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Optimum Topical Delivery of Adrenergic Agonists to Oral Mucosa Vasculature

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Abstract

Purpose

Identify an orotopical vehicle to deliver an α-adrenergic vasoconstrictor to submucosal vasculature that is readily palatable to cancer/bone marrow transplant patients that suppresses chemo-radiotherapy-associated oral mucositis.

Methods

A [3H] norepinephrine ligand binding assay was developed to quantify receptor binding in hamster oral mucosa. Vehicle components (alcohols, polyols, cellulose, PVP) were tested versus [3H] norepinephrine binding. Vehicle refinement was also done to mask phenylephrine bitter taste and achieve human subject acceptance. The optimized vehicle was tested with α-adrenergic active agents to suppress radiation-induced oral mucositis in mice.

Results

The ligand binding assay quantified dose- and time-dependent, saturable binding of [3H] norepinephrine. An ethanol:glycerol:propylene glycol:water (6:6:8:80) vehicle provided the best delivery and binding. Further vehicle modification (flavoring and sucralose) yielded a vehicle with excellent taste scores in humans. Addition of phenylephrine, norepinephrine or epinephrine to the optimized vehicle and painting into mouse mouths 20 min before 19 Gy irradiation conferred significant suppression of the weight loss (P < 0.001) observed in mice who received oral vehicle.

Conclusion

We identified a highly efficient vehicle for the topical delivery of phenylephrine to the oral mucosa of both hamster and human subjects. This will enable its testing to suppress oral mucositis in an upcoming human clinical trial.

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Abbreviations

OM:

Oral mucositis

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by grants from the Wisconsin Alumni Research Foundation (WARF, University of Wisconsin-Madison) and ProCertus BioPharm, Inc. (Madison, WI).

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Authors and Affiliations

  1. McArdle Laboratory for Cancer Research, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA

    Cheryl M. Soref & William E. Fahl

  2. ProCertus BioPharm, Inc., Madison, Wisconsin, USA

    Cheryl M. Soref & William E. Fahl

  3. 1400 University Avenue, Madison, Wisconsin, 53706, USA

    William E. Fahl

Authors
  1. Cheryl M. Soref
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  2. William E. Fahl
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Correspondence to William E. Fahl.

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Soref, C.M., Fahl, W.E. Optimum Topical Delivery of Adrenergic Agonists to Oral Mucosa Vasculature. Pharm Res 32, 492–499 (2015). https://doi.org/10.1007/s11095-014-1477-1

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  • DOI: https://doi.org/10.1007/s11095-014-1477-1

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