses for transdermal medication administration.

REFERENCES:

1. Sundar VD, Divya P, Dhanaraju MD. Design, development, and characterization of tramadol hydrochloride-loaded transethosomal gel formulation for effective pain management. Indian J Pharm Sci. 2020; 54(2): 88-97. doi:10.36468/pharmaceutical-sciences.2020.88-97

2. Agarwal R, Sahoo PK. Ethosomes: The novel drug delivery carrier. Sch Acad J Pharm. 2018 Jun;7(6):266-73.

3. Bajaj K, Parab B, Shidhaye S. Nano-transethosomes: A novel tool for drug delivery through skin. Indian J Pharm Educ Res. 2021 Jan; S1-S10. doi:10.5530/ijper.56.1.143

4. Shaji J, Bajaj R. Transethosomes: A new prospect for enhanced transdermal delivery. Int J Pharm Sci Res. 2018;9(7):2681-85.

5. Jayaprakash R, Hameed J, Anupriya A. An overview of transdermal delivery system. Asian J Pharm Clin Res. 2017; 10(10): 36-40.

6. Gondkar SB, Patil NR, Saudagar RB. Formulation development and characterization of drug-loaded transethosomes for transdermal delivery: Review article. Int J ChemTech Res. 2017; 10(6): 535-44.

7. Shaji J, Bajaj R. Formulation development of 5-fluorouracil transethosomes for skin cancer therapy. Int J Pharm Pharm Res. 2017; 11(1): 454-64.

8. Chaurasiya P, Ganju E, Upmanyu N, Ray SK, Jain P. Transferosomes: A novel technique for transdermal drug delivery. J Drug Deliv Ther. 2019; 9(1): 279-85.

9. Moolakkadth T, Aquil M, Ahad A, Imam SS, Iqbal B, Sultana Y, et al. Development of transethosome formulation for dermal fisetin delivery: Box-Behnken design, optimization, in vitro skin penetration, vesicle-skin interaction, and dermatokinetic studies. Artif Cells Nanomed Biotechnol. 2018; 46(sup2): 755-65. doi:10.1080/21691401.2018.1484949

10. Ascenso A, Raposo S, Batista C, Cardoso P, Mendes T, Praça FG, et al. Development, characterization, and skin delivery studies of related ultradeformable vesicles: Transfersomes, ethosomes, and transethosomes. Int J Nanomedicine. 2015; 10: 5837-51. doi:10.2147/IJN.S86551

11. Babasahib SK, Born RW, Raghavendra NM. Transethosomal hybrid composites of naproxen-sulphapyridine in hydrogel carrier: Anti-inflammatory response in complete Freund’s adjuvant-induced arthritis rats. Artif Cells Nanomed Biotechnol. 2022; 50(1): 59-70. doi:10.1080/21691401.2022.2021336

12. Tiwari A, Mishra MK, Nayak K, Yadav SK, Shukla A. Ethosomes: A novel vesicular carrier system for therapeutic applications. IOSR J Pharm. 2016; 6(9): 25-33.

13. Song H, Wen J, Li H, Meng Y, Zhang Y, Zhang N, et al. Enhanced transdermal permeability and drug deposition of rheumatoid arthritis via sinomenine hydrochloride-loaded antioxidant surface transethosome. Int J Nanomedicine. 2019; 14: 3177-88. doi:10.2147/IJN.S204657

14. Honeywell-Naguyen PL, Bouwstre JA. Vesicles as a tool for transdermal delivery. Drug Discov Today Technol. 2005; 2(1): 67-74.

15. Dhopavkar S, Karu P. Transferosomes: A boon for transdermal delivery. Indo Am J Pharm Sci. 2017; 4(9): 2908-19.

16. Abdulbaqi IM, Darwis Y, Assi RA, Khan NAK. Transethosomal gel as carrier for transdermal delivery of colchicine: Statistical optimization, characterization, and ex vivo evaluation. Int J Nanomedicine. 2018; 12: 795-813. doi:10.2147/IJN.S165361

17. Shankar V, Ramesh S, Siram K. Ethosomes: An exciting and promising alcoholic carrier system for targeting androgenic alopecia. Alopecia Intech Open. 2018; 113-24.

18. Garg V, Singh H, Bhatia A, Razak, Singh SK, Singh B, et al. Systematic development of transethosomal gel system of piroxicam: Formulation, optimization, in vitro evaluation, and ex vivo assessment. AAPS PharmSciTech. 2016; 18(1): 58-71. doi:10.1208/s12249-016-0507-4

19. Mishra KK, Kaur CD, Verma S, Sahu AK, Dash DK, Kashyap P, et al. Transethosomes and nanoethosomes: Recent approach on transdermal drug delivery system. Nanomedicine IntechOpen. 2019; 2: 33-54.

20. Farooq M, Usman F, Zaib S, Shah HS, Jamil QA, Sheikh AA, et al. Fabrication and evaluation of voriconazole-loaded transethosomal gel for enhanced antifungal and antileishmanial activity. Molecules. 2022; 27: 3347. doi:10.3390/molecules27093347

21. Albash R, Abdelbary AA, Refai H, El-Nabarwai MA. Use of transethosomes for enhancing the transdermal delivery of olmesartan medoxomil: In vitro, ex vivo, and in vivo evaluation. Int J Nanomedicine. 2019; 14: 1953-68. doi:10.2147/IJN.S197206

22. Kumar L, Utreja P. Formulation and characterization of transethosomes for enhanced transdermal delivery of propranolol hydrochloride. Micro Nanosyst. 2020; 12: 38-47.

23. Shaji J, Parab SS. Formulation development of tranexamic acid-loaded transethosomal patch for melasma.

24. Verma A, Mishra M. Formulation and characterization of transethosomal-loaded nanoparticles of irbesartan. Int J Pharm Res Scholars. 2021; 10(1): 28-35.

25. Gadad AP, Patil AS, Singh Y, Dandagi PM, Bolmal UB, Basu A. Development and evaluation of flurbiprofen-loaded transethosomes to improve transdermal delivery. Indian J Pharm Educ Res. 2020; 54(4): 954-62. doi:10.5530/ijper.54.4.39

26. Akhtar N, Varma A, Pathak K. Ethosomes as vesicles for effective transdermal delivery: From bench to clinical implementation. Curr Clin Pharmacol. 2016; 11(3): 168-90. doi:10.2174/1574884711666160520120439

27. Kesharwani R, Patel DK, Sachan A, Kumar V, Mazumdar B. Ethosomes: A novel approach for transdermal and topical drug delivery. World J Pharm Pharm Sci. 2015; 4(6): 348-59.

28. Rai S, Pandey V, Rai G. Transfersomes as versatile and flexible nano-vesicular carriers in skin cancer therapy: The state of the art. Nano Rev Exp. 2017; 8(1): 132-48. doi:10.1080/20022097.2017.1311484

29. Bragagni M, Mennini N, Maestrelli F, Cirri M, Mura P. Comparative study of liposomes, transfersomes, and ethosomes as carriers for improving topical delivery of celecoxib. Drug Deliv. 2012; 19(7): 354-61. doi:10.3109/10717544.2011.607050

30. Kumar A, Pathak K, Bali V. Ultra-adaptable nanovesicular systems: A carrier for systemic delivery of therapeutic agents. Drug Discov Today. 2012; 17(21-22): 1233-41. doi:10.1016/j.drudis.2012.05.007

31. Anwar E, Ramadon D, Ardi GD. Novel transethosome containing green tea (Camellia sinensis L. Kuntze) leaf extract for enhanced skin delivery of epigallocatechin gallate: Formulation and in vitro penetration test. Int J Appl Pharm. 2018; 10(1): 299-302. doi:10.22159/ijap.2018v10i1.24271

32. Zahid SR, Upmanyu N, Dangi S, Ray SK, Jain P, Parkhe G. Ethosome: A novel vesicular carrier for transdermal drug delivery. J Drug Deliv Ther. 2018; 8(6): 318-26.

33. Vijeta B, Namrata M, Alagusundaram M. Ultra deformable vesicular system loaded bioactive/phytoconstituents for targeted drug delivery for the treatment of rheumatoid arthritis–An overview. Lat Am J Pharm. 2023 Mar 27; 42(1): 171-81. doi:10.26452/rlajps.v42i1.5295

34. Ma M, Wang J, Guo F, Lei M, Tan F, Li N. Development of nanovesicular systems for dermal imiquimod delivery: Physicochemical characterization and in vitro/in vivo evaluation. J Mater Sci Mater Med. 2015; 26(6): 192. doi:10.1007/s10856-015-5479-9

35. Salem HF, Nafady MM, Kharshoum RM, El-Ghafar OAA, Farouk HO. Mitigation of rheumatic arthritis in a rat model via transdermal delivery of dapoxetine HCl amalgamated as a nanoplatform: In vitro and in vivo assessment. Int J Nanomedicine. 2020; 15: 1517-35. doi:10.2147/IJN.S236349

36. Nimmy JK, Krishnakumar DB, Nair SK. Ethosomal gel: A review. Eur J Pharm Med Res. 2017; 4(4): 301-5.

37. Cevc G. Transfersomes, liposomes, and other lipid suspensions on the skin: Permeation enhancement, vesicle penetration, and transdermal drug delivery. Crit Rev Ther Drug Carrier Syst. 1996; 13(3-4): 257-88. doi:10.1615/CritRevTherDrugCarrierSyst.v13.i3-4.40

38. Benson HAE. Transdermal drug delivery: Penetration enhancement techniques. Curr Drug Deliv. 2005; 2(1): 23-33. doi:10.2174/1567201052907228

39. Ali S, Shabbir M, Shahid N. The structure of skin and transdermal drug delivery system: A review. Res J Pharm Technol. 2015; 8(2): 103-9.

40. Godin B, Touitou E. Ethosomes: New prospects in transdermal delivery. Crit Rev Ther Drug Carrier Syst. 2003; 20(1): 63-102. doi:10.1615/CritRevTherDrugCarrierSyst.v20.i1.30

41. Bolzinger MA, Briançon S, Pelletier J, Chevalier Y. Penetration of drugs through skin, a complex rate-controlling membrane. Curr Opin Colloid Interface Sci. 2012; 17(3): 156-65. doi:10.1016/j.cocis.2012.03.007

42. Verma P, Pathak K. Therapeutic and cosmeceutical potential of ethosomes: An overview. J Adv Pharm Technol Res. 2010; 1(3): 274-82. doi:10.4103/0976-2094.70719

43. Walve JR, Bakliwal SR, Rane BR, Pawar SP. Transfersomes: A surrogated carrier for transdermal drug delivery system. Int J Appl Biol Pharm Technol. 2011; 2(1): 204-13.

44. Singh D, Pradhan M, Nag M, Singh MR. Vesicular system: Versatile carrier for transdermal delivery of bioactives. Artif Cells Nanomed Biotechnol. 2015; 43(4): 282-90. doi:10.3109/21691401.2014.898036

45. Banerjee V, Joshi P, Upadhyay A, Jain V, Mangal A. Design, formulation, and evaluation of soluble soft gel ocular insert of ketorolac tromethamine using modified locust bean gum. J Drug Deliv Ther. 2019 Aug 13; 9(4-s): 232-9. doi:10.22270/jddt.v9i4-s.3559

Received on 15.09.2022 Revised on 05.05.2024

Accepted on 20.02.2025 Published on 01.07.2025

Available online from July 05, 2025

Research J. Pharmacy and Technology. 2025;18(7):3352-3357.

DOI: 10.52711/0974-360X.2025.00485

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