Strategies To Stabilize Dalbavancin in Aqueous Solutions; Section 3: The Effects of 2 Hydroxypropyl-β-Cyclodextrin and Phosphate Buffer with and without Divalent Metal Ions

Purpose New formulations of the glycopeptide drug dalbavancin containing 2-hydroxpropyl-ss-cyclodextrin (2HP ss CD) with or without divalent metal ions in phosphate buffer (pH 7.0) were tested to evaluate whether these excipients influence the aqueous solution stability of dalbavancin. Method Recovery of dalbavancin from phosphate buffered solutions at pH 7.0 with different concentrations of 2HP ss CD and a divalent metal ion -(Ca2+, -Mg2+, or -Zn2+) was evaluated by RP-HPLC and HP-SEC after four weeks of storage at 5 degrees C and 55 degrees C. A long-term study of formulations with 2HP ss CD and -Mg2+ was carried out over six months at 5 degrees C, 25 degrees C, and 40 degrees C using RP-HPLC. Results Dalbavancin solutions with either 5.5 mM or 55 mM 2HP ss CD were significantly more stable with -Mg2+ than with the other divalent metal ions, both at 55 degrees C for four weeks and at 40 degrees C for six months. Dalbavancin was found to be more stable in aqueous solutions at a concentration of 1 mg/mL than at 20 mg/mL with 2HP ss CD and -Mg2+ at 40 degrees C for six months. Conclusion The results suggest that 2HP ss CD forms an inclusion complex with dalbavancin that slows the formation of the major degradant, mannosyl aglycone (MAG). The effect of 2HP ss CD is increased in the presence of -Mg2+ and phosphate at pH 7.0, and the complex is more stable at a dalbavancin concentration of 1 mg/mL than at 20 mg/mL. These observations point towards the possibility of formulating a dalbavancin injection solution with a long shelf life at room temperature and physiological pH.