Method for producing ginkgo extracts
Inventors
Waimer, Frank • Reinhard, Steffen • Hauer, Hermann
Assignees
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Publication Number
US-10028986-B2
Publication Date
2018-07-24
Expiration Date
Abstract
The present invention relates to an improved multistep method for the production of an extract of Ginkgo biloba leaves for use as a drug.
Core Innovation
The invention relates to a method for producing a dry extract of Ginkgo biloba leaves with specified contents of flavonoids, bilobalide, ginkgolides A-C, and low ginkgolic acids. The method uses extraction with extract solvent selected from aqueous acetone, aqueous alkanol of 1 to 3C-atoms, and anhydrous methanol, followed by vacuum distilling and obtaining a concentrated aqueous solution.
A key aspect is the sequence of concentrating and phase partitioning involving a methyl ethyl ketone or methyl ethyl ketone-acetone fraction. After precipitation and ammonium sulfate extraction with methyl ethyl ketone or methyl ethyl ketone-acetone, the phase is concentrated and separated into first and second portions, and an adjusted extraction solution is formed by adding water and methyl ethyl ketone prior to extracting with a methyl ethyl ketone/aliphatic solvent mixture having a boiling point of 60 to 100°C to obtain a water-methyl ethyl ketone phase and a methyl ethyl ketone-aliphatic solvent phase.
The invention then combines the second portion of the concentrate with the selected phase from the adjusted extraction solution in order to obtain a solution, followed by further concentration and diluting. The method continues with multiple extracting with butanol or pentanol, converting to an aqueous ethanolic solution that is extracted with an aliphatic solvent having a boiling point of 60 to 100°C, and concentrating the water phase under reduced pressure and at a temperature of not more than 60 to 80°C to obtain the dry extract with a water content of less than 5% by weight.
Claims Coverage
The independent claims are directed to a multistep method that includes defined extraction, vacuum distillation/concentration, precipitation and separation, ammonium sulfate extraction, controlled methyl ethyl ketone or methyl ethyl ketone-acetone fractionation with phase partitioning, and subsequent solvent partitioning and concentration to obtain a dry Ginkgo biloba extract meeting specified compositional ranges. The inventive features are expressed through process step structure and specific solvent and phase constraints totaling at least seven core feature groups.
Dry Ginkgo biloba leaf extraction with controlled solvent system
A method for producing a dry extract of Ginkgo biloba leaves comprising extracting fresh or dried green leaves at about 40 to 100°C with an extract solvent selected from aqueous acetone, an aqueous alkanol of 1 to 3C-atoms, and anhydrous methanol to obtain a crude extract solution.
Vacuum distilling to concentrated aqueous solution
Vacuum distilling the crude extract solution to remove the extract solvent to a maximum content of 10% by weight to obtain a concentrated aqueous solution, wherein if anhydrous methanol is used, water is added at the last distillation step.
Precipitation by dilution and cooling and separation of precipitate
Diluting the concentrated aqueous solution with water to a solids content of 5 to 25% by weight, cooling to a temperature below 25°C, keeping cool until formation of a precipitate and separating the formed precipitate to obtain a diluted aqueous solution.
Ammonium sulfate extraction into methyl ethyl ketone or methyl ethyl ketone-acetone phase
Adding ammonium sulfate to the diluted aqueous solution to a concentration of at least 30% by weight and extracting with an extraction solvent selected from methyl ethyl ketone or a mixture of methyl ethyl ketone and acetone, separating the aqueous phase from the methyl ethyl ketone or methyl ethyl ketone-acetone phase to obtain a methyl ethyl ketone or methyl ethyl ketone-acetone phase.
Concentrating methyl ethyl ketone or methyl ethyl ketone-acetone phase to defined solids
Concentrating the methyl ethyl ketone or methyl ethyl ketone-acetone phase to a solids content of 40 to 80% by weight to obtain a concentrate.
Adjusted first portion extraction to form water-methyl ethyl ketone and methyl ethyl ketone-aliphatic phases
Separating the concentrate into a first and second portion, wherein the first portion is 10 to 60% by weight; adding water and methyl ethyl ketone to the first portion to produce an adjusted extraction solution with solids content of not more than 60% by weight and a methyl ethyl ketone content of not more than 30% by weight; extracting the adjusted extraction solution with a mixture of methyl ethyl ketone and an aliphatic solvent having a boiling point of 60 to 100°C in a ratio of 7/3 to 9/1 (m/m) to obtain a water-methyl ethyl ketone phase and a methyl ethyl ketone-aliphatic solvent phase.
Combining portions and downstream solvent partitioning to dry extract
Combining the second portion of the concentrate with the water-methyl ethyl ketone phase or the methyl ethyl ketone-aliphatic solvent phase to obtain a solution; concentrating and diluting; multiply extracting the solution with butanol or pentanol to obtain a butanol or pentanol phase; diluting by addition of water and ethanol to obtain an aqueous ethanolic solution; extracting the aqueous ethanolic solution with an aliphatic solvent having a boiling point of 60 to 100°C and separating the aqueous phase to obtain a water phase; and concentrating the water phase under reduced pressure and at a temperature of not more than 60 to 80°C to obtain the dry extract with water content of less than 5% by weight.
Dry extract composition targets
A dry extract of Ginkgo biloba leaves having 22.0% by weight to 27.0% by weight flavonoids calculated as flavon glycosides, 2.6% by weight to 3.2% by weight bilobalide, 2.8% by weight to 3.4% by weight ginkgolides A, B and C, and not more than 5 ppm ginkgolic acids.
The inventive coverage centers on obtaining a concentrated aqueous solution, precipitating and separating, extracting with ammonium sulfate into methyl ethyl ketone or methyl ethyl ketone-acetone and concentrating it, then separating and adjusting a first portion for constrained methyl ethyl ketone content before phase partitioning with a defined methyl ethyl ketone/aliphatic solvent mixture, followed by further butanol or pentanol partitioning and aqueous ethanolic extraction steps to produce a dry extract with explicitly defined flavonoid, bilobalide, ginkgolide A-C, and ginkgolic acid ranges.
Stated Advantages
Produces a dry Ginkgo biloba leaf extract meeting specified compositional ranges for flavonoids, bilobalide, ginkgolides A-C, and not more than 5 ppm ginkgolic acids.
Documented Applications
Production of a dry extract of Ginkgo biloba leaves with European Pharmacopoeia specifications for flavonoids, bilobalide, ginkgolides A-C, and low ginkgolic acids, including comparative data against EP 431536 B1 and an Example 1 (invention).
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