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

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.

Keywords: captisol; cyclodextrin; ketamine; ketamine formulation; osmolality; subcutaneous injection.

Figure 1

Proposed salt formation and complexation of ketamine with Captisol^® to form KetCap.

Figure 2

Dilution vs. osmolality of Ketamine HCl and formulations. Measured osmolalities of Ketamine HCl, KetCap, and Ketamine-HCl-Captisol^® at different concentrations obtained following dilution of 100 mg/mL stock formulations. Data presented as mean ± SEM. N = 3.

Figure 3

Titration of 100 mg/mL Ketamine, KetCap, and Ketamine-HCl-Captisol^® Formulations with 1M HCl. Starting pHs 5.50 ± 0.01. Experiments carried out on a 2 mL volume. Data presented as mean ± SEM. N = 3.

Figure 4

Relationship of ketamine concentration on pH, for Ketamine HCl, KetCap, and Ketamine-HCl-Captisol^® formulations. Data presented as mean ± SEM. N = 3.