Development of Cordycepin Formulations for Preclinical and Clinical Studies

Abstract

There is extensive literature on in vivo studies with cordycepin, but these studies were generally conducted without validation of the various formulations, especially in terms of the solubility of cordycepin in the dosing vehicles used. Cordycepin is a promising drug candidate in multiple therapeutic areas, and there is a growing interest in studies aimed at assessing the pharmacological activity of this compound in relevant animal disease models. It is likely that many reported in vivo studies used formulations in which cordycepin was incompletely soluble. This can potentially confound the interpretation of pharmacokinetics and efficacy results. Furthermore, the presence of particles in intravenously administered suspension can cause adverse effects and should be avoided. Here, we present the results from our development of simple and readily applicable formulations of cordycepin based on quantitative solubility assessment. Homogeneous solutions of cordycepin were prepared in phosphate-buffered saline (PBS) at different pH levels, suitable as formulations for both intravenously and oral administration. For the purpose of high-dose oral administration, we also developed propylene glycol (PPG)-based vehicles in which cordycepin is completely soluble. The stability of the newly developed formulations was also assessed, as well as the feasibility of their sterilisation by filtration. Additionally, an HPLC-UV method for the determination of cordycepin in the formulations, which may also be useful for other purposes, was developed and validated. Our study could provide useful information for improvement of future preclinical and clinical studies involving cordycepin.

The polyadenylation inhibitor cordycepin reduces pain, inflammation and joint pathology in rodent models of osteoarthritis

“…Control group included those having sham surgery, in which the ligament was visualised but not transected. From week 14 to 16 mice were orally gavaged every other day with 200 µl cordycepin (8 mg/kg) or vehicle (23% propylene glycol [PPG] in distilled water) 34 . Pain behaviour was measured once weekly following model induction and then twice weekly following cordycepin treatment, until week 16.…”

A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin

“…Prior to pharmacokinetic studies, jugular vein cannulation surgery was performed under general anaesthesia (<3% isoflurane inhalation) for blood sampling or intravenous drug administration. Following two nights of recovery from surgery, the animals were intravenously or orally administered with the PBS-based formulation (5.5 mg/mL cordycepin) developed in a previously reported study 22 . The dose was 8 or 20 mg/kg for intravenous administration and 8 or 80 mg/kg for oral administration.…”

“…Cordycepin has been reported to have a diverse range of pharmacological effects of which the most well-studied areas include anti-inflammation, anti-proliferation and pro-apoptosis 19–21 . The wide range of potential therapeutic applications of cordycepin has drawn substantial research interest in the compound which resulted in numerous preclinical in vivo efficacy studies in different species 22 . Reports include claims of efficacy in animal models of bone loss 23 , vascular disorder 24 , cognitive dysfunction 25 , sleep disorders 26 , cancer 21,27 , neuronal degeneration 28 , hyperlipidaemia 29 , oxidative stress 30 , hyperglycaemia 31 , asthma and lung inflammation 32 and viral infection 33 .…”

Therapeutic Potential and Biological Applications of Cordycepin and Metabolic Mechanisms in Cordycepin-Producing Fungi

“…Previous work demonstrated that phosphate-buffered saline (PBS, pH 4.0) is a suitable solvent for COR in intravenous and oral treatments at low doses. Propylene glycol (PPG) is more applicable than PBS at pH 4.0 as a COR solvent for oral treatments [136]. Complex mechanisms of action: COR inhibits and/or induces multiple medicinal targets in a dose-dependent, condition-dependent and nonspecific manner: Different concentrations of COR exhibit diverse effects on MA-10 mouse Leydig tumor cells (MLTCs).…”

“…Previous work demonstrated that phosphate-buffered saline (PBS, pH 4.0) is a suitable solvent for COR in intravenous and oral treatments at low doses. Propylene glycol (PPG) is more applicable than PBS at pH 4.0 as a COR solvent for oral treatments [136].…”