title: Stability of lyophilized teriparatide, PTH(1-34), after reconstitution.
abstract: The peptide teriparatide, also known as parathyroid hormone (1-34), PTH(1-34), was developed for intranasal delivery, requiring extended stability of the reconstituted product for up to four weeks at room temperature. Lyophilized formulations of PTH(1-34), containing glycine and trehalose and using lactate as the buffer, are stable for months upon storage. However, the physical stability of the peptide after reconstitution unexpectedly varied considerably, depending on peptide concentration and storage temperature, with precipitation seen within two to four weeks in some samples. By comparison, equivalent samples that did not undergo lyophilization did not display any precipitation upon storage in the liquid state for as long as twelve weeks. PTH(1-34) appears to adopt a higher order structure that is perturbed by the combined stresses of freezing and drying, leading to greater propensity to aggregate, which is accentuated at higher peptide concentrations and at higher temperatures. The precipitation seems to be correlated with increased amounts of subvisible particles. This study shows the importance of peptide conformation in long-term stability and illustrates the ability of lyophilization to cause increased propensity to aggregate, even in a peptide.
authors.affiliation: Azelon Pharmaceuticals, West Conshohocken, PA, USA.
authors.forename: Gene
authors.initials: G
authors.lastname: Merutka
authors.affiliation: Department of Chemistry, Colorado State University, Fort Collins, CO, USA; Legacy BioDesign LLC, Johnstown, CO, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Murphy
authors.affiliation: Department of Chemistry, Colorado State University, Fort Collins, CO, USA; Legacy BioDesign LLC, Johnstown, CO, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Payne
authors.affiliation: West Coast BioDesign LLC, Santa Barbara, CA, USA.
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Wilson
authors.affiliation: Legacy BioDesign LLC, Johnstown, CO, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Matsuura
authors.affiliation: Department of Chemistry, Colorado State University, Fort Collins, CO, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Henry
authors.affiliation: Department of Chemistry, Colorado State University, Fort Collins, CO, USA; Legacy BioDesign LLC, Johnstown, CO, USA. Electronic address: manning@legacybiodesign.com.
authors.forename: Mark Cornell
authors.initials: MC
authors.lastname: Manning
mesh_terms: D004355:Drug Stability; D005612:Freeze Drying; D010281:Parathyroid Hormone / Q000737:chemistry* / Q000592:standards*; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D019379:Teriparatide / Q000737:chemistry* / Q000592:standards*
chemical_list: D010281:Parathyroid Hormone; D019379:Teriparatide
keywords: Aggregation; Higher order structure; Intranasal peptide formulation; PTH(1-34); Peptide conformation; Teriparatide