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)
  • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • 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
  • A61K2236/30—Extraction of the material
  • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
• • 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
  • A61K2236/35—Extraction with lipophilic solvents, e.g. Hexane or petrol ether
• • 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
  • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
• • 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
  • A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization

Definitions

• the present invention relates to a process for the preparation of a milk thistle fruit extract, in particular a flavanolignan preparation with increased release rate and improved absorbability and its use, in particular for the therapy and prophylaxis of liver diseases.
• the milk thistle (Milk thistle, Silybum marianum or Carduus marianus) is a cultivated especially in southwest and central Europe (Austria, Hungary) plant and is naturalized in Eurasia, North America and South America next to Australia. Other growing areas are located in China.
• the efficacy of the drug milk thistle (seeds and fruits) in the prophylaxis and treatment of various forms of liver and bile dysfunction is known.
• the drug consists of the mature, liberated from the pappus fruits with a minimum content of Sylimarin of 1.5% (Pharmacopoea Europaea (Ph "Eur.), European Pharmacopoeia 2007) .
• Terminal ancient are tinctures (mostly alcoholic extracts from the drug In particular isolated silymarin is particularly suitable (eg DE 1 923 982, DE 1 767 666 (Madaus)).
• Silymarin is a flavanolignan complex or polyhydroxyphenylchromanones and was first isolated from the plant in the 1960's (Doctoral Thesis Janiak Bernhard, June 1960, FU-Berlin (DE 2020407), Pelter A., Hansel R., Tetrahedron Letters, 25 , (1968)).
• Silymarin consists of a mixture with the flavonolignan complex I-IV in the main constituents of the four flavanolignans, silylbin (silybinin) (silymarin I), silydianin (silymarin II) and silychristin (silymarin III)
• the fruits of the milk thistle are used for extract production.
• Such extracts of milk thistle and methods are already available in the prior art its preparation is described, for example as disclosed in DE 1 923 982, DE 29 14 330 (Madaus).
• the raw material here: plant drug
• the raw material is usually degreased, extracted, filtered, (concentrated) and purified.
• Such a composition allows a release rate of silymarin of 30 - about 40% (measured according to Ph. Eur. 5.7, 2.9.3 (01/2006: 20903 in the currently valid version, eg by means of basket method, paddle model).
• a release rate of silymarin of 30 - about 40% (measured according to Ph. Eur. 5.7, 2.9.3 (01/2006: 20903 in the currently valid version, eg by means of basket method, paddle model).
• flavano lignans e.g. by means of polyalcohols, aminosugars, esters or by means of inclusion compounds, such as cyclodextrin (EP 0 422 497 Bl (Madaus)), or complex compounds, e.g. by phosphatidylcholine.
• inclusion compounds such as cyclodextrin (EP 0 422 497 Bl (Madaus)
• complex compounds e.g. by phosphatidylcholine.
• the object is to provide an improved milk thistle fruit extract, in particular one which has an advantageously increased silymarin release rate while retaining the native character.
• the extract should be largely produce without additives, additives, carriers, wetting agents.
• the object is achieved by providing a process for producing a milk thistle fruit extract, wherein in the following steps
• Polarity such as ethyl acetate, ethanol,
• Solvent of similar polarity and then mixed in hexane or a solvent of similar polarity and concentrated, preferably at a pressure of 1-100 mbar, and the resulting ethanol-water phase is separated, e.) Dried and, if necessary, comminuted f.) in anhydrous alcohol, preferably ethanol is taken up, g.) if necessary. Filed and concentrated and h.) Dried and, if necessary, comminuted.
• the additional step f. Leads to a significant increase in the silymarin release rate to 80% (see comparative examples). This is particularly advantageous since a lower dosage of the milk thistle fruit extract according to the invention is achieved. Furthermore, it is advantageous that a quality is achieved, as is achieved in the prior art only by means of additives, additives, carriers and wetting agents.
• anhydrous alcohol in step f.) Preferably comprises C 1 -C 4 alcohols, more preferably ethanol, such as 99%, even 99.5% pure.
• the invention also relates to a method for producing a milk thistle fruit extract with a Silymarin release rate of 80% or more, wherein an extract containing 15-85 wt.%, In particular 30-65 wt.% Silymarin is taken up with anhydrous alcohol, if necessary. Filtered and concentrated and then dried and optionally. Crushed becomes.
• simarin refers to a substance mixture which contains (at least) the four substances silybin, silydianin, silychristin and isosilbin in different concentrations. It is immaterial in what proportions these substances are present to each other and whether other substances are present in the mixture. However, it is preferred that these substances meet the requirements of Ph. Eur. Or DAB, as amended. This is the case according to the invention.
• a "silymarin release rate of 80% and more" means that the active ingredients are at least 80% soluble in aqueous solution (standard according to Ph. Eur., See examples).
• process step f Substantially reduces the crystalline fractions in the extract obtained and a milk thistle fruit extract having a substantially amorphous crystal modification is obtained.
• the invention therefore relates to a novel milk thistle fruit extract or flavanolignan preparation which has essentially an amorphous crystal modification (see comparative experiments of the X-ray structure analysis in FIG. 1).
• the invention relates to a novel milk thistle fruit extract or flavanolignan preparation consisting of an amorphous crystal modification, wherein the crystalline fraction is less than 20%, preferably less than 10%, more preferably less than 7%, even 5%.
• the invention therefore furthermore relates to a medicament comprising a milk thistle fruit extract according to the invention or its use for the prophylaxis and treatment of liver and bile dysfunctions, in particular of toxic liver damage (fatty liver, alcohol), hepatoses such as fungal poisoning, acute liver failure, liver necrosis, liver dystrophy, liver cirrhosis, Liver fibrosis, liver enlargement and fatty liver, hepatic insufficiency, hepatitis, especially hepatitis C.
• toxic liver damage fatty liver, alcohol
• hepatoses such as fungal poisoning, acute liver failure, liver necrosis, liver dystrophy, liver cirrhosis, Liver fibrosis, liver enlargement and fatty liver
• hepatic insufficiency hepatitis, especially hepatitis C.
• the invention relates to a pharmaceutical formulation
• a pharmaceutical formulation comprising a medicament according to the invention consisting of a milk thistle fruit extract according to the invention.
• the milk thistle fruit extracts according to the invention can be prepared in the form of pharmaceutical preparations in dosage units.
• the preparation is in the form of individual parts, e.g. Tablets, dragees, capsules, pills, suppositories and ampoules, the active substance content of which corresponds to a fraction or a multiple of a single dose.
• the dosage units may be e.g. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose.
• a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose.
• non-toxic, inert pharmaceutically acceptable excipients are meant solid, semi-solid or liquid diluents, fillers and formulation aids of any kind.
• Tablets, dragees, capsules, pills, granules, suppositories, solutions, juice, suspensions and emulsions may be mentioned as preferred pharmaceutical formulations.
• Tablets, dragees, capsules, pills and granules may contain the active substance (s) in addition to the usual excipients, such as a) fillers and extenders, for example starches, lactose, cane sugar, glucose, mannitol and silicic acid, b) binders, eg Carboxymethylcellulose, alginates, gelatin,
• Polyvinylpyrrolidone c) humectants, e.g. Glycerine, d) disintegrants, e.g. Agar-agar, calcium carbonate and sodium carbonate, e) dissolution inhibitor, e.g. Paraffin and f) absorption enhancer, e.g. quaternary ammonium compounds, g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, h) adsorbents, e.g. Kaolin and bentonite and i) lubricants, e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under a) to i).
• disintegrants e.g. Agar-agar, calcium carbonate and sodium carbonate
• dissolution inhibitor e.g. Paraffin and f
• absorption enhancer e.g. quaternary ammonium compounds
• wetting agents e.g.
• the tablets, coated tablets, capsules, pills and granules may be provided with the usual coatings and sheaths which optionally contain opacifying agents and may also be composed in such a way that they release the active substance only or preferably delayed in a specific part of the intestinal tract, optionally Embedding masses eg Polymer substances and waxes can be used.
• the active substance (s) may optionally also be present in microencapsulated form with one or more of the excipients specified above.
• Suppositories may contain, besides the active ingredient (s), the usual water-soluble or water-insoluble excipients, e.g. Polyethylene glycols, fats, e.g. Cocoa fat and higher esters (e.g., C14 alcohol with C16 fatty acid) or mixtures of these substances.
• active ingredient e.g. Polyethylene glycols
• fats e.g. Cocoa fat and higher esters (e.g., C14 alcohol with C16 fatty acid) or mixtures of these substances.
• Solutions and emulsions in addition to the active substance or the usual excipients such as solvents, solubilizers and ⁇ emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, Peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances.
• solvents such as solvents, solubilizers and ⁇ emulsifiers
• solubilizers and ⁇ emulsifiers for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
• suspensions may contain the customary carriers such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose,
• liquid diluents for example water, ethyl alcohol, propylene glycol
• suspending agents for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose
• the mentioned formulation forms may also contain colorants,
• Preservatives and odor and flavor improving additives e.g. Peppermint oil and eucalyptus oil and sweeteners, e.g. Saccharin, included.
• Comparative extracts (Silibinin Ch. -B .: 194051, Ch. -B .: 7085i) were prepared as described above, with Silibinin Ch. -B.
• step f. Converts the previously poorly soluble silibinin mixture consisting of amorphous and crystalline structure into an amorphous crystal modification (see FIG. 1) (ie the crystal lattice structure is changed), which has a better solubility or drug release result.
• FIG. 1 shows the modified crystal modification from the comparison of silibinin Ch. -B .: 194051 and silibinin Ch. -B .: 7085i by means of X-ray structural analysis (conditions according to Example 2).
• the values of Xc were determined from the sum of the ranges of all narrow points (the crystalline phase) in the angular range of the study.
• the values of Xa were determined by determining the areas of the broad spots or 'halos' (the amorphous phase). G. ) Results
• Figures 2 and 3 show the diagrams obtained in the complete angle measuring range. These are sample mixtures of crystalline and amorphous phases.

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• 2008
  • 2008-08-23 DE DE102008039271A patent/DE102008039271A1/de not_active Withdrawn
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  • 2008-12-23 JP JP2010538335A patent/JP5442632B2/ja active Active
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  • 2008-12-23 MX MX2010006982A patent/MX2010006982A/es active IP Right Grant
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