RU2777185C1 - Solubilisate with curcumin and at least one thc cannabinoid as an additional active substance - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to the production of a solubilisate containing curcumin and tetrahydrocannabinol (THC) and to an application thereof in the food, cosmetic, and pharmaceutical industries. Proposed is a solubilisate consisting of three or more than three components, namely, consisting of curcumin in an amount 10% wt. or less, of at least tetrahydrocannabinol (THC) as at least one additional active substance, and an emulsifier of polysorbate 80, or a mixture of polysorbate 80 and polysorbate 20, or a mixture of polysorbate 80 and at least one sucrose ester and edible fatty acids in an amount of at least 70% wt. of the emulsifier. Also proposed are a capsule, a food product, a dietary supplement, a beverage, and a cosmetic product containing the solubilisate; a method for producing the solubilisate; and a method for preventing diseases including the administration of the solubilisate to the consumer in a dose of 0.5 to 1 mg/kg body weight once a day.

EFFECT: creation of a stable water-soluble combination of active substances, prevention of precipitation of curcumin and oxidation of THC.

42 cl, 3 ex

Description

The invention relates to a solubilizate containing curcumin and at least the cannabinoid THC. In addition, the invention relates to a liquid containing such a solubilisate, to a capsule filled with such a solubilisate or liquid, and to a dietary supplement and/or a pharmaceutical preparation containing such a solubilisate.

Curcumin is considered the active substance based on its various potential pharmacological properties. For example, there is evidence for the antioxidant and also anti-inflammatory effects of curcumin, as well as its effectiveness against viruses and bacteria and against cancer. Therefore, indications may be, for example, Parkinson's disease, Alzheimer's disease, diabetes mellitus, colorectal tumors, pancreatic cancer and liver dysfunction.

Cannabinoids are transformation products and synthetic analogues of certain terpene phenols, which are found mainly in plants of the hemp genus (Cannabis).

The term "hemp plant" or "cannabis plant" encompasses the wild type of Cannabis sativa as well as its variants, including Cannabis chemovar which naturally contains varying amounts of different cannabinoids, Cannabis sativa subsp. or hybrids.

The cannabis plant contains at least 113 cannabinoids from the group of terpene phenols. One of these cannabinoids is delta(Δ)9-tetrahydrocannabinol (THC).

As a psychoactive substance, tetrahydrocannabinol (THC) is believed to cause mainly the psychedelic effects of cannabis products. The plant naturally contains THC in the form of two THC acids, which are converted to THC when the plant material is heated.

In addition to the psychedelic effects, THC has been credited with valuable medicinal properties such as analgesic and relaxing effects, appetite-enhancing effects, antioxidant and neuroprotective effects, and glaucoma relief.

In addition, cannabis contains many non-cannabinoid substances with diverse pharmacological properties. There is some evidence that cannabinoids such as cannabinol (CBN), cannabidiol (CBD) and others alter the effects of delta(Δ)9-THC.

Synthetic cannabinoids can be obtained semi-synthetically, i.e. from cannabinoids of natural origin, or completely synthetically from simple raw materials. There are also other plants capable of producing active substances that act in the human body through the same mechanisms as hemp cannabinoids.

In the context of this application, the term "cannabinoid" includes not only natural and synthetic cannabinoids, but also phytocannabinoids. The latter include, for example, N-isobutylamides from Echinacea and beta-caryophyllene, which is found in various aromatic plants, as well as yangonine from the kava plant (Piper methysticum) and various catechins from the tea plant (Camellia sinensis).

To enter the bloodstream after oral administration, the active substance must pass through the hemobarrier of the small intestine, then be metabolized in the liver and enter the hepatic vein as a bioavailable fraction. The rest of the total active substance that enters and is released in the body is either decomposed by microorganisms in the intestine, or excreted with feces or bile.

The inventor has already created a curcumin solubilisate that has a significantly increased bioavailability compared to native curcumin. This solubilizate is described in International Patent Publication WO 2014094921 A1. In a number of studies, it was surprisingly found that due to its high bioavailability, this curcumin solubilisate of a certain composition unexpectedly showed a stronger effect on reducing the symptoms of the disease associated, in particular, with inflammation or cancer.

Toxicity due to micellization of the active substance according to the invention, in comparison with its native form, can be ruled out on the basis of studies with MTT cell viability tests. Cell viability testing using the MTT test is based on the reduction of the yellow water-soluble dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to the blue-violet water-insoluble formazan.

Therefore, the author of the invention set himself the task of developing such a composition that would make available to the human or animal body the healing or healing properties of curcumin in its combination with at least THC, as one of the cannabinoids, as an additional active substance. In particular, the aim of the invention is to provide the highest possible bioavailability of curcumin in combination with at least one cannabinoid.

Another object of the invention is to provide nutritionally and/or pharmacologically acceptable THC. More specifically, it is an object of the invention to provide THC in a form which, when mixed with water, produces a mixture without cloudiness visible to the human eye.

These tasks are solved in a surprisingly simple way using the solubilisate according to paragraph 1. This solubilisate consists of or contains curcumin in an amount less than or equal to 10 wt.%, preferably less than or equal to 8 wt.%, more preferably from 3 wt.% to 7 wt.%, most preferably from 1 wt.% to 3 wt.%; at least THC as an additional active substance, and at least one emulsifier having a hydrophilic-lipophilic balance (HLB) value of less than 18, preferably from 13 to 18, in particular polysorbate 80 or polysorbate 20, or at least one sucrose edible fatty acid ester (EC-approved as food additive E473) or a mixture of at least two emulsifiers selected from the group consisting of polysorbate 20, polysorbate 80 and sucrose edible fatty acid ester.

The invention also provides a solubilisate comprising, in particular, consisting of THC in an amount of less than or equal to 10 wt.%, preferably less than or equal to 5 wt.%, most preferably from 0.3 wt.% to 3 wt.%; and at least one emulsifier having an HLB value below 18, preferably between 13 and 18, in particular polysorbate 80 or polysorbate 20 or at least one sucrose ester of edible fatty acids, or a mixture of at least two emulsifiers selected from the group consisting of polysorbate 20, polysorbate 80 and esters of sucrose and edible fatty acids.

Such a solubilisate can be used in mixtures with curcumin solubilisates. The latter may also contain additional active substances. Moreover, the THC solubilisate as such has the advantage that it contains THC in a form suitable for oral administration, for example as a beverage or capsule filler. The solubilization of THC according to the invention provides an effective protection of this active substance from oxidation. Due to the improved protection of THC from oxidation, the invention makes it possible to obtain products with a longer shelf life.

In a preferred embodiment of the invention, the solubilisate is provided in a form that can be taken orally, in particular at a dose of curcumin from 0.5 mg/kg body weight to 1 mg/kg body weight, preferably at a dose of 0.81 mg/kg body weight in particular once a day.

In the context of the present application, the term "active substance" refers to a substance that is present in a pharmaceutically effective amount and is preferably added in order to achieve a pharmaceutical effect. In the present case, the name of the respective active substance is understood to include also substances which are converted in the body into the active substance and/or into its biologically active form.

In the context of this application, the active substance is THC. "Actives" as used herein includes secondary phytochemicals that are produced by plants as chemical compounds, neither during energy metabolism nor during anabolic or catabolic metabolic reactions. One group of secondary phytochemicals and therefore active substances in the context of the present application are flavonoids. Active substances in the context of the present application also include naturally occurring polyphenols such as resveratrol or polyphenols from licorice and naturally occurring phenols, in particular chalcones such as xanthohumol. This also includes plant extracts, i.e. substances that have been extracted from plants or parts of plants using an extractant. They include extracts from hops. The active substance is considered an "extract" even if it is still dissolved in the extractant. The term "essence" can also be used to refer to an extract.

"Active substances" in the context of the present application also includes enzymes. An example of an enzyme as an "active substance" in this application is serrapeptase. However, the application is not limited to this enzyme only.

The frankincense resin extract, Boswellia serrata extract, contains several pentacyclic triterpenes, often referred to collectively as boswellic acids ("common BAs"). The term "boswellic acids" refers to a group of chemical compounds of natural origin from the resin of the frankincense trees mentioned above. The two basic structures are α-boswellic acid and β-boswellic acid. Certain derivatives of boswellic acids are also known, in particular compounds which bear a keto group at position 11 and/or which are acetylated at position 3. Boswellic acids currently considered to be of pharmacological significance include α-boswellic acid (αBA) and β-boswellic acid (βBA) and their derivatives, 11-keto-β-boswellic acid (KBA); CAS 17019-92-0), 3-O-acetyl-11-keto-β-boswellic acid (AKBA); CAS 67416-16-9), 3-O-acetyl-α-boswellic acid (AαBA) and 3-O-acetyl-β-boswellic acid (AβBA). In particular, the AKBA derivative is believed to have an anti-inflammatory effect.

In the context of this application, the term "Boswellia", in particular in the term "Boswellia solubilisate" is used in the sense that the term "Boswellia" refers to the active substances from the resin of the frankincense tree, i. at least one boswellic acid and/or at least one boswellic acid derivative. The term "boswellic acid solubilizate" refers to a micellar mixture of at least one boswellic acid, which may also contain at least one boswellic acid derivative.

Xanthohumol is a naturally occurring flavonoid found in hops. It is a prenylated plant polyphenol that is classified as a chalcone and has so far only been identified in hops. Bitter hop varieties have significantly higher xanthohumol content than aromatic varieties. In tests, it was found that xanthohumol is effective against the emergence and development of cancer cells. Moreover, in laboratory experiments it has been found that xanthohumol is able to protect the nerve cells of the brain and, thus, may be able to help slow down the course of diseases such as Alzheimer's disease or Parkinson's disease.

Serratiopeptidase or serrapeptase is a proteolytic enzyme produced by the bacteria Serratia, which live in the gut of the silkworm. Serrapeptase is believed to have beneficial effects in relieving pain, inflammation, traumatic swelling, and excess mucus production from the body. It is believed to be effective as an anti-inflammatory and analgesic, similar to acetylsalicylic acid, ibuprofen, or other non-steroidal analgesics. It is also believed to induce fibrinolytic anti-inflammatory and anti-edematous activity in tissue. Like all enzymes, serrapeptase is sensitive to the acids produced by the stomach. Therefore, its presence in the composition, which provides passage through the stomach, is the subject of the invention.

The solubilizate according to the invention may contain one or more boswellic acids and/or one or more boswellic acid derivatives in an amount less than or equal to 10 wt.%, preferably less than or equal to 5 wt.%, most preferably from 2 wt.% to 4 wt.%.

Due to the high proportion of Boswellia, the invention in a preferred embodiment provides that the solubilisate contains an extract obtained by extraction with ethyl acetate from the resin of the plant Boswellia serrata as a source of one or more boswellic acids and/or one or more boswellic acid derivatives, the boswellic acids being contained in said extract in an amount of at least 85 wt.%.

The solubilizate according to the invention may contain xanthohumol in an amount less than or equal to 10 wt.%, preferably less than or equal to 5 wt.%, most preferably from 1 wt.% to 3 wt.%.

Due to the high proportion of xanthohumol, the invention in a preferred embodiment provides that the solubilizate contains an alcohol (ethanol) extract of hop solid resins as a source of xanthohumol, and the amount of xanthohumol in said extract is from 65 wt.% to 95 wt.%, preferably the amount is from 80 wt.% to 92 wt.%. In particular, the products "Xantho-Flav Pure" or "Xantho-Flav", discussed in detail below, can be used as a source of xanthohumol in the context of the invention. The solubilizate according to the invention may contain serrapeptase in an amount of up to 3 wt.%, preferably from 0.1 wt.% to 2 wt.%, most preferably from 0.18 wt.% to 0.35 wt.%.

In addition, a solubilisate consisting of or containing curcumin and at least THC as an additional active substance can also be advantageously provided or used in the context of the invention for use as an antibiotic and/or as a pharmaceutical preparation for the treatment and/or prevention of diseases, including inflammation, cancer, Alzheimer's disease, Parkinson's disease, obesity, high cholesterol, high blood sugar, diabetes, metabolic syndrome and/or autoimmune diseases, multiple sclerosis (MS); to reduce visceral fat, for thermogenesis, to reduce cholesterol, in particular LDL-cholesterol (where LDL stands for low-density lipoprotein) and/or blood glucose and/or triglycerides in the blood, to improve the density of macular pigment (in the retina), to reduce oxidative stress and / or to reduce the accumulation of fat in hepatocytes, in particular as a pharmaceutical preparation for the treatment and / or prevention of fatty liver, Friedreich hereditary ataxia (disorder of movement coordination), lysosomal diseases in particular, Tay-Sachs disease (early childhood amaurotic idiocy), atherosclerosis, heart disease, arthritis.

In particular, the invention provides solubilisates as described above for use as an anti-inflammatory drug and/or as an antibiotic and/or as a pharmaceutical effective against cancer, Alzheimer's disease, Parkinson's disease, obesity, high cholesterol, elevated blood sugar, diabetes, metabolic syndrome and/or autoimmune diseases, multiple sclerosis (MS); to reduce visceral fat, for thermogenesis; as a pharmaceutical preparation for lowering cholesterol, in particular LDL-cholesterol; and/or as a pharmaceutical preparation with the effect of lowering blood glucose and/or blood triglycerides, to improve the density of macular pigment (in the retina), to reduce oxidative stress and/or to reduce fat accumulation in hepatocytes, in particular as a pharmaceutical preparation with an effect against fatty liver, Friedreich hereditary ataxia, lysosomal diseases, in particular Tay-Sachs disease, atherosclerosis, heart disease, arthritis.

Depending on the additional components that are contained in the solubilizate in order to promote the formation

Depending on the additional components that are contained in the solubilisate in order to ensure stable micelles of the active substances, the emulsifier content, in particular the polysorbate content, can be at least 70 wt.%, preferably from 75 wt.% to 95 wt.% , most preferably from 79 wt.% to 88 wt.%, in the context of the invention.

Depending on the specific application, the solubilizate according to the invention may contain, for example, up to 20 wt.%, preferably up to 15 wt.%, ethanol, and/or up to 25 wt.%, preferably from 12 wt.% to 20 wt. %, most preferably up to 10 wt.% glycerol, and/or additionally up to 10 wt.%, preferably up to 7 wt.%, water. The addition of ethanol reduces the emulsifier content, in particular the polysorbate content, which is an advantage given the maximum allowable daily intake (ADI) for polysorbate (25 mg/kg body weight), as recommended by WHO. The emulsifier content, in particular polysorbate, can also be reduced by adding glycerol.

The solubilisates of the invention have a narrow particle size distribution with small average particle sizes even under physiological conditions of the gastric canal; the distribution of micelles by diameter in the solubilisate, diluted with distilled water in a ratio of 1:500 at pH 1.1 and 37°C, ranges from about d ₁₀ = 6 nm to about d ₉₀ = 20 nm. These values were determined from the volume distribution. The details of the granulometric analysis of micelles of solubilisates are set forth below.

Evidence of improved bioavailability (compared to compositions of at least THC, or of curcumin and THC as an additional active substance, which were not micellized according to the invention) is obtained by measuring the turbidity of the solubilisate, which is much more accessible to measurement methods. In the case of the composition according to the invention, the turbidity of the solubilizate is preferably less than 25 formazine nephelometric units (FNU), preferably less than 5 FNU, more preferably less than 3 FNU, as measured by scattered light using an infrared light source in accordance with the specifications of ISO 7027 when diluted solubilizate with water in a ratio of 1:50 or 1:500 under physiological conditions (pH 1.1 and 37°C).

In order to provide oral administration of the solubilisate according to the invention in a simpler and more convenient way for the consumer or the patient, the invention also provides a capsule filled with the solubilisate described above, and the capsule is a soft gelatin capsule or a hard gelatin capsule or a soft gelatin capsule or a hard gelatin-free capsule, for example, cellulose capsule.

Moreover, in the context of the invention, the solubilizate according to the invention can be introduced into other fluids, in particular liquids. At the same time, small micelles filled with the active substance are retained. Thus, the invention also provides a fluid containing a solubilisate as described above, the fluid being selected from the group consisting of foodstuffs, dietary supplements, beverages, cosmetics and pharmaceutical products. In the context of the invention, the fluid may in particular comprise a solubilisate diluted with water.

In addition, the invention provides a method for the treatment and/or prevention of diseases, including inflammation, cancer, Alzheimer's disease, Parkinson's disease, obesity, high cholesterol, high blood sugar, diabetes, metabolic syndrome and/or autoimmune diseases, multiple sclerosis (MS ); to reduce visceral fat, for thermogenesis, to reduce cholesterol, in particular LDL-cholesterol and/or blood glucose and/or blood triglycerides, to improve the density of macular pigment (in the retina), to reduce oxidative stress and/or to reducing the accumulation of fat in hepatocytes, in particular as a pharmaceutical preparation for the treatment and / or prevention of fatty liver, Friedreich hereditary ataxia, lysosomal diseases, in particular Tay-Sachs disease, atherosclerosis, heart disease, arthritis, according to which the solubilisate according to the invention, in particular , in capsule or liquid form, is administered to the consumer of the dietary supplement or to the patient, in particular orally, in particular once a day.

To obtain a solubilisate according to the invention containing curcumin and at least one THC as an additional active substance, it is possible either to mix together the solubilisates prepared separately, or to prepare a solubilisate directly on the spot, which contains curcumin and at least one cannabinoid as an additional active substance .

Thus, the solubilisate according to the invention is administered to the consumer of the dietary supplement or to the patient at a dose of curcumin from 0.5 mg/kg of body weight to 1 mg/kg of body weight, preferably at a dose of 0.81 mg/kg of body weight, in particular, once a day .

Also, the solubilisate according to the invention is administered to the consumer of the dietary supplement or to the patient at a dose of Boswellia from 1 mg/kg of body weight to 2 mg/kg of body weight, preferably at a dose of 1.62 mg/kg of body weight, in particular, once a day.

Similarly, the solubilizate according to the invention is administered to the consumer of the dietary supplement or the patient at a dose of xanthohumol from 0.5 mg/kg of body weight to 1 mg/kg of body weight, preferably at a dose of 0.81 mg/kg of body weight.

In addition, the invention provides a process for the preparation of a solubilizate as described above. If co-micelleization of curcumin and at least one cannabinoid as an additional active substance is required, the invention provides the following first variant of the preparation process with the following steps:

(a) providing polysorbate 80 and/or polysorbate 20 and/or at least one sucrose edible fatty acid ester and/or a mixture of emulsifiers selected from the group consisting of polysorbate 20, polysorbate 80 and sucrose edible fatty acid esters acids;

(b) adding THC, in particular in the form of THC oil (tetrahydrocannabinol oil);

(c) adding curcumin powder;

wherein step (a) comprises heating to a temperature of 40°C to 62°C, preferably to a temperature of 45°C to 57°C, most preferably to a temperature of 48°C to 52°C;

and according to which stage (b) includes heating to a temperature of from 82°C to 97°C, preferably to a temperature of from 83°C to 92°C, most preferably to a temperature of from 85°C to 89°C; and

according to which this temperature is maintained in stage (c).

This preparation method makes it possible to obtain a solubilizate which, when diluted with water, is capable of forming micelles loaded with curcumin and at least THC as an additional active substance. For this purpose, it is also possible to mix at least two active substances with each other in a preparatory step, under suitably adapted temperature control, and then add them in combined form as a mixture.

In the context of the invention, THC is used in particular in the form of THC oil. In principle, any product can be used as a source of THC within the scope of the invention. For example, THC oils can be used, in particular oils known as "full spectrum" THC oils, pastes, powders, crystalline forms and/or isolates, i. all of the products mentioned contain THC. In principle, it is also possible to use extracts of THC to obtain the solubilizate according to the invention. Said products may be products which contain primarily THC, such as the product known as "THC oil". However, it is also possible to provide mixtures consisting mainly of THC but containing some proportions of at least one other cannabinoid, and such THC products are referred to in the context of the invention as "THC".

During step (b), additional active substances can also be introduced, such as, for example, Boswellia serrata extract and/or xanthohumol.

Additionally or alternatively, additional active substances, such as, for example, serrapeptase, can be introduced in step (c). In addition to or as an alternative to the additional actives in step (c), MCT oil may be added, i.e. medium chain triglycerides.

In particular, in this case, before step (b), step (b1) is carried out by adding water at a temperature of 40°C to 62°C, preferably at a temperature of 45°C to 57°C, most preferably at a temperature of 48°C. C to 52°C.

Additionally or alternatively, in step (b1) the addition of ethanol can also be carried out at a temperature of from 40°C to 62°C, preferably at a temperature of from 45°C to 57°C, most preferably at a temperature of from 48°C to 52° C.

The invention also relates to solubilisates which, when diluted with water, form micelles loaded with only one curcumin, or alternatively with only one other active substance, at least immediately after their preparation. Thus, the invention also provides a process for the preparation of a solubilisate as described above by mixing a solubilisate of curcumin and a solubilisate of at least one THC, in particular in a 1:1 ratio of the individual solubilisates.

To this end, the invention provides a process for the production of a THC solubilisate with the following steps:

(a) providing polysorbate 80 and/or polysorbate 20 and/or at least one sucrose edible fatty acid ester and/or a mixture of emulsifiers selected from the group consisting of polysorbate 20, polysorbate 80 and sucrose edible fatty acid esters acids;

(b) adding THC, for example as THC oil;

wherein step (a) is heated to a temperature of at least 40°C to 62°C, preferably to a temperature of 45°C to 57°C, most preferably to a temperature of 48°C to 52°C; and

according to which in step (b) heating is carried out to a temperature of from 82°C to 97°C, preferably to a temperature of from 83°C to 92°C, most preferably to a temperature of from 85°C to 89°C.

It is also possible in step (a) to raise the temperature to a level in the range of 82°C to 97°C, preferably to a temperature of 83°C to 92°C, most preferably to a temperature of 85°C to 89°C. In preparation for this, you can perform the stage

(a1) mixing glycerin and THC, for example, in the form of THC oil, to form a solution;

wherein step (a1) is heated to a temperature of 82°C to 97°C, preferably to a temperature of 83°C to 92°C, most preferably to a temperature of 85°C to 89°C.

Within the scope of the invention, it is also possible to carry out the step in the preparatory step

(a11) mixing water and at least one sucrose ester of an edible fatty acid,

wherein step (a11) is heated to at least 40°C to 62°C, preferably 45°C to 57°C, most preferably 48°C to 52°C;

and stage

(a12) adding polysorbate 20 and/or polysorbate 80 to the mixture obtained in step (a11),

wherein in step (a12) heating is carried out to a temperature of 82°C to 97°C, preferably to a temperature of 83°C to 92°C, most preferably to a temperature of 85°C to 89°C.

After step (a1) or after step (a11) or after step (a12), the cannabinoid is added in step (b).

Hereinafter the invention is explained in more detail by means of examples of its implementation. The following components are used:

Curcumin

The curcumin used was a product called "Turmeric Oleoresin Curcumin Powder 95%" (95% curcumin powder concentrate from turmeric extract essential oil), product code EP-5001, from Green Leaf Extraction Pvt Ltd., Kerala, India. Curcumin powder has CAS number 458-37-7. It is a natural product obtained by solvent extraction from the rhizome of Curcuma longa (Curcuma longa). The curcumin content of the powder is at least 95% according to the manufacturer. This curcumin content is determined by the ASTA 18.0 method.

As an alternative to Green Leaf "oleoresin turmeric 95%" curcumin powder (see above), for example, 95% curcumin extract from Neelam Phyto-Extracts, Mumbai, India, or curcumin may also be used in the embodiments described below. BCM-95-SG or Curcumin BCM-95-CG from eurochem GmbH, Gröbenzel, Germany, or Curcuma Oleoresin 95% from Henry Lamotte OILS GmbH, Bremen, Germany.

THC

THC oil was used as the source of THC.

Boswellia

In the context of the present application, the term "Boswellia" refers in particular to an extract from the resin of the frankincense tree. In particular, an extract from the species Boswellia serrata was used, which is an extract obtained by extraction with ethyl acetate from the resin of a plant with the botanical name Boswellia serrata, and which has the product code "HC22519", from the manufacturer Frutarom Belgium N.V., Londerzel, Belgium. The solubilisate containing this extract is also called "boswellic acid solubilisate" due to its content of boswellic acids.

In addition to frankincense resin extracts, boswellic acids and/or boswellic acid derivatives can also be used to realize the solubilisates of the invention. In particular, the following may be considered: alpha-boswellic acid (CAS number 471-66-9), beta-boswellic acid (CAS number 631-69-6) and derivatives thereof; 3-O-acetyl-alpha-boswellic acid (CAS no. 89913-60-0), 3-O-acetyl-beta-boswellic acid (CAS no. 5968-70-7), 11-keto-beta-boswellic acid (KBA , CAS number 17019-92-0) and 3-O-acetyl-11-keto-beta-boswellic acid (AKBA, CAS number 67416-61-9).

Xanthohumol

"Xantho-Flav" or "Xantho-Flav Pure" products of the trade name "Hopsteiner" from Simon H. Steiner, Hopfen, GmbH, Mainburg, Germany, were used as a source of xanthohumol. Both products are natural, derived from hops. The active substance is a hop polyphenol - xanthohumol. It is a yellow powder with 65% to 85% xanthohumol in Xantho-Flav and at least 85% in Xantho-Flav Pure according to the manufacturer.

Xanthohumol (XN) and Isoxanthohumol (IX) concentrations in "Xantho-Flav Pure" were quantified by the manufacturer by UV spectrophotometric analysis or HPLC EBC 7.8 (EBC = color saturation index) using an external calibration standard - pure XN (at 370 nm) or pure IX (at 290 nm). "Xantho-Flav Pure" contains a very high concentration of prenylated flavonoid xanthohumol. In the embodiments of the invention in the context of the present application, "Xantho-Flav Pure" with lot number 9432 was used.

Serrapeptase

A product called serratiopeptidase 20000 U(enzymatic units)/mg from Shaanxi Pioneer Biotech Co. Ltd. with lot number PBD 20170708, was used as serrapeptase. It is a grayish white to light brown powder. The enzyme unit (U) is a unit of measure that was later replaced by katal (kat) to denote enzymatic activity. Because the numerical values change with the unit katal, the enzymatic unit (U) continues to be used in medicine and clinical chemistry. One enzyme unit U corresponds to the conversion (conversion) of one micromol of substrate per minute.

Polysorbate 80

The material "TEGO SMO 80 V" was used as a source of polysorbate 80.

FOOD" with specification code "K04 EU-FOOD" from Evonik Nutrition & Care GmbH, Essen, Germany. The product meets EU requirements as food additive E 433. As an alternative to the mentioned product TEGO SMO 80 V from Evonik, you can also use TEGO SMO 80 V from InCoPA Gmbh, Illertissen, Germany, or Crillet 4/Tween 80-LQ-(SG) from CRODA GmbH, Nettetal, Germany, or Lamesorb SMO 20 and Kotilen-O/1 VL from Univar or from Kolb Distributions AG, Hedingen, Switzerland, as polysorbate 80 in the embodiments described below.

Polysorbate 20

The source of polysorbate 20 was "TEGO SML 20 V FOOD" with specification code "K09 EU-FOOD" from Evonik Nutrition & Care GmbH, Essen, Germany. The product meets the EU requirements as food additive E 432. As an alternative to the mentioned product TEGO SML 20 from Evonik, Crillet 1/Tween 20-LQ-(SG) from CRODA GmbH, Nettetal, Germany, can be used as polysorbate 20 in the context of the invention.

Esters of sucrose and edible fatty acids

The sucrose edible fatty acid ester used was the sucrose ester of the product called "DUB SE 15 P" from the manufacturer Stéarine Dubois. This ester is approved for use in the EU as a food additive E473

Ethanol

In the context of this application, ethanol was purchased from Berkel Pfälzische Spritfabrik GmbH & Co. kg. According to the specification for "undenatured neutral alcohol 1411U taxed", the ethanol content of this product is approximately 92.6 to 95.2 wt.%.

Glycerol

The product used as glycerin in the context of this application was "Glycamed 99.7%" (Glycamed) from Glaconchemie GmbH, Merseburg, Germany. The glycerin content of this product is at least 99.5% according to the manufacturer.

Medium chain triglycerides

Medium chain triglycerides (MCTs) are triglycerides found in medium chain fatty acids. Medium chain fatty acids include caproic acid, caprylic acid, capric acid and lauric acid. They are saturated fatty acids found in naturally occurring tropical vegetable fats such as coconut oil and palm kernel oil. To a small extent, they are also found in milk fat. However, pure MCT oils do not exist in nature, pure MCT oils can be obtained synthetically. Individual MCTs or mixtures of different MCTs can be used as a source of medium chain triglycerides within the scope of the invention. Medium chain triglycerides were used as an MCT oil called Delios VK Kosher manufactured by Cognis GmbH, Monnheim, Germany, or as an MCT oil (70/30) called Rofetan GTCC 70/30 manufactured by DHW Deutsche Hydrierwerke Rodleben GmbH, Dessau- Rosslau, Germany, CAS number 73-398-61-5.

In addition, medium chain triglycerides can be used in the form of the product ROFETAN DTCC 70/30 (European Pharmacopoeia). It is a caprylic/capric acid triglyceride with CAS number 73398-61-5. The product complies with the monograph "Medium chain triglycerides" of the European Pharmacopoeia (valid on the date of application). Manufacturers are Ecogreen Oleochemicals DHW, Deutsche Hydrierwerke GmbH, Rodleben, Germany.

If water is added during the preparation of the solubilizate, then distilled water is used.

The micelle sizes in the water-diluted solubilisates of the invention were measured according to the principle of dynamic light scattering using laser light at a wavelength of 780 nm, unless otherwise indicated. Particle size measurements were performed using a ParticleMetrix NANO-flex particle backscatter analyzer. The measurement principle is based on dynamic light scattering (DLS) in a 180° heterodyne backscattering setup.

To experimentally determine the turbidity of the solubilisates according to the invention, a standard suspension is used to calibrate the turbidity meters. Therefore, instead of the measured light intensity, the concentration of the calibration suspension is indicated. Thus, when measuring any arbitrary suspension, the result of the measurement means that the corresponding liquid causes the same light scattering as the standard suspension at the specified concentration. Formazin is the international standard for turbidity. The most common units include the designation FNU, i.e. formazine nephelometric units. This is a unit used in water treatment, for example, to measure at an angle of 90° in accordance with the requirements of ISO 7072.

To obtain a solubilisate according to the invention, comprising the active substances curcumin and THC as an additional active substance, one can either mix separately prepared solubilisates with each other, or directly prepare a solubilisate that contains curcumin and THC or several additional active substances.

Curcumin solubilisates

An example of obtaining 7% curcumin solubilisate. For this, 925 g of polysorbate 80 and 75 g of curcumin powder 95% (= 71.2 g of curcumin) are used.

Polysorbate 80 is heated to a temperature of 48 to 52°C. The curcumin powder is added to the polysorbate under stirring conditions while subsequently heating to a temperature of 95 to 97°C. The powder is added at an appropriate rate so that it is uniformly distributed in the emulsifier during mixing. After cooling to a temperature below a maximum of 60°C, the curcumin solubilizate is bottled. This solubilisate was used to prepare curcumin solubilisate with Boswellia.

When diluted with water at a ratio of 1:500 at pH 1.1 and a temperature of 37°C, 7% curcumin solubilizate shows an average turbidity of 0.9 FNU (formazine nephelometric units).

However, it should be noted that the content of curcumin can be further increased without adverse effects, for example, in terms of micelle stability.

However, polysorbate 80 can be completely or partially replaced by polysorbate 20 or esters of sucrose and edible fatty acids. For example, to prepare a curcumin solubilisate with Polysorbate 20 alone, 894 grams of Polysorbate 80 and 106 grams of 95% curcumin powder can be used. Polysorbate 20 is heated to a temperature of from about 63°C to about 67°C. Under stirring conditions, the curcumin powder is slowly added to the polysorbate 80. During the addition of the curcumin powder, heating is continued to a temperature of from about 83°C to about 87°C. The resulting solubilizate is slowly cooled to a temperature below about 45°C, after which it is ready for bottling.

The rest of the production of these options is as described above. Approximately 11% solubilisates can be obtained by this method.

To prepare 10% THC oil solubilisate (anhydrous), use the following:

900 g polysorbate 80 and 100 g THC oil.

Polysorbate 80 is heated to a temperature ranging from 48°C to 52°C. The THC oil is added to the polysorbate under stirring conditions while the temperature is subsequently raised to between 85°C and 89°C. After cooling to below a maximum of 60°C, the THC oil solubilisate is bottled.

When diluted 1:50 with water at pH 1.1 and 37° C., the anhydrous 10% THC oil solubilisate shows a turbidity of 2.9 FNU.

The anhydrous THC solubilisate of the invention, in particular the THC solubilisate of the above example, is particularly suitable as a capsule content.

Another example of a cannabinoid solubilisate of the invention is a 10% THC oil solubilisate for which the following is used:

100 g THC oil, 27 g sucrose ester of edible fatty acids, 54 g water, 22.5 g glycerol and 796.5 g polysorbate 80.

Water and glycerin are mixed and heated to a temperature ranging from 48°C to 52°C. The sucrose ester is introduced with vigorous stirring. Stirring is carried out with an intensity sufficient for the sucrose ester to dissolve in water and glycerin. Polysorbate 80 is then added with stirring and homogenized while heating to a temperature ranging from 85°C to 89°C. Mixing is carried out with an intensity sufficient to ensure that polysorbate 80 is evenly distributed. After cooling with stirring to a temperature below 60°C, THC oil is introduced with vigorous stirring and completely homogenized while reheating to a temperature in the range from 85°C to 89°C. Mixing is carried out with an intensity sufficient to ensure that the THC oil is evenly distributed. The product is then cooled to below 60°C and bottled. After that, it is stored in the dark at a temperature not exceeding 25°C.

12% boswellic acid solubilisate

The following is used: 76 g 80% Boswellia serrata extract (= 60.8 g boswellic acid), 24 g water, 400 g polysorbate 20.

Water is mixed with boswellia powder while being heated to a temperature ranging from 87 to 93°C. Polysorbate 20 is introduced under conditions of maintaining the specified temperature. The emulsifier is added with continued stirring at such a rate that the liquids stably homogenize with the formation of a solubilisate. During cooking, excessive foaming may occur. This can be ignored if a clear solubilisate is visible at the bottom of the collecting container during filling.

1.5% serrapeptase solubilisate

The following is used: 15 g serrapeptase: serratiopeptase 20,000 enzyme units (U)/mg = 300,000,000 U, 15 g water, 16.5 g MCT oil (MCT=medium chain triglycerides), 953.5 g polysorbate 80.

At a temperature ranging from 18 to 22°C, water is mixed with serrapeptase and the mixture is homogenized. This means that the serrapeptase is distributed as evenly as possible in the water. This creates conditions for a more complete dissolution of serrapeptase in water. During heating to a temperature ranging from 83 to 87°C, the MCT oil is introduced into the mixture of water with serrapeptase with constant stirring. Stirring is carried out sufficiently intensively to ensure uniform dissolution of serrapeptase in water. At the same temperature, polysorbate 80 is added with stirring and homogenized. The mixing intensity is sufficient to evenly distribute polysorbate 80. The product is cooled to below 60°C and bottled. Then it is stored in the dark at a temperature not exceeding 25°C.

300,000 U/g corresponds to 15 mg/g 1.5% serrapeptase in enzyme units (U). When diluted with water in a ratio of 1:50, the turbidity of this solubilisate was determined under physiological conditions at pH 1.1 and 37°C. The result of the determination was 1.8 FNU (formazine nephelometric units).

10% Xantho-Flav solubilisate (corresponding to 7.5% xaxanthohumol solubilisate) with ethanol

For this xanthohumol solubilizate variant of the invention, the following was used:

100 g of Xantho-Flav (=75 g of xanthohumol), 150 g of ethanol (96%): neutral alcohol brand 1411U and 750 g of polysorbate 80.

First, the Xantho-Flav powder is dissolved in ethanol while heating to a temperature ranging from 48 to 52°C. A homogeneous solution is obtained. Polysorbate 80 is then added to the Xantho-Flav solution in ethanol while heating to a temperature ranging from 83 to 87°C. The addition is carried out at such a rate that the two liquids are well homogenized with stirring. The obtained solubilizate is cooled to a temperature below 60°C, bottled and stored in the dark and refrigerated, i.e. at temperatures below 25°C.

The solubilisates described above can be used to obtain a solubilisate according to the invention containing curcumin and at least one THC as an additional active substance, by mixing. This is described below with reference to Embodiment 1.

In the context of the present application, checking whether the homogenization of the components to form the solubilisate of the invention is sufficiently complete to be used in the preparation of any solubilisates is carried out by measuring the transparency of the product, which indicates a completely completed micellization, using a laser beam. Such measurement with a laser beam can be carried out, for example, by illuminating the sample with a commercially available laser pointer, in particular with a wavelength in the range from 650 nm to 1700 nm (spectral color red), and then visually inspecting the illuminated or irradiated solubilisate. Verification is not achieved by sampling, i.e. outside the reaction vessel, but in the reaction vessel. The laser beam is directed through a sight glass located on the front of the reaction vessel, perpendicular to the reaction vessel. If a simple luminous dot appears on the rear inner surface of the reaction vessel, with no scattering at all, then the resulting particle structures in the reaction vessel are smaller than the wavelength of visible light, which is a visual confirmation that the micellization process is complete.

Example 1

Solubilisate 1.4% curcumin / 2.4% boswellic acid / 1.5% xanthohumol / 0.2% THC oil / 0.3% serrapeptase.

The following is used according to the respective formulations as described above:

200 g 7% curcumin solubilisate, 200 g 12% boswellia solubilisate, 200 g 7.5% xanthohumol solubilisate, 200 g 10% anhydrous THC oil solubilisate and 200 g 1.5% solubilisate serrapeptases.

All five solubilisates can be heated to a temperature in the range of 50°C to 60°C to reduce their viscosity and thus increase their fluidity. They are then mixed together with agitation. After obtaining a homogeneous finished product, the latter is optionally cooled to a temperature below 60°C and bottled.

Before further processing, such as filling capsules, it is advisable to stir the product again to homogenize it and, if necessary, to heat it moderately for this purpose, i.e. to a temperature of about 40°C to 50°C.

When diluted with water at a ratio of 1:50 at pH 1.1 and a temperature of 37°C, the solubilizate shows an average turbidity of 3.4 FNU (formazine nephelometric units).

Example 2

Directly prepared solubilisate 1.4% curcumin / 2.4% boswellic acids / 1.5% xanthohumol / 0.2% THC oil / 3% serrapeptase.

The following is used:

15 g curcumin powder 95%, 30.4 g Boswellia serrata extract (24.3% boswellic acid), 20 g Xantho-Flav powder (at least 70% xanthohumol = 15 g xanthohumol), 20 g THC oil, 3 g serrapeptase (60,000,000 enzyme units), 12.6 g water, 20 g ethanol, 3.3 g MCT oil, 160 g polysorbate 20 and 715.7 g polysorbate 80.

Polysorbate 80 and Polysorbate 20 are mixed at a temperature of from 48°C to 52°C with stirring, the intensity of which is sufficient to obtain a homogeneous mixture. Next, water and ethanol are added with stirring, the intensity of which is sufficient to obtain a homogeneous mixture at a temperature ranging from 48°C to 52°C. Xanthohumol and boswellia are slowly mixed in with constant stirring. The temperature is then raised to 63 - 67°C with vigorous stirring. After that, curcumin, serrapeptase, THC oil and MCT oil are introduced into the mixture. The focus should be on ensuring good mixing and homogeneity of the product. If necessary, pauses are provided between the addition of one substance and the addition of the next substance. The addition is carried out slowly enough under agitation conditions so that the specific ingredient being added is evenly incorporated into the preparation.

The temperature rises further to a level ranging from 85°C to 89°C. The heating is carried out with constant stirring and slowly enough so that the heated mixture remains homogeneous and to obtain a transparent product. After cooling to below 60°C, the product is bottled. The product has a dark color and is viscous, it is stored in the dark at a temperature not exceeding 25°C. Before further processing, such as filling capsules, it is advisable to stir the product again to homogenize it and, if necessary, to heat it moderately for this purpose, i.e. to a temperature of about 40°C to 50°C.

Example 3

Solubilisate: 3% curcumin / 3.2% boswellic acid / 1.6% xanthohumol / 1% THC oil.

The following is used:

40.5 g 80% Boswellia serrata extract (32.4% boswellic acid), 31.5 g curcumin powder 95% (29.925 g curcumin), 20.7 g Xantho-Flav powder containing at least 80% xanthohumol (16.5 g xanthohumol), 54.3 g water, 45 g ethanol, 315 g polysorbate 20, 483 g polysorbate 80, 10 g THC oil.

When heated to a temperature in the range from 48 to 52°C, Polysorbate 20 and Polysorbate 80 are homogenized with stirring with each other, while simultaneously dissolving one in the other. While maintaining the specified temperature, the mixture of emulsifiers is mixed with water and ethanol with vigorous stirring, the intensity of which is sufficient for uniform distribution of water and ethanol in the emulsifier solution. At a constant temperature, an extract of Boswellia serrata and xanthohumol are introduced into a mixture of emulsifiers diluted with water under stirring conditions. The addition is carried out at a slow enough speed so that the Boswellia serrata extract and extrahumol are evenly drawn into the dilute emulsifier solution while stirring. The temperature is then raised to 63 - 67°C with vigorous stirring. Curcumin powder is added with stirring. The temperature is raised further to a level in the range from 85°C to 89°C under conditions of stirring, the intensity of which is sufficient to evenly distribute and homogenize the curcumin in the preparation. After that, THC oil is introduced into the mixture with stirring, the intensity of which is sufficient for uniform distribution and homogenization of the THC oil.

The mixture is then cooled to a temperature below or equal to 45°C. A dark yellow viscous preparation containing solubilisate of curcumin, boswellic acid, xanthohumol and THC oil is bottled and stored in the dark in a refrigerated mode, i.e. at temperatures below 25°C. The solubilizate and its aqueous solution are stably homogeneous and soluble in a crystal clear form.

It will be apparent to a person skilled in the art that the invention is not limited to the examples described above, but may vary in many ways. In particular, features of the separately illustrated examples may be combined or substituted. This applies in particular to the composition of the emulsifiers and to the composition of the active ingredients of the solubilisate according to the invention.

Claims (42)

1. Solubilizate consisting of three or more than three components, namely curcumin in an amount of less than or equal to 10 wt.%, from at least tetrahydrocannabinol (THC) as at least one additional active substance; and emulsifier polysorbate 80, or a mixture of polysorbate 80 and polysorbate 20, or a mixture of polysorbate 80 and at least one ester of sucrose and edible fatty acids in an amount of at least 70 wt.% emulsifier. 2. Solubilizate according to claim 1, which contains curcumin in an amount less than or equal to 8 wt.%. 3. Solubilizate according to claim 2, which contains curcumin in an amount of from 3 wt.% to 7 wt.%. 4. Solubilizate according to claim 2, which contains curcumin in an amount of from 1 wt.% to 3 wt.%. 5. Solubilizate according to any one of claims 1 to 4, which additionally contains up to 20 wt.% ethanol. 6. Solubilizate according to claim 5, which additionally contains up to 15 wt.% ethanol. 7. Solubilizate according to any one of claims 1 to 6, which additionally contains up to 25 wt.% glycerol. 8. Solubilizate according to claim 7, which additionally contains from 12 wt.% to 20 wt.% glycerol. 9. Solubilizate according to claim 7, which additionally contains up to 10 wt.% glycerol. 10. Solubilizate according to any one of claims 1 to 9, which additionally contains up to 10 wt.% water. 11. Solubilizate according to claim 10, which additionally contains up to 7 wt.% water. 12. The solubilizate according to any one of claims 1 to 11, which additionally contains, as at least one additional active substance, one substance or more substances selected from the group including secondary phytochemicals, natural phenols, plant extracts and enzymes. 13. The solubilisate according to claim 12 which contains flavonoids as secondary phytochemicals. 14. The solubilizate according to claim 12 which contains chalcones such as xanthohumol as natural phenols. 15. The solubilizate according to claim 12, which contains serrapeptase as an enzyme. 16. The solubilizate according to claim 12, which contains boswellia as a plant extract. 17. The solubilizate according to any of the preceding claims, which is suitable for the manufacture of an anti-inflammatory dietary supplement or as a pharmaceutical product for the prevention of the following diseases: cancer, Alzheimer's disease, Parkinson's disease, obesity, high cholesterol, high blood sugar, diabetes, metabolic syndrome and/or autoimmune diseases, multiple sclerosis (MS); to reduce visceral fat, for thermogenesis; to lower cholesterol, in particular LDL-cholesterol; with the effect of reducing blood glucose and/or triglycerides in the blood, to improve the density of macular pigment (in the retina), to reduce oxidative stress and/or to reduce the accumulation of fat in hepatocytes, in particular with an effect against fatty liver, Friedreich hereditary ataxia , lysosomal diseases, in particular Tay-Sachs disease, atherosclerosis, heart disease, arthritis. 18. Solubilizate according to claim 1, which contains from 75 wt.% to 95 wt.% of an emulsifier. 19. Solubilizate according to claim 1, which contains from 79 wt.% to 88 wt.% of the emulsifier. 20. The solubilizate according to any one of the preceding claims, wherein the micelle diameter distribution in the solubilizate diluted 1:500 with distilled water under physiological conditions pH 1.1 and 37°C is from about d ₁₀ = 6 nm to about d ₉₀ = 20 nm. 21. The solubilizate according to any one of the preceding claims, wherein the turbidity of the solubilizate is less than 25 formazine nephelometric units (FNU), preferably less than 5 FNU, most preferably less than 3 FNU, as shown by scattered light measurements using infrared light in accordance with ISO 7027 at dilution of the solubilizate with water in a ratio of 1:50 or 1:500 under physiological conditions pH 1.1 and 37°C. 22. An oral capsule, characterized in that it is filled with a solubilisate according to any one of the preceding claims and is a soft gelatin capsule or a hard gelatin capsule, or a soft gelatin-free capsule or a hard gelatin-free capsule, such as a cellulose capsule. 23. Food product in the form of a fluid, characterized in that it contains a solubilizate according to any one of claims 1 to 21. 24. A food product according to claim 23, characterized in that it comprises a solubilisate diluted with water. 25. Dietary supplement in the form of a fluid medium, characterized in that it contains a solubilizate according to any one of claims 1 to 21. 26. Dietary supplement according to claim 25, characterized in that it includes a solubilisate diluted with water. 27. Drink in the form of a fluid, characterized in that it contains a solubilizate according to any one of claims 1 to 21. 28. Drink according to claim 27, characterized in that it includes a solubilisate diluted with water. 29. Cosmetic product in the form of a fluid, characterized in that it contains a solubilizate according to any one of claims 1 to 21. 30. Cosmetic product according to claim 29, characterized in that it comprises a solubilisate diluted with water. 31. A method for preventing diseases, including inflammation, cancer, Alzheimer's disease, Parkinson's disease, obesity, high cholesterol, high blood sugar, diabetes, metabolic syndrome and/or autoimmune diseases, multiple sclerosis (MS); to reduce visceral fat, for thermogenesis, to reduce cholesterol, in particular LDL-cholesterol, and/or blood glucose and/or triglycerides in the blood, to improve the density of macular pigment (in the retina), to reduce oxidative stress and/or to reduce the accumulation of fat in hepatocytes, in particular for the prevention of fatty liver, Friedreich hereditary ataxia, lysosomal diseases, in particular Tay-Sachs disease, atherosclerosis, heart disease, arthritis; characterized in that the solubilizate according to any of the preceding claims 1 to 21 is administered to the consumer at a dose of curcumin from 0.5 mg/kg of body weight to 1 mg/kg of body weight once a day. 32. The method of claim 31 wherein the solubilisate is administered to the user at a curcumin dose of 0.81 mg/kg body weight. 33. A process for producing a solubilisate according to any one of claims 1 to 21, with the following steps: (a) providing an emulsifier of polysorbate 80, or a mixture of polysorbate 80 and polysorbate 20, or a mixture of polysorbate 80 and at least one ester of sucrose and edible fatty acids ; (b) adding THC; (c) adding curcumin powder; while stage (a) is carried out at a temperature in the range from 40°C to 62°C, and stage (b) is carried out at a temperature in the range from 82°C to 97°C, while stage (c) includes maintaining the specified temperature. 34. The method of claim 33, wherein step (a) is carried out at a temperature in the range of 45°C to 57°C. 35. The method of claim 33, wherein step (a) is carried out at a temperature in the range of 48°C to 52°C. 36. The method according to any one of claims 33 to 35, wherein step (b) is carried out at a temperature in the range from 83°C to 92°C. 37. The method according to any one of claims 33 to 35, wherein step (b) is carried out at a temperature in the range of 85°C to 89°C. 38. The method according to any one of claims 33 to 37, in which, before step (b), step (b1) of adding water is carried out at a temperature of from 40°C to 62°C, preferably at a temperature of from 45°C to 57°C, most preferably at a temperature of 48°C to 52°C. 39. The method according to claim 38, wherein in step (b1) the addition of ethanol is also carried out at a temperature of 40°C to 62°C, preferably at a temperature of 45°C to 57°C, most preferably at a temperature of 48°C up to 52°C. 40. The method according to any one of claims 33 to 39, wherein at least one additional active substance is administered in step (b). 41. The method according to claim 40, wherein in step (b) an extract of Boswellia serrata and/or xanthohumol is administered as at least one additional active substance. 42. The method according to claim 40 or 41, wherein in step (b) serrapeptase is administered as at least one additional active substance.