Stable formulations of linaclotide
Inventors
Mo, Yun • Fretzen, Angelika • Cali, Brian • Dedhiya, Mahendra
Assignees
Allergan Pharmaceuticals International Ltd • Ironwood Pharmaceuticals Inc
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Publication Number
US-10675325-B2
Publication Date
2020-06-09
Expiration Date
Abstract
The present invention relates to stable pharmaceutical compositions comprising linaclotide or pharmaceutically acceptable salts thereof, as well as to various methods and processes for the preparation and use of the compositions.
Core Innovation
The disclosure describes stable oral formulations of linaclotide in which linaclotide is combined with a cation, notably Ca2+, and a sterically hindered amine, including histidine or meglumine. The formulations are characterized by molar-ratio constraints between Ca2+ and histidine and between histidine and linaclotide.
The stabilization approach is described as synergistically improving stability of linaclotide against moisture-driven degradation processes. The document reports improved resistance against hydrolysis, deamidation, isomerization, and multimerization, and it contrasts performance across different amino acids, including histidine versus leucine/lysine/arginine.
The compositions optionally further include a polymer, such as polyvinyl alcohol (PVA) and/or polyvinyl pyrrolidone (PVP). The document also reports degradant profiles under stressed conditions, including hydrolysis products and imine products, and it includes additional degradation-related species such as Asp-7, Cys1-IMD product, oxidation product, acetylation product, multimer, reduced form linaclotide, and scrambled-form linaclotide.
Claims Coverage
The partial claim set provided includes one independent claim defining the core formulation, with additional dependent claims refining the composition using quantitative molar-ratio constraints, defined linaclotide amounts, and optional polymer selection and weight ranges. The independent claim centers on Ca2+ and histidine together with linaclotide under specific molar-ratio limits.
Molar-ratio controlled linaclotide with Ca2+ and histidine
A pharmaceutical composition comprising linaclotide, Ca2+ or pharmaceutically acceptable salt thereof and histidine, wherein the composition has a molar ratio of Ca2+:histidine of less than 1.5:1 and a molar ratio of histidine:linaclotide is between 120:1 and 80:1.
Sterically hindered amine selection and Ca2+ synergy
The composition includes histidine as the sterically hindered amine in combination with Ca2+ and linaclotide, constrained by the specified molar ratios.
Dual constrained Ca2+ and histidine ratio
The composition specifies that the molar ratio of Ca2+ to histidine is between about 1.3:1 and 0.7:1.
Dual constrained histidine-to-linaclotide ratio
The composition of claim 1 has specific molar ratios of histidine to linaclotide within the stated ranges.
Linaclotide amount in a defined microgram range
The composition includes linaclotide in an amount from 0.001 μg to 300 μg.
Polymer selection from PVP and PVA
The composition is one in which the polymer is selected from polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) and a mixture thereof.
PVA weight percentage range
The composition includes polyvinyl alcohol (PVA) in an amount ranging from 1% to 5% by weight.
Overall, the claim set provided emphasizes a linaclotide formulation defined by specific molar-ratio relationships among Ca2+, histidine, and linaclotide, with optional refinement by defined linaclotide content and inclusion of polymer selected from PVP and/or PVA, including a PVA weight percentage range.
Stated Advantages
Improves stability of linaclotide against moisture-driven degradation including hydrolysis, deamidation, isomerization, and multimerization.
Provides improved stability performance compared across amino acid types, including histidine versus leucine/lysine/arginine.
Documented Applications
No documented applications found
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