Medium chain fatty acid esters of beta-hydroxybutyrate and butanediol and compositions and methods for using same

Inventors

Verdin, EricUlrich, Scott MichaelNewman, John C.

Assignees

J David Gladstone InstitutesUniversity of California San Diego UCSDIthaca College

Publication Number

US-10889538-B2

Publication Date

2021-01-12

Expiration Date

2037-06-02

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Abstract

Aspects of the present disclosure include fatty acid β-hydroxyester compounds (e.g., fatty acid esters of β-hydroxybutyrate), fatty acid esters of butanediol, and pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions having one or more fatty acid β-hydroxyester compounds and/or one or more fatty acid esters of butanediol. Methods for treating a subject by administering one or more esters to the subject are also provided. Kits containing one or more of the subject esters are also described.

Core Innovation

The invention provides fatty acid β-hydroxyester compounds, such as fatty acid esters of β-hydroxybutyrate, fatty acid esters of butanediol, and their pharmaceutically acceptable salts. It also includes pharmaceutical compositions containing one or more of these compounds, methods for treating subjects by administering these esters, and kits comprising the esters. These compounds are designed to release β-hydroxybutyrate or butanediol via ester hydrolysis, resulting in increased ketone body concentrations and sustained ketone production in the subject.

The problem addressed is the difficulty of adherence and side effects associated with ketogenic diets, which are used to stimulate ketone body production for treating disorders like epilepsy, dementia, and diseases of aging. Ketogenic diets are typically high-fat, low-carbohydrate diets that can be unpalatable and cause gastrointestinal problems, kidney stones, and high cholesterol. The disclosed compositions seek to provide an alternative to ketogenic diets for elevating ketone bodies in the body while potentially avoiding these drawbacks.

Claims Coverage

There are multiple inventive features covered by the claims related to the compounds, compositions, and methods described herein.

Method of reducing epileptiform activity and treating various diseases by administering specific compounds

A method of reducing epileptiform activity in the brain of a subject and/or treating conditions such as Alzheimer's disease, epilepsy, Parkinson's disease, heart failure, traumatic brain injury, stroke, and others, by administering a therapeutically effective amount of a compound of Formula I, wherein R1 is H or C(1-6) alkyl or substituted alkyl, and R2 and R3 are unsubstituted or substituted C(4-30) alkyl.

Compound structure with specific alkyl substitutions for therapeutic use

Compounds of Formula Ia and Ib with R1 as an unsubstituted C(1-6) alkyl such as methyl, and R2 and R3 as unsubstituted C6 or C8 alkyl, used in methods to reduce epileptiform activity and treat specific diseases.

Formulation of compounds in ingestible compositions for therapeutic application

Providing the compounds in ingestible compositions, including food supplemented with the compounds, present in amounts ranging from about 1% to 25% by weight, optionally combined with ketogenic diet components having fat to protein and carbohydrate ratios from about 2:1 to 10:1.

Oral preparation compositions with preservatives and flavoring agents

Oral formulations comprising the compounds along with preservatives such as sodium benzoate or methylparaben, flavoring agents, binders like cellulose or gelatin, and prepared as syrups, elixirs, or suspensions for administration.

The claims cover methods of treatment using defined fatty acid β-hydroxyester compounds, their specific structural variants, pharmaceutical compositions including food supplements and oral preparations, all aimed at reducing epileptiform activity and treating various diseases by increasing ketone levels.

Stated Advantages

The subject novel fatty acid β-hydroxyester compounds and esters of butanediol increase blood β-hydroxybutyrate levels to similar extents as ketogenic diets or fasting, providing a sustained ketone source.

Compounds reduce epileptiform spikes associated with Alzheimer’s disease models efficiently and sustainably, improving cognition and survival in tested animals.

The compounds provide an alternative to ketogenic diets, overcoming difficulties like poor palatability and side effects associated with such diets.

Documented Applications

Treatment of Alzheimer's disease by reducing epileptiform activity and improving cognition.

Treatment of epilepsy by reducing epileptiform spike activity.

Treatment of Parkinson's disease, heart failure, traumatic brain injury, stroke, hemorrhagic shock, acute lung injury after fluid resuscitation, acute kidney injury, myocardial infarction, myocardial ischemia, diabetes, glioblastoma multiforme, diabetic neuropathy, prostate cancer, amyotrophic lateral sclerosis, Huntington's disease, cutaneous T cell lymphoma, multiple myeloma, peripheral T cell lymphoma, HIV, Niemann-Pick Type C disease, age-related macular degeneration, gout, atherosclerosis, rheumatoid arthritis, and multiple sclerosis.

Use in food supplements containing the compounds for ketogenic diet support.

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