A PHASE IIA OPEN LABEL STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND EFFICACY OF S-1226 ADMINISTERED BY NEBULIZATION IN SUBJECTS WITH CYSTIC FIBROSIS LUNG DISEASE

Rationale: There are approximately 35,000 people with Cystic Fibrosis (CF) in North America. This condition is characterized by impaired airway clearance resulting in chronic infection and bronchiectasis. Current airway clearance treatments include nebulized hypertonic saline and Recombinant Human DNase, which may be limited by bronchospasm and cost, respectively. S-1226, a novel biophysical therapeutic agent combines carbon dioxide (CO2) enriched air (a bronchodilator) with nebulized perflubron (PFOB), (a synthetic surfactant). They act synergistically to open airways, enhance mucus clearance, and increase blood oxygenation. We report preliminary results from a Phase II clinical trial. Methods: An open label, single-center, Phase IIa study of subjects (≥14 years) with mild-moderate (FEV1 40-80%) CF lung disease treated with multiple ascending doses of S-1226 (week one), followed by the highest tolerated dose for 5 consecutive days (week two). Each dose of S-1226 comprised three successive treatments of 3mL of perflubron nebulized (Circulaire II) for two-minutes with CO2 concentrations ranging from 4 to 12%. The oxygen concentration was maintained at ambient levels. Treatments were administered twice daily. Efficacy measurements included spirometry, lung clearance index (LCI), lung volumes, blood oxygenation (SPO2), sputum weight and the respiratory domain of quality of life (QOL) questionnaire (CFQ-R). Safety included adverse event (AE) and tolerance monitoring, vital signs, and assessment of end-tidal CO2. Results: We report preliminary data on safety and efficacy for six CF subjects. All subjects tolerated all doses of S-1226. There were 5 reported AEs in 3 subjects. All were mild and resolved spontaneously. End-tidal CO2 immediately after treatment was comparable to baseline. SpO2 (baseline 91-95%) rapidly improved in all subjects with treatment. Five of six subjects had improvements in their LCI. Three subjects that were compliant in collecting mucus showed increases of 14%, 29% and 64% over baseline. Percent predicted FEV1 response was variable, decreasing initially with return to baseline values at two weeks. Four of the six subjects reported improvements in CFQ-R scores, three of which showed a clinically important difference (> 4 points). An important observation was that S-1226 controlled irritant (but not productive) cough in all five subjects and at all concentrations of S-1226. Conclusions: All doses of S-1226 were safe and well tolerated. Treatments with up to 12% extrinsic CO2 over short periods of time did not result in an elevation of end-tidal CO2. The preliminary efficacy results, including overall improved oxygen saturation, CFQ-R scores, increased expectorated mucus and LCI values provide evidence for potential beneficial effects of S-1226 for CF lung disease but require larger trials and longer-term treatments to fully assess efficacy in CF.

Formation and Physical Stability of Zanthoxylum bungeanum Essential Oil Based Nanoemulsions Co-Stabilized with Tea Saponin and Synthetic Surfactant

The purpose of this work was to evaluate the possibility of adding tea saponin (TS) to reduce the synthetic surfactant concentration, and maintain or improve the shelf stability of nanoemulsions. The Zanthoxylum bungeanum essential oil (2.5 wt%) loaded oil-in-water nanoemulsions were co-stabilized by Tween 40 (0.5–2.5 wt%) and TS (0.1–5 wt%). A combination of several analytical techniques, such as dynamic laser scattering, interfacial tension, zeta potential, and transmission electron microscope, were used for the characterization of nanoemulsions. Low levels of TS (0.1–0.5 wt%) with Tween 40 had significant effects on the emulsification, and a nanoemulsion with the smallest droplet diameter of 89.63 ± 0.67 nm was obtained. However, in the presence of high TS concentration (0.5–5 wt%), micelles generated by the non-adsorbed surfactants in the aqueous lead to droplets growth. In addition, the combinations of Tween 40 and TS at the high level (>3.5 wt%) exerted a synergistic effect on stabilizing the nanoemulsions and preventing both Ostwald ripening and coalescence. The negative charged TS endowed the droplets with electrostatic repulsion and steric hinderance appeared to prevent flocculation and coalescence. These results would provide a potential application of natural TS in the preparation and stabilization of nanoemulsions containing essential oil.

Comparative Study of Physicochemical Properties of Nanoemulsions Fabricated with Natural and Synthetic Surfactants

This work aims to evaluate the effect of two natural (whey protein isolate, WPI, and soy lecithin) and a synthetic (Tween 20) emulsifier on physicochemical properties and physical stability of food grade nanoemulsions. Emulsions stabilized by these three surfactants and different sunflower oil contents (30% and 50% w/w), as the dispersed phase, were fabricated at two levels of homogenization pressure (500 and 1000 bar). Nanoemulsions were characterized for droplet size distribution, Zeta-potential, rheological properties, and physical stability. Dynamic light scattering showed that droplet size distributions and D50 values were strongly affected by the surfactant used and the oil content. WPI gave similar droplet diameters to Tween 20 and soy lecithin gave the larger diameters. The rheology of emulsions presented a Newtonian behavior, except for WPI-stabilized emulsions at 50% of oil, presenting a shear-thinning behavior. The physical stability of the emulsions depended on the surfactant used, with increasing order of stability as follows: soy lecithin < Tween 20 < WPI. From our results, we conclude that WPI is an effective natural replacement of synthetic surfactant (Tween 20) for the fabrication of food-grade nanoemulsions.

Application of Green Surfactants in the Remediation of Soils Contaminated by Hydrocarbons

Among the innovative technologies utilized for the treatment of contaminated soils, the use of green surfactants appears to be a biocompatible, efficient, and attractive alternative, since the cleaning processes that normally use synthetic surfactants as additives cause other problems due to toxicity and the accumulation of by-products. Three green surfactants, i.e., two biobased (biobased 1 and biobased 2) surfactants produced by chemical synthesis and a microbial surfactant produced from the yeast Starmerella bombicola ATCC 22214, were used as soil remediation agents and compared to a synthetic surfactant (Tween 80). The three surfactants were tested for their ability to emulsify, disperse, and remove different hydrophobic contaminants. The biosurfactant, which was able to reduce the water surface tension to 32.30 mN/m at a critical micelle concentration of 0.65 g/L, was then used to prepare a commercial formulation that showed lower toxicity to the tested environmental bioindicators and lower dispersion capacity than the biobased surfactants. All the green surfactants showed great emulsification capacity, especially against motor oil and petroleum. Therefore, their potential to remove motor oil adsorbed on different types of soils (sandy, silty, and clay soil and beach sand) was investigated either in kinetic (flasks) or static (packed columns) experiments. The commercial biosurfactant formulation showed excellent effectiveness in removing motor oil, especially from contaminated sandy soil (80.0 ± 0.46%) and beach sand (65.0 ± 0.14%) under static conditions, while, in the kinetic experiments, the commercial biosurfactant and the biobased 2 surfactant were able to remove motor oil from all the contaminated soils tested more effectively than the biobased 1 surfactant. Finally, the S. bombicola commercial biosurfactant was evaluated as a soil bioremediation agent. In degradation experiments carried out on motor oil-contaminated soils enriched with sugarcane molasses, oil degradation yield in the sandy soil reached almost 90% after 60 days in the presence of the commercial biosurfactant, while it did not exceed 20% in the presence of only S. bombicola cells. These results promise to contribute to the development of green technologies for the treatment of hydrophobic pollutants with economic gains for the oil industries.

Non-Edible Oil Based Surfactant For Enhanced Oil Recovery

After the primary and secondary oil recoveries, a substantial amount of oil is left in the reservoir which can be recovered by tertiary methods like the Alkaline-Surfactant Flood. Reasons for having some unproduced hydrocarbon in the reservoir include and not limited to the following; forces of attraction fluid contacts, low permeability, high viscous fluid, poor swept efficiency, etc. Although, it is possible to commence waterflooding together chemical injection at the start of production. Reservoir simulation with commercial simulator, could guide in selecting the most appropriate period to commence chemical flooding. In this study, the performance of a new synthetic surfactant produced from Jatropha Curcas seed was compared with that of a selected commercial surfactant in the presence of an alkaline and this shows that the non-edible Jatropha oil is a natural, inexpensive and a renewable source of energy for the production of anionic surfactants and a good substitute for commercial surfactants like Sodium Dodecyl Sulphate (SDS). The Methyl Ester Sulfonate (MES) surfactant showed no precipitation or cloudiness during stability test and was able to reduce the Interfacial Tension (IFT) to 0.018 mN/m and 0.020 mN/m in the presence of sodium carbonate and sodium hydroxide respectively as alkaline at low surfactant concentration. The optimum alkaline surfactant formulation in terms of oil recovery performance obtained from the core flooding experiment corresponds to a concentration of sodium carbonate (0.5wt%), sodium hydroxide (0.5wt%) mixed in distilled water and Methyl Ester Sulfonate (MES) surfactant (1wt%). The injection of 0.5 percentage volume of alkaline surfactant slug produced an incremental oil recovery of 26.7% and 29% respectively. With these incremental oil recoveries, increasing demand for hydrocarbons product could be met, and returns on investment portfolio will be improved.

Potential of Salicylic Acid and Synthetic Surfactant on Anthracene and Fluoranthene Remediation by Impatiens Balsamina

Plant growth regulators and synthetic surfactants are choices for enhancing the efficiency of PAH phytoremediation. In this study, the use of salicylic acid alone, surfactant alone (Triton X-100 or Tween 80), or salicylic acid together with Triton X-100 or Tween 80 on anthracene and fluoranthene removal by Impatiens balsamina were investigated. On days 15 and 30 of the experiment, the spraying of salicylic acid as 0.01 mM and watering of 1X CMC of Triton X-100 or Tween 80 were performed. Then, the plant growth parameters and anthracene or fluoranthene remaining in the soil were analyzed on day 45 of the experiment. The results revealed that I. balsamina did not enhance anthracene (77.4 % remained) and fluoranthene (74.6 % remained) removal when compared with unplanted soil (63.8 % of anthracene and 70.0 % of fluoranthene remained). Salicylic acid spraying in combination with watering of Triton X-100 (47.1 % anthracene remained) or Tween 80 (59.7 % anthracene remained) enhanced anthracene removal in unplanted soil; however, enhanced fluoranthene removal was not observed. In planted soil, salicylic acid spraying alone, Tween 80 watering alone or salicylic acid spraying in combination with synthetic surfactant (Triton X-100 or Tween 80) watering slightly enhanced anthracene removal (54.9-58.0 % of anthracene remained) but not fluoranthene (67.9 - 81.9 % of fluoranthene remained). The results revealed that planting contaminated soil with I. balsamina was not suitable to stimulate anthracene and fluoranthene degradation in this study. Biostimulation of unplanted soil with synthetic surfactant and salicylic acid was suitable to stimulate the removal of anthracene from the soil.