Compositions and methods for the reduction or prevention of hepatic steatosis
Inventors
Zemel, Michael • Bruckbauer, Antje
Assignees
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Publication Number
US-9724319-B2
Publication Date
2017-08-08
Expiration Date
Abstract
Methods useful for reducing or preventing hepatic steatosis are provided herein. Such methods may comprise administering to a subject in need thereof a sirtuin pathway activator and/or PDE5 inhibitor alone or in combination with an amount of a branched amino acid in free amino acid form, or a metabolite thereof. Also provided herein are compositions and kits for practicing any of the methods described herein.
Core Innovation
The invention relates to pharmaceutical compositions and methods for reducing or preventing hepatic steatosis, fatty liver disease, NAFLD/NAFL, and NASH, including NASH-related cirrhosis. The described approach uses co-administration of leucine and/or a metabolite thereof together with metformin and sildenafil. The leucine component is provided as a free amino acid and the metabolite is selected from β-hydroxy-β-methylbutyrate (HMB) and keto-isocaproic acid (KIC).
The compositions are formulated such that the leucine and/or leucine metabolite, metformin, and sildenafil are co-administered to a subject in need thereof, and specified weight-percentage relationships are defined among (a), (b), and (c). The composition is substantially free of free amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. Prophylactic and therapeutic use are described in connection with treating hepatic lipid accumulation and inflammatory injury endpoints.
The problem addressed is hepatic steatosis and fatty liver disease progressing to NAFLD/NAFL and NASH, including NASH-related cirrhosis, which involves hepatic lipid accumulation and inflammatory injury. The invention describes combination therapies designed to improve outcomes more than single agents, including measures such as hepatic lipid vacuoles, liver triglycerides, serum ALT and serum AST, and gene expression changes related to lipogenic and inflammatory markers. Documented examples report that the combination achieves greater reduction of hepatic steatosis and NASH-related injury than administration of the leucine component alone.
Claims Coverage
The patent content provided identifies one independent claim (clm-00001) that contains three core co-administered inventive components and additional constraints. The main inventive features are governed by the selected leucine form, the inclusion of metformin and sildenafil, the defined wt % relationships, and the explicit exclusion of multiple other free amino acids.
Co-administered leucine, metformin, and sildenafil composition
A composition comprising an amount of leucine in the form of a free amino acid and/or an amount of a metabolite thereof, an amount of metformin, and an amount of sildenafil, wherein the metabolite is selected from β-hydroxy β-methylbutyrate (HMB) and keto-isocaproic acid (KIC).
Defined wt % relationships among the three components
A composition in which the amount of leucine and/or a metabolite thereof is about 50–95 wt % of the total wt of (a), (b), and (c), the amount of metformin is about 5–50 wt % of the total wt of (a), (b), and (c), and the amount of sildenafil is 0.1 to 10 mg and about 0.01–1 wt % of the total wt of (a), (b), and (c).
Substantially free exclusion of specified other free amino acids
A composition formulated for administration in which the composition is substantially free of free amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
Greater reduction of hepatic steatosis or NASH than leucine alone
A method comprising administering the composition to a subject in need thereof, wherein the administration reduces hepatic steatosis and/or non-alcoholic steatohepatitis to a greater extent than administration of (a) alone.
Across the provided independent claim and the identified dependent claim refinement for efficacy comparison, the inventive coverage centers on a co-administered leucine (free amino acid) and/or HMB/KIC combination with metformin and sildenafil, constrained by defined wt % relationships and an explicit substantial exclusion of many other free amino acids, and associated with a greater reduction of hepatic steatosis or non-alcoholic steatohepatitis than leucine alone.
Stated Advantages
Reduces hepatic steatosis and/or non-alcoholic steatohepatitis to a greater extent than administration of (a) alone.
Improves inflammatory injury and hepatic lipid accumulation endpoints relative to single-agent administration, as documented by the described measurements.
Documented Applications
Reducing or preventing hepatic steatosis and fatty liver disease, including NAFLD/NAFL and NASH, including NASH-related cirrhosis.
Use of the pharmaceutical composition as prophylactic and therapeutic administration to a subject in need thereof for hepatic steatosis and/or non-alcoholic steatohepatitis reduction.
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