Recrystallization of Adenosine for Localized Drug Delivery

• Published in: Molecular pharmaceutics Vol. 19; no. 9; pp. 3394 - 3404
• Main Authors: Velankar, Ketki Y., Mou, Mingyao, Hartmeier, Paul R., Clegg, Benjamin, Gawalt, Ellen S., Jiang, Mo, Meng, Wilson S.
• Format: Journal Article
• Language: English
• Published: American Chemical Society 05.09.2022
• Subjects: immunomodulation; drug delivery; inflammation; highly concentrated formulations; albumin; pharmaceutical crystals
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.2c00527

Adenosine (ADO) is an endogenous metabolite with immense potential to be repurposed as an immunomodulatory therapeutic, as preclinical studies have demonstrated in models of epilepsy, acute respiratory distress syndrome, and traumatic brain injury, among others. The currently licensed products Adenocard and Adenoscan are formulated at 3 mg/mL of ADO for rapid bolus intravenous injection, but the systemic administration of the saline formulations for anti-inflammatory purposes is limited by the nucleoside’s profound hemodynamic effects. Moreover, concentrations that can be attained in the airway or the brain through direct instillation or injection are limited by the volumes that can be accommodated in the anatomical space (<5 mL in humans) and the rapid elimination by enzymatic and transport mechanisms in the interstitium (half-life <5 s). As such, highly concentrated formulations of ADO are needed to attain pharmacologically relevant concentrations at sites of tissue injury. Herein, we report a previously uncharacterized crystalline form of ADO (rcADO) in which 6.7 mg/mL of the nucleoside is suspended in water. Importantly, the crystallinity is not diminished in a protein-rich environment, as evidenced by resuspending the crystals in albumin (15% w/v). To the best of our knowledge, this is the first report of crystalline ADO generated using a facile and organic solvent-free method aimed at localized drug delivery. The crystalline suspension may be suitable for developing ADO into injectable formulations for attaining high concentrations of the endogenous nucleoside in inflammatory locales.