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W/O/W nanoemulsion O/W nanoemulsion 1 Friedrich-Schiller-University Jena, Department of Pharmaceutical Technology, Germany 2 Sopharcos, Germany 3 Jena University Hospital, Center of Electron Microscopy, Germany O/W and W/O/W nanoemulsions as natural dermal drug delivery systems Schmidt, Felix 1 ; Blume, Gabriele 2 ; Thamm, Jana 1 ; Steiniger, Frank 3 ; Fischer, Dagmar 1 [email protected] CRS Germany Local Chapter 21 th annual meeting 2-3 March 2017, Marburg mean SD mean SD O/W 0.988 0.017 1.38097 0.00156 W/O/W 1.005 0.001 1.36564 0.00138 liposomes 1.018 0.001 1.36194 0.00112 Physical properties Density 20 °C [g/cm 3 ] Refractive index 20 °C g 589 nm Introduction Conclusion Nanoemulsions are small, kinetically stable drug carriers. Aim of this study was to optimize an O/W and a W/O/W system regarding natural, renewable oils and emulsifiers to formulate a repro- ducible, stable, skin friendly, penetrating and low irritating formulation for different pharmaceutical and cosmetic applications. Flexible liposomes consisting of phosphatidylcholine (Lipoid S 75®) were used as control delivery system for hydrophilic and lipophilic substances to show the advantages of the O/W and W/O/W nano- emulsions, composed of Imwitor 375®, sunflower oil or ethyl oleate. o O/W and W/O/W nanoemulsions preserved with 14% (w/w) propylene glycol were highly stable and pH skin neutral under the tested conditions. o The simultaneous decrease of pH value and increase of zeta potential of both nanoemulsions after 90 days at 40 °C seemed not to affect the stability of the systems. o No toxic or irritating effects could be observed in the HET-CAV. o O/W and W/O/W nanoemulsions are promising candidates for an efficient dermal drug delivery in pharmacy and cosmetics. Stability of particle size and zeta potential. Hydrodynamic diameter and polydispersity (PDI) of (a) liposomes, (b) O/W and (c) W/O/W nanoemulsions indicated, that all nanocarriers were stable over 3 months at different temperatures. The zeta potential of (b, c) nanoemulsions slightly increases, especially at 40 °C. Properties of carriers, preserved with 14% propylene glycol. Density, refractive index and pH value were investigated to characterize the formulations and adjust measurements of size, polydispersity and zeta potential by dynamic light scatting. After 24 hours of incubation no adverse effects were obtained for any carrier system, preserved with 14% propylene glycol. The irritating potential of the formulations was investigated in an ex ovo test at the chick area vasculosa of hen’s eggs (HET-CAV). Evaluation regarding vascular lysis, thrombosis, hemorrhage and death for 24 hours. chick area vasculosa yolk sack embryo Transfer of pre-incubated (72 hours) hen’s eggs into Petri dishes with Ringer solution (pH 7.4). Schematic preparation Topical application of the samples (5 μL). 8 °C 24 °C 40 °C 0 1 7 30 90 0 1 7 30 90 0 1 7 30 90 liposomes [14% (w/w) propylene glycol] 0 50 100 150 200 Hydrodynamic diameter [nm] [d] Liposomes 0.0 0.1 0.2 0.3 0.4 PDI PDI -40 -35 -30 -25 -20 -15 -10 -5 0 zeta potential zeta potential [mV] a 8 °C 24 °C 40 °C 0 1 7 30 90 0 1 7 30 90 0 1 7 30 90 W/O/W [14% (w/w) propylene glycol] 0 50 100 150 200 Hydrodynamic diameter [nm] [d] W/O/W nanoemulsion 0.0 0.1 0.2 0.3 0.4 PDI PDI -40 -35 -30 -25 -20 -15 -10 -5 0 zeta potential zeta potential [mV] c 8 °C 24 °C 40 °C 0 1 7 30 90 0 1 7 30 90 0 1 7 30 90 O/W [14% (w/w) propylene glycol] 0 50 100 150 200 Hydrodynamic diameter [nm] [d] O/W nanoemulsion 0.0 0.1 0.2 0.3 0.4 PDI PDI -40 -35 -30 -25 -20 -15 -10 -5 0 zeta potential zeta potential [mV] b 0 15 30 45 60 75 90 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.6 5.8 6.0 6.2 6.4 6.6 6.8 °C pH value O/W [14% (w/w) propylene glycol] W/O/W [14% (w/w) propylene glycol] liposomes [14% (w/w) propylene glycol] 8 24 40 8 24 40 8 24 40 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.6 5.8 6.0 6.2 6.4 6.6 6.8 pH value [d] Stability of pH. left:-pH values remained stable after storage at 24 °C for at left:-least 90 days. right:-O/W and W/O/W nanoemulsions showed a tem- right:-perature depended stability after 3 month. nano O/W [14% (w/w) propylene glycol] W/O/W [14% (w/w) propylene glycol] liposomes [14% (w/w) propylene glycol] Transmission Electron Microscopy of the systems HydroTops is a multiple water-in-oil-in-water (W/O/W) nanoemulsion suitable to encapsu- late lipophilic and hydrophilic drugs. Only one emulsifier is required to prepare the W/O/W emulsion in one step. LipoTops, an oil-in-water (O/W) nanoemulsion, is a carrier system for lipophilic drugs and oils. In contrast to microemulsions the ratio of oil :l water is 20 : 5, the system is more skin friendly, dilutable and temperature stable. High pressure homogenization under continuous ice cooling [20 ≤ ϑ ≤ 30 °C] O/W [540 bar, 1 min] liposomes [540 bar, 2 min] W/O/W [340 bar, 1 min] Production of the different systems Mixing of the hydrophilic phase by Ultra-Turrax® [9000 rpm, 1 min] Stirring of emulsifiers, preservative & lipophilic ingredients [ϑ ≤ 50 °C] Comparative electron micro- graphs illustrated the struc- tural differences between the systems. left:-The bilayer structure of left:-liposomes confirmed left:-with CryoTEM. right:-The multiple core of right:-W/O/W nanoemulsion right:-after freeze fracture. O/W [14% (w/w) propylene glycol] 1 cm W/O/W [14% (w/w) propylene glycol] 1 cm Solvent control II: Sörensen phosphate buffer [pH = 6.5] 1 cm Solvent control I: Water 1 cm Positive control: Sodium dodecyl sulfate [1% (w/w) in water] 1 cm liposomes [14% (w/w) propylene glycol] 1 cm Negative control: Sodium chloride [0.9% (w/w) in water] 1 cm Ex ovo compatibility. top-row:-Only the positive top-row:-control led to top-row:-hemorrhage. right-row:-After applying the right-row:-formulations on right-row:-top of the CAV, no right-row:-adverse effects right-row:-could be visually right-row:-observed after right-row:-24 hours. Biological assay Characterization & stability
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