Vol 2, Issue 3, 2020 (112-123)

http://journal.unpad.ac.id/idjp

*Corresponding author,

e-mail : soraya@unpad.ac.id (S. R. Mita)

https://doi.org/10.24198/idjp.v2i3.29154

Formulation, Characterization, and Herbal Drug Delivery Applications of Ethosome,

Transfersome, and Transethosome

Luthfia Azzahra

, Soraya R. Mita

, Sriwidodo

Faculty of Pharmacy, Padjadjaran University, Sumedang, Indonesia

Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Padjadjaran

University, Sumedang, Indonesia

Received : 06 Sept 2020, Revised : 09 Sept 2020, Accepted : 20 Sept 2020, Published : 29 Des 2020

ABSTRACT

Herbal compounds have different physicochemical properties. Its use on the oral route

often has low biological availability. Therefore, alternative transdermal routes are used

through the skin. The stratum corneum skin layer is the most difficult layer to penetrate.

Therefore it is necessary to use a drug delivery system such as ethosome, transfersome or

transethosome to increase transdermal drug delivery. This review article aims to look at

the potential of ethosome, transfersome, and transethosome in increasing their ability to

deliver herbal drugs in terms of their formulation and characterization. Literature

searches were performed using online search engines namely NCBI and Google Scholar

with the keywords ‘Transdermal Drug Delivery System’, 'Ethosome', 'Transfersome', and

'Transethosome'. The result showed compositions of ethosomes are phospholipids, water,

and ethanol. The composition of transfersome is phospholipid, water, and edge activator.

Transethosomes are a combination of phospholipids, water, ethanol, and edge activators.

The role of ethanol and edge activator is thought to increase skin permeation.

Transdermal drug delivery systems can be used on herbal drugs to increase transdermal

drug delivery.

Keywords: Transdermal, Ethosome, Transfersome, Transethosome, Herbal.

1. Introduction

Currently, the use of herbal compounds

as active substances in medicine is increasing

rapidly. There are many active substances

derived from plants. These active substances

have different physicochemical properties.

Catechin by oral route has low bioavailability

due to poor membrane permeability and low

absorption on the gastrointestinal tract (1,2).

Curcumin by oral route has a high rate of

metabolism and poor absorption which limits

the bioavailability, and it has a poor solubility

on water (3). Resveratrol, a phenolic

compound, by oral route has low

bioavailability due to low intestinal absorption

and catabolism (4). Fisetin by oral route has

low bioavailability (44.1%) (5), it is lipophilic

and goes through enzymatic degradation also

first-pass metabolism (6,7). Capsaicin or CAP

is lipophilic which affects its oral

bioavailability and its intravenous half-life is

very short (7.06 minutes) (8). Apigenin has

low bioavailability due to its poor water

solubility (9). This limits the potential

pharmacological activity of the active

substances. Many phyto-compounds are

dealing with the same problems mentioned

above.

In order to improve its bioavailability, to

avoid the first-pass metabolism and enzymatic

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113

degradation, a transdermal route through the

skin is used. In the transdermal system, drugs

penetrate from the outermost layer to the

blood vessels through the layers of the skin

(10). Transdermal drug delivery systems have

many advantages, for example, avoidance of

first-pass metabolism by the liver (first-pass

effect/pre-metabolism), controlled delivery of

medications, and improved patient

compliance, as they are noninvasive and can

easily be self-administered, with transdermal

drug delivery system, the drug can avoid

degradation in the gastrointestinal tract (11).

Several things need to be underlined is as

drug's bioactivity, skin characteristic,

formulation utilized, the adhesive that will be

used, and the physicochemical factors

affecting penetration process through the skin

(12).

Stratum corneum as the main challenge

is hydrophobic. Drug delivery tools such as

ethosome, transfersome, and transethosome

can be utilized on the transdermal route (11).

This development occurs to increase drug

permeation, optimize the work of the existing

drug, improve patient compliance, therapeutic

index, and bioavailability of drugs (13). The

present review will focus on formulation

including preparation and characterization

results of ethosome, transfersome, and

transethosome as transdermal herbal drug

delivery system.

2. Method

This review compiled studies published

in various databases which are PubMed

(NCBI) and Google Scholar. Studies obtained

using the keywords “Ethosome”,

“Transfersome”, “Transethosome”, “Skin”,

and “Herbal”. Articles published before 2010,

reviews, non-English studies, and unrelated

studies, such as routes other than the

transdermal route and not including

characterization results, were excluded. From

284 studies obtained in April-May 2020, we

included 21 studies in this review.

Figure 1. Flowchart of Methodology

3. Result

The results of the formulation can be seen in

Table 1

Table 1. Formulation Result

Formulation

Characterization

Application

References

Ethosome

Consists of

water,

phospholipid,

and ethanol.

The characterization

can be done by

running several tests

such as particle size,

polydispersity index,

zeta potential,

entrapment efficiency

and vesicle structures.

Many researches

used ethosome as

herbal drug

delivery system,

12 journals were

obtained. The

research showed

great results and

(20-31)

Keywords: Transdermal,

Ethosome, Transfersome,

Transethosome

(n= 284)

Exclusion:

Review articles

Non-English articles

Article not using phyto-compunds

Article using routes other than

transdermal

Articles obtained:

(n= 21)

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114

The characterization

results from ethosome

as drug delivery

system showed good

results.

ethosome

improves the drug

delivery.

Transfersome

Consists of

water,

phospholipid,

and edge

activator.

The characterization

can be done by

running several tests

such as particle size,

polydispersity index,

zeta potential,

entrapment efficiency

and vesicle structures.

The characterization

results from

transfersome as drug

delivery system

showed good results.

Many researches

used transfersome

as herbal drug

delivery system, 7

journals were

obtained. The

research showed

great results and

transfersome

improves the drug

delivery.

(32-37)

Transethosome

Consists of

water,

phospholipid,

ethanol, and

edge

activator.

The characterization

can be done by

running several tests

such as particle size,

polydispersity index,

zeta potential,

entrapment efficiency

and vesicle structures.

The characterization

results from

transethosome as drug

delivery system

showed good results.

There are only a

few research used

transethosome as

drug delivery

system, 2 journals

were obtained. The

research showed

great results and

transethosome

improves the drug

delivery.

(38-39)

4. Discussion

The transdermal drug delivery system;

ethosome, transfersome, and transethosome

has basic composition which is phospholipid

and water. Ethanol is used in ethosome and

transethosome, edge activator is used in

transfersome and transethosome. The

phosphatidylcholine head is water-soluble and

the tail part is lipid-soluble (14).

Transfersome contains water,

phospholipid (lipid bilayer), and edge

activator. Ethosome contains water,

phospholipid (lipid bilayer), and ethanol.

Transethosome fuses ethanol and edge

activator as a penetration enhancer, and water

and phospholipid as vesicle former.

Mechanism of penetration

Ethosome has a penetrating mechanism

into the skin. Ethanol in the ethosome

penetrates intracellular lipids and escalates the

fluidity of cell membrane lipids, besides

decreasing the level of lipid density of the

membrane cell layer, so that the active

substance in the ethosome can penetrate

through the stratum corneum, the outer layer

of skin which is lipophilic (16).

Also, the

ethanol and phospholipid content in ethosomes

increases the elasticity of the ethosomal

vesicles so that they can penetrate deeper (15).

The penetration mechanism of transfersome is

the vesicles maintain their structure or it fuses

with the lipid layers of skin (17).

Transfersome can easily change their shape to

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115

cross the skin layer due to the edge activator

action responding to mechanical stress,

directing inside the vesicle to a region with a

smaller curve, reducing the membrane elastic

energy to a minimum level (18). Transfersome

can slide through small channels, crossing the

stratum corneum (19).

Table 2. Application of Ethosome

No.

Phyto-compound/Plants

Ethanol

concentration

Reference

EGCG (Camellia sinensis

L. Kuntze)

Ethanol 95% (5%)

(20)

Curcumin (Rhizoma

Curcumae Longae)

Ethanol:Water

(3:7)

(21)

Charantin (Momordica

charantiaI Linn.)

Ethanol 96% (30%)

(22)

Capsaicin

Ethanol (75%)

(23)

Eugenol (Sygizium

aromaticum)

Ethanol (30%)

(24)

Apigenin (Petroselinum

crispum)

Ethanol:PEG (20-

50%)

(25)

Sesamum indicum L. Seed

extract

Ethanol (10-40%)

(26)

Seabuckthorn leaf extract

Ethanol (40%)

(27)

Sophocarpine (Sophora

alopecuroides)

Ethanol (10%)

(28)

10.

Cryptotanshinone (Salvia

miltiorrhiza)

Ethanol (30-40%)

(29)

11.

Phenylethyl Resorcinol

Ethanol (30%)

(30)

12.

Mangiferin (Mangifera

indica)

Ethanol (20%)

(31)

1. EGCG (Camellia sinensis L. Kuntze)

Epigallocatechin gallate (EGCG) has

low penetration, ethosome is used with

mechanical dispersion and thin layer hydration

(TLH) method. Ethanol 95% on 5%

concentration was used. Characterization

results showed ethosome had a spherical

shape, polydispersity index 0.05 which was

qualified, zeta potential range was -60.00mV/-

67.00 mV, which proven its stability (20).

2. Curcumin (Rhizoma Curcumae Longae)

Due to curcumin’s low water solubility

(lipophilic), several transdermal drug delivery

systems were prepared (Propylene glycol

liposomes (PGL), Liposomes, and Ethosome).

Ethanol injection method was used. Ethosome

used ethanol:water 3:7, PGL used propylene

glycol as a penetration enhancer. Results

showed ethosome particle size was 289 ±

132,1 nm) and entrapment efficiency was

57,9 ± 4.72% PGL had the smallest particle

size (182.4 ± 89.2 nm), spherical, good

particle distribution, and showed no

aggregation. Ethosome had small aggregation

using the method earlier. The entrapment

efficiency of PGL showed the highest rate

of>90%. PGL has the highest potential as a

transdermal drug delivery system (21).

3. Charantin (Momordica charantiaI Linn.)

Charantin have low penetration through

the skin; to overcome this, ethosome was used

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116

as a transdermal delivery system. The method

used was TLH. Ethanol 96% equal 30% on the

formulation was used. Characterization results

showed ethosome had a spherical shape,

particle size 1083.33 ± 15.27 nm,

polydispersity index (0.42 ± 0.02), stable (zeta

potential -54.33±0.75 mV), and entrapment

efficiency 91.50 ± 0.40%. Ethosome is highly

potential as a transdermal drug delivery

system for charantin (22).

4. Capsaicin

Capsaicin loaded ethosome were

prepared using four different methods, which

are the hot method, cold method, classic

method, and injection method.

Characterization results showed the hot

method to be the most effective with high

stability, spherical shape (50-300 nm), EE

81.40%, zeta potential 4.28+4.07 mV mV,

homogenous, and uniform distribution using

75% ethanol on the formulation

(polydispersity index 0.162) (23).

5. Eugenol (Sygizium aromaticum)

Eugenol loaded ethosome was prepared

using the hot method. Ethanol used in the

formulation equal to 30% The result showed

that eugenol concentration influenced particle

size and entrapment efficiency. Particle size

44.21 nm, zeta potential −40.3 ± 1.7 mV,

polydipersity index 0.189±0.051, and EE 82%.

Ethosome is highly potential for the

transdermal delivery system (24).

6. Apigenin (Petroselinum crispum)

Apigenin loaded ethosome was prepared

using the classic injection method.

Ethanol:Propylene glycol was used as

penetration enhancer with various

concentration (20-50%). The result showed

encapsulation efficiency increase with

phospholipid concentration. Particle size

ranged from 36.61 ± 1.78 to 698.33 ± 124.30

nm, zeta potential 10.14 ± 2.04 and 27.67 ±

3.23 mv, EE ranged from 61.69-85.21%.

Phospholipid and ethanol concentration

improved skin deposition. Optimized

ethosome showed better activity rather than

basic liposomes. It is highly potential (25).

7. Sesamum indicum L. Seed extract

Ethosome were used as a transdermal

delivery system to reduce the pre-metabolism

effect on Sesamum indicum. The method used

was solvent dispersion or cold method.

Ethanol used in the formulation ranged from

10-40%. Characterization result showed a

good polydispersity index (0.114 to 0.348),

and ZP were between −17.0 mV/47.7 mV,

stable according to zeta potential result, the

shape was spherical (139.7 ± 10.55–231.8 ±

12.43 nm) (26).

8. Seabuckthorn leaf extract

Seabuckthorn leaf, contain phenolic

active substances. Ethosome were used as a

transdermal delivery system. The cold method

with modification was used. Ethanol used in

the formulation ranged from 10-40%. The

result showed ethosome had a smooth surface,

vesicle size 96.98-395 nm, polydispersity

index 0.041-0.392, formulation of 40%

ethanol, 3% phospholipid, and 75% ethanolic

extract showed good entrapment efficiency,

91.09±0.64% (27).

9. Sophocarpine (Sophora alopecuroides)

Sophora alopecuroides loaded ethosome

were prepared used the transmembrane pH-

Gradient method with 10% ethanol. Particle

size 142±15.5 nm and EE more than 90%. The

result showed good entrapment efficiency; the

method successfully enhanced the stability and

drug delivery (28).

10. Cryptotanshinone (Salvia miltiorrhiza)

Ethosome loaded cryptotanshinone

(CPT) was prepared using the classic method.

Ethanol as penetration enhancer was used (30-

40%). The characterization result showed

vesicle had good vesicle size (69.1±1.9 nm),

polydispersity index 0.185±0.017, and EE was

40.31±0.67%. Ethosome formulation is an

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117

effective dermal delivery system and highly

promising for the future (29).

11. Phenylethyl Resorcinol

Phenylethyl Resorcinol (PR) had poor

water solubility and low stability. Ethosome is

used as a transdermal delivery system to

protect active substances using 30% absolute

ethanol. TLH is used to prepare the vesicle.

The particle size range was 214-890 nm; the

phospholipid concentration increased the

vesicle size, contrary to ethanol. The zeta

potential range was -33 mV to -35.6 mV. EE

was higher than 50% (30).

12. Mangiferin (Mangifera indica)

Ethosome is used to increase the

bioavailability of Mangifera indica extract.

The hot method was used to prepare ethosome

using 20% ethanol. The EE range was 65.31-

89.38%. The zeta potential score was 8.8 mV.

The average size was 926 nm (31).

Table 3. Application of Transfersome

No.

Phyto-compound/Plants

Edge activator

References

Resveratrol

Tween 80, Tween 20

(32)

EGCG (Camellia sinensis L.

Kuntze)

Span 80

(33)

Parkia speciosa Hassk. Extract

Tween 80

(34)

Resveratrol

Sodium cholate

(35)

Berberine, Berbamine (Berberis

aristata)

Span 80 : PC (15:85)

(36)

Quercetin

Tween 80

(37)

Quercetin flavonoids (Malus

domestica Mill)

Span 80

(33)

1. Resveratrol

Resveratrol, polyphenol active

substances used transfersome as a transdermal

delivery system. A non-ionic edge activator is

used such as Tween 80 and Tween 20. Particle

size 40.13±0.51 nm, spherical shaped.

Polydispersity index was 0.266 ± 0.009, zeta

potential was −23.93 ± 0.31mV, and EE was

59.01 ± 1.02%. The stability and solubility

were improved (32). Another research

conducted by (35) using an edge activator,

sodium cholate. Characterization result

showed particle size 105.4±7.9, poldispersity

index 0.1, zeta potential -22.4±0.2 mV (35).

2. EGCG (Camellia sinensis L. Kuntze)

Green tea contains epigallocatechin

gallate (EGCG). EGCG loaded transfersome

were prepared using a TLH method. Span 80

was used as edge activator. The result showed

ethosome had a spherical shape (107.82±0.44

nm), good polydispersity index (0.07±0.01),

stable (zeta potential -40.3±1 mV) and EE was

63.16±0.65%. EGCG loaded ethosome

showed better in vitro penetration rather than

the non-transfersome one (38)(39).

3. Parkia speciosa Hassk. Extract

Parkia speciosa has flavonoids and

phenolics active substances which are difficult

to penetrate through the skin, to overcome

this, transfersome were used as a transdermal

delivery system. Tween 80 was used as an

edge activator. The method used for

transfersome preparation was TLH. The result

showed spherical shape, particle size 495.6

nm, polydispersity index 0,484. Zeta potential

-21.4 mV. EE was 91.6884 ± 0.0261%.

Overall the Parkia speciosa extract loaded

ethosome showed better stability and more

soluble than the pure extract (34).

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118

4. Berberine, Berbamine (Berberis

aristata)

Berberis aristata has antipsoriatic

activity. To develop it, transfersome were used

as a transdermal delivery system. The method

used is lipid film hydration, using different

edge activator (Tween 80, Span 80, and

sodium deoxycholate). Characterization

showed 330±19 nm particle size and the

polydispersity index was 0.29±0.007, and zeta

potential range was −35.2 mV. EE was

78.0±1.12%. It is highly potential compared to

conventional drugs (36).

5. Quercetin

Quercetin loaded transfersome were

prepared using the injection method. Edge

activators used were Tween-80, sodium

cholate, sodium decanoate, and sodium

oleate). Transfersomes with Tween-80 led to

high zeta potential [(-38.0±1.5) mV],

cumulative permeation were (9.37±2.59) and

remarkably enhances the cumulative

permeation and retention (37).

6. Quercetin flavonoids (Malus domestica

Mill)

Transfersome as a transdermal delivery

system were used. The preparation used a

TLH, using Span 80 as an edge activator. The

result showed a good polydispersity index

(0.078-0.273), particle size 106.44±2.70 nm,

and zeta potential of −49.96±2.05 mV, EE was

78.78±0.46%. proofing the stability of the

vesicle (33).

Table 4. Application of Transethosome

No.

Phyto-compound/Plants

Ethanol and Edge activator

References

Fisetin (Cucumis sativus)

Ethanol and Sodium

Cholate

(38)

EGCG (Camellia sinensis L.

Kuntze)

Ethanol and Span 80

(39)

1. Fisetin

Fisetin used transethosome as a

transdermal delivery system. Ethanol and edge

activator (Sodium cholate) was used as a

penetration enhancer. The thin lipid film

method was used in the preparation. Results

showed good characterization, vesicle size of

74.21 ± 2.65 nm, zeta potential of 11.0 mV,

entrapment efficiency of 68.31 ± 1.48%.

Transethosomes vesicles formulation was

found to be a potentially useful drug carrier

for fisetin dermal delivery (38).

2. Green tea (EGCG)

Transethosome was used as a transdermal

delivery system using a TLH method. Span 80

and ethanol were used as a penetration

enhancer. Transethosome with green tea

extract equivalent to 3% EGCG, 4% Lipoid

P30, 0.75% Span 80, and 30% ethanol had the

best characteristic including spherical shape,

smallest particle size (35.35 nm), 0.319 PDI,

and zeta potential of -29.97±3.05 mV. EE was

45.26%±8.15%. Transethosome can increase

the skin penetration of green tea leaf extract

(39).

Formulation

The formulation of ethosome,

transfersome, and transethosome varies. The

ethanol in ethosome cause the ethosome to

become elastic, encourages the vesicles shape

and increase the stability, with the increasing

concentration of ethanol, the vesicle size

would decrease (14), but increasing ethanol

concentration above the optimum level would

increase the vesicle size, also decreasing the

entrapment efficacy and it would cause a leak,

moreover it could solubilize the vesicle

structure.

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119

The phospholipid is a vesicle forming

component. There is synthetic and natural

phospholipid. It is important to choose the

right type of phospholipid because it can affect

the size, zeta potential, stability, entrapment

efficacy, and the penetration of vesicles.

Generally, the phospholipids concentration

range is 0.5%-5% (30). The higher the

concentration, the vesicle size will moderately

get bigger. The entrapment efficiency will

increase significantly in a certain

concentration (40).

Edge activators are surfactants. It has a

high span of curvature. It can destabilize the

lipid bilayers and builds the deformability of

the bilayers of the vesicles. Many research

concluded edge activators improve skin

penetration, and it affects the charge and

particle size of vesicles. Another edge

activator is dimethyl sulfoxide; it enhances the

penetration in a topical formulation. Tween 80

at 10%-50% concentration was reported to

reduce the size of the vesicle and increase the

vesicle stability and skin permeation

properties, it mainly solubilizes the system and

prevents vesicle fusion.

Other edge activators

such as oleic acid affect the vesicular size, zeta

potential, elasticity, and permeation on the

skin by increasing the fluidity of the stratum

corneum (21,30,41,42).

Preparation

Thin layer hydration

The phospholipid and other lipophilic

substances dissolved in ethanol, the aqueous

phase was sonicated at 60

C for 30 minutes.

The lipid phase poured to a round-bottomed

flask and then it was evaporated to remove the

ethanol. The lipid film was hydrated with

aqueous phase in a closed container, and then

it was sonicated at 60

C for 30 minutes (30).

Hot method

Lipids are dispersed into the water at

40°C to form a colloidal phase. In different

containers, edge activator/ethanol and glycol

are mixed. The active substance is mixed into

an appropriate solubility solvent. The organic

phase is poured into the aqueous phase, then

stirs the mixture until it’s evenly mixed (43).

Cold method

The active substance, phospholipid, edge

activator/ethanol, and glycol are mixed and

stirred vigorously with a mixer until dissolved

then heated to a temperature of 30°C. In

different containers, the water is heated to a

temperature of 30°C. Then mix the water into

the ethanol mixture, stir vigorously (43).

Classic method

Phospholipids and plant extracts are

dissolved into edge activator/ethanol, and then

heated 30°C. Add redistilled water, stir at a

speed of 700 rpm. Vesicles are homogeneous

by passing them on a polycarbonate

membrane (43).

Mechanical dispersion method

Phospholipids and plant extracts are

dissolved in chloroform: ethanol 3: 1 and/or

edge activator. The organic solvent is

evaporated with a vacuum evaporator, then

vacuum for 1 night after that, it was hydrated

to obtain ethosomes (43). The size of the

ethosome can be adjusted by sonication or

extrusion. (44).

Sonication

The use of sonication with high intensity

can induce chemically and physically. The

physical effect of sonication is emulsification,

usually used for dispersion of fillers in basic

polymers and emulsification of inorganic

particles in polymers. The chemical effect of

sonication is to cause molecules to interact,

which then causes chemical changes. The

interaction is based on ultrasonic wavelengths

that are higher than the wavelengths of

molecules. In sonication, a sonicator probe or

ultrasonic bath can be used. In this method, a

uniform ethosome suspension is produced.

According to research conducted by (45) that

the size of the vesicles produced by sonication

is smaller than the extrusion method.

However, the efficiency of vesicle sorption

carried out by the extrusion method is higher

than sonication (45).

Extrusion

In extrusion, it is normally done by

consecutively extruding the ethosome vesicle

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120

system under moderately low pressure for

quite a while or a cycle going through a

polycarbonate membrane with a pore size of

50-400 nm. Nonetheless, in this method there

are two ways, extrusion should be possible by

extruding several times through one

membrane with one pore size or can be done

in stages with a membrane that is stacked with

different sizes of pores. By shrinking the pore

size of the membrane, the size of the ethosome

produced will shrink as well. The outcome of

the process is a more uniform size of the

colloid ethosome with a low polydispersity

index value (40).

Characterization

The efficiency of drug sorption can be

measured by ultracentrifugation techniques,

small centrifugation columns, and also the

fluorescence spectrophotometer. The stability

is evaluated based on sorption efficiency and

particle size, this depends on the composition

of the phospholipids in the vesicle (46). The

table below shows the minimum and

maximum number for each characterization of

the vesicular system (20,47):

Characterization needs to be done to

confirm that the vesicle qualified and stable.

Table 5. Characterization

No.

Characterization

Score

References

Particle size

< 300 nm

(20,47)

Polydispersity index

0 – 0,5

(20,47)

Zeta potential

> +30 mV or < -30 mV

(20,47)

Particle Size Analyzer

Particle Size Analyzer is a common

method that is widely used for image analysis.

PSA usually uses a wet method which is

considered more accurate when compared to

the dry method or the sieve method and image

analysis. Nanoparticle samples tend to have

high agglomeration (easy to clot) so that it is

more suitable to use the wet method. The wet

method will provide measurable results in the

form of distribution, where the measurement

results are assumed to describe all sample

conditions (48).

Zeta Potential

Zeta potential is a measure of the

magnitude of the electrostatic charge of

particles in dispersion, following the study of

the stability of nanoparticle suspension. Zeta

potential above the absolute value of 30 mV is

called obligatory to assure fine colloidal

stability (49). Zeta potential has a role in

physical stability; zeta nanoparticle potential

also influences the effectiveness of vesicles as

a drug conductor (50).

Transmission Electron Microscopy

In the standard TEM operation mode,

which is generally alluded to as amplitude or

contrast-diffraction imaging, only a tiny bit of

electrons that have gone through the sample is

utilized to shape the final image that is greatly

enlarged (51).

5. Conclusion

The transdermal drug delivery system

above proved their potential to deliver many

phyto compound derived from plants with

different physicochemical properties. The

formulation, which is penetration enhancer

such as ethanol and edge activator improves

the characterization result.

References

1. Giudicessi JR, Ackerman MJ.

Determinants of incomplete penetrance

and variable expressivity in heritable

cardiac arrhythmia syndromes. Transl

Res. 2013;161(1):1–14.

2. McClements DJ. Encapsulation,

protection, and release of hydrophilic

active components: Potential and

limitations of colloidal delivery systems.

Adv Colloid Interface Sci. 2015;219:27–

53.

3. Zhang L, Zhu W, Yang C, Guo H, Yu

A, Ji J, et al. A novel folate-modifed

L. Azzahra et al / Indo J Pharm 3 (2020) 112-123

121

self-microemulsifying drug delivery

system of curcumin for colon targeting.

Int J Nanomedicine. 2012;7:151–62.

4. de Oliveira MTP, Coutinho D de S, de

Souza ÉT, Guterres SS, Pohlmann AR,

Silva PMR, et al. Orally delivered

resveratrol-loaded lipid-core

nanocapsules ameliorate LPS-induced

acute lung injury via the ERK and

PI3K/Akt pathways. Int J

Nanomedicine. 2019;14:5215–28.

5. Seguin J, Brullé L, Boyer R, Lu YM,

Ramos Romano M, Touil YS, et al.

Liposomal encapsulation of the natural

flavonoid fisetin improves

bioavailability and antitumor efficacy.

Int J Pharm. 2013;444(1–2):146–54.

6. Bothiraja C, Yojana BD, Pawar AP,

Shaikh KS, Thorat UH. Fisetin-loaded

nanocochleates: Formulation,

characterisation, in vitro anticancer

testing, bioavailability and

biodistribution study. Expert Opin Drug

Deliv. 2014;11(1):17–29.

7. Kadari A, Gudem S, Kulhari H, Bhandi

MM, Borkar RM, Kolapalli VRM, et al.

Enhanced oral bioavailability and

anticancer efficacy of fisetin by

encapsulating as inclusion complex with

HPβCD in polymeric nanoparticles.

Drug Deliv. 2017;24(1):224–32.

8. Tavano L, Alfano P, Muzzalupo R, De

Cindio B. Niosomes vs microemulsions:

New carriers for topical delivery of

Capsaicin. Colloids Surfaces B

Biointerfaces. 2011;87(2):333–9.

9. Zhang J, Liu D, Huang Y, Gao Y, Qian

S. Biopharmaceutics classification and

intestinal absorption study of apigenin.

Int J Pharm. 2012;436(1–2):311–7.

10. Donnelly R., Singh TR., Morrow D.,

Woolfson A. Microneedle-Mediated

Transdermal and Intradermal Drug

Delivery. Hoboken, New Jersey: Wiley;

2012.

11. Pirvu CD, Hlevca C, Ortan A, Prisada R.

Elastic vesicles as drugs carriers through

the skin. Farmacia. 2010;58(2):128–35.

12. Kalpana S P, Mikolaj M, Courtney L S,

Nicole K B, Priyanka G, Audra L S.

Challenges and opportunities in

dermal/transdermal delivery. Ther Deliv.

2010;11(11083):109–31.

13. Almandil NB. Healthcare professionals’

awareness and knowledge of adverse

drug reactions and pharmacovigilance.

Saudi Med J. 2016;37(12):1350–5.

14. Touitou E, Dayan N, Bergelson L,

Godin B, Eliaz M. Ethosomes - Novel

vesicular carriers for enhanced delivery:

Characterization and skin penetration

properties. J Control Release.

2000;65(3):403–18.

15. Romero EL, Morilla MJ. Highly

deformable and highly fluid vesicles as

potential drug delivery systems:

Theoretical and practical considerations.

Int J Nanomedicine. 2013;8:3171–86.

16. Dave V, Kumar D, Lewis S, Paliwal S.

Ethosome for enhanced transdermal

drug delivery of aceclofenac. Int J Drug

Deliv. 2010;2(1):81–92.

17. Chen J, Lu WL, Gu W, Lu SS, Chen ZP,

Cai BC. Skin permeation behavior of

elastic liposomes: Role of formulation

ingredients. Expert Opin Drug Deliv.

2013;10(6):845–56.

18. Elsayed MMA, Cevc G. The vesicle-to-

micelle transformation of phospholipid-

cholate mixed aggregates: A state of the

art analysis including membrane

curvature effects. Biochim Biophys Acta

- Biomembr. 2011;1808(1):140–53.

19. Cevc G, Vierl U, Mazgareanu S.

Functional characterisation of novel

analgesic product based on self-

regulating drug carriers. Int J Pharm.

2008;360(1–2):18–28.

20. Makula A, Maddela R, Pilli NR,

Maddela S, Pulipati CR, Polagani SR. A

novel and Rapid LC–MS/MS assay for

the Determination of Mycophenolate

and Mycophenolic Acid in Human

Plasma. J Young Pharm. 2017;9(1):107–

14.

21. Zhao YZ, Lu CT, Zhang Y, Xiao J, Zhao

YP, Tian JL, et al. Selection of high

efficient transdermal lipid vesicle for

curcumin skin delivery. Int J Pharm.

2013;454(1):302–9.

L. Azzahra et al / Indo J Pharm 3 (2020) 112-123

122

22. Surini S, Arnedy AR, Iswandana R.

Development of ethosome containing

bitter melon (Momordica charantia

Linn.) fruit fraction and in Vitro skin

penetration. Pharmacogn J.

2019;11(6):1242–51.

23. Majeed I, Raza SA, Akhtar N, Siddiqui

FA, Iqbal B. Formulation and in-vitro

characterization of Capsaicin loaded

ethosomes. Pak J Pharm Sci.

2019;32(6):2849–57.

24. Jin P, Yao R, Qin D, Chen Q, Du Q.

Enhancement in Antibacterial Activities

of Eugenol-Entrapped Ethosome

Nanoparticles via Strengthening Its

Permeability and Sustained Release. J

Agric Food Chem. 2019;67(5):1371–80.

25. Shen LN, Zhang YT, Wang Q, Xu L,

Feng NP. Enhanced in vitro and in vivo

skin deposition of apigenin delivered

using ethosomes. Int J Pharm.

2014;460(1–2):280–8.

26. Somwanshi SB, Hiremath SN.

Development and evaluation of novel

ethosomal vesicular drug delivery

system of Sesamum indicum L. seed

extract. Asian J Pharm.

2018;12(4):S1282–90.

27. Nimisha, Srivastava K, Singh AK.

Formulation and evaluation of

seabuckthorn leaf extract loaded

ethosomal gel. Asian J Pharm Clin Res.

2015;8(5):309–12.

28. Zhou Y, Wei Y, Liu H, Zhang G, Wu X.

Preparation and in vitro evaluation of

ethosomal total alkaloids of Sophora

alopecuroides loaded by a

transmembrane pH-gradient method.

AAPS PharmSciTech. 2010;11(3):1350–

29. Yu Z, Lv H, Han G, Ma K. Ethosomes

Loaded with cryptotanshinone for acne

treatment through topical gel

formulation. PLoS One. 2016;11(7):1–

11.

30. Limsuwan T, Boonme P, Khongkow P,

Amnuaikit T. Ethosomes of Phenylethyl

Resorcinol as Vesicular Delivery System

for Skin Lightening Applications.

Biomed Res Int. 2017;2017.

31. Sundari BT, Rao PS, Sireesha K, Sai

YK, Sundari BT, Sireesha K, et al.

Formulation and Evaluation of

Ethosomal Gels of Mangifera Indica

Leaf Extract. 2017;4(06):1755–61.

32. Wu PS, Li YS, Kuo YC, Tsai SJJ, Lin

CC. Preparation and evaluation of novel

transfersomes combined with the natural

antioxidant resveratrol. Molecules.

2019;24(3):1–12.

33. Zesiorani NF, Anwar E. Transfersome

gel formulation of an ethanol extract of

apples (malus domestica mill)

containing antioxidants and in vitro

penetration testing using franz diffusion

cells. Int J Appl Pharm. 2017;9:32–7.

34. Fitrya F, Fithri NA, Winda M, Muharni

M. Ethanol extract of Parkia

speciosaHassk.loaded transfersome:

Characterization and optimization. J

Pharm Pharmacogn Res. 2020;8(3):167–

76.

35. Scognamiglio I, De Stefano D, Campani

V, Mayol L, Carnuccio R, Fabbrocini G,

et al. Nanocarriers for topical

administration of resveratrol: A

comparative study. Int J Pharm.

2013;440(2):179–87.

36. Chester K, Zahiruddin S, Ahmad A,

Khan W, Paliwal S, Ahmad S.

Bioautography-based Identification of

Antioxidant Metabolites of Solanum

nigrum L. and Exploration Its

Hepatoprotective Potential agChester, K.

et al. (2017) ‘Bioautography-based

Identification of Antioxidant

Metabolites of Solanum nigrum L. and

Explorati. Pharmacogn Mag. 2017;13

(Suppl(62):179–88.

37. Yaowen L, Shengyun Y, Xiaoying L,

Qiuxia W. Effect of Formulation on

Transdermal Delivery of Quercetin

Transfersomes. CJPH. 2017;48(04):523.

38. Moolakkadath T, Aqil M, Ahad A,

Imam SS, Iqbal B, Sultana Y, et al.

Development of transethosomes

formulation for dermal fisetin delivery:

Box–Behnken design, optimization, in

vitro skin penetration, vesicles–skin

interaction and dermatokinetic studies.

L. Azzahra et al / Indo J Pharm 3 (2020) 112-123

123

Artif Cells, Nanomedicine Biotechnol.

2018;46(sup2):755–65.

39. 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(Special Issue 1):299–

302.

40. Abdulbaqi IM, Darwis Y, Khan NAK,

Assi RA, Khan AA. Ethosomal

nanocarriers: The impact of constituents

and formulation techniques on

ethosomal properties, in vivo studies,

and clinical trials. Int J Nanomedicine.

2016;11:2279–304.

41. Ascenso A, Raposo S, Batista C,

Cardoso P, Mendes T, Praça F garcia, et

al. Development, characterization, and

skin delivery studies of related

ultradeformable vesicles: transfersomes,

ethosomes, and transethosomes. Int J

Nanomedicine. 2015;10:5837–51.

42. Song CK, Balakrishnan P, Shim CK,

Chung SJ, Chong S, Kim DD. A novel

vesicular carrier, transethosome, for

enhanced skin delivery of voriconazole:

Characterization and in vitro/in vivo

evaluation. Colloids Surfaces B

Biointerfaces. 2012;92:299–304.

43. Fatima Grace X, Suganya K,

Shanmuganathan S. Development of

Terminalia Chebula loaded ethosomal

gel for transdermal drug delivery. Asian

J Pharm Clin Res. 2018;11(12):380–3.

44. Pirrung M. The Synthetic Organic

Chemist’s Companion. New Jersey:

John Wiley & Sons Inc; 2007.

45. Maestrelli F, Capasso G, González-

Rodríguez ML, Rabasco AM, Ghelardini

C, Mura P. Effect of preparation

technique on the properties and in vivo

efficacy of benzocaine-loaded

ethosomes. J Liposome Res.

2009;19(4):253–60.

46. Maurya SD, Prajapati SK, Gupta AK,

Saxena GK, Dhakar RC. Formulation

development and evaluation of ethosome

of stavudine. Indian J Pharm Educ Res.

2010;44(1):102–8.

47. Pan L, Wang H, Gu K. Nanoliposomes

as vehicles for astaxanthin:

Characterization, in vitro release

evaluation and structure. Molecules.

2018;23(11).

48. Panigrahi L, Pattnaik S, Ghosal saroj K.

Design and Characterization of

Mucoadhesive Buccal Patches of

Salbutamol Sulphate. Acta Pol Pharm -

Drug Res. 2004;61(5):351–60.

49. Jonassen H. Polysaccharide based

nanoparticles for drug delivery

applications (Thesis). Oslo: University

of Oslo; 2014.

50. Honary S, Zahir F. Effect of Zeta

Potential on the Properties of Nano-

Drug Delivery Systems - A Review (Part

1). Trop J Pharm Res. 2013;12(2):255–

64.

51. Smith DJ. CHAPTER 1:

Characterization of nanomaterials using

transmission electron microscopy. In:

Nanocharacterisation Edition: 2. 2nd ed.

Arizona, USA; 2015. p. 1–29.