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Transfersome: a vesicular drug delivery with enhanced permeation

Nurul Arfiyanti Yusuf1,2, Marline Abdassah1, Rachmat Mauludin3, I Made Joni4, Anis Yohana Chaerunisaa1*

1 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Padjadjaran University, Jatinangor, Indonesia. 2 Department of Pharmaceutics, Sekolah Tinggi Ilmu Farmasi Makassar, Makassar, Indonesia. 3 Department of Pharmaceutics, School of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia. 4 Department of Physics, Faculty of Mathematics and Natural Sciences, Padjadjaran University, Jatinangor, Indonesia.

Correspondence: Anis Yohana Chaerunisaa, Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Padjadjaran University, Jatinangor, Indonesia. anis.yohana.chaerunisaa @ unpad.ac.id


ABSTRACT

Transdermal drug delivery offers numerous advantages in comparison to conventional delivery methods. However, the stratum corneum as the first layer has been the limiting barrier to some drugs so that no compilation permeable is applied to the skin. Permeation enhancers are now a solution for limitation in transdermal delivery systems, which are available as chemical or physically permeation enhancers. But sometimes these systems still have skin safety issues. Vesicle is a system that delivers hydrophilic and hydrophobic compounds and macromolecular drugs as well as targeted delivery to organs. Transfersome is an elastic vesicle with the capability of deforming its molecule while penetrating into the skin, which is effective in increasing the penetration of drugs with high and low molecular weights. Transfersomes are formed from phospholipids and surfactants known as edge activators. The flexibility of transfersome is affected by the ratio of surfactant and phospholipid. Transfersome has been prepared by various methods including high-pressure homogenization, reverse-phase evaporation, thin-film dispersion, sonication/vortex, and ethanol injection. Evaluation of transfersome included physical and chemical characterization, as well as permeation evaluation in both ex vivo and in vitro studies. In conclusion: Vesicular transfersome is a system that offers an increased effect of drug permeation into the skin with deforming capabilities due to the presence of edge activators. The surfactant and phospholipid ratio determines the ability of the system in enhancing drug permeation.

Keywords:  Transdermal, Vesicular, Transfersome, Permeation


Introduction  

The permeation of the drug into the systemic circulation across the skin is allowed through Transdermal delivery, thereby avoiding the first-pass effects of the liver during oral administration. The limitation of this administration is skin permeability to hydrophilic and lipophilic macromolecules and molecules [1]. Drug penetration in the skin can be disrupted by a barrier called the stratum corneum. The stratum corneum makes delivery not achieve the expected effectiveness.

Various methods are utilized for increasing the permeation of transdermal administration. In chemical methods, the use of permeation enhancers such as polyalcohol, pyrrolidone, fatty acids, terpenes, surfactants, etc. is applied . The physical method is also used through the skin by involving the disruption of the skin structure by iontophoresis, sonophoresis, or electroporation, ultrasound, microneedle. However, this physical method will affect skin safety for long-term use [1].

Vesicle is the most widely accepted formulation technique for transdermal drug delivery that increases hydrophilic and lipophilic permeation. In this system, macromolecular drugs act as drug carriers and provide controlled and sustainable drug delivery with safety for the skin due to biodegradable materials of macromolecules. Various types of vesicle delivery are being developed at this time such as liposome, ethosome, invasome, and ultra vesicle, namely transfersome, which can be deformed [2].

The new vesicular derivative "Transfersome" offers the ability to increase the permeation of some drugs. They are artificial vesicles designed to be involved in exocytosis. They are suitable for controlled or targeted drug delivery. It has been proposed as a new class of liposomes, which is also known as an elastic liposome or ultra-deformed liposome that can increase liposome penetration. Several studies have reported that transfersome is an effective carrier for non-invasive transdermal administration. Transfersome vesicles can penetrate through pores smaller than their diameter through the stratum corneum [3].

The most outer layer of the body that provides many functions like protection, homeostasis, and barrier to the external environment is the skin. The stratum corneum composed of 70-80% protein keratine and lipid, provides the principal barrier function of the skin [4]. The barrier of chemicals and biochemistry consists of macrophages, antimicrobial peptides, hydrolytic enzymes, acids, and lipids. Immunological barriers consist of cellular and humoral constituents of the immune system [5]. Stratum corneum is a barrier of the permeation rate from transdermal drug delivery, with inter-cell space composed of an exclusive lipid mixture [6]. The stratum corneum as the main barrier in transdermal administration has the obstructive property, making the drug delivery for medical use to be controlled.

Enhancer Permeation

Physical enhancers: Iontophoresis is a non-invasive permeation technology that physically facilitates transdermal delivery of hydrophilic and ionic compounds across intact skin [7]. The ultrasound method interacts with the structural lipids present in the intercellular channels of the stratum corneum, which is similar to the postulated impacts of some chemical transdermal enhancers, which act through disrupting lipids. The summary of the method, including its advantages and disadvantages is shown in Table 1. The mechanisms of enhancers are different. Mostly, the common goal of the enhancers is disrupting the stratum corneum structure and creating “pores” that are large enough for the passage of molecules. The size of disruption generally is on the nanometer scale, to allow the delivery of small drugs. In some cases, macromolecules is also possible with the risk of causing some clinical damages.

 

 

Table 1. Summary of Enhanced Permeation Transdermal Delivery

Methods

Advantages

Limitation

Chemical enhancer

Increases penetration through the skin; gives systemic and local effects [8]

Only for drugs with low molecular weight; skin irritation Immunogenicity [8]

Iontophoresis

Increasing the penetration of drug of intermediate size [7]

Low transfer efficiency; only for charged drugs [8]

Ultrasound

At low frequencies, increase skin permeability

does not induce the transport of high molecular weight proteins [9].

Microneedle

Permit the transfer of microparticles, supramolecular complexes, and macromolecules

The safety evaluation should be done due to minor skin abrasions that possibly occur in daily life

Vesicle Delivery

Improving the delivery of hydrophilic, poorly soluble, and macromolecular drugs; ability to target organ for drug delivery, biodegradable, lack toxicity [7]

Need special handling to maintain stability, the price is relatively expensive [7]

 

 

Vesicle Delivery System

Vesicular delivery is one of the most widely used methods in the formulation of a delivery system through which vesicle skin can act as a drug carrier to deliver drug molecules that are trapped into the skin. These vesicles act as permeation enhancers following the permeation of intercellular lipid lamellae in the skin layer. Types of vesicle delivery system as well as its limitation and advantage are shown in Table 2.

Various literature shows the benefits of the vesicular system in increasing drug permeation. Conventional liposomes are limited to the upper surface with nominal penetration into the stratum corneum. Impaired lipid structure of the intercellular stratum corneum by phospholipids also increases drug permeation. Phospholipids are a group of lipids, which tend to form lipid bilayers due to their amphiphilic properties. Different flexible carrier systems such as ethosome, liposome, transfersome, niosome, flexisome, and aquasome were developed and successfully incorporated into the delivery system of skin for various therapeutic agents such as anticancers but some of the structural lipid carriers have been modified.

 

 

Table 2. Summary of Vesicle Delivery

Type of Vesicle Delivery

Composition Vesicle

Advantages

Limitation

Liposome

Phospholipid + Lipid

Phospholipid vesicle, biocompatible, biodegradable

Less skin permeation, less stable [10]

Niosome

Nonionic surfactant + Lipids

Non-ionic surfactants vesicles, more stability

Less skin permeation easy to handle

Ethosome

Phospholipid + Ethanol (up to 50%)

High permeation enhancer [11]

Skin irritation [10]

Invasome

Phospholipid + Ethanol + Terpene

High permeation enhancer than ethosome [12]

Less skin permeation than transfersome [12]

Transfersome

Phospolipid + Edge Activators

Suitable for hydrophilic and lipophilic drugs; proper for drugs with either low and high molecular weight; biodegradable; high skin penetration due to high deformability; biocompatible; and more stable

None [10]

 

 

Transfersome as Vesicle Delivery System

Transfersome is a type of vesicle with the ability to increase transdermal permeation in many drugs with low and high molecular weights. It can deform while penetrating into the skin and form a complex, which easily adapts to its environment and responsive to stress. Transfersomes form elastic vesicles, which can change shape when they pass through the cell membrane. The ultra deformable properties are obtained because the liquid core is surrounded by a complex bilayer lipid. The composition of transfersome as a bilayer makes them elastic vesicles. Therefore, they can pass through various transport barriers very efficiently and act as a drug delivery system for controlled release [3]. Table 3 shows materials used in many formulations of transfersome.

 

 

Table 3. Materials in many types of Transfersome

No

Active Pharmaceutical Ingredient

Composition

Ref

Phospholipid

Edge Activators

1

Adapalene & Vitamin C

Lecithin soya

Tween 80, Sodium deoxycholate

[13]

2

Asenapine Maleate

Soy phosphatidylcholine (SPC)

Sodium deoxycholate

[1]

3

Baicalin

Soy Phosphatidylcholine(Lipoid S75)

Tween 80

[14]

4

Capsaicin

Phospholipon 90G

Tween 80

[15]

5

Cilnidipine

Phospholipon® 90G

Sodium cholate

[2]

6

Diclofenac Sodium

Soya Lecithin

Span 80

[16]

7

Diclofenac Sodium

Soya phosphatidylcholine (Emulmetik 930)

Tween 80

[8]

8

Diflunisal

L-alpha-Lecithin

Sodium Cholate

[10]

9

Dexamethasone

Soyaphosphatidylcholine

Sodium deoxycholate

[3]

10

DSPE-PEGPheo A (DPP)

Without lipid bilayer

Tween 80

[17]

11

Epigallocatechin-3-gallate (EGCG)

Soy Phosphatidylcholine

Sodium Cholate

[18]

12

Eprosartan mesylate

Phospholipid

Sodium Deoxycholate

[19]

13

Eprosartan mesylate

Phospholipid 90G

Sodium Deoxycholate

[20]

14

Phenylethyl resorcinol

L-a-phosphatidylcholine

Tween 20, 80, Span 20, 80, Sodium Deoxycholate

[12]

15

Genistein

Phosphatidylcholine (Lipoid S100)

Tween 80, Sodium Deoxycholate

[21]

16

Ginsenoside

Lipoid S75-3

Tween 80

[11]

17

Human Growth Hormone (hGH),

Lecithin soybean phospholipids

Sodium Deoxycholate, SLS, Brij 35

[22]

18

Ketoconazole

Phospholipon 90G & Lipoid S100

Tween 80

[23]

19

Ketoconazole

Lecithin

Tween 80

[24]

20

Lidocaine

Soybean phosphatidylcholine

Sodium Cholate, Span 80

[6]

21

Meloxicam

Phosphatidylcholine

Hexadecylpyridinium chloride(HPC), Sodium hexadecyl sulfates (SHS), sodium dodecyl sulfate (SDS), dodecylpyridinium chloride (DPC), Dicetylphosphate (DCP), stearylamine (SA)

[25]

22

Minoxidil & Caffeine

Soybean phosphatidylcholine

Tween 80 & 20

[26]

23

Ondansetron

Phosphatidylcholine

Sodium Taurocholate

[27]

24

Ostole

Soya Phosphatidylcholine

Tween 80

[28]

25

Ovalbumin

Soy Phosphatidylcholine

Sodium Cholate

[29]

26

Paromomycin Sulfate

Soya bean Phosphatidylcholine

Sodium Cholate

[30]

27

Monophosphoryl lipid A (MPL)

Egg Phosphatidylcholine

Tween 80

[31]

28

Piperin

Hydrogenated Phosphatidyl Choline

Span 80, Tween 80

[32]

29

Quercetin

Phosphatidylcholine

Tween 80

[33]

30

Raloxifen

Phospholipon 90G

Sodium deoxycholate

[34]

31

Raloxifen

Phospholipon 90G & 90H

Sodium cholate, Sodium deoxycholate

[35]

 

32

Raloxifen

Phospholipon 90G

Sodium cholate

[36]

33

Resveratrol

Soy phosphatidylcholine

Tween 80, Sodium cholate, Sodium deoxycholate

[37]

34

Resveratrol

Phosphatidylcholine

Tween 20, Plantacare® 1200 UP, and Tween 80

[38]

35

Risperidone

Soya Lecithin (L-a-phosphatidylcholine)

Sodium deoxycholate, Tween 80

[39]

36

Sertraline

Soya lecithin

Span 80

[40]

37

Sildenafil citrate

L-a-phosphatidylcholine

Span 80, Tween 80

[41]

38

Sildenafil citrate

L-a-phosphatidylcholine

Span 60 & 80

[42]

39

Sinomenine HCl

Egg phosphatidylcholine

Sodium deoxycholate

[43]

40

Tacrolimus

Lipoid E80

Sodium deoxycholate, Span 80, Tween 80

[44]

41

Timolol

Egg Lα phosphatidylcholine (EPC)

Tween 20

[45]

42

Timolol

L-a-phosphatidylcholine

Tween 80

[46]

43

Tocopherol

Lipoid S75

Tween 20,40,60,80

[47]

44

Valsartan

Phospholipon 90G

Sodium deoxycholate

[48]

45

Zolmitriptan

Soya Lecithin

Tween 80

[49]

 

 

Preparation of Transfersome

Thin-lm dispersion method

Thin-lm dispersion method requires surfactants and phospholipids (as edge activators) to prepare a thin film. It is used to prepare multilamellar vesicles. A phospholipids and edge activators solution is made in a mixture of methanol and chloroform solvent. The solution is transferred into a round bottom flask with constant stirring and elevated temperature (higher than the lipids glass transition temperature) at decreased pressure. Then, using aqueous media, a film of edge activator and lipids, formed on the walls flask is hydrated. The drug is dissolved in this media. During hydration, the lipids swell and form bilayer vesicles [48].

Reverse Evaporation Method

Lipids are dissolved in organic solvent in a round bottom flask. Aqueous media containing edge activators are added under nitrogen purging. Depending on the solubility, the drug can be added to the aqueous or lipid medium. The formed system is then sonicated until it becomes a homogeneous dispersion and is separated 0.5h after sonication. After that, the solvent is removed under reduced pressure and the system converts to a viscous gel followed by vesicle formation. The residual solvents and non-encapsulated materials are removed using the dialysis of centrifugation.

High-Pressure Homogenization Method

Commonly, good-quality transfersomes are prepared by high-pressure homogenization method combining film dispersion method

Vortex/Sonication Method

Edge activators and phospholipids are mixed by vigorous shaking and agitation to be suspended in phosphate buffer. Then, the suspension is sonicated using a vortex or sonicator. This is further extruded through membranes of various sizes to obtain the vesicles of desired sizes

Ethanol Injection Method

The aqueous solution that contains the drug is heated with continuous stirring at a fixed temperature. The ethanolic solution of edge activators and phospholipids is poured dropwise into the aqueous solution. The lipid molecules precipitate and form bilayer structures as the solution comes in contact with aqueous media. This method has several advantages including simplicity, and reproducibility on scale-up [49].

 

The quality of transfersome after production can be conducted by the evaluation as follows:

Determination of the eciency of entrapment

For estimating the amount of drug trapped in the vesicles, ultracentrifugation was used to separate the drug from the vesicular systems. Then, the supernatants are collected. Then, the quantity of unentrapped is determined [10]. The drug entrapment percentage (EE%) is calculated from 3 replicates as follows:

 

EE% =Total amount of drug added-Amount of untrapped drugTotal a amount of drug added × 100

(1)

 

Zeta potential, vesicle size, and size distribution measurements

The particle distribution and size, as well as zeta potential value of the vesicles, can be evaluated by dynamic light scattering (DLS) using a Zeta-Sizer. The sample is diluted with a proper medium at room temperature prior to measurements. All data are performed in triplicate [28].

Morphology of Transfersome

  • Transmission electron microscopy (TEM)

Morphological evaluation of vesicles can be performed by Transmission electron microscopy. The vesicle formulations have to be diluted at 1:100 (v/v) using water. Afterwards, surface shape and features are studied at proper magnication [50].

  • SEM

The morphological evaluation of the vesicles can also be conducted by scanning electron microscopy. A drop of vesicle sample is added on the glass. A gold sputter coater is applied to the samples [15].

  • Freeze-Fractured microscopy

This technique can be used to observe the morphology of the transfersomes. A drop of vesicle dispersion is placed on a copper block and is frozen quickly in nitrogen slash. The sample is then fractured in a freeze-fracture apparatus continued by rotary-shadowed with platinum-carbon at 10ºC. The shadowed surface is coated with carbon, and observed using a TEM [25].

  • Optical Microscope

The mean size of vesicle and morphology of the transfersomes is determined by using an optical microscope. The average size measured should be more than100 particles [25].

Number of Vesicle per Cubic

The vesicles are counted using optical microscopy and Neubauer chamber. Then, the number of vesicles in 1 ml of dispersions is calculated with the formula:

 

Concentration = Number of vesicle x 10000Number of square x dilution factor

(2)

 

Thermal Behavior

DSC is utilized to investigate thermal behavior. DSC is used to measure the phase transition temperature (Tm) of the drug and transfersome. The measurements are collected under a nitrogen atmosphere. The differential thermal curves for each sample is compared.

  • DSC for Physicochemical Drug and Excipients In Transfersome

DSC is used to identify and study the interaction and physicochemical compatibility of the drug with polymers, and diluents when used in transfersomes [1].

  • DSC for studying the Transfersomal-treated and Untreated Skin

The changes in the stratum corneum structure are assessed from the obtained thermograms [31].

 

Hydration %=

 

Weight of hydrated stratum corneum-Weight of dry stratum corneumWeight of dry stratum corneum

(3)

 

FTIR (Fourier Transforms Infrared)

FTIR spectra of the sample are used to detect functional groups, identify compounds, and analyze mixtures of analyzed samples without destroying the sample.

Turbidity Measurement

The turbidity of transfersome formulation was determined using the buffer as blank. The transfersomes are diluted with water and sonicated for 5 minutes. The turbidity of the sample is then measured with a UV-vis spectrophotometer [40].

Drug loading

The drug loading percentage in transfersome is determined by high-speed centrifugation of the transfersomes. The supernatant is siphoned-off and free concentration of the drug is measured [6].

Determination of the Drug Content

The quantity of drug within the transfersomal dosage form is determined against ethanol as blank [40].

Interfacial Behaviour Studies of Lipid Monolayers

Investigations of the interfacial behavior of adjuvant and lipid monolayers are conducted using a Langmuir-Blodgett with an area (A) at ambient temperature [31].

Degree of Deformability

The deformability measurement is a unique and important parameter of transfersomal formulations. It can dierentiate transfersomes from other vesicular carriers such as liposomes. The deformability test is performed by the extrusion method. The particle size and distribution of vesicles are monitored by DLS measurement before and after ltration. The degree of deformability is determined using the formula [3]:

 

D = J(rxrp)2

(4)

 

Where,

D = vesicle membrane deformability

rp = pore size of the barriers

rx = vesicle size (after pass)

J = amount of suspension extruded within 5min

In Vitro Study of Drug Release

Drug release from transfersomes can be measured by a modified release drug study that measures drug release from a dialysis bag installed in the dissolution chamber [46].

Permeation Study

  • In vitro Permeation Study

The in vitro drug release study can be done using Franz-diffusion cells. The membrane is put between the receptor and donor compartments and centrifuged at 100 rpm and 37 ± 0.5ºC. At pre-determined time intervals, samples are collected and replaced with a fresh medium. The aliquot samples are filtered through a 0.45µm membrane [49]. In vivo permeation of active drug as transfersome delivery had been extensively studied and are shown in Table 4.

  • Ex-Vivo Permeation Study

Using Franz-type diusion cells that fit with skin as a membrane, the in vitro skin permeation experiments are conducted. Firstly, the frozen skin is thawed at the room temperature. The reception solution is kept in a stirred circulating water bath. The skin in the Franz diusion cells is equilibrated. Through plotting the mean cumulative permeated amounts/cm2 of skin against time, the permeation prole for transfersome is obtained [49]. Ex vivo permeation of active drug as transfersome delivery has also been extensively studied (Table 5).

 

 

Table 4. In Vitro Permeation Study of Transfersome

Active Pharmaceutical Ingredients

Instrument Permeation Study

Membrane

Instrument of Analysis

Year

Ref

Dexamethasone

A locally fabricated diusion cell.

Cellophane membrane

HPLC

2003

[3]

Diclofenac Sodium

Franz diusion cells

Cellulose membrane

HPLC

2017

[8]

Genistein

Franz diusion cells

Cellulose membrane

HPLC

2019

[21]

Ketoconazole

Franz diffusion cells

Cellulose membrane

Spectrophotometer

2012

[24]

Minoxidil and Caffeine

Franz diusion cells

Artificial membrane

Spectrophotometer

2018

[26]

Raloxifene Hydrochloride

Franz diffusion cells

Dialysis membrane

Spectrophotometer

2018

[35]

Resveratrol

Franz diusion cells

Strat-M® Membrane(Merck, Darmstadt, Germany)

HPLC

2019

[38]

Sertraline

Franz diffusion cells

Cellulose membrane

HPLC

2012

[40]

Sildenafil

Franz diusion cells

Synthetic nylon membrane

Spectrophotometer

2015

[41]

Timolol Maleate

Franz diffusion cells

Cellophane membrane

Spectrophotometer

2016

[46]

Franz diffusion cells

Cellulose membrane

HPLC

2016

[45]

Tacrolimus

Franz diusion cells

Nylon66 filters

HPLC

2013

[44]

Zolmitriptan

Franz diffusion cells

Dialysis membrane

Spectrophotometer

2018

[49]

 

Table 5. In Vitro Permeation Study of Transfersome

Active Pharmaceutical Ingredients

Instrument Permeation Study

Membrane

Instrument Analysis

Year

Ref,

Adapalene

Franz diusion cells

Goat skin

Spectrophotometer

2020

[13]

Asenapine maleate

Franz diusion cells

Rats skin

HPLC

2016

[1]

Baicalin

Franz diusion cells

Pig skin

HPLC

2018

[14]

Capsaicin

Franz diusion cells

Rats skin

Confocal Laser Scanning Microscope

2015

[15]

Cilnidipine

Diusion cells

Rats skin

Spectrophotometer

2019

[2]

Dexamethasone

Locally fabricated diusion cell

Rats skin

HPLC

2003

[3]

Diclofenac Sodium

Franz diusion cells

Rats skin

HPLC

2013

[16]

DPP {1,2-distearoyl-snglycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)2000] (DSPE-PEG(2000)-NH2)}

Franz diusion cells

Mice skin

Confocal Laser Scanning Microscope

2016

[17]

Diflunisal

Franz diusion cells

Rats skin

HPLC

2019

[10]

Epigallocatechin

Vertical diffusion cells

Rats skin

HPLC

2017

[18]

Eprosartan Mesylate

Franz diusion cells

Rats skin

HPLC

2017

[19]

 

Microneedle roller

Rats skin

HPLC

2017

[20]

Ginsenoside

Franz diusion cells

Human cadaver skin

HPLC

2015

[11]

hGH (Human Growth Hormone)

Franz diusion cells

Rats skin

ELISA

2019

[22]

Ketoconazole

Franz diusion cells

Goat vaginal tissue

Spectrophotometer

2017

[23]

Lidocaine

Diffusion cell

Rats skin

Spectrophotometer

2019

[6]

Meloxicam

Side-by-side diffusion cell

Mice skin

HPLC

2013

[25]

Ondansetron

Vertical diffusion cells

Rats skin

HPLC

2018

[27]

Osthole

Side-by-side diffusion cell

Porcine skin

HPLC

2016

[28]

Ovalbumin

Franz diusion cells

Porcine skin

Fluorescence spectroscopy

2017

[29]

Paromomycin

Franz diusion cells

Mice skin

HPLC

2012

[30]

Phenylethyl Resorcinol

 

Franz diusion cells

Pig skin

HPLC

2018

 

[12]

Peptide monophosphoryl lipid A

Franz diusion cells

Pig skin

Fluorescence spectroscopy

2012

[31]

Piperin

Diffusion cell

Pig skin

Spectrophotometer

2012

[32]

Quercetin

Franz diusion cells

Rats skin

Spectrophotometer

2020

[33]

Raloxifene Hydrochloride

Hanson diffusion cell

Rats skin

HPLC

2014

[34]

Franz diusion cells

Rats skin

Spectrophotometer

2018

[35]

Franz diusion cells

Rats skin

Spectrophotometer

2019

[36]

Resveratrol

Franz diusion cells

Pig skin

HPLC

2013

[37]

Risperidone

Franz diusion cells

Porcine skin

Spectrophotometer

2017

[39]

Sentraline

Franz diusion cells

Rats skin

Spectrophotometer

2012

[40]

Sildenafil citrate

Franz diusion cells

Rats skin

HPLC

2016

[42]

Sinomenine Hydrochloride

Franz diusion cells

Rats skin

HPLC

2017

[43]

Tacrolimus

Franz diusion cells

Rats skin

HPLC

2013

[44]

Tocopherol

Franz diusion cells

Pig skin

HPLC

2018

[47]

Valsartan

Franz diusion cells

Rats skin

HPLC

2012

[48]

 

 
  1. The enhancement ratio (ER) is determined as follows [2]:

ER=Steady state flux of transfersome formulaSteady state flux of control

(5)

 

  1. The cumulative amount of permeated drug is plotted as a function of time. The lag time (LT, h) and steady-state permeation rate (Jss) are calculated from the X-intercept and slope of the linear portion, respectively. The ER can be calculated as follows

ER=Transdermal flux from vesicular formulationTransdermal flux from plain drug

(6)

 

  1. The ER, permeability coefcient (Kp), and ux (Jmax) for the transport of drug from transfersomal compared to the marketed product) is calculated using this formula [13]:

Jmax=Amount of drug permeateTime x Area of release membrane

(7)

 

Kp=Jmax drug concentration in the donorInitial

(8)

 

ER=Jmax of test formulationJmax of marketed product

(9)

  1. The cumulative amount of permeated drug per unit area can be plotted as a function of time. The flux can be calculated from the slope of the linear portion. The 𝐾𝑝 of the drug across the membrane is calculated using relation derived from Fick’s first diffusion law that is expressed as follows [16]:

K p=JC

(10)

where 𝐶 is the drug concentration and 𝐽 is the flux in the donor compartment.

  1. The permeation parameters including J, Kp, and ER of the drug in form of vesicles have been studied and calculated by El Salim et al. [10]. J (μg/cm2.h) of the permeated drug from vesicles has been calculated from the slope of the plot of the cumulative quantity of drug permeated/cm2 of the membrane at a steady-state against time. The steady-state Kp of the drug in the form of vesicles crossing membrane has been calculated as follows:

Kp=JC

(11)

where J is the ux and C is the drug concentration in the donor compartment. The penetration enhancing eect of vesicles is calculated in terms of ER as follows:

ER=Kp of drug in vesicular hydrogelKp of drug in hydrogel

(12)

 

  1. The cumulative amount (Qt,µg/cm2) of drug that permeated through the membrane per unit area of skin is calculated as follows [12]:

Qt=CnV+i-1n-1CiSA

(13)

 

Where, Qt is the cumulative amount of drug permeated (µg/cm2), A is effective diffusion surface area, S is the sampling aliquot volume, V is the volume of individual Franz diffusion cell (ml), Ci is the drug concentration determined at No.n sampling interval (µg/ml), and Cn is the drug concentration from n sampling interval (µg/ml). The Qt amount is plotted as a function of time and the steady-state flux (Jss) is calculated from the slope of the plot. The value of the Kp for the drug is calculated by the equation:

Kp=JssC0

(14)

 

Where C0 is the initial concentration of drug in the donor compartment.

  1. The formula for the amount of accumulated permeation is obtained using the following equation:

 

Q=VSx (Ci )

(15)

 

Q%=QQ0x 100%

(16)

 

V, Ci, and Q0 are the volume of Franz diffusion cell, accepting liquid.

  1. Drug Retention

Evaluation of the drug retention in the skin is carried out by washing the skin with pH 7.4 PBS several times, cut into small pieces, and keeping in methanol for 24h to extract the drug deposited in the skin. The processed skin is then sonicated for 20minutes and centrifuged [16].

  1. Penetration Behaviour

Study on permeation behavior of the drug either in free form or it is as vesicles can be conducted by performing the following methods:

  • CLSM

Confocal laser scanning microscopy (CLSM) is used to assess the penetration behavior of the selected uorescently-loaded vesicular formulations. CLSM study excised in membrane skin is treated with rhodamine-loaded optimized transfersomes formulation for 24h. After that, the excised rat skin is rinsed with DD water and subjected to glass slides. Skin morphology can be visualized by confocal microscope [3].

  • Fluorescence microscopy

Fluorescence microscopy can be carried out for conrming the penetration ability of vesicles containing the drug. Preparation of vesicles in the presence of 6-carboxyuorescein and rhodamine provides the uorescence labeling ability. The uorescence marker-loaded formulation is topically applied to the skin. After 3hr of application, the skin is removed, cut into small pieces, xed by conventional procedures, and evaluated under a uorescence microscope. Skin treated with no formulation is used as the control [3].

Conclusion

Vesicular transfersome is a system that offers an increased effect of drug permeation into the skin with deforming capabilities supported by edge activators. The phospholipid and surfactant ratio determines the transfer permeation ability thus formulation of transfersome requires optimization of variables involved, including the process parameters and ratio of each of the components in the formulation.

Acknowledgments: The authors thank Directorate of Higher Education, Ministry of Education, Republic of Indonesia for funding the research  project connected to this review as Grant for  Disertation of Doctoral Student year 2020.

Conflict of interest: None

Financial support: None

Ethics statement: None

References

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