Ethosomes: A carrier for Transdermal Drug Delivery System

 

Muskan M. Maniyar*, Amol S. Deshmukh, Suvarna J. Shelke

Department of Pharmaceutics, S.M.B.T. College of Pharmacy, Nandi-Hills, Dhamangaon, Nashik, India.

*Corresponding Author E-mail: maniyarmuskan9@gmail.com

 

ABSTRACT:

In our five sense organs skin is the biggest organ which prevents entry of different foreign particles into the systemic circulation. For our body drug is also considered as a foreign particle hence it is difficult task to reach the drug into systemic circulation through the transdermal route without invasion. Now a day’s many novel formulations are present in the market which allows the transfer of drug through the transdermal route without invasion like liposomes, phytosomes, neosomes and ethosomes. But with the help of ethosome formulation it becomes very easy to transfer the drug into systemic circulation through the transdermal route. Large drug molecules can be delivered to site of action by ethosomes. Ethosomes are the bilayer lipid vesicles which allow the transfer of drug into the deep skin layers and into the blood. It contains large amount of ethanol and penetration enhancers are incorporated into it to enhance the rate of penetration. It contains the phospholipid bilayer with polar head and nonpolar tail. At the center ethanolic cavity is present which is filled with the hydroethanolic solution. We can incorporate all types of drug into the ethosome i.e., lipophilic, hydrophilic, and amphiphilic and this property makes it unique from other dosage forms. Further we can formulate cream, gel or patches of ethosomes. Cellutight EF, Nanominox, Noicellex, Supravir cream these are some examples of marketed ethosomal formulations. This review summarizes the types of ethosomes i.e., classical ethosomes, binary ethosomes and transethosomes. And also includes advantages, disadvantages, therapeutic applications, methods of preparation and characterization of the ethosomes.

 

KEYWORDS: Ethosomes, Phospholipids, Penetration enhancers, Transdermal, hydroethanolic solution.

 

 

INTRODUCTION:

Ethosomes are the bilayer lipid vesicles which allow the transfer of drug into deep skin layers and systemic circulation. (as shown in Fig.1) Ethosomes are composed of outer lipid bilayer and aqueous core filled with hydroethanolic solution of drug. The size of ethosomes ranges from tense of nanometers to microns. Hydrophilic, lipophilic and amphiphilic all types of drugs can be incorporated in the ethosomes. Hydrophilic drugs cannot pass through the skin hence penetration enhancers are used to increase the permeation of drug through the skin.1,2

 

 

Figure1: Ethosome structure

 

Types of ethosomes:

1.     Classical ethosomes

2.     Binary ethosomes

3.     Transethosomes

 

1.     Classical ethosomes: Classical ethosomes are made up of high concentration of ethanol (45%), phospholipids and water.3,4 These are smaller than classical liposomes hence having higher entrapment efficiency.5,6 It has better skin penetration and stability profile. Classical ethosomes are having negative potential.7,8

2.     Binary ethosomes: In this type of ethosome another type of alcohol is added.9,10 For example, Isopropyl alcohol and propylene glycol. These are having negative potential.11,12

3.     Transethosomes: These are similar to the classical ethosomes but have some additional compounds like penetration enhancer or edge activators. Transethosomes entrap drugs with molecular weight 130.077 Da to 200-325 Da. These are having eitherpositive or negative potential. 13,14

 

Advantages of ethosomes15,16

1.     It allows higher penetration of drug through the transdermal route.

2.     Ethosomes are formulated in gel or cream form hence it is easy to administer.

3.     Large drug molecules can be delivered to site of action by ethosomes, e.g. Proteins and peptides.

4.     There is less risk in the development of large scale formulations of ethosomes.

5.     It gives sustained drug delivery.

 

Disadvantages of ethosomes 17

1.     Poor yield is obtained.

2.     Product may loss during transfer from organic media to aqueous media.

3.     High manufacturing cost.

 

Therapeutic applications of ethosomes 1, 2                                      

1.     Antibiotics by oral route givefewer efficacies as compared to topical delivery in the form of ethosomes.

2.     Ethosomes containing anti-arthritis drug gives site specific action.

3.     Hormones can deliver by ethosomes not only to prevent first pass effect but also increases bioavailability.

4.     DNA can be delivered topically to express the gene in skin cells.

5.     Cosmeceutical products are formulated in the form of ethosomes to increase its permeation through the skin.

 

Methods of preparation:

1.     Cold method

2.     Hot method

3.     Classic mechanical dispersion method

4.     Classic method

 

 

1.     Cold method 12

 

 

2.     Hot method 12

 

3.     Classic mechanical dispersion method12,18

 

4.     Classic method16

 

Table 1: Characterization of ethosomes

Sr. No

Parameters

Methods of determination

1.

Vesicle shape

Transmission electron microscopy (TEM), Scanning electron microscopy (SEM)19

2.

Vesicle size

Dynamic light scattering (DLS)

3.

Zeta potential

By using zeta-meter

4.

Drug content

High performance liquid chromatography (HPLC), Ultraviolet spectrophotometry (UV)20

5.

Entrapment efficiency

Ultracentrifugation

6.

Skin penetration

Confocal laser scanning microscopy (CLSM)19

7.

In-vitro dissolution

Franz diffusion cell

 

Evaluation of ethosomes20,21

1.     Vesicle skin interaction study:

Different visualization strategies e.g. for assessing the method of improved skin permeation of ethosomal formulations. Transmission electron microscopy, eosinhematoxyl staining, fluorescence microscopy, and laser microscopy (CSLM) confocal scanning were used. Such image strategies additionally provided a much better understanding regardingmodulation of the structure and cyst penetration pathways once employed in combination. Liposomes free from alcohol penetrate nearly negligible. In comparison, the ethosomal carrier was wont to observe improved distribution of 6 CF and Rhodamine 123 in terms of depth and amount (dermis layer).

 

2.     Use scanning electron microscopy to investigate membrane vesicle interactions:

This involves applying 0.2ml of vesicle suspension to filter membranes with a pore size of 50nm and placing them in diffusion cells. The filter's upper surface was exposed to the air, while the lower surface was in contact with phosphate buffer saline solution (having pH6.5). After 1 hour, the filters were removed and the samples were prepared for SEM studies by overnight fixation in Karnovsky's fixative at 4°C, accompanied by dehydration with graded ethanol solutions (30, 50, 70, 90, 95, and 100percent v/v in water).

 

3.     Permeation experiments on the skin:

The hair of test animals (rats) was carefully cut short (2 mm) with scissors, and the abdominal skin was extracted from the underlying connective tissue with a scalpel. The excised skin was placed on aluminum foil and also the dermal aspect of the skin was gently excited off for any adhering fat and/or connective tissue tissue. The effective volume permeation area of the diffusion cell and receptor cell was 1.0cm2 and 10ml, respectively. The 32°C±1°C temperature was maintained. The receptor compartment was filled with phosphate buffered saline solution (10ml pH 6.5). It sandwiched the donor and receptor compartments with excised tissue. Applied to the stratum surface of the skin was ethosomal formulation (1.0ml). Samples (0.5ml) were taken at 1, 2, 4, 8, 12, 16, 20 and 24 hour time intervals via the sampling port of the diffusion cell and analyzed employing a high performance liquid action assay.

 

4.     Analysis of stability:

The stability of the vesicles was calculated by keeping them at a temperature of 4°C±0.5°C. After 180 days, the vesicle size, zeta potential, and trapping efficiency were determined using the method described previously.

 

5.     Drug absorption research21

In 24 well plates (Corning Inc.) with 100μl RPMI medium, drug absorption into MT 2 cells (1106cells/ ml) was measured. Cells were incubated with 100μl of the drug solution in phosphate buffer saline solution (pH 7.4), ethosomal formulation, or advertised formulation, and drug absorption was measured using HPLC assay analysis of the drug content.

 

6.     HPLC analysis:

The amount of drug permeated in the receptor compartment was calculated by HPLC assay using a 70:20:10v/v methanol: distilled water: acetonitrile mixture as a mobile phase during in vitro skin permeation experiments and in MT 2 cells.

 

7.     Analytical statistics21

ANOVA was used to assess the statistical significance of all the data generated, followed by studenized range testing. The findings were interpreted with a P<05 confidence limit using the PRISM programme.

 

CONCLUSION:

It is all over that ethosomes provides higher penetration than alternative topical formulations with none invasion. The massive molecules like proteins and peptides will be simply delivered by ethosomes. It’s terribly straight forward technique as compared to iontotherapy and phonophoresis.

 

REFERENCES:

1.      Grace X. Development of terminalia chebula loaded ethosomal gel for transdermal drug delivery. Asian journal of pharmaceutical and clinical research. Dec.2018;11(12):380-383. DOI:10.22159/ajpcr.2018.v11i12.20764

2.      Kalra N, Choudhary S, Arora P, Arora N. Ethosomal drug delivery system: A newer approach. Asian journal of pharmaceutical research and development.2020;8(5):158-162. DOI:http://dx.doi.org/10.22270/ajprd.v8i5.835

3.      Saudagar RB, Samuel S. Ethosomes: Novel noninvasive carrier for transdermal drug delivery. Asian J. Pharm. Tech. 2016;6(2):135-138. DOI:10.5958/2231-5713.2016.00019.2

4.      Roge AB, Sakhare RS, Bakal RL, Channawar MA, Bakde BV, Gawnde SR, Chandewar AV. Ethosomes: Novel approach in transdermal drug delivery system. Research J. Pharma. Dosage form and Tech. 2010; 2(1):22-27.

5.      Kundlik G, Patil UK. Formulation and characterization of ethosomal formulation of ciclopirox olamine. Research J. Pharma. Dosage Forms and Tech. 2012; 4(5):285-289.

6.      Mishra AD, Khunt DM, Ghayal AH, Patel CN, Shah DR. Formulation and optimization of ethosomes for transdermal delivery of felodipine. Research J. Pharm. and Tech. 2012; 5(12):1509-1517.

7.      Patel A, Sharma RK, Trivedi M, Shivaprakash, Panicker A. Ethosomes: A novel tool for transdermal drug delivery. Research J. Pharm. and Tech. 2013;6(8):838-841.

8.      Jondhalekar TM, Aher SS, Saudagar RB. Transethosome: Novel vesicular carrier for enhanced transdermal drug delivery system. Research J. Pharm. and Tech. 2017; 10(6):1816-1819. DOI: 10.5958/0974-360X.2017.00320.1

9.      Gondkar SB, Patil NR, Saudagar RB. Formulation development and characterization of etodolac loaded transethosomes for transdermal delivery. Research J. Pharm. and Tech. 2017; 10(9):3049-3057. DOI:10.5958/0974-360X.2017.00541.8

10.   Pandey S, Mishra SK, Sharma N. Ethosomes- A novelize vesicular drug delivery system. Research J. Pharm. and Tech. 2017; 10(9):3223-3232. DOI:10.5958/0974-360X.2017.00572.8

11.   Sahu SK, Ram A. Evaluation of linezolid loaded ethosomes for treatement of deep skin infections in diabetic model. Research J. Pharm. and Tech. 2018; 11(7):3023-3030. DOI:10.5958/0974-60X.2018.00557.7

12.   Deshmukh AS, Mahale VG, Mahajan VR. Liquisolid compact techniques: A review. Research J. Dosage Forms and Tech. 2014; 6(3):161-166.

13.   Pandey V, Golhani D and Shukla R. Ethosomes: versatile vesicular carriers for efficient transdermal delivery of therapeutic agents, Drug Delivery. 2015;22(8):988-1002.  DOI:10.3109/10717544.2014.889777

14.   Kulkarni S, Mishra KP, Sharma SB and Jain S, Ethosomes: A promising way for transdermal drug delivery, International Journal of Pharmaceutical Sciences and Research. 2015;6(9):3663-70. DOI: 10.13040/IJPSR.0975-8232.

15.   Jain S, Patel N, Madan P, Lin S. Quality by design approach for formulation, evaluation and statistical optimization of diclofenac-loaded ethosomes via transdermal route. Pharm Dev Technol. 2015;20(4):473–489.   DOI: 10.3109/10837450.2014.882939

16.   Zhang Z, Wo Y, Zhang Y. In vitro study of ethosome penetration in human skin and hypertrophic scar tissue. Nanomedicine: Nanotechnology, Biology and Medicine. 2012;8(6):1026–1033. doi.org/10.1016/j.nano.2011.10.006

17.   Mishra D, Mishra PK, Dabadghao S, Dubey V, Nahar M, Jain NK. Comparative evaluation of hepatitis B surface antigen-loaded elastic liposomes and ethosomes for human dendritic cell uptake and immune response. Nanomedicine. 2010;6(1):110-118. DOI: 10.1016/j.nano.2009.04.003

18.   Hua S. Lipid-based nano-delivery systems for skin delivery of drugs and bioactives. Frontiers in pharmacology. 2015;6:219. DOI:10.3389/fphar.2015.00219

19.   Sarwa KK, Suresh PK, Rudrapal M, Verma VK. Penetration of tamoxifen citrate loaded ethosomes and liposomes across human skin: a comparative study with confocal laser scanning microscopy. Current Drug Delivery. 2014;11(3):332-337.

20.   Zhou Y, Wei Y, Liu H, Zhang G, Wu X. Preparation and in vitro evaluation of ethosomal total alkaloids of Sophora alopecuroidesloaded by a transmembrane pH-gradient method. American Association of Pharmaceutical Scientists. 2010;11(3):1350-1358. DOI: 10.1208/s12249-010-9509-6 

21.   Li G, Fan Y, Fan C, et al. Tacrolimus-loaded ethosomes: physicochemical characterization and in vivo evaluation. European Journal of Pharmaceutics and Biopharmaceutics. 2012;82(1):49-57. DOI:10.1016/j.ejpb.2012.05.011

 

 

 

 

Received on 20.06.2021         Modified on 27.01.2022

Accepted on 07.05.2022   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2022; 12(3):225-228.

DOI: 10.52711/2231-5691.2022.00037