Larazotide formulations
Inventors
Radhakrishnan, Balasingham • MADAN, Jay P. • Musso, Gary F.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12337024-B2
Publication Date
2025-06-24
Expiration Date
Abstract
The present invention provides, in part, compositions comprising a peptide that is larazotide or larazotide derivative, or salt thereof, contained within a matrix that provides for controlled release and sustained release formulations. The present invention contemplates that these compositions, formulations and methods can be useful for treating diseases and disorders of the small bowel.
Core Innovation
Larazotide, or a larazotide derivative, or a salt thereof, is provided in an oral composition as an effective amount contained within a biodegradable or erodible polymer matrix comprising microcrystalline cellulose. The composition provides for sustained release of the peptide in simulated intestinal fluid having a pH of 7.0 for at least about 120 minutes.
The composition further comprises an enteric coating that is resistant to dissolution in simulated gastric fluid or simulated intestinal fluid having a pH of 5.5 or less, such that the composition provides for less than about 25% release of the peptide after two hours in said simulated gastric fluid or simulated intestinal fluid. The enteric-coated formulation is configured to limit peptide release under conditions at or below pH 5.5 while enabling sustained release at a pH of about 7.0.
The disclosure relates the oral composition to small-bowel delivery for disorders associated with intestinal barrier dysfunction. Documented examples include an improvement of “leaky gut” using a mouse serum FITC-dextran reduction model, and effects on transepithelial resistance (TEER) in an ex vivo ischemic jejunum model, including an inverse dose response favoring low or fractional dosing.
Claims Coverage
The patent includes at least one independent claim with three main inventive features.
Biodegradable matrix of microcrystalline cellulose for sustained release at pH 7.0
An oral composition comprising an effective amount of larazotide, a larazotide derivative, or a salt thereof, contained within a biodegradable or erodible polymer matrix comprising microcrystalline cellulose that provides for sustained release of the peptide in simulated intestinal fluid having a pH of 7.0 for at least about 120 minutes.
pH-5.5-or-less resistant enteric coating limiting release after two hours
The composition further comprises an enteric coating that is resistant to dissolution in simulated gastric fluid or simulated intestinal fluid having a pH of 5.5 or less, wherein the composition provides for less than about 25% release of the peptide after two hours in said simulated gastric fluid or simulated intestinal fluid.
Release in jejunum and ileum of a human patient
The composition releases the peptide or salt thereof in the jejunum and ileum of a human patient.
Sustained release at pH 7.0 for at least about 180 minutes
The composition provides for sustained release of the peptide in simulated intestinal fluid having a pH of about 7.0 for at least about 180 minutes.
Enteric coating formed from a copolymer of methyl acrylate, methyl methacrylate, and methacrylic acid
The enteric coating comprises a co-polymer of methyl acrylate, methyl methacrylate, and methacrylic acid.
Enteric-coating copolymer functional-group ratio of about 1:10
The ratio of free carbonyl groups to ester groups in the enteric-coating co-polymer is about 1:10.
Triethyl citrate plasticizer in the enteric coating
The enteric coating comprises a plasticizer which is triethyl citrate.
Overall claim coverage emphasizes an oral larazotide composition where the peptide is embedded in a microcrystalline-cellulose biodegradable or erodible matrix for sustained release at intestinal pH, while an enteric coating resists dissolution at pH 5.5 or less and limits early release under acidic conditions. The dependent claims further specify enteric-coating composition and functional constraints and refine release location and sustained-release duration.
Stated Advantages
Sustained release of larazotide in simulated intestinal fluid at pH 7.0 for at least about 120 minutes.
Resistance to dissolution of the enteric coating in simulated gastric fluid or simulated intestinal fluid having a pH of 5.5 or less.
Limited peptide release under acidic conditions, providing for less than about 25% release after two hours at pH 5.5 or less.
Sustained release at pH 7.0 for at least about 180 minutes in certain embodiments.
Directed small-bowel delivery by releasing the peptide or salt thereof in the jejunum and ileum of a human patient.
Documented Applications
Treatment of disorders associated with intestinal barrier dysfunction, including fatty liver diseases (NAFLD/NASH) and cancer via potentiation of immunotherapy.
Celiac disease is included among disorders associated with intestinal barrier dysfunction addressed by the disclosure.
“Leaky gut” improvement evaluated using a mouse serum FITC-dextran reduction model.
Ex vivo ischemic jejunum effects evaluated using transepithelial resistance (TEER).
Interested in licensing this patent?