INTRODUCTION:

The novel drug delivery system is a kind of fresh born drug delivery system that helps to reshape loads of drugs and help eradicate the problem associated with these drugs. This challenging area evolves multiple new drug delivery systems¹.

With the help of this novel drug delivery system, new as well as the drugs which already exist exhibits better therapeutic efficacy that drives the drug to the specific site in a controlled and sustained manner to achieve the particular demand of drug of the body^2-4. Enveloping drugs in vesicular structures allow the drug to remain in systemic circulation for a longer period of time and cuts down the toxic effect of those drugs by decreasing dosing frequency⁵. The only concern about vesicular drug delivery systems is their stability due to the formation of vesicles. Few toxic and dose-related side effects can be overcome by this drug delivery system^6-8. Vesicular drug delivery shows improvement in bioavailability especially for poorly soluble drugs which finally cut down the cost of therapy.

The vesicular systems are composed of coextensive lipid bilayers with precise amphiphilic building blocks, which are filled with water^9,10. The most important agenda is to take care of drug loss, drug degradation, eradication of intolerable side effects, and enrichment of the drug available to the particular site. Novel vesicular drug delivery system includes liposome, niosome, promiosome, ethosome, transfersome, and protransfersome etc.

After eras of research, transport of drug through the barrier of the stratum corneum remains a problem still now so that it is challenging to develop a new transdermal drug delivery system. Though the vesicular system has many advantages in transdermal drug delivery but the major challenge in their development at the industrial and clinical level is their substandard stability¹¹.

Enhancement of the stability of a vesicular system is a challenge, can be overcome by an advanced vesicular delivery system - Transferosome. Transferosome is a derivational term. Here, the meaning of the Latin word “Transfere” is “to carry across” and the meaning of the Greek word “Soma” is “body”. So Transferosome means “carrying body”. Transferosome is conceived of surfactant, phospholipid, and water for promoting transdermal delivery. They are (quasi) metastable, which allows the vesicle membrane to be ultra-flexible. The vesicles are ultra deformable that compressed to move through pores of stratum corneum with minimal loss of drug than other conventional drug delivery system. Using gelling agent known as transfersomal gel is used to deliver the transfersomes in the form of a gel that increases skin penetration and delivers drug at a controlled rate. The maximum size of transfersome is 300 nm, which can penetrate through the skin^12,13.

But the major drawback of transfersomal drug delivery is their low viscosity. The weak interaction between the surfactants and biocompatible gels is responsible for the customization of the rheological behavior of transfersomal suspension¹⁴. Thus, transfersomal gel can be prepared by incorporating the transfersomal suspension into the preformed gel matrix which is more useful in transdermal application^15,16.

Historical background:

The term Transferosome has come under limelight firstly by Cevc and it was an interesting topic of many patents and pieces of literature in the 1990s (Transfersomes, a trademark of IDEA AG, Munich, Germany)¹⁷. The first-generation vesicle that has ultra deformation capability is known as transfersome. It is generally accepted that restricted permeation of liposomes in the stratum corneum, does not show effect in the case of cosmetics¹⁸. Transfersomes are declared to infuse as intact vesicles through the skin layers to the complete circulation^19,20.

Advantages of Transfersomes:

(i) The presence of both hydrophilic and hydrophobic moieties in transfersomes can put up drugs that have a wide range of solubility.

(ii) The deformable property of transfersome can pass through the tiny pores of the skin without loss.

(iii) Transfersome can entrap both low and high molecular weight drugs efficiently.

(iv) The encapsulated drug in transfersome can remain protected from enzymatic, metabolic degradation.

(v) They can be used for both topical and systemic delivery of drugs.

(vi) They can behave as a depot formulation when they release the contained drug in a controlled manner²¹.

Disadvantages of Transfersomes:

(i) Transfersome is chemically unstable.

(ii) The purity of phospholipids used in transfersome may be the other drawback to be considered at certain times.

(iii) They are cost-effective.

Mechanism of Action:

The present scenario of investigation shows that the transfersomes are drug emigrants that can move across the skin. In research it is found that the ability of penetration of these carriers is based on two main factors: the bilayered carriers have elevated elasticity (deformability) and the reality of an osmotic gradient across the skin. Transfersomes can produce a transepidermal osmotic gradient with the help of edge activators because of the property of deformability; and finally, it gets compressed while it moves through the pore of the skin. The penetration of the transfersome depends on transport hydrostatic force difference or passage of transfersomes doesn’t impair anyway throughout the whole stratum corneum, i.e. hydrotaxis is the cause of penetration for transfersome and elastomechanics drives permeation²². The deformability of transfersome is self-optimizing which helps to alter its membrane. The mechanism of the materials used in transfersome is liable for its deformability as at the site of tension it starts to aggregate but when the mechanism is less elastic then dilution occurs, so that active rate of membrane deformation decreased and finally it helps the highly elastic particles to go throughout the pores. The perfect ratio of surfactant and phospholipid creates a deformable property of the membrane which leads the transferosme through pores of the skin and the epithelial obstacle. These vesicles are not completely ruptured in the skin as the membrane has high flexibility and this ultra deformable transfersome alters their membrane composition efficiently and locally when they are forced to go through a tiny pore of the skin. This actively cuts down the energetic cost of deformation of the vesicular membrane and allows flexible particles to enter the skin and finally, it crosses the pores rapidly²³. The mechanism presents the vesicles as a drug carrier, where deformable vesicles carry drug molecules within it and enters the stratum corneum under the guidance of in vivo transcutaneous hydration gradient²⁴.

MATERIALS FOR TRANSFERSOMES:

Transfersome is a lipid cluster having self adaptability. It is comprised of phospholipids i.e. phosphatidylcholine that forms lipid bilayer when comes in contact with the aqueous environment and closes to form a vesicle. The biocompatible surfactant or an amphiphilic drug can be used as a softening component of the bilayer which is added to increase flexibility and permeability of the lipid bilayer. The other component is known as edge activator. A single chain surfactant was normally used as a good edge activator that causes destabilization of the lipid bilayer results in increasing fluidity and elasticity. Van den berg in 1998 discovered elastic vesicles as a new edge activator that is having non-ionic surfactant within it^25,26. The flexible property of tranfersomal membrane can be changed if suitable surface-active agents are mixed in the proper ratio. The resulting flexibility and permeability are optimized, which make an adjustment between the local concentration of each bilayer component and the local stress experienced by the bilayer, therefore, transfersome vesicle can carry its shape to surrounding stress easily and efficiently. Vesicles can be ruptured whenever it is applied to the skin but this flexibility also removes this risk and helps them to obey the natural water gradient across the epidermis, if it is applied under a non-occlusive state. The composition of vesicles is phospholipids (egg phosphatidylcholine, soya phosphatidylcholine, and dipalmitylphosphatidylcholine, etc), surfactants (ethanol, methanol) and hydrating medium of saline phosphate buffer (pH 6.5). There are dyes such as Nile red, Rhodamine 123 that are utilized for Confocal Scanning Laser Microscopy analysis^27,28.

METHODS OF PREPARATION:

Rotary film evaporation method:

Bangham discovered the rotary film evaporation method which is also popular as the hand-shaking process²⁴.

Figure 1: Preparation of Transfersomes by Rotary film evaporation method

Ethanol injection method²⁵

Figure 2: Preparation of Transfersomes by Ethanol injection method

Reverse-phase evaporation method²⁶

Figure 3: Preparation of Transfersomes by Reverse-phase evaporation method

Vortexing sonication method²⁷

Figure 4: Preparation of Transfersomes by Vortexing sonication method

Freeze–thaw method²⁸

Figure 5: Preparation of Transfersomes by Freeze–thaw method

Characterization of Transfersome Formulations:

Drug excipient interaction study:

Fourier Transform Infrared spectrophotometer (FTIR) exhibits graphical representation of pure drug, a mixture of the soya lecithin and drug, and a mixture of excipients (Span 80, Span 60, Span 20, Tween 20, etc) and the drug. For the sample preparation potassium bromide is used and within a spectral range of 450−4000 cm⁻¹ data are collected. If the graphical representation shows no overlap between individual components, proves that components are not interacting with each other^29,30.

Preformulation studies of drug:

Before incorporating the drug in formulation, Preformulation studies are a vital detection process for the physical and chemical properties of the drug³¹.

Physical appearance:

Organoleptic characteristics such as color, odor, and taste of the drug in powder form are examined³¹.

Melting Point:

The melting point of the drug is detected with the help of a capillary method or digital melting point apparatus^26-28. It is one of the important specifications for disclosing the purity of drugs. The drug sample becomes hot in a fuse capillary tube and the rate is 5ºC/min³².

Solubility study:

Solubility studies are carried out with distilled water, 0.1N hydrochloric acid, methanol, ethanol, and Phosphate buffer pH 7.4 at room temperature (25±2º C). Solute or drug in excess amount is needed in solvent to produce supersaturation^32-34. Then it is shaken mechanically for around 48 hours at 25ºC and equilibrium state is achieved. Membrane filter having porosity 0.45µ is used to filter the aliquots and solubility analysis is performed by UV spectrophotometer^35,36.

pH measurement:

Digital pH meter is essential for pH detection of the formulation. In this method, a specific amount of drug in powder form is accurately weighed. Then it is dissolved in a certain amount of ethanol when the drug is insoluble in distilled water and made up the volume with distilled water by the sonication method using a sonicator^37-39. The solution is then filtered using filter paper and digital pH meter helps to determine the pH of the filtrate^40,41.

Determination of Wavelength Maxima:

Accurately 10 mg of the drug is weighed and dissolved in 100 ml of phosphate buffer having pH 7.4. From this stock solution, 1 ml of is pipette out and by phosphate buffer having pH 7.4made up the volume up to the final mark. The scan value of the solution is detected by using a UV spectrophotometer.

Morphology and Structure of transfersomes:

The structure and morphology of the transfersomes consisting of drugs are detected by using Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). Transfersomes are diluted in distilled water and a drop of the diluted suspension is mounted on a clean slide. Staining agent like 1% phosphotungestic acid (dissolved in distilled water), is used for better visualization or to increase the contrast of the image and observed after drying. An optical microscope is used for visualization of vesicles that are produced without sonication. Make a thin film by spreading the suspension on the slide and a coverslip is utilized to cover the sample. After drying it out, the sample is placed under optical microscope observation⁴².

Entrapment efficiency:

Centrifugation helps to calculate percentage entrapment efficiency. Phosphate buffer saline (PBS) with pH7.4 is needed to disperse different transfersomal formulations. A centrifuge is applied to centrifuge the formulations for 40 min at 10000 rpm. The supernatant (clear solution) is used for the determination of free drug after centrifugation. UV spectrophotometer is essential to detect the absorbance of that clear solution at the maximum wavelength of the drug^43-45.

The percentage of drug encapsulation is determined by the following equation:

Where, the concentration of an unentrapped drug is C_fand the concentration of a total drug is C_t.

Entrapment efficiency (%) = [(C_t − C_f) / C_t] × 100

Vesicle size and size distribution:

Previously, the vesicle size of tranfersome is determined without sonication by optical microscopy (a stage eyepiece micrometer) which is calibrated with a micrometer scale^46,47. After sonication, the Polydispersity Index (PDI) measurement is done by dynamic light scattering with the Zetasizer after sonication^48,49.

Drug content determination:

Transfersomes consist drug is mixed with gel, is transfersomal gel. The evaluation of drug content in transfersomal gel is performed by dissolving a certain amount of the formulation in a specific amount of ethanol for lysis of vesicles. Mix the solution properly by sonicator. The analysis is done by measuring the absorbance of the solution and the formulation against ethanol as a blank with a UV-Visible spectrophotometer at the maximum wavelength of the drug³⁸.

Measurement of elasticity of Transfersomes:^29,35

Transfersome can cross stratum corneum instead of the liposome. To prove this statement degree of deformability test is an important and unique parameter of transfersomes. The deformability of Transfersomes can be determined by the extrusion method. At first Transfersomal formulations are passed through a pore of known size (50 nm) at constant pressure for 5 minutes. Vesicle size and size distributions are observed by using digital microscopy. The degree of deformability of transfersomes can be measured by using the formula mentioned below;

E = J × (r_v/r_p)²

Here, E = vesicles membrane’s elasticity; J = amount of suspension which will be extruded in 5 min.; r_v= vesicle size; r_p = pore diameter.

Counting of number of vesicles per cubic mm:

The number of transfersomal vesicles per cubic mm is counted by optical microscopy and haemocytometer. Before sonication, transfersomal vesicles are diluted five times with 0.9% of NaCl solution. The vesicles are counted in 80 small squares and can be determined for by the following formula^27,46

Total no. of vesicles per cubic mm=(Total no. of vesicles counted × dilution factor × 4000)/Total no. of squares counted

Penetration ability:

Penetration capability of Transfersomes can be detected by fluorescence microscopy^37,47.

Occlusion effect:

Skin occlusion study is essential for determining drug permeation study for topical preparations. Hydrotaxis means the movement of water from the dry surface to water-rich deeper regions of the skin. This is the vital driving force for determining the permeation capability of vesicles through the skin. Occlusion prevents water evaporation from the skin and affects hydration^37,48.

Surface charge and charge density:

Zeta sizer plays an important role in detecting surface charge and charge density of Transfersomes^37,49.

Viscosity measurement and rheological behaviour of transfersomal gel:

The determination of the viscosity of the different transfersomal gel is carried out at different angular velocities by using Brookfield viscometer at 32.0 ± 0.1°C⁵⁰. The rheological study of the transfersomal gel formulations is evaluated by using cone and plate viscometer. Different shear rate range shows different types of rheological behaviours at room temperature. Determination of the flow index and consistency index is performed by the Power law equation:

τ = Krn

Here, τ = shear stress, K = consistency index, r = shear rate, n = flow index

Let’s take log on both sides, Log τ = Log K + n log r

Rheological behavior is determined by the plotting of log of shear rate versus the log of shear stress. Here, the flow index is calculated from the slope of the plot, and the consistency index is calculated from the Y-intercept.

In vitro drug release studies through semi-permeable membrane:

Semi-permeable membrane or Franz Diffusion cell is used to evaluate in vitro permeation study of the drug from transfersomal gel formulation. Before the study, the Franz diffusion cell or semi-permeable membrane must be validated. Diffusion cell apparatus is used to mount on the cell and apparatus have a diffusion area of 2.303 cm². The receptor compartment contains phosphate buffer at pH 7.4. The agitation speed for the receptor fluid is 100 rpm, and throughout this process, temperature should be maintained at 37 ± 0.5°C. In the donor compartment, different transfersomal gels are applied through semi-permeable membrane. At the perfect time interval, sample aliquot is replaced with an equal amount of fresh diffusion medium. Finally, the cumulative amount of the formulation that shows permeation ability through the membrane is determined and represents a graph plot against time^31,41.

Release kinetics:

A graph is plotted for different kinetic models following the report of in vitro permeation study. Zero-order kinetics display the cumulative percent of drug permeated versus Time and first-order kinetics display the log cumulative percentage of drug remaining versus Time graphical representation. Higuchi’s model displays a graphical representation of the cumulative percent drug permeated versus square root of time. The drug release mechanism can be calculated by putting data to Korsmeyer- Peppas equation which displays a graphical representation of the log cumulative percentage of drug released versus log time. The value coming from the slope of the straight line is applied in exponent n detection. The diffusion mechanism is known as fickian when n=0.5 and the mechanism is non-fickian when it is 0.5<n <1.0. If n = 1 it is Case II (relaxational) transport and if n > 1 it is super case II transport⁴².

Ex Vivo Drug Permeation with the Utilization of Franz Diffusion Cell:

Preparation of Wistar rat skin to study skin permeation:

Hairless animal skin is essential for drug permeation study. An animal hair clipper is needed to remove hair from the dorsal skin of the sacrificed animal. After eliminating subcutaneous tissue and residual adhering fat of the dermis are rinsed properly with isopropyl alcohol. The animal skin is cleaned effectively with Phosphate Buffer Saline pH 7.4. Utilization of aluminium foil helps to wrap the skin thoroughly and the skin is stored in a deep freezer (−20°C)⁴².

Skin permeation studies:

Depending on the evaluation report such as drug content, entrapment efficiency, and permeation of different transfersomal formulations skin permeation studies are performed. The animal skin is utilized for this evaluation by using Franz Diffusion cell. The cumulative amount of drug permeated through the skin is determined with a drug solution, transfersomal suspension, and control gel. The evaluation reports are compared with each other. Graphical representation of the cumulative amount of drug permeated through the skin against time is plotted and the flux is detected by calculating the amount of drug permeated unit cm² unit hour⁴².

Skin irritation studies:

The utilization of the Ammar technique is for detecting the hypersensitivity reaction on the skin in skin irritation studies. There are four groups of guinea pigs (three animals in each group). Here, the first group of animals is known as the control group. There is no drug distribution for the control group. Transfersomal gel (dose equivalent 10 mg/kg) and control gel are delivered to the second group and the third group respectively. And the last group will consume a drug solution for 7 days continuously. Here, a score displays quality and quantity such as 4 stands for scar formation and severe erythema and edema, 3 stands for moderate, 2 stands for well defined, 1 stands for slight, and 0 stands for none⁴³.

Stability Studies:

Stability is a condition of being stable. When a formulation persists the same, the formulation is stable. There is no change within the physical, chemical, toxicological, and therapeutic properties for a specified period of time. Room temperature must be controlled for the optimized formulation of transfersome, is kept in glass vials. The formulations are stored in a refrigerator at 4–8°C for 3 months. There are some specifications such as drug leakage, morphology, and drug entrapment are determined with specified pre-determined time intervals like at 0, 15, 30, 45, 60, 75, 90 days continuously⁴⁴.

In vivo studies using the modified forced swim model test (FST):

Three groups of Swiss mice (three mice in each group) are individually compelled to swim inside vertical Plexiglas cylinders consisting of water and temperature is controlled at 25 ± 2°C. The height of the cylinder is 60 cm and the width is 20 cm. Water is filled up to 30 cm of the height of the cylinder filed so that the mice do not get any support by using their paws or tail. Here, the first group of animals is known as the control group. There is no drug distribution for the control group. Transfersomal gel (dose equivalent 10 mg/kg) and control gel are delivered to the second group and the third group respectively. The FST has two phases: An initial 15 minutes pretest is essential at the first phase of FST. The second phase is for only 5 minutes test after 24 hrs of the pretest. Taking out the mice is an important step after every session. Then the mice are dried properly. After that, they and spotted into heated cages for 10min, and again placed to their cages. All specifications such as swimming, struggling, and the total duration of immobility are determined by the second phase of the test for 5 minutes. If the mice show swimming capability, it is named as swimming. The movement of mice by their forepaws inside and outside of the water, it is called as struggling. When the mice are steady in a particular position but they can float upright position of the water and head will be above water, then the mice are recognised as immobile⁴⁴.

Statistical analysis:

Student’s unpaired t-test is essential for the statistical analysis. Results from the slope of the linear portion of the cumulative amount permeated versus time Steady-state flux can be detected. Lag time (T_lag) calculation is done after the extrapolation of the linear portion of the cumulative amount permeated versus time curve to the abscissa. The progressed ratio of the flux (E_pen) can be determined as: E_pen = P_treatment/ P_control

Here, the flux of formulation is P_treatmentand the flux of the control group is P_control⁴².

Applications of Transfersomes:

Enormous molecular weighted substances such as insulin, interferon, protein, peptides, steroids, etc can be effortlessly transported across the skin in the form of transfersomes. They are used as a carrier to deliver large molecules through the skin. Large molecules will not disintegrate in the GI tract, they are not administered orally. Since transfersomes get equal bioavailability in comparison with a subcutaneous infusion. Transfersome consisting of human serum albumin exhibits effective response when it is administered through the transdermal route.

Drug coupled with transfersome offers minimum clearance through blood vessels, transfersome shows maximum activity when it is delivered in the peripheral subcutaneous tissue. Transcutaneous delivery offers better activity as compared to other routes such as the hepatitis-B vaccine and zidovudine displayed 12 times higher AUC and higher bioavailability. NSAIDs may cause various GI symptoms. So, they can be overwhelmed by transdermal conveyance by transfersomes – ultra deformable and flexible vesicles. The transfersomal formulation revealed their improved immune response by epicutaneous application such as immunogenic bovine serum albumin loaded transfersomes exhibit active immunological activity^45,46.

Longer exposure in the sun may cause Actinic keratosis. That basically found on the chest, face, balding scalp, neck, the back of arms, shoulders, and hands of adults. Actinic keratosis can be painful or itchy. It can be treated with diclofenac loaded transferosomal gel and ingenolmebutate gel^47,48. Basal cell carcinoma is popular in the white skin population most importantly in the USA, Australia, South Wales, etc but it is uncommon in dark skin races. Fadel et al. reported that indocyanine green can be used within a transfersome to treat this type of disease^49,50. Kaposi’s sarcoma (KS) was first found by Moritz Kaposi in 1872. At that time KS remains a rare tumor. KS associated with immunosuppression in a renal transplant patient was first found in 1969. This deformable nanovesicles loaded with paclitaxel can be used to treat this condition⁵¹.

Table 1: Lists of recent researches on transfersome⁵¹

Drugs	Therapeutic Category
Doxorubicin hydrochloride (DOX), 5-Fluorouracil, Gemcitabine, Raloxifene hydrochloride, Celecoxib, Vinblastine	Anticancer
Diclofenac Sodium, Piroxicam, Ketoprofen, Tanshinone	Non-steroidal anti-inflammatory drug (NSAID)
Osthole	Anti-fibrotic, anti-inflammatory
Itraconazole, Terbinafine, Bifonazole, Ketoconazole, Miconazole Nitrate, Fluconazole	Antifungal
Timolol maleate,	Non-selective β-adrenergic receptor antagonist
Asenapine Maleate, Sertraline	Antipsychotic
Capsaicin	Antiarthritic
Cinnamic acid	Anti-inflammatory, Antioxidant
Catechin, Dipotassium Glycyrrhizinate, Etoricoxib, Curcumin	Anti-inflammatory
Ketotifen	Antihistaminic
Metronidazole	Anti-amoebic
Sildenafil	Anti hypertensive
Clindamycin Phosphate	Antibiotic
Insulin, Repaglinide	Anti diabetic

CONCLUSION:

Transfersomes are flexible vesicles and capable of crossing skin pores which are narrower than their size. They easily can cross stratum corneum and exhibit better therapeutic action. It is already proved that transfersomes can deliver maximum amounts of therapeutic agents through the skin. Ketoprofen and insulin are the most promising transfersomal formulation available in the market and this formulation enhances their therapeutic activity. Transfersome is useful for cancer treatment such as melanoma, AKs, SCC, KS, and basal cell carcinoma. Researchers have indicated that various types of Transfersomes will be developed and offered for potential dermal and transdermal applications.

CONFLICT OF INTEREST:

The authors declared that there are no conflicts of interest related to this article.

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Received on 03.10.2020 Modified on 24.05.2021

Research J. Pharm. and Tech. 2022; 15(6):2793-2800.

DOI: 10.52711/0974-360X.2022.00467