Three Birds, One Excipient: Development of an Improved pH, Isotonic, and Buffered Ketamine Formulation for Subcutaneous Injection

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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.

The paper gives a good review on SBECD: “At least nine FDA-approved drug products contain Captisol® [5]. For instance, 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]. Captisol® is used as a suitable replacement for co-solvents such as propylene glycol, as in the case of Evomela, an FDA-approved melphalan injectable for cancer treatment [7]. Orally administered antipsychotics ziprasidone and aripiprazole have been formulated with Captisol® to produce formulations suitable for intramuscular (IM) injection [2]. While there are diverse applications for this excipient, most research and existing applications involve complexation of small organic molecules with Captisol® to improve solubility.”

Pharmaceutics 14 00556 g001 550
Figure 1. Proposed salt formation and complexation of ketamine with Captisol® to form KetCap.

Wallach, J.; Gamrat, J.; Jauhola-Straight, R.; Becker, J.; Eckrich, T. Three Birds, One Excipient: Development of an Improved pH, Isotonic, and Buffered Ketamine Formulation for Subcutaneous Injection. Pharmaceutics 202214, 556.

This work has been granted a United States Patent; US Patent No. 10,973,780.

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