Enhanced oral absorption and biodistribution to submandibular salivary glands of D-limonene in Sprague Dawley rats via a liquid-lipid formulation approach

Leah Wright; Anthony Wignall; Santhni Subramaniam; Hayley B Schultz; Paul Joyce; Clive A Prestidge

doi:10.1016/j.ijpharm.2025.125179

Enhanced oral absorption and biodistribution to submandibular salivary glands of D-limonene in Sprague Dawley rats via a liquid-lipid formulation approach

Int J Pharm. 2025 Jan 6:670:125179. doi: 10.1016/j.ijpharm.2025.125179. Online ahead of print.

Authors

Leah Wright¹, Anthony Wignall¹, Santhni Subramaniam¹, Hayley B Schultz¹, Paul Joyce¹, Clive A Prestidge²

Affiliations

¹ UniSA: Clinical & Health Sciences, University of South Australia, Adelaide, Australia.
² UniSA: Clinical & Health Sciences, University of South Australia, Adelaide, Australia. Electronic address: [email protected].

PMID: 39778728
DOI: 10.1016/j.ijpharm.2025.125179

Abstract

Decreased saliva production due to salivary gland damage can result in difficulty speaking and swallowing, significantly reducing quality of life for head and neck cancer patients receiving radiotherapy. It is therefore imperative that treatment options are available to mitigate the effects of these debilitating side effects. D-limonene, a naturally occurring terpene, has shown protective effects on saliva production during radiotherapy treatment of mice, however the lipophilic nature of the molecule has necessitated a high oral dose to facilitate sufficient absorption. In this study, lipid-based drug delivery systems have been utilised to formulate D-limonene in order to reduce undesirable gastrointestinal side effects and increase solubility for enhanced absorption. Lipid-based formulations produced up to 180-fold increased solubility over pure D-limonene, coupled with enhanced storage stability and protection against oxidation. Furthermore, pharmacokinetic evaluation of optimised lipid-based formulations in Sprague Dawley rats displayed up to a 51.25-fold increase in bioavailability relative to pure oral D-limonene. Finally, elevated levels of lipid-formulated D-limonene were localised within the submandibular salivary glands, indicating potential for local action on saliva production. Overall, the administration of D-limonene utilising lipid-based formulations shows significant promise for advancing prevention and treatment strategies for xerostomia.