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-10702576-B2
Publication Date
2020-07-07
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 invention relates to stable solid oral linaclotide formulations for treating gastrointestinal disorders. The formulations include linaclotide and a cation, specifically Ca2+ or a pharmaceutically acceptable salt thereof, together with histidine. The composition is characterized by defined molar ratios of Ca2+:histidine and histidine:linaclotide to support stability.
The invention further defines the stabilization approach using histidine as a sterically hindered amine and a cation to provide synergistic stabilization. In addition to the Ca2+ and histidine components, the formulation can include polymers such as polyvinyl alcohol (PVA) or polyvinyl pyrrolidone (PVP) as part of the solid oral dosage form. The document also describes various solid oral dosage forms and formulation embodiments such as capsule, tablet, bead, and granule.
The invention addresses impurity and degradant formation associated with linaclotide instability, including degradation driven by moisture. The document describes degradation pathways and product types, including hydrolysis, formaldehyde imine products, oxidation products, acetylation products, multimerization products, and reduced or scrambled forms, and discusses how total degradants are handled in the specification. Stability and dissolution assessment under stressed conditions are described with reported purity and degradant profiles for different amino acid stabilizers such as histidine.
Claims Coverage
The independent claim covers administering, in a patient, a pharmaceutical composition containing linaclotide, Ca2+ (or a pharmaceutically acceptable salt), and histidine, with specified molar-ratio constraints, for treating selected gastrointestinal disorders. The inventive features are focused on the specific disorder selection and the defined Ca2+:histidine and histidine:linaclotide molar ratios.
Selected gastrointestinal disorder treatment by administering a defined linaclotide composition
A method of treating a gastrointestinal disorder in a patient by administering to a patient in need thereof a pharmaceutical composition comprising linaclotide, Ca2+ or pharmaceutically acceptable salt thereof and histidine, wherein the gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, chronic constipation, and opioid induced constipation.
Synergistic stabilization with Ca2+:histidine molar ratio below 1.5:1
A composition having a molar ratio of Ca2+:histidine of less than 1.5:1 in the administered pharmaceutical composition comprising linaclotide, Ca2+ or pharmaceutically acceptable salt thereof and histidine.
Specified histidine:linaclotide molar ratio between 120:1 and 80:1
A composition having a molar ratio of histidine:linaclotide between 120:1 and 80:1 in the administered pharmaceutical composition comprising linaclotide, Ca2+ or pharmaceutically acceptable salt thereof and histidine.
Overall claim coverage centers on treating irritable bowel syndrome, chronic constipation, or opioid induced constipation by administering a linaclotide composition containing Ca2+ (or a salt) and histidine, with the Ca2+:histidine ratio constrained to less than 1.5:1 and the histidine:linaclotide ratio constrained to between 120:1 and 80:1.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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