SK962012A3 - -Glucan complexes, process for preparing and use thereof - Google Patents

Abstract

The present invention relates to β-glucan complexes with at least one complexing agent selected from: quercetin, taxifoline, naringin, silibine, silibinin, gallic acid, chlorogenic acid, salicylic acid, acetylsalicylic acid, taurine, nicotinamide, isonicotinic acid, pyridoxine, diosmin, hesperidinic acid , escin, troxuretine, ascorbic acid, isoascorbic acid, citric acid, hydroxycitric acid, tartaric acid, boswellic acids, rosmaric acid, glycolic acid, eicosapentaenoic acid, docosahexaenoic acid, aspartic acid, tannic acid, quinic acid, L-lysine, p acid -aminobenzoic, folic acid, pantothenic acid, choline chloride, glutaric acid, caffeine, L-glutamic acid, N-acetyl-L-glutamic acid, L-carnitine, lactic acid, caffeic acid, ferulic acid, 3,3'- thiodipropionic, coenzyme Q10, alginic acid, arginine, asparagine, cy stein, methionine, thiamine, L-carnitine, scopoletin, curcumin, polycosanol, theaine, theobromine, leucine, lycopene, resveratrol, pterostilbene, glutathione, melatonin, chondroitin, glucosamine, donepezil, hydroxyurea, 4-acetamidophenol, 4-aminosalicylic acid, hydrochlorothiazide , telmisartan, agomelatine, tenofovir, emtricitabine, tamsolusin, desloratadine, metoprolol, carbamazepine, giclazide, amiloride, quinacrine, karsalam, duloxetine, ibuprofen, naproxen, diclofenac, piroxicam, furosemide, allopurinol, silodosin, rivoroxaban, acetazolamide, diltiazem, prasgrel, cloroxin, cloroxin , prednisone, methotrexate, mercaptopurine, almorexant, laropiprant, sitagliptin, rivaroxaban, vildagliptin, solifenacin, silodosin, galantamine, trimethazine, amlopidine,

Description

Technical field

The present invention relates to complexes of β-glucan with complex-forming agents and to a process for their preparation and use. The complexes are suitable for pharmaceutical use or as nutritional supplements in the compositions.

Field of the invention

Glucans are long-chain polysaccharides, the only component of which is glucose, in the chain bound by the bonds at positions 1 and 3. Smaller side chains branch from the polysaccharide backbone at positions 1 and 6. For this reason, β-1 is reported in some literature sources 3-glucan as well as B-1,3 / 1,6 glucan. In 2011, Saccharomyces cerevisiae glucans were authorized in the European Union as a novel food ingredient. A description of β-glucans, their biological activities, and the differences between cereal afungal β-glucans are given by Novák M. in: Chemické listy 101, 872-880, 2007; Šturdík E. in: Nová Biotechnologica V-I (2005), 105-121 and Vetvička V. in: Chemické listy, 2004, vol. 98, no. 11, p. 963. The term 'nutraceutical' was first used in 1989 and refers to products that are used to prevent or stabilize degenerative diseases of a building or function of an organism. The group includes trace elements, phenolic acids, vitamins, various alkaloids, oligo and polysaccharides including fiber, amino acids and protein substances, bioflavonoids, anthocyanins, fatty acids or structured fats (fats with different fatty acids on individual glycerol chains) and the like. to live bacteria. A number of glucan-containing nutraceutical preparations have been described, and there are several dozens of β-glucan dietary and nutritional supplements on the market. Dietary supplements are produced in various forms such as capsules, capsules, tablets, syrup, elixir, drops. For the purposes of the present invention, the compounds known as pharmaceutical active ingredients are selected as the complexing agent (complexing partner). The list of such substances includes e.g. EAFUS / FDA and GRAS / FDA database. In general, nutraceuticals and pharmaceutically active substances (APIs) can be administered in various forms e.g. as salts, derivatives (prodrugs) or in various physical forms as amorphous, crystalline polymorphs or as co-crystals (molecular complexes or adducts in the case of high molecular weight substances). However, the nomenclature is inconsistent and the term co-crystal replaces, in particular in the patents, the broader term (molecular) complex. Organic substance crystals organized by non-covalent non-bonding interactions are considered supramolecular formations. In the formation of the molecular complex, mutual recognition and subsequent arrangement of the super structure based on intermolecular interactions occur. The conformational flexibility of the glucan spiral with the revelation of complementary functional groups plays a crucial possibility in the subsequent intermolecular interaction. In the re-denaturation step, the native architecture of the molecule is at least partially restored.

The process for the preparation of the molecular complexes of β-glucan and pharmaceutical active substances (nutraceuticals and APIs) according to the invention represents a contribution to the simple and designed preparation of combination drugs and controlled release drugs. Modification of β-glucan with nutraceutical and / or API yields substances with more favorable properties, especially in terms of formulation for oral administration, reduction of toxicity at the site of drug accumulation, transport of the active substance to the target site, stability, solubility and also technological operations (grinding, drying) .

BACKGROUND OF THE INVENTION

Molecular drug complexes are described in a number of articles such as:

Crystal Engineering Approach to Forming Cocrystals of Amine Hydrochlorides with Organic Acids. Molecular Complexes of Fluoxetine Hydrochloride with Benzoic, Succinic, and Fumaric Acids. JACS, 2004, 126: 13335-13342 and US Patents 2008/45481, 2008/51453, WO 2010/17343.

The pH-temperature complexation of β-glucan and congo red was studied by Ogawa in: Biosci Biotechnol Biochem. 1994 Oct; 58 (10): 1870-2.

The preparation of soluble oligonucleotide-β-glucan conjugates is described in JP 2003/127783, 2004/331758. DMSO and water are used as solvents.

U.S. Pat. No. 5,741,495 protects beta glucan microparticles incorporated by diffusion of cytochrome C and cow serum albumin.

The water-soluble β-glucan complexes of pharmaceutical active ingredients such as doxorubicin, paclitaxel, valsartan, thioguanine, sunitinib, olanzapine are protected by WO 2011/063776. The preparation consists of adding an API solution in water to a 2% glucan solution in water followed by 0.1-5% addition of an organic solvent.

JP 2011/132223 discloses a process for the preparation of more soluble forms of paclitaxel, Q10, cinnamic acids than β-glucan complexes.

Co-crystals, in particular imatinib mesylate with functionalized polysaccharides, are disclosed in WO 2010/081443. Crystalline or amorphous complexes are prepared from water-soluble tyrosine kinase inhibitors and polymorphic tectons. Examples 15-17 show the crystallization of the complex from water after mixing about 1% solutions of glucan and imatinib mesylate.

A method for preparing a water-soluble or dispersible hydrophobic complex of carborane and glucan is disclosed in WO2011 / 065481, JP 2008/222585.

The preparation and characterization of a oat β-glucan-tea polyphenol complex is described by Wu (J. Agric. Food Chem. 2011, 59, 10737-10746). The preparation of the complex consists in dissolving β-glucan and polyphenols in phosphate buffer, followed by purification from phosphate ions by dialysis and lyophilization.

The complexation of β-D-glucan with zearalenone is studied in Biomacromolecules. 2004 Nov-Dec; 5 (6): 2176-85, and Biomacromolecules. 2006 Apr; 7 (4): 1147-55.

The inclusion complexes of β-glucan and paclitaxel, naproxen, and luteolin are disclosed in Cyclic β-Glucans from Microorganisms, Production, Properties and Applications, Geetha, 2013, XI, ed. Venkatachalam, Gummadi, Sathyanarayana, Doble, Mukesh.

Low solubility and unsatisfactory physicochemical properties e.g. stability may be improved in some nutraceuticals and drugs o.i. using an alternative complex form. Quantified differences of some physicochemical parameters (solubility, dissolution rate, hydroscopicity ...) to the original forms allow to estimate their efficiency, availability and stability. The aim is therefore to obtain forms having low hygroscopicity, high stability and good processability for pharmaceutical operations and stabilization of the drug formulation.

The prior art used water-soluble glucan at a concentration of about 1-2% aqueous or aqueous-organic solution. In this embodiment, a low volumetric yield is employed and the diluted solutions have to be concentrated. The known processes have been limited to water-soluble active substances. We have found that by using a specific pH value in the preparation of complexes in solutions and even in suspension, these disadvantages can be overcome and the complexes prepared by the process of the invention in high purity and yield. The advantage is that the complexing agents themselves are specifically used for pH adjustment. It has further been found that the grinding or mixing of the components in suspension can also be advantageously used for the preparation of the complexes according to the process of the invention. The present invention solves the problems of preparing more technologically easier to handle and more stable forms of β-glucan molecular complexes and complexing agents. The process for the preparation of β-glucan molecular complexes and complexing agents selected from the group of nutraceuticals and / or APIs of the invention is a simple and designed process for the preparation of controlled release drugs. By modifying β-glucan with a nutraceutical and / or API in this way, substances with more favorable properties are obtained, in particular with respect to the formulation of formulations for oral and rectal administration, transport of the active substance to the target site, stability of the dosage form and technological operations (grinding, drying).

SUMMARY OF THE INVENTION

The invention solves the above problems by preparing complexes of β-glucan with complex-forming agents.

A first object of the invention are complexes of β-glucan and at least one complex-forming agent, the complexes being formed by the supramolecular bonds of glucan and complementary groups of complex-forming agents.

A further object of the invention are complexes wherein nutraceuticals and / or pharmaceutically active substances are selected as complex-forming substances: quercetin, taxifoline, naringin, silibine, silibinin, gallic acid, chlorogenic acid, salicylic acid, acetylsalicylic acid, taurine, nicotinamide, pyridoxine, pyridoxine, pyridoxine, pyridoxine diosmin, hesperidin, escin, troxuretin, ascorbic acid, isoascorbic acid, citric acid, hydroxycitric acid, tartaric acid, boswellic acid, rosemic acid, glycolic acid, eicosapentaenoic acid, docosahexaenoic acid, aspartic acid, lysic acid, tannic acid, , p-aminobenzoic acid, folic acid, pantothenic acid, choline chloride, glutaric acid, caffeine, L-glutamic acid, N-acetyl-L-glutamic acid, Lkamitin, lactic acid, coffee acid, ferulic acid, 3,3 ' thiodipropionic, coenzyme Q10, ky alginic, arginine, asparagine, cysteine, methionine, thiamine, L-carnitine, scopoletin, curcumin, polycosanol, theanine, theobromine, leucine, lycopene, resveratrol, pterostilbene, glutathione, melatonin, chondroitin, glucosiline, glucosiline, glucosiline, glucosiline, , 4-aminosalicylic acid, hydrochlorothiazide, telmisartan, agomelatine, tenofovir, emtricitabine, tamsolusin, desloratadine, metoprolol, carbamazepine, giclazide, amiloride, quinacrine, carsalam, duloxetine, ibuprofen, siloxosin, naproxen, siloxin, naproxen, siloxin, naproxen, naproxen, acetazolamide, diltiazem, prasugrel, cloroxin, prednisone, methotrexate, mercaptopurine, almorexant, laropiprant, sitagliptin, rivaroxaban, vildagliptin, solifenacin, silodosin, galantamine, trimethazine, amlopidin, rorperipine, nisedilacon, nifediplamin, nifediplamin, nifedillamin oxaliplatin, paclitaxel, docetaxel, imatinib, sunitinib, ibandronate, zolendronate, glipizide, metformin, acid to valproic acid and salts thereof, if possible.

A further object of the invention is a process for the preparation of complexes, characterized in that at least one complex-forming substance from the group of nutraceuticals or pharmaceutical active substances is reacted in a water or water-miscible organic solvent with β-glucan in water or a water-miscible solvent at a defined pH .

in

Another object of the invention is to provide β-glucan complexes and complexing agents for compositions suitable for pharmaceutical use or as nutritional supplements.

It is another object of the invention to provide β-glucan complexes and complexing agents suitable for stabilizing complexing agents.

Due to the structure of β-glucan, it is obvious that in addition to the complexation of the active substances, these can also be co-precipitated. The proportion of the individual interactions is controlled by the chemical structure and molecular weight of the active substance and by the method of preparation of the complex such as concentration, pH, temperature, solvent. The discovery of novel molecular complexes of β-glucan complex forming substances from the group of nutraceuticals and pharmaceutically active substances as pharmaceutically usable forms provides opportunities to improve the properties and effects of pharmaceutical products. This expands the range of forms whose formulations are available for formulation design. The invention also relates to solvates of the complexes and their polymorphic modifications.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to complexes of β-glucan with complex-forming agents and to a process for their preparation and use. The complexes are suitable for pharmaceutical use or as nutritional supplements in the compositions. It is known that individual β-glucans differ in configuration, branching, molecular weight, solubility and three-dimensional structure, and these differences are also reflected in possible modifications of the preparation of the compounds of the invention. The β-glucan complexes with the at least one complex-forming agent consist of glucan and substances selected from the group of nutraceuticals and / or pharmaceutically active agents. The complexes may also include one or more solvent or water molecules per complex unit. It has been found that when β-glucan and the selected nutraceutical and / or API as a partner form complexes, this has new unexpected properties. It is known that the effect of nutraceuticals increases when used together. Selected nutraceuticals are implicated in the prevention and treatment of diabetic cataract, improvement of brain metabolism, neuropathy and retinopathy. A combination of nutraceuticals, e.g. With vitamin C, a synergistic complex is formed, whereby vitamin C regenerates vitamin E. It affects the formation of red blood cells, the renewal and growth of muscle mass and other tissues, and often have diuretic effects, thereby lowering blood pressure. Since β-glucan itself has favorable properties, it is advantageous to prepare a common form of glucan and nutraceuticals and drugs. Controlled release of the complexed drug is particularly preferred for some combinations. These new forms have altered solubility and increased stability compared to the original form of the API or nutraceutical, regardless of whether this was in the form of a salt, hydrate or solvate. The changes are further reflected in new morphology and viscosity, which allows for better processability than e.g. grinding or filling. Particularly preferred is the stabilizing effect of the partner for the preparation of the dosage form, as it is also associated with setting the appropriate pH of the formulation and stabilizing the active ingredient. The prepared complexes thus enable targeted transport of the active substance and its protection by the biodegradable carrier from hydrolytic reactions. They exhibit high stability, low hygroscopicity of solid forms, good processability in technological operations and stability of liquid formulations such as syrups, creams, injections.

The present invention provides polysaccharide complexes of pharmaceutically active substances selected from the group of nutraceuticals and / or active pharmaceutical substances. Quercetin, taxifoline, naringin, silibine, silibinin, gallic acid, chlorogenic acid, salicylic acid, acetylsalicylic acid, taurine, nicotinamide, isonicotinic acid, pyridoxine, diosmine, hesperidin, escin, ascorbic acid, troxuretic are used as complexing agents , isoascorbic acid, citric acid, hydroxycitric acid, tartaric acid, boswellic acid, rosemic acid, glycolic acid, eicosapentaenoic acid, docosahexaenoic acid, aspartic acid, tannic acid, quinic acid, L-lysine, p-aminobenzoic acid, folic acid, pantothenic acid, choline chloride, glutaric acid, caffeine, L-glutamic acid, N-acetyl-L-glutamic acid, Lkamitin, lactic acid, coffee acid, ferulic acid, 3,3' -iodipropionic acid, coenzyme Q10, alginic acid, arginine, asparagine, cysteine, methionine, thiamine, L-carnitine n, scopoletin, curcumin, polycosanol, theanine, theobromine, leucine, lycopene, resveratrol, pterostilbene, glutathione, melatonin, chondroitin, glucosamine, donepezil, hydroxyurea, 4-acetamidophenol, 4-aminosalicylic acid, hydrochlorothiazanebine, hydrochlorothiazide, tele-thiazide, , tamsolusin, desloratadine, metoprolol, carbamazepine, giclazide, amiloride, quinacrine, karsalam, duloxetine, ibuprofen, naproxen, diclofenac, piroxicam, furosemide, allopurinol, silodosine, rivoroxidone, cliltoxin, prazolamatophor, acetazoatnis , laropiprant, sitagliptin, rivaroxaban, vildagliptin, solifenacin, silodosin, galantamine, trimethazine, amlopidine, nifedipine, risperidone, alprazolam, entacapone, leucovorin, dacarbazine, ibacron, zinc, oxalipelitin, oxetipellate, oxetipellate , metformin, valproic acid and salts thereof, if possible. It is known to the person skilled in the art that extracts containing said substances can also be used. E.g. for silibinin (silybin) seed extract of Sylibum marianum or Linum usitatissumum; for rosemic acid e.g. Mellisa officinalis, for resveratrol extract of polyphenols e.g. from red grapes, for Daidzein, Formononetine, Genistein & Biochanin A (Isoflavonoids) from Trifolium pratense L., for β-boswellic acids Boswellia serrata (Salai guggal), for epigallocatechin gallate tea polyphenol extract, for escin extract from Aescumum hypocast, L. for curcumin, curcuminoids referred to as Curcuma longa complex, for quercetin a bioflavonoid complex, and the like.

The preparation process according to the invention is characterized in that:

(a) dissolve or suspend β-glucan in water or in a water-miscible organic solvent or mixtures thereof and occasionally adjust the pH; and

b) adding the complexing agent and adjusting the pH and alternatively

(c) adding another complex-forming substance; and

d) adding an anti-solvent, and isolating the complex or alternatively distilling off the solvent; and

e) isolating the complex

According to the present invention, in step (a), solvents selected from the group of dimethylacetamide, dimethylformamide, C1-C3 alcohols, dimethylsulfoxide, propylene carbonate, acetic acid, pyridine, morpholine, diethylene glycol, methoxyethanol, ethoxyethanol, acetone and water are used or combinations. It is prepared most often by mixing aqueous or aqueous-organic solutions. When a complex formulation solution is used directly to form the formulation, the condition for selecting the solvent is its pharmaceutical acceptability and dispersibility in aqueous media. In the case of suspension, the swelling effect is used, in an alkaline medium at a pH of 7.5 to 12.5, preferably 7.9-9.5. In some cases, it is also possible to use alkali metal salts, for example glutathione sodium salt, and to buffer them by adding another nutraceutical or metal hydroxides such as e.g. sodium hydroxide, potassium hydroxide or ammonium hydroxide. In step (a) a temperature of 10 to 80 ° C is used, preferably a temperature of 20-45 ° C. It will be appreciated that the individual components may be added depending on their solubility in different solvents. If a combination of solvents is used, a large amount of additional solvent may lead to precipitation of the substances from the reaction medium. It is therefore advantageous to add additional solvent with stirring and gradually. Conversely, in some cases, a large amount of solvent may lead to a dilute solution from which the product precipitates only after a long time or after partial concentration. By the process of the invention, complex formation is specifically achieved by changing the pH during the action of the nutraceutical and / or API. The desired pH is 2.1 to 7.0, preferably 3.2 to 6.5. This is carried out by the process of the invention in step (b), for example, directly by adding an organic acid such as e.g. tartaric acid or ascorbic acid. Generally, stronger acids, e.g. hydrochloric acid, sulfuric acid, phosphoric acid. However, it is particularly advantageous to combine glucan and nutraceutical in the form of an organic acid, e.g. tartaric or ascorbic acid or alternatively a salt thereof. When a pharmaceutically active substance is used in the form of its corresponding salt, for example sulfate, phosphate, hydrochloride, the desired value can also be balanced with a suitably selected amount of such a salt to the glucan. The pH can also be adjusted using a suitable accepted solvent such as acetic acid and solutions thereof. Subsequently, another nutraceutical or API can be added. The reaction mixture is stirred or ground to form a complex. The term complex refers to a chemically and physically stabilized complex formed by a combination of β-glucan and a nutraceutical or a pharmaceutical active under conditions that form a stable complex. The skilled artisan will appreciate that, depending on the conditions of preparation, some of the active ingredients need not be incorporated into the complex with β-glucan but also present in the form of a co-precipitate. Such active substance co-precipitates contain a homogeneously distributed active substance on the glucan surface. The proportion of the individual non-covalent interactions is controlled, inter alia, by the chemical structure, the effective size and molecular weight of the active substance, the degree of "chain opening" and the source of the glucan, and the method of complex preparation. Complexes and co-precipitates can be quantified e.g. adsorption isotherm, gel filtration. The presence of the coprecipitate in the obtained complex substance is advantageous in some cases because of the suppression of particle aggregation. In some cases, the coprecipitate content is less than 0.5 wt%, or less than 0.1 wt%. It is preferred that the co-precipitate in the complex be less than 1% by weight, but may reach up to 25% by weight. The complex most often takes the form of a precipitate upon addition of the anti-solvent in step (d) but alternatively it may be in the form of a paste, a crystalline form or an amorphous form. The isolation in step (e) is carried out after distilling off the solvents e.g. lyophilization or filtration, preferably under reduced pressure, or centrifugation. The filter cake may be washed with an inert solvent under isolation conditions such as C 1 -C 4 alcohols, acetone, and aqueous solutions thereof. It is understood that a combination of a number of compatible nutraceuticals, e.g. ascorbic acid-resveratrol, ascorbic acid-quercetin, tartaric-nicotinamide, ascorbic-nicotinamide. The complexes may further be incorporated by a pharmaceutically acceptable agent e.g. anthocyanidins, respectively. their glycosides, tocopherol polyethylene glycol succinate, tocopherol polyethylene glycol palmitate, or a phospholipid complexing agent. The solids to glucan ratios may vary from 0.1 to 55% by weight, for the nutraceutical or API, according to the desired therapeutic effects. However, it is preferable to adjust the ratio according to the strength of the desired formulation in the formulation. For the purposes of the invention, selected substances are generally referred to as pharmaceutical active ingredients, i.e., substances falling within the definition of: AAPS PharmSci 2003; 5 (3) Article 25 (http://www.pharmsci.org) and GRAS or EAFUS listed nutraceuticals as well as excipients accepted in pharmacy. For the purposes of the invention, quercetin, taxifoline, naringin, silibine, silibinin, gallic acid, chlorogenic acid, salicylic acid, acetylsalicylic acid, taurine, nicotinamide, isonicotinic acid, pyridoxine, diosmin, hesperidine, escin, troxuretine, ascorbic acid, ascorbic acid, citric acid, hydroxycitric acid, tartaric acid, boswellic acid, rosemic acid, glycolic acid, eicosapentaenoic acid, docosahexaenoic acid, aspartic acid, tannic acid, quinic acid, L-lysine, p-aminobenzoic acid, folic acid, pantothenic acid, choline chloride , glutaric acid, caffeine, L-glutamic acid, A-acetyl-L-glutamic acid, L-carnitine, lactic acid, coffee acid, ferulic acid, 3,3'-thiodipropionic acid, coenzyme Q10, alginic acid, arginine, asparagine , cysteine, methionine, thiamine, L-carnitine, scopoletin, curcumin, polycose nol, theanine, theobromine, leucine, lycopene, resveratrol, pterostilbene, glutathione, melatonin, chondroitin, glucosamine, donepezil, hydroxyurea, 4-acetamidophenol, 4-aminosalicylic acid, hydrochlorothiazide, telmisartan, agomelatine, desusoline, tenofovine, tenofovine, tenofovine , giclazide, amiloride, quinacrine, karsalam, duloxetine, ibuprofen, naproxen, diclofenac, piroxicam, furosemide, allopurinol, silodosin, rivoroxaban, acetazolamide, diltiazem, prasugrel, cliptanin, clagoxin, prednisone, methotlopine, , solifenacin, silodosine, galantamine, trimethazine, amlopidine, nifedipine, risperidone, alprazolam, entacapone, leucovorin, dacarbazine, 5-fluorouracil, oxaliplatin, paclitaxel, docetaxel, imatinib, metformronate, sunitinib, ibandendolib, ibisendolib, ibisendolib, ibisendolib, ibisendolib, ibisendolib. It will be appreciated that the compounds may also be in the form of pharmaceutically acceptable salts such as e.g. hydrochloride, hydrobromides or sodium or potassium salts. The prepared complexes or co-precipitates are characterized by standard techniques e.g. by measuring conductivity, FT-IR, NMR, XRPD, UV and DSC. As it is practical for the formation of macromolecular complexes, the weight ratios of the reactants and the weight of the reactants are based on the weight of the mixture. extracts, in some cases elemental analysis or HPLC is preferred. In general, the optimum drug loading is dependent on the release period and the strength of the active agent. The homogeneous mixture of glucan and nutraceutical and / or API can also be dispersed in aqueous or aqueous organic solutions, and after complex formation, the resulting product is isolated e.g. evaporation of the solvents, filtration, centrifugation or lyophilization. The resulting substance is ground or micronized. Preferred product particle sizes are from 1 µm to 500 µm, preferably below 25 µm.

The complexes obtained according to the invention can be used for the prevention or treatment of various diseases. For example, when applied as an antioxidant, their primary activity lies in their ability to quench free radicals and their antioxidant activity generally increases with the number of hydroxyl groups and is potentiated by their presence in the nutraceutical molecule as a complexing partner. Their use includes, but is not limited to, for the preparation of nutraceuticals and medicaments for the prevention and treatment of chronic venous insufficiency, detoxication, allergies, arthritis, atherosclerosis, colorectal cancer, diabetes, improvement of brain metabolism, neuropathy and retinopathy, high cholesterol, high blood pressure , inflammation, stroke, digestive ulcer disease, mycoses, dermatitis, neurodegenerative diseases such as Alzheimer's disease, recovery from ischemic stroke or infectious diseases caused by bacteria. The β-glucan and nutraceutical complexes prepared by the process of the invention can assist in detoxification of the colon.

The invention also relates to solvates of the complexes and their polymorphic modifications. The discovery of new β-glucan complexes and nutraceuticals and / or APIs as pharmaceutically useful compounds provides new opportunities for improving the properties and effects of pharmaceutical products. The molecular complex may also be formed by a number of complementary nutraceuticals. This further extends the repertoire of the formulations I have available for formulation design. It is obvious that the substances prepared by the process according to the invention in the formulation can be supplemented by the addition of e.g. piperine or phospholipid complexes. The inventors have found that the above-mentioned glucan complexes can surprisingly form a suitable matrix for stabilizing complex-forming substances without loss of biological activity. This is noteworthy since many of these substances are known to be sensitive to process or storage conditions. The stability of the novel complexes was monitored by exposure to defined moisture. These were left to the point where the equilibrium was reached. The water content was determined gravimetric for each form (% of the water content was determined by the feedstock). It has been observed that the complex formed by β-glucan and a nutraceutical such as tartaric acid, ascorbic acid, isoascorbic acid and lactic acid agalantamine hydrobromide is substantially less hygroscopic than galantamine hydrobromide alone at 95% r.h. and a temperature of 25 ° C. It was found that the chamber (Aquadyne DVS-2, conditions:% RV-5%, dm / dt 0.008% mg / min 10min., Repeated cycles) after 95% RH exposure, at 25 ° C a sample of β-glucan complex (S. cerevicae) -accorbic acid-galantamine hydrobromide absorbed 0.12% water while galantamine hydrobromide alone absorbed 3.6% water. In the case of the β-glucan (S.cerevicae) -isoascorbic acid-alanine hydrobromide complex, a value of 0.4% was achieved and the isoascorbic acid absorbed 5% of water. The lower hygroscopicity of the complexes prepared according to the invention is advantageous for processing and storage in crystalline form. Consequently, a further advantage of the co-crystals of the present invention is the uniformity of the product and the stability thereof, as a result of which their mechanical processing properties (filtration, drying, milling, etc.) are improved. When used as pharmaceuticals, the complexes of the invention are administered in the form of pharmaceutical compositions. The compositions may be formulated for any route of administration, and the preparation of a suitable pharmaceutical composition for a particular mode of administration is well known to those skilled in the art of pharmacy. Accordingly, the present invention also relates to pharmaceutical compositions comprising a therapeutically significant amount of complexes of glucan with complexing agents together with a pharmaceutically acceptable diluent or carrier. The stabilizing effect of glucan in the preparation of syrups as a dosage form or the grinding of the raw material is significant. According to another aspect of the invention, the formulations may be prepared in the form of solutions or suspensions of molecular crystals in a pharmaceutically acceptable solvent. Complexing with glucan prevents the reaction of the reactive group of the nutraceutical and / or API with water, oxygen or other substances in the formulation. Thus, the stability of the nutraceutical and API in the composition of the invention is improved by forming a complex of the invention. It will be understood that the selection of a particular type, and amount of glucan in the composition to achieve the desired properties can be readily made by one of ordinary skill in the art. In a preferred form, the pharmaceutical compositions of the invention are formulated for creams or injections, e.g. for intravenous administration. A typical composition for injection comprises a sterile isotonic aqueous solution and a co-solvent e.g. ethanol, polyethylene glycol. Such a formulation may include a chelating agent, lecithin, and an antioxidant, but an advantage of the invention is the use of a complex whose partner / s combines the above properties. The method of preparation according to the invention depends on the skill of the person skilled in the art. The glucan, nutraceutical and / or API complexes of the present invention can advantageously be formulated into pharmaceutical compositions. In this case, the main active ingredient is used in combination with some of the elements such as binders, fillers, lubricants, diluents, stabilizers, chelating agents, disintegrants, lubricants as desired. It is advantageous to combine in the formulations where the new complexes the nutraceuticals form other known nutraceuticals or excipients such as vitamins, flavonoids.

Solid oral dosage forms are, for example, hard gelatin capsules and tablets. In the compositions of the present invention, the amount of the complex ranges from 5% to 85%, most preferably 5% to 50% by weight. Diluents that may be included in the present invention are preferably selected from the group of natural or artificial carbohydrates such as lactose, sucrose, glucose, starches, sorbitol and microcrystalline cellulose. Preferred binders are starches, sugars, cellulose and derivatives thereof, gelatin and polyvinylpyrrolidone. Starch and microcrystalline cellulose are preferred for use as good disintegrants. Particularly preferred is Avicel (TM), a type of commercial microcrystalline cellulose. Lubricants used for solid dosage forms are selected from the group consisting of talc, silica, magnesium stearate, glidant, aerosol, stearic acid and stearin. Applications are injections containing 1 to 2 mg / ml glucan complex, nutraceutical and / or API per total injection volume. Water and pharmaceutically acceptable solvents in a volume of 10 to 70% by volume of injection are used as diluent. As pharmaceutically acceptable solvents, ethanol, propylene glycol, polyethylene glycol and the like are used. Generally, e.g. hydrochloric acid, citric acid, tartaric acid, ascorbic acid, ethylenediaminetetraacetic acid. However, according to the process of the invention, if these substances are already incorporated into the complex, it is not necessary to add them separately. The injections may further comprise a pharmaceutically acceptable stabilizer. Also in this case it is suitable to use as a pharmaceutically acceptable stabilizer a nutraceutical partner e.g. L14 cysteine, 3,3'-thiodipropionic acid, ascorbic acid, gallic acid, ethylenediaminetetraacetic acid and salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The compounds of the invention were characterized by FT-IR spectrum, Raman spectrum, UV-VIS spectrum, melting point, DSC / TGA and XRPD.

Picture no. 1a-g represents Fourier transform infrared spectra of FTIR of selected complexes measured on a Spectrometer Nicolet, Impact 410. ATR measurement technique, Omnic program version 5.2 was used for measurement.

Picture no. la: β-glucan (lower line), β-glucan-folic acid-curcumin complex, curcumin, folic acid (upper line)

Picture no. lb: β-glucan (lower line), β-glucan-ascorbic acid nicotinamide complex, ascorbic acid-nicotinamide (upper line)

Picture no. lc: β-glucan (lower line), β-glucan-curcumin complex, curcumin (upper line)

Picture no. Id: β-glucan (lower line), β-glucan-folic acid complex, folic acid (upper line)

Figure No: β-glucan (lower line), β-glucan-coenzyme Q10 complex, coenzyme Q10 (upper line)

Figure 1f: β-glucan (lower line), β-glucan-allopurinol complex, allopurinol (upper line)

Figure 1g: β-glucan (lower line), β-glucan-ibuprofen complex, ibuprofen (upper line)

Picture no. 2a-d shows photographs from a polarizing microscope (Nikon Eclipse LV IPOPOL) of β-glucan and selected complexes

Picture no. 2a: β-glucan, β-glucan-quercetin complex (right)

Picture no. 2b: β-glucan-curcumin complex, curcumin (right)

Picture no. 2c: β-glucan-coenzyme Q10 complex, coenzyme Q10 (right)

Picture no. 2d: β-glucan-folic acid complex, folic acid (right)

Picture no. 3a-c represent selected diffractograms (XRPD-X-ray powder diffraction). The measurement was performed on a powder diffractometer: Bragg-Brentano diffractometer Philips PW 1730/1050, with cobalt lamp: B-filtered CoKa radiation, voltage 40 kV / 35 mA, range 3 ° - 51 ° 2Θ, step 0.02 °. Key inter-plane distances and relative intensities to the figures are shown in the accompanying table.

Picture no. 3a: ascorbic acid (lower line), β-glucan-ascorbic acid complex (middle line), β-glucan (upper line).

Picture no. 3b: ascorbic acid (bottom line), nicotinamide, β-glucan acid ascorbic-nicotinamide complex (middle line), glucan (upper line)

Picture no. 3c: β-glucan (lower line), β-glucan-coenzyme Q10 complex (upper line)

Figures 4a-b show records obtained by Differential Compensation Calorimetry (DSC). DSC measurements were performed using a Perkin-Elmer DSC-7 instrument (PerkinElmer, USA) with Pyris software. The temperature scale was calibrated using In, Sn and Zn. The enthalpy scale was calibrated for the enthalpy of melting In. The 3-4 mg samples were placed in a standard molded aluminum dish using nitrogen as the purge gas. Endothermic peaks are upward on the recordings. Records are corrected to baseline. The heating rate was 10 ° C / min, in the temperature range 100-250 ° C.

Figure 4a, DSC record: physical mixture of glucan curcumin 9: 1 (lower line), complex glucan curcumin 9: 1, glucan, curcumin (upper line)

Figure 4b, DSC record: 1: 1 glucan-ascorbic acid complex (lower line), 1: 1: 1 glucan-ascorbic acid-nicotinamide complex, glucan, ascorbic acid 1: 1 physical mixture (upper line)

Figures 5a-e show UV-VIS spectra obtained by Spekord M 40 UV-VIS spectrophotometer, Zeiss Jena UV-VIS with quartz cuvettes 1.0 cm having a resolution of 0.06-0.12 nm in the region of 200400 nm. Samples were prepared as solutions in 50% methanol (UV).

Figure 5a, UV spectrum: β-glucan (lower line), β-glucan-quercetin complex, quercetin (upper line)

Figure 5b, UV spectrum: β-glucan (lower line), β-glucan-ascorbic acid-nicotinamide complex, ascorbic acid-nicotinamide (upper line)

Figure 5c, UV spectrum: β-glucan (lower line), β-glucan-curcumin complex, curcumin (upper line)

Figure 5d, UV spectrum: β-glucan (lower line), β-glucan-coenzyme Q10 complex, coenzyme Q10 (upper line)

Figure 5e, UV spectrum: β-glucan (lower line), β-glucan-folic acid complex, folic acid (upper line)

Figure 6a HPLC record of β-glucan (Saccharomyces cerevisiae) -boswelic acid (BSWA) complex: 11-keto-BSWA, 3-Acetyl-11-keto-BSWA, beta-BSWA, 3-acetylbeta-BSWA

Figure 6b HPLC record of β-glucan (Schizophyllium commune) -boswelic acid (BSWA) complex: 11-keto-BSWA, 3-acetyl-11-keto-BSWA, beta-BSWA, 3-acetylbeta-BSWA

Figure 7a Distribution and particle size of β-glucan complex, micronized

Figure 7b Distribution and particle size of β-glucan complex

Graph no. 1: Effect of the addition of glucan as a change in conductivity (solid circles) and pH (solid squares) of an aqueous solution of ascorbic acid.

Figure 2: Effect of ethanol addition as a change in conductivity (solid circles) and pH (solid squares) of an aqueous solution of β-glucan-ascorbic acid complex.

The following examples describe the preparation of the complexes of the present invention. The examples serve to further illustrate the present invention without limiting its practice to the examples described herein.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of the β-glucan (Saccharomyces cerevisiae)-citric acid-salicylic acid complex

To 60 mg of dry β-glucan (Saccharomyces cerevisiae) was added 2 ml of 10% acetic acid and the mixture was stirred at 37 ° C while gradually adding citric acid to pH 2.17. Subsequently, 13mg of salicylic acid was added in one portion and the mixture was stirred for 30 minutes while cooling to 20 ° C and allowed to stand at 20 ° C for 12 hours. Subsequently, 3.5m ethanol was added sequentially and allowed to stand at 5 ° C for 12 hours, pH 2.83. The precipitate was centrifuged, washed with water and 3 x 3 ml 50% ethanol and dried at 40 ° C to constant weight.

Subsequently, the product was milled in a vibratory ball mill for 10 minutes. 65 mg of β-glucan (Saccharomyces cerevisiae) - citric acid salicylic acid complex was obtained. The substance was characterized by XRPD, IR, DSC and X-ray structure analysis. Salicylic acid content (HPLC) 18.4 pg mg ^-1 . The loss on drying was determined by thermogravimetry (TG) <0.21%.

Example 2

Preparation of β-glucan (Saccharomyces cerevisiae) -accorbic acid hydroxyurea complex.

To 100 mg of β-glucan (Saccharomyces cerevisiae) was added 2.1 ml of water, and the mixture was stirred with a gradual addition of 12.5 mg of ascorbic acid for 12 hours at 45 ° C, and the pH of the mixture was adjusted to 3.85. Subsequently, 10 mg hydroxyurea was added and stirred overnight. 5.0 ml of ethanol was added to the reaction mixture and allowed to stand for 1 hour. The solid was centrifuged, washed with water and 2 x 3 ml ethanol and dried at 40 ° C to constant weight. 80 mg of β-glucan (Saccharomyces cerevisiae) -ascorbic acid-hydroxyurea were obtained. Drying loss determined by thermogravimetry (TG) <1.9%.

Example 3

Preparation of β-glucan-allopurinol complex

To 350mg of glucan was added 8ml of water and adjusted to pH 12.35 with 10% NaOH. The mixture was sonicated 2x15 min in an ultrasonic bath. Subsequently, 40 mg of allopurinol was added and the pH was adjusted to 6.07 by the addition of 10% HCl. The mixture was sonicated 2 x 20 min. The mixture was allowed to stand overnight in the refrigerator. Subsequently, 9 ml of ethanol was added and the mixture was allowed to stand for 6 hours in a refrigerator. The product was centrifuged, washed with 2 x 3 ml 60% ethanol and dried at 45 ° C under vacuum. The solid was centrifuged, washed with water and 2 x 3ml 96% ethanol and dried at 40 ° C to constant weight. 80 mg of β-glucan-allopurinol complex was obtained, content (UV) 6.8 pg mg ^-1 . Drying loss determined by thermogravimetry (TG) <2.8%.

Example 4-16

Analogously to Example 2, a series of complexes was prepared using the above-mentioned active substances (APIs), respectively. salts, partner and solvent thereof.

Example API solvent partner Example 4 duloxetine Methanol / water Hypericum perforatum extract (70%) Example 5 piroxicam Methanol / water ascorbic acid Example 6 sitagliptin DMF glutamic acid, Example 7 methotrexate acetone / water EDTA Na Example 8 docetaxel DMF / water 5-fluorouracil Example 9 silodosin ethanol / water nicotinamide Example 10 vildagliptin methanol isoascorbic acid Príkladll quetiapine ethanol / water trehalose / fumaric acid

Example 12 ibuprofen DMSO lysine Example 13 solifenacin methanol anticarboxylic acid Example 14 caffeine Water taurine Example 15 5-fluororacil pyridine quercetin Example 16 4-acetamidophenol acetone / water caffeine

Example 17

Preparation of β-glucan (Schizophyllium commune) -imatimb mesylate-curcumin complex

To 350 mg of β-glucan (Schizophyllium communé) in 4 ml of dimethyl sulfoxide was added 35 mg of imatinib mesylate and 12.5 mg of curcumin. The mixture was stirred overnight at 22 ° C. To the reaction mixture at pH 5.85, 8 ml of water was gradually added with vigorous stirring and allowed to stand for 12 hours. 4.5 ml of acetone was added, stirred for 12 hours and the reaction mixture was centrifuged, washed with water 2x2.5 ml and 2 x 3 ml acetone and dried at 40 ° C. 180 mg of β-glucan-imatinib mesylate-curcumin complex were obtained. Drying loss determined by thermogravimetry (TG) <2.8%.

Example 18

Preparation of β-glucan-folic acid complex

To 350mg of rye glucan was added 8ml of dimethylsulfoxide and the pH was adjusted to 11.00 by the addition of 10% NaOH. The mixture was sonicated 2x15 min in an ultrasonic bath. Subsequently, 35 mg of folic acid was added and the pH was adjusted to 10.54. The mixture was sonicated twice for 20 minutes, then 18 ml of water was added and the pH was adjusted to 4.59 by addition of 10% HCl. The mixture was allowed to stand overnight in the refrigerator. 3ml of ethanol was added and the mixture was again allowed to stand in the refrigerator for 6 hours. The product was centrifuged, washed with 2 x 3 ml 60% ethanol, 3 x 3 ml 96% ethanol and dried at 45 ° C under vacuum. 325 mg of β-glucan-folic acid complex were obtained. Drying loss determined by thermogravimetry (TG) <0.15%.

Example 19

Preparation of β-glucan-tamsolusin-citric acid complex

To 100 mg of β-glucan (Pleurotus ostreatus') was added 3.5 ml of water and 20 mg of tamsolusin hydrochloride and a few drops of acetic acid, and the mixture was stirred overnight at 35 ° C. 8.5 mg of sodium citrate was added to the reaction mixture at pH 5.8. The pH was adjusted to 3.85 with hydrochloric acid and stirred for 12 hours. 19

The solid was centrifuged, washed with water and 2 x 3ml 96% ethanol and dried at 40 ° C to constant weight. 80 mg of β-glucan-tamsolusin-citric acid complex were obtained. Drying loss determined by thermogravimetry (TG) <2.8%.

Example 20

Preparation of β-glucan complex (Pleurotus os / rheotic-ascorbic acid-nicotinamide

To 60mg of glucan in a grinding vessel, volume 10 ml (stainless steel) was added 30mg of L-ascorbic acid and 10mg of nicotinamide and mixed with a spatula. Subsequently, 0.5 ml of 80% 2-propanol and a 2 mm grinding ball (stainless steel) were added. The suspension was milled 2 x 0.5 hours after mixing (release of the walls) in a MM200 mill at 12 / s and allowed to stand overnight. The product was removed and dried at 45 ° C. 50 mg of β-glucan complex (Pleurotus ostreatusykysdvd. Ascorbic-nicotine amide) were obtained. Drying loss determined by thermogravimetric (TG) <0.22%.

Example 21

Preparation of β-glucan-ascorbic acid-resveratrol complex

3.5 ml of water was added to 350 mg of glucan and the pH was adjusted to 12.1 by addition of 10% NaOH. The mixture was sonicated 2x15 min in an ultrasonic bath. Subsequently, 150 mg of red grape polyphenol extract (containing 10% resveratrol) was added, the mixture was sonicated twice for 20 minutes, and then 127 mg of ascorbic acid was added and the pH adjusted to 3.55 by addition of 10% HCl. The mixture stood overnight in the refrigerator. 8 ml of 2-propanol were added with stirring and the mixture was again allowed to stand in the refrigerator for 12 hours. The product was centrifuged, washed with 2 x 3 ml 60% 2-propanol and dried at 45 ° C under vacuum. It was then milled and mixed with 400 mg of tocopherol polyethylene glycol succinate (TPGS, Eastman-Kodak) at 65-70 ° C. After cooling to 5-10 ° C in the refrigerator, the pasty product was triturated. 690 mg of dispersion of β-glucan-ascorbic acid-resveratrol complex in TPGS was obtained.

Example 22

Preparation of β-glucan-ascorbic acid-coenzyme Q complex

In a manner analogous to Example 17 except that coenzyme Q was used and the complex obtained was subsequently mixed with 400 mg of tocopherol polyethylene glycol succinate (TPGS, Eastman-Kodak) at 65-70 ° C. 485 mg of a dispersion of β-glucan acid ascorbic-coenzyme Q complex in TPGS was obtained.

Example 23

Preparation of β-glucan-curcumin complex

To 350mg of glucan was added 8ml of dimethylsulfoxide and 35mg of curcumin. The mixture was sonicated 2x15 min in an ultrasonic bath. 16 ml of water was added sequentially and the pH was adjusted to 3.85 by the addition of 10% HCl. The mixture was allowed to stand overnight in the refrigerator. The reaction mixture was centrifuged, washed 3 times with 10ml 60% ethanol and dried at 45 ° C under vacuum. The obtained β-glucan-curcumin complex was then mixed with 100mg of phosphatidilcholine and soya lecithin (1: 1) at 55-60 ° C. 325 mg of β-glucan-curcumin complex dispersion were obtained.

Example 24

Preparation of β-glucan (Pleurotus osŕreatas) -accorbic acid-curcumin complex

Composition of one 500mg tablet:

β-glucan complex (Pleurotus ostreatus) -acid \ ma ascorbic-curcumin 225mg (32.7pg mg ^_1 , 4.2pg mg ^-1 ) silymarin (as 80% extract) 25.0mg coenzyme Q10 10mg calcium hydrophosphate 200.0mg silica 5.0mg stearate Magnesium 10 mg coating (hydroxypropylcellulose mixture, talc, glycerin, microcrystalline cellulose, titanium dioxide, chlorophyllin) 25 mg.

Example 25

Preparation of β-glucan-curcumin complex

Composition of one 500mg capsule:

β-glucan-curcuminoid complex 350mg (such as curcumin, demetoxycurcumin and bisdemetoxycurcumin)

Microcrystalline cellulose - bulking agent

Magnesium stearate - anti-caking agent

Gelatin - capsule shell

Example 25

Syrup of β-glucan complex (Pleurotus ostreatus-oyster Q 10-ascorbic acid (5 ml) contains β-glucan complex (Pleurotus ostreatus) -coenzyre Q 10-ascorbic acid 120mg (28.1pg mg ' ¹ , 42.12pg mg ¹ )) niacin 1, 35 mg, pantothenic acid 0.45 mg vitamin B6 0.15 mg vitamin BI 0.10 mg folic acid 10.00 pg biotin 1.25 pg vitamin B12 0.10 pg lecithin 45.0mg

Example 26

Preparation of β-glucan complex (Pleurotus os / reato-aventyl hydrochloride)

To 20ml of a 2% β-glucan solution (Pleurotus ostreatus) was added 5mg aventyl hydrochloride and the mixture was stirred for 24 hours at 20 ° C and filtered through a Nylon filter (0.22pm). The reaction mixture was lyophilized. 6mg of the β-glucan complex (Pleurotus ostreatus} - &quot; drzyl \ hydrochloride) was obtained.

Examples 27 to 32

Analogously to Example 26, a series of complexes was prepared using the aforementioned pharmaceutically active substances and / or the like. salts and solvents thereof.

Example Pharmaceutical active substances solvent Example 27 chondroitin sulfate Water Example 28 caffeine sulfate water / ethanol Example 29 clopidogrel bisulfate / salicylic acid Water Example 30 ezatiostat HCl water / acetone Example 31 chondroitin sulfate / glucosamine Water Example 32 ascorbic acid / hesperidin water / DMSO Example 33 folic acid / curcumin pyridine Example 34 folic acid / 5-fluorouracil dimethylacetamide

Example 33

Preparation of β-glucan-ascorbic acid complex

350mg of β-glucan is swelled in 3.5ml of 10mmol sodium ascorbate solution for 6 hours at pH 9.8. 7 ml of acetic acid was added and the pH was adjusted to 4.35 and the mixture was left in the refrigerator overnight. The reaction mixture was centrifuged, washed 3x with 10 ml of 90% acetone and dried at 45 ° C under vacuum. 250mg of βglucan-ascorbic acid complex was obtained. A portion of the sample was dialyzed against deionized water and lyophilized.

Example 34

Preparation of β-glucan-boswelic acid complex

350mg of micronized glucan and 100mg of Boswelia serrata extract were added to 8ml of water. The pH was adjusted to 12.3 by addition of sodium hydroxide and left in an ultrasonic bath for 2 x 15 minutes and stirred for 6 hours. Subsequently, the pH was adjusted to 3.34 and the mixture was sonicated in an ultrasonic bath for 2 x 15 minutes and left in the refrigerator overnight. To the reaction mixture was added 8 ml of ethanol, the mixture was centrifuged, washed 3x with 10 ml of 60% ethanol, 1x with 10 ml of ethanol 96% and dried at 45 ° C under vacuum. 426mg of β-glucan-boswelic acid complex was obtained. Boswelic acid content (BSWA) by HPLC: 6.78 pg mg ^-1 (11-keto-BSWA), 2.99 pg mg ^-1 (3-acetyl-11-keto-BSWA), 27.58 pg mg ^-1 (beta-BSWA), 9.20pg mg ^-1 (3-acetyl-betaBSWA).

Claims (10)

PATENT CLAIMS Complexes of β-glucan with at least one complex-forming agent wherein the complex-forming agent is a pharmaceutical active agent. A process for the preparation of complexes according to claim 1, characterized in that the complex-forming substances are pharmaceutical active substances selected from the group of quercetin, taxifoline, naringin, silibine, silibinin, gallic acid, chlorogenic acid, salicylic acid, acetylsalicylic acid, taurine, nicotinamide, isonicotinic acid , pyridoxine, diosmine, hesperidin, escin, troxuretine, ascorbic acid, isoascorbic acid, citric acid, hydroxycitric acid, tartaric acid, boswellic acid, rosemic acid, glycolic acid, eicosapentaenoic acid, docosahexaenoic acid, aspartic acid, aspartic acid, L-lysine, p-aminobenzoic acid, folic acid, pantothenic acid, choline chloride, glutaric acid, caffeine, L-glutamic acid, N-acetyl-L-glutamic acid, L-carnitine, lactic acid, coffee acid, ferulic acid, 3,3'-thiodipropionic acid, coe Q10, alginic acid, arginine, asparagine, cysteine, methionine, thiamine, L-carnitine, scopoletin, curcumin, polycosanol, theanine, theobromine, leucine, lycopene, resveratrol, pterostilbene, glutathione, melatonin, glucose, chondroitin, chondroitin, chondroitin 4-acetamidophenol, 4-aminosalicylic acid, hydrochlorothiazide, telmisartan, agomelatine, tenofovir, emtricitabine, tamsolusin, desloratadine, metoprolol, carbamazepine, giclazide, amiloride, quinacrine, carsalam, duloroxetin, pienopuremine, ibenoprofen, ibuprofen, ibuprofen, ibuprofen, , acetazolamide, diltiazem, prasugrel, cloroxin, prednisone, methotrexate, mercaptopurine, almorexant, laropiprant, sitagliptin, rivaroxaban, vildagliptin, solifenacin, silodosine, galantamine, trimethazine, amlopidin, risouracin, risouracin, rifedacin, rifedacin, nifedidine, rifedacin , oxaliplatin, paclitaxel, docetaxel, imatinib, sunitinib, ibandronate, zolendronate, glipizide, metfo and, if possible, valine, valproic acid and salts thereof. Process for the preparation of complexes according to claim 1 and 2, characterized in that: (a) dissolve or suspend β-glucan in water or an organic solvent miscible with water or mixtures thereof and occasionally adjust the pH; and b) adding a complexing agent and adjusting the pH or alternatively (c) adding another complex-forming substance; and d) adding an anti-solvent, or alternatively distilling off the solvent; and e) isolating the complex Process for the preparation of complexes according to claims 1 to 3, characterized in that the glucan and the at least one complex-forming substance are allowed to interact with each other in a solvent followed by evaporation. A composition comprising at least one complex according to claims 1 and 2 prepared by evaporating solvents from the complex or isolated from a suspension thereof. 6. A composition according to claims 1-5 comprising two complex-forming agents. Use of the complexes according to any one of the claims 1 to 6, characterized in that they are used for the preparation of nutritional supplements and medicaments for the prevention and treatment of chronic venous insufficiency, detoxication, allergies, arthritis, atherosclerosis, colorectal cancer, diabetes, improvement of brain metabolism, neuropathy and retinopathy , high cholesterol, high blood pressure, inflammation, stroke, digestive ulcer disease, mycoses, dermatitis. A process for stabilizing complex-forming substances according to claims 1, 2 and 3, characterized in that a complex with glucan is formed. Complexes according to any one of Claims 1 to 5, characterized in that the proportion by weight of complex-forming substances is from 0.01 to 50% by weight. 10. A process for stabilizing complex-forming agents according to claim 2,8 and 9, wherein the glucan complex stabilizes the nanoparticle of the complex-forming agent.