DNP and DNP prodrug treatment of neuromuscular, neurodegenerative, autoimmune, developmental, traumatic brain injury, concussion, dry eye disease, hearing loss and/or metabolic diseases
Inventors
Geisler, John Gerard • Alonso, Robert • Crooks, Peter Anthony • Penthala, Narsimha Reddy • Albayati, Zaineb
Assignees
BioVentures LLC • Mitochon Pharmaceuticals Inc
Publication Number
US-10548900-B2
Publication Date
2020-02-04
Expiration Date
2037-03-07
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Abstract
A composition and method of treatment of neuromuscular, neuromuscular degenerative, neurodegenerative, autoimmune, developmental, traumatic, hearing loss related, and/or metabolic diseases, including spinal muscular atrophy (SMA) syndrome (SMA1, SMA2, SMA3, and SMA4, also called Type I, II, III and IV), traumatic brain injury (TBI), concussion, keratoconjunctivitis sicca (Dry Eye Disease), glaucoma, Sjogren's syndrome, rheumatoid arthritis, post-LASIK surgery, anti-depressants use, Wolfram Syndrome, and Wolcott-Rallison syndrome. The composition is selected from the group consisting of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP, bipartite 2,3-dinitrophenol, 2,4-dinitrophenol, 2,5-dinitrophenol, 2,6-dinitrophenol, 3,4-dinitrophenol, or 3,5-dinitrophenol (2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP) prodrugs; Gemini prodrugs, bioprecursor molecules, and combinations thereof. A dose of the composition for treatment of neurodegenerative diseases may be from about 0.01 mg/kg of body weight to about 50 mg/kg of body weight of the patient in need of treatment. A dose of the composition for treatment of metabolic diseases may be from about 1 mg/70 kg of body weight to about 100 mg/70 kg of body weight of the patient in need of treatment, and a maximum dose per day is about 200 mg/70 kg of body weight of the patient in need of treatment.
Core Innovation
The invention provides compositions and methods for treating a wide range of neuromuscular, neurodegenerative, autoimmune, developmental, traumatic brain injury, concussion, dry eye disease, hearing loss, and metabolic diseases. The compositions include various isomers and prodrugs of dinitrophenol (DNP), such as 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, and 3,5-DNP, as well as specialized derivatives including Gemini prodrugs, bioprecursor molecules, and formulations for controlled or sustained release. These formulations aim to deliver DNP or its active form systematically with improved safety and efficacy by modulating pharmacokinetics and bioavailability.
The problem addressed by the invention is the lack of disease-modifying drug therapies for numerous severe and chronic diseases, including but not limited to various neurodegenerative, neuromuscular, autoimmune, developmental, and metabolic disorders that currently have only palliative or minimally effective treatments. There is a profound unmet medical need for therapies that can alter disease progression, prevent disability, and address root causes of disease, such as mitochondrial dysfunction and oxidative stress.
The invention also introduces advanced prodrug strategies, including the design of water-soluble derivatives and nanoparticle depot formulations, to enable extended and controlled release of DNP. These approaches ensure that the prodrug remains stable in the gastrointestinal tract and is converted to its active form in systemic circulation. The compositions may be administered in various dosage forms, including immediate, sustained, or controlled release, and through multiple routes such as oral, intravenous, subcutaneous, topical, or transdermal administration.
Overall, the invention broadly claims the use of DNP and its prodrugs/bioprecursors to treat multiple diseases by mechanisms such as increasing energy expenditure, reducing oxidative stress, and modulating mitochondrial function, with specific examples and dosage regimens provided for different disease indications.
Claims Coverage
There are four independent claims, each highlighting a distinct inventive feature related to dinitrophenol prodrugs, Gemini prodrugs, bioprecursors, and depot nanoparticle formulations.
Dinitrophenol prodrugs with specified structural formulas
A composition comprising a dinitrophenol prodrug having a formula selected from specific isomers of DNP, including 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, and 3,5-DNP prodrugs. The prodrugs are designed to be stable at a range of pH values (1-2, 4.5, and 5-9), enabling oral administration and absorption while ensuring conversion to active drug in plasma.
Gemini prodrug compositions of DNP
A composition comprising a 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP 'Gemini' prodrug represented by a specified formula (Formula VII in the patent). These Gemini prodrugs are structurally unique and exhibit pH stability suitable for oral administration and controlled release.
Bioprecursors of 2,4-dinitrophenol
A composition comprising a 2,4-DNP bioprecursor represented by Formula VIII or Formula IX, which is stable across gastric and intestinal pH ranges. These bioprecursors are designed to release active 2,4-DNP through oxidative metabolism in the body.
Depot nanoparticle formulations of DNP prodrugs
A depot nanoparticle formulation comprising a dinitrophenol prodrug, selected from the specified structural formulas, to enable sustained or controlled release of DNP. The prodrug in this formulation maintains stability across gastric and intestinal pH ranges, facilitating slow absorption and prolonged therapeutic levels.
The independent claims establish new pharmaceutical compositions and drug delivery approaches for DNP and its derivatives, focusing on stability, controlled release, and bioprecursor activation for treating multiple diseases.
Stated Advantages
The prodrugs are stable in the gastrointestinal tract and release the parent drug systemically, allowing oral administration with controlled conversion in plasma.
Depot nanoparticle formulations enable slow, sustained release at low doses, potentially reducing toxicity and improving patient compliance due to less frequent dosing.
The compositions can abolish overt reactive oxygen species (ROS) production, improve mitochondrial quality, induce Brain Derived Neurotrophin Factor (BDNF), and increase cAMP, resulting in broad neuroprotection.
The prodrugs and formulations provide increased water solubility and potentially improved bioavailability compared to parent DNP.
Phosphate prodrugs are highly soluble, stable in GI fluids, and rapidly hydrolyzed by intestinal enzymes, enhancing absorption and systemic delivery.
Flexible dosing forms facilitate immediate, sustained, or controlled release, and may be tailored for oral, intravenous, subcutaneous, topical, or transdermal administration.
Documented Applications
Treatment of neuromuscular, neuromuscular degenerative, neurodegenerative, autoimmune, developmental, traumatic brain injury, concussion, hearing loss, and metabolic diseases, including spinal muscular atrophy (SMA) types I–IV, traumatic brain injury (TBI), keratoconjunctivitis sicca (Dry Eye Disease), glaucoma, Sjogren's syndrome, rheumatoid arthritis, post-LASIK surgery, anti-depressant-induced syndromes, Wolfram Syndrome, and Wolcott-Rallison syndrome.
Treatment of major neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.
Treatment of multiple sclerosis (MS), Batten Disease (neuronal ceroid lipofuscinoses), amyotrophic lateral sclerosis (ALS), various ataxias, muscular dystrophies (including Duchenne and Becker types), and cognitive disorders associated with neuromuscular disease.
Intervention in epilepsy, seizures (various forms), and related neurological disorders.
Treatment of metabolic syndrome, obesity, type 1 and type 2 diabetes, maturity onset diabetes of the young (MODY), and nonalcoholic steatohepatitis (NASH).
Prevention and treatment of hearing loss due to noise exposure, aging, ototoxic drugs, genetic factors, traumatic brain injury, and concussion.
Pharmaceutical compositions for administration as tablets, capsules (with or without filler), rapidly dissolving forms, intravenous, subcutaneous, topical, or transdermal forms, and as depot nanoparticle formulations.
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