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Publication Number
US-10206973-B2
Publication Date
2019-02-19
Expiration Date
Abstract
The present invention provides lyophilized formulations of active agents, particularly of TAT-NR2B9c, as chloride salts. TAT-NR2B9c has shown promise for treating stroke, aneurysm, subarachnoid hemorrhage and other neurological or neurotraumatic conditions. The chloride salt of TAT-NR2B9c shows improved stability compared with the acetate salt form of prior formulations. Formulations of the chloride salt of TAT-NR2B9c 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 relates to chloride salt forms of the peptide TAT-NR2B9c (SEQ ID NO:6), including variants that differ from TAT-NR2B9c by up to 5 amino acid substitutions, insertions or deletions. The chloride salts are characterized by having greater than 99% of the anions be chloride.
The invention further defines prelyophilized, lyophilized (freeze-dried), and reconstituted formulations of the peptide chloride salt. These formulations include a histidine buffer and a sugar (trehalose), with a defined pH range of about 6-7 for the histidine buffer.
A key part of the disclosure is that the chloride salt shows unexpectedly improved chemical stability compared to acetate-salt and saline-derived lyophilized formulations. The stability is described under ambient and accelerated conditions over extended durations, and the disclosure includes comparative chemical stability data and predictive shelf-life improvements using HPLC and RP-HPLC/MS assays.
The disclosed compositions are framed for clinical and disease contexts including stroke, aneurysm, subarachnoid hemorrhage, and CNS neurotrauma, including clinical-use logistics such as ambulance storage.
Claims Coverage
The document includes two independent claims directed to a chloride salt form of TAT-NR2B9c and a reconstituted formulation comprising that chloride salt, buffer, and sugar. Across the claim families, the inventive features are refined by specifying peptide and anion purity requirements, buffer and sugar identities, pH and concentration ranges, and constraints on residual acetate and trifluoroacetate anions.
Chloride salt with predominant chloride anions
A chloride salt of a peptide which is TAT-NR2B9c (SEQ ID NO:6) or differs from TAT-NR2B9c by up to 5 amino acid substitutions, insertions or deletions, wherein greater than 99% of anions in the salt are chloride.
Reconstituted formulation with defined peptide concentration, buffer, and sugar
A reconstituted formulation comprising a chloride salt of TAT-NR2B9c at a concentration of 15-25 mg/ml, a buffer and a sugar.
Overall, claim coverage is concentrated on a chloride salt form of TAT-NR2B9c with a stringent chloride-anion dominance requirement and on reconstituted formulations that combine the chloride salt at a defined concentration with a buffer and a sugar, further narrowed by specific histidine and trehalose selection and quantitative limits on acetate and trifluoroacetate anions.
Stated Advantages
Unexpectedly improved chemical stability of the chloride salt over acetate-salt and saline-derived lyophilized formulations.
Improved stability under ambient and accelerated conditions for extended durations, including predictive shelf-life improvements.
Documented Applications
Use in disease contexts including stroke.
Use in disease contexts including aneurysm.
Use in disease contexts including subarachnoid hemorrhage.
Use in disease contexts including CNS neurotrauma.
Clinical-use logistics including ambulance storage.
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