Transfersome® vesicles are ultradeformable drug carriers for the local treatment of diseases in superficial and deeper dermal tissues. A new all-purpose Transfersome® formulation was developed in this work using bilayer forming SPC and bilayer softening amphiphile C18:1EO20. Lipid bilayer saturation with C18:1EO20 was reached at an effective surfactant to lipid molar ratio of Resat = 0.25 mol/mol, confirmed in triplicate by static and dynamic light scattering, and continuous membrane adaptability assay. Time-resolved dynamic light scattering showed biphasic solubilisation kinetics above the solubilisation limit of Resol = 3 mol/mol and enabled deducing molecular properties of C18:1EO20 like the effective diffusion constant, Deff = 2.8 x 2.8 x 10-10 m2s-1, or the surface excess Γ ~ 0.1 nm2. With Resat = 0.25 mol/mol the bending rigidity of surfactant-free SPC liposomes could be reduced by a factor of ~ 8 to κc = 2.5 kBT. Combination of such flexible SPC/C18:1EO20 bilayer vesicles with negatively charged ketoprofen, positively charged bupivacaine, or uncharged ethanol could synergistically reduce the membrane bending rigidity in concentration, pH, and ionic strength dependent manner to the thermal energy level at at κc ≈ kBT. Potentiometric partition measurements with uncharged ketoprofen and bupivacaine yielded partition coefficient values in a lipid bilayer/water system comparable to those in a 1-octanol/water system, being log PNmem = 3.0 - 3.3 for ketoprofen and log PNmem = 2.1 - 2.4 for bupivacaine. In dependency on the bulk salt concentration and electrostatics, the partition coefficient for ionized ketoprofen ranged from log PImem = 0.15 to 1.18 and for ionized bupivacaine from log PImem = 1.2 to 1.6, both significantly higher compared to 1-octanol/water values.