EP2755639A2 - Solutions solides de polyphénols - Google Patents

Solutions solides de polyphénols

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Publication number
EP2755639A2
EP2755639A2 EP12729035.1A EP12729035A EP2755639A2 EP 2755639 A2 EP2755639 A2 EP 2755639A2 EP 12729035 A EP12729035 A EP 12729035A EP 2755639 A2 EP2755639 A2 EP 2755639A2
Authority
EP
European Patent Office
Prior art keywords
solid solutions
polyphenols
derivatives
solid
resveratrol
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Withdrawn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
EP12729035.1A
Other languages
German (de)
English (en)
Inventor
Jochen Kalbe
Olaf Hansen
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.)
2Lution GmbH
Original Assignee
2Lution 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 2Lution GmbH filed Critical 2Lution GmbH
Priority to EP12729035.1A priority Critical patent/EP2755639A2/fr
Publication of EP2755639A2 publication Critical patent/EP2755639A2/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Withdrawn legal-status Critical Current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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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)
    • A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine

Definitions

  • the invention relates to a process for the preparation of solid solutions of polyphenols and derivatives thereof in a carrier material, the solid solutions of poly phenols obtainable by this process and their use as medicaments, cosmetics and dietary supplements, in particular for use in the prevention and treatment of cancers, coronary Heart diseases, vascular diseases, in particular cardiovascular diseases, metabolic diseases, neurodegenerative diseases as well as aging and cellular degeneration processes (anti-aging).
  • the invention also solid solutions of resverotrol, curcumin and resverotrol or curcumin-halfigen extracts in a carrier material.
  • the class of polyphenols is a collective name for aromatic compounds containing two or more phenolic hydroxyl groups or phenol and phenol ether groups in the molecule. Polyphenols can in turn belong to different substance classes. Polyphenols are widespread in nature and occur there as free or etherified polyphenols. Many polyphenolic compounds are also included in the group of phytochemicals.
  • polyphenols as bioactive substances in plants mainly functions as dyes, flavors, tannins and as protective mechanisms against pest infestation, for example, or UV damage (transmitter molecules, pheromones, feeding defense, etc.), as well as antioxidants, fungicides or antimicrobial [bactericidal , antibacterial) agents too.
  • polyphenols are basic building blocks of important biopolymers such as lignin or suberin.
  • polyphenols originate or are obtained predominantly from natural sources, for example by extraction and purification from the polyphenol-containing plant constituents, these are often in the form of mixtures of various plant constituents, from which the concrete individual compounds can be extracted and isolated by further purification steps such mixtures are usually so-called plant extracts or natural extracts.
  • polyphenols also includes natural or artificial polyphenol mixtures, in particular extracts such as natural product or plant extracts containing such polyphenols.
  • polyphenols are considered beneficial to health and are used both as cosmetic and pharmaceutical agents or as dietary supplements.
  • Numerous polyphenols for example, their antioxidant, anti-inflammatory and anti-carcinogenic effect are known.
  • Flavonoids and anthocyanins protect body cells against free radicals and slow down cell oxidation and thus have an advantageous effect on cellular and aging-related degeneration processes (anti-aging, life-prolonging function). Further positive effects are evident, for example, in the Reduction of plaque formation In the blood vessels, and thus in a preventive effect against coronary heart disease and vascular, in particular cardiovascular diseases such as, arteriosclerosis,
  • beneficial effects of polyphenols in the prevention and treatment of neurodegenerative diseases such.
  • WO 2006/076681 A2 describes positive effects of compounds from the substance classes of flovones, silibens, flavanones, isoflavanones, catechins, chalcones, tannins and anthocyanldins on sirtuin activation and thus in the treatment of neurodegenerative diseases.
  • compositions and dietary supplements are known in which the natural substances from the group of polyphenols are selected.
  • CN 1 65091 1 are customary pharmaceutical formulations containing the polyphenols esveratrol (stiibenoid) and ginko extract and their use in the field of cardiovascular and cerebrovascular diseases and in dementia.
  • WO 98/809533 A1 and WO 97/36497 A2 are cocoa extracts enriched with cocoa polyphenols, in particular with procyanidines, and their preparation, in which connection reference is also made to numerous of the abovementioned positive effects of these polyphenols.
  • WO 2008/1 34648 A2 relates to polyphenol-enriched cocoa products, wherein herein an enrichment with polyphenols from the Group of silibene as in particular with the stilbenoid resveratrol is the subject of the invention,
  • US 201 0/0255088 discloses a combination preparation in which a low-melting capsule of chocolate for sublingual administration is chosen as the preferred form for an active ingredient combination of poorly soluble aspirin and resveratrol. The improved bioavailability is then achieved by the sublingual administration,
  • WO 2009/08901 1 A2 describes liquid and semi-solid Resveratroi formulations (for example creams, emulsions, gel formulations).
  • the crystalline, sparingly soluble resveratrol is dissolved with polymers such as polyvinylpyrrolidone (PVP) and emulsified by means such as stabilized surfactants or phospholipids, whereby a reduction of the precipitation Nelgung and recrystallization and thus an improvement in the solubility of the resveratrol is achieved in the liquid formulation,
  • PVP polyvinylpyrrolidone
  • WO 2006/076681 A2 already mentioned above, mentions conventional formulations, such as in particular fast-melting tablets, gel formulations or nanoparticles, as suitable application forms. With regard to the improvement of bioavailability, the application of physical techniques such as electrotransport or
  • the particle size of the crystalline resveratrol is reduced by wet grinding and the milled resveratrol crystal particles are stabilized with a protective colloid such as gelatin or modified starch.
  • a protective colloid such as gelatin or modified starch.
  • Application forms are described as aqueous suspensions and conventional administration forms such as powders, beads or granules.
  • the resveratrol crystal particles and the protective colloid are present in the powder formulations in the form of physical mixtures (solid dispersions).
  • the crystalline resveratrol particles are present with a gelatin coating or embedded in gelatin.
  • a solid solution in which not only the carrier material but also the active substance such as resveratrol or curcumin per se is in the form of a solid solution is not disclosed herein.
  • the inventors of the present invention have surprisingly found that polyphenols in the form of a solid solution in a carrier material as an application form have a significantly increased water solubility and an improved bioavailability.
  • DE 1 001 3289 A1 describes solid solutions of the active ingredient torasemide, in which thermoplastic synthetic polymers, cellulose derivatives, polyethylene glycols, modified starches, sugar alcohols and natural binders such as gelatin or vegetable polymers can be used as carrier material. Solid solutions of polyphenols, in particular resveratrol and curcumin are not described herein
  • WO 201 0/1 02245 A1 mentions the possibility of improving the bioavailability of resveratrol by providing it in the form of solid dispersions.
  • the carrier material mentioned is exclusively N-vinylpyrrolidone, in which the resveratrol is preferably in non-crystalline form. Solid solutions in gelatin are not mentioned
  • solid dispersions in contrast to solid solutions, solid dispersions have undissolved or particulate (crystalline) constituents.
  • dispersions are a mixture of at least two substances that do not or hardly dissolve or chemically bond with each other. These may be suspensions or emulsions, but by definition no solutions,
  • DE 3914170 C1 and EP 0227050 Bl describe lozenges in which active pharmaceutical ingredients or else plant extracts or herbal active substances, such as, for example, Glycyrrhizin or arnica extract dissolved in an aqueous gelatin suspension and then solidify.
  • the object of these documents is to provide an improved process with high dosing accuracy for the preparation of uniform, symmetrical gelatine pastilles.
  • a possible influence on the solubility or bioavailability of the ingredients used or even on polyphenols is not mentioned herein.
  • gelatin lozenges obtainable by the described processes form solid solutions or that they can be obtained by such a process. Only gelatin lozenges which may contain liquorice or nicotine exciracts are disclosed herein.
  • lozenge formulations in particular based on vegetable carrier materials such.
  • B. based on gum arabic, tragacanth or on the basis of gelatin are the subject of the publications DE 441 5999 AI, DE 201 0281 7 U l and US 5,633,005.
  • the pastilles described therein are referred to as "solid solutions.”
  • DE 441 5999 A1 merely discloses the suitability of such pastilles for the formulation of active compounds from the group of antacids and US Pat. No.
  • the flavonoid polymer-Rezepturassen may be in liquid, semi-solid and solid form in which the flavonoids are stabilized by the proteinogenic polymer carrier, solid formulations, which are also referred to as "solid solutions", but in the significant process of the In principle, herein only recipe masses are used with a high solvent content and in particular the flavonoids are introduced into the carrier material in dissolved form or transferred in the recipe mass, for example by salt formation in a soluble form before the recipe mass is solidified, the high solvent content to solidify the recipe mass by consuming drying methods such as in particular by spray or freeze-drying again, however, this additional step of drying is, for example, in terms of ö more economical process management disadvantageous.
  • a freeze-dried pellet is characterized by a porous, network-like structure due to the process, as described in a further patent DE 4201 1 72 C 1 of the same patent owner.
  • a conventional drying process is carried out following the cryopelletting, only bulky granules can be obtained.
  • Spray-dried products are available only in powder form. Powdered or granular compositions must then additionally be converted into suitable administration forms such as hard gelatin capsules, compressed tablets or the like for administration. Solid solutions Can not be obtained in the form of large-sized one-piece shaped body for administration as a single dose.
  • the object of the present invention was thus to provide a new, improved method for providing suitable administration systems and administration forms for polyphenols, in particular for sparingly soluble, crystalline polyphenol compounds, wherein the polyphenols have increased water solubility and improved bioavailability.
  • polyphenols (or the equivalently used term “pol phenol compound”) comprises natural, synthetic and semi-synthetic aromatic compounds which contain two or more phenolic hydroxyl groups or phenol or phenol ether groups in the molecule contain . Accordingly, in particular those compounds are included which, in their structural formula, have at least one structural element of the formula (1) wherein R 1 and R 2 are the same and have the meaning of hydroxy (-OH), or wherein R !
  • At least one of the substituents R 'or R 2 may be derivatized and for example via a glycosidic bond with a sugar residue in the form of a glycoside, as described below, or as an ester, a sulfate or in the form of a Salt present.
  • polyphenols encompasses, in particular, natural polyphenols, in particular the polyphenols, which are widespread in nature and can occur as free or etherified polyphenols, as well as those which are included in the group of phytochemicals.
  • polyhenols encompasses both monomeric and oligomeric (dimeric, trimeric, tetrameric, etc.) Polyphenoics, as well as extracts, in particular natural product extracts and plant extracts, which contain at least one of the polyphenol compounds according to the invention or derivatives thereof,
  • the polyphenols according to the invention may belong to different substance classes, such as in particular the substance classes comprising alkali earths such.
  • the substance classes comprising alkali earths such.
  • the polyphenols are preferably selected from the groups comprising alkaloids, plant dyes, anthocyanins, anthocyanidins, proanthocyanidins (in particular oligomeric proanthocyanidins), procyanidins, chalcones, flavonoids "isoflavonoids, stilbenoids” gallates and tannins, and derivatives thereof.
  • the polyphenol compounds are selected from the group comprising plant dyes, especially water-insoluble plant dyes »and anthocyanins» oligomeric proanthocyanidins, flavonoids, isoflavonoids and stilbenoids, as well as their derivatives.
  • polyphenols from the group of water-insoluble plant dyes and from the group of stilbenoids and their derivatives.
  • sirtuin-activating action preference is given to those polyphenol compounds which have a sirtuin-activating action and, correspondingly, an increase in the activity or protein levels of sirtuin (SIRT-1 to SIRT-7), in particular sirtuin-1 (SIRTI) or sirtuin -2 (Sir2), effect in the organism.
  • SIRT-1 to SIRT-7 sirtuin-1
  • Sir2 sirtuin-2
  • Sirtuins regulate cell defense against DNA damage and biological stress, whereby sirtuins, in particular SIRT-1, have a positive regulatory function on cell health and associated diseases.
  • Polyphenol compounds which have an advantageous effect on sirtuin activity are in particular selected from the groups of flavones, silibens and stilbenoids, flavanones, isofiavone catechins, chalcones, tannins and anthocyanidins or derivatives thereof,
  • the polyphenol compounds from one or more of the abovementioned classes of substances include in particular compounds such as resveratrol, curcumin, piceatannol, butein, luteolin, 3,6,3 ', 4'-tetrahydroxyfalone, apigenin, orin quercetin, rutin , Kaempferol, Myricetin, Isorhamnetin, Fisefin, Catechin, Gallocatechin, Epicatechin, Epigailocatechingallat, Hesperidin, Hesperetin, Naringin, Naringenin, Eriodictyol, Taxifolin »Genistein, Daidzein, Licoricidin.
  • compounds such as resveratrol, curcumin, piceatannol, butein, luteolin, 3,6,3 ', 4'-tetrahydroxyfalone, apigenin, orin quercetin, rutin , Kaempferol, Myricetin, Isorhamnetin,
  • Preferred sirtuin-activating polyphenols include in particular resveratrol, butein, piceatannol, isoliquiritlgenin, flsetin, luteolin, 3, 6, 3 ', 4'-tetrahydroxyfalsone, quercetin and derivatives thereof (in particular the resveratrol and piceatannol glycosides Piceid and astringin),
  • resveratrol, piceatannol, quercetin and curcumin preference is given to resveratrol, piceatannol and curcumin
  • preference being given to resveratrol and curcumin, and also derivatives thereof in particular the resveratrol and piceatannol glycosides Piceid and Astringin
  • Extracts for the purposes of the present invention relate to polyphenol-containing extracts, in particular plant extracts or natural extracts which contain at least one of the polyphenol compounds or their derivatives according to the invention.
  • polyphenol-containing extracts include in particular extracts from grapes such as grapes, grape seeds -, grapevine or berry extracts (eg Vineafrol®, Vineatrol®20, Vineatrol®30 etc.), cocoa extracts, turmeric extract, tea extracts (eg green tea or black tea extracts, eg Teavigo® ), Extracts from olives, olive leaves or olive oil (eg Polyphen-Oil TM, OieaSelect TM, Hytolive®, Hidrox® and other commercially available products and other polyphenolic plant extracts,
  • extracts from grapes, grape seeds or grape vines eg, Vineafrol®, Vineatro! ® 20, Vineatrol® 30
  • turmeric extracts eg, Vineafrol®, Vineatro! ® 20, Vineatrol® 30
  • Vineatrol extracts have a composition of about 1 0 to 40% (preferably 20 to 30%) resveratrol monomers and oligomers, ca, 2 to 8% (preferably ca, 5%) trans resveratrol and ca. 2 to 8% (preferably ca, 5%) Epsilon-Viniferln on.
  • very particular preference is given to solid solutions in which the polyp enols and their derivatives are selected from Resveratro! and curcumin and derivatives thereof, as well as extracts of grapes, grape seeds, grapevine extract and turmeric extract,
  • derivatives of the polyphenols according to the invention or polyphenol! Compounds, in particular their glycosides, esters, sulfates and salts or complexes,
  • Ether derivatives are by definition encompassed by the term "polyphenols" according to the invention.
  • glycosides are selected from the group of glycosides, These have an oxygen radical attached to a sugar residue (-0- sugar residue), preferably in the form of a so-called glycosidic bond (O-glycosidic bond),
  • a glycosidic bond therein denotes the chemical bond between the anomeric Carbon atom of the sugar residue (glycon) and the heteroatom of an aglycone, corresponding to the oxygen atom through which the sugar moiety is attached to the main body »wherein the bridge oxygen atom comes from the alcohol or phenol function (or ether function) of the main body (aglycone), respectively
  • glycosides compounds which contain such a glycosidic bond are termed glycosides.
  • the aldehyde function of the aldoses eg, glucose
  • the ketofunction of the ketoses eg, fructose
  • the aldehyde function of the aldoses eg, glucose
  • the ketofunction of the ketoses eg, fructose
  • the condensation product of an aldehyde or ketone eg in F orm of the cyclic Haibacetais] and one or two alcohols to form the Vollacetals.
  • Preferred glycosidically bound sugar residues are selected from an oxygen (O-glycosidic) bonded to the phenyl nucleus Sugars and sugar acids, particularly preferred sugar residues are glucose (to form glucosides) and glucuronic acid (to form glucuronides),
  • polyphenol derivatives according to the invention are glycosides of resveratrol and piceatannol, in particular the glucosides Piceid and Astringin
  • Salts of the polyphenols of the invention relate in particular to pharmaceutically acceptable salts which are used with pharmaceutically acceptable bases "such as, for. Salts with alkali or alkaline earth hydroxides, such as NaOH, KOH, Ca (OH) 2 , Mg (OH) 2 , ammonium hydroxide, etc. , Amine compounds, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, 2-amino-2-methyl-propanoi- (II), 2-amino-2-methylpropanediol (1,3) , 2-amino-2-hydroxyl-methyl-propane! Ol (1,3) (TRIS) etc carbonates such as sodium carbonate or potassium carbonate, blcarbonate etc.
  • pharmaceutically acceptable bases such as, for. Salts with alkali or alkaline earth hydroxides, such as NaOH, KOH, Ca (
  • particularly preferred polyphenolic compounds are selected from resveratrol and derivatives thereof, as well as from curcumin and derivatives thereof or from extracts containing them,
  • Resveratrol occurs as a trans and cis isomer:
  • trans-resveratrol cis-esveratrol where the trans form is the more stable isomer.
  • Further designations are 3,4,5-stiloenol, trans-3,5,4-trichloroxystilbene ( ⁇ ) -5- ( ⁇ ⁇
  • resveratrol may be in monomeric or oligomeric (especially dimeric, trimeric tetramerer, etc.) form.
  • resveratrol encompasses the trans- and cis-configuration " monomeric and oligomeric forms and mixtures thereof, with trans-esveratrol being preferred.
  • Oligomeric resveratrol compounds include in particular:
  • Very particularly preferred oligomeric resveratrol compounds are the dimeric viniferins, such as epsilon-viniferin and iso-epsilon-viniferin.
  • esveratrol also preferably occurs in the form of the glycoside derivative such as 3-.beta.-D-glucopyranoside, also referred to as trans-piceide, in which the glycosidically linked sugar moiety is glucose and such resveratrol-glycoside derivatives (resveratrol-glucosides) the formula:
  • polyphenoi from the group of Stllbenoide is Piceatannoi
  • Resveratrol is known for its antioxidant properties, its anti-carcinogenic effects and for its positive effects in the treatment of atherosclerosis, hyperlipidemia, coronary heart disease, vascular diseases, especially cardiovascular diseases.
  • vascular diseases vascular diseases, metabolic diseases such as diabetes, neurodegenerative diseases, aging-related and cellular degeneration processes, inflammatory processes, skin diseases (eg dermatitis), etc.
  • Esveratrol is particularly suitable for use in the prevention and treatment of aging-related and cellular degeneration processes, for example in the case of cell damage due to toxic or free-radical influences and thus in the prevention and treatment of cancers, as well as in the area of anti-aging (life-prolonging function ).
  • Piceatannol also develops a positive effect in these areas and is thus suitable for the corresponding use
  • resveratrol (as well as piceatannol) can be used both in crystalline (also co-crystalline) and in amorphous (also polyamorphic) form,
  • curcumin is a natural, sparingly soluble in water plant dye, which occurs especially in the goldenseal Curcuma longa (curcumin), curcumin is also synthetically produced, curcumin has in addition to its coloring properties also over flavoring and flavoring properties and is therefore an essential component of curry powder,
  • Curcumin belongs to the group of curcuminoids, a group of substituted bis (hydroxycinnamoly) -methane dyes, in particular curcumin, and derivatives thereof, such as desmethoxycurcumenine and bis-demethoxycurcumin:
  • the solubility in particular the solubility in water, aqueous solutions or physiological media of pharmaceutical active substances is a fundamental prerequisite for their bioavailability, in particular in the case of oral or parenteral administration.
  • the dissolution rate may be the rate-limiting step for the subsequent absorption of poorly soluble drugs, which often have problems in terms of their Biover Berggbarkelt particularly for poorly soluble active "and drugs.
  • At a low dissolution rate correspondingly low amounts of active ingredient are available for cellular absorption and, as a result, only a partial absorption of the applied dose of active ingredient occurs while unresolved portions are excreted again unused.
  • Active ingredients are presented in suitable carrier formulations and application forms which are generally well known.
  • Solid solutions can in principle by melting or by solution process with subsequent coprecipitation of drug and carrier maferia! as well as by combining the two methods.
  • Freeze-drying, spray-drying and vacuum drying are suitable as methods for precipitation from a solution, an essential prerequisite being the choice of suitable solvents for pharmaceutical substances and adjuvants.
  • melt-embedding methods preferred in the present invention are much simpler and more economical to carry out.
  • Known melt embedding processes include rapid supercooling of a melt by melt solidification, spray solidification and hot spin milling, and extrusion processes (eg, melt extrusion). Methods of melt extrusion are characterized by a low temperature load of the materials used. Spray hardening processes are characterized by a high dosing accuracy, which makes them particularly advantageous for the economical production of pharmaceutical products.
  • the drug is molecularly dispersed in a carrier material! or binder.
  • a carrier material or binder.
  • readily soluble hydrophilic carrier materials a strong increase in the dissolution rate of the drug can thus be achieved since the molecular distribution in the carrier already provides the active ingredient dissolved and can be readily released on contact with the dissolution medium.
  • the dissolution rate is determined by the hydrophilic carrier and the incorporated molecular disperse active ingredient has a higher thermodynamic solubility than all its crystalline forms due to the omission of the enthalpy of fusion during the dissolution process.
  • Solid solutions can be formed both with crystalline and with amorphous supports and with binders such as, for example, from DE 1 001 3289 A1, since it acts in the solid state Support as a solid solvent for the drug molecules,
  • binders such as, for example, from DE 1 001 3289 A1
  • the drug is either incorporated into the crystal lattice or located in the space between the lattice molecules of the carrier material.
  • substitution-wise solid solutions or interstitial solid solutions When using amorphous support materials, one usually speaks of glassy solid solutions, which have the greatest similarity to liquid solutions due to their irregular structure.
  • Crystalline solid solutions are less preferred than glass-like or non-crystalline solid solutions in that "under certain circumstances strong lattice forces or strong binding forces between the dissolved active substance molecules and the lattice molecules can occur " which preclude rapid dissolution of the carrier or rapid release of the drug
  • Another advantage of solid solutions as application forms for poorly soluble, especially crystalline active ingredients can also be seen in the fact that frequently occurring recrystallization is reduced during storage, by the drug drug solution in the carrier material are immobilized and separated in the carrier material before and due to the associated lack of molecular mobility prevents recrystallization,
  • solid dispersion and “solid suspension” are also known from the prior art.
  • solid dispersion usually denotes the generic term for the two different application forms “solid suspension” and “solid solution”,
  • Solid suspensions differ from the solid solutions described above in that, in such systems, the active agent is usually still particulate in crystalline or in the form of amorphous particles embedded in the carrier material, whereby the above-mentioned disadvantages of particulate systems remain targeted production of solid suspensions, the introduction of the drug into the carrier material by melting the carrier is far below the melting point of the drug, wherein the drug does not dissolve in the melt of the carrier and remain size and crystallinity of the drug.
  • this process usually involves a physical change of the active ingredient in the form of a Change in the crystal form, for example, by the appearance of metastable crystal forms and amorphous suspended drug components.
  • the inventive method is characterized in that in a 30 - 205 ° C warm liquid or semi-solid solution or suspension of a carrier material at least one polyphenol or derivative thereof and optionally further carrier materials, active ingredients and / or adjuvants are mixed and the thus available
  • the resulting formulation mass is preferably converted into the desired form by cooling down to room temperature by suitable methods such as, for example, spraying, extruding or pouring into molds or shaping powder trays. Such methods of shaping are known in principle.
  • the molten liquid or semi-solid solution or suspensions of the support material is molten in the 30 to 205 ° C. so that, in principle, the process is carried out using a 30-205 ° C. melt of the support material
  • the temperature of the solution, suspensions or melt of the carrier material is to be chosen in principle depending on the carrier material used. For example, when using Sparmateriallen based on natural polysaccharides such as gelatin, particularly when using temperatures of 30-80 ° C, preferably chosen between 40 and 70 C C, more preferably between 45 and 60 ° C.
  • temperatures between 40 and 80 ° C preferably between 50 and 70 ° C are preferably selected.
  • temperatures between 1 60 and 205 ° C are preferably selected.
  • polyvinylpyrrolidone and Polyethylengiycolen (PEG's) are preferably temperatures between 40 and 1 70 ° C chosen.
  • melting point-lowering auxiliaries are known to the person skilled in the art, Giycerin is preferably used here. However, small quantities of solvents such as water, ethanol etc. be used. Preferred is a melting temperature of 30 to 1 40 ° C, more preferably 30 to 1 00 ° C.
  • liquid or r " solid solution or suspensions or melt is characterized in particular by their flowability or pourability, whereby the possibility of molding according to one of the methods of the invention" In particular the casting in suitable forms, is possible.
  • the Poiyphenol- compounds are mixed in solid or in crystalline form in the molten carrier material.
  • a dissolution or dissolution is not required and usually not provided for.
  • Cooling to room temperature in the context of the present invention means a cooling to a temperature below 26 ° C, preferably between 1 7 and 25 ° C, preferably between 1 9 and 21 ° C., The cooling can be either using an active cooling with conventional coolants be done or simply by standing or, storage of the molded recipe mass until it reaches a temperature equalization to ambient or room temperature.
  • the adjuvant particularly preferred according to the invention is not glycerol as organic solvent in this Meaning is understood. Particular preference is given to working without the addition of organic solvents to the recipe mass.
  • the consistency, softness and elasticity of the available solid solutions have an advantageous effect and, as mentioned above, can have a desired melting point-lowering effect. Accordingly, it is preferred to use recipe masses with a water content of> 3% by weight and ⁇ 20 wt .-%, preferably from 5 to 1 wt .-% to use, particularly preferred are recipe masses having a water content below 1 5 wt.% As in particular having a water content of 5 to 1 5 wt -.%.
  • water is added as solvent to the recipe mass, preferably not more than 20% by weight, preferably up to a maximum of 1.5% by weight, of water is added. This is particularly preferred when using support materials based on natural polymers such as in particular plant polysaccharides or so-called plant gums such. Gum arabic.
  • the auxiliaries used which can be used in the form of water-containing preparations or aqueous formulations or aqueous solutions, and thus also remain in the solidified solid solutions due to the lack of a drying step.
  • the Glycerol which is particularly preferred according to the invention, can be used as plasticizer and melting point-lowering auxiliary and is preferably added in the form of an 85% Giycerin solution with a corresponding water content of 15% by weight.
  • the recipe masses may contain up to 1 5 wt .-%, preferably> 3 to ⁇ 1 5 wt -%, more preferably 5 to 1 4 wt .-% water, this is particularly preferred Use of support materials based on natural polymers such as in particular gelatin.
  • the water fractions preferred according to the invention can also be obtained by suitable measures of rewetting or setting the moisture content of the solidified solid solutions. This can be done in principle by known methods for air conditioning or humidity adjustment, such as by storage under suitable, climate-controlled environmental conditions z. a relative humidity between 20 - 95%.
  • a recipe mass which contains at least 23% by weight, preferably> 30% by weight, more preferably> 50% by weight, more preferably> 60% by weight, of glycerol (when an 85% glycerol solution is used in this case the water content already charged).
  • glycerol when an 85% glycerol solution results accordingly a recipe mass with at least 23% by weight of glycerol and 4% by weight of water, preferably> 30% by weight of glycerol and> 5% by weight of water, more preferably> 50% by weight of glycerol and> 8.8% by weight.
  • % Water more preferably> 60% by weight glycerol and> 1 0.6% by weight water,
  • the weight ratio of carrier material to glycerol, preferably of gelatin to glycerol, in the formulation mass is ⁇ 1, preferably ⁇ 1, more preferably ⁇ 0.75, even more preferably ⁇ 0.5.
  • the proportion by weight of glycerol is greater than that of the carrier material (preferably gelatin).
  • the carrier materials of the solid solutions are selected from known binders as mentioned for example in DE 1 001 3289A1 and which are hereby fully included in the disclosure, natural polymers, modified natural and semi-synthetic polymers, sugar alcohols and synthetic polymers .
  • hydrophilic i. water-wettable carrier materials which are at least partially soluble or swellable in aqueous systems
  • Support materials from the group of natural polymers include in particular so-called structure-forming hydrocolloids, ie partially water-soluble or water-swellable natural structure-forming polymers such as structure-forming hydrocolloids from the groups of protein-based hydrocolloids, polysaccharides and / or glucosaminoglycans,
  • Support materials selected from the group of polysaccharides include, for example: the group of so-called plant gums comprising in particular agar-agar, gellan, guar gum, guar gum, gum arabic, locust bean gum, karaya, tara gum, tragacanth xanthan gum etc.
  • alginic acid and alginates especially sodium alginate or calcium alginate or mixtures thereof (alginic acid and alginates may also be included in the group of plant gums), galactomannan, carrageenan, pectins, natural starches such as corn starch, potato starch, tapioca starch, starch from arrowroot or katakuri (Japanese canine tooth) or sago, dextrans, dextrin, maltodextrins, chitosan, glucans such as ⁇ -1,3-glucan or ⁇ -1,4-glucan, cellulose, etc.
  • Preferred polysaccharides are alginates, pectins, guar gum, agar agar, gum arabic, galactomannan, xanthan and natural starches. Particularly preferred is gum arabic.
  • Glucosaminoglycans include, for example, hyaluronic acid, chondroitin sulfate, dermatan sulfate, eratan sulfate, heparan sulfate, heparin, etc.
  • Support materials from the group of semi-synthetic or modified natural polymers include, for. Polylactides or polylactic acids (PLA), polyglycolic acid (PGA), polycaprolactones (PCL), polyhydroxonone (PDO), polylactide-co-glycolide (PLGA), polytrimethylene carbonate, cellulose ethers, synthetic cellulose derivatives such as alkylcelluloses such as, B. Methylcellulose or ethylcellulose, hydroxyalkylcelluloses such. Hydroxypropylcellulose, hydroxyalkyl-alkylcelluloses, e.g.
  • B Celluloseacetatphthalathat and modified starches or starch degradation products such.
  • Support materials from the group of synthetic polymers include thermoplastic compounds and z.
  • the support materials are preferably selected from the group of natural polymers, in particular from the group of proteinogenic polymers and from vegetable polymers such as in particular from the group of polysaccharides (in particular plant gums) and from the group of semi-synthetic and modified natural polymers.
  • the carrier materials are particularly preferably selected from the group comprising gelatin, gum arabic, guar gum, alginates, tragacanth, xanthan, celluloses and cellulose derivatives, and starch and starch derivatives or in each case mixtures thereof.
  • carrier materials are gelatin and gum arabic, most preferably the carrier material is gelatin.
  • Particularly preferred according to the invention is a process for preparing solid solutions of polyphenols and derivatives thereof in a carrier material, comprising the steps:
  • step b) shaping the recipe mass obtained from step b) by suitable methods such.
  • the suitable processes for shaping the recipe mass designated in step c) include, in principle, known processes such as pouring (pouring) into suitable molds, spraying, extrusion, spinning processes such as hot-melt spinning, etc. Corresponding methods are known to a person skilled in the art.
  • the shaping preferably takes place by filling into suitable molds, in particular in hollow molds or in so-called powder trays (for example from starch). Corresponding methods are known in particular from pastille production.
  • the recipe mass can either be filled directly into the desired final packaging, for example in binder form and solidified therein, or removed from the chosen mold after solidification and the solid solution thus obtained may optionally be subjected to an aftertreatment such as cleaning (removal of powder residues) the Pulverhorden), grinding, Rondieren, waxing or oiling or overdrafting with brighteners and packaging.
  • the solidified moldings can also be subjected to the above-mentioned remoistening at this point.
  • the present invention also provides the solid solutions of polyphenols and derivatives thereof obtainable by the processes shown in a carrier material.
  • solid solution denotes solid or semi-solid (soft, elastic) storage-stable preparations of polyphenols in a carrier matrix.
  • the polyphenolysis according to the invention are preferably in the carrier material
  • the polyphenols according to the invention are present in the carrier material substantially non-crystalline,
  • these may also be dispersed in the form of amorphous agglomerates homogeneously in the carrier matrix, the size of such agglomerates preferably in the range ⁇ 1 ⁇ , preferably ⁇ 0.5 ⁇ m, more preferably ⁇ 0.2 ⁇ m, more preferably ⁇ 0.05 ⁇ m.
  • essentially non-crystalline means that ⁇ 5%, preferably ⁇ 2%, more preferably ⁇ 1%, particularly preferably ⁇ 0.5% of the polyphenols according to the invention are present in the solid solution in crystalline form or in the form of amorphous agglomerates,
  • Solid solutions in the sense of the present invention are characterized in that they are substantially free of particulate constituents, such as crystalline particles and / or amorphous agglomerates. Essentially free of such particulate constituents, the absence of such particles denotes a size of> 50
  • solid solutions in the sense of the present invention are characterized in that ⁇ 3%, preferably ⁇ 2%, more preferably ⁇ 1%, particularly preferably ⁇ 0.5%, particulate constituents, such as crystalline particles and / or amorphous agglomerates a particle size> 50 nm are contained therein,
  • the solid solutions according to the invention are free from polyphenols according to the invention in the form of crystalline or amorphous agglomerates (in particular those having a particle size> 50 nm),
  • particulate constituents such as crystalline fractions or amorphous agglomerates
  • X-ray diffraction X-ray diffraction, X-ray diffraction, X D
  • corresponding particulate components are detectable from a size of 50 nm, so that the method also for identifying and determining the inventively preferred Particle sizes and their proportions according to the invention in the solid solutions is suitable.
  • the polyphenols show no absorption bands in the X-ray diffraction pattern in the solid solutions in the X-ray structure analysis or, using the X-ray diffraction methods according to the invention, no absorption bands in the X-ray diffraction pattern / X-ray diffraction diagram,
  • the application form of the solid solution is particularly advantageous for these poorly soluble crystalline polyphenol compounds for pharmaceutical and cosmetic use and as a dietary supplement with high bioavailability to make effectively administered.
  • the subject of the present invention is also solid solutions of Resveratrol, curcumin or resveratrol- or curcumin-containing extracts in a Strommateriai, regardless of the specific composition of the solid solution or a specific manufacturing method, Accordingly, solid solutions of resveratrol, curcumin or resveratrol or curcumin-containing extracts with other known methods for Hersannon solid solutions are obtained, especially those in which a drying of the recipe mass is made, for example, when using recipe masses with higher solvent or, Water contents, Preference is given to such solid solutions as are obtainable by the process according to the invention. Also preferred are such solid solutions of resveratrol, curcumin or Resveratrol- or
  • Curcumin-containing extracts wherein the carrier material is gelatin or gum arabic.
  • Preferred embodiments of such gelatin or gelatin-glycerin compositions in particular include those as shown in the preceding ,
  • step a) preferably an aqueous solution or suspension of gum arabic is prepared (with respect to preferred water contents, reference is made to the above statements) and in step d) the Solidification by drying the molded recipe paste at temperatures between 30 and 70 ° C, preferably between 40 and 60 ° C.
  • solid solutions of resveratrol, curcumin or resveratrol or curcumin-containing extracts in the context of the present invention are characterized by the properties described above in connection with the solid solutions of polyphenols. In particular, these are distinguished by the above-described characteristics such as particle size, crystallinity the active ingredients and representability in the X - ray structure analysis, etc.
  • compositions of the invention comprise solid solutions of polyphenols and derivatives thereof, in particular of resveratrol, curcumin or resveratrol- or curcumin-containing extracts, in a carrier material which additionally comprises at least one further cosmetically and / or pharmaceutically active ingredient and / or at least one conventional ingredient pharmaceutical / cosmetic excipient.
  • a carrier material which additionally comprises at least one further cosmetically and / or pharmaceutically active ingredient and / or at least one conventional ingredient pharmaceutical / cosmetic excipient.
  • Further pharmaceutically or cosmetically active active substances are preferably selected from those which are suitable and intended for prevention or treatment in one of the indications according to the invention. Particularly preferred are, for example, additional active substances from the group comprising: active pharmaceutical ingredients such as
  • Anti-inflammatory drugs / anti-inflammatory drugs eg. Indomethacin, diclofenac, naproxen, ketoprofen, ibuprofen, flurbiprofen, saiicylic acid and derivatives such as acetylsalicylic acid (ASS), oxicame; Steroid hormones, e.g.
  • B betamethasone, dexamethasone, methylprednisolone, ethinylestradiol »medroergotamine, dihydroergotoxine; Agents for the treatment of inflammatory joint diseases and gout, z, B, benzbromarone, allopurinol; Active ingredients for the treatment of inflammatory bowel disease; anti-inflammatory agents; Venous therapeutics and agents for the treatment of heart diseases, e.g.
  • anticoagulants such as heparin preparations, coumarin derivatives, platelet aggregation inhibitors such as ASA or clopidogrel, vasoactive substances such as prostaglandins or herbal vein therapeutics such as horse chestnut extract, nitrates, beta-blockers or Caiclumkanalblocker etc. ; Flavones, flavonoids (for example, from cocoa), vitamins such as vitamin A, vitamin C, vitamin E, tocotrienols, alpha and gamma tocopherol, vitamin B l, vitamin B2, vitamin B6, vitamin B 1 2, vitamin D3, vitamin K.
  • Particularly preferred active substances are selected from the agents for the treatment of inflammatory joint diseases, chronic inflammatory
  • Adjuvants include, for example, organic or inorganic adjunct materials commonly used for pharmaceutical purposes, especially for solid drug formulations, such as excipients (such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calclium phosphate, calcium carbonate), disintegrants (e.g. Starch, hydrolyzed starch,
  • Carboxymethyl cellulose calcium salt of carboxymethylcylulose, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate,
  • adjusting agents such as phospholipids, Lec ithin, surfactants, etc.
  • buffering agents such as phospholipids, Lec ithin, surfactants, etc.
  • wetting agents such as methylcellulose
  • gelling agents e.g., methylcellulose
  • shining agents coloring agents and / or flavoring agents (such as fruit flavors) and taste masking agents (such as cyclodextrins).
  • Preferred auxiliaries are melting point-lowering auxiliaries and plasticizers, in particular glycerol and glyceryl distearate, emulsifiers, in particular lecithin, flavorings, in particular fruit flavors, sweeteners, in particular sweeteners, such as acesulfame-K and sugar substitutes, such as maltitol, sorbitol, etc., and taste masking agents.
  • the invention further relates to solid solutions of poly phenols and derivatives thereof, in particular solid solutions of resveratrol, curcumin or resveratrol or curcumin-haitigen extracts, in a carrier material for use as a medicament and the use of such solid solutions for the preparation of a medicament,
  • the invention relates to solid solutions of poly phenols and derivatives thereof, in particular solid solutions of resveratrol, curcumin or resveratrol or curcumin-haitigen extracts, in a carrier material for use in the prevention and treatment of cancers, coronary heart disease, vascular diseases, in particular cardiogenic vascular diseases (such as cardio-protection, arteriosclerosis, thrombosis, vasoconstriction, atheroma formation, etc.), metabolic diseases (such as diabetes, obesity, obesity and weight management), inflammatory processes, especially inflammatory joint diseases (such as osteoarthritis, rheumatoid arthritis, osteoarthritis, etc.
  • vascular diseases in particular cardiogenic vascular diseases (such as cardio-protection, arteriosclerosis, thrombosis, vasoconstriction, atheroma formation, etc.)
  • metabolic diseases such as diabetes, obesity, obesity and weight management
  • inflammatory processes especially inflammatory joint diseases (such as osteoarthritis, rheumatoid
  • the prevention and treatment of cancers comprises the three main stages of carcinogenesis (tumor development): initiation, promotion and progression.
  • cancers includes in particular the following tumor types: adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neuroma, ampoule carcinoma, anal carcinoma, astrocytomas, basalioma, pancreatic cancer, connective tissue tumor, bladder cancer, bronchial carcinoma, non-small cell lung carcinoma, breast cancer, Burkitt's lymphoma, Corpus carcinoma, CUP syndrome, Colon cancer »Small bowel cancer, small intestine tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancers, Ewing tumors, gastrointestinal tumors, gall bladder cancer, bile carcinomas, uterine cancer, cervical cancer, glioblastomas, gynecological tumors, ear, nose and throat tumors, hematological neoplasms, hairy cell leukemia , Urethral cancer, skin cancer, brain tumors (gliomas), brain metastases
  • the invention also relates to combination preparations containing one or more of the solid solutions according to the invention and at least one further cosmetically or pharmaceutically active compound which is in particular a compound for the treatment of cancers, coronary heart diseases, vascular diseases, in particular cardiovascular diseases, Metabolic diseases (such as diabetes), inflammatory processes and neurodegenerative diseases and aging and cellular degeneration processes (such as dementia, Alzheimer's disease, Parkinson's, anti-aging etc.), And the associated symptoms,
  • the solid solutions according to the invention are very particularly preferred for the prevention and treatment of cancers, cardiovascular and vascular diseases and aging-related and cellular degeneration processes (dementia disorders,
  • solid solutions according to the invention and the combination preparations according to the invention are particularly suitable for use as medicaments! intended for oral administration.
  • Wavelength detector 31 0 nm
  • a polycrystalline sample (eg, a powder) is irradiated with a narrow beam of Cu Ka X-rays.
  • the X-rays are diffracted at the crystal lattice of the examined substance and the diffraction intensity is measured as a function of the diffraction angle 2 ⁇ .
  • Crystalline samples show a diffraction pattern of many sharp lines that can be used like a fingerprint of the lattice structure, while amorphous materials give only a faint, broad curve,
  • the samples are usually used without any special pretreatment.
  • the samples are optionally easily ground before the measurement.
  • the X-ray diffraction image is acquired with the following instrumental parameters: Radiation: Cu Ka: 40 kV, 40 mA
  • Scan area at least 2-40
  • Time per measuring time 37 ⁇ 1 seconds (total measuring time approx., 1 0 min.)
  • the X-ray diffraction pattern of the test substance corresponds to that of the reference substance if the positions and relative intensities of the strong and medium bands within ⁇ 0, 1 0 ° (2 ⁇ ) are congruent under the same measurement conditions (otherwise ⁇ 0,20 0 (2 ⁇ )) and no additional peaks and no amorphous background compared to the reference substance appears,
  • the noise floor comprises at least 50 data points over a range that does not indicate peaks. It may occur on one or both sides of the peaks.
  • Manufacturer's game 1
  • Glycerin 85% corresponds to 580.0 g
  • Grapevine extract (Vineatrol 30) 33.3 g (4.2% by weight)
  • the gelatin is successively stirred and brought to the solution.
  • the vine extract, the glycerol distearate, the acesulfame potassium (acesulfame-K) and the wild berry flavor are stirred in succession until a homogeneous solution is formed.
  • the solid solution moldings obtainable in this way can either be solidified directly in the final packaging, for example in suitable blister packs, or can subsequently be removed from the mold and sent for further fabrication.
  • the dosage of drug administration via such shaped bodies in the use according to the invention can thus be regulated via the selected form and the active ingredient concentration used.
  • the solid solutions thus obtainable are particularly suitable for oral administration,
  • FIG. 2 shows the X-ray spectrogram of the solid solution according to Preparation Example 1.
  • Figures 2 and 3 show that the crystalline resveratrol used from the vine extract in the solid solution shows no absorption bands in the X-ray structure analysis and thus dissolved in the carrier material, without kristaliine or particulate portions (with a particle size> 50 nm) is present.
  • Glycerin 85% corresponds to 574.27 g
  • the resulting hot recipe mass is poured into plastic molds to 0.8 g heavy moldings and immediately by cooling (about 4 ° C) to room temperature and thus to
  • the solid solution moldings obtainable in this way can either be solidified directly in the final packaging, for example in suitable blister packs, or can subsequently be removed from the mold and sent for further fabrication. Depending on the configuration of the plastic mold so shaped body of the solid solutions can be obtained in the desired sizes and shapes.
  • Dosage of drug administration via such shaped bodies in the use according to the invention can thus be regulated via the selected form and the active ingredient concentration used.
  • the solid solutions thus obtainable are particularly suitable for oral administration.
  • FIG. 4 shows the X-ray spectrogram of the solid solution according to Preparation Example 2.
  • FIG. 5 shows the X-ray spectrogram of the trans-resveratrol from Cupsidatum Longa used in preparation example 2,
  • Figures 4 and 5 show that the crystalline trans-resveratrol from Cupsidatum Longo used in the solid solution shows no absorption bands in the X-ray structure analysis and thus dissolved in the support material, without crystalline or particulate portions (with a particle size> 50 nm).
  • Figure 6 shows the X-ray spectrograms of the solid solutions according to manufacture examples 1 and 2 and the resveratrol compounds used therein.
  • Production Example 3 shows the X-ray spectrograms of the solid solutions according to manufacture examples 1 and 2 and the resveratrol compounds used therein.
  • Sorbitol 1 40.0 g (6.4% by weight)
  • Aroma Currant 1 0.0 g (0.5% by weight)
  • the solid solution moldings obtainable in this way are in the form of pastilles and are subsequently freed of starch and treated superficially with an oil / wax gelling agent and the rest
  • Glycerin 85% corresponds to 1174.3 g
  • Grapevine extract (Vineatrol 30) 33.3 g (1, 8% by weight)
  • Curcumin extract (95%) 52.6 g (2.9% by weight)
  • shaped body of the solid solutions can be obtained in the desired sizes and shapes.
  • the Dosage of drug administration via such shaped bodies in the use according to the invention can thus be regulated via the chosen form and the active ingredient concentration used.
  • the solid solutions thus obtainable are particularly suitable for oral administration.
  • Illustration 1 schematic representation for the determination of S / N
  • Figure 3 X-ray spectrogram of resverafrol-containing extract
  • Figure 4 X-ray spectrogram of a solid solution of trans-

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Abstract

L'invention concerne un procédé de préparation de solutions solides de polyphénols et de dérivés de ceux-ci dans un matériau support.
EP12729035.1A 2011-05-30 2012-05-30 Solutions solides de polyphénols Withdrawn EP2755639A2 (fr)

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EP3698644A1 (fr) * 2019-02-20 2020-08-26 Kl-Teho Oy Appât de pêche, composition moulable pour la fabrication de l'appât de pêche, procédé de fabrication de l'appât de pêche et utilisation de la composition moulable
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