Transethosome: Novel Vesicular Carrier for Enhanced Transdermal Drug Delivery System

 

T. M. Jondhalekar¹*, S. S. Aher², R. B. Saudagar²

¹Department of Quality Assurance, R. G. Sapkal College of Pharmacy, Anjaneri, Nashik-422213, Maharashtra, India.

²Department of Pharmaceutical Chemistry, R. G. Sapkal College of Pharmacy, Anjaneri, Nashik- 422213, Maharashtra, India.

 

ABSTRACT:

Transethosomes are noninvasive delivery carriers that enable drugs to reach the deep skin layers and the systemic circulation. Although transethosome systems are conceptually sophisticated, they are simple in their preparation, safe for use a combination that can highly expand their application. Transethosome are gaining popularity in designing drug delivery systems for topical and transdermal use for their capability to reach deep skin layers and systemic circulation. The dermal route has been recognized as one of the highly potential routes of systemic drug delivery and provide the advantage of avoidance of the first pass effect, ease of use and withdrawal (in case of side effects) and better patient compliance. Transethosome have both ethanol and penetration enhancer due to which drug penetrates through stratum corneum by increase fluidity of cell membrane lipids. The present review includesthe composition, mechanism of penetration, advantage, method of preparation and characterization of transethosome.

 

 

 

 

INTRODUCTION:

Nanocarriers improve the pharmacokinetics and increase the biodistribution of drug to the target organ, resulting in improve efficacy. Toxicity of drug is reduced due to preferential accumulation of drug at target sites than in healthy tissues. Hence nanocarriers provide a means for sustained and controlled release of drug.^[1] Currently, there are many types of UDV that have been successfully developed for the both pharmaceutical and cosmeceuticals, particularly liposome, ethosome, transferosome and more recently transethosome (figure no.1) ^[2].

 

Conventional liposome do not penetrate deep into skin but remain confined to the upper layer of the stratum corneum ^[3,4]. Hence new class of ultra deformable lipid carriers such as Transfer some and ethosome were developed to enhance transdermal delivery of drug. These carriers are extremely flexible and can squeeze through pores smaller than its own diameter. Due to its elasticity they can easily penetrate the skin and deliver the drug encapsulated within the carrier. Transferosome are elastic carriers containing edge activator. Edge activator destabilize the lipid bilayer of transferosome and increase its flexibility ^[5,6]. Ethosomes are ultra deformable carriers containing high concentration of ethanol. Enhanced skin permeation of drug incorporated in this carrier is due to the interdigitation effect of ethanol on the lipid bilayer of the carrier and increases the fluidity of lipids of the stratum corneum ^[7]. Ethosomes and Transfersomes are excellent carrier for the transdermal drug delivery as it contains high concentration of ethanol and edge activator respectively. Both ethanol and edge activator act as a penetration enhancer. Hence carriers which consist both these penetration enhancer will further accentuate the transdermal delivery of the drug. It will enhance transdermal permeation of drug to the dermal layer through the stratum corneum due to its ultradeformable nature. Transethosome are elastic vesicles which contain high concentration of ethanol with edge activator ^[8]. Transethosomes are lipid vesicles based on transfersomes and ethososmes. These novels UDV were firstly introduce by Song et al in 2012 and are characterized by having a high content of ethanol (up to 30%) together with an EA. Transethosome may contain both advantages of transfersomes and ethosmes. Therefore, the mechanism of skin penetration might be a fusion of both mechanisms ^[8]. Transethosome have shown an irregular spherical shape and higher values in both vesicle elasticity and skin penetration studies. This fact may be due to presence of both ethanol and edge activator that causes a rearrangement in the lipid bilayer of these vesicles ^[8].

 

Figure 1: Schematic representation of ultradeformable vesicles.

Notes: (A) Transfersomes. (B) Ethosomes. (C) Transethosomes.

 

Need for Transdermal Drug Delivery:

Despite the challenges, TDD offers several unique advantages including relatively large and accessible surface area for absorption, ease of application and termination of therapy. Further, evolution of better technologies for delivery drug molecules, safe penetration enhancer and the use of vesicular carrier have rejuvenated the interest for designing TDD system for drug that were thought to be unfit for transdermal delivery.

 

ADVANTAGE OF TRANSETHOSOMES ^[9-13].

1.      They are biocompatible and biodegradable as they are made from natural phospholipids similar to liposomes. They are having high entrapment efficiency, in case of lipophilic drug near to 90%.

2.      They protect the drug from metabolic degradation. They act as depot; release their drug slowly and gradually.

3.      They can be used in both way topical as well as systemic delivery of drug.

4.      They can be used for low molecular as well as high molecular weight drug.

5.      They are highly flexible so have high flux rate across the skin and high rate of penetration as compare to other vesicles.

 

Table no. 1: COMPOSITION FOR TRANSETHOSOME

CLASS	EXAMPLE	USES
Phospholipid	Soyaphosphatidylcholine Dipalmitoylphosphatidylcholine Distearoyl phosphatidylcholine	Vesicles forming component
Alcohol	Ethanol	For providing flexibility
Surfactant	Sod.deoxycholate Tween-80 Span-80	Penetration enhancer
Buffering agent	Saline phosphate buffer(pH 7.4)	As a hydrating medium
Dye	Rhodamine-123	For CSLM study

 

MECHANISM OF TRANSETHOSOME:^[14-17].

The drug absorption probably occurs in following two phases

1.      Ethanol effect

2.      Transethosome effect

 

Figure 2 Schematic representations of ultradeformable vesicles permeation and penetration through the skin.

Ethanol effect:

Ethanol penetrates into intercellular lipids and decreases the density of lipids multilayer of cell membrane and provide the flexibility.

 

Transethosome effect:

Transethosome act as penetration enhancer that disrupt the intercellular lipids from stratum corneum which ultimately widens the pores of the skin and facilitate the molecular interaction and penetration of system across the skin.

 

METHOD OF PREPARATION

1.      Cold method

2.      Hot method

3.      Thin film hydration

4.      Classic method

 

Cold method:

This is the most common method utilized for the preparation of transethosomal formulation. In this method Phospholipid, drug and other lipid materials were dissolve in ethanol in a covered vessel at room temperature by vigorous stirring with the use of mechanical stirrer. Penetrationenhancer was added during stirring. Stirring is continued for about 30-35 minutes. This mixture is heated to 30⁰  c in a separate vessel is added to the mixture in the form of fine stream, which then stirred for 5 min in a covered vessels. The vesicle size of Transethosome is reduced by using sonication and formulation stored in refrigerator ^[19].

 

Hot method:

In this method, phospholipid is dispersed in water by heating in a water bath at 40⁰ c until a colloidal solution is obtained. In a separate vessel ethanol and penetration enhancer are mixed and heated to 40^oc, the organic phase is added to the aqueous one. The drug is dissolved in water or ethanol depending on its hydrophilic/hydrophobic properties. The vesicles size of transethosomal formulation can be decreased to the desired extent using probe sonication ^[20].

 

Thin film hydration:

Soya phosphotidyl choline, permeation enhancers and Drug were dissolved in 30 ml chloroform: methanol (2:1, v/v). The lipid mixture was deposited as a thin film in a round bottom flask by rotary evaporating the chloroform: methanol under reduced pressure at 35± 1 C, Which was applied for 1 hr. to ensure total removal of solvent traces. The lipid film was hydrated with 10 ml phosphate buffer solution and achieved within the elutes ^[22].

 

Classic method:

The phospholipid and drug are dissolved in ethanol and heated to 30⁰c ±1⁰c in a water bath. Double distilled water is added in a fine stream to the lipid mixture, with constant stirring at 700rpm in a closed vessel. The resulting vesicle suspension is homogenized by passing through a polycarbonate membrane using a hand extruder for three cycles ^[23].

 

Method of Characterization of Transethosomes formulation:

1.      Transmission electron microscopy (TEM) and Scanning electron microscopy (SEM) ^[24]: Visualization of transethosomes can be done using transmission electron microscopy (TEM) and by scanning electron microscopy (SEM). Visualization by electron microscopy reveals antransethosomal formulation exhibited vesicular structure 300-400 nm in diameter. The vesicles seem to be malleable as evident by their imperfect round shape.

2.      Vesicles size and zeta potential ^[25]: Zeta potential is an important parameter that affects the aggregation of vesicles and depicts the physical stability of vesicular systems and it can be measured by Zeta meter.

3.      Entrapment efficiency ^[26]: The entrapment efficiency of transethosomes can be measured by the ultracentrifugation technique.

4.      Surface tension activity measurement^[4]: Ring method in a Du Nouy ring tensiometer

5.      Drug content: Drug content of the ethosomes can be determined using UV spectrophotometer. This can also be quantified by a modified high performance liquid chromatographic method.

6.      Transition temperature ^[27]: The transition temperature of the vesicular lipid systems can be determined by using differential scanning calorimetry.

7.      Penetration and permeation studies^[28]: Depth of penetration from transethsome can be visualized by confocal laser scanning microscopy (CLSM)

8.      Stability of Transethosome ^[29]: The ability of transethosomal formulation to retain the drug was checked by keeping the preparation at different temperature, i.e. 25±2⁰c (room temperature), 37±2⁰c and 45±2⁰c for different periods of time. The stability of transethosome can also be determined quantitatively by monitoring size and morphology of the vesicles using DLS and TEM.

 

 

Table no 2:Characterization of transetrhosome^[29-30]

Parameter	Importance	Method
Size and shape	Determine skin penetration	SEM, TEM, DLS
Zeta potential	Stability of vesicles	Zeta Meter
Entrapment efficiency	Suitability of method	Ultracentrifugation
Drug content	Important in deciding the amount of vesicle preparation to be used	UV, HPLC
Stability studies	To determine the shelf life of vesicle formulation	SEM, TEM, HPLC
Invitro dissolution	Determine the drug release rate from vesicle	Franz diffusion cell
Skin permeation	Determines rate of drug transport through skin	CLSM

 

APPLICATIONS OF TRANSETHOSOMES:^[21]

a)      In the treatment herpetic infection

b)     Transcellular Delivery

c)      Ethosomes are used in pilosabeceous targeting

d)     Transdermal Delivery of Hormones

e)      Delivery of Anti-Arthritis Drug

f)      Delivery of Antibiotic

 

 

CONCLUSION:

Transethosomes has initiated a new area in vesicular research for transdermal drug delivery. Transethosomes are characterized by simplicity in their preparation, safety and efficacy and can be tailored for enhanced skin permeation of active drugs. The main limiting factor of transdermal drug delivery system i.e. epidermal barrier can be overcome by Transethosomes to significant extent. Transethosomes have been tested to encapsulate hydrophilic drugs, cationic drugs, proteins and peptides. Thus, transethosomal formulations possess promising future in effective transdermal delivery of bioactive agents. Transethosomal carrier opens new challenges and opportunities for the development of novel improved therapies. Further, research in this area will allow better control over drug release in vivo and long term safety data, allowing the therapy more effective.

 

 

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