DE202020005452U1 - Composition containing natural lipophilic compounds - Google Patents

Abstract

Composition containing natural lipophilic compounds, characterized in that
- the composition contains resveratrol together with curcumin as lipophilic compounds and
- One or more nonionic or anionic emulsifiers and
- comprises one or more solid matrix-forming agents, wherein
Resveratrol and curcumin are formed soluble in a solid solvent system together with an emulsifier or more emulsifiers and a matrix-forming agent or more matrix-forming agents and the composition is produced by means of hot melt extraction.

Description

The invention relates to a composition containing natural lipophilic compounds.

In relation to the background of the invention, it should be noted that according to the Biopharmaceutical Classification System (BCS), Class IV compounds exhibit the lowest oral bioavailability, very low solubility and very low intestinal permeability among all pharmaceutical classes of drugs. Therefore, these drugs require a more compatible and efficient delivery system. Since their solubility in various media is a limitation, loading polymeric drugs with a modified approach could prove to be a solution for them. The rate of absorption of drugs in the gastrointestinal tract (GI-T) is influenced by a number of factors, such as the physico-chemical nature, the size and molecular weight of the compounds, the metabolism, the physiological functions, the structure and surface of the intestinal cells, etc. .. Notwithstanding this complexity, the Amidon et al. and Lipinski et al. developed Biopharmaceutical Classification System (BCS) clearly that the synthetically obtained drugs, which were produced on a large scale through the introduction of high-throughput screening (HTS) and combinatorial chemistry, on the other hand, were confronted with challenges from poorly water-soluble drugs.

• in Verbindungen der Klasse I, die eine hohe Löslichkeit, eine hohe Permeabilität und eine gute, nur durch die Geschwindigkeit der Magenentleerung kontrollierte Resorption aufweisen;
• in Verbindungen der Klasse II, die eine niedrige Löslichkeit, eine hohe Permeabilität und eine eingeschränkte, durch die Lösungsgeschwindigkeit des Wirkstoffes bestimmte Resorption aufweisen;
• in Verbindungen der Klasse III, die eine hohe Löslichkeit, eine niedrige Permeabilität und eine von den physikalisch Wirkstoffeigenschaften unabhängige Resorption aufweisen;
• in Verbindungen der Klasse IV, die eine niedrige Löslichkeit, eine niedrige Permeabilität und eine unbestimmte Resorption aufweisen.

Based on the Biopharmaceutical Classification System (BCS), drugs are divided into four categories depending on their solubility and permeability properties, and the absorption properties are also considered:

• in compounds of class I, which have a high solubility, a high permeability and good absorption controlled only by the speed of gastric emptying;
• in compounds of class II, which have a low solubility, a high permeability and a restricted absorption determined by the dissolution rate of the active substance;
• in compounds of class III, which have a high solubility, a low permeability and an absorption independent of the physically active substance properties;
• in class IV compounds that have low solubility, low permeability and indefinite absorption.

When this classification system was subsequently examined in detail, it turned out that the drug formulation and its carrier system are equally responsible for determining the rate of absorption and the extent of absorption in the GI-T, which increases the bioavailability and therapeutic effect of the classified drugs. Several approaches to improve drug delivery through increased solubility and permeability have been continuously developed and modified, especially for compounds of Class II and IV. The approaches such as complexation, micronization, crystal modification, increasing the solubility of drugs, etc. are still explored, but these Techniques have limitations, primarily to improve the solubility and permeability of Class IV drugs. Consequently, the best approach to improving the bioavailability of these drugs would be to return to the lead optimization phase within drug development and modify their structures to obtain the appropriate physico-chemical properties that enable higher solubility and thereby higher bioavailability.

Several types of solid-state dispersions (SDs) have been developed over the past few decades, which are not all the same in terms of the physical state of the active ingredient in the matrix. The most common and attractive systems are amorphous solid suspensions or solutions in which the active compound is in amorphous form or molecularly dispersed. The amorphous state or the molecular dispersion of an active ingredient shows a typically higher oral bioavailability compared to the crystalline form, since both distributions have a higher free energy and a better thermodynamic activity.

Amorphous SDs can be made by various manufacturing methods such as solvent evaporation, spray drying, melting, or hot melt extrusion (HME). In the various patents / patent applications, several methods are proposed for the production of formulations of lipophilic active ingredients, including resveratrol and curcumin, with polymer matrices in order to achieve better solubility in aqueous media and thus higher bioavailability:

So goes out FR 2 758 459 an immediate release composition containing fenofibrite and a process for the preparation of this medicinal composition in which the desired higher Bioavailability is to be achieved by pulverizing the active ingredient into finely comminuted form with a size smaller than 20 µm. The method comprises the preparation of a suspension of the fenofibrate, which is comminuted to a size of less than 20 μm, in a solution of a hydrophilic polymer, optionally using a surface-active agent, and then applying the suspension to a hydrosoluble carrier.

WO 2018/203294 describes a composition in which better bioavailability and solubility in an aqueous medium are also to be achieved by micronization. A liquid pharmaceutical composition is described with a stable colloidal dispersion comprising polymeric particles of zein and β-cyclodextrin in suspension in a hydroalcoholic continuous phase, the particles having an average diameter of less than 1 μm, preferably in the range of 100 nm to less than 1 µm, the pharmaceutical composition containing at least one active ingredient incorporated into the particles, such as resveratrol and curcumin.

Out US 6,221,399 B1 discloses a method of a solid interpolymer complex for use as a controlled release matrix for oral administration in which the controlled release is effected by preparing solid particles of the interpolymer complex by spray drying.

EP 2 581 089 B1 describes a method for producing a polyphenol composition, comprising a step in which a hardly water-soluble polyphenol and one or more representatives of methylated compounds of hardly water-soluble polyphenols, including resveratrol and curcumin being used as compounds to be dissolved, a heat treatment at 100 ° C to 180 ° C in the presence of an aqueous medium, and in a further step, the solution exposed to the heat treatment is cooled to 90 ° C or less at a cooling rate of 1 ° C / s or more and 100 ° C / s or less.

Out WO 2009/040818 A1 shows a solid composition which forms a colloidal nanodispersion on contact with aqueous media, the composition comprising at least one lipophilic active ingredient, such as resveratrol, which is positioned in close contact with a polymer matrix made of an amphiphilic and a hydrophilic polymer. The lipophilic active ingredient has modified physicochemical properties, which are represented either by a reduced enthalpy of fusion or by both a reduced enthalpy and a reduced temperature of melting, compared to the same loose initially crystalline lipophilic active ingredient that is used as the starting point for the production of the Composition is used.

So far, all such efforts by means of known SDs with regard to resveratrol and / or curcumin have been unsuccessful, especially in medical and economic terms. No significantly higher solubility and no significantly higher bioavailability of resveratrol and / or curcumin in the human organism could be achieved or demonstrated.
With regard to resveratrol, the review "Resveratrol and its Human Matabolites - Effects on Matabolic Health and Obesity" by Margherita Springer and Sofia Moco, Nutriens 2019,11,143, clearly shows the very low bioavailability of the various dosage forms of resveratrol known and examined up to that point.

As a solvent-free, one-step, continuous process, hot melt extrusion (HME) offers an attractive alternative to other techniques, which is why there has been a growing interest in this method over the last 10-15 years.

So beats WO 2019/159 174 propose to provide a solid solution composition by means of HME, which comprises one or more cannabinoids, one or more nonionic emulsifiers and one or more solid matrix formers, wherein the one or more cannabinoids are dissolved together with the emulsifier and the solid matrix former in a solid solvent system.

During an HME process, a material melts or softens under increased temperature / pressure and is pressed through a nozzle by means of a rotating screw (s). There are a large number of downstream processes that can even be combined so that a large number of dosage forms (e.g. pellets, tablets, granules) can be designed. The intensive mixing achieved by the screw (s) generally leads to an even distribution of auxiliary substances and active ingredients. The release rate and the stability of the formulation can be tailored depending on the choice of polymer matrix and additives. The main excipient used in HME is a polymeric lipid-based carrier.
The selection of a suitable polymer requires knowledge of its physicochemical properties. Polymers used in HME should exhibit thermoplastic behavior, i.e. they should soften at the processing temperature without decomposing and solidify on leaving the nozzle.
The selection of suitable polymers and functional auxiliaries (eg plasticizers, antioxidants, pore formers) is therefore of great importance in the development of amorphous SDs.
The thermal stability is a first prerequisite, but other parameters are also important in order to ensure the mixing of active ingredients and excipients and the thermodynamic stability of the final dosage form. Physico-chemical properties such as solubility parameters, glass transition temperature, melting temperature, hygroscopicity, hydrogen-binding donor or acceptor groups and mechanical properties are all key parameters that contribute to achieving the desired improvement in solubility, bioavailability and stability.
The use of lipid-based excipients can be a key to the formulation and stabilization of lipophilic compounds.

The aim of the invention is therefore to overcome the above-mentioned challenges in order to formulate a lipophilic and a hydrophilic-lipophilic model compound with lipid-based amorphous solid-state dispersions (SDs). The formulation of such compositions should be able to overcome the high crystal energy.

In addition, there is still and to this extent a need for formulations which include immediate release and improved bioavailability and solubility of lipophilic active ingredients, in particular lipophilic active ingredients with significantly higher melting points.
There is also a need to provide pharmaceutically effective compositions in a simple and convenient dosage form for therapeutic purposes.
The object of the invention is to meet these needs.

• - die Zusammensetzung als lipophile Verbindungen Resveratrol zusammen mit Curcumin enthält und
• - einen oder mehrere nichtionische und/oder anionische Emulgatoren sowie
• - einen oder mehrere feste matrixbildende Mittel

umfasst, wobei
Resveratrol und Curcumin zusammen mit einem Emulgator oder den mehreren Emulgatoren und einem matrixbildenden Mittel oder mehreren matrixbildenden Mitteln in einem festen Lösungsmittelsystem löslich ausgebildet sind und die Zusammensetzung mittels Heißschmelzextraktion hergestellt ist.According to the invention, the object is achieved by a composition containing natural lipophilic compounds, wherein

• - the composition contains resveratrol together with curcumin as lipophilic compounds and
• - One or more nonionic and / or anionic emulsifiers as well
• - one or more solid matrix-forming agents

includes, where
Resveratrol and curcumin together with an emulsifier or the plurality of emulsifiers and a matrix-forming agent or a plurality of matrix-forming agents are formed soluble in a solid solvent system and the composition is produced by means of hot melt extraction.

Typically, the composition has the property that upon contact with an aqueous liquid, such as a body fluid, it releases a multiplicity of particles, the particles having an average particle size of about 150 nm and resveratrol and curcumin being essentially dissolved in the released particles are.

The resveratrol of the formula 3,5,4'-trihydroxy-trans-stilbene is preferably selected from the group of the families Dipterocarpaceae, Paeoniaceae, Vitaceae, Leguminosae, Gnetaceae, Cyperaceae, Polygonaceae Gramineae and Poaceae and the one curcumin has the formula (1E, 6E ) -1,7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-diones. According to a further embodiment of the invention, the at least one nonionic emulsifier is selected from the group consisting of polysorbates, polysorbate 80, polyoxyl hydrogenated castor oil, sucrose ester, sucrose distearate, tocopheryl polyethylene glycol 1000 succinate, sorbitan fatty acid esters, sorbitan monooleate, polyglyceryl fatty acid esters or combinations thereof .

Another embodiment provides that the at least one emulsifier is selected from nonionic or anionic surfactants with a hydrophilic-lipophilic balance value (HLB value) of about 10 to about 16 and a second emulsifier is selected from nonionic or anionic or hydrophilic hydrophobic surfactants with an HLB value of about 4 to about 12.

Particularly preferred is at least one solid matrix-forming agent selected from the group consisting of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g. Soluplus®), polyvinyl alcohol (PVA), crosslinked copolymer of acrylic acid and a hydrophobic C10-30 alkyl acrylate comonomer, gelatin, hydroxypropylmethyl cellulose (e.g. Methocel), methyl cellulose, hydroxypropyl cellulose ( Klucel), hydroxyethyl cellulose (e.g. Natrosol), sodium carboxymethyl cellulose, acrylate copolymers, ammonio-methacrylate copolymer type A or B, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer (e.g. from Eudragit & trade), methacrylic acid-ethyl acrylate copolymer (e.g. Kolico vinyl alcohol-copolymer ® IR), polyvinylacetate-co-crotonic acid, polymethyl methacrylate and grafted polyethylene oxide, lignins, polyvinylpyrrolidone-co-vinyl acetate (e.g. Kollidon VA64), polyvinylpyrrolidone (e.g. Kollidon K90), cellulose acetate phthalate, cellulose acetate phthalate, phylloscylmethyl cellulose acetate, carbo-methyl cellulose methacrylate, phylloxylmethyl cellulose, carboxylmethyl cellulose, carbo-ethyl cellulose methoxylmethyl cellulose, carbo-ethyl cellulose methoxylmethyl cellulose, carbo-ethyl cellulose methoxylmethyl cellulose, carbo-ethyl cellulose methoxylmethyl cellulose, phylloxypropylmethyl cellulose, polyvinylpyrrolidium-phthalate propyl acetate, polyvinylpyrrolidone-co-vinylacetate, lignins, grafted polyethylene oxide, polyvinylpyrrolidone-co-vinylacetate, polyvinylpyrrolidone-co-vinylacetate, , Polymethacrylic acid-co-ethyl acrylate, polymethacrylic acid-co-methyl methacrylate, polymethacrylic acid-co-ethyl acrylate, polymethacrylic acid-co-methyl methacrylate, polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PDLA), polylactide Co-glycolic acid (PLGA), polyethylene oxide-polypropylene oxide block copolymer (e.g. Poloxamer from Carbowax ™), polyethylene glycol (PEG1000, PEG1500, PEG 2000, PEG4000, PEG6000, PEG8000) and of mixtures thereof.

A second solid, matrix-forming agent is preferably selected from the group consisting of beeswax, carnauba wax, cetyl palmitate, glyceryl behenate, behenic acid, behenyl alcohol, glyceryl monostearate, glyceryl palmitostearate, glyceryl stearate, hydrogenated castor oil, microcrystalline silicon acid, stearic acid, silicone wax, paraffin wax, stearic acid, silicone wax , PEG wax or Carbowax.

Typically, at least 80% of the resveratrol and curcumin, as measured by differential scanning calorimetry, are completely dissolved in the solid composition.

According to a further preferred embodiment, the ratio of resveratrol and curcumin to at least one emulsifier is from about 5: 1 to about 1:20 and the ratio of a) the resveratrol and curcumin to b) the mixture of the at least one emulsifier and the at least one solid matrix-forming agent about 2: 1 to about 1:20.

1. a) aus einer zur oralen Verabreichung geeigneten Darreichungsform besteht, ausgewählt aus der Gruppe bestehend aus Tabletten, Kapseln, Teilchen, Granulaten, Lutschtabletten, Süßigkeiten, Toffees, Schokoladen und Keksen oder aus einem Beutel, einer Einheitsdosispackung oder suspendiert ist in einer Flüssigkeit oder einem Gel, wobei
   • - die Darreichungsform nach Kontakt mit der Körperflüssigkeit eines Menschen im unteren Darm und im Dickdarm zerfällt und dadurch mindestens etwa 20% (w/w) des Resveratrol und Curcumins am distalen Jejunum und am Dickdarm freigesetzt sind oder
   • - die Darreichungsform säurebeständig ist oder Enzyme und in der Lage ist, sich im unteren oder distalen Darm und im Dickdarm zu zersetzen, oder anzuschwellen, wodurch mindestens etwa 50% (w/w) des einen oder der mehrerer Resveratrols und Curcumins im distalen Jejunum und/oder im Dickdarm freigesetzt sind oder
   • - die Dosierungsform aus einer Kapsel, einer Tablette oder einem Beutel, gefüllt mit Granulat, besteht und die Dosierungsform mindestens 50 mg Resveratrol und mindestens 100 mg Curcumin, mindestens 1-50 mg D-α-Tocopherylpolyethylenglykolsuccinat (Vitamin E TPGS oder TPGS), mindestens 1-50 mg Saccharose-Distearat oder Polyglycerylester und mindestens 1-100 mg Polyvinylcaprolactam-Polyvinylacetat-Polyethylenglykol-Pfropf-Copolymer oder Polymethacrylsäure, Polymethylmethacrylat oder Polyacrylat-Polymer oder Polyacrylat-Copolymer oder Poloxamer 407 umfasst oder
2. b) als ein Kit zur therapeutischen Behandlung von entzündlichen Darmerkrankungen und anderen Darmerkrankungen, die das allgemeine Wohlbefinden und die Wachsamkeit der Patienten verbessert, bereitgestellt ist in Darreichungsformen mit unterschiedlicher Dosis eines entzündungshemmenden Resveratrol und Curcumins oder Derivaten davon für eine Tagesdosis von insgesamt bis zu 2.000 mg des Wirkstoffes. oder
3. c) zur Behandlung einer gastrointestinalen Erkrankung in einer therapeutisch wirksamen Dosis bereitgestellt ist und die
   • - durch systematische Resorption zu einem messbaren Resveratrol- und Curcumin-Blutspiegel führt und
   • - eine lokale Abgabe des Resveratrol und des Curcumins an eine oder mehrere Regionen des Gastrointestinaltraktes, ausgewählt aus den Ilium, Jejunum, distalen Jenunum und dem Kolon, bewirkt, wobei die Zusammensetzung Partikel enthält, die
     • 1) nicht pH-resistent sind und
     • 2) solche Partikel enthält, die pH-resistent sind und ein verzögertes Zeit- oder Enzymfreisetzungsprofil aufweisen oder die nur ein verzögertes Zeit- oder Enzymfreisetzungsprofil besitzen,
     oder
4. d) zur therapeutischen Behandlung arteriosklerotischer Herz-Kreislauf-Erkrankungen geeignet ist, oder
5. e) zur therapeutischen Behandlung entzündlicher Nervenerkrankungen geeignet ist oder
6. f) zur therapeutischen Behandlung oder therapeutischen Begleitbehandlung von onkologischen Erkrankungen geeignet ist.

Furthermore, the object is achieved by a pharmaceutically effective formulation which contains the aforementioned composition, the formulation

1. a) consists of a dosage form suitable for oral administration, selected from the group consisting of tablets, capsules, particles, granules, lozenges, sweets, toffees, chocolates and biscuits or from a bag, a unit dose pack or is suspended in a liquid or a gel , in which
   • - the dosage form disintegrates after contact with the body fluid of a person in the lower intestine and in the large intestine and as a result at least about 20% (w / w) of the resveratrol and curcumin are released on the distal jejunum and on the large intestine or
   • - the dosage form is acid-resistant or enzymes and is able to decompose or swell in the lower or distal intestine and in the large intestine, whereby at least about 50% (w / w) of the one or more resveratrols and curcumin in the distal jejunum and / or are released in the colon, or
   • - the dosage form consists of a capsule, a tablet or a bag filled with granules, and the dosage form consists of at least 50 mg resveratrol and at least 100 mg curcumin, at least 1-50 mg D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS or TPGS), at least 1-50 mg sucrose distearate or polyglyceryl ester and at least 1-100 mg polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or polymethacrylic acid, polymethyl methacrylate or polyacrylate polymer or polyacrylate copolymer or poloxamer 407 comprises or
2. b) as a kit for the therapeutic treatment of inflammatory bowel diseases and other intestinal diseases, which improves the general well-being and alertness of the patient, is provided in dosage forms with different doses of an anti-inflammatory resveratrol and curcumin or derivatives thereof for a total daily dose of up to 2,000 mg of the active ingredient. or
3. c) is provided for the treatment of a gastrointestinal disease in a therapeutically effective dose and which
   • - systematic absorption leads to measurable resveratrol and curcumin blood levels and
   • a local delivery of resveratrol and curcumin to one or more regions of the gastrointestinal tract selected from the ilium, jejunum, distal jenunum and colon, the composition containing particles which
     • 1) are not pH resistant and
     • 2) contains particles that are pH-resistant and have a delayed time or enzyme release profile or which only have a delayed time or enzyme release profile,
     or
4. d) is suitable for the therapeutic treatment of arteriosclerotic cardiovascular diseases, or
5. e) is suitable for the therapeutic treatment of inflammatory nervous diseases or
6. f) is suitable for the therapeutic treatment or therapeutic accompanying treatment of oncological diseases.

In the embodiments mentioned, the weight ratio of resveratrol to curcumin is in the range from 0.5 to 1 to 1 to 2.5.

The present invention is characterized by the advantage that, through the combination of lipid-based auxiliaries with inorganic carriers, extruded amorphous solid dispersions of resveratrol in combination with curcumin can be provided as lipophilic model compounds and these model compounds have a particularly high solubility in aqueous media and thus a significantly higher solubility Have bioavailability in particular because of the prevention of the usual, rapid metabolism. The significantly increased release of the inventive composition in the human intestine also promotes the absorption of resveratrol and curcumin by the human cells. The conversion into the body's own substances that takes place in these cells with the associated change in energy (assimilation) ultimately leads to a significantly higher bioavailability of the active ingredients than previously achieved.

To this extent, the invention has great potential for improving the effectiveness of dosages, especially in the case of pharmaceuticals. But also for food technologies and especially food supplements there are new possibilities with improved sustainability.

In particular, it speaks for the inventive achievement that by means of the hot melt extrusion from resveratrol in combination with curcumin amorphous solid dispersions can be produced thermally stable without decomposition of the polymeric inert carrier, although these lipophilic active ingredients have significantly different and high melting points (resveratrol with 253 ° C - 260 ° C and curcumin at 183 ° C).

The invention is also characterized in that the composition according to the invention enables the production of therapeutically usable agents and natural product compositions in which the synergistic effect of resveratrol and curcumin is demonstrated in a sustainable manner and regardless of age.

Resveratrol is known to have a wide range of biological properties, including antioxidant, cardioprotective, neuroprotective, anti-inflammatory, and anti-cancer effects.
Turmeric, a spice long recognized for its medicinal properties, has attracted interest in both the medical / scientific world and culinary enthusiasts as it is the primary source of the polyphenol, curcumin. It helps treat oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, and hyperlipidemia.

The herbal active ingredients used in the compositions of the present invention are standardized herbal extracts. It is important that these materials which are used to prepare the composition of the invention are of vegetable origin. For example, the plant material containing resveratrol was harvested in the field, resveratrol was found in red wines and in various other human foods.
To date, 92 new resveratrol compounds, including 39 dimers, 23 trimers, 13 tetramers, 6 resveratrol monomers, 6 hexamers, 4 pentamers and 1 octamer, have come from the Dipterocarpaceae, Paeoniaceae, Vitaceae, Leguminosae, Gnetaceae, Cyperaceae, and Polygonaceae Gramineae families Poaceae reported. Of these families, the Dipterocarpaceae, which contain 50 resveratroles, make up the majority, with 7 Dipterocarpaceae genera are involved, including Vatica, Vateria, Shorea, Hopea, Neobalanocarpus, Dipterocarpus, and Dryobalanops.

Turmeric, a rhizomatous, herbaceous, perennial plant (Curcuma longa) from the ginger family is obtained in various forms well known to those skilled in the art, including as dried plant material from roots, leaves, sprouts, flowers and whole plants and as aqueous and non-aqueous extracts and oils.

An essential part of the invention is the production of the composition according to the invention by means of the hot melt extrusion process (HME).

Of particular interest in this context is hot melt mixing, which uses a twin screw extruder instead of a single screw extruder to more efficiently mix the therapeutic compound with an inert carrier to form a solid dispersion. Typically, the working areas of a single screw and twin screw extruder are heated to expedite mixing of the therapeutic compound with the carrier.
In the prior art, in some cases, heating the zone of the hot melt extruder to a temperature above the melting point of the therapeutic compound is unsuitable as this temperature may exceed the melting temperature of the inert carrier and cause it to degrade. In addition, in the prior art, some therapeutic compounds self-decompose on hot melt.

There was therefore the need to provide a method which makes it possible to transfer therapeutic compounds with a high melting point from highly crystalline to amorphous and which do not decompose when the melting point is almost reached. The present invention meets these needs by using a solubilizer. Suitable solubilizers are block copolymers, for example nonionic synthetic block copolymers of ethylene oxide and propylene oxide, such as Poloxomer 407, in particular F127. In another embodiment, solubilizers also include other surfactants in addition to the class of block copolymers already mentioned.
The specified solubilizer makes it possible to lower the processing temperature of the therapeutic preparation in order to maintain its integrity and at the same time ensure the transition of the physical state from crystalline and / or thermally unstable to amorphous. In addition, the process makes it possible to use carriers or polymers for the compositions according to the invention which normally decompose at high temperatures, which at the same time ensures greater versatility of the compositions.

The invention is to be clarified with the following exemplary embodiment.

The substances listed in the table below are used with the proportions mentioned.
The amounts given represent the mean value from two test series.

Execution example:

Resveratrol,

mit einer Reinheit von 99,84 %,

Curcumin,

mit einer Reinheit von 95,5 %;

Polyethylenglykol 2000,

als hydrophiles nichtionisches Tensid;

Poloxamer 407,

als hydrophiles nichtionisches Tensid;

β-Cyclodextrin,

als Mittel, das mit einem hydrophoben Inneren und einem hydrophilen Äußeren Komplexe mit hydrophoben Verbindungen bildet und einem pharmakologischen Präparat Löslichkeit und Stabilität verleiht; Einschlussverbindungen von Cyclodextrinen mit hydrophoben Molekülen sind in der Lage, in Körpergewebe einzudringen und können deshalb verwendet werden, um biologisch aktive Verbindungen unter bestimmten Bedingungen und an bestimmten Orten freizusetzen;

Vitamin E TPGS,

als eine mit Wasser mischbare Form von Vitamin E, bestehend aus einem hydrophoben Vitamin E-Teil und einer hydrophilen PEG-Kette;

Compritol 888 ATO,

als Mittel zur Bildung einer Lipidbarriere bei der Heißschmelzextrusion und als Träger für den Schutz empfindlicher Wirkstoffe und für Nanopartikel-Technologien zur Verbesserung der Wirkstoffverträglichkeit;

Aerosil 200,

als Mittel zur Beeinflussung der Rheologie und zu Thixotropiekontrolle sowie als Antiabsetz-, Verdickungs- und Antiabsackmittel und zur Verbesserung des freien Flusses;

Polyvinylalkohol PVA,

als Mittel zur Verbesserung der Löslichkeit aktiver Inhaltsstoffe von Extrudaten und der Stabilität von Extrudatmaterialien.

Overview of the starting substances of the composition produced by the hot melt process Wt.% substance Amount (gr) 16.67 Resveratrol; 99.84 200.00 17.50 Curcumin ,; 95.5 210.00 3.33 Polyethylene glycol 2000 40.00 30.00 Poloxamer 407 360.00 10.00 β-cyclodextrin 120.00 4.17 Vitamin E TPGS 50.00 1.67 Compritol 888 ATO 20.00 2.50 Aerosil 200 30.00 14.17 Polyvinyl alcohol PVA 170.00 100.00 1,200.00

Resveratrol,

with a purity of 99.84%,

Curcumin,

with a purity of 95.5%;

Polyethylene glycol 2000,

as a hydrophilic nonionic surfactant;

Poloxamer 407,

as a hydrophilic nonionic surfactant;

β-cyclodextrin,

as an agent which forms complexes with hydrophobic compounds with a hydrophobic interior and a hydrophilic exterior and imparts solubility and stability to a pharmacological preparation; Inclusion compounds of cyclodextrins with hydrophobic molecules are able to penetrate into body tissues and can therefore be used to release biologically active compounds under certain conditions and at certain locations;

Vitamin E TPGS,

as a water-miscible form of vitamin E, consisting of a hydrophobic vitamin E part and a hydrophilic PEG chain;

Compritol 888 ATO,

as a means for forming a lipid barrier during hot melt extrusion and as a carrier for the protection of sensitive active ingredients and for nanoparticle technologies to improve drug compatibility;

Aerosil 200,

as agents for influencing the rheology and for thixotropy control as well as anti-settling, thickening and anti-sagging agents and for improving the free flow;

Polyvinyl alcohol PVA,

as a means of improving the solubility of active ingredients of extrudates and the stability of extrudate materials.

The substances mentioned were mixed in a batch of 1,200 g for 10 minutes before the extrusion process. A Turbula TF 2 mixer (Switzerland) was used. The powder premixed in this way was then poured into the funnel of the extruder. The extrusion then took place in a single-screw laboratory hot-melt extruder (Thermo Fischer HME PolyLab-OS, Germany), which is equipped with a nitrided single screw made of stainless steel DIN 1.8550 with a diameter of 19.05 mm (3/4 ").

The extrusion process was carried out at 80 rpm and a feed rate of 1 kg / h and the temperature was kept at 105 ± 1 ° C.

Unlike pellets obtained by wet granulation, the hot melt extrusion process of the present invention does not require a granulating liquid such as water, methanol, ethanol, isopropanol or acetone.

The extrudate obtained in this way was comminuted into granules, which form the inner phase of the pharmaceutical composition. One skilled in the art can determine the required granule size for a particular pharmaceutical composition being developed. A suitable particle size is, for example, less than or equal to 1000 microns, 750 microns, 500 microns or 250 microns.

In a further batch of the same composition of the starting materials, as listed in the table of the exemplary embodiment, the extrudate was formed directly into tablets at an extrusion temperature of 130 ° C., comminuted into microparticles or processed into another form, as is known to a person skilled in the art .
The granules were obtained in the form of particles of an encapsulated therapeutic agent or a controlled release layer as a sustained release agent. The resulting granules are particles of a therapeutic agent coated or substantially encased in a granular excipient layer or, in another embodiment, particles of a therapeutic agent encapsulated or substantially encapsulated in a granular excipient.

After the granules had been obtained, they were processed into oral forms, such as solid oral dosage forms such as tablets, pills, lozenges, microtablets, capsules or sachets, with additional standard excipients being added to form the outer phase of the pharmaceutical composition. The outer phase of the pharmaceutical composition can also contain an additional therapeutic agent. These solid oral dosage forms include, for example, standard oral dosage forms.

Examples of these standard carriers include release retardants, plasticizers, disintegrants, binders, lubricants, glidants, stabilizers, fillers and diluents. In order to impart certain oral properties to the solid oral form, a skilled user can easily select one or more of the above-mentioned excipients with simple standard experiments. The amount of each excipient used is varied within a common range.

Examples of pharmaceutically acceptable disintegrants include starch, clays, celluloses, alginates, gums, crosslinked polymers, e.g. crosslinked polyvinylpyrrolidone or crospovidone (e.g. Polyplasdone XL from Ashland Inc.), crosslinked sodium salt of carbohydrate or carbohydrate croscarmellose (e.g. AC- DI-SOL from FMC), as well as the cross-linked calcium salt of carboxymethyl cellulose, soy polysaccharides and guar gum. The amount of disintegrant is between about 0% and about 10% by weight based on the weight of the composition. In one embodiment, the amount of disintegrant is from about 0.1% to about 1.5% by weight based on the weight of the composition.

Examples of pharmaceutically acceptable binders include starches, celluloses and their derivatives, e.g. microcrystalline cellulose (e.g. Avicel PH from FMC), hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose (e.g. Methocel from Dow Chemical Corp.), sucrose, dextrose, corn syrup, polysaccharides and gelatin . The amount of binder is between about 0% by weight and about 50% by weight, for example 10-40% by weight, based on the weight of the composition.

Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable lubricants include colloidal silicon dioxide, magnesium trisilicate, starch, talc, tricalcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, cellulose and cellulose-cellulose. The amount of size is between about 0% and about 10% by weight based on the weight of the composition. In one embodiment, the amount of size is from about 0.1% to about 1.5% by weight based on the weight of the composition. The amount of lubricant is from about 0.1% to about 10% by weight.

Examples of pharmaceutically acceptable excipients and pharmaceutically acceptable diluents include powdered sugar, pressed sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. The amount of filler and / or diluent is, for example, from about 15% to about 40% by weight based on the weight of the composition.

In the hot melt extruder, the mixture is heated to temperatures (s) below the melting point of the therapeutic preparation and the melting point of the solubilizer. While heating, the mixture is mixed with the screw (s) of the hot melt extruder. The mixture was held at an elevated temperature and stirred for a time sufficient to form a granular product. After the mixture has passed the entire length of the cylinder, a granular product which is an extrudate is obtained and the granular mixture is cooled.

The term “therapeutic compound” in this context is to be understood as a compound which is suitable as a component of a pharmaceutical composition for administration to humans, for example for the prevention, treatment or reduction of symptoms of a certain disease or a certain circumstance under which the Man suffers.

The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for contact with human tissue according to medical requirements, without undue toxicity, irritation, allergic reaction and other complications with a reasonable benefit / risk -Relationship.

In this context, the term “therapeutic compound” means any compound, substance, medicament, drug, or active ingredient that is therapeutic or pharmacological Has an effect and which is suitable for administration to a human, in the form of a composition which is primarily suitable for oral administration.

The term "sparingly soluble" refers to compounds with low or very low solubility, as defined in the US Pharmacopoeia, e.g. when a part of the compound to be dissolved requires around 100 to 10,000 parts of solvent.

The term “crystalline” or “crystalline form” in this context refers to a physical state that is characterized by an ordered three-dimensional arrangement of atoms, ions, molecules or molecular associations. Crystal forms are characterized by the presence of a crystal lattice made up of asymmetrical units that are in well-defined symmetry in the lattice cells that are repeated in three-dimensional space. In contrast to the specified term, the term “amorphous” or “amorphous form” refers to an unorganized (disordered) structure.

The physical state of the therapeutic compound is determined using standard analytical methods such as X-ray diffraction, polarized light microscopy and / or differential scanning calorimetry.

As used herein, the term “thermally labile therapeutic” agent refers to a therapeutic agent that spontaneously degrades or decomposes when the therapeutic agent is heated above or close to its melting point.

In this context, the term “high melting point” refers to the melting point or the lowest temperature in the range of the melting point, which is greater than or equal to 253 ° C for resveratrol and 183 ° C for curcumin.

Examples of therapeutic classes of therapeutic compounds include antacids, anti-inflammatory drugs, coronary dilators, brain dilators, peripheral vasodilators, anti-infectives, psychotropic drugs, antimanics, stimulants, antihistamines, cancer therapeutics, laxatives, decongestants, therapeutic agents, enteric sedatives, vitamins, enteric sedatives. vasodilator, antiarrhythmic, antihypertensive therapeutic preparations, vasoconstricting agents and agents for the treatment of migraine, anticoagulants and antithrombotic therapeutic preparations, analgesics, antipyretics, hypnotics, sedatives, antiemetics, drugs against nausea, compounds, anticonvulsant and therapeutic agents, hypoglycemic drugs, hypoglycemic drugs, neuromuscular hypoglycemic drugs and antithyroid drugs, diuretics, antispasmodics, uterine relaxants, mineral and food additives, anti-obesity therapeutics, anabolic Therapeutics, erythropoietic therapeutics, antiasthmatic therapeutics, expectorants, antitussives, mucolytics, therapeutics against urinary poisoning as well as oral or local substances, anti-obesity therapeutics, anabolic therapeutics, erythropoietic therapeutics, antiasthmatic therapeutics in therapeutic or topical compounds, expectorants, therapeutics the oral cavity, as well as antitussives, mucolytics.

The therapeutic compounds are included in the pharmaceutical compositions of the present invention in a therapeutically effective amount or concentration. The indicated therapeutically effective amount or concentration is known to a person skilled in the art and varies depending on the therapeutic agent used and the indicated indication. For example, the amount of the therapeutic compounds according to the present invention is between about 0.05% by weight and about 99% by weight, based on the weight of the pharmaceutical composition. In one embodiment, the amount of the therapeutic compound is between about 10% by weight to about 95% by weight based on the weight of the pharmaceutical composition.

As used herein, the term "carrier" refers to a pharmaceutically acceptable matrix suitable for making a solid or molecular dispersion of a therapeutic compound. Suitable carriers are primarily polymers or copolymers or mixtures thereof. The types of polymers include, but are not limited to, water-soluble, water-swellable, and water-insoluble polymers and combinations thereof.

An example of a suitable block copolymer is Poloxamer 188 sold under the tradename Pluronic F68.

• Homopolymere und Copolymere von N-Vinyllactamen, Homopolymere und Copolymere von N-Vinylpyrrolidon (z.B. Polyvinylpyrrolidon), Copolymere aus N-Vinylpyrrolidon und Vinylacetat oder Vinylpropionat, hochmolekulare Polyalkylenoxide wie Polyethylenoxid und Polypropylenoxid sowie Copolymere aus Ethylenoxid und Propylenoxid, Vinylacetat-Polymere, wie z.B. Copolymere aus Vinylacetat und Crotonsäure, insbesondere hydrolysiertes Polyvinylacetat, Polyvinylalkohol und Oligo- und Polysaccharide, wie Carrageenane, Galaktomannane und Xanthan oder Mischungen aus einer oder mehreren dieser Verbindungen.

Other examples of polymers include, but are not limited to:

• Homopolymers and copolymers of N-vinyllactams, homopolymers and copolymers of N-vinylpyrrolidone (e.g. polyvinylpyrrolidone), copolymers of N-vinylpyrrolidone and vinyl acetate or vinyl propionate, high molecular weight polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, for example copolymers of vinyl acetate and crotonic acid, in particular hydrolyzed polyvinyl acetate, polyvinyl alcohol and oligo- and polysaccharides, such as carrageenans, galactomannans and xanthan, or mixtures of one or more of these compounds.

Suitable carriers are above all compounds which are characterized by low glass transition temperatures (Tg). Examples of low Tg carriers include PVP K30, PVP K17, and PVP / VA.

In addition to the polymer, the carrier can contain other pharmaceutically acceptable ingredients such as plasticizers.

In this context, the term “plasticizer” refers to a material that is included in the pharmaceutical composition to reduce the Tg and viscosity of the polymer melt by increasing the free volume between the polymer chains.

• Wasser, Zitronensäureester (z.B. Triethylcitrat, Triacetin), niedermolekulare Polyalkylenoxide (z.B. Polyethylenglykole, Polypropylenglykole, Polyethylen-/Propylenglykole), Glycerin, Pentaerythrit, Monoacetat, Diacetat, Triacetat oder Natriumdiethylsulfosuccinat und therapeutische Verbindungen in freier Form.

The plasticizers include, but are not limited to:

• Water, citric acid esters (e.g. triethyl citrate, triacetin), low molecular weight polyalkylene oxides (e.g. polyethylene glycols, polypropylene glycols, polyethylene / propylene glycols), glycerol, pentaerythritol, monoacetate, diacetate, triacetate or sodium diethyl sulfosuccinate in free form and therapeutic compounds.

The concentration of the plasticizer is between about 0% by weight and 15% by weight, for example between 0.5% by weight to 5% by weight, based on the weight of the pharmaceutical composition. Examples of plasticizers are also im Handbook of Pharmaceutical Additives, Ash et al., Gower Publishing (2000) , contain.

As used herein, the term “solubilizer” refers to a material that is capable of dissolving or partially dissolving a therapeutic compound and / or polymer. Surfactants are particularly suitable as solubilizers.

The term “surfactant” used in this context includes nonionic surfactants, anionic surfactants, etc., as well as suitable combinations of two or more of these surfactants of a known type.

An example of a suitable surfactant is first of all the Poloxamer 407 (e.g. Pluronic F127 from BASF or Synperonic PE / F 127 from Croda). A solubilizer is used, if appropriate, together with a plasticizer and a carrier.

The amount of the solubilizer is about 5% by weight to about 40% by weight based on the total weight of the extrudate composition.

Similarly, the amount of therapeutic preparation is from about 0.01% to about 50% by weight based on the weight of the extrudate composition and the amount of carrier is from about 1% to about 99% by weight the weight of the composition.

In this context, the term “granulation from the melt” refers to a typical method for obtaining a molecular dispersion of the original highly crystalline and / or thermally unstable therapeutic agent using a hot melt extruder.
The hot melt extruder typically consists of one or more rotating screw (s) in a stationary cylinder with a nozzle and an optional forming head located at one end of the cylinder. As a result of the rotation of the screw (s) in the cylinder, a uniformly distributed mixture of the materials (eg therapeutic agent, release agent and other necessary auxiliary substances) is achieved over the entire length of the screw (s).
Conventionally, a hot melt extruder comprises three zones: a feed zone, a heating zone and a metering zone. In the loading zone, the raw materials are fed into the extruder, for example by means of a funnel. The raw materials are filled directly into the funnel without solvents. The untreated components are heated to the desired processing temperature in the heating zone. The processing temperature does not exceed the decomposition temperature of the materials. For example, the degradation temperature of Poloxamer 407 is 175 ° C. The processing temperature is therefore varied in the range from about 50.degree. C. to below 175.degree. C., for example from 150.degree. C. to about 170.degree. The heating zone is followed by a dosing zone in which the mixing materials can optionally be passed through an extruder forming head in order to obtain a specific material shape. The types of hot melt extruders used in the process of the invention include single and twin screw extruders.

In a further example, the formulation was initially mixed with the substances according to the exemplary embodiment for 1 minute and the resulting mixture was then transferred to the feed zone or the funnel of a twin-screw extruder. A twin screw extruder suitable for this is the Thermo Haake PolyLab extruder No. 567-2020 from Thermo Fisher Scientific GmbH, Karlsruhe, Germany.) The specified hot melt extruder has a mixing zone. The hot melt extruder was heated to a temperature of 150 ° C. The material runs through the hot melt extruder for approx. 2 minutes.
A semi-solid extrudate was obtained at a temperature of approx. 100 ° C. In order to cure the extrudate quickly, it was placed in a refrigerator. However, the extrudate can also be hardened by air cooling. The extrudate was then comminuted.

The finished, dry, granular composition obtained by the process according to the invention has one, two or more lipophilic active ingredients which contain a polymer with the properties of a hydrophilic-hydrophobic matrix. This matrix is obtained in such a way that the lipophilic active ingredient has a reduced melting enthalpy or at least a reduction in both the melting enthalpy and the melting point of the lipophilic active ingredient compared to the lipophilic main active ingredient used as starting material for the preparation of the composition.

The high solubility achieved with the composition according to the invention through hot melt extrusion in terms of the release of resveratrol and curcumin was investigated and demonstrated in a study in a standardized microemulsion system, here SMEDDS (self-microemulsifying drug delivery system) in vitro using high-performance liquid chromatography (HPLC). For this purpose, the intestinal conditions of a hungry and a saturated person were simulated. An extruded pharmaceutical composition, produced from the substances according to the exemplary embodiment, was used.

The release (solubility) of the extrudate with resveratrol and curcumin was compared with different dispersions containing raw resveratrol and raw curcumin. For this purpose, raw resveratrol (obtained from Japan, Lot # 093016TR) with a purity of 99% and raw curcumin-Ionga powder with a purity of 95% (obtained from India LOT # AB88703) were used. The raw resveratrol and raw curcumin were added to HPLC grade acetonitrile, glacial acetic acid and water (obtained from J.T. Baker, Germany).

A standard stock solution was prepared by dissolving 20 mg of crude resveratrol and 20 mg of crude curcumin in 20 ml of acetonitrile (the concentration was thus about 1.0 mg / ml).

For the sample to be tested, 25 mg of the composition extruded according to the invention were placed in a 25 ml volumetric flask and then diluted to a volume of 25 ml with a diluent and mixed in the process.

The HPLC analysis was carried out on HPLC systems from Summit Dionex (Germany) with photodiode array (PDA) and UV-VIS detectors and Chromeleon version 6.80 software packages.
A column from Dr. Maisch GmbH, Reprosil-Pur, C-18-AQ, 5μ, 250x4.6 mm with Phenomenex Security Guard C18 4 × 3.0 mm was used.

• Temperatur der Säule: 35°C;
• Flussrate: 1,0 ml/min;
• Detektionswellenlänge: 306 nm für Resveratrol; 425 nm für Curcumin;
• Injektionsvolumen: 5 µl.
• Laufzeit: 15 min;
• Verdünnungsmittel: 50% Acetonitril und 50% Wasser;
• RT von Resveratrol: etwa 3,5 min;
• RT von Curcumin: etwa 9 min.

Composition of the mobile phase: 500ml water, 500ml acetonitrile and 20ml acetic acid ice water;

• Column temperature: 35 ° C;
• Flow rate: 1.0 ml / min;
• Detection wavelength: 306 nm for resveratrol; 425 nm for curcumin;
• Injection volume: 5 µl.
• Duration: 15 min;
• Diluent: 50% acetonitrile and 50% water;
• RT of resveratrol: about 3.5 min;
• RT of curcumin: about 9 min.

For the in vitro release of resveratrol and curcumin according to SMEDDS, a 1,000 ml solution with FaSSIF, FeSSIF and 0.0175 molar sodium lauryl sulfate solution was used as the solution medium with stirring at 100 rpm and 37 ° C.

According to the specifications of the standardized test procedure SMEDDS, the intestinal conditions of a hungry person are simulated using a digestive fluid "FaSSIF" and the intestinal conditions of a saturated person using a digestive fluid "FeSSIF", both fluids being made from FaSSIF / FeSSIF powder from Biorelevant.com Ltd ., London.

In addition, in accordance with SMEDDS specifications, 1,000 ml of 0.0175 molar anionic sodium lauryl sulfate solution (SLS) was used as a surfactant for the medium for comparison.

Samples of 5 ml each were taken after 0, 15, 30, 45 and 120 minutes. At the same time, an equivalent volume of 5 ml each of fresh solution medium was added to compensate for the volume removed. The sample was filtered through a 0.45 µm filter and the concentration of resveratrol and curcumin was determined by means of HPLC analysis. The investigation was carried out in accordance with internationally recognized USP standards. These allow a maximum of 5% deviation in both directions.

The results are in Tables 1 to 4 and the 1 to 8th shown.

Tables 1 to 4 and the 1 to 8th show that the solubility of resveratrol and curcumin essentially depends on the conditions in the human body under which the dissolution is to take place.
It is particularly evident that the degree of solubility of resveratrol and curcumin from the inventive composition extruded by means of HME is in each case significantly higher in the intestinal area than that of raw resveratrol and raw curcumin in their dispersions. The significantly higher solubility in the intestinal area, which is proven in this way, is a prerequisite for the significantly higher bioavailability of the two active ingredients in the human organism and convincingly demonstrates the particular advantage of the invention.

So far, the rapid metabolism of the active ingredients when unextruded solid dispersions or other unextruded dosage forms are taken orally has prevented resveratrol and curcumin from reaching the intestine in a therapeutically effective amount. The extrudate according to the invention also solves the problem of metabolism and convincingly demonstrates another particular advantage of the invention.

The prevented metabolism, the high solubility achieved and the resulting significantly higher bioavailability in the human intestinal area are of far-reaching importance, especially since they are age-independent. The therapeutic effects of resveratrol and curcumin known from science are also substantially supported in an economically advantageous manner by their synergistic action according to the invention.

The following is intended to illustrate the potential of the composition according to the invention for the formation of pharmaceutically effective formulations and in particular for their oral administration. The following statements are presented in such a way that they familiarize those who have ordinary skills in the relevant field with the potential inherent in the invention, in particular its scope, without restricting the invention and its scope.
The introduction of novel polymers for HME will help overcome the current limitations of drug-polymer matrix incompatibilities.

The suitability and effectiveness of pharmaceutical formulations which were produced using the composition according to the invention were investigated in standard clinical trials. Administration in the form of tablets, capsules, liquids, syrups or powders (in bags) or dispersible tablets for suspension, which were added to the water, which have therapeutically effective amounts of the invention and release them into the blood, were used. The doses were in the range of 2.5 mg to 250 mg of the therapeutically active compound per day for people with a body weight of 75 kg, for example in an adult, and with the aid of standard animal models.
In individual cases, the pharmaceutically effective formulation contains doses with particles that are not pH-resistant or with particles that are pH-resistant and / or have a delayed time and enzyme release profile.

Resveratrol possesses a wide range of biological properties, including antioxidant, cardioprotective, neuroprotective, anti-inflammatory, anti-cancer and blood sugar-lowering properties, and life-prolonging effects. Resveratrol has traditionally been offered and used on the market for stomach pain, hepatitis, arthritis, urinary tract infections, fungal diseases or for the treatment of skin inflammations.
However, the biological potential of resveratrol lies mainly in the area of cardioprotective systems, in the treatment of arteriosclerotic cardiovascular diseases, as well as inflammatory nervous and oncological diseases, and also in the area of epigenetic modifications.
Resveratrol is able to inhibit all stages of carcinogenesis (e.g. onset, promotion and progression of cancer) and, moreover, not only acts as a chemopreventive agent, but also has chemotherapeutic properties, with its anti-inflammatory, antioxidant, pro-apoptotic and antiproliferative effects are linked.

In particular, the present invention is directed to the use of pharmaceutically effective formulations for the therapeutic treatment of arteriosclerotic cardiovascular diseases and of inflammatory nervous and oncological diseases.
Aside from these uses, resveratrol, like its derivatives, is one of the most promising compounds in the field of anti-inflammatory drug discovery. It has also been shown to be able to initiate caloric restriction effects and to have various mechanisms in place to influence the onset and progression of many diseases. Although there is an abundance of in vitro and vivo evidence that resveratrol could be a promising therapeutic agent, further clinical studies must confirm the potential of resveratrol given by the higher solubility and bioavailability found even more comprehensively and precisely, especially in the synergistic effect of Resveratrol along with curcumin.

Curcumin has received worldwide attention for its multiple health benefits, which appear to work primarily through its antioxidant and anti-inflammatory mechanisms. These benefits are best achieved when curcumin is combined with active ingredients like piperine, which further increase its bioavailability. Research suggests that curcumin may help treat oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, and hyperlipidemia. It can also help treat inflammation and muscle soreness from exercise, thereby improving recovery and subsequent performance in active people. In addition, a relatively low dose can provide health benefits for people who have not been diagnosed with health problems.

Compositions according to the invention of resveratrol and curcumin as an essential component of pharmaceutical formulations and in corresponding dosage forms are highly effective in the prevention and treatment of various types of cancer, namely under anti-inflammatory, anti-carcinogenic, cardioprotective, vasoprotective, vasodilating, phytoestrogenic, neuroprotective and inflammatory aspects.

In addition to their high effectiveness, which is achieved through the improved solubility in aqueous media and the resulting significantly increased bioavailability, the compositions according to the invention also cause significantly fewer side effects than the currently available pharmaceutical and herbal active ingredients and active ingredient combinations. They can therefore be used as a replacement for these existing synthetic and herbal active ingredients and combinations of active ingredients.
They help treat oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, and hyperlipidemia.
Tables 1 to 4 Table 1 Overview of the degree of release (in%) of HME resveratrol in FeSSIF, FaSSIF and in 0.0175 M SLS at the respective times Time (min) HME resveratrol in FeSSIF -% HME-Resveratrol in FaSSIF -% HME resveratrol in 0.0175 M SLS -% 0 0.0 0.0 0.0 15th 1.9 0.5 1.3 30th 18.0 2.4 8.5 45 42.0 10.8 36.5 60 60.0 29.9 65.8 90 68.3 60.0 93.6 120 71.9 85.4 103.8 Table 2: Overview of the degree of release (in%) of the HME curcumin in FeSSIF, FaSSIF and in 0.0175 M SLS at the respective times Time (min) HME curcumin in FeSSIF -% HME curcumin in FaSSIF -% HME curcumin in 0.0175 M SLS -% 0 0.0 0.0 0.0 15th 16.0 18.8 28.7 30th 35.4 16.9 41.3 45 46.1 15.3 58.0 60 51.3 14.0 69.7 90 53.9 14.5 78.1 120 56.1 13.5 81.2 Table 3: Overview of the degree of release (in%) of HME resveratrol compared to raw resveratrol in FeSSIF at the respective times Time (min) raw resveratrol in FeSSIF -% raw resveratrol in FaSSIF -% raw resveratrol in 0.0175 M SLS -% 0 0.0 0.0 0.0 15th 3.1 0.1 6.3 30th 6.2 3.8 17.5 45 29.1 10.0 35.4 60 34.5 15.0 55.9 90 36.3 24.6 73.8 120 37.4 31.0 79.9 Table 4: Overview of the degree of release (in%) of crude curcumin in FeSSIF, FaSSIF and in 0.0175 M SLS at the respective times Time (min) raw curcumin in FeSSIF -% raw curcumin in FaSSIF -% raw curcumin in 0.0175 M SLS -% 0 0.0 0.0 0.0 15th 0.1 0.6 9.8 30th 0.5 1.3 18.4 45 1.7 2.6 24.4 60 1.8 4.1 40.3 90 2.5 5.7 42.6 120 3.2 6.9 47.4

QUOTES INCLUDED IN THE DESCRIPTION

This list of the documents listed by the applicant was generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Patent literature cited

• FR 2758459 [0007]
• WO 2018/203294 [0008]
• US 6221399 B1 [0009]
• EP 2581089 B1 [0010]
• WO 2009/040818 A1 [0011]
• WO 2019/159174 [0014]

Non-patent literature cited

• Handbook of Pharmaceutical Additives, Ash et al., Gower Publishing (2000) [0070]

Claims (11)

Composition containing natural lipophilic compounds, characterized in that - the composition contains resveratrol together with curcumin as lipophilic compounds and - one or more nonionic or anionic emulsifiers and - one or more solid matrix-forming agents, wherein resveratrol and curcumin together with an emulsifier or a plurality of emulsifiers and a matrix-forming agent or a plurality of matrix-forming agents are formed soluble in a solid solvent system and the composition is produced by means of hot melt extraction. Composition according to Claim 1 , characterized in that it releases a plurality of particles upon contact with a liquid, the particles having an average particle size of about 150 nm and resveratrol and curcumin being substantially dissolved in the released particles. Composition according to Claim 1 , characterized in that the resveratrol of the formula 3,5,4'-trihydroxy-trans-stilbene is selected from the group of the families Dipterocarpaceae, Paeoniaceae, Vitaceae, Leguminosae, Gnetaceae, Cyperaceae, Polygonaceae Gramineae and Poaceae and the curcumin has the formula ( 1E, 6E) -1,7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-diones. Composition according to Claim 1 , characterized in that at least one nonionic emulsifier is selected from the group consisting of polysorbates, polysorbate 80, polyoxylhydrogenated castor oil, sucrose ester, sucrose distearate, tocopheryl polyethylene glycol 1000 succinate, sorbitan fatty acid ester, sorbitan monooleate, derivative glyceride or saline oxyzenic acid ester, polyglyceryl fatty acid ester or combinations thereof. Composition according to Claim 4 , characterized in that at least one emulsifier is selected from nonionic or anionic surfactants with an HLB value of about 10 to about 16 and a second emulsifier is selected from nonionic or anionic hydrophilic or hydrophobic surfactants with an HLB value of about 4 to about 12 or from anionic surfactants. Composition according to Claim 1 , characterized in that at least one solid matrix-forming agent is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), polyvinyl alcohol (PVA), cross-linked copolymer of acrylic acid and a hydrophobic C10-30 alkyl acrylate comonomer, gelatin , Hydroxypropylmethyl cellulose (Methocel), methyl cellulose, hydroxypropyl cellulose (Klucel), hydroxyethyl cellulose (Natrosol), sodium carboxymethyl cellulose, acrylate copolymers, ammonio methacrylate copolymer type A or B, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, polyvinyl alcoholic acid copolymer, methacrylic acid copolymer, methacrylic acid copolymer Graft copolymer, polyvinyl acetate-co-crotonic acid, polymethyl methacrylate and grafted polyethylene oxide, lignins, polyvinylpyrrolidone-co-vinyl acetate, polyvinylpyrrolidone, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, carboxymethylethyl cellulose, hydroxetaine propylmethyl cellulose t-phthalate, maltodextrin, dextran, polymethacrylic acid-co-ethyl acrylate, polymethacrylic acid-co-methyl methacrylate, polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PDLA), polylactide-co-glycolic acid (PLGA ), Polyethylene oxide-polypropylene oxide block copolymer (poloxamer), polyethylene glycol (PEG1000, PEG1500, PEG 2000, PEG4000, PEG6000, PEG8000) and mixtures thereof. Composition according to Claim 1 , characterized in that a second solid matrix-forming agent is selected from the group consisting of beeswax, carnauba wax, cetyl palmitate, glyceryl behenate, behenic acid, behenyl alcohol, glyceryl monostearate, glyceryl palmitostearate, glyceryl stearate, hydrogenated castor oil, microcrystalline wax, silicone alcohol, stearic acid alcohol, silicone , waxy polymethylsiloxane, PEG wax and Carbowax. Composition according to at least one of the Claims 1 to 7th , characterized in that at least 80% of the resveratrol and the curcumin, measured by differential scanning calorimetry, are completely dissolved in the solid composition. Composition according to Claim 1 and 3 to 5 , characterized in that the ratio of resveratrol and curcumin to at least one emulsifier is from about 5: 1 to about 1:20. Composition according to Claim 1 and 3 to 7th , characterized in that the ratio of a) the resveratrol and the curcumin to b) the mixture of the at least one emulsifier and the at least one solid matrix-forming agent is about 2: 1 to about 1:20. Pharmaceutically effective formulation containing a composition according to Claims 1 to 10 , a) in a dosage form suitable for oral administration selected from the group consisting of tablets, capsules, particles, granules, lozenges, sweets, toffees, chocolates and biscuits or consists of a bag, a unit dose pack or is suspended in a liquid or a gel , whereby - the dosage form disintegrates after contact with the body fluid of a person in the lower intestine and in the large intestine and as a result at least about 20% (w / w) of the resveratrol and curcumin are released on the distal jejunum and the large intestine or - the dosage form is acid-resistant or enzymes releases and is able to decompose or swell in the lower or distal intestine and large intestine, whereby at least about 50% (w / w) of the resveratrol and curcumin are released in the distal jejunum and / or in the large intestine or - the dosage form consists of a capsule, tablet or sachet filled with granules and the dosage form at least 50 mg resveratrol and at least 100 mg curcumin, at least 1-50 mg D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS or TPGS), at least 1-50 mg sucrose distearate or polyglyceryl ester and at least 1-100 mg polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol Comprises graft copolymer or polymethacrylic acid, polymethyl methacrylate or polyacrylate polymer or copolymer or poloxamer 407; or b) which is provided as a kit for the therapeutic treatment of inflammatory bowel diseases and other intestinal diseases, which improves the general well-being and alertness of the patient, in dosage forms with different doses for a total daily dose of up to 2,000 mg of an anti-inflammatory resveratrol and curcumin or Derivatives thereof; or c) which is provided for the treatment of a gastrointestinal disease in a therapeutically effective dose which - through systematic absorption leads to a measurable resveratrol and curcumin blood level and - a local delivery of resveratrol and curcumin to one or more regions of the gastrointestinal tract, selected from the ilium, jejunum, distal jenunum and the colon, the composition containing particles, - which are not pH-resistant and - those particles which are pH-resistant and have a delayed time or enzyme release profile or which only have one have a delayed time or enzyme release profile; or d) which is suitable for the therapeutic treatment of arteriosclerotic cardiovascular diseases; or e) which is suitable for the therapeutic treatment of inflammatory nervous diseases; or f) which is suitable for the therapeutic treatment or accompanying treatment of oncological diseases.

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