Buffered formulations of exendin (9-39)
Inventors
Xiong, Xiaofeng • Odink, Debra • Craig, Colleen M. • Smith, Christine M. N. • McLaughlin, Tracey L.
Assignees
Leland Stanford Junior University • Amylyx Pharmaceuticals Inc
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Publication Number
US-11020484-B2
Publication Date
2021-06-01
Expiration Date
Abstract
Provided herein are liquid pharmaceutical formulations comprising exendin (9-39) or a pharmaceutically acceptable salt thereof and a tonicity modifier in a physiologically acceptable buffer having a pH in the range of about 5 to about 6. In some embodiments, the buffered liquid formulation comprises exendin (9-39) or a pharmaceutically acceptable salt thereof in an acetate buffer or a citrate buffer. Methods of treating or preventing hyperinsulinemic hypoglycemia in a subject comprising administering to the subject the buffered liquid formulation are also provided.
Core Innovation
The invention relates to a liquid pharmaceutical formulation comprising exendin (9-39) or a pharmaceutically acceptable salt thereof together with a tonicity modifier in a physiologically acceptable buffer having a pH in the range of above 5.1 to 6. The formulation is characterized in that the exendin (9-39) or the pharmaceutically acceptable salt thereof does not exhibit detectable aggregation in the formulation. The formulation is intended for administration to a human subject.
The formulation uses physiologically acceptable buffers at a pH of about 5 to 6, including acetate/citrate and other buffer systems described as physiologically acceptable buffers. The description includes embodiments using tonicity modifiers such as mannitol to achieve an isophysiological osmolality, and optionally includes salt forms associated with acetate or trifluoroacetate. The invention contrasts this buffered liquid format with compositions comprising exendin (9-39) in 0.9% normal saline.
The invention further provides an improved pharmacokinetic profile when the liquid pharmaceutical formulation is administered to a human, compared to a composition comprising the same dose of exendin (9-39) or its pharmaceutically acceptable salt formulated in 0.9% normal saline. The described pharmacokinetic results include higher Cmax and improved exposure metrics such as AUC, including later Tmax and higher trough concentration. The description also states reduced detectable aggregation/precipitation during storage and improved potency/purity over time versus the saline-reconstituted comparator.
Claims Coverage
The independent claims focus on a buffered liquid formulation of exendin (9-39) with a tonicity modifier and a defined pH range, characterized by lack of detectable aggregation and improved human pharmacokinetics versus 0.9% normal saline. The inventive features emphasized across the claim set include the formulation conditions, the aggregation criterion, the pharmacokinetic endpoint, and subcutaneous dosing regimens.
Buffered liquid formulation with tonicity modifier in pH 5.1 to 6
A liquid pharmaceutical formulation comprising exendin (9-39) or a pharmaceutically acceptable salt thereof and a tonicity modifier in a physiologically acceptable buffer having a pH in the range of above 5.1 to 6.
No detectable aggregation in the liquid formulation
Wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof does not exhibit detectable aggregation in the formulation.
Improved human pharmacokinetic profile versus 0.9% normal saline
When administered to a human subject, the liquid pharmaceutical formulation has an improved pharmacokinetic profile as compared to a composition comprising the same dose of exendin (9-39) or a pharmaceutically acceptable salt thereof formulated in 0.9% normal saline.
Higher Cmax versus 0.9% normal saline comparator
A liquid pharmaceutical formulation that, upon administration to a human, yields a higher Cmax for exendin (9-39) than a comparison composition containing the same dose of exendin (9-39) or its pharmaceutically acceptable salt formulated in 0.9% normal saline.
Subcutaneous once-daily dosing in a defined range
Subcutaneous administration to a subject of a liquid pharmaceutical formulation containing exendin (9-39) at a once-daily dosage of about 30 mg to about 75 mg.
Overall, the claim coverage is centered on a buffered liquid exendin (9-39) formulation with a tonicity modifier and pH above 5.1 to 6, satisfying a no detectable aggregation condition, and demonstrating improved pharmacokinetics in humans versus 0.9% normal saline. Dependent claim refinements specify particular formulation constraints and pharmacokinetic endpoints such as higher Cmax, and further include subcutaneous treatment regimens with defined once-daily dosage ranges.
Stated Advantages
Reduced detectable aggregation/precipitation during storage, including testing at 50°C.
Improved potency/purity over time versus exendin (9-39) in 0.9% normal saline.
Improved pharmacokinetic profile in humans compared with the same dose formulated in 0.9% normal saline.
Higher Cmax in humans compared with a 0.9% normal saline comparator.
Improved exposure metrics including AUC and later Tmax, and higher trough concentration.
Documented Applications
Treating or preventing hyperinsulinemic hypoglycemia, including post-bariatric hypoglycemia (PBH), using subcutaneous administration regimens described in the document.
Clinical examples reporting improved OGTT metabolic outcomes and symptom reductions with the buffered liquid formulation versus lyophilized/saline comparator.
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