title: Insulin-like growth factor-I aerosol formulations for pulmonary delivery.
abstract: Injectable insulin-like growth factor-1 (IGF-I) is therapeutically deployed for severe IGF-I deficiency and clinically explored for various other indications such as muscle wasting disease. In the present study, liquid IGF-I formulations for pulmonal application were screened with regard to buffer type (acetate, citrate, histidine, and succinate), sodium chloride concentration (50-150 mM), and pH value (4.5-6.5). Methionine 59 oxidation (Met(o)) was observed in acetate buffer along with reducible dimer and trimer formation at low pH. Oxidation correlated with formation of covalent, reducible aggregates, and complete loss of potency was observed for severely aggregated samples. Bioactivity was partly retained in cases where complete oxidation but limited aggregation was found. In contrast, IGF-I integrity was preserved in histidine buffer during accelerated stability. After delivery from air-jet or vibrating-mesh nebulizers, limited Met(o) formation and no aggregation was observed. Nebulization performance regarding aerosol output rate, mass median aerodynamic diameter, and fine particle fraction for liquid IGF-I formulation was comparable to 0.9% sodium chloride reference, confirming the suitability for pulmonal application. In conclusion, different IGF-I liquid formulations were studied and compositions were identified maintaining bioactivity and chemical stability throughout storage at accelerated conditions for up to 4 months as well as compatibility with air-jet and vibrating-mesh nebulizers.
authors: Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Germany.
authors: Oliver
authors: O
authors: Germershaus
authors: Isabel
authors: I
authors: Schultz
authors: Tessa
authors: T
authors: Lühmann
authors: Moritz
authors: M
authors: Beck-Broichsitter
authors: Petra
authors: P
authors: Högger
authors: Lorenz
authors: L
authors: Meinel
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D002021:Buffers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D006133:Growth Substances / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D009330:Nebulizers and Vaporizers; D010084:Oxidation-Reduction; D010316:Particle Size; D055550:Protein Stability; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D019141:Respiratory System Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D054712:Salinity; D012995:Solubility
chemical_list: D000336:Aerosols; D002021:Buffers; D005079:Excipients; D006133:Growth Substances; C583557:IGF1 protein, human; D011994:Recombinant Proteins; D019141:Respiratory System Agents; D007334:Insulin-Like Growth Factor I
keywords: Aerosol; IGF-I; IGF-I aggregation; IGF-I oxidation; Nebulization; Protein formulation