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Publication Number
US-11266714-B2
Publication Date
2022-03-08
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 lyophilized or freeze-dried formulations comprising TAT-NR2B9c (NA-1) as a chloride salt. The formulations are characterized by a high chloride content in which greater than 95% by moles of all anions in the salt are chloride, and the chloride salt is incorporated into a formulation containing optional histidine buffer and trehalose.
The problem addressed is that prior formulations based on other salt forms, such as acetate/saline forms, exhibit reduced lyophilized-state stability. The invention is presented as improving stability of the lyophilized-state product relative to acetate/saline formulations, including improved retention of main peak purity and reduced impurity growth during accelerated and longer timepoint storage.
The chloride salt is prepared by anion exchange, including pathways such as exchanging trifluoroacetate for acetate and then acetate for chloride, and/or exchanging trifluoroacetate for chloride. The resulting chloride-salt formulations are described as suitable for ambient or near-37°C storage, including use in emergency settings where administration may occur without requiring diagnosis.
Claims Coverage
The independent claim set includes one independent method claim covering preparation of a chloride-salt peptide formulation, with the core requirement that >95% (by moles) of all anions in the salt are chloride, followed by incorporation of the chloride salt into the formulation. The dependent claims refine the formulation composition and processing conditions.
Chloride-salt preparation for a TAT-NR2B9c formulation
Synthesizing a chloride salt of a peptide that is TAT-NR2B9c (SEQ ID NO:6) or differs from TAT-NR2B9c by up to 5 amino acid substitutions, insertions or deletions.
High chloride anion content in the salt
Wherein greater than 95% by moles of all anions in the salt are chloride.
Incorporation of the chloride salt into a formulation
Incorporating the chloride salt into a formulation.
Overall, claim coverage centers on producing a chloride salt of TAT-NR2B9c (or a limited variant) with an anion composition where greater than 95% by moles of all anions are chloride, and then incorporating that chloride salt into a formulation.
Stated Advantages
Improved lyophilized-state stability versus acetate/saline formulations.
Better retention of main peak purity during storage compared with acetate.
Reduced impurity growth during storage compared with acetate.
Enables ambient/near-37°C storage suitable for emergency use.
Documented Applications
Emergency use/scene-of-illness administration (e.g., ambulances) where a diagnosis may not be required.
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