Protein nebulization II. Stabilization of G-CSF to air-jet nebulization and the role of protectants

• Published in: International journal of pharmaceutics 1996-02, Vol.127 (2), p.191-201
• Main Authors: Niven, Ralph W., Prestrelski, Steven J., Treuheit, Michael J., Ip, Anna Y., Arakawa, Tsutomu
• Format: Article
• Language: English
• Subjects: Aggregation; Biological and medical sciences; Degradation; G-CSF; General pharmacology; Medical sciences; Nebulization; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Protein; Pulmonary delivery; Stability; Surface tension
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/0378-5173(95)04209-1

Air-jet nebulization induces aggregation and degradation of granulocyte-colony stimulating factor (G-CSF). The air-water interface as a site for destabilization of G-CSF is investigated and possible mechanisms of stabilization by polyethylene glycol (PEG) and Tween 80 are proposed. Equilibrium surface tension measurements show that G-CSF is highly surface-active, but dynamic surface tension measurements made using a maximum bubble pressure surface tensionometer show that G-CSF and surfactants have little surface activity in the interval between formation and destruction of aerosol generated within a nebulizer. Bubbling of air through solutions of 4 mg/ml G-CSF for up to 1 h resulted in ≈ 10% aggregation of total protein suggesting that destabilization at the air-water interface occurs. Polyethylene glycol (PEG) and Tween 80 are effective in reducing aggregation and degradation of G-CSF but their respective modes of protection differ. Protection is improved by increasing the PEG molecular weight and concentration indicating that PEG may influence stability through steric effects. In contrast, the protective effects of Tween 80 appear to relate to the micellar properties and not to the surface activity of the surfactant.