Deformable lipid vesicles:
Intensive investigations led to the introduction and development, of a new class of highly deformable (elastic or ultraflexible) liposomes that have been termed Transfersomes®. While conventional liposomes were reported to have mainly localizing or rarely transdermal effects, deformable liposomes were reported to penetrate intact skin, carrying therapeutic concentrations of drugs, but only when applied under non-occluded conditions. Deformable liposomes (Transfersomes®) are the first generation of elastic vesicles introduced by Cevc and Blume (1992) [29]. Transfersomes are highly efficient edge activator -based ultra flexible vesicles capable of, noninvasively, trespassing skin by virtue of their high, self-optimizing deformability. They consist of phospholipids and an edge activator. Transfersomes for enhanced transepidermal delivery of Diclofenac sodium, an edge activator is often a single chain surfactant, having a high radius of curvature, which destabilizes lipid bilayers of the vesicles and increases deformability of the bilayers [30]. They are liquid-state vesicles with a highly deformable membrane [31, 32] which permits their easy penetration through skin pores much smaller than the vesicles’ size. They have been proven to be superior to conventional gel-state and even liquid-state vesicles in terms of both [33, 34], the enhancement of drug permeation and interactions with human skin [35, 36]. The ultra-flexible carrier’s hydration sensitivity and its unique driving force create an unprecedented opportunity to control the depth of the carriers’ migration, by selecting different drug dose and/or carrier dose per area (Fig.3). Transfersomes can effectively protect the drug against undesired rapid clearance into cutaneous blood vessels and are capable of retaining the drug long enough, on, in and below the skin barrier. Furthermore, they can cross the stratum corneum independent of drug concentration. Occluded passive penetration improved estradiol skin penetration from liposomes relative to control. Iontophoretic studies revealed the superiority of ultradeformable vesicles regarding drug skin penetration and deposition compared to traditional liposomes [37, 38]. Iontophoresis with ultradeformable liposomes improved estradiol transepidermal penetration in vitro [39]. The improvement in drug penetration was suggested to be due partly to the high deformability of the vesicular membrane. This vesicular elasticity would have resulted in penetration of some vesicles through the skin under the stress imparted by the applied electric current [40]. Penetration enhancers were able to give more deformable vesicles than conventional liposomes with a good drug entrapment efficiency and stability [41]. In vitro skin penetration data showed that Penetration Enhanced Vesicles were able to give a statistically significant improvement of minoxidil deposition in the skin in comparison with classic liposomes and penetration enhancer-containing drug ethanolic solutions without any transdermal delivery [42, 43].

Deformable liposomes were also reported to improve both in vitro skin permeation and deposition of cyclosporin A [44], methotrexate [45], and melatonin [46]. They significantly improved ketotifen skin delivery, with greater improvement of ketotifen skin deposition than improvement of ketotifen skin permeation, hence were suggested to be more useful for dermal than for transdermal delivery of ketotifen [47]. They were also reported to improve only skin deposition of 5-fluorouracil [48] and dipotassium glycyrrhizinate [49], hence were considered only useful for dermal delivery of these drugs. Reported success of deformable liposomes to deliver macromolecules and proteins such as insulin through intact human skin with efficiency comparable with subcutaneous administration led to their introduction as possible carriers for non-invasive gene delivery and transcutaneous immunization. Investigated deformable cationic liposomes, prepared using a cationic lipid, 1, 2-dioleoyl-3-trimethylammoniumpropane, and sodium cholate, as gene delivery system. In vitro transfection efficiency of plasmid DNA was assessed by the expression of green fluorescent protein (GFP) [50]. This formulation was capable of transfecting several cell lines. It was also tested for in vivo transfection efficiency and its retention time within the organs, by applying the complexes on hair-removed dorsal skin of mice, non-invasively. It was found that genes were transported into several organs for 6 days once applied on intact skin, suggesting promising properties for non-invasive gene delivery. In another study, deformable liposomes prepared using egg-phosphatidylcholine could also deliver genetic materials (GFP) into mice transdermally [51].

Figure 3. The schematic drawing of skin permeation of lipid vesicles (A) lipid vesicles with permeation enhancer (B) and flexible vesicles (C); the direct transfer of drug is due to the interaction of skin lipids and vesicles; flexible vesicles permeation due to the hydration or osmotic gradient.

Vesicular carriers with promising results in dermal and transdermal drug delivery are ethosomes. Discovered by Touitou et al. (1997) [52], ethosomes contain phospholipids, alcohol (ethanol/isopropyl alcohol) in relatively high concentration and water. The use of high ethanol content was first described for ethosomes. Due to the inter-digitation effect of ethanol on lipid bilayers, it was believed that high concentrations of ethanol are damaging to liposomal formulations. However, ethosomes which are novel permeation-enhancing lipid vesicles embodying high concentration (20–45%) of ethanol were developed and investigated. Ethosomes are most commonly prepared by the lipids and the drug is dissolved in ethanol. The aqueous component is added slowly in a fine stream at constant rate in a well-sealed container with constant mixing. Mixing is then continued for additional few minutes. These vesicular carriers having the size range of few nanometers to microns are claimed to be most suited for the transdermal drug delivery of bioactives. Unlike classical liposomes, ethosomes were shown to permeate through the stratum corneum barrier and were reported to possess significantly higher transdermal flux in comparison to liposomes. The exact mechanism for better permeation into deeper skin layers from ethosomes is still not clear however the synergistic effects of combination of phospholipids and high concentration of ethanol in vesicular formulations have been suggested to be responsible for deeper distribution and penetration in the skin lipid bi-layers [53-56]. Ethosomal carriers have been shown to be effective permeation enhancers. The delivery of biologically active agents has been well reported. Dayan and Touitou reported the facilitation of probe penetration to a greater skin depth with ethosomal carriers, and also relatively high fluorescence intensity, compared to a hydroethanolic solution and conventional liposomes, using various probes of different nature, like D-289 and Rhodamine Red [57].

Recently studies reported for the delivery of anti-HIV/AIDS drugs via ethosomes.  The encapsulation of AZT in ethosomes and compared its transdermal potential with liposomes and hydroethanolic and ethanolic solutions of the drug [58]. Intercellular and intracellular drug delivery of lamivudine was improved from ethosomes using visualization techniques and cell line study. The results concluded that ethosomes could be advantageous in terms of transdermal drug delivery of the anti-HIV/AIDS agents [59, 60].

Table 1. Some recently reported studies investigating efficiency and applications of ethosomes as carriers for transdermal delivery of drugs






AUC was about 64% greater with ethosomes than with commercial gel [61].


Suppression of carrageenan-induced aseptic paw edema

(anti-inflammatory action)

Development of edema was prevented entirely only in pretreated (ethosomal patch) group of mice. Delta in paw thickness of pretreated mice was statistically different from that of the non-pretreated mice starting from 1 h post-carrageenan injection and lasting until the end of the inflammation course [62]


In vivo antibacterial efficiency

Ethosomal erythromycin resulted in complete inhibition of infection while hydroethanolic erythromycin solution caused deep dermal and subcutaneous abscesses within 5 days after challenge [63].



Suppression of

chemically induced erythema (anti-inflammatory action)

Ethosomes reduced the erythema more rapidly with respect to drug solutions. Ethosomes also showed sustained effect [64].


In-vitro permeation through Rat abdominal skin

Addition of cholesterol significantly improved skin delivery from ethosomes [65].

Azelaic acid

Diffusion through synthetic membranes

 Ethosomes having the highest ethanol concentration released the drug more rapidly [66].


Diffusion across Rabbit pinna skin

Ethosomes improved cumulative drug permeated [47]

hepatitis B

surface antigen

in vitro qualitative and quantitative uptake by human dendritic cells

Ethosomes coupled with their skin navigating potential, make it an attractive vehicle for development of a transcutaneous vaccine against hepatitis B in preference to elastic liposomes [67].


Dermal and transdermal delivery of an anti-psoriatic agent

Ethosomes with some visual penetration pathways and corneocytes swelling, a measure of retentive nature of formulation [68].



encapsulated liposome versus ethosome for skin delivery

the penetration ability of ethosomes was greater than that of liposomes [69]


skin permeation

Formulation revealed a greater mobility of skin lipids on application of ethosomes as compared to that of ethanol or plain liposomes [70].

Vesicles, have been intensively studied as drug carrier systems for dermal and transdermal administration of drugs. Since liquid-state vesicles have been proven to be superior to rigid gel-state vesicles in terms of enhanced drug penetration, and elastic vesicles have been shown to be superior to conventional gel-state and even liquid-state vesicles in terms of interactions with human skin and enhanced drug penetration a series of liquid-state vesicles with elastic membranes were developed [71].



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