Enhancing the Spreading Behavior of Drug Formulations on Pulmonary Airway: Effect of Catanionic Surfactant Mixtures

Lungs carry a great potential to be used in drug delivery since they have a large surface area and possess low catabolic enzymatic activity. Pulmonary airways are covered with mucus layer, which acts as a biological barrier against the foreign particles, dusts and pathogens and while this natural barrier protects the lungs, it also obstructs the drug delivery through the lungs[1]. Efficient spreading of the therapeutic agents on the airways is the one of the key parameters for successful drug delivery through the lungs. Particularly in case of lung diseases such as cystic fibrosis, the viscosity and the thickness of the mucus layer increases and it becomes harder for drug formulations to spread on the airways. Therefore, importance of effective spreading of the therapeutics on the airway increases. Commonly, aerosolized formulations are used for the treatment of such diseases. Although spreading experiments have been conducted with different types of formulations on mucus-mimicking subphases, an effective formulation could not have been developed, yet[2]. Basically, spreading of the formulations on a viscous surface such as mucus, depend on both the surface tension difference between the phases and surface tension gradient between the center and the edge of the spreading film in the radial direction[3]. This gradient triggers the Marangoni forces and as a result, spreading occurs in the direction from lower surface tension to higher. As lower surface tension provides higher surface tension gradient, spreading behavior can be enhanced by adding surface-active molecules to the formulations.

From this point of view, in this study catanionic (cationic+anionic) surfactant mixtures are used owing to their advantageous interfacial and bulk properties such as possessing lower CMC and providing lower surface tension value than its individual components. Catanionic surfactant mixtures composed of Dodecyltrimethyl ammonium bromide (DTAB) and Dioctyl sulfosuccinate sodium salt (AOT) mixed at various mole ratios are prepared and their spreading performances on both mucin and cystic fibrosis mucus model are investigated for the first time in the literature. Characterizations of the catanionic mixtures are implemented with the surface tension measurements and light scattering analysis. Spreading experiments are utilized via tracking the movements of tracer particles by a tracking tool and analyzing their spreading characteristics by fitting the spreading radius of the tracking particles to a power-law. Also, contact angle measurements of the mixtures are performed.

Surface tension measurements of the mixtures with different ratios of DTAB/AOT have showed that a synergistic interaction is obtained between the components of the mixtures, as expected. Synergistic interaction provided lower CMC values for the mixtures, and accordingly the equilibrium surface tension of the solutions had reached to lower values than the surface tension of the molecules contributing to the mixture. Decrement of the surface tension value had directly affected the spreading behavior of the mixtures. This interaction had also seen as an increment in the micelle sizes and the increasing asymmetry at the structures.

Spreading behaviors of the mixtures are analyzed by comparing the spreading radii of the chosen tracer particle when pure DTAB, pure AOT or the mixtures are applied to the surface of mucin. Due to its cationic structure, DTAB solution has not spread at all, whereas the spreading radius of the tracer particle, when pure AOT solution had been introduced to the surface, is determined as 11.67±0.23 mm. It is obtained that catanionic surfactant mixtures at all mixing ratios spread more than 10 mm. Especially, mixtures with the mole ratios of X_DTAB=0.8 and X_DTAB=0.7 provided superior spreading performances than both of the individual components of the mixtures even though the mole fraction of DTAB in the mixture is at least 7 times higher than AOTs. Spreading radii for these mixtures are obtained as 13.21±0.35 and 13.96±0.43 mm, respectively. Moreover, for every mixing ratio, both DTAB-rich and AOT-rich mixtures have spread faster than the pure AOT and pure DTAB. Above all, the spreading regime of the DTAB-rich mixtures is determined as Marangoni-dominant, which means that superspreading of the droplets on the mucin is observed. Even on the cystic fibrosis sputum model, the spreading of the droplet has been enhanced compared to pure surfactants and the spreading of the mixtures are again in the Marangoni-dominant region.

In the light of the results, we propose that this type of mixtures can be used successfully for enhancing the spreading behavior of the formulations that will be used in the treatment of lung diseases.

REFERENCES
[1] B.S. Schuster, J.S. Suka, G.F. Woodworth, J. Hanes, Biomaterials, 34 (2013) 3439-3446

[2] K. Koch, B. Dew, T.E. Corcoran, T.M. Przybycien, R.D. Tilton, S. Garoff, Molecular Pharmaceutics, 8 (2011) 387–394.

[3] R. Sharma, T.E. Corcoran, S. Garoff, T.M. Przybycien, E.R. Swanson, R. D. Tilton, ACS Applied Materials & Interfaces, 5 (2013) 5542-5549.