EP3364989A1 - Procédé de production d'extraits spéciaux de symphytum - Google Patents

Procédé de production d'extraits spéciaux de symphytum

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Publication number
EP3364989A1
EP3364989A1 EP16785167.4A EP16785167A EP3364989A1 EP 3364989 A1 EP3364989 A1 EP 3364989A1 EP 16785167 A EP16785167 A EP 16785167A EP 3364989 A1 EP3364989 A1 EP 3364989A1
Authority
EP
European Patent Office
Prior art keywords
precipitate
phase
extract
symphytum
mucus
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16785167.4A
Other languages
German (de)
English (en)
Inventor
Peter Häcker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Procter and Gamble Co
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP3364989A1 publication Critical patent/EP3364989A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/30—Boraginaceae (Borage family), e.g. comfrey, lungwort or forget-me-not
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/10—Preparation or pretreatment of starting material
    • A61K2236/15—Preparation or pretreatment of starting material involving mechanical treatment, e.g. chopping up, cutting or grinding
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/55—Liquid-liquid separation; Phase separation

Definitions

  • the invention relates to the field of production of special extracts. It relates in particular to a process for the preparation of a special extract of Symphytum, a special extract of Symphytum and a process for the preparation of a first, slime-free and / or a second mucilaginous extraction phase, and a process for the slime polysaccharide precipitation in a suspension system from Symphytum and a method for the selective removal of pyrrolizidine alkaloids from an extract phase of Symphytum and / or a separated from an extract phase precipitate of Symphytum according to the preamble of the corresponding independent claims.
  • Symphytum also called comfrey
  • Symphytum is a traditional medicinal plant whose effects were already known in ancient times.
  • the anti-inflammatory, analgesic and tissue regenerating properties are attributed to both the comfrey, consisting of the fresh and / or dried aerial parts, and the comfrey root, consisting of fresh and / or dried subterranean parts.
  • the indication of comfrey root extracts has been confirmed by evidence of percutaneous efficacy in ankle distorsion.
  • comfrey was found to be clinically effective and significantly superior in terms of the reduction of pain, inflammation, swelling, restriction of movement, and global efficacy.
  • the constituents of the comfrey plant contain 0.6-4.7% allantoin, abundant mucus polysaccharides (25-30%) comprising fructose and glucose units, phenolic acids such as rosmarinic acid (up to 0.2%), chlorogenic acid (0.012%) and caffeic acid (0.004%) and alpha- Hydroxycaffeic acid, glycopeptides, amino acids and triterpene saponins in the form of monodesmosidic and biosmosidic glycosides.
  • Symphytum contains pyrrolizidine alkaloids in the form of their N-oxides.
  • Symphytum has around 150 different pyrrolizidine alkaloids, the most important of which are 7-acetyl-lycopene amines, 7-acetyl intermediates, together with small amounts of Intermedine, Lycopsamine and Symphytine.
  • the total amount of pyrrolizidine alkaloids varies from 0.013% to 1.2%, also for method specific reasons (analysis).
  • the pyrrolizidine alkaloids Echimidine and Symlandine are not found in Symphytum officinale.
  • the pyrrolizidine alkaloids may be mutagenic or carcinogenic substances, for which reason the internal use of the drug, as well as preparations prepared therefrom, is completely dispensed with.
  • This object solves a process for the production of a special extract from Symphytum, as well as a process for producing a first, mucus-free extraction phase from Symphytum, a process for producing a second, mucilaginous extraction phase from a first mucus-free extraction phase
  • the process for producing a special extract from Symphytum comprises at least one, in particular all, of the following steps:
  • differential precipitation of mucus polysaccharides in the suspension system comprising the following steps:
  • a suspension system of Symphytum may be slimy and therefore viscous since Symphytum has mucilages, called mucus polysaccharides. Viscosity in this context means higher viscosity than water at room temperature.
  • the Schleimpolysaccharide dissolve colloidally in the suspension system or are digested or swollen as part of extractives in the suspension system.
  • an extract solution of Symphytum instead of a suspension system.
  • Such an extract solution could be provided by macerating plant parts in a solvent, especially an alcoholic solvent, especially an aqueous-alcoholic solvent.
  • the extraction system is not necessarily in a suspended form, therefore, the following description of the invention may be applied to extraction systems prepared by other extraction methods in place of the
  • Suspension system can be read. In such a case, the reading must be adapted to the description accordingly.
  • Symphytum is a generic term for all Symphytum subspecies. Symphytum may have, for example, Symphytum officinale L. The methods described here can be applied not only to a specific subspecies of Symphytum, such as Symphytum officinale L., but to all Symphytum species. Symphytum officinale, Symphytum x uplandicum, Symphytum asperum, Symphytum bulbosum, Symphytum tuberosum and / or Symphytum peregrinum are preferably used for the method, Symphytum officinale being particularly preferred.
  • Special extracts for example from plants, differ from conventional extracts in that in addition to pure extraction, further processing steps are carried out during production.
  • the production of a special extract is a complex, multi-step extraction and purification process. In doing so, undesirable ingredients, such as pyrrolizidine alkaloids, can be removed and the desired agents that determine the effectiveness of the special extract can be enriched.
  • the extraction residue is to be understood as a solid residual phase or raffinate, it has, for example, the solid parts of the plant, which are not dissolved in the extract phase.
  • the extraction residue is separated from the suspension system prior to precipitation of the mucus polysaccharides.
  • the first precipitate is separated from the first extract phase, since the extraction residue has already been separated as raffinate from the suspension system.
  • the concentration of active ingredient in the special extract can be increased. Unwanted by-products are removed during extraction or further processing steps and the special extract can thus be better tolerated.
  • the composition and amount of ingredients may optionally be standardized and / or quantified. This guarantees a consistent quality of the special extract.
  • high molecular weight mucous polysaccharides may be precipitated in the slimy suspension system and separated after precipitation from an extract phase (liquid phase).
  • the extract phase may also be referred to as a primary extract become.
  • the precipitate and the separated primary extract or the separated extract phase can be purified individually from plant substances with harmful potential, such as pyrrolizidine alkaloids, and reunited or combined after the pyrrolizidine alkaloid purification. This makes it possible that the special extract has only a low pyrrolizidine alkaloid content, which allows the use of the special extract in the therapeutic area can be made possible.
  • the precipitation of colloidally dissolved mucus polysaccharides in the suspension system of Symphytum may have a differential mucus precipitation.
  • differentially or stepwise specific extractive substances such as undesired and / or effective mucous polysaccharides, can be precipitated from the suspension system and optionally separated from the extract phase as insoluble aggregates.
  • the special extract may have a pyrrolizidine alkaloid content of not more than 0.5 ppm, in particular not more than 0.1 ppm. This makes it possible that the special extract of Symphytum can be safely processed into a cream and / or ointment for therapeutic treatment, in particular for the therapeutic treatment of pain, inflammation, swelling, movement restrictions, bruises, strains, exudations, arthritis , Back pain, muscle problems and / or joint problems can be used.
  • the suspension system in which the mucus polysaccharides are colloidally dissolved can be prepared and / or provided by a batchwise extraction. This makes it possible to extract different extractive substances effectively during the individual discontinuous extraction steps from the plant Symphytum.
  • the discontinuous extraction can have a polarity-controlled discontinuous extraction, wherein the discontinuous extraction can be achieved or made possible by the multistage setting of the polarity of the extraction phase.
  • the discontinuous or multi-stage extraction can also be referred to as fractionated extraction in the present case.
  • the discontinuous extraction may comprise the following steps:
  • the mucus polysaccharides are not yet colloidally dissolved, that is not yet open or swollen. Therefore, the first extraction phase is low in viscosity and unaffected by the mucus polysaccharides. This makes it possible that in the substantially mucus-free, first extraction phase, the extractive substances, such as, for example, the active ingredients, can be efficiently released and easily dissolved.
  • the extractive substances such as, for example, the active ingredients
  • the mucus polysaccharides can be colloidally dissolved and digested in a second step in the preparation of the mucus-containing, second extraction phase from Symphytum and can thus be made particularly good and easily accessible for the special extract.
  • the first, essentially slime-free, extraction phase may be by a process comprising at least one of the following steps:
  • Low molecular weight alcohol is understood as an alcohol having a maximum of ten carbon atoms, for example, ethanol, propanol, isopropanol, etc.
  • a preferred alcohol is ethanol.
  • the process for producing a substantially slime-free, first extraction phase as such is associated with the process for producing a special extract by a common inventive idea, namely the improvement or simplification of the production of a special extract from Symphytum.
  • the process for preparing the first, substantially mucus-free extraction phase from Symphytum can also be considered as an independent process or in the context of the process for the preparation of the special extract or individually in conjunction with one of the other processes described in this text.
  • the provided fresh, frozen and / or dried plant parts of Symphytum may have aerial and / or subterranean plant parts of Symphytum.
  • the frozen plant parts can also be frozen.
  • the use of frozen plant parts has the advantage that enzymatic decomposition processes in the plant parts can be prevented or minimized, for example after harvesting. As a result, biochemical processes of post-harvest physiology and spoilage can be prevented, thus ensuring optimum preservation of any active ingredients.
  • the plant parts are provided in fresh, frozen, frozen and / or dried form pre-shredded to a size of 0.5 cm to 2.5 cm.
  • the pre-shredded plant parts are further comminuted by wet comminution and / or turboextraction, wherein the plant parts can be comminuted to a size of 0.1 mm to 1 mm.
  • a suspension system of the finely divided plant parts and a solvent which is added for the wet comminution and / or the turboextraction to the pre-shredded Pfianzen.
  • the solvent may have low molecular weight alcohol having an alcohol content of 65-75% by volume, in particular of 70% by volume.
  • the cutting forces and the shearing forces result in a comminution of the starting material (pre-shredded plant parts), in which the cell walls are increasingly torn open. In doing so, the cell walls of the plant material are optimally broken up. With the help of the shear forces it comes next to a crushing of the plant particles to a suspension.
  • the plant parts are highly comminuted using a solvent, thereby greatly increasing the surface area of the plant parts, thus enabling cell disruption and optimizing the contact between the solvent and the plant parts for extraction.
  • the diffusion and dissolution processes are greatly accelerated.
  • the turboextraction can also be called vortex extraction.
  • the pre-shredded plant parts are comminuted to the desired size with the addition of a low molecular weight alcohol in a suitable cutting and / or grinding device.
  • the low molecular weight alcohol may have an alcohol content of 65-95% by volume, in particular of 65-75% by volume, in particular of 70% by volume.
  • the alcohol content By adjusting the alcohol content to 65-95% by volume, swelling, dissolution and / or digestion of the mucus polysaccharides is prevented, whereby mainly slime-free active ingredients are dissolved out of the plant parts.
  • polyphenols which make up part of the active ingredients of Symphytum, can be dissolved particularly well in the extraction phase from an alcohol content of about 65% by volume. Since the first, essentially slime-free extraction phase has only a minimal amount of mucous polysaccharides, the extraction of, for example, polyphenols can be carried out particularly efficiently.
  • the alcohol content of the first extraction phase can be adjusted to 70% by volume.
  • an antibacterial effect of the first extraction phase can be determined.
  • the first, substantially slime-free extraction phase unfolds a germ-reducing effect, which may be advantageous, inter alia, for further processing and / or for use in a special extract and can ensure compliance with legal requirements.
  • the temperature of the extraction phase to 45 ° C to 80 ° C, in particular to 50 ° C - 70 ° C, in particular to 54-56 ° C can be increased.
  • the exchange processes in the extraction of active ingredients can be improved and on the other
  • enzymes and / or proteins that are in the extraction phase may be (selectively) denatured.
  • enzymatic degradation and / or conversion processes in the slime-free, first extraction phase can be prevented.
  • the mucus-containing, second extraction phase can be prepared by maceration, in particular by stirring, the first extraction phase, wherein the alcohol content (low molecular weight alcohol) of the second extraction phase to 45% by volume - 55% by volume, in particular to 49% by volume - 51% by volume, in particular 50 vol% is set.
  • the process for producing a mucous-containing, second extraction phase as such is associated with the process for producing a special extract by an inventive idea, namely the improvement by optimized process steps or partial steps of the preparation of a special extract from Symphytum.
  • the process for preparing the second phase of mucus extraction from Symphytum can also be considered as an independent process or in the context of the process for the preparation of the special extract.
  • the adjustment of the alcohol content can be effected by the addition of water to the first, substantially slime-free, extraction phase.
  • This increases the polarity of the extraction phase, which leads to swelling and thus to a colloidal dissolution of the mucus polysaccharides.
  • the second extraction phase or the suspension system of Symphytum has a high proportion of active ingredients. In this way, a further stage of the discontinuous extraction can be achieved.
  • the water content of the extraction phase can be increased and the alcohol content of the mucous-containing, second extraction phase can be increased to 45% by volume. 55% by volume.
  • the polarity of the second extraction phase is increased compared to the first extraction phase.
  • the second extraction phase therefore has in addition to the colloidally dissolved, developed Schleimpolysacchariden also in the first extraction phase readily soluble active ingredients, such as the polyphenols, in a high concentration.
  • the second extraction phase may also be referred to as a suspension system which is slimy.
  • the mucus-containing, second extraction phase can be prepared at room temperature. However, the preparation of the second extract phase is possible even at higher temperatures, as long as a decomposition of thermolabile mucus polysaccharides and / or the conversion of Schleimpolysaccharide is not promoted.
  • the method for precipitating, in particular for differential, mucus polysaccharides in a suspension system of Symphytum as precipitate as such is associated with the process for producing a special extract by an inventive idea, namely the improvement or simplification of the production of a special extract from Symphytum .
  • the method of differential precipitation of mucus polysaccharides in the suspension system as a precipitate may also be considered as an independent process or in the context of the process for preparing the special extract or individually in conjunction with any of the other processes described herein.
  • slimy suspension systems from Symphytum can be used, which by a alternative extraction and not be prepared by means of a batch extraction.
  • the precipitation of mucus polysaccharides as precipitate may have a differential mucus precipitation.
  • differentially specific substances such as undesirable and / or effective mucilages, can be precipitated in the suspension system and optionally separated from the extract.
  • the differential mucus precipitation may comprise at least one of the following steps:
  • first differential mucus precipitation of high molecular weight mucus polysaccharides as first precipitate in a provided suspension system separation of a first precipitate, optionally as part of an extraction residue, and recovery of a first extract phase
  • the high molecular weight Schleimpolysaccharide can be separated from the mucus-containing suspension system by the first differential mucus deposition.
  • the separation can be carried out by sedimentation and subsequent sifting of the first precipitate, optionally as part of an extraction residue, and in particular by pressing.
  • the separation can also be carried out by other known methods, such as filtration, decantation, sieving, centrifuging and / or pressing.
  • the raffinate which may also have the extraction residue in addition to the first precipitate, can be recycled to the process for producing the special extract. This makes it possible that the high molecular weight Schleimpolysaccharide the first precipitate may optionally be used for further use.
  • the first extract phase can be separated specifically from the high-molecular mucus polysaccharides.
  • the high molecular weight mucus polysaccharides do not penetrate through the skin unlike low molecular weight mucus polysaccharides and therefore can not currently be used as a potential drug component.
  • the high-molecular mucus polysaccharides have no therapeutic potential from today's perspective.
  • the ineffective high molecular mucus polysaccharides are removed from the extract and, on the other hand, the first extract phase becomes less viscous than the suspension system and thus more easily processable.
  • the low-molecular mucus polysaccharides which are of interest as active ingredients for the special extract, can be precipitated specifically after separating the high-molecular mucus polysaccharides from the thin first extract phase and as a disperse, second precipitate or precipitate from the fluid, second extract phase be separated.
  • the second precipitate can be separated from the second extract phase by a known method such as filtration, decantation, sieving, centrifuging and / or pressing, and so recovered. This results in a second, colloidally disperse precipitate, which has the low molecular weight mucus polysaccharides and which is usually present in colloidally dissolved form in the second extract phase.
  • the second precipitate may be present as a very finely powdered precipitate.
  • the second precipitate can be dried after separation. This makes it possible that the precipitate can be stored in the dried state.
  • the second precipitate can be lyophilized, for example. Since lyophilization is a particularly gentle drying method, which is carried out at low pressure, oxidation of the second precipitate can be prevented. However, any other drying method for drying the second precipitate is conceivable.
  • the pH of the slimy suspension system of Symphytum can be adjusted to 4 to 5, wherein the suspension system before the precipitation can have a pH of 6 to 6.5.
  • the precipitated high molecular mucus polysaccharides can be separated as already described.
  • the first extract phase After separating the first precipitate from the first extract phase, the first extract phase has a lower viscosity than the slimy suspension system. As a result, the first extract phase can be well processed and the handling for further washout and / or precipitation processes is improved.
  • the additional extraction which can be accompanied by the first differential mucus precipitation and the associated change in polarity, can be used to optimize the multistage, discontinuous extraction by means of a further process step or a further pH-modified stage.
  • the suspension system of Symphytum is provided by the described discontinuous extraction, the first extraction phase is prepared in a first step.
  • this first extraction phase with a relatively high alcohol content as described, specifically alcohol-soluble extractives dissolved from the plant parts.
  • the second extraction phase is prepared with a lower alcohol content, while the mucus polysaccharides are digested by swelling and dissolved colloidally.
  • a third step because of the renewed change of the polarity, further extractive substances can be released from the plant parts in an acidic environment.
  • the third step is only possible if the extraction residue was not removed before the first differential mucus precipitation.
  • the pH of the first extract phase can be adjusted to 2.5-3.5.
  • a fine, colloidally disperse, second precipitate forms, which can initially remain in suspension, whereby a good separation without lumps is possible.
  • the fine second precipitate may have a light beige color. Due to the fine surface structure of the precipitated second precipitate, the precipitate can be efficiently purified from undesirable by-products such as pyrrolizidine alkaloids. Furthermore, the fine, second precipitate can be separated from the first extract phase by one of the methods already described and known.
  • the pH of the slimy suspension system in particular the second, mucus-containing extraction phase and / or the first extract phase can be adjusted by means of a catalyst and / or with the aid of an acid.
  • a catalyst also called cation exchanger
  • the acid catalyst may have sulfonic acid groups on the polymer surface. In this way, an ion exchange can take place on the surface of the catalyst, whereby cations are bound.
  • mucus polysaccharides By reducing the pH, mucus polysaccharides selectively precipitate from the extract (suspension system and / or first extract phase) and form a (first and / or second) precipitate.
  • ionic Pyrrolizidin- alkaloids can be attached by ion exchange on the catalyst, resulting in a partial reduction of undesirable pyrrolizidine alkaloids in the extract, especially in the first extract phase and / or in the second extraction phase comes.
  • the pH of the suspension system and / or the first extract phase can be adjusted in acidic form with the aid of a cation exchanger, wherein the cation exchanger can be designed on the basis of an organic polymer resin and wherein the cation exchanger can in particular have sulfonic acid groups on the polymer surface ,
  • the acid for adjusting the pH may be a mineral or organic acid.
  • the lowering of the pH value leads to selective precipitation of the mucus polysaccharides as described above, but without depletion of undesired pyrrolizidine alkaloids.
  • the extraction solution can already be pre-purified by pyrrolizidine alkaloids, since the acidic catalyst a portion of the dissolved pyrrolizidine alkaloids on the catalyst surface can bind.
  • the purification of the second precipitate by the selective removal of pyrrolizidine alkaloids from the second precipitate may comprise the following steps:
  • Resuspension of the second precipitate in a wash solution especially in a wash solution comprising an acid, low molecular weight alcohol,
  • the mucous polysaccharides of the precipitate remain insoluble and the pyrrolizidine alkaloids are dissolved in the wash solution and thus can be washed or extracted from the precipitate.
  • the alcohol content of the washing solution is 65-95% by volume, in particular 78% by volume - 82% by volume.
  • the second precipitate purified from pyrrolizidine alkaloids after washing can be separated from the washing solution in a known manner, such as sedimentation and siphoning or similar process steps.
  • a washing solution with an alcohol content of 65-95% by volume is also referred to below as a high-percentage alcohol.
  • the pH of the acidic wash solution may be 2-4, in particular 2.5-3.5, in particular at least 3.
  • Resuspending may use a 1:10 ratio of precipitate to wash solution.
  • the ratio refers to the mass of the precipitate and the washing solution.
  • the purification of the second precipitate by the selective removal of pyrrolizidine alkaloids from the second precipitate may alternatively comprise the following steps: Resuspension of the second precipitate, in particular a lyophilized second precipitate, in high-percentage, low molecular weight alcohol, in particular ethanol,
  • the second precipitate of pyrrolizidine alkaloids can be purified.
  • the mucus polysaccharides do not dissolve in high-percent alcohol, but the pyrrolizidine alkaloids are well soluble in alcohol. In this way, the pyrrolizidine alkaloids can be dissolved out of the second precipitate without dissolving the effective Schleimpolysaccharide from the second precipitate.
  • the pyrrolizidine alkaloids can be bound and removed from the suspension by means of ion exchange from the suspension on the catalyst as already described.
  • the amount of acidic catalyst can be adjusted to the amount of resuspended second precipitate, in particular equal amounts of catalyst and precipitate can be used for purification.
  • the same amount in this context means equal mass.
  • the catalyst can be separated from the fine resuspended second precipitate and the second precipitate subsequently separated from the liquid high percent alcohol solution. The separation can be carried out as already described by a known method, such as sedimentation and siphoning or decanting or the like.
  • the high-percentage, low-molecular-weight alcohol may have 80% by volume to 98% by volume, in particular 96% by volume, of low molecular weight alcohol.
  • Resuspending the second precipitate can adjust the amount (mass) of precipitate to the amount of alcohol.
  • a portion of the second precipitate can be resuspended in 5 to 10 parts of alcohol.
  • the resuspension and pyrrolizidine alkaloid purification may optionally be repeated with the purified second precipitate, whereby the pyrrolizidine-alkaloid content of the precipitate may be further reduced.
  • the purified second precipitate may have a maximum of 1 ppm, in particular a maximum of 0.5 ppm, in particular a maximum of 0.1 ppm of pyrrolizidine alkaloids. This makes it possible that the purified second precipitate can be used from a toxicological point of view without concern in the special extract.
  • the selective removal of pyrrolizidine alkaloids (PA) from the second extract phase may comprise at least one of the following steps:
  • the purified, in particular concentrated, second extract phase, in particular the purified second extract phase a maximum of 0.5 ppm Pyrrolizidin- alkaloids, in particular at most 0.25 ppm pyrrolizidine alkaloids, in particular at most 0.1 ppm pyrrolizidine alkaloids.
  • the pyrrolizidine alkaloid purification of the second extract phase with the aid of a stationary phase can be realized, for example, by the chromatographic, in particular column chromatographic, purification.
  • the chromatographic, especially column chromatographic, purification of the extract phase, in particular the second extract phase pyrrolizidine alkaloids can be removed from the second extract phase.
  • the removal of the pyrrolizidine alkaloids can be carried out in particular by means of the already described acid catalyst on a gel-like polymer basis.
  • the catalyst may have sulfonic acid groups on the polymer surface. In this way, an ion exchange can take place, which can be described by the following formula:
  • PA + is an ionic pyrrolizidine alkaloid catalyst-PA is ⁇ H a bound form of the catalyst and pyrrolizidine alkaloid and H + is a proton.
  • the pH of the second extract phase can be adjusted to 5.5-7, in particular to 6.2-6.5.
  • the further processing, such as concentration, of the purified extract phase can be improved.
  • the purified second extract phase can be concentrated. Due to the concomitant reduction in the volume while maintaining the same amount of active substances or extractives, the active ingredient concentration of the pyrrolizidine alkaloid-purified second extract phase can be increased. To this way, the preparation of the special extract can be improved and a drug extract ratio (DEV) can be defined.
  • the concentration can be carried out, for example, by means of a distillation, in particular a vacuum distillation.
  • the alcohol content of the special extract can be reduced after mixing. Thereby, the stability of the special extract in the further processing into a galenic preparation can be improved.
  • the process for producing a special extract of Symphytum having a pyrrolizidine alkaloid content of not more than 0.5 ppm, in particular not more than 0.1 ppm may comprise the following steps:
  • a method is provided with which a special extract with a pyrrolizidine alkaloid content of not more than 0.5 ppm, in particular not more than 0.25 ppm, can be produced.
  • the invention relates to a special extract, which can be prepared by the described method.
  • the special extract of Symphytum can be used in therapy.
  • the special extract of Symphytum can be used especially for external use in therapy.
  • the special extract of Symphytum can be used for cosmetic purposes.
  • the special extract can be used especially in the treatment of pain, inflammation, swelling, restricted mobility, bruises, strains, exudations, arthritis, back pain, muscle discomfort and / or joint discomfort.
  • one aspect of the invention for improving the production of a special extract from Symphytum relates to a process for producing a substantially mucus-free, suspended, first extraction phase from Symphytum comprising the following steps:
  • a further aspect of the invention for improving the production of a special extract from Symphytum relates to a method for producing a second, mucilaginous extraction phase from a provided first, substantially mucus-free extraction phase from Symphytum, wherein the second, mucilaginous extraction phase by maceration, in particular by agitation, the first Extraction phase is prepared, wherein the alcohol content of the extraction phase is adjusted to 45% by volume - 55% by volume, in particular to 50% by volume, as already described.
  • Another aspect of the invention for improving the production of a special extract from Symphytum relates to a method of fouling mucus polysaccharides (SPS) having differential slime precipitation, the differential slime precipitation comprising the steps of: - First differential mucus precipitation of high molecular weight Schleimpolysacchariden as a first precipitate in a suspension system of Symphytum, separation of the first precipitate and optionally an extraction residue as a raffinate and recovery of a first extract phase; second differential mucus precipitation of low molecular weight mucus polysaccharides as a second precipitate from the first extract phase, separation of the second precipitate and recovery of a second extract phase.
  • SPS mucus polysaccharides
  • Another aspect of the invention for improving the production of a special extract from Symphytum relates to a method for the selective removal of pyrrolizidine alkaloids (PA) from a precipitate precipitated from a suspension system of Symphytum and separated from an extract comprising the following steps:
  • Resuspension of precipitated and separated precipitate in a washing solution in particular in a washing solution having an acid, low molecular weight alcohol, wherein the alcohol in particular has a pH of 2-4, and
  • the resuspending and cleaning with the purified precipitate is repeatable; and wherein the purified precipitate in particular has at most 1 ppm, in particular not more than 0.5 ppm, in particular not more than 0.1 ppm, of pyrrolizidine alkaloids.
  • the invention for improving the production of a special extract from Symphytum relates to methods for the selective removal of pyrrolizidine alkaloids from an extract phase precipitated and separated from a precipitate in a suspension system of Symphytum, comprising at least one of the following steps:
  • the purified, in particular concentrated, extract phase has a maximum of 0.5 ppm of pyrrolizidine alkaloids, in particular a maximum of 0.1 ppm of pyrrolizidine alkaloids.
  • a first differential slime precipitation step is initiated by the addition of acid catalyst in protonated (H + ) form.
  • the catalyst is an acid catalyst based on a gelled polymer and has sulfonic acid groups on the polymer surface.
  • the pH of the second extraction phase 2 is adjusted to 4-5 and high molecular mucus polysaccharides are precipitated as the first precipitate Nl.
  • the liquid extract phase also called first extract phase A, is separated from the disperse extraction residue by pressing out the sediment phase or the extraction residue.
  • the first extract phase A which is subjected as a filtrate a further proton exchange with the addition of the above-mentioned acidic catalyst for at least 60 minutes, until the stable reaching of pH 2.5-3.5.
  • second precipitate N2 quantitative precipitation of the mucus polysaccharides occurs as second precipitate N2.
  • the acid catalyst is then screened off and the disperse, second precipitate N2, also called slime precipitate, removed by centrifuging the disperse system of the resulting second extract phase B.
  • the filtered second extract phase B is then chromatographed as a mobile phase in a chromatography column, which is filled as a stationary phase with acidic cation exchanger.
  • the eluate contains residual pyrrolizidine alkaloids of not more than 0.1 ppm (LC-MS / MS).
  • the stationary phase used is the polymer-based acidic catalyst described above.
  • the eluate is adjusted to pH 6.2 with sodium hydroxide solution, concentrated by vacuum distillation and with ethanol (96% vol). added.
  • the pyrrolizidine-alkaloid-purified, second precipitate N2 is suspended and dissolved and then additionally supplemented with purified water.

Abstract

L'invention concerne un procédé de production d'un extrait spécial de symphytum, qui comprend au moins une, en particulier la totalité, des étapes suivantes consistant à : - produire un système de suspension à partir de symphytum ; - effectuer une précipitation différentielle de polysaccharides de mucus dans le système de suspension, la précipitation différentielle comprenant les étapes suivantes : - une première précipitation de mucus différentielle de polysaccarides de mucus de poids moléculaires élevés comme un premier précipité dans le système de suspension, séparation du premier précipité et d'un résidu d'extraction en tant que raffinat et récupération d'une première phase d'extrait ; - seconde précipitation différentielle de mucus de polysaccharides de mucus de faibles poids moléculaires en tant second précipité à partir de la première phase d'extrait, séparation du second précipité et récupération d'une seconde phase d'extrait ; - élimination sélective d'alcaloïdes de pyrrolizidine du second précipité et/ou de la seconde phase d'extrait ; et - combinaison du second précipité, en particulier du second précipité purifié des alcaloïdes de pyrrolizidine, et de la seconde phase d'extrait, en particulier de la seconde phase d'extrait purifiée des alcaloïdes de pyrrolizidine, pour obtenir l'extrait spécial.
EP16785167.4A 2015-10-22 2016-10-24 Procédé de production d'extraits spéciaux de symphytum Withdrawn EP3364989A1 (fr)

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EP15191070.0A EP3159002A1 (fr) 2015-10-22 2015-10-22 Procede de fabrication d'extraits speciaux de symphytum
PCT/EP2016/075487 WO2017068175A1 (fr) 2015-10-22 2016-10-24 Procédé de production d'extraits spéciaux de symphytum

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KR (1) KR20180073607A (fr)
CN (1) CN108348564A (fr)
AU (1) AU2016341398A1 (fr)
BR (1) BR112018008080A2 (fr)
CA (1) CA3001077A1 (fr)
CL (1) CL2018001047A1 (fr)
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EP3412299B1 (fr) 2017-06-09 2022-08-31 SMC - Research AG Procédé de mise en pot lors de la fabrication d'extraits spéciaux de symphytum
WO2020015983A1 (fr) * 2018-07-17 2020-01-23 Frutarom Schweiz Ag Procédé d'élimination d'impuretés de préparations végétales
CN110407951B (zh) * 2019-09-07 2021-04-06 美健极生物工程技术(广州)有限公司 一种天然来源的多糖及促进皮肤修复、提高皮肤弹性进而制备化妆品的用途
PL3871672T3 (pl) 2020-02-27 2022-09-26 The Procter & Gamble Company Komfreiny – hamujące ekspresję genów prozapalnych lignany arylonaftalenowe oraz kompozycja farmaceutyczna je zawierająca
FR3111349B1 (fr) * 2020-06-11 2023-07-21 Robertet Sa Procédé d'extraction/purification des alcaloïdes pyrrolizidiniques
CN115403587B (zh) * 2022-09-26 2024-03-01 复旦大学附属中山医院 一类中草药肝损伤相关生物标志物的化学合成方法
HUP2200389A1 (hu) 2022-09-29 2024-04-28 Rotachrom Tech Zrt Eljárás fekete nadálytõ gyökér-kivonatok pirrolizidin alkaloid tartalmának csökkentésére folyadék-folyadék kromatográfiával

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AT403347B (de) * 1994-03-21 1998-01-26 Schnecker Jutta Dipl Ing Dr Verfahren zur herstellung eines symphytum-pflanzen-extraktes
US20100303935A1 (en) * 2009-05-29 2010-12-02 Squires Meryl J Medicinal Composition

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CL2018001047A1 (es) 2018-08-24
AU2016341398A1 (en) 2018-05-10
US20180303890A1 (en) 2018-10-25
BR112018008080A2 (pt) 2018-10-23
RU2018117717A (ru) 2019-11-22
KR20180073607A (ko) 2018-07-02
JP2018535209A (ja) 2018-11-29
WO2017068175A1 (fr) 2017-04-27
CN108348564A (zh) 2018-07-31
EP3159002A1 (fr) 2017-04-26
MX2018004902A (es) 2018-11-09

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