Nanoscale Navigation: A Review On Transfersomes for Transdermal Drug Delivery

Girisha Chaudhari¹*, Sofiya Morris¹, Dr. Ashish Jain².

 1. Department of Pharmaceutics, Shri D. D. Vispute College of Pharmacy and Research Center, New Panvel- 410 206, Maharashtra, India

2. Pharmacognosy and Phytochemistry, Shri D. D. Vispute College of Pharmacy and Research Center, New Panvel- 410 206, Maharashtra, India.

*Correspondence: girishachaudhari111@gmail.com

INTRODUCTION

To achieve high therapeutic activity and patient compliance, a unique kind of pharmaceutical delivery system is being created. Numerous drug delivery techniques have been developed as a result of improvements in therapeutic activity; nonetheless, there are unresolved issues with some of these systems. Orally administered drugs face harsh environment in the gastrointestinal GI tract, where the majority of medicines deteriorate under a variety of pH conditions, have challenges with solubility and most importantly, experience first-pass metabolism. The negative effects of intravenous formulation include the absence of medication reversal, hypersensitive response, and the possibility of infection, embolism, and expense. Certain medications have an unpleasant taste, and the process of swallowing such a bitter medication in oral delivery, as well as the pain associated with the needle in parenteral delivery, minimizes adherence by patients [1]. Recently, the route via the skin has emerged as one of the most effective and creative domains of concentration for drug delivery research, with over 40% of medication candidates undergoing clinical assessment with epidermal or topical systems which minimizes the side effects of other conventional routes [2].

During therapy, the novel drug delivery system is designed to deliver the medication concerning or as required by the body. These vesicles are described as “Bingham bodies” and were initially identified as having a biological basis by Bingham in 1965. Vesicular drug delivery approaches have been shown to enhance the solvency, stability, biodegradability and therapeutic index of drug molecules. Targeted vesicles can be divided into different types based on their composition such as lipoidal bio carriers targeted at homogeneous sites: Liposomes, niosomes, emulsomes, enzymosomes, ethosome, sphingosome, transferosome, pharmacosomes and virosomes [3].

In 1991, for the first time, Gregor Cevc came up with the term “Transfersomes” and concept. A complex aggregate with great adaptability and stress response is called a transfersome. The most preferred configuration is a versatile vesicle that encloses an aqueous interior within a complex phospholipid bilayer. The form of the bilayer and its local composition are intertwined to ensure that the vesicle can act as a self-organizing and self-regulating entity. This makes it possible for Transfersomes to be used as drug carriers for non-invasive site-directed drug delivery and controlled release of therapeutic agents after transit through various types of transport barriers [4]. It is generally recognized that traditional liposomes can only penetrate outer stratum corneum layers thus limiting their ability to target drugs or cosmetics in the skin. However, Transfersomes are alleged to be able to cross intact skin layers as complete vesicles until they reach the systemic circulation. Also identified as deformable vesicles, it was proved in vitro that Transfersomes enhance percutaneous absorption of several drugs [5].

The German company IDEA AG trademarked the term Transfersome (based on a patented technique for controlled drug delivery) since Trans refers to ‘carrying-body’, and the name is a fusion of the Latin verb transferre, this implies ‘to carry across’, and the Greek word some, which ‘Implies body’.  A synthetic vesicle called transfersomes mimics cell vesicles character and it’s therefore a very good candidate for regulated, and perhaps targeted, drug-administration [6]. In 2007 the Swiss regulatory body (Swiss medic) authorized the commercialization of the NSAID Ketoprofen in a transfersomes formulation under the brand name Diractin. Both liposomal and niosomal delivery techniques have low skin permeability, vesicle rupture, drug leakage and vesicle aggregation and fusion which makes them not suitable for transdermal administration.  A new ‘Transfersome’ carrier technology that can carry high and low molecular weight drugs – Trans dermally has just been described to overcome these issues [7].

Structure and Composition of transfersome: A lot of phospholipids, surfactants and alcohol and colorants, buffering agents are used in the formulation of transfersomes. Below all ingredients are included in the formulation of transfersomes.

1.        The main component is Phospholipids, it is a vesicle forming Components. For egg. Soya phosphatidylcholine, egg phosphatidylcholine, dipalmitoyl phosphatidylcholine.

2.        The second most important component is the Surface active agent that provides flexibility to the membrane. For that, we can use sodium cholate, sodium deoxycholate, tween 80, and span 80.

3.        For a solvent Alcohol can be used like ethanol or methanol.

4.        As a hydrating agent buffer solution can be used like saline phosphate buffer, tris buffer (pH 6.5)

5.        For better Confocal Scanning electron microscope study pigments can be used like Rhodamine-123, Rhodamine DHPE and Nile red.[7]

Figure 1. Structure of transfersome

MECHANISM OF ACTION: [8]

1.        The lipid vesicles move to a greater water concentration as a result of the interplay between the lipid residue and adjacent water, which attracts water molecules and results in hydration.

2.        The transdermal osmotic gradients produced the disparity in water content between the dermis and epidermis enabling transfersome to enter into skin.

3.        Medicate entrance instrument the strategy of sedate infiltration may be partitioned into three categories.

4.        Transfersome cause hydration by pushing their way through the skin’s hydrophilic pores, resulting in the slow release of the drugs that attach to be intended organ.

5.        Transfersome works as penetration enhancers by disturbing the intercellular lipids within the stratum corneum, thereby widening pores and facilitating molecular interaction into the framework.

Figure 2.  Mechanism of action

Advantages: [9]

Without experiencing appreciable loss, transfersome deformed and flow through thin constrictions

1.    Entrapment efficiency of lipophilic medicines are nearly ninety percentage.

2.    More deformability facilitates easier penetration of intact vesicles.

3.    They may transport drugs with low and high molecular weight, including Insulin, gap junction protein, reproductive hormones, analgesics, anesthetics, corticosteroids and albumin.

4.    A range of medical chemicals with different degrees of solubility may be held by transfersome because of their architecture, which is composed of both hydrophobic and hydrophilic moieties.

5.    Act as sustained as a depot for a longer duration of time.

6.    For systemic as well as topically applicable.

7.    Due to their natural phospholipid composition, which resembles liposomes, they are both biocompatible and biodegradable.

8.    They prevent the metabolic breakdown of the medicine enclosed.

9.    Scaling up straightforward activities that don’t need any tedious procedures, needleless usage or modifications unsuited for pharmaceutical application is simple.

Disadvantage: [9]

1.    Prone to chemical instability as a result of oxidative degradation.

2.    One of them is that the natural purity of phospholipids works against transfersomes as a delivery system.

3.     Preparations for transfersomes are costly.

METHOD OF PREPARATION

1.                  Thin film hydration method: First mix phospholipids in a ratio of chloroform: methanol and add a drug and bit of edge activator in a set ratio. Then, let the mixture dry under a vacuum to get rid of all liquid and convert it into a thin film. This leaves a thin layer at the flask bottom, which is further hydrated with buffer and let for one day for swelling at room temperature. Formed dispersion can be checked under an optical microscope or TEM. These dispersions passed through a polycarbonate membrane, size between 220 to 450 nm. Sonicate based on the desired size [10].

Figure 3. Thin film hydration method

2.                  Vortexing sonication method: The Vortexing sonication method begins by blending phospholipids, the active pharmaceutical compound and an edge activator within a phosphate-buffer saline (PBS) solution. This mixture is then subjected to Vortexing until it achieves a homogeneous milky white suspension. Following vortexing, the suspension undergoes sonication for a brief period. Subsequently, the sonicated suspension is extruded through a polycarbonate membrane filter with pore sizes as small as 100 nanometers [11].

Figure 4 Vortexing Sonication method

3.                  Ethanol infusion method: Phospholipid, active substances and an edge activator are dissolved under magnetic rotation for a predetermined amount of time until a clear solution is obtained, which creates the organic phase. Simultaneously, water-soluble components are dissolved in a phosphate buffer solution to create an aqueous phase. After that, both solutions are heated to a 45-50 o C range. Next, with continuous stirring, the phospholipids solution is progressively added to the aqueous solution after that, the dispersion is moved to a vacuum evaporator where it is sonicated to reduce the size of the vesicles and make it easier to remove the ethanol. [12]

Figure 5. Ethanol injection method

4.                  Freeze-thaw method: This process involved subjecting a suspension of multilamellar vesicles to a sequence of altering cycles of freezing at cryogenic temperature and then exposing the suspension to elevated temperature. Following preparation, the suspension is placed into a tube and submerged in a water bath set at a high temperature to facilitate thawing. This cycle is repeated approximately eight or nine times. [13]

Figure 6: Freeze-Thaw method

5.                  Reverse phase evaporation method: Lipids dissolved in organic solvents are transferred into a round bottom flask. Nitrogen purging is done, followed by introducing an aqueous medium containing edge activators. The drug can be added to either an aqueous or lipid medium depending on solubility characteristics. The mixture is then sonicated until it becomes uniformly dispersed and remains stable for at least thirty minutes post-sonication. Next, the organic solvent is removed under reduced pressure, forming a thick gel followed by vesicle formation. Centrifugation or dialysis can be used to remove non-encapsulated and leftover solvents.[13]

Figure 7. Reverse Phase evaporation method

FACTORS AFFECTING TRANSFERSOME: Numerous process factors may have an impact on the transfersome qualities throughout the process of creating an optimal formulation. These factors mostly relate to the production of transfersomes formulations, which are denoted by the following,

1.                  Effect of Phospholipids: Edge Activator: The characteristics of vesicles, such as their size, charge and ability to entrap drugs are influenced by various factors. These include the concentration of surfactant, length and number of carbon chains in the surfactant molecules, hydrophilic nature of the head group and competition for space within the lipid bilayer and surfactant hydrophilic-lipophilic balance HLB value. Generally, higher surfactant concentration, longer and more numerous hydrocarbon chains, greater hydrophilicity of the head group and higher HLB value lead to smaller vesicle size being produced [14].

2.                  Effect of various solvents: There are several solvents utilized including methanol and ethanol. The compatibility of formulation ingredients with the solvent and their solubility in it determine which solvents are the best. For optimal film-forming capability and enhanced stability upon hydration, it is desirable for all components, including the drug and excipients, to fully dissolve in the solvent, resulting in a clear and transparent solution. The formulation's solvents may also serve as penetration enhancers, increasing the drug concentration flow across a membrane. William and Barry (2004) report that ethanol was employed in several trials to increase the flow of levonorgestrel, hydrocortisone, 5-fluorouracil and estradiol through rat skin. [15]

3.                  Impact of different edge activators (surface active agents): Transfersomes, being meticulously optimized ultra-flexible lipid vesicles, process the unique ability to swiftly deform under external pressure. This characteristic facilitates their passage through skin pores, which are notably smaller than the vesicles themselves. Specific edge activators, along with their respective concentration are crucial for maximizing membrane deformability. This improvement is credited to the combined efficacy of transfersome in serving as both drug carriers and enhancers of permeation.[16]

4.                  Effect of hydration medium: The choice between saline phosphate buffer with a pH range of 6.5-7 and water serves as crucial for achieving an optimal balance in the formulation characteristics, biological applicability and delivery method. Maintaining an appropriate pH level in the hydration medium is essential to ensure that medication remains in its unionized form, thereby enhancing its entrapment within transfersomes and facilitating penetration through the cellular membrane. This is particularly significant due to the similarity between the lipid bilayer of the transfersome and the phospholipid layer of the cell membrane, enabling intracellular transportation of the medications. [15]

CHARACTERIZATION OF TRANSFERSOME:

1.                  Entrapment Efficiency: The centrifuge technique was used to calculate the percentage entrapment efficiency. 10 ml of PBS pH 6.8 or 7, was used to distribute 100 mg of the transfersomal formulation after it had been weighed. The resultant transfersomal mixture was centrifuged for 40 min at 10000 rpm. The amount of free drug can be determined using the clear fraction or supernatant. The concentration of the medication in the resultant solution was measured at that wavelength using UV spectrophotometer. The following formula was used to determine the % of drug encapsulation.

Entrapment Efficiency % = [Ct- C f / C t]*100

Where C t is the concentration of the total drug

                                  C f is the concentration of the entrapped drug [17, 18]

2.                  Vesicles size distribution and zeta potential analysis: Vesicles were analyzed using Zetasizer which revealed information about average diameter, size distribution profile and zeta potential was examined to determine the penetrative ability of transfersome by an assessment of their colloidal characteristics and vesicles durability.[19]

3.                  Degree of deformability: Transfersomal formulation deformability research was conducted using a home build apparatus against conventional liposome preparations. The experiment involved forcing vesicle suspension through a polycarbonate filter, quantity of suspension and tracking size before and after filtering. The degree of deformability was determined using a formula,

D= J*(r v/ r p)2

Where, D= deformability of vesicle membrane

             J= amount of suspension

            R v = size of vesicles after pass

            Rp = pore size of the barrier [20]

4.                  Turbidity and vesicle diameter: The opacity of various elastic liposomal formulations was gauged utilizing a Nephelometer with PBS pH 6.5 or 7 acting as the comparative standard. To ascertain the vesicle diameter, either Dynamic Light Scattering (DLS) or photon correlation spectroscopy techniques were employed. Post preparation in distilled water filtration through a 0.2-micrometre membrane filter, the sample underwent dilution with filtered saline before undergoing size assessments through DLS or photon correlation spectroscopy methodologies. [21]

5.                  Number of vesicles per cubic mm: For optimization of composition and another variable, this parameter holds significant importance. Haemocytometers present a viable option for diluting transfersome formulation (sans sonication) by a factor of five in a 0.9 % sodium chloride solution, facilitating optimal microscopy investigation.[21]

6.                  Stability: The specimens were kept between 4 and 25 degree Celsius for 21 days to assess the stability of the chosen transfersomal formulation and ascertain the values of EE, ZP, VS and PDI at certain intervals (0,7,14 and 21 days). [22]

7.                  In vitro study (Drug release kinetics): This study was conducted to measure the amount of drug-permeated hairless rat skin using Franz diffusion cell. The skin was clamped between the cell’s Donor and receptor compartments, filled with phosphate buffer saline and elastic liposome respectively. The cell was maintained at 37± 1 degree Celsius and samples were taken out every 24 hours. The HPLC technique was used to measure the medication’s penetration. The steady-state penetration rate, lag time and slope of the linear pattern were calculated. [23]

8.                  Confocal laser scanning microscopy study (CLSM): To thoroughly examine the structure and function of the skin. CLSM was coupled with novel skin-staining techniques based on fluorescent, highly deformable vesicles i.e. transfersome applied topically. This made it possible to distribute labels in the fluorescent mode and examine skin structure in the reflected mode at the same time [24].

APPLICATIONS:

1.                  Delivery of anti-oxidant drugs:

Resveratrol is one type of polyphenol with anti-inflammatory, antioxidant, anti-allergy and anticancer qualities which is unstable under environmental conditions. So, transfersome offers a solution for its protection. The author's findings indicate that transfersome effectively enhances the stability, solubility, bioavailability and safety profile of resveratrol. Consequently, the potential integration of it into cosmetics, food products and pharmaceuticals holds promise as a viable formulation strategy in the future. [25]

2.                  Delivery of insulin:

Cevc G et al, in 1998 reported that insulin, the therapeutic chemical can be delivered transdermal without intrusive procedures via transfersome. They produce clinically substantial hypoglycemia in humans and rats with high repeatability and effectiveness when loaded with insulin and administered in a tolerable quantity. [26]

3.                  Delivery of protein and peptide:

Conjugation of proper moieties with the protein, such as conjugating a protein with PEG, which increases the protein solubility and shields it from enzyme degradation, can also change the biopharmaceutical characteristics of protein or peptides. Another method for changing the pharmacokinetic and pharmacodynamic properties of proteins and peptides is protein lipidization. For effective therapeutic effects, several innovative drug delivery methods can be researched for protein and peptide administration via buccal and transdermal route [27]. Large protein molecules and other physiologically active compounds are soluble in lecithin organogels while maintaining their original structure and characteristics. The lecithin gels micelles, for instance, solubilize a sizable quantity of ascorbic acid and hydrophilic acids without distorting them. [28]

4.                  Delivery of Corticosteroids:

The Corticosteroids have also been delivered via transfersome. By maximizing the amount of medication applied topically, transfersome enhances the site specificity and overall drug safety of corticosteroid administration into the skin. The biological activity of transfersome-based corticosteroids can be achieved at doses many times lower than those of the formulation now in use to treat skin conditions. [29]

5.                  Delivery of Interleukins:

A naturally occurring protein having antiviral, antiproliferative and some immunological modulatory qualities leukocyte produces Interferon. Transfersome have also been used to carry interleukins and interferon. Medicament delivery technologies like transfersome may be able to stabilize labile medication and offer regulates release of the administered medicament. The production of interleukins 2 and interferon-containing transfersome for potential transdermal use. They said that they provided transfersome-trapped IL 2 and INF at concentrations appropriate for immunotherapy. [30]

6.                  Delivery of NSAIDs drugs:

During the preformulation phase, assessing the in vitro skin permeability of different vesicular formulations containing Diclofenac Sodium can aid in predicting the most suitable formulation for enhancing drug penetration through rat skin in topical applications. The author’s results demonstrated that the vesicular system, especially when incorporated into gel formulation, exhibited significantly increased permeability. [31]

7.                  Delivery of anesthetics:

Matthew Robert et al, reported a sustained-release lidocaine delivery method by preparing transfersome. They were prepared by using the basic method of lipid film hydration techniques. [32]

8.                  Delivery of herbal drugs:

The researcher investigated the potential of transfersome to facilitate the transport of Eulophia macrobulbon (EM) extract across the membrane, focusing on its traditional use in Thai medicines for treating gangrene. Their finding indicates that the formulated transfersome significantly improves the skin penetration of EM extract. They explored various factors influencing transfersome properties and their ability to enhance skin penetration, including extract loading, type of phosphatidylcholine, the transition temperature of phosphatidylcholine and the hydrophilic-lipophilic balance (HLB) value of the surfactant. [33]

9.                  Delivery of Anticancer drugs:

The topical use of carvedilol as a skin cancer chemoprevention strategy. It talks about the creation and assessment of a transfersome system loaded with carvedilol for improved skin delivery using the thin film hydration approach. It was discovered that the transfersome method worked well to penetrate the skin, distribute it and stop the proliferation of skin cancer cells. Additionally, it was demonstrated that batch number F18 delivered carvedilol into the skin more effectively than free carvedilol. [34]

10.              Delivery of antihistamine drug:

Raut S et al, reported that the transfersome loaded with Ebastine by thin film hydration method exhibited the most entrapment efficiency, reaching 79.92 ± 1.19 %. The goal of the study is to better understand how to treat Urticaria by improving the bioavailability of a transfersomal nano gel loaded with ebastine. [35]

LIST OF DRUGS FOR TRANSFERSOME:

CONCLUSION:

In practical research, nano lipid carriers are being extensively studied and used for transdermal and transcutaneous delivery system over the Horney layer. Because of their notable action, ultra-deformable vesicles such as transfersome readily surpass the limitation of standard liposomes and reach the deeper layer of skin. The presence of surfactant in transfersome, which helps to provide flexibility for penetration is responsible for the deformability feature. It is still necessary to work on creating these novel capsules and developing them from the pilot size to the big industrial scale to ensure that the final product maintains its particle dimensions, hardness and encapsulation. Although the suitability of transfersome has been confirmed by previous clinical experiments, further research is needed to develop novel strategies for combining these approaches with other technologies that are used to improve penetration and patient compliance. 

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