稳定水溶液中达巴万星的策略；第 1 节：金属离子和缓冲液的影响。

Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-1: the Effects of Metal Ions and Buffers.

机构信息

Hikma Pharmaceuticals, Bedford, OH, 44146, USA.

Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115, USA.

出版信息

Pharm Res. 2023 Oct;40(10):2469-2478. doi: 10.1007/s11095-023-03588-9. Epub 2023 Sep 11.

DOI:10.1007/s11095-023-03588-9

PMID:37697173

Abstract

PURPOSE

The effect of monovalent (Na and K) and divalent (Ca, Mg, and Zn) metal ions combined with citrate or acetate buffers (pH 4.5) on the stability of dalbavancin in aqueous solutions was investigated.

METHOD

RP-HPLC and HP-SEC were used to evaluate the stability of aqueous solutions of dalbavancin in different combinations of buffers and metal ions after four weeks of storage at 5°C and 55°C. A long-term study of formulations with divalent metal ions was conducted over six months at 5°C., 25°C and 40°C using RP-HPLC.

RESULTS

All formulations in citrate buffered solutions precipitated. Dalbavancin solutions in 10 mM acetate buffer at 55°C were more stable in 10 mM CaCl, 5 mM ZnCl and 10 mM MgCl than those containing 2 mM NaCl or 5 mM KCl, although the MgCl formulations precipitated slightly. No significant effect was observed for any of the divalent metal ions at 40°C for six months.

CONCLUSION

Dalbavancin's stability in solution was improved by a combination of acetate and divalent metal ions at 55°C for four weeks. No effect was observed with acetate or metal ions alone, and no effect was observed after six months at 40°C suggesting that acetate and divalent metal ions together interact with dalbavancin via a thermally activated step to inhibit hydrolysis of the drug.

摘要

目的

考察单价（Na 和 K）和二价（Ca、Mg 和 Zn）金属离子与柠檬酸盐或醋酸盐缓冲液（pH4.5）组合对达巴万星在水溶液中稳定性的影响。

方法

采用反相高效液相色谱法（RP-HPLC）和高效凝胶渗透色谱法（HP-SEC）评估了在 5°C 和 55°C 下储存 4 周后，达巴万星在不同缓冲液和金属离子组合下的水溶液稳定性。采用 RP-HPLC 对含有二价金属离子的制剂进行了长达 6 个月在 5°C、25°C 和 40°C 的稳定性研究。

结果

所有柠檬酸盐缓冲溶液中的制剂均发生沉淀。在 55°C 下，10 mM 醋酸盐缓冲液中的达巴万星在 10 mM CaCl2、5 mM ZnCl2 和 10 mM MgCl2 中比含有 2 mM NaCl 或 5 mM KCl 的溶液更稳定，尽管 MgCl2 制剂略有沉淀。在 40°C 下放置 6 个月，任何二价金属离子对达巴万星均无明显影响。