Stabilization of a polypeptide in non-aqueous solvents

Wang, Wei; Martin-Moe, Sheryl; Pan, Clark Q.; Musza, László; Wang, Y. John

doi:10.1016/j.ijpharm.2007.09.012

Cited by 11 publications

(9 citation statements)

References 31 publications

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“…These conformational changes can increase the stability of oxytocin in aqueous medium as they will prevent dimerization and further aggregation by hydrophobic interactions among oxytocin molecules. Metal salts are often used to stabilize peptides or proteins by chelation or ionic interactions (22). Wang et al .…”

Section: Discussionmentioning

confidence: 99%

“…examined the peptide (P66) stability in the presence of ZnCl 2 , MgCl 2 , and CaCl 2 in non aqueous solution, and found that in the presence of 1 mM ZnCl 2 , P66 was significantly stabilized. However in the aqueous solution (pure water), these ions did not show any stabilizing effect (22). In our experiments, the addition of calcium, magnesium, and zinc ions in combination with citrate buffer had a large impact on oxytocin stability in contrast to similar experiments in pure water or acetate buffer.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A New Strategy to Stabilize Oxytocin in Aqueous Solutions: I. The Effects of Divalent Metal Ions and Citrate Buffer

Avanti

Amorij

Setyaningsih

et al. 2011

AAPS J

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In the current study, the effect of metal ions in combination with buffers (citrate, acetate, pH 4.5) on the stability of aqueous solutions of oxytocin was investigated. Both monovalent metal ions (Na+ and K+) and divalent metal ions (Ca2+, Mg2+, and Zn2+) were tested all as chloride salts. The effect of combinations of buffers and metal ions on the stability of aqueous oxytocin solutions was determined by RP-HPLC and HP-SEC after 4 weeks of storage at either 4°C or 55°C. Addition of sodium or potassium ions to acetate- or citrate-buffered solutions did not increase stability, nor did the addition of divalent metal ions to acetate buffer. However, the stability of aqueous oxytocin in aqueous formulations was improved in the presence of 5 and 10 mM citrate buffer in combination with at least 2 mM CaCl2, MgCl2, or ZnCl2 and depended on the divalent metal ion concentration. Isothermal titration calorimetric measurements were predictive for the stabilization effects observed during the stability study. Formulations in citrate buffer that had an improved stability displayed a strong interaction between oxytocin and Ca2+, Mg2+, or Zn2+, while formulations in acetate buffer did not. In conclusion, our study shows that divalent metal ions in combination with citrate buffer strongly improved the stability of oxytocin in aqueous solutions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A New Strategy to Stabilize Oxytocin in Aqueous Solutions: I. The Effects of Divalent Metal Ions and Citrate Buffer

Avanti

Amorij

Setyaningsih

et al. 2011

AAPS J

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“…This has been done using nonaqueous solvents (33,89), although these same solvents can also affect conformation, viscosity, and solvent dielectric, so the effect might not be entirely due to modulation of acid-base properties. The effect of viscosity has been described for model peptides (90,91).…”

Section: Control Of Deamidation Ratesmentioning

confidence: 99%

Stability of Protein Pharmaceuticals: An Update

Manning¹,

Chou²,

Murphy³

et al. 2010

Pharm Res

1,001

782

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In 1989, Manning, Patel, and Borchardt wrote a review of protein stability (Manning et al., Pharm. Res. 6:903-918, 1989), which has been widely referenced ever since. At the time, recombinant protein therapy was still in its infancy. This review summarizes the advances that have been made since then regarding protein stabilization and formulation. In addition to a discussion of the current understanding of chemical and physical instability, sections are included on stabilization in aqueous solution and the dried state, the use of chemical modification and mutagenesis to improve stability, and the interrelationship between chemical and physical instability.

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“…A viscosity factor may also be affecting results. Samples that had been previously acidified before formulating in DMSO have subsequently been shown to limit dimerization 5. This appears to also be the case in the acetic acid‐treated sample presented in Figure 4.…”

Section: Discussionmentioning

confidence: 74%

“…Use of such a short‐lived peptide for therapeutic purposes would require frequent administration, which would be practically and economically prohibitive. To increase the duration of action for this relatively unstable peptide drug, various drug‐delivery and stabilizing approaches have been investigated 3–5…”

Section: Introductionmentioning

confidence: 99%