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Publication Number
US-11911438-B2
Publication Date
2024-02-27
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 patent discloses chloride-salt lyophilized formulations of the peptide TAT-NR2B9c (SEQ ID NO:6/NA-1), including forms that differ from TAT-NR2B9c by up to 5 amino acid substitutions, insertions or deletions. The core structural feature is that at least 95% by moles of all anions in the salt are chloride, and the formulations are further characterized by defined limits or ratios of chloride relative to acetate and trifluoroacetate anions. The description ties this counterion selection to improved stability compared with acetate salts.
The disclosure defines preparation approaches centered on counterion exchange, including exchanging trifluoroacetate/acetate to chloride, and supports chloride-salt products with substantially reduced acetate and trifluoroacetate anion impurity. The patent specifies optional features related to high chloride-anion content and describes lyophilized and prelyophilized formulations using histidine buffer and trehalose at a pH in the range of 6–7. Concentration ranges and formulation constraints are described in connection with the stabilized chloride-salt peptide.
The patent also presents documented stability evidence and usability support for ambient-temperature handling. It includes buffer/pH screening showing best stability around pH 6.0–6.5 and analytical comparisons of TAT-NR2B9c chloride versus acetate-salt formulations using HPLC, including assays described for TFA and MSA methods, along with glass-transition assessment by DSC. The description further includes in vivo efficacy evidence for neurological/neurotraumatic conditions using the 3PVO stroke model, including rat experiments across multiple formulations, and states that the stabilized product supports storage and use without reliance on cold-chain handling, including storage in ambulances.
Claims Coverage
The partial claim set includes two independent claims. Across the independent claims, the inventive coverage centers on chloride-salt forms of TAT-NR2B9c (or variants with up to 5 amino acid changes) with strong quantitative control of chloride versus acetate and trifluoroacetate anions, and a formulation with a chloride:acetate:trifluoroacetate anion molar ratio greater than 95:1.
Chloride salt of TAT-NR2B9c with chloride as predominant anion
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 at least 95% by moles of all anions in the salt are chloride.
Formulation with chloride-dominant anion ratio over acetate and trifluoroacetate
A formulation comprising 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 the molar ratio of chloride to acetate and trifluoroacetate anions in the formulation is greater than 95:1.
Overall, the independent claims require chloride as the predominant anion in either the salt itself (≥95% by moles of anions are chloride) or in the formulation via a chloride:acetate:trifluoroacetate anion molar ratio greater than 95:1, applied to TAT-NR2B9c or variants differing by up to 5 amino acid substitutions, insertions, or deletions.
Stated Advantages
Improved stability versus acetate salts for TAT-NR2B9c chloride (TAT-NR2B9c-Cl) compared with acetate-salt formulations.
Improved usability for ambient-temperature handling, including storage in ambulances.
Documented Applications
Neurological/neurotraumatic conditions including stroke, supported by in vivo rat 3PVO stroke model efficacy across multiple formulations.
Subarachnoid hemorrhage.
General administration use involving reconstitution with water or normal saline for administration.
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