Larazotide acetate compositions
Inventors
Callens, Roland • Blondeel, Georges • Delplanche, Thierry
Assignees
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Publication Number
US-9051349-B2
Publication Date
2015-06-09
Expiration Date
Abstract
The invention provides crystalline forms of the peptide Gly-Gly-Val-Leu-Val-Gln-Pro-Gly (SEQ ID NO 1), and salts of the peptide, which may further have associated water molecules. These salts and hydrated salts of the peptide and compositions comprising these materials have advantageous pharmaceutical properties.
Core Innovation
The invention relates to larazotide as a crystalline acetate salt of the peptide Gly-Gly-Val-Leu-Val-Gln-Pro-Gly (SEQ ID NO:1). The crystalline acetate salt is defined by an X-ray powder diffraction (XRPD) pattern with specific peaks at 9.08±0.2, 9.52±0.2, 10.34±0.2, and 14.24±0.2 degrees 2θ. The description also addresses crystalline acetate forms including Forms A and A′ and their solid-state identification by XRPD peak sets.
The problem addressed in the background is polymorphism and hydrate behavior, including differences between crystalline materials and amorphous material and how solid-state form affects quality and stability. The document characterizes how moisture sorption/desorption and moisture uptake hysteresis relate to solid-state form and associated performance. The discussion further includes behavior differences for hydrates, including stoichiometric and non-stoichiometric hydrates.
The invention provides crystalline acetate forms and acetate salts/hydrates of larazotide, characterized and compared with amorphous larazotide acetate. Comparative performance described in the document includes lower moisture uptake, lower CMC (lower solubility), improved moisture stability at 40°C/75% RH versus amorphous material, and differing deamidation stability relative to chloride. The document also reports acetate-content dependent solid-state preparation ranges and associated water-content ranges that relate to the crystalline acetate material.
Claims Coverage
The independent claim covers the solid-state identity of a crystalline acetate salt of the peptide (SEQ ID NO:1) using an XRPD peak pattern with four specified peaks, and the claim set refines this identity through additional XRPD peaks and quantitative acetate-content limitations. Based on the provided claim text, there is 1 independent claim, with multiple dependent refinements that further constrain peak inclusion and acetate concentration ranges.
Crystalline acetate salt defined by an XRPD pattern
A crystalline acetate salt of the peptide Gly-Gly-Val-Leu-Val-Gln-Pro-Gly (SEQ ID NO:1) having an XRPD pattern comprising peaks at 9.08±0.2 degrees 2θ, 9.52±0.2 degrees 2θ, 10.34±0.2 degrees 2θ, and 14.24±0.2 degrees 2θ.
Crystalline acetate salt with additional XRPD peaks
The crystalline acetate salt further comprises specific XRPD peaks at 18.23±0.2 degrees 2θ, 19.08±0.2 degrees 2θ and/or 21.31±0.2 degrees 2θ.
Crystalline acetate salt characterized by selected XRPD peak combination
A crystalline acetate salt is characterized by an XRPD diffraction pattern that includes peaks at 14.24±0.2 degrees 2θ and 18.23±0.2 degrees 2θ.
Crystalline acetate salt having acetate at about 20 to 30 mole% relative to peptide
The claim specifies a crystalline acetate salt where the acetate is present at about 20 to 30 mole% relative to the peptide.
Crystalline acetate salt having acetate at less than about 15 mole%
The crystalline acetate salt specifies that the acetate is present at a concentration of less than about 15 mole%.
Crystalline acetate salt having acetate between about 4 and about 8 mole%
The claim specifies a crystalline acetate salt where the acetate content is between about 4 and about 8 mole percent.
Across the independent claim and its refinements, the inventive subject matter is constrained to a crystalline acetate salt of the specified larazotide peptide (SEQ ID NO:1) defined by particular XRPD peak requirements, with further refinements requiring additional XRPD peaks and limiting acetate content by mole% ranges.
Stated Advantages
Lower moisture uptake.
Lower CMC (lower solubility) compared with amorphous material.
Improved moisture stability at 40°C/75% RH versus amorphous material.
Differing deamidation stability compared with chloride.
Documented Applications
Solid-state identification and characterization of larazotide crystalline acetate forms (including Forms A and A′) using XRPD peak sets.
Moisture uptake/moisture stability evaluation for larazotide crystalline acetate versus amorphous larazotide acetate under 40°C/75% RH conditions.
Comparison of solubility-related behavior using CMC between crystalline acetate and amorphous material.
Assessment of deamidation stability comparing larazotide acetate with larazotide chloride.
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