IDEA AG - Scientific FAQ

<h1 align="left">Scientific FAQ</h1> <p align="left"><b>What is the difference between liposomes and Transfersomes®?</b></p> <p align="left"><b>Liposomes</b> ("lipid bodies"), most generally speaking, are thermodynamically stable lipid vesicles with an aqueous core and at least one surrounding bilayer.</p> <p align="left">Most often, liposomes are made of lipids (such as phosphatidylcholines) with a tendency to form extended, quasi-planar membranes. In order to improve the stability of such vesicles, cholesterol or some other membrane stiffening agent is frequently included in the bilayer. Alternatively, liposomes are prepared from the lipids below the chain-melting phase transition temperature. In either case, the lipid bilayer becomes more robust and less permeable, but also more rigid and less flexible. Fluid membranes, which are as deformable as the red blood cells (elastic energy at least one order of magnitude higher than the thermal energy) are normally not used for drug delivery due to their bilayer leakiness and poor vesicle stability<a name="transfersome"></a>.</p> <p> <b>Transfersomes</b>® ("carrying bodies"), in the broadest sense of the word, are bi- or multi-component aggregates capable of crossing semi-permeable barriers and of transferring material between the application and the destination sites on either barrier side. This is made possible by the unmatched self-regulatory capability of Transfersomes®. </p> <p align="left">Typically, Transfersomes® are lipid droplets, sufficiently deformable to penetrate pores much smaller than their own size. This requires an elastic bilayer energy of the order of thermal energy (RT) or less and, membrane ability to change easily the vesicle surface area to volume ratio. Reversible lipid bilayer poration is the prerequisite for the later capability.</p> <p align="left">Most often, Transfersomes® are locally and controllably destabilised, but generally stable, mixed lipid vesicles. Such (quasi)metastability makes the vesicle bilayer ultraflexible and thus the vesicle highly deformable. It is chiefly the unusually strong and ambient stress-dependent lipid bilayer adaptability that allows the Transfersome® vesicle to accommodate to a 'confining pore' and thus to trespass such a pore. A typical Transfersome® is therefore characterised by a bilayer that is locally more permeable and is at least tenfold more elastic than the membrane of a conventional lipid vesicle, liposome (see previous text).</p> <p align="left"><b>What makes Transfersomes®more stable than liposomes?</b></p> <p align="left">An important difference between Transfersomes® and liposomes is the much higher hydrophilicity of the former. This forces Transfersome® membranes to swell more than conventional lipid vesicle bilayers. Higher membrane hydrophilicity and flexibility both help Transfersomes® to avoid aggregation, and thus fusion, which is observed with liposomes exposed to an osmotic stress.</p> <p align="left"><b>How large are typical Transfersomes®?</b></p> <p align="left">The size of a typical Transfersome® is comparable to the diameter of liposomes used in pharmaceutical formulations. However, the mixed lipid micelle, with which an ultradeformable vesicle may share the same basic components, is typically two to ten times smaller.</p> <p align="left"><b>How safe are Transfersomes® on the skin?</b></p> <p align="left">Phospholipid suspensions comprising liposomes were reported to be harmless and non-irritating to the skin after repeated epicutaneous administration; they may even have an advantageous cosmetic effect. Macroscopic observations made with Transfersomes® point in the same direction: the test with such ultradeformable vesicles on the skin <i>in vitro</i> in a microscopic toxicity assay revealed no differences between saline, as a negative control, and various Transfersome® formulations. Different in vivo studies, including especially a 6- week and 3-month safety study in human and 6-month study in pigs, have also confirmed minimum local side effects of Transfersome<b>® </b>formulations on the skin. If any, such side effect were of transient nature.</p> <p align="left">From the point of view of systemic toxicity, the situation is even more favourable.</p> <p align="left"><b>Are Transfersomes® systemically toxic?</b></p> <p align="left">No, they are not. Phosphatidylcholine is found in the human plasma at a concentration of up to 2 g/l. This explains why related phosphatidylcholines are used as emulsifiers in soy-oil microemulsions for the parenteral nutrition; 80% pure soy phosphatidylcholine is also used in an injectable drug formulation of Valium MM TM (Hoffman-La Roche), without a measurable danger.</p> <p align="left">The total phospholipid amount to be placed on the skin in the form of Transfersome® suspension is expected to be less than 1 g/day. This is only 20% of the phospholipid quantity that may daily be infused intravenously in the form of parenteral formulations containing similar lipids. It is also less than 20% of the natural variability of phosphatidylcholine concentration in the plasma of an average healthy subject.</p> <p align="left">In accordance with such estimates no systemic side effects were detected in the pigs treated with a similar dose of Transfersome® suspension in the skin for 6 months, twice daily, or in the humans treated with empty carriers for at least 3 months.</p> <p align="left"><b>What happens to Transfersomes® in a body?</b></p> <p align="left"> The fate of aggregates that have crossed the skin barrier depends on the dose applied per unit area.</p> <p align="left">When a low amount of material is applied, Transfersomes® distribute in the skin below the stratum corneum. Here, they are degraded and re-used in cell membranes by cellular biochemical machinery. </p> <p align="left">When an intermediate area dose is used, enough Transfersome® material is delivered into the skin to allow vesicle migration into the deep tissues below the application site. This is enabled by the fact that Transfersomes® are too large to enter cutaneous blood capillaries, which are the main local sink for the small chemical entities. In the given situation, Transfersomes® are not numerous enough to fill both the skin and subcutaneous tissue to maximum possible amount. Vesicles are therefore discharged and degraded in the peripheral tissues, including the skin and subcutaneous fat as well as muscles, in a natural fashion. </p> <p align="left">Applying a very large dose per area saturates the skin and underlaying tissues. The local biochemical and cellular machinery then cannot cope with the applied liquid material. The excess vesicles are then driven further into the body through fenestrations in cutaneous lymphatic capillaries, which are less abundant but much more leaky than blood capillaries. Through the lymph, vesicles first enter into the draining lymph nodes and then reach the systemic blood circulation.</p> <p align="left">In serum, all vesicles start to exchange molecules with lipoproteins. Transfersomes®, therefore, ultimately release their payload and vanish everywhere in the body. The vesicles that have made their way into the liver also have a good chance to be taken up by the local cells in a natural process of particle elimination. In either case, the main Transfersome® ingredients are re-utilised for cell membrane rebuilding, and for other endogenous biological needs.</p> <p align="left"><b>Which drugs can be associated with Transfersomes®?</b></p> <p align="left"> In principle, Transfersomes® can accomodate any kind of molecules: very lipophilic substances are incorporated into lipid bilayer; water soluble compounds find shelter in the aqueous vesicle core; and amphiphatic molecules typically adsorb to the lipid-water interface. Larger molecules tend to adhere to vesicles through a combination of several interactions. Practical limitations to drug loading in Transfersomes® are therefore more dose than composition-related.</p> <p align="left"><b>How is a drug released from Transfersomes®?</b></p> <p align="left">Water soluble drugs leak from a vesicle when their concentration outside the vesicles is lower than within the vesicles. This is not the case on or in the skin, because of initial water evaporation. However, such gradient is established in the water-rich living skin, which explains why Transfersomes® start to release encapsulated drugs in such tissue. The process can be slowed down by the measures that have also proven useful for retaining drugs in conventional lipid vesicles, liposomes. </p> <p align="left"> Fat soluble drugs are strongly anchored in Transfersome® enclosing lipid bilayer. Such drugs therefore do not leak from, but reather must be leached out, a lipid vesicle. The proximity of Transfersomes® and cell membranes, or receptors, is a prerequisite for this. Such vicinity is normal in highly loaded target tissues, but depends on carrier properties and on local drug concentration. In any case, release of fatty drugs from Transfersomes® is much slower than release of water soluble substances. The desirable prolongation of drug action is thus achieved.</p> <p align="left">Amphiphatic molecules combine the features of water and fat soluble compounds. Such molecules consequently have intermediate release characteristics.</p> <p><a href="../index.html"><----</a> | <a href=".././index.html" target="_top" onmouseover="putstattext('What is special about IDEA?'); return true;">Home</a> | <a href="../about-us/index.html" target="_top" onmouseover="putstattext('About IDEA history, people, external collaboratory and future plans.'); return true;">About us</a> | <a href="../corporate_factsheet/index.html" target="_top" onmouseover="putstattext('Corporate Factsheet'); return true;">Corporate Factsheet</a> | <a href="../science/index.html" target="_top" onmouseover="putstattext('Academic collaborations, publications, etc.'); return true;">Science</a> | <a href="../publications/index.html" target="_top" onmouseover="putstattext('Publications'); return true;">Publications</a> | <a href="../product_opportunities/index.html" target="_top" onmouseover="putstattext('IDEA offers better compliance, local drug targeting and patent protection.'); return true;">Product opportunities</a> | <a href="../financial/index.html" target="_top" onmouseover="putstattext('Investors and basic financial data.'); return true;">Finance</a> | <a href="../press_releases/index.html" target="_top" onmouseover="putstattext('Original texts.'); return true;">Press releases</a> | <a href="../latest_newsletter/index.html" target="_top" onmouseover="putstattext('IDEAS latest newsletter'); return true;">Latest newsletter</a> | <a href="../press_clippings/index.html" target="_top" onmouseover="putstattext('IDEA in the press.'); return true;">Press clippings</a> | <a href="../conferences/index.html" target="_top" onmouseover="putstattext('Here you will find many dates where you can meet us and where we can talk...'); return true;">Conferences</a> | <a href="../career/index.html" target="_top" onmouseover="putstattext('We constantly seek best talents and dedication, offering much in return.'); return true;">Career</a> | <a href="../contact/index.html" target="_top" onmouseover="putstattext('We would like to hear from you!'); return true;">Contact</a> | Scientific FAQ | <a href="../glossary/index.html" target="_top" onmouseover="putstattext(''); return true;">Glossary</a> | <a href="../sitemap/index.html" target="_top" onmouseover="putstattext('Get an impression on IDEA!'); return true;">Site Map</a> | <a href="../search/index.html" target="_top" onmouseover="putstattext('Find documents based on keywords!'); return true;">Search</a> |  </p>