IDEA AG - Science

Technological platform

Transfersome® is a complex, most often vesicular, aggregate optimised to attain extremely flexible and self-regulating membrane, which makes the vesicle very deformable. Transfersome® vesicle can therefore cross microporous barriers very efficiently, even when the available passages are much smaller than the average aggregate size.

When a Transfersome® formulation is applied on the skin and allowed to dry, the vesicles are attracted by the intracorporal moisture into the body. The aggregates then penetrate the skin without compromising the protective properties of the organ.

Transfersome® consists of, mainly natural, amphipatic compounds suspended in a water-based solution, sometimes containing biocompatible surfactants. Similar to a liposome, a Transfersome® has a lipid bilayer that surrounds an aqueous core. In contrast to a liposome, a Transfersome® bilayer contains at least one component that softens the membrane and makes it more flexible. This allows an easy and rapid change of Transfersome® shape (see the shape changes in the animation below). [rotating Transfersome® image]

The basis for an easy shape adaptation is the local bilayer adjustment to ambient stress via a molecular positive feedback in each carrier (see changing colours in the Transfersome® animation). The resulting, unusually high, membrane adaptability is reflected in the characteristic flux of Transfersome® suspension through a barrier with the pores of an average size considerably smaller than the typical vesicle size: with increasing force (head pressure) the suspension transport rate increases in a sigmoidal fashion until a maximum flow is reached. The maximum flow value is nearly identical to that of the suspending liquid and is determined chiefly by fluid viscosity. In contrast, the transport rate for liposome suspension remains low in very broad force ranges, until such vesicles become comparable to pore size. (An exception are the pressures or forces that are high enough to break such conventional lipid vesicles down to pore size.)

Skin as a Transport Barrier

Skin is one of the best biological barriers. Its outermost part, the horny layer (stratum corneum), reaches less than 10% into the depth of the skin but contributes over 80% to the skin permeability barrier. This body protecting layer consists of overlapping, flat corneocytes organized in columnar clusters (see the illustration on the right). The clusters are sealed with multi-lamellar lipid sheets that are covalently attached to the cell membranes and are tightly packed together. Generally, the average number and the degree of order in the inter cellular lipid lamellae increases toward the skin surface.

The stratum corneum, which comprises of stacks of flat, partially overlapping cells sealed with inter-cellular lipids, is the main transport obstacle in the skin. It is also the first line of body defence against the exogenous pathogens.

The changes in the stratum corneum structure are accompanied by a continuous but nonlinear change in the local water content near the skin surface: whereas only 15-25% of water are found on the outside of the organ, much higher water content (>75%) is measured in the living, deeper skin. The peak in the skin permeability barrier is located in the inner half of the horny layer, where the intercellular lipid seals are already formed, but not yet compromised by the skin cell detachment. The skin thus prevents both the loss of body fluids and molecules on the one hand, and the in-flow of pathogens, toxics, as well as drugs on the other.

The few small molecules that have crossed the horny layer are cleared from the skin through the cutaneous blood microcirculation close to the organ's surface. Owing to the fact that the total cutaneous blood vessels surface exceeds, by far, that of the skin, such clearence is very efficient and fast compared to the kinetics of small molecules diffusion across the skin barrier. Drug accumulation deep under the skin is therefore difficult, if not impossible, in particular when the mechanism of drug transport is diffusion; this is always the case with conventional transdermal delivery systems.

The Transfersome® mediated administration of low molecular weight drugs tends to shift the drug distribution towards the deep tissue under the application site. One of the chief reasons for this is the large size of the carrier vesicles, which results in the slow clearance of Transfersomes® from the skin and allows for the desired drug accumulation at the application site.

Mechanism of Carrier Transport

The skin, simply speaking, is a nanoporous barrier. Pores in the skin are normally so narrow that they only permit the passage of entities smaller than a millionth of a millimeter. This precludes any conventional aggregate carrier from crossing the skin barrier.

The results measured to date suggest that the passage of a Transfersome® across the skin is a function of vesicle membrane flexibility, hydrophilicity, and the ability to retain vesicle integrity, while the aggregate undergoes a dramatic change in shape. A Transfersome® thus acts as a nano-robotic molecular "injector" capable of penetrating, rather than perforating the skin barrier. The current view of the Transfersome® mechanism of action is described as follows:

[schematic representation of an ultradeformable, mixed lipid vesicle penetrating a narrow pore...]

A simulation of an ultradeformable, mixed lipid vesicle penetrating a narrow pore, owing to the shape-induced demixing of bilayer components (compare the distribution of red an blue molecules in the bilayer), vesicle diameter, and pore width adaptation.

When a suspension of Transfersome® vesicles is placed on the surface of the skin the water evaporates from the skin surface and the vesicles start to dry out. Due to the strong hydrophilicity of major Transfersome® ingredients, the vesicles are attracted to the areas of higher water content in the narrow gaps between adjoining cells in the skin. The phenomenon, together with the vesicle's extreme ability to deform, enables each Transfersome® to temporarily open the pores through which water normally evaporates between the cells. This creates 20-30 nm wide pathways between the skin cells, two orders of magnitude wider than the original nanopores. Such newly activated inter-cellular passages can accommodate sufficiently deformable vesicles maintaining their integrity but changing their shape to fit the channel; the calculated sequence in the above illustration highlights the process. Insufficiently deformable entities fail to pass through the channels. Along these said pathways in the horny layer, a Transfersome® reaches regions of high water content in the deeper skin layers. Subsequently, the vesicles that have crossed the skin barrier are distributed between the cells. Being too large to enter the blood vessels locally, a Transfersome® bypasses the cutaneous capillary bed and reaches the subcutaneous tissue. Ultimately, the vesicle may arrive into the systemic blood circulation via the fenestrated lymphatic system, which has openings (fenestrations) of sufficient width; most often, however, the vesicles applied locally are ultimately bio-processed and their building blocks are re-utilised in peripheral tissues below the application site.

The large number of hydrophilic, i.e. water-loving, molecules or groups united in a single Transfersome® entity enhances the aggregate sensitivity to the driving force that stems from the water concentration gradient across the skin. This phenomenon enhances the propensity of the ultradeformable Transfersomes® to move across the skin barrier. It explains the unusually high efficiency of suitable mixed lipid vesicle transport across the skin compared to liposomes (rigid vesicles) or mixed micelles (small, rigid aggregates of Transfersome® components). Liposomes cannot deform sufficiently to open or fit the channels. while mixed micelles lack the strength necessary to open and cross such channels. The widely divergent skin penetration profiles measured for the different aggregate suspensions corroborate this conclusion.

Skin Penetration Pathway for a Transfersome®

[image]
The confocal laser scanning microgaph of fluorescent ultradeformable vesicles: hydrophilic intercellular channels between cells in the stratum corneum are opened by the skin penetrating Transfersomes®.

Various methods can be used to break through the skin barrier forcefully. The skin (cutis) poration by electrical or mechanical means creates a few wide, hydrophilic passages through the organ which typically compromise the skin barrier for a day, at least. The less aggressive iontophoresis produces narrower electrical breaks through the skin (with pores of less than 20 nm size), which add up to approximately 0.005% of the total skin surface. In contrast to this, Transfersome® vesicles generate wider, more numerous and more uniformly distributed , but also only transiently open pathways across the organ; a birds-eye view of the skin after epicutaneous Transfersomes® application illustrates the phenomenon (see the picture on the left). The resulting passages make approximately 80% of the skin surface accessible for carrier mediated transport. They are too small, however, to allow simultaneous passage of pathogens, such as viruses or bacteria.

Due to the large number of Transfersome®-specific pathways in the skin, the transport through shunts, such as hair follicles or gland openings, is also not significant.