(T1330-12-78) Thermally Gelling Hypromellose Liquid Sprays for Oropharyngeal Targeting

Purpose:

Purpose: To evaluate the potential of utilizing thermally gelling liquid sprays incorporating Hypromellose or hydroxypropyl methylcellulose (HPMC) for targeted drug delivery to the oropharynx by determining: (1) a suitable aerosol spray pattern of HPMC for oropharyngeal targeting using a high viscosity spray bottle, and (2) a suitable concentration of a rapid gelling aid to trigger thermal gelation (Tgel) at body temperature (37 °C). Oral Human Papillomavirus (HPV) is a prevalent disease that poses a significant risk of developing into oropharyngeal cancer.¹ Targeted drug delivery to the oropharynx through a thermally gelling liquid spray that incorporates a mitogen-activated protein/extracellular signal-regulated kinase enzyme (MEK) inhibitor drug could effectively prevent and treat HPV-related oropharyngeal cancers. HPMC has been long known to exhibit thermal gelation properties², and has potential to be used for liquid spray formulations, providing favorable properties for targeted drug delivery to the oropharynx³.

Methods: Spray pattern: HPMC solutions (Methocel^® E6 or E50; IFF Pharma Solutions, Wilmington, DE) containing blue food coloring at varying concentrations and molecular weights were tested using a high viscosity spray bottle (Cuisinart, Stamford, CT), positioned with a standardized USP aerosol cascade impaction induction port distance of 7.9 cm from a white paper target. A single spray atomization was actuated, and the resulting features of the spray dispersion radius and impact droplet size were evaluated by circling the outermost observed spray droplets from the center of impact, and by visual inspection of droplet pattern. Each concentration was additionally tested with the inclusion of Transcutol^® (Gattefossé USA, Paramus, NJ) at 15% w/v to investigate its potential impact on the spray pattern properties. Thermal gelation of sprays: Concentrations of 1-2.5% w/v of the gelling aid sodium fluoride (NaF; Sigma-Aldrich, Inc. St. Louis, MO) were added to a standard 2% w/v HPMC E6 + 5% w/v Transcutol solution. Rheological studies were conducted to determine the Tgel, observed as a rapid increase in elastic storage modulus (G’).

Results: For spray pattern determination, 2% w/v HPMC E6 was determined to be the optimal concentration for use with the high viscosity spray bottle at room temperature, due to its ease of spray, optimal targeted spray radius, and little coalescence of the impacted droplets (Figure 1). Furthermore, and in all cases, our observations were that the addition of 15% w/v Transcutol had no detrimental effect on spray properties. Thus, we opted to continue further investigations using the 2% w/v HPMC E6 + Transcutol formulation. To find body temperature Tgel, a calibration curve was generated for various NaF concentrations with 2% w/v HPMC E6 +5% w/v Transcutol spray solutions, versus gelation temperature (Figure 2). It was found that a concentration of 1.66% NaF resulted in gelation at 37°C.

Conclusion: Favorable spray properties and gelation temperatures are important factors in investigating optimal drug delivery systems, and the results of these tests demonstrate that a 2% w/v HPMC+ 5% w/v Transcutol with a 1.7% NaF w/v concentration shows potential for targeted delivery of MEK inhibitors to the oropharynx for sustained release.

References: 1. Walboomers, J.M.M., M.V. Jacobs, M.M. Manos, F.X. Bosch, J.A. Kummer, K.V. Shah, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. The Journal of Pathology 1999;189:12-19.
2. Sarkar N. Thermal gelation properties of methyl and hydroxypropyl methylcellulose. Journal of applied polymer science. 1979 Aug 15;24(4):1073-87.
3. McConville J.T., Sadeghi E. Oral Gelling Liquid Formulations. (2022). US11, 369,631 B1.

Acknowledgements: The authors would like to acknowledge support for this project from International Flavors and Fragrances (IFF) and Gattefossé USA.

Figure 1. Spray dispersion radius and impact droplet size of thermally gelling HPMC solutions. (A) 5% w/v HPMC E50, (B) 5% w/v HPMC E50 + 15% w/v Transcutol, (C) 2% w/v HPMC E50, (D) 2% w/v HPMC E50 + 15% w/v Transcutol, (E) 2% w/v HPMC E6, (F) 2% w/v HPMC E6 + 15% w/v Transcutol, (G) 1% w/v HPMC E50, (H) 1% w/v HPMC E50 + 15% w/v Transcutol.

Figure 2. Thermal gelation temperature of 2% w/v HPMC E6 + 5% Transcutol with various NaF concentrations.
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