EP4135656A1 - Formulation de taxifoline comprenant de la thiamine - Google Patents

Formulation de taxifoline comprenant de la thiamine

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Publication number
EP4135656A1
EP4135656A1 EP21717913.4A EP21717913A EP4135656A1 EP 4135656 A1 EP4135656 A1 EP 4135656A1 EP 21717913 A EP21717913 A EP 21717913A EP 4135656 A1 EP4135656 A1 EP 4135656A1
Authority
EP
European Patent Office
Prior art keywords
taxifolin
thiamine
formulation
cyclodextrin
formulation according
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.)
Pending
Application number
EP21717913.4A
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German (de)
English (en)
Inventor
David OFNER
Felix Carlo WERKMANN
Felix ROLKA
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.)
Evanium Healthcare GmbH
Original Assignee
Evanium Healthcare 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 Evanium Healthcare GmbH filed Critical Evanium Healthcare GmbH
Publication of EP4135656A1 publication Critical patent/EP4135656A1/fr
Pending legal-status Critical Current

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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • 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
    • A61K31/352—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 condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K36/13—Coniferophyta (gymnosperms)
    • A61K36/15—Pinaceae (Pine family), e.g. pine or cedar
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to formulations of taxifolin with thiamine as a dosage form for oral intake, in particular as a food supplement.
  • This ionotropic receptor consists of five subunits (two a, two ß, one g / d / e / q / tt), whereby tonic receptors, which consist of one d subunit in combination with two a4 or a6 and two ß3 subunits, are particularly important are sensitive to ethanol.
  • flavonoids based on the structure of the flavonoid taxifolin, have a positive effect on alcohol consumption, especially with regard to neurological damage and alcohol-related sequelae such as hangover symptoms. This is due to an interaction with ethanol-sensitive GABA A receptors, whereby it was found for the first time that these flavonoids act specifically as negative modulators.
  • the flavonoids are used for this in the form of a complex with ⁇ -cyclodextrin or as a solid dispersion in basic polymethacrylate, since, surprisingly, a significant effect could only be found in this formulation.
  • Thiamine is also known as vitamin B1 and, in the form of the cofactor thiamine pyrophosphate (TPP), plays a role in important metabolic processes such as carbohydrate metabolism. It has now been found that the combination of thiamine and taxifolin offers significant advantages, two points playing an important role in this regard.
  • AKG a-ketoglutarate
  • Fig. 2 Formation of glutamate Alcohol-related sequelae and alcohol-related nerve damage are directly related to a decrease in GABA A receptor density during alcohol consumption and the associated overexcitation of neurons (rebound) after alcohol consumption. Since the excitatory neurotransmitter glutamate counteracts the inhibitory effect of the neurotransmitter GABA, this effect is further intensified by an increased glutamate concentration. This leads to an overexcitation of the nerve cell, whereby on the one hand cell death can occur due to excitotoxicity, on the other hand negative sequelae can also occur ("hangover symptoms"). A combination of thiamine and taxifolin is therefore particularly beneficial from a nutritional point of view for this application.
  • taxifolin and thiamine are advantageous, since it was surprisingly and for the first time found that thiamine can reduce oxidized taxifolin and thus strengthen and prolong the effect of the flavonoid in vivo.
  • the oxidation of taxifolin takes place first on the unstable catechol group with the formation of an orthoquinone, as a result of which the flavonoid loses its physiological effect.
  • Thiamine is now able to effectively reduce the oxidized orthoquinone group back into the effective flavonoid taxifolin with a catechol group in vivo.
  • thiamine is first converted into the thiol form by flydroxide ions with the opening of the thiazole ring, which then reduces the orthoquinone with the formation of a disulfide bridge. This can counteract oxidation of the flavonoid, which increases its effectiveness.
  • Fig. 4 Interaction between taxifolin and thiamine
  • thiamine is unable to oxidize flavonoids with a double bond at position 2,3 such as quercetin effectively reduce.
  • the thiol form of thiamine also adds more to these oxidized flavonoids / orthoquinones via Michael addition, which is why the effectiveness of these flavonoids and of thiamine in combination is even reduced in vivo.
  • the invention therefore provides a formulation for oral ingestion, comprising (i) taxifolin or a pharmaceutically acceptable salt, derivative or
  • Methacrylic acid and / or methacrylate where taxifolin (a) is present as a complex with the ⁇ -cyclodextrin or (b) as a solid dispersion with the basic (co) polymer of methacrylic acid and / or methacrylate.
  • taxifolin is in the form of an inclusion complex with ⁇ -cyclodextrin.
  • the complex formation increases the solubility and dissolution of the taxifolin and significantly improves its biological effectiveness.
  • the unstable catechol group of taxifoline is included and thus protected from oxidation, as 1 H-NMR and FT-IR spectroscopy show. This prevents the formation of an orthoquinone group through oxidation of the taxifoline during storage, which also prevents the thiamine from degrading with the formation of a disulfide bridge.
  • Contrary to the professional Opinion it was found that only ß-cyclodextrin, but not g-cyclodextrin, is able to include the catechol group.
  • ⁇ -cyclodextrin is preferably used in a molar ratio of ⁇ -cyclodextrin: taxifolin of 0.5: 2 to 2: 0.5, preferably in a ratio of 0.8: 1 to 1.5: 1 molar ratio of ß-cyclodextrin: taxifolin of about 1: 1.
  • ß-Cyclodextrin is a cyclic oligosaccharide that is composed of seven a-1,4-glycosidically linked glucose molecules. It can be present in a formulation according to the invention in underivatized or derivatized form in which, for example, one or more hydroxyl groups of glucose units carry substituents.
  • the C6 carbon atom on one or more glucose units of the ⁇ -cyclodextrin can be alkoxylated or hydroxyalkylated.
  • the hydrogen atom of the hydroxyl group on the C6 carbon atom of one or more glucose units can be replaced by C 1-18 alkyl or C1-18 hydroxyalkyl groups.
  • sulfoalkyl cyclodextrins especially sulfoethyl, sulfopropyl and sulfobutyl- ⁇ -cyclodextrins are of interest.
  • a formulation according to the invention with ⁇ -cyclodextrin and taxifolin can also contain one or more water-soluble polymers. This can effectively prevent recrystallization of the active ingredient Taxifolin and thus maintain the high initial concentration for a long time. Very low polymer concentrations are often sufficient to achieve the desired effect.
  • the water-soluble polymer is contained in solution preferably in an amount of at least 0.0025% w / v, in particular 0.0025-1.0% w / v, more preferably 0.025-0.5% w / v, for example 0.25 % w / v.
  • the polymer: flavonoid mass ratio is preferably between 1: 0.5 and 1:80, in particular between 1: 3 and 1:15. In practice, mass ratios in the range between 1: 6 and 1: 8 have proven to be optimal.
  • water-soluble polymers particularly suitable according to the invention are polyethylene glycol, for example PEG 6000, polyvinyl alcohol, poloxamer, for example Poloxamer 188 and mixtures thereof, for example mixtures of PEG and PVA (Kollicoat® IR). These polymers are built up from ethylene oxide blocks and show very promising properties. The interactions with the hydroxyl groups of taxifolin are not so strong that precipitation occurs, at the same time the polymers also interact with the hydroxyl groups of ß-cyclodextrin. This increases the complex stability.
  • the increase in complex stability can be explained by the fact that the polymer interacts with the active ingredient and the ß-cyclodextrin and thus stabilizes the active ingredient in the cavity of the cyclodextrin (ternary complex). This must be taken into account when choosing the right polymer, because if the interaction with the active ingredient is too strong, the polymer active ingredient flocculates complex and Ks sinks. If the interaction with the cyclodextrin is too strong, the polymer and active ingredient compete for the CD cavity and Ks also drops. Finally, it must be ensured that the polymer must not or only slightly increase the viscosity of the solution, since otherwise the CD complex formation is made more difficult.
  • a formulation according to the invention with ⁇ -cyclodextrin or a basic (co) polymer of methacrylic acid and / or methacrylate and taxifolin can also contain choline salts / (2-hydroxyethyl) trimethyl ammonium salts.
  • choline salts / (2-hydroxyethyl) trimethyl ammonium salts such as choline chloride, choline bitartrate or choline citrate have surprisingly proven to be helpful additives in tests.
  • Formulations containing choline cations showed both faster dissolution, less recrystallization and higher overall solubility. This is due to two mechanisms: Because of the quaternary alkylammonium group in solution, choline cations disrupt the formation of hydrogen bonds and accordingly reduce hydrophobic effects.
  • Choline compounds are preferably used in a taxifolin: choline mass ratio of 5: 1 to 1:20, based on the pure mass of the choline cation. A ratio of 2: 1 to 1: 2.5 has proven to be particularly advantageous; the optimum is 1: 0.85. All salts of the choline cation can be used as choline compounds, compounds with organic, multi-protonic acid anions (choline bitartrate or choline bitartrate) being preferred because of their acidic effect. This keeps the concentration of the hydroxide ions necessary for opening the thiazole ring low during storage, so that the degradation of the thiamine by oxidation can be further reduced.
  • choline compounds have an important function in the triglyceride metabolism of the liver cells, with a deficiency in choline leading to an increased production of triglycerides.
  • ADH alcohol dehydrogenase
  • ADH aldehyde dehydrogenase
  • NAD +-dependent processes - such as ß-oxidation - are inhibited by alcohol consumption.
  • the intake of choline is beneficial in order to avoid further accumulation of triglycerides.
  • taxifolin as a ß-cyclodextrin complex or as a solid dispersion in basic polymethacrylate is particularly advantageous in order to minimize degradation of taxifolin and to ensure optimal release, stability and water solubility.
  • taxifoline in the form of a ß-cyclodextrin complex or as a solid dispersion in basic polymethacrylate is also of great importance in order to ensure storage stability in combination with thiamine. Therefore, the use of choline compounds for the treatment and prevention of alcohol-related liver diseases and liver damage in combination with thiamine and taxifolin (in the form of a ß-cyclodextrin complex or as a solid dispersion in basic polymethacrylate) is particularly advantageous.
  • a solid dispersion with basic polymers or copolymers of methacrylic acid and / or methacrylate there is a solid dispersion with basic polymers or copolymers of methacrylic acid and / or methacrylate.
  • suitable polymethacrylates are Eudragit®E, Eudraguard®protect or Kollicoat®Smartseal.
  • solubility is due to the intermolecular interactions between the carbonyl group of the methacrylic ester and the Hydroxyl groups (or similar groups) of taxifolin attributed. This stabilizes the taxifolin in its amorphous form, which considerably improves its solubility in water. In contrast to other polymers such as PVP, the aminoalkyl groups of Eudragit, which are cationic in the protonated state, make the polymer water-soluble, even if it interacts strongly with the taxifolin.
  • taxifolin By forming a solid dispersion of taxifolin in a basic (co) polymer of methacrylic acid and / or methacrylate polymethacrylate, unwanted interactions between taxifolin and thiamine can also be prevented. This is due to the fact that taxifolin enters into ionic interactions with these polymers, in particular between the aminoalkyl radical of the polymer and the hydroxyl groups of the catechol group of the flavonoid, as could be demonstrated by FT-IR spectroscopy. This can also prevent the formation of an orthoquinone group through oxidation of the taxifoline during storage, which also prevents the thiamine from degrading with the formation of a disulfide bridge.
  • the solid dispersion is prepared by melt extrusion of the polymer with the flavonoid or by dissolving the polymer and the flavonoid in a common solvent such as ethanol or acetone and then removing the solvent such as by spray drying.
  • a microencapsulation of the thiamine has surprisingly turned out to be very useful.
  • Various coating materials are available for this, for example hydrogenated lipids from vegetable oils such as palm fat, carnauba or beeswax, cellulose derivatives such as ethyl cellulose, gum arabic, fatty acids, di- and monoglycerides, starch or starch derivatives and polymethacrylates.
  • hydrogenated palm fat lipids, carnauba wax, fatty acids, di- and monoglycerides, acidic / neutral polymethacrylates and ethyl cellulose are highlighted. This avoids the degradation of the thiamine with the formation of disulfide bridges during storage.
  • taxifolin also inhibits the absorption of thiamine by interacting with the intestinal thiamine transporters in the intestine
  • the development of suitable galenics to solve this problem was also part of the invention. It has been shown that an instant-release formulation of taxifolin in combination with an extended-release formulation of thiamine leads to the optimal absorption of both active ingredients. Because while the flavonoid is already dissolved in the stomach a few minutes after ingestion and is absorbed in the front areas of the GI tract, the thiamine is absorbed late over a longer period of time and in the rear sections of the GI tract, which means that there are no negative interactions .
  • taxifolin is the formation of an inclusion complex with ß-cyclodextrin or the formation of a solid dispersion in basic polymethacrylates.
  • extended-release formulation of thiamine is microencapsulation, in particular palm fat lipids, carnauba wax, fatty acids, di- and monoglycerides, neutral / acidic polymethacrylates and ethyl cellulose that are hydrogenated with the coating materials.
  • Thiamine is preferably used in isolated form as thiamine mononitrate or thiamine hydrochloride.
  • Thiamine hydrochloride is particularly preferred, since tests have shown that the nitrate group can oxidize taxifolin to orthoquinone with the formation of nitrite, which in turn leads to the degradation of the thiamine. In contrast, the chloride ions are inert and are therefore preferred. Since the reduction of nitrate to nitrite is pH-dependent and takes place increasingly in the acidic environment of the stomach, an extended-release formulation for thiamine nitrate is particularly advantageous. Taxifolin can optionally be used in the form of pharmaceutically acceptable salts, derivatives or prodrugs, in particular with glycosyl, ether or ester groups at the positions of OFI groups. Examples of glycosides are monosaccharides and oligosaccharides.
  • ethers are alkyl ethers, aryl ethers and hydroxyalkyl ethers.
  • Suitable esters are, for example, carbonates, carbamates, sulfamates, phosphates / phosphonates, neutral or anionic carboxylic acid esters, and amino acid esters. These derivatives are converted back into the main active ingredient taxifolin by enzymatic cleavage in the body
  • mono- and oligoglycosyl residues preferably comprise flexosyl residues, in particular ramnosyl residues and glucosyl residues.
  • flexosyl radicals are allosyl, altrosyl, galactosyl, gulosyl, idosyl, mannosyl and talosyl.
  • mono- and oligoglycosyl radicals can comprise pentosyl radicals.
  • the glycosyl residues can be linked ⁇ - or ⁇ -glycosidically to the base body.
  • a preferred disaccharide is, for example, 6-0- (6-deoxy- ⁇ -L-mannopyranosyl) - ⁇ -D-glucopyranoside.
  • Taxifolin is preferably used in the form of an extract from crushed larch wood, since high concentrations of this flavonoid can be found in the wood, especially in the stumps.
  • other flavonoids are contained in comparatively high concentrations, which can also be effectively reduced by thiamine.
  • Aromadendrin and Eriodictyol are particularly interesting in this context.
  • these flavonoids are characterized by a single bond at position 2,3. Extract from larch wood is clearly preferred because, in contrast to most plant extracts, which would also contain taxifolin, only a very small proportion of flavonoids with a Has a double bond to 2,3 such as quercetin. Preference is given to using an extract of the Dahurian larch (Larix gmelinii), which can be obtained by ethanol-water extraction and has a taxifoline content of at least 88%, preferably a purity between 90% and 97%, a purity of 90% is particularly preferred. 93%.
  • the total dosage of taxifoline can be between 10 mg to 500 mg (preferably 30-400 mg, particularly preferably 50-150 mg, optimally 100 mg).
  • the thiamine dosage can be between 0.1 mg and 250 mg (preferably 1-100 mg, particularly preferably 5-50 mg, optimally 10 mg).
  • the total dosage can be divided into several dosage units.
  • Ratios between taxifolin: thiamine of 700: 1 to 1: 1 have proven to be sensible, in particular between 100: 1 and 3: 1.
  • a ratio between 20: 1 and 5: 1 is best, with a ratio in the range of 10: 1 being the optimum.
  • the formulation according to the invention for oral ingestion can furthermore comprise one or more pharmacologically acceptable auxiliaries and / or carriers and / or one or more further ingredients.
  • vitamins especially B vitamins
  • their pharmaceutically acceptable salts, derivatives and prodrugs for example of the vitamins riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folic acid, cobalamin, ascorbic acid, retinol, cholecalciferol, tocopherol, phylloquinone .
  • various minerals and trace elements as well as their pharmaceutically acceptable salts and complexes can be included, for example calcium, magnesium, potassium, sodium, chromium, copper, manganese, molybdenum, selenium, zinc, cobalt, Silicon, iodine and fluorine.
  • vitaminoids as well as their pharmaceutically acceptable salts, derivatives and prodrugs, for example of choline, coenzyme Q10 (ubiquinone-10), L-carnitine and various amino acids
  • pharmaceutically acceptable salts, derivatives and prodrugs for example of glycine, L -Proline, L-tyrosine, L-glutamine, L-cysteine, L-asparagine, L-arginine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine , L-tryptophan, L-valine, L-alanine, L-aspartic acid, L-glutamic acid and L-serine.
  • the formulation according to the invention is designed so that it can be taken orally.
  • the formulation can be in the form of a powder, granulate, capsule, tablet, chewable tablet, effervescent tablet, dragee, sachet or solution / suspension for oral intake and the total amount taken can be divided into several dosage units.
  • Administration in the form of compressed products such as tablets, film-coated tablets, chewable tablets and effervescent tablets is particularly preferred.
  • auxiliaries which can be mixed with the active ingredients of the composition, in particular polyethylene glycol, polyvinyl alcohol, silicon dioxide,
  • Starch derivatives such as maltodextrin, potato starch or sodium starch glycolate (Explotab®), metal stearates such as magnesium stearate, surfactants such as lauryl sulfate, titanium dioxide, carbonates, sugar and sugar alcohols, talc, cellulose derivatives such as flydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose or carboxymethycellulose known to the person skilled in the art If s and additives.
  • the composition can be mixed, granulated and / or compressed in the usual way or also tabletted / compressed in tablet form, the tablet preferably being coated with a film (film tablet).
  • Such formulations can be prepared in a customary manner with which the person skilled in the art is familiar.
  • solid formulations for oral administration can also contain customary hi-fi and carrier substances, such as extenders, for example lactose, dextrose, sucrose, cellulose, corn starch or potato starch; Lubricant, for example silicate, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; Binders, for example starches, gum arabic, gelatin, methyl cellulose, carboxymethyl cellulose or polyvinylpyrrolidone; Disintegrants, for example starch, alginic acid, alginates or sodium starch glycolates, foaming mixtures; Dyes; Sweeteners; Wetting agents such as lecithin, polysorbates, lauryl sulfates; as well as other customary formulation auxiliaries.
  • extenders for example lactose, dextrose, sucrose, cellulose, corn starch or potato starch
  • Lubricant for example silicate, talc, stearic acid, magnesium or calcium stearate and /
  • Liquid formulations for oral administration can be, for example, dispersions, syrups, emulsions and suspensions.
  • a syrup can contain, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol as a carrier.
  • Suspensions and emulsions can be used as carriers e.g. a natural resin, agar, sodium alginate, pectin, methyl cellulose,
  • the formulations according to the invention can be used for the prevention and / or treatment of alcohol intoxication, sequelae and diseases associated with alcohol consumption, or alcoholism.
  • alcohol intoxication includes physical and / or psychological dependence on alcohol (addiction syndrome). It has been found that the administration of a formulation according to the invention can counteract the development of a dependency syndrome and can thus be used to prevent alcoholism. If alcoholism is already present, a formulation according to the invention is a
  • Treatment possible including alcohol cessation and / or alcohol withdrawal.
  • Withdrawal symptoms can occur when alcohol consumption is reduced or stopped suddenly. Withdrawal symptoms include nausea, nervousness, insomnia, an urge to drink alcohol, irritability and
  • the term “alcohol intoxication” encompasses all stages of acute alcohol intoxication. Depending on the blood alcohol concentration, a distinction is made between the stages of excitation (0.2-2.0% o), hypnosis (2.0-2.5% o), anesthesia (2, 5-4.0% o) and asphyxia ( over 4.0% o). Flavonoids of the formula
  • a hangover is understood here as the malaise and impairment of physical and mental performance as a result of excessive alcohol consumption.
  • a hangover mainly includes the symptoms headache, stomach pain, nausea and vomiting, concentration disorders, increased tendency to sweat, stomach and muscle pain, depressive mood and general malaise on the following days, especially on the day after excessive alcohol consumption.
  • the formulation according to the invention is preferably administered orally in tablet form.
  • the use of taking the preparation according to the invention can take place before, during or after taking alcohol. It is preferred to take it 30 minutes to 120 minutes before the start of alcohol consumption. Taking the inventive preparation with a (high-fat) meal has proven to be advantageous.
  • Fig. 2 Labeled dissolution graphic for the dissolution behavior of
  • taxifolin and the respective cyclodextrin (ß / CAVAMAX W7, HP-ß or y) were weighed in a molar ratio of 1: 1, dissolved in D2O / DMSO (80/20 v / v) and used for Stirred for 3 h at room temperature and 600 rpm. The sample was then measured.
  • the reference solutions (Taxifolin, ß-CD, HP-ß-CD and g-CD) were only dissolved in D2O / DMSO (80/20 v / v) and then measured. The results are shown in FIG.
  • g-CD With g-CD, the signals of protons H6 and H8 in particular, but also, albeit less pronounced, those of protons H2 and H3 are shifted. This indicates that rings A and partly C are embedded in the CD cavity. This also agrees with the prevailing opinion that g-CD mainly includes polycyclic aromatics due to its ring size.
  • the following conformation of the flavonoid in the y-CD cavity can be predicted on the basis of 1 H-NMR spectroscopy: The different position of the flavonoid in the CD cavity naturally influences the interactions of the flavonoid with thiamine. Only a complex with ß-cyclodextrin can prevent unwanted redox reactions during storage, while g-cyclodextrin has no influence on this.
  • V 900ml
  • T (in) 125 ° C
  • Pump rate 20%
  • Aspirator 100%
  • spray gas 55 mm
  • T (out) 71 ° C
  • the solution was vacuum filtered (0.45 ⁇ m membrane filter) in order to remove undissolved flavonoid and cyclodextrin residues and the filtrate was then cooled to -80 ° C. in centrifuge tubes for 24 h and thus frozen. After that, the tubes were placed in the freeze dryer given and the pressure set to 0.05 mbar and the temperature to -30 ° C. The solution was freeze-dried in this way for 96 hours.
  • Centrifuge tubes cooled to -80 ° C for 24 h and thus frozen. The tubes were then placed in the freeze dryer and the pressure was set to 0.05 mbar and the temperature to -30 ° C. The solution was freeze-dried in this way for 96 hours.
  • Taxifolin and ß-cyclodextrin or g-cyclodextrin were weighed in a molar ratio of 1: 1 and mixed together in a mortar.
  • DSC dynamic differential calorimetry
  • thermogram of the g-CD complex differs quite fundamentally from the thermograms of the ß-CD complexes. It is true that the y-CD complex sample also no longer has a characteristic active substance peak that corresponds to the physical mixture (phys. Mix. 1: 1). This indicates complete encapsulation, as no more free flavonoid can be detected. However, this sample shows a broad peak in the range of 245 ° C - 250 ° C, the area of which clearly exceeds that of the physical mixture.
  • 500 mg of the sample was in a vial with 6 ml of dist. Added water to make a saturated solution and shaken for 60 min. The solution was then transferred into a vial using a syringe with an HPLC filter (0.22 ⁇ m), 10: 1 with distilled water. Diluted water to avoid oversaturation and then measured (HPLC DAD-254 nm). The taxifolin concentration in mg / ml was calculated on the basis of the peak area, taking into account the dilution.
  • Inclusion complexes with ß-CD and to a lesser extent with g-CD increase the saturation solubility of the flavonoid taxifolin. This effect is particularly pronounced in the case of the spray-dried formulation SD ß. However, the saturation solubilities of the g-CD complexes are significantly lower than those of the ß-CD complexes.
  • the physical 1: 1 mixtures also achieved very good results, which is due to the formation of complexes in solution.
  • the physical mixture actually represents the maximum possible upper limit for improving solubility, since the complex can form under maximum saturation, i.e. optimal conditions. Nevertheless, the taxifolin concentration of the formulation SD ß exceeds this value. This is probably due to oversaturation of the solution due to the small particle size and thus the large surface area of the material.
  • opalescent suspension of a g-CD complex was prepared (250 mg g-CD complex powder in 20 ml distilled water) and then 10 g flarnea was added. The suspension cleared after stirring for 10 minutes at 600 rpm completely without increasing the temperature. By breaking up the aggregates, the solubility could be massively increased.
  • a supersaturated taxifolin / ß-CD complex solution was first prepared by adding an excess of equimolar taxifolin / ß-CD complex and then heating to 35 ° C. and filtering it off.
  • Various water-soluble polymers were then added (0.25% w / v) as well as choline bitartrate and L-carnitine tartrate (ratio of taxifolin: choline / carnitine cations 1: 0.85) to reduce the influence of polymers / alkylammonium cations on complex formation or Investigate solubility.
  • the solution was left to stand for 96 hours and then the recrystallization was compared with the reference solution.
  • the interaction with the hydroxyl groups of the flavonoid is not so strong that precipitation occurs, at the same time the polymers also interact with the hydroxyl groups of the cyclodextrin. This increases the complex stability.
  • PVA polyvinyl alcohol
  • the interaction of the hydroxyl groups of the polymer with the flavonoid and the cyclodextrin is less pronounced than with the ethylene oxide polymers. This showed that the use of water-soluble polymers increases the complex stability and improves the dissolution behavior.
  • the hydroxyl group and the carboxyl group function as structure-forming elements, which can form hydrogen bonds and counteract the effect of the alkylammonium group. It was found that in the case of choline compounds, on the other hand, the structure-breaking component predominates and, in particular in the case of taxifolin / ß-CD formulations and solid dispersions of taxifolin / basic polymethacrylate, leads to an improvement in the solubility or the physicochemical properties.
  • the XRD method is the method of choice to demonstrate the complete, amorphous embedding of an active ingredient in the polymer matrix.
  • the crystallinity of the sample is determined, which provides information on the arrangement of the active substance molecules. Since the polymer matrix, in contrast to the active ingredient, is amorphous, crystalline peaks indicate incomplete embedding. If, on the other hand, the sample is amorphous, it is a solid solution.
  • amorphous samples usually show a significantly better dissolution behavior than crystalline ones, which is why an increase in bioavailability is possible with an amorphous sample.
  • the diffraction diagram shows that both Taxifolin and the physical mixture of Taxifolin / Eudragit® E100 are crystalline. As expected, the polymer is amorphous. The physical mixture also shows superimposed X-ray diffraction patterns of Taxifolin and Eudragit® E100. In addition, all three formulations are amorphous and do not differ from the reference polymer.
  • CSE 2: 1 is a solid dispersion, whereby the flavonoid Taxifolin is completely embedded in the polymer matrix.
  • FT-IR spectroscopy is used to analyze the molecular interactions between the functional groups of the flavonoid and the basic polymethacrylate.
  • the peak is broadened at 3435 cnr 1, this is due to the presence of a protonated ammonium group as the R-N + -H absorbed stretching vibration in precisely this area and widens the band thereby.
  • the peaks at 2770 cm -1 and 2820 cm -1 also clearly lose intensity or disappear completely, which suggests that the tertiary amino group of the polymer is involved in ionic interactions with the flavonoid
  • Taxifolin 10 mg of taxifolin (Lavitol® 98.9% purity) was placed in a vial with 5 ml of 0.1 N HCl to make a saturated solution and shaken for 60 min. The solution was then transferred into a vial by means of a syringe with an HPLC filter (0.22 ⁇ m) and then measured. Sample measurement
  • a saturated solution of the sample in 0.1 molar HCl solution was made up at room temperature.
  • the solution was then transferred into a vial by means of a syringe with an HPLC filter (0.22 ⁇ m), appropriately diluted and the taxifolin concentration of the solution was determined by HLPC.
  • the solid dispersion with Eudragit® E dissolves the crystalline structure (see XRPD analyzes) and thus increases the water solubility.
  • the crystalline structure is also dissolved by encapsulating each individual taxifolin molecule; at the same time, the CD as a "Trojan horse” increases the water solubility and wettability. Both should lead to an improvement in the dissolution behavior.
  • the instant-release formulation is considered optimal if 85% of the active ingredient has dissolved in the first 15 minutes. Since gastric emptying in an empty state is a first-order reaction (50% emptying in 10-20 minutes), with 85% dissolution in the first 15 minutes, it can be assumed that the formulation behaves like a solution and therefore optimally. This allows a optimal absorption behavior of thiamine and taxifolin can be guaranteed with simultaneous administration.
  • Taxifolin represents the reference value here.
  • the Eudragit® E formulation also achieves a very rapid release of the flavonoid, with 82.2% of the flavonoid already dissolving at the first measurement point.
  • the release of the taxifolin is limited to a maximum of 85%. Both formulations thus meet the requirements as optimal instant-release formulations which enable a taxifolin / thiamine combination to be formulated.
  • both formulations enable good storage stability, in that unwanted redox reactions between the taxifolin and the thiamine can be avoided during the storage period.
  • this is due to the inclusion of the catechol group, while in the solid dispersion in basic polymethacrylate, ionic interactions between the hydroxyl groups of the catechol group and the aminoalkyl radical of the polymer are decisive.
  • the mixtures were placed in glass petri dishes and stored open for 3 months in a climatic cabinet at 40 ° C. and 75% humidity (accelerated stability test).
  • the samples were then halved and the amount corresponding to 50 mg thiamine weighed (564 mg taxifolin / thiamine, 2697 mg FD-y / thiamine, 2429 mg FD ß / thiamine and 1579 mg Eudragit®E CSE 2: 1 / thiamine).
  • the samples were then extracted with 50ml 45 ° C hot solvent (ethanol for the Taxifolin-pure, FD-g and FD ß mixture and petroleum ether for the Eudragit® E CSE 2: 1 mixture) to dissolve the thiamine degradation products and then filtered.
  • the finished solutions contained the equivalent amount of degradation product of 50 mg thiamine / 50 ml solvent.
  • a reference solution was prepared containing the equivalent concentration of thiamine disulfide (53 mg thiamine disulfide hydrate in 50 ml ethanol or petroleum ether).
  • Thiamine disulfide could be detected for the mixtures taxifolin / thiamine and FD-y / thiamine, whereby less degradation was visible in the FD-g than in the pure taxifolin / thiamine sample.
  • the FD ß sample and the Eudragit® E CSE 2: 1 sample did not contain any thiamine disulfide or any other degradation product. Thiochrome could not be detected in any sample under UV light.
  • the taxifolin formulations with ß-CD and basic polymethacrylate were the only formulations able to prevent the degradation of thiamine to thiamine disulfide. This is due to the encapsulation of the catechol group by ß-CD or the ionic interactions between taxifolin and the basic polymethacrylate.
  • the sample with Eudragit® E had to be extracted with petroleum ether, otherwise the polymer would also have dissolved and would have been stained by the Dragendorff reagent.
  • Three aqueous solutions were prepared in beakers, containing I) 100mg Taxifolin in 150ml dist. Water II) 100mg Taxifolin + 13mg Thiamine HCl in 150ml dist. Water and III) 100mg taxifolin + 13mg thiamine HCl + 373mg ß-CD in dist. Water. The samples were stored open and protected from light at room temperature and the color of the solution was checked every 24 hours.
  • Results The results are summarized in a table.
  • a delay in the oxidation of taxifolin can be seen through the addition of thiamine or ß-CD, whereby the oxidation decreased in the order taxifolin (ref.)> Taxifolin / thiamine> taxifolin / thiamine / ß-CD.
  • the addition of thiamine can delay the degradation of taxifolin, whereby thiamine disulfide as well as various degradation products and / or adducts are formed in the process, which cause the solution to turn yellow. This also confirms the advantageous combination in vivo, whereby thiamine can reduce oxidized taxifolin and thus prolong the effect.
  • the addition of ß-CD now delays the taxifolin oxidation in the first step, which means that the thiamine is only oxidized later.
  • Dose corresponds to 1 tablet, ingredients per tablet, oblong form:
  • Dose corresponds to 1 hard capsule, ingredients per hard capsule size 0 (gelatine): 200 mg basic methacrylate copolymer (Eudraguard protect®, Evonik Nutrition & Care GmbH), 100 mg taxifolin-rich extract from Larix gmelinii (Lavitol® from Ametis JSC, taxifolin content 90, 5%), 20mg silicon dioxide, 13mg thiamine hydrochloride (Food Grade, BASF).
  • the formulation with basic polymethacrylate is also easy to implement and can be produced on an industrial scale.
  • Formulation with ß-cyclodextrin + thiamine microencapsulated, dose corresponds to 1 tablet, ingredients per tablet, oblong shape 21 mm x 9 mm:

Abstract

La présente invention concerne des formulations de taxifoline comprenant de la thiamine sous une forme galénique destinée à être administrée par voie orale, en particulier en tant que complément alimentaire ou aliment à des fins médicales spéciales (FSMP).
EP21717913.4A 2020-04-16 2021-04-15 Formulation de taxifoline comprenant de la thiamine Pending EP4135656A1 (fr)

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WO2009018326A2 (fr) * 2007-07-31 2009-02-05 Limerick Biopharma, Inc. Procédés et compositions d'analogues de pyrone solubles
RU2498801C1 (ru) * 2012-08-14 2013-11-20 Открытое Акционерное Общество Завод Экологической Техники И Экопитания "Диод" Раствор стабилизированного дигидрокверцетина
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