Preparation and use of a composition for prevention and mitigation of the effects of radiation
Inventors
Compadre, Cesar M. • Breen, Philip • Aykin-Burns, Nukhet • Hauer-Jensen, Martin • Enriquez, Raul G. • Kharade, Sujay • Malagon, Omar • Ordonez, Yadira • Ojeda, Edgar • Thakkar, Shraddha • Pineda, E. Nathalie • Jones, Darin
Assignees
UNIVERSIDAD TECNICA PARTICULAR DE LOJA • US Department of Veterans Affairs • BioVentures LLC
Publication Number
US-9993456-B2
Publication Date
2018-06-12
Expiration Date
2034-09-15
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Abstract
Plant extracts, compositions, pharmaceutical compositions and methods of making and using the same are provided herein. The compositions comprise γ-tocotrienol (GT3) and δ-tocotrienol (DT3) in ratios wherein the DT3 is predominate. The compositions are useful for radioprotection and radiomitigation in subjects in need thereof.
Core Innovation
This invention provides compositions comprising δ-tocotrienol (DT3) and γ-tocotrienol (GT3) in ratios where DT3 predominates, methods of preparing these compositions from plant extracts such as annatto seeds via extraction and chromatographic purification, and methods of using these compositions to prevent and mitigate the effects of radiation. The compositions have total tocotrienol content between 15% and 95%, with tocopherols reduced to less than 1% or absent, achieving effective radioprotective activity without toxicity.
The problem addressed is that commercially available tocotrienols are difficult to purify from natural oils which contain complex mixtures of tocotrienols and tocopherols, making pure tocotrienols expensive and hard to obtain at high enough concentrations for some applications. Additionally, tocopherols may interfere with the bioavailability and bioactivity of tocotrienols. There is a need for safe and effective radioprotectors for subjects exposed to radiation, such as cancer patients undergoing radiotherapy or individuals exposed to accidental releases of nuclear material.
The core innovation includes a method for preparing annatto seed extracts enriched in DT3 and GT3 with specific ratios (between 2:1 and 10:1, preferably about 7:1), and low or absent tocopherol content, using solvent extraction followed by chromatographic enrichment with hexane-based solvents. The compositions demonstrate synergistic radioprotective effects greater than the individual tocotrienols alone, preserving mitochondrial function and cell viability after oxidative and radiation-induced stress. Pharmaceutical compositions comprising these extracts and methods of administration to subjects in need of radioprotective, antioxidant, anti-inflammatory, immunoregulatory, or cholesterol-lowering treatments are also disclosed.
Claims Coverage
The patent includes two independent claims covering methods of preparing annatto seed extracts with specific tocotrienol ratios and methods of treating subjects with such compositions for radioprotection.
method of preparing annatto seed extract with specific tocotrienol ratio
A method involving extracting oil from annatto seeds and enriching tocotrienols from the oil via chromatography using hexane-based solvents, resulting in a composition with a δ-tocotrienol to γ-tocotrienol ratio between 7:1 and 9:1, total tocotrienols between 15% and 95%, and tocopherols less than 1%.
method of treating a subject with tocotrienol composition for radioprotection
Administering an effective amount of an annatto seed extract composition with a δ-tocotrienol to γ-tocotrienol ratio between 7:1 and 9:1, total tocotrienols between 15% and 95%, and tocopherols less than 1% to subjects in need of radioprotection or treatment from radiation exposure.
The independent claims focus on the method of preparing an annatto seed extract composition enriched in δ- and γ-tocotrienols with low tocopherol content using specific chromatographic techniques and the method of treating subjects with these compositions to achieve radioprotective effects.
Stated Advantages
The compositions provide effective radioprotection and radiomitigation at doses that do not cause toxicity.
The compositions demonstrate synergistic radioprotective effects beyond individual tocotrienol constituents.
The compositions preserve mitochondrial respiration and cell viability after oxidative and radiation insult.
The purified compositions with low tocopherol content improve bioavailability and bioactivity compared to commercially available tocotrienol mixtures.
The DG-3 composition provides 100% survival in mice exposed to lethal doses of radiation.
The compositions can be formulated as pharmaceutical compositions suitable for various administration routes.
Documented Applications
Use as a radioprotectant and radiomitigator for subjects exposed to radiation, including patients undergoing radiotherapy and persons exposed to accidental radiation releases.
Treatment of conditions requiring antioxidants, anti-inflammatory agents, immunoregulatory agents, anti-thrombotic agents, anti-atherogenic agents, hypocholesterolemic agents, or HMG-CoA reductase inhibitors.
Therapeutic use for diseases and conditions including cancer, cardiovascular diseases, elevated cholesterol and lipid levels, age-related macular degeneration, cataracts, glaucoma, chronic pain, chronic fatigue syndrome, fever, edema, diabetes mellitus, signs of aging, rheumatoid diseases, septic shock, inflammatory and autoimmune diseases, and Alzheimer's disease.
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