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-β-cyclodextrin (2HPβCD) 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 2HPβCD and a divalent metal ion (Ca, Mg, or Zn) was evaluated by RP-HPLC and HP-SEC after four weeks of storage at 5°C and 55°C. A long-term study of formulations with 2HPβCD and Mg was carried out over six months at 5°C, 25°C, and 40°C using RP-HPLC.

Results: Dalbavancin solutions with either 5.5 mM or 55 mM 2HPβCD were significantly more stable with Mg than with the other divalent metal ions, both at 55°C for four weeks and at 40°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 2HPβCD and Mg at 40°C for six months.

Conclusion: The results suggest that 2HPβCD forms an inclusion complex with dalbavancin that slows the formation of the major degradant, mannosyl aglycone (MAG). The effect of 2HPβCD is increased in the presence of Mg 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.