Rational design of new product candidates: The next generation of highly deformable bilayer vesicles for noninvasive, targeted therapy

Amphipat bilayer vesicles are a subgroup of “fat-and-water” mixtures useful as drug carriers. Scrutinising amphipat aggregation in terms of the popular molecular descriptors (esp. the Israelachvili's form-factor or HLB number) is “too static” to foretell reliably and quantitatively bilayer vesicle formation. A better predictor introduced in this work is the effective area per lipid chain (cross-section of a “tail”, Ac), which also correlates, quasi-exponentially, with the ease of bilayer vesicle formation and bilayer deformability. The latter is highest near an uppermost, bilayer-compatible but nearly headgroup independent, Ac-value reachable on different paths to bilayer solubilisation. The deformable bilayer vesicles class is thus more diverse than had previously been recognised. It includes phospholipid or phospholipid-surfactant blends (1st generation), synergistic phospholipid-amphipat or drug mixtures (2nd generation), and novel (non-phospholipid) amphipat combinations with appropriate effective tail(s) cross-section (3rd generation). Typically, vesicularisation ability and bilayer adaptability of such preparations is proportional, and arguably depends upon, the dynamic and stress-dependent molecular re-arrangement during aggregate formation and bilayer adaptation. In the previously described formulations such re-arrangement took place within or across the mixed lipid bilayer. This work shows that water-soluble molecules redistribution near a bilayer surface can be similarly effective. The new mechanism for bilayer properties modulation thus potentially avoids using harsher molecules in the adaptable vesicles, and can utilise buffers, microbicides, etc., in their stead. A plethora of amphipats can comprise hyper-adaptable vesicles of the new generation, including some that are more stable than the previously recognised ones. Encompassing well-chosen hydrophilic additive(s) and/or drug(s), such hyper-adaptable vesicles can be blended into fluid or semisolid preparations suitable for non-invasive, and potentially parenteral, applications. Pharmacologically relevant examples include, but are not limited to, the composite adaptable phospholipid-free vesicles loaded with anti-mycosis drugs (such as terbinafine), surfactant-free preparations of non-steroidal anti-inflammatory drugs (such as indomethacin or ketoprofen), etc. Further interesting implementations of the new technology contain hyper-adaptable drug-free vesicles that suppress human skin inflammation after local application better than hydrocortisone and broadly similar to conventional topical NSAIDs. The carriers described in this work thus provide unprecedented options for cutaneous or targeted subcutaneous deposition of drugs and/or for the sustained delivery of the corresponding carrier associated therapeutic agents.

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