Lyophilized formulation of TAT-NR2B9C with acetylation scavenger
Inventors
Garman, Jonathan David • Hofmann, Frieder
Assignees
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Publication Number
US-10206878-B2
Publication Date
2019-02-19
Expiration Date
Abstract
The present invention provides lyophilized formulations of active agents, particularly of TAT-NR2B9c including histidine, trehalose and lysine. TAT-NR2B9c has shown promise for treating stroke, aneurysm, subarachnoid hemorrhage and other neurological or neurotraumatic conditions. Such formulations are stable at ambient temperature thus facilitating maintenance of supplies of such a formulation in ambulances for administration at the scene of illness or accident or in transit to a hospital.
Core Innovation
The invention provides a prelyophilized formulation at a pH of 6-7 that includes a peptide having the amino acid sequence of SEQ ID NO: 6 or SEQ ID NO: 7, or differing therefrom by up to 5 substitutions, deletions or insertions, histidine, trehalose, and lysine. The peptide is present at about 70-120 mg/ml, histidine at about 20-50 mM, trehalose at about 100-200 mM, and lysine at about 700-750 mM. The formulation is designed as a precursor that can be lyophilized to form a stable product for emergency administration.
The problem addressed is the need for ambient-temperature stability enabling emergency administration of a PSD-95 inhibitor peptide, including use for stroke and neurological or neurotraumatic conditions. The disclosed formulation strategy uses specific excipients and a pH range of 6-7 to support lyophilized and prelyophilized stability. The document also identifies that degradation impurities correspond to acetylation, linking impurity formation to acetylation processes.
To reduce acetylation-related impurities and improve shelf life and purity retention at elevated temperatures, the invention uses lysine as an acetylation scavenger in the formulation. The document compares bulking agents and describes trehalose as favored over dextran-40 and mannitol. Overall, lyophilized and prelyophilized compositions are characterized for solid-state and thermal behavior, including glass transition temperature, Tg, and are shown to maintain performance under accelerated temperature conditions by decreasing acetylation-related degradation impurity formation.
Claims Coverage
The independent claim set covers a prelyophilized formulation with a defined peptide identity, pH 6-7, and fixed concentration ranges for histidine, trehalose, and lysine. The claims further extend to a lyophilized formulation prepared from the prelyophilized formulation, with the overall scope centered on the same formulation concept.
P h-6-7 prelyophilized formulation with peptide, histidine, trehalose, and lysine
A prelyophilized formulation at a pH of 6-7 comprising a peptide having the amino acid sequence of SEQ ID NO: 6 or SEQ ID NO: 7 or differing therefrom by up to 5 substitutions, deletions or insertions; histidine; trehalose; and lysine, wherein the peptide is at a concentration of 70-120 mg/ml, the concentration of histidine is 20-50 mM, the concentration of trehalose is 100-200 mM and the concentration of lysine is 700-750 mM.
Lyophilized formulation prepared by lyophilizing the prelyophilized formulation
A lyophilized formulation is prepared by lyophilizing the prelyophilized formulation.
Coverage is anchored in a pH 6-7 prelyophilized formulation containing the specified PSD-95 inhibitor peptide sequences or variants plus histidine, trehalose, and lysine at defined concentration ranges. Claim scope also includes conversion into a lyophilized formulation.
Stated Advantages
Enables ambient-temperature stability for emergency administration.
Reduces acetylation-related impurities by using lysine as an acetylation scavenger.
Improves shelf life and purity retention at elevated temperatures.
Trehalose is favored as a bulking agent over dextran-40 and mannitol.
Documented Applications
Emergency administration for stroke and neurological or neurotraumatic conditions, including ambulance use.
Therapeutic contexts including aneurysm and subarachnoid hemorrhage and traumatic CNS injury.
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