Abstract
Subcutaneous (SC) ketamine has been found to be effective in pain management, though reports of injection site irritation and sterile abscesses exist with currently available ketamine HCl formulations. Such adverse SC reactions are commonly associated with low pH, high osmolality and/or high injection volumes. An optimal SC formulation of ketamine would thus have a pH and osmolality close to physiological levels, without compromising on concentration and, thus, injection volume. Such a formulation should also be buffered to maintain the pH at the acceptable level for extended time periods. As many of these physicochemical properties are interrelated, achieving these aims represented a significant challenge in formulation development. We describe the development of a novel Captisol®-based formulation strategy to achieve an elevated pH, isosmotic and buffered formulation of ketamine (hence, three birds, one excipient) without compromising on concentration. This strategy has the potential to be readily adapted to other amine-based APIs.
Highlights
Subcutaneous (SC) ketamine has been found to be effective in pain management, though reports of injection site irritation and sterile abscesses exist with currently available ketamine HCl formulations
The FDA-approved antiarrhythmic, Nexterone, contains amiodarone HCl complexed with Captisol® to allow for a bolus IV injection while reducing the adverse hypotensive effects observed with previous formulations [6]
SC ketamine is effective in pain management, reports of injection site irritation and sterile abscesses exist with ketamine HCl formulations [18,19]
Summary
Cyclodextrins are cyclic oligomers composed of varying numbers of glucopyranose monomers. Cyclodextrins have become common excipients of pharmaceutical formulations Their utility comes from the fact that cyclodextrins form inclusion complexes with small organic molecules. Pharmaceutics 2022, 14, 556 stability of small organic molecule active pharmaceutical ingredients for use in intravenous (IV) and other parenteral injection formulations [4]. The FDA-approved antiarrhythmic, Nexterone, contains amiodarone HCl complexed with Captisol® to allow for a bolus IV injection while reducing the adverse hypotensive effects observed with previous formulations [6]. SC ketamine is effective in pain management, reports of injection site irritation and sterile abscesses exist with ketamine HCl formulations [18,19] We hypothesize that these adverse reactions are due, at least in part, to a low pH and/or high osmolality characteristic of commercial ketamine HCl formulations. The approach described has the potential to be adapted for other amine-based APIs
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