Transfersomes: Pioneering Nanocarriers for Enhanced Drug Delivery

Rutuja Kadam , Dr. Avinash Hosmanii , Sampada Potdar, Rutuja Savakhande , Shweta Patil,

doi:10.5281/zenodo.14950131

Review Paper | Open Access
Volume 03 | Issue 03 | Article Id IJPS/250302194

Transfersomes: Pioneering Nanocarriers for Enhanced Drug Delivery
Rutuja Kadam * Dr. Avinash Hosmanii Sampada Potdar Rutuja Savakhande Shweta Patil
Department of pharmaceutics, Government College of pharmacy karad

Abstract

The advantages of transdermal drug delivery over traditional methods make it seem like the most important drug delivery method. There are several ways to boost transdermal delivery, including as iontophoresis, electrophoresis, sonophoresis, microneedles, vesicular systems (liposomes, niosomes, and elastic liposomes like ethosomes and transfersomes), and chemical permeation enhancers. The transfersomal system outperformed all of these tactics in terms of efficiency. An edge activator and a lipid bilayer containing phospholipids make up the ultradeformable vesicles known as transferosomes. Transferosomes are more effective than liposomes at delivering higher concentrations of active substances to deeper layers of the skin following topical therapy. In general, molecules that weigh more than 500 Daltons are unable to pass through skin. Consequently, only a few drugs can be administered by this method. Therefore, the medication can be encapsulated in a transferosome to resolve this problem. This paper attempts to clarify the idea of transfersomes, the process, several ways to prepare and manufacture materials, characteristics that affect transfersomes, and their most recent uses in the delivery of pharmaceuticals.

Keywords

Transferosomes, Phospholipid, Edge activator, Vesicular drug delivery system

Introduction

In addition to intravenous and oral methods, transdermal administration is another practical and appropriate way to provide medications. Patients are spared the agony of intravenous injections, and it is especially necessary for diseases involving motion sickness, nausea, and vomiting. ^[¹^,²^] The transdermal route offers a number of benefits over other conventional routes, including preventing liver metabolism, reducing undesirable side effects, delivering drugs efficiently with a short half-life, improving pharmacological and physiological response, reducing blood level fluctuations, and most importantly—improving patient compliance. ^[³^,⁴^] One of the main issues with dermal and transdermal drug delivery methods is the permeability of the stratum corneum. Made up of flattened, keratinized epidermal cells, the stratum corneum is the outermost layer of the epidermis. Chemical transfer is hampered by watertight cells with a strong, flexible membrane, making this mode of administration inadequate for therapeutic use. A new method for getting beyond the stratum corneum barrier without damaging it is to encapsulate the medication in a vesicular system. Vesicles are composed of an interior hydrophilic core enclosed in a bilayer wall of phospholipids or surfactants, according to structural analysis. Many researchers have introduced different types of alterations to make a novel vesicles which have significantly improved their penetration across the entire skin. A few examples of such modified vesicles include transferosomes, invasomes, flexosomes, ethosomes, menthosomes & niosomes^.[⁵^] Using a specific type of composite body called "transferosomes" and rational membrane design, a novel vesicular drug carrier system is created. Transfersomes are the most promising way to build an unique dosage form that delivers the medicine slowly and safely with minimal side effects. Transferosome is a trademark of IDEA AG and refers to patented drug delivery. The name is a mix of transfero and soma. Transferosome means to carry across in Latin, and soma means body in Greek, therefore it is a “carrying body”. Transferosomes are artificial vesicles meant to mimic a cell vesicle or a cell in exocytosis, making them ideal for controlled and potentially targeted medication delivery^[6].

TRANSFEROSOMES:

The term "Transfersome" refers to an artificial vesicle that is intended to mimic the properties of a cell vesicle or a cell that is exocytosing, making it appropriate for controlled and possibly targeted drug administration. An extremely flexible and stress-responsive complex aggregation, a transfersome is a highly deformable vesicle with an aqueous core encased in a complex lipid bilayer. Because the structure of the bilayer and the local composition are interdependent, the vesicle is self-regulating and self-optimizing. This makes the transfersome more capable of successfully navigating a range of transit obstacles. ^[7]

Transdermal delivery makes drug distribution simple, which makes it a desirable approach. In cutaneous and transdermal drug delivery systems, the stratum corneum permeability is a major issue. The stratum corneum, which is formed of flattened, keratinized epidermal cells, is the outermost layer of the epidermis. The robust, flexible membrane of watertight cells prevents the transmission of chemicals, making this mode of administration inadequate for therapeutic use.^[8] In order to get across the barrier of skin penetration, transfersomes squeeze themselves along the stratum corneum's intracellular sealing lipid. This is allowed for by the high vesicle deformability, which allows entry owing to the surrounding mechanical stress in a self-adapting way^.[9]

HISTORICAL BACKGROUND:

Cevc^[10]chased the term" transferosome," which refers to the first generation of ultra deformable vesicles and has been the focus of multitudinous patents and publications since the 1990s Transfersomes, a trademark of IDEA AG, Munich, Germany). The skin saturation and penetration of these elastic vesicles affect from a synergic medium among the carrier parcels and the access enrichment capability. Transfersomes are supramolecular, ultradeformable lipid packets of summations made up of at least one interior waterless member girdled by a lipid bilayer with acclimated characteristics that are suitable when surfactants( edge activator( EA)) are present in the vesicular membrane. Although liposomes are generally allowed to only access the remotest subcaste of the stratum corneum, giving them a localizing effect for medicines or cosmetics within the skin, transfersomes are said to inoculate as complete vesicles through the layers of the skin to the entire rotation. On the base of confirmation, thenon-steroidalanti-inflammatory drug( NSAID) ketoprofen was successful and veritably well- liked by consumers. Swiss Croaker, a nonsupervisory body in Switzerland, approved ketoprofen in 2007. It was retailed under the brand name" Ketoprofen transdermal" and produced by" IDEA AG" medicinals Pvt. Ltd^{.[11- 15]}

COMPOSITION OF TRANSFEROSOMES^.^[16]

Despite TFS's enhanced stability profile, this deformable nanosystem is mostly made up of a number of components.Nevertheless, some are used in the synthesis of TFS, while others, including phospholipid and edge activator, are essential for maintaining its structural integrity and are covered in depth below.Table I is a list of all the frequently used ingredients for TFS production.

Table 1: Composition Of Transferosome

Examples	Class	Uses

Egg phosphotidylcholine,soya phosphotidylcholine,dipalamitoyl phosphotidylcholine.	Phospholipid	Vesicle forming agent.
Sod.cholate,sod.deoxycholate,Tween 80,span 80,Tween 20	Surfactant	Vesicle forming componenent (edge activator)
Ethanol,Methanol,Choloroform,Isopropyl Alcohol	Solvent	As a solvent
Saline phosphate buffer(pH 6.4),Phosphate Buffer (pH 7.4)	Buffering agent	As a medium

ROLE OF EACH INGREDIENT^{:[17,18,19,20,21,22,23]}

1.Phospholipid:

Amphipathic phospholipids (having both hydrophilic and hydrophobic parts) create vecicles by arranging themselves into a lipid bilayer in aqueous fluids.
The main component of phospholipids, which come in both hydrogenated and unhydrogenated forms, is phosphatidylcholine.
As opposed to hydrophilic medications, which are entangled in the core region of the vesicles facing the head section, hydrophobic drugs are caught in the tail portion of the phospholipid bilayer structure.
Phospholipids' fatty acid chains accelerate the production of bilayers, which leads to varying vesicle sizes depending on the method and energy intake.

2.Edge Activator:

The three primary characteristics of vesicles that are impacted by edge activators are vesicular size, entrapment efficiency, and elasticity.
Diclofenac sodium-loaded TFS were made and refined with various edge activators.The formulation included bile salts, spans, and tween as edge activators.
Maximum deformability was demonstrated by the formulation, made with 85:15%w/w phosphatidylcholine:edge activator, regardless of the type of edge activators.
Tween 80 exhibited the maximum deformability or elasticity among EAs when compared to bile salts (sodium cholate and sodium deoxycholate) and spans (Span 80 and Span 85).
Moreover, it was noted in stability testing that EA with the highest elasticity demonstrated greater drug leakage because of the creation of temporary pores in lipid bilayers.
After 90 days, span 80 displayed the highest retained drug (70.53%) and tween 80 the lowest (48.01%).
Additionally, edge activators have an impact on the vesicles' entrapment effectiveness.
The formulation of griseofulvin was tuned for the types and concentrations of edge activator, and ultra-deformable liposomes were made.The maximum entrapment efficiency of 63.44 ± 0.45% was obtained for Span 85, followed by 59.36 ± 0.32% for Span 80, 55.52 ± 0.35% for Tween 80, and finally, 49.16 ± 0.56% for sodium deoxycholate.
Because spans are naturally lipophilic, they have a greater affinity for lipids, which leads to significant drug entrapment.According to reports in the literature, vesicles with edge activators that have lower HLB values are smaller.The observed correlation between vesicle size and edge activator HLB can be attributed to a decrease in surface energy.

STRUCTURE OF TRANSFEROSOME.

Figure 1: Diagrammatic representation of Transferosome

ADVANTAGES OF TRANSFEROSOME^{:[24,25,26,27]}

Because transfersome carriers contain both hydrophilic and hydrophobic moieties, they are a special kind of drug carrier system that can deliver therapeutic drugs with a broad range of solubility.
Transfersome carriers are very adaptable and effective in containing a wide range of drugs, almost regardless of their polarity, size, structure, or molecular weight.
High vesicle deformability allows for both topical and systemic therapies and makes it easier for medications to pass through the skin without causing any detectable loss of intact vesicles.
Transfersomes' ultra-deformability and elastic qualities allow them to squeeze over extremely tight skin barrier constrictions, such as those that are 5–10 times smaller than the vesicle diameter.
Preventing first-pass metabolism, a significant disadvantage in oral medication delivery, and maximizing the drug's bioavailability.
Reduce the drug's unwanted side effects and shield it from metabolic breakdown; additionally, short half-life medications are useful.

DISADVANTAGES OF TRANSFEROSOME^;[28]

The inability to get pure phospholipids is a disadvantage of using transferosomes; therefore, synthesized phospholipids can also be employed as a substitute.

The high cost of the technology and raw ingredients needed to make lipid excipients makes it costly to create transferosomes.
Barrier role of the skin changes with age and is different from person to person and from one site to another site of the skin on the same person.
There is a possibility of allergic reactions and skin irritation.

LIMITATION OF TRANSFEROSOME^;[29,30,31]

Transfersomes are prone to oxidative destruction, which makes them chemically unstable.

Transfersomes' use as drug delivery vehicles is further hindered by the purity of natural phospholipids.
The preparations of transfersomes are costly.

STRUCTURE OF SKIN;

About 15% of an adult's body weight is made up of the skin, making it the biggest organ in the body. Along with preventing excessive water loss from the body and playing a part in thermoregulation, it also protects the body from external physical, chemical, and biological threats. The mucous membranes that cover the body's surface are part of the continuous skin^.[32]An average adult's skin has a surface area of around 2 m2, absorbs almost one-third of the blood that circulates throughout the body, and acts as a permeability barrier to prevent the transdermal absorption of different biological and chemical agents. The underlying blood circulation network is isolated from the external environment by the skin. It acts as a defense against assaults from microbes, chemicals, and physical forces. It maintains body temperature by acting as a thermostat. In addition to protecting the human body from UV radiation, it is crucial for controlling blood pressure. The primary determinant of medication penetration and absorption via the dermis is the skin^{. [10]}

Despite having numerous histological and anatomical layers, skin is commonly described in terms of the three main tissue layers—the epidermis, dermis, and hypodermis.

Epidermis
Dermis
Hypodermis ^[34]

Figure 2: Structure of skin

Subcutaneous fat layer:

The layer that connects the dermis to the body's underlying tissues is called the hypodermis, or subcutaneous fat layer. This layer covers most parts of the body in a thick layer several centimeters thick. Insulation and mechanical protection against physical stress are the main functions of this layer of adipose tissue. Major blood vessels and nerves are delivered to the skin by the subcutaneous adipose layer, which may eventually offer a quick supply of high-energy molecules. ^[35]

Dermis:

The dermis includes sweat glands like eccrine and apocrine, pilosebaceous units like hair follicles and sebaceous glands, nerve endings, and blood and lymphatic arteries. It comprises the majority of human skin and gives the epidermis physiological support. This layer, which is typically described as simply gelled water, provides a slight barrier to the majority of polar drugs when it comes to transdermal drug delivery; nevertheless, when highly lipophilic compounds are being administered, the dermal barrier should be addressed.

Epidermis:

The epidermis consists of 10–20 cell layers. Additionally, this pluristratified epithelium contains Langerhans' cells, which are involved in immunological responses and antigen presentation, and melanocytes, which contribute to skin pigmentation. Like all epithelium, the dermal vascular network provides nourishment to the epidermis. Numerous layers make up the epidermis. Stratum germinativum is the most basic layer of the epidermis. Above the base layer are the stratum corneum, stratum lucidum, stratum granulosum, and stratum spinosum.

Stratum Corneum:

Multilayer corneocytes that are flat, polyhedral, nonnucleated, and 2-3 μm thick make up the stratum corneum, which is 10-20 μm thick. Mostly composed of insoluble bundled keratins, corneocytes are held together by covalently bound lipids and cross-linked proteins within a cell envelope. The membrane junctions known as corneodesmosomes serve to stabilize the stratum corneum by joining corneocytes. Lipids that comprise the intercellular gap between corneocytes are mostly derived by exocytosis of lamellar structures during keratinocyte terminal development.

To maintain the integrity of the epidermal barrier, these lipids are necessary. The stratum corneum serves as the skin's main defense against permeability and penetration. With a penetrating molecule that penetrates the watery environment of the underlying living epidermis and upper dermis as well as the lipophilic stratum corneum to reach the dermal vasculature, the skin can be conceptualized as a bilaminated membrane in the most basic sense.

HOW TRANSFEROSOME WORK? ^[9,36,37]

The presence of edge activators / surfactants plays a pivotal role in the enhancement of permeation of transferosomes topically & transdermally. Several researchers have reported the mechanism by which the edge activators/ surface active agents enhance the penetration of these vesicles^.[38,39,40]It has been reported that existence of particular molecular inclination of surfactants, supports the vesicles to pervade the SC and in due course upsurge the drug’s transdermal permeation^.[^40]

TRANSFEROSOMES VS OTHER CARRIER SYSTEM:

Liposome:

Research on liposomes for many decades has been conducted to provide the medications via topical and transdermal methods. However, because of their stiff shape, liposomes cannot enter the deeper layer of skin and instead remain atop the stratum corneum.Unlike liposomes, TFS can pass through the SC barrier and deliver medications to the skin's inner layers.The edge activator makes TFS more flexible than liposomes ^[41].According to a study comparing liposomes and TFS, the former had a lower entrapment efficiency (49.76 ± 2.71%) than the latter (81.97 ± 1.5%) ^[42]. In contrast to liposomes, TFS demonstrated greater entrapment efficiency and deformability, according to another study comparing the two^[43].

Ethosome:

Ethosomes can readily pass through the epidermal barrier and are also flexible.Ethosomes and TFS vary mostly in their vesicle makeup.Phospholipids and edge activators make up TFS, whereas phospholipids and ethanol make up ethosomes.Furthermore, ethosomes' increased ethanolic concentration may result in cutaneous irritation ^[44].

Micelle:

Furthermore, there are two ways in which TFS differ from mixed micelles.The body of a TFS vesicle is filled with water, whereas a micelle is just a fatty droplet.Thus, while mixed micelles can only entrap lipophilic medicines, TFS can transport both hydrophilic and hydrophobic medicines.In terms of size, TFS are typically one to two orders of magnitude bigger than typical lipid micelles ^[45].

Microneedle:

Although they both have the ability to deliver drug molecules into deep dermal tissue, TFS and microneedles have distinct methods of penetration. As the name suggests, the microneedle device consists of 10–50 µm wide and 10–2000 µm high micron-sized needles that are aligned on a patch ^[46]. TFS convey drug molecules across the stratum corneum, whereas microneedles send them directly into the tissues of the dermis, avoiding the stratum corneum barrier.There are further limitations related to the microneedle delivery system, including the possibility of localized inflammation at the application site, the danger of microneedle tip breaking, and skin irritation from an allergic reaction ^[47].

Hydrogel:

Due to physical or chemical cross-linking of the individual polymer chain, hydrogels are a three-dimensional (3D) system of hydrophilic polymers that can expand and retain a significant quantity of water while maintaining structure ^[48].Both hydrophobic and hydrophilic parts make into the structure of TFS, which allows them to carry both kinds of medicinal molecules.Since the hydrogels' structure is mostly hydrophilic in nature, they are incompatible with lipophilic medicinal compounds ^[49]. One similarity between TFS and hydrogels is that they both exhibit a high level of biocompatibility and biodegradability.

Cubosome:

Cubosomes are sustainable lipid-based nano-delivery systems made up of a stabilizing agent and phospholipid (such phytantriol and glyceryl monooleate) ^[50].However, TFS are made up of phospholipids (such as egg phosphatidylcholine and soy phosphatidylcholine) and edge activator.The findings of a published study comparing TFS with cubosomes revealed that TFS had a high entrapment efficiency of 84.20%, but cubosome vesicles only shown 59.82% entrapment ^[51].Similar to TFS, cubosomes function as drug repositories and offer focused, regulated delivery ^[52].

Figure 3: Transferosome Vs Other Carrier System

TRANSFEROSOME UNDER CLINICAL TRIAL:

A number of transfersome-based formulations are now being assessed at different stages of clinical studies. To treat osteoarthritis in the knees, for example, a phase III clinical trial was carried out to investigate the safety and effectiveness of ketoprofen integrated in transfersomes (Diractin®). It has been shown that the drug encapsulated in transfersomal carriers exhibits comparable fewer adverse effects and greater therapeutic efficacy in treating knee osteoarthritis pain over a six-week treatment period when compared to a placebo ^[53]. Similarly, topical application of insulin-loaded transfersomes (Transfersulin®) for hypoglycemic effects is being investigated under early-stage clinical trials. Transfersulin® was found to lower blood glucose levels in rabbits with alloxan-induced diabetes during the preclinical study ^[54]. A randomized controlled trial was conducted to evaluate the risk-benefit ratio of topical triamcinolone acetonide in transfersomes versus commercially available triamcinolone acetonidecontaining cream and ointment. It has been determined that the risk-benefit ratio of topical triamcinolone acetonide may be considerably enhanced by transfersomes ^[55]. As a result, transfersomes are recognized as the most exceptional and revolutionary transdermal medication carrier available today ^[56].

RECENT RESEARCH ACTIVITIES ON TRANSFEROSOME^:[57]

Table 2: Recent research activities on transferosome

Drug	Category	Therapeutic activity
Dexamethasone	Corticosteroid	Anti-edema activity
Diclofenac	NSAID	Formulation optimization
Tacrolimus	Immunosupressive	Atopic dermatitis
Pentoxifylin	Xanthinese derivative	Chronic occulusive arterial disease.
Eprosartan mesylate	Angiotensin receptor blocker	Management of Hypertension
Ciprofloxacin	Quinoline antibiotic	Otitis media
Timolol maleate	Non selective B adrenergic blocker	Management of hypertension
Ketoconazole	Azole antifungal	Antimicrobial activity
Diclofenac diethylamine,curcumin	NSAID and natural phenol curcuminiod	Analgesic and antiinflammatory
Itraconazole	Antifungal triazole	Formulation optimization
Parmomycin sulfate	Antibiotic	Cutaneous leishmanisis
Risperidone	Antipsychotic	Formulation optimization
Minoxidil and caffeine	Antihypertensive Vasodilator	Alopecia
Raloxifene hydrochloride	Selective oestrogen receptor modulator	Treatment of oesteoporosis
Sinomenine hydrochloride	Alkaloid	Rheumatism
Embelin	Benzoquinone derivative	Treatment of cancer
Stavudine	Reverse transcriotase inhibitor	Prevention and tratment of HIV/AIDS

PATENT ON TRANSFEROSOME^:[58]

Table 3: Some US Patent on transferosome

Application number of patent	Applicant	Result
US20020048596A1(2002)	Gregor cevc	The patent claim the use of nsaid in transferosome for transport through natural barrier and constriction of skin.
US7175850B2(2007)	IDEA,AG Munich(DE)	Described the administaration of corticosteroids via transferosome on mice skin for edema suppression activity. They were tested against commercial reference cream.
US20070042030A1(2007)	IDEA,AG Munich(DE)	It is non invasive and painless therapy,resulted in >90% of the applied drug dose reaching the desitend organ of the body.
US7591949 B2 (2009)	IDEA,AG,Munich (DE)	Claimed the penetrant capability of transferosome because these deformable complex droplets adapt the pore of the skin along the natural moisture gradient rather than coalescing locally.

METHOD OF PREPARATION OF TRANSFEROSOME ^{[59,60,61,62,63,64]}

1.Rotary Film Evaporation method:

2.Reverse Phase Evaporation Method

The design will now change to a viscous gel, and then the vesicles will be arranged. Dialysis or centrifugation can be used to make the nonencapsulated material and leftover solvents indifferentiable.

3.Vortexing sonication method:

4.Ethanol Injection Method

EVALUATION OF TRANSFEROSOME^:[65]

Transferosomes are referred to as liposomes, niosomes, or micelles. It is necessary to address the following transferosome characterisation requirements.

1.Vesicle size distribution and zeta potential; Vesicle size, size distribution, and zeta potential were evaluated using the Malvern Zetasizer Dynamic Light Scattering instrument.

(Total number of Transferosomes counted × dilution factor × 4000) / Total number of squares counted is the total number of Transferosomes per cubic mm.

2.Vesicle morphology: Number of vesicles per cubic mm: The dynamic light scattering (DLS) method or photon correlation spectroscopy may be used to measure the vesicle diameter. For photon correlation spectroscopy or dynamic light scattering (DLS) experiments, samples were prepared in distilled water, filtered through a 0.2 mm membrane filter, and then diluted with filtered saline. TEM, phase contrast microscopy, and other techniques can be used to view transferosome vesicles. By monitoring the size and shape of vesicles over time, one can estimate their stability. Whereas TEM looks for mean size, DLS looks for structural changes. This is an essential part of optimizing the process's composition and other components. Formulations of non-sonicated transferosomes are diluted five times in a solution of sodium chloride (0.9 percent). For additional research, an optical microscope and a hemocytometer may be employed. The following formula is used to count and compute the transferosomes in 80 tiny squares:

3. Entrapment efficiency. The proportion of medication entrapment is used to compute entrapment efficiency. A mini-column centrifugation technique was used to separate the unentrapped medication in order to ascertain the entrapment efficiency. 0.1 percent Triton X-100 or 50 percent n-propanol were used to rupture the vesicles during centrifugation.

The entrapment efficiency is expressed as:

4. Drug content : According to the pharmacopoeia drug's analytical method, one of the instrumental analytical techniques, such as the modified high-performance liquid chromatography method (HPLC) with a UV detector, column oven, auto sample, pump, and computerized analysis software, may be used to determine the drug content.

5. Degree of deformability or permeability measurement : Permeability analysis is one of the most crucial and unique features for characterizing transferosomes. The deformability test uses pure water as a control. The process of creating transferosomes involves passing them through a huge number of different-sized pores. Particle size and size distributions are recorded using dynamic light scattering (DLS) measurements following each pass.

6.Penetration ability : Fluorescence microscopy can be used to evaluate the penetration capacity of transferosomes.

7.Surface charge and charge density :. Zetasizer can be used to measure the surface charge and charge density of transferosomes.

8. In vitro drug release: The penetration rate is determined using an in vitro drug release research. Prior to more costly in vivo study, the formulation is optimized using data from in vitro trials, the time required to reach steadystate permeation, and the permeation flow at a steady-state. Transferosome suspension is incubated at 37°C for several hours in order to measure drug release. Samples are obtained at various points in time, and the free drug is separated by microcolumn centrifugation. The initial amount of drug entrapped is used as the starting point for an indirect calculation of the amount of drug released.

9.In vitro Skin permeation Studies :This study made use of a modified Franz diffusion cell, which has an effective diffusion area of 2.50 cm2 and a receiver compartment capacity of 50 ml. Goat skin was used in an in vitro drug research in a phosphate buffer solution (pH 7.4). The skin from the abdomen of a fresh goat that was acquired from the slaughterhouse was used for the penetration tests. A typical saline solution was used to moisturize the skin following the removal of the abdominal hairs.

The adipose tissue layer was removed by rubbing the skin’s adipose tissue layer with a cotton swab. The skin was maintained at 0-40°C in an isopropyl alcohol solution. The treated skin was placed horizontally atop the receptor compartment of the Franz diffusion cell, with the stratum corneum side looking upwards toward the donor compartment. The effective penetration area from the donor compartment to the receptor compartment was 2.50cm2, and the receptor compartment had a capacity of 50 ml. A magnetic bar was used to swirl 50 ml of phosphate-buffered saline (pH 7.4) into the receptor compartment at 100RPM.

The formulation was applied to the skin (equivalent to 10 mg of medicine), and the diffusion cell’s top was covered. 1 ml aliquots of the receptor medium were taken at regular intervals and replaced with an equal quantity of fresh phosphate buffers to maintain sink conditions (pH 7.4). Correction factors were used to compute the release profile for each aliquot. The materials were examined using any instrumental analytical approach.

10.Physical stability :The original quantity of medication entrapped in the formulation was determined, and it was preserved in sealed glass ampoules. The ampoules were stored at 4 ± 2°C, 25 ± 2°C, and 37 ± 2°C for at least three months. Samples from each ampoule were analyzed after 30 days to check whether there was any pharmaceutical leaking. By keeping the original drug entrapment at 100%, the percent drug loss was calculated.

APPLICATION OF TRANSFEROSOME^:^{[64,65,66,67,68,69,70]}

When it comes to topical drug administration, transferosomes—lipid-based nanosystems—offer benefits like improved solubility and permeability for medications with low bioavailability . In numerous trials, they have been used to administer a variety of medications, including as ferulic acid and antifungal agents. Here are a few noteworthy uses of transferosomes:

Delivery of insulin:

Transferosomes are a successful non-invasive therapeutic delivery system for these big molecular weight medications. Insulin is often supplied through an uncomfortable subcutaneous method. Transfersulin, which is insulin encapsulated in transferosomes, solves all of these issues. The initial indications of systemic hypoglycemia appear 90 to 180 minutes after applying transfersulin to intact skin, depending on the particular carrier composition.

Carvedilol Nano lipid Transferosomes:

A Box-Behnken design was used in a study to encapsulate carvedilol, a medication with a limited bioavailability (25–35%), in transferosomes loaded with nanostructured lipid carriers (NLC). Comparing the modified formulation to a traditional formulation, better dermato pharmacokinetic and pharmacodynamic characteristics were observed.

Antifungal Agent Transferosomes:

The Rotary Flask Evaporation-Sonication method was used to create transferosomes with an antifungal drug. The Plackett-Burman design was used to determine important formulation and process factors, such as the volume of ethanol and hydration medium, the amount of lipid and surfactant, and the hydration time, that have an impact on vesicle size .

Anti-cancer drugs transferosomes:

The transdermal delivery of anti-cancer medications such as methotrexate was investigated using transferosome technology, with encouraging outcomes and a viable therapeutic approach, especially for the treatment of skin cancer. In addition to various therapeutic uses, research has demonstrated the potential of transferosomes in delivering phytoconstituents with anticancer effects. Transferosomes may be useful for the targeted delivery of anti-cancer drugs, according to these findings, and they merit more research in the area of cancer treatment. Transferosome-embedded paclitaxel hydrogels were used by Jiang et al. (2018) to exhibit successful topical chemotherapy for melanoma, demonstrating effective tumor tissue penetration with components of sodium deoxycholate, tween 80, and phosphatidylcholine .

Non-steroidal anti-inflammatory drugs [NSAIDs] transferosomes:

There are serious gastrointestinal adverse effects from several NSAIDs. Transferosome-based transdermal distribution provides an answer to these problems. Research on diclofenac and ketoprofen shows encouraging outcomes. Notably, in 2007, Swissmedic, a regulatory body in Switzerland, approved a transferosome formulation of ketoprofen, which was to be sold under the name "Diractin." IDEAAG states that other therapeutic solutions using transferosome technology are still in the clinical development stage. Conversely, non-steroidal anti-inflammatory medications, or NSAIDs, are used to treat fever, pain, and inflammation. Their prospective application in the pharmacotherapy of cancer, diabetes, cardiovascular, and neurological illnesses has been assessed .

CONCLUSION:

The transdermal route has been the most popular way to administer drugs due to its special and adaptable qualities. But the main issue with transdermal distribution is that the stratum corneum is impenetrable, which makes it impossible for medications to enter at all. Therefore, the transferosomal system focuses on successfully delivering amphiphilic substances as well as hydrophilic and hydrophobic medications. Transferosomes are a good and appropriate method because of their increased topical applications, greater loading capacity, decreased dosing frequency, and improved stability features. Site-specific active drug delivery is a promising application for transferosomes, which are also used in a variety of cosmetic procedures. There are still a number of issues that need to be addressed with regard to purity, retention properties, and oxidative degradation. Therefore, additional considerations and technology developments are necessary for every prospective process improvement. Additionally, to enable future prospects of these brilliant nanocarriers, improvement in synergistic potential of components and active compounds also has to be researched across the globe. It is also emphasized that in order to obtain the data necessary to determine the safety aspect of difficult medications prior to industrial scale-up, advanced research based on convincing preclinical and clinical investigations is needed. Advances in scientific perspectives are still required for the creation of novel transferosomes, which are likely to concentrate on better treatment plans employing more sophisticated, promising, and well-structured new techniques. To reduce the current disadvantages of transferosomes, it is also critical to investigate novel medicinal excipients with extra properties. Industrial pharmaceutical firms may investigate novel prospects for important developmental properties of transferosomes with suitably customized features in the future.

REFERENCES

Habib B.A., Tag R. and Nour S.A., Factorial design approach for optimization of a gel formulation for in vitro iontophoretic transdermal delivery of granisetron, Bulletin of Faculty of Pharmacy, Cairo University, 49, (2008),305-313.
Hu L., Damaj B.B., Martin R. and Michniak Kohn B.B., Enhanced in vitro transbuccal drug delivery of ondansetron HCl, Int. J. Pharm, 404, (2011):66-74.
Modi CD and Bharadia PD: Transfersomes: New dominants for transdermal drug delivery. American Journal of Pharmaceutical Technology 2012; 2(3): 71-91.
Prajapati ST, Patel CG and Patel CN: Transfersomes: A vesicular carrier system for transdermal drug delivery. Asian Journal of Biochemical and Pharmaceutical research 2011; 1(2): 507-24.
Habib B.A., and AbouGhaly M.H.H., Combined mixture-process variable approach: a suitable statistical tool for nanovesicular systems optimization, Expert Opin. Drug Delivery. 13, (2016):1-12.
Solanki D, Kushwah L,Motiwale M.Chouhan,V. "Transferosomes-a review." World journal of pharmacy and pharmaceutical sciences . 2016 Aug 12;5(10): 435-49.
Rajkumar, J., RK Sree Lakshmi, and Shalini Vineesha. "A New Approach to Transdermal Drug Delivery Using Transfersomes-Based Nanoencapsulation: A Research Update." Asian Journal of Pharmaceutical Research and Development 10.1 (2022): 64-70.
W.F. Lever and G.Schaumburg-Lever. Histopathology of the skin. J.B.LippincottCompany, seventh edition edition, 1990.
Cevc G, Blume G. Lipid vesicles penetrate into skin owing to the transdermal osmotic gradients and hydration force. Biochim Biophys Acta. 1992;1104:226–232.
Cevc G, Blume G. New highly efficient formulation of diclofenac for the topical, transdermal administration in ultradeformable drug carriers, transfersomes. Biochimica Et Biophysica Acta. 2001;1514(2):191–205.
Biju S, Talegaonkar S, Mishra P, Khar R. Vesicular systems: an overview. Indian J Pharm Sci. 2006 Mar 1;68:(2).
Dayan N, Touitou E. Carriers for skin delivery of Trihexiphenidyl HCl ethosomes vs liposomes. Biomaterials. 2000;21:1879–1885.
Hofer C, Hartung R, Gobel R, New ultradeformable drug carriers for potential transdermal applicationof interleukin-2 and interferon-alpha theoretic and practical aspects. World J Surg. 2000 Oct;24(10):1187–1189.
Manosroi A, Jantrawuta P, Manosroi J. Anti-inflammatory activity of gel containing novel elastic niosomes entrapped with diclofenac diethylammonium. Int J Pharm. 2008 Aug 6;360(1-2):156–63.
Zheng WS, Fang XQ, Wang LL, Zhang YJ. Preparation and quality assessment of itraconazole transfersomes. Int J Pharm. 2012 Oct 15;436(1-2):291–8.
Ravi, Kumar, Manvir Singh, and A. C. Rana. "Transferosomes: A novel approach for transdermal drug delivery." The International Research Journal of Pharmacy 3.1 (2012): 24-28.
Khatoon K, Rizwanullah M, Amin S, Mir SR, Akhter S. Cilnidipine loaded TFS for transdermal application: formulation optimization, in-vitro and in-vivo study. Journal of Drug Delivery Science and Technology. 2019;54:101-303.
Joshi A, Kaur J, Kulkarni R, Chaudhari R. In-vitro and ex-vivo evaluation of raloxifene hydrochloride delivery using nano-transfersome based formulations. Journal of Drug Delivery Science and Technology. 2018 Jun 1;45:151–8.
Sana E, Zeeshan M, Ain QU, Khan AU, Hussain I, Khan S, Lepeltier E,Ali H. Topical delivery of curcumin-loaded TFS gel ameliorated rheumatoid arthritis by inhibiting NF-κβ pathway. Nanomedicine. 2021 Apr 1;16(10):819–37.
Ishii F, Nii T. Lipid emulsions and lipid vesicles prepared from various phospholipids as drug carriers. Colloid and interface science in pharmaceutical research and development: Elsevier; 2014 Jan 1. pp. 469–501.
Zeb A, Qureshi OS, Kim H-S, Cha J-H, Kim H-S, Kim J-K. Improved skin permeation of methotrexate via nanosized ultradeformable liposomes. Int J Nanomed.2016 Aug 8:3813-24
El Zaafarany GM, Awad GAS, Holayel SM, Mortada ND. Role of edge activators and surface charge in developing ultradeformable vesicles with enhanced skin delivery. Int J Pharm. 2010;397(1–2):164–72.
Aggarwal N, Goindi S. Preparation and evaluation of antifungal efficacy of griseofulvin loaded deformable membrane vesicles in optimized guinea pig model of Microsporum canis—Dermatophytosis. Int J Pharm. 2012;437(1–2):277–87.
Modi, C.; Bharadia, P. Transfersomes: New dominants for transdermal drug delivery. Am. J. PharmTech. Res. 2012, 2, 71–91.
Li, J.; Wang, X.; Zhang, T.; Wang, C.; Huang, Z.; Luo, X.; Deng, Y. A review on phospholipids and their main applications in drug delivery systems. Asian J. Pharm. Sci. 2015, 10, 81–98
Bnyan,R.;Khan,I.;Ehtezazi,T.;Saleem,I.;Gordon,S.;Neill,F.O.;Roberts,M. Surfactant e?ects on lipid-based vesicles properties. J. Pharm. Sci. 2018, 107, 1237–1246
Kumar, A. Transferosome: A recent approach for transdermal drug delivery. J. Drug Deliv. Ther. 2018, 8, 100–104.
Kodi, S. R., & Reddy, M. S. (2023). Transferosomes: A Novel Topical Approach. Journal of Drug Delivery and Therapeutics, 13(2), 126-131
Modi CD, Bharadia PD, “Transfersomes: New Dominants for Transdermal Drug Delivery”, Am. J. PharmTech Res., 2012, 2 (3), 71-91.
Kombath RV, Minumula SK, Sockalingam A, Subadhra S, Parre S, Reddy TR, David B, “Critical issues related to transfersomes – novel Vesicular system”, Acta Sci. Pol., Technol. Aliment., 2012, 11 (1), 67-82.
Walve JR, Bakliwal SR, Rane BR, Pawar SP, “Transfersomes: A surrogated carrier for transdermal drug delivery system”, International Journal of Applied Biology and Pharmaceutical Technology, 2011, 2 (1), 201-214.
Eldhose, M. P., Mathew, F., & Mathew, N. J. (2016). Transfersomes–a review. Int J Pharm Pharm Res, 6, 436-452.
Chandran, S. M., Jaghatha, T., Wesley, J., Remya, S. B., & Aparna, P. (2018). A REVIEW ON TRANSFERSOMES. Indo American Journal of Pharmaceutical Sciences, 5(4), 2405-2411.
Vashisth, T., Hooda, R., Qureshi, S. M. S., Pandey, B., & Mathew, N. A. (2024). A COMPREHENSIVE REVIEW ABOUT THE DEVELOPMENT, CHARACTERIZATION AND SKIN DELIVERY STUDIESOF ULTRADEFORMABLE VESICLES: TRANSFERSOMES.
Joseph, T. M., & Luke, P. M. (2020). Transferosomes: Novel Delivery System for Increasing Theskin Permeation of Drugs. Int J Med Phar Sci| Vol, 10(02), 1.
Cevc G., Gebauer D., Stieber J., Schätzlein A. and Blume G, Ultraflexible vesicles, Transfersomes, have an extremely low pore penetration resistance and transport therapeutic amounts of insulin across the intact mammalian skin. BBA, 1368(2), 201-215 (1998)
Cevc G., Schätzlein A., and Blume G, Transdermal drug carriers: Basic properties, optimization and transfer efficiency in the case of epicutaneously applied peptides, Journal Control Release (JCR), 36(1-2), 3-16 (1995)
Khan M.A., Pandit J., Sultana., Sultana Y.S., Ali A., Aqil M. and Chauhan M., Novel carbopol-based transfersomal gel of 5- fluorouracil for skin cancer treatment: in vitro characterisation and in vivo study, Drug Deliv, 22(6), 795802 (2015)
Meng S., Zhang C., Shi W., Zhang X.W., Liu D.H, Wang P., Li J.X. and Jin Y. Preparation of osthole-loaded nano-vesicles for skin delivery: characterisation, in vitro skin permeation and preliminary in vivo pharmacokinetic studies, Eur. J. Pharm. Sci, 92, 49–54 (2016)
Zaafarany G.M., Awad G.A., Holayel. and Mortada N.D., Role of edge activators and surface charge in developing ultradeformable vesicles with enhanced skin delivery, Int J. Pharm, 397 (1-2), 164–172 (2010)
Alvi IA, Madan J, Kaushik D, Sardana S, Pandey RS, Ali A. Comparative study of TFS, liposomes, and niosomes for topical delivery of 5-fluorouracil to skin cancer cells: preparation, characterization, in-vitro release, and cytotoxicity analysis. Anticancer Drugs. 2011;22(8):774–82.
Sudhakar CK, Jain S, Charyulu RN. A comparison study of liposomes, TFS and ethosomes bearing lamivudine. Int J Pharm Sci Res. 2016;7(10):4214.
Duangjit S, Obata Y, Sano H, Onuki Y, Opanasopit P, Ngawhirunpat T, et al. Comparative study of novel ultradeformable liposomes: menthosomes, TFS and liposomes for enhancing skin permeation of meloxicam. Biological and pharmaceutical bulletin. 2014:b13–00576.
Garg V, Singh H, Bimbrawh S, Kumar Singh S, Gulati M, Vaidya Y, et al. Ethosomes and TFS: principles, perspectives and practices. Curr Drug Deliv. 2017;14(5):613–33.
Cevc G, Schätzlein AG, Richardsen H, Vierl U. Overcoming semipermeable barriers, such as the skin, with ultradeformable mixed lipid vesicles, TFS, liposomes, or mixed lipid micelles. Langmuir. 2003;19(26):10753–63
Hao Y, Li W, Zhou X, Yang F, Qian Z. Microneedles-based transdermal drug delivery systems: a review. J Biomed Nanotechnol. 2017;13(12):1581–97.
Waghule T, Singhvi G, Dubey SK, Pandey MM, Gupta G, Singh M. Microneedles: A smart approach and increasing potential for transdermal drug delivery system. Biomed Pharmacother. 2019;109:1249–58.
Bahram M, Mohseni N, Moghtader M. An introduction to hydrogels and some recent applications. Emerging concepts in analysis and applications of hydrogels: IntechOpen; 2016.
Narayanaswamy R, Torchilin VP. Hydrogels and their applications in targeted drug delivery. Molecules. 2019;24(3):603.
Gaballa SA, El Garhy OH, Abdelkader H. Cubosomes: composition, preparation, and drug delivery applications. Journal of advanced Biomedical and Pharmaceutical Sciences. 2020;3(1):1–9.
Rattanapak T, Young K, Rades T, Hook S. Comparative study of liposomes, TFS, ethosomes and cubosomes for transcutaneous immunisation: characterisation and in vitro skin penetration. J Pharm Pharmacol. 2012;64(11):1560–9.
Barriga HMG, Holme MN, Stevens MM. Cubosomes: the next generation of smart lipid nanoparticles? Angew Chem Int Ed. 2019;58(10):2958–78
Qadri, G. R., Ahad, A., Aqil, M., Imam, S. S., & Ali, A. (2017). Invasomes of isradipine for enhanced transdermal delivery against hypertension: formulation, characterization, and in vivo pharmacodynamic study. Artificial cells, nanomedicine, and biotechnology, 45(1), 139-145
Sudhakar, C. K., Upadhyay, N., Jain, S., & Charyulu, R. N. (2012). Ethosomes as non-invasive loom for transdermal drug delivery system. Nanomedicine and drug delivery, 11(10), 2557.
Mishra, V., Bansal, K. K., Verma, A., Yadav, N., Thakur, S., Sudhakar, K., & Rosenholm, J. M. (2018). Solid lipid nanoparticles: Emerging colloidal nano drug delivery systems. Pharmaceutics, 10(4), 191.
Paliwal, S., Tilak, A., Sharma, J., Dave, V., Sharma, S., Verma, K., ... & Sadhu, V. (2019). Flurbiprofen-loaded ethanolic liposome particles for biomedical applications. Journal of microbiological methods, 161, 18-27.
Vasanth, S.; Dubey, A.; Ravi, G.S.; Lewis, S.A.; Ghate, V.M.; El-Zahaby, S.A.; Hebbar, S. Development and investigation of vitamin c-enriched adapalene-loaded transfersome gel: A collegial approach for the treatment of acne vulgaris. AAPS Pharm. Sci. Tech. 2020, 21, 61.
Sarmah, Prasurjya Jyoti, Bhupen Kalita, and Anil Kumar Sharma. "Transfersomes based transdermal drug delivery: an overview." Int J Adv Pharm Res 4.12 (2013): 2555-63.
Marwah H, Garg T, Rath G, Goyal AK. Development of transferosomal gel for trans-dermal delivery of insulin using iodine complex. Drug Deliv. Taylor & Francis. 2016;23:1636–44.
Malakar J, Sen SO, Nayak AK, Sen KK. Formulation, optimization and evaluation of transferosomal gel for transdermal insulin delivery. Saudi Pharm J. 2012;20:355–63.
Sunitha M, Anusha M. TransferosomesNovel Drug delivery system - A review IJCRT. 2020;8:2320-2882.
Chaurasiya P, Ganju E, Upmanyu N, Ray S, Jain P. Transfersomes: a novel technique for transdermal drug delivery. J Drug Deliv Ther. 2019;9:279–85.
Gupta A, Aggarwal G, Singla S, Arora R. Transfersomes: A Novel Vesicular Carrier for Enhanced Transdermal Delivery of Sertraline: Development, Characterization, and Performance Evaluation. Sci Pharm. 2012;80:1061–80.
Patel NN, Vikran, Roopchandani K, Gupta A. Proniosomes for improved transdermal drug delivery - A review. Pharma Res. 2013;8:62–82.
Joseph, Tomy Muringayil, and P. Mereena Luke. "Transferosomes: Novel Delivery System for Increasing Theskin Permeation of Drugs." Int J Med Phar Sci| Vol 10.02 (2020): 1.
Sachan, Roopesh, et al. "Drug carrier transfersomes: A novel tool for transdermal drug delivery system." International Journal of Research and Development in Pharmacy and Life Sciences 2.2 (2013): 309-316.
Selvaraj BR, Sridhar SK, Kesavan BR, Palagati S. Application of statistical tooling techniques for designing of carvedilol nanolipid transferosomes and its dermatopharmacokinetic and pharmacodynamic studies. Pharmaceutical Nanotechnology. 2020 Dec 1;8(6):452-70.
Patel B, Parikh RH. Preparation and formulation of transferosomes containing an antifungal agent for transdermal delivery: Application of Plackett-Burman design to identify significant factors influencing vesicle size. Journal of Pharmacy and Bioallied Sciences [Internet]. 2012 Jan 1;4(5):60.
Jiang T, Wang T, Li T, Ma Y, Shen S, He B, Mo R. Enhanced transdermal drug delivery by transfersome-embedded oligopeptide hydrogel for topical chemotherapy of melanoma. ACS nano. 2018 Sep 5;12(10):9693-701.
Ozleyen A, Yilmaz YB, Donmez S, Atalay HN, Antika G, Tumer TB. Looking at NSAIDs from a historical perspective and their current status in drug repurposing for cancer treatment and prevention. Journal of Cancer Research and Clinical Oncology. 2023 May;149(5):2095-113..