PL241424B1 - Turmeric extract formulation containing curcuminoids, method of its preparation, beverage, beverage concentrate, dietary supplement, pharmaceutical composition containing the formulation, and use of the formulation in dietary supplements and pharmaceutical products activating acetaldehyde metabolism - Google Patents

Abstract

The subject of the invention is a dry curcumin formulation, a method of its preparation, a beverage concentrate, a drink, a dietary supplement, a pharmaceutical composition containing a curcumin formulation, and its use in products that activate acetaldehyde metabolism, including as an anti-hangover agent.

Description

PL 241 424 B1

Description of the invention

TECHNICAL FIELD

The subject of the invention is a curcumin formulation in dry form containing curcuminoids of turmeric extract dispersible in water and a method for producing a curcumin formulation in dry form from turmeric extract formulation, beverage, beverage concentrate, dietary supplement. A pharmaceutical composition containing a formulation and possible uses of a water-dispersible turmeric extract formulation in beverages and their concentrates, dietary supplements and pharmaceutical products activating acetaldehyde metabolism are also described.

STATE OF TECHNOLOGY

According to the World Health Organization, alcohol (ethanol) is at the top of the list of risk factors that threaten the health of the population. However, due to the widespread acceptance of its consumption, the scale of medical problems caused primarily by the toxic effects of ethanol metabolites is constantly growing. Acetaldehyde is one of the best described toxicologically substances formed during the metabolism of alcohol. Acetaldehyde is the first product of ethanol oxidation. It is a compound 30 times more toxic, mutagenic and carcinogenic than ethanol, with documented multi-organ effects, especially in the liver and lungs. The conversion of ethanol to acetaldehyde is catalyzed by alcohol dehydrogenase (ADH), while the main enzyme catalysing the oxidation of acetaldehyde to low-toxic acetic acid is aldehyde dehydrogenase (ALDH). So far, 19 ALDH isoenzymes encoded by different gene loci and showing a wide variety of substrate specificity have been identified. Despite the existence of many molecular forms of ALDH, only the enzymes encoded by the ALDH1 and ALDH2 genes participate in the degradation of acetaldehyde. Cytosolic ALDH1 is found in many tissues, including the brain, but the catalytic efficiency of this enzyme is low (Km about 50 μM). Mitochondrial ALDH2 (Km < 5 μM; pH 7.5) has a much greater affinity for acetaldehyde, which occurs not only in hepatocytes, but also in other types of cells, e.g. gastric epithelium, glia and neurons. The loss of ALDH2 enzyme activity is the result of a single-point, nonsense mutation in the gene at position 1510, which results in a G-to-A substitution in exon 12. ALDH2 activity is closely related to racial affiliation: the mutation leading to loss of enzyme activity occurs mainly in oriental populations ( Japan, Taiwan, China, Korea, Hong Kong, Singapore, Vietnam, Malaysia, etc.) and affects up to 50% of the population, while in representatives of the Caucasian race these values oscillate between 8-10%. The phenomenon of reduced ALDH2 activity also occurs in patients with cirrhosis, regardless of the etiology of this disease and the amount of alcohol consumed. The concentration of acetaldehyde in the blood, which is a derivative of the amount of alcohol consumed and the activity of alcohol dehydrogenase, which determines the rate of elimination of this compound, has a significant impact on the occurrence and course of many diseases of the liver, cardiovascular system, bronchial asthma, Alzheimer's disease and cancers of the respiratory system and gastrointestinal tract. food. Due to the very unfavorable biological effects of acetaldehyde, it is in the interest of public health to reduce its level in the human body as quickly and as effectively as possible. On the market of dietary supplements and medical preparations, there are preparations with anti-inflammatory effects and preparations to supplement the deficit of vitamins, electrolytes and minerals with symptomatic effects, mitigating the effects of alcohol and acetaldehyde poisoning, and a few preparations with a preventive effect, the function of which is to support the work of the liver and accelerating the metabolism of alcohol and its metabolites, such as Morning Recovery (MoreLabs) or G ETADAY (Drink6 Iberia S.L.U.) based on herbal extracts with the active substance DHM (dihydromyricetina) and herbs used in Ayurvedic medicine, e.g. extract of ginseng and fig prickly pear.

In ReadyQ (Handok) the active substance is DHM and curcumin, and in alcorythm® (Nomi Biotech Corporation) curcumin. Due to the low native bioavailability, despite the clearly positive effect of curcumin on the activation of acetaldehyde metabolism, the use of curcumin is limited, and in preparations containing curcumin it is necessary to use substances supporting bioavailability, such as piperine, which significantly negatively affect the taste of the preparation and cause irritation of the mucosa in people sensitive. The lack of water-dispersible curcumin formulations with increased bioavailability and high stability, based on ingredients approved for use in the food and pharmaceutical industries, are characterized by

EN 241 424 B1, which have a neutral taste and smell, is a serious technical limitation for the development of preventive preparations based on the use of curcuminoids, including those that activate the metabolism of acetaldehyde.

Curcuma longa, commonly called turmeric, is a tropical plant of the Zingiberaceae family, native to South Asia. Turmeric rhizomes have traditionally been used as a coloring ingredient, but also as a spice. Turmeric is quite commonly used as a spice, but also as an additive to food and beverages (Govindarajan, 1980; Salzer et al., 1975). Dried turmeric rhizomes contain 3-5% essential oils and 0.0-6.0% curcuminoids such as curcumin, demethoxy-curcumin and bis-demethoxy-curcumin. These curcuminoids may occur in different amounts and proportions to each other, which depends on the biological and environmental factors related to the cultivation of the rhizome itself, and in the case of oleoresin or extracts, on the technology of their production. In addition to the coloring and spice properties, turmeric, and especially the curcuminoids contained in it, have various medicinal properties confirmed by pharmacological studies conducted on various animals. Turmeric extracts have anti-inflammatory, anti-fungal and anti-cancer effects (Amalraj et al., 2017; Yamamoto et al., 1997; Apisariyakul et al., 1995; Ruby et al., 1995). In order to be able to affect living organisms (humans and animals), curcuminoids must first be delivered to the body and then absorbed from the digestive tract into the bloodstream (Amalraj et al., 2017; Jager et al., 2014).

Curcuminoids are compounds that do not dissolve in water, and what is more, their solubility in vegetable and animal fats is very limited and does not exceed 1 mg ml ^-1 , which significantly hinders the bioavailability of curcuminoids from the gastrointestinal tract. Curcuminoids dissolve best in organic solvents such as acetone, then ethyl acetate, methanol and ethanol (in the case of ethanol, in order to increase the solubility of curcuminoids, it is required to heat the solution to the boiling point, i.e. approx. 78 ° C, which causes thermal decomposition of curcuminoids) (Amalraj et al., 2017; Anderson et al., 2000). Due to the toxicity of solvents, solutions obtained in this form cannot be administered to living organisms. Methods and ways of dissolving or dispersing curcuminoids in water are sought so that they can be introduced into the human or animal body in this form. Studies have shown that the physical or chemical form of curcuminoids plays a key role in their bioavailability. It has been shown that the dispersion of curcuminoids in an aqueous environment significantly improves their bioavailability (Jager et al., 2014). In addition, the purpose of developing water-soluble or dispersible curcuminoid formulations is to facilitate their combination with the appropriate flavor and aroma composition, thanks to which they can be much more willingly consumed by humans and animals. Curcuminoids in concentrated form, like powdered turmeric itself, have a very intense, characteristic taste and are bitter, which practically disqualifies the possibility of eating them directly. In this form, they can either be encapsulated or used as a food supplement. The development of a curcuminoid formulation that enables their dispersion in an aqueous environment is a major technological challenge, also due to the low fat solubility of curcuminoids (fat solubility < 1 mg g ^-1 , while curcuminoids are completely insoluble in water). In the case of products intended for food, the formation of the dispersion system must be carried out with organic solvents allowed in food production, which must then be removed from the final product. Moreover, their content in the final product must meet the legal requirements on the approximation of the laws of the Member States on extraction solvents used in the production of foodstuffs and food ingredients (Directive 2009/32/EC of the European Parliament and of the Council of 23 April 2009).

Many methods of obtaining water-dispersible curcuminoid formulations are described in the world literature. A very common method of obtaining water-dispersible curcuminoids is dissolving them in 70-80% ethanol together with β-cyclodextrin, and then heating and stirring for at least 4 h at 70°C (Mangolim et al., 2014; Marcolino et al. ., 2011). Solvents (ethanol and water) are removed most often by spray drying, but also by vacuum evaporation or freeze-drying. This method of obtaining water-dispersible curcuminoids has several disadvantages. The first one is the unfavorable chemical transformations of curcuminoids in a water-ethanol environment related to their thermal decomposition. Research by Wang et al. (1999) showed that curcuminoids in an aqueous environment under the influence of elevated temperature, even at the most favorable pH of the environment (curcuminoids are most stable at pH between 3 and 6) decompose. Wang et al., (1999) showed that curcumin heating

PL 241 424 B1 at 37°C for 2 h causes as much as 10% loss of this compound. Formulation of curcuminoids dispersing in water should be carried out at possibly low temperatures, especially in the process of combining them with the water phase. An additional disadvantage of the formulation using β-cyclodextrin is its limited use in food production, β-cyclodextrin (E 459) can be used in the production of e.g. beverages, but its content cannot be higher than 1 g kg ^-1 (Commission Regulation (EU ) No. 1129/2011). This limits the possibility of introducing any amount of curcuminoids into the finished product.

Other formulations of water-dispersing curcuminoids are those compounds adsorbed on silicates, e.g. silicon dioxide (Martins et al., 2013). The use of curcuminoids adsorbed on silicon dioxide (E 551) in the production of e.g. beverages is quite limited, because such a formulation is not thermodynamically stable and such particles sediment quickly. This is due to the high density of silicon dioxide and curcuminoids associated with it.

There are many different formulations of curcuminoids available on the world market, however, not all of them may be suitable for the production of beverages, i.e. their dispersion in water. Meriva® produced by Indena SpA (Italy) consists of 18-20% curcuminoids adsorbed on microcrystalline cellulose with the addition of soy lecithin (Cuomo et al., 2011). This product is more suitable for the preparation of solid preparations or as a food additive, but other than beverages, due to the lack of solubility of microcrystalline cellulose, which falls out of solution and sediments. LongVida® produced by Verdure Sciences (USA) is a preparation that contains approx. 20% of curcuminoids suspended in fat particles with a solid consistency at room temperature with the addition of phosphatidylcholine (Gota et al., 2010). The preparation is basically used for the production of dietary supplements in the form of tablets or capsules, it can also be added to various foods, however, it is not suitable for the permanent dispersion of curcuminoids in water. CurQfen® produced by Akay Flavors & Aromatics Pvt. Ltd., MicroActive Curcumin produced by BioActives LLC (USA) contains approx. 25% curcuminoids suspended in short-chain triacylglycerols with the addition of free fatty acids and polyglycerol esters. The formulation is stabilized with hydroxypropyl methylcellulose, sodium alginate and microcrystalline cellulose (Madhavi et al., 2014). This formulation has been developed mainly for the production of tablets/capsules containing highly bioavailable curcumin. Micronized Curcumin produced by Raps GmbH & Co., KG (Germany) contains approx. 25% curcumin powder dispersed in triacetin (glycerol triacetate) and a mixture of lipids obtained from soybean, oil palm and rapeseed (Schiborr et al. 2014). The preparation is not soluble in water and is not suitable for obtaining stable curcuminoids dispersed in water. NovaSOL® produced by FRUTAROM from Israel is a micellar curcumin with a concentration of approx. 7% in Tween-80 (Schiborr et al., 2014). The preparation cannot be used in food, as Tween-80 is not approved for use in food in many countries, including the EU. CurcuWin® produced by OmniActive Health Technologies (India) contains 20-28% turmeric extract (a mixture of three curcuminoids), which is suspended in a mixture of 63-75% polyvinylpyrrolidone (E1201), 10-40% cellulose derivatives with the addition of 1-3% of natural antioxidants (Jager et al., 2014). The preparation enables the production of tablets/capsules, but is not suitable for the production of beverages. CURCUGREEN® (BCM-95®) produced by Arjuna Natural Extracts Ltd., (India) is an essential oil consisting of 45% ar-turmerone and curcuminoids (Antony et al., 2008). CURCUGREEN® (BCM-95®) is water insoluble and not suitable for beverage production. Curcumin C3 Complex® + Bioperine® produced by Sabinsa USA is a mixture of piperine and curcuminoids without any special formulation (Shoba et al., 1998). The preparation is not suitable for dispersion in water. CAVACURMIN® produced by Wacker Chemie AG, (Germany) contains approx. 15% curcuminoids in combination with γ-cyclodextrin (Puroura et al., 1998). This product disperses in water, however, at high temperature, curcuminoids with cyclodextrins conjugates are formed (described earlier), and this promotes the thermal breakdown of curcuminoids. In addition, γ-cyclodextrin is not authorized for use in food in the EU and the preparation cannot be used in the production of food, including beverages. Theracurmin™ manufactured by Theravalues Corp. (Japan) is a nano-colloidal preparation containing up to 30% of curcuminoids. The preparation additionally contains glycerin and Ghatti gum (Sasaki et al., 2011). The product disperses well in water, it is suitable for the production of beverages, however, at the moment it cannot be used for food production, because Ghatti gum is not approved for food production as an additive in the EU. In addition, due to the content of maltose and maltodextrin pre

PL 241 424 B1 Theracurmin™ parat is characterized by a sweet taste, which limits its use in food products. The content of maltose and maltodextrin in Theracurmin™ preparation, due to their high glycemic index and high calorific value, makes it impossible to use it for the production of low-calorie drinks or for special purposes, e.g. for diabetics or overweight people.

All the commercially available curcumin formulations described above were developed to maximize the bioavailability of curcuminoids, omitting the technological aspects necessary to develop a formulation suitable for water dispersion and, consequently, for the production of beverages.

DISCLOSURE OF THE INVENTION

TECHNICAL PROBLEM

The technological problem resulting from the state of the art is the lack of a water-dispersible turmeric extract powder formulation, assuming that the turmeric extract contains high concentrations of curcuminoids, preferably min. 90% w/w curcuminoids, including curcumin, demethoxy-curcumin and bisdemethoxy-curcumin, the dispersion of which in water will be stable, with no observable and noticeable sedimentation or creaming process for a long time. After dissolving the formulation in water, the system should be uniformly colored. Preferably, the content of turmeric extract in the final formulation is at least 10%. All substances used in the production of formulations should be allowed for use in food, including in the EU, in accordance with the currently applicable regulations in this regard. The emulsification process should preferably take place at maximum room temperature (20°C ± 2°C) to avoid thermal degradation of the curcuminoids. Higher temperature results in a decrease in viscosity and thus an increase in particle size distribution, which adversely affects the stability of the dispersion system.

PURPOSE OF THE INVENTION

The object of the invention is to overcome the indicated disadvantages of the state of the art. This goal was achieved by developing a formulation solution as well as a method of its production and a product obtained in this way, enabling the preparation of a water-dispersible formulation of turmeric extract with increased stability, increased homogeneity, and in the method of producing the curcumin formulation in the form of an emulsion solution and in a dry form, all substances used in the production process are substances approved for use in food production.

The inventors of the invention surprisingly found that the use of an unobvious system of excipients, preferably in the form of starch octanyl succinate and cellulose derivatives as a carrier, and the use of an organic solvent approved for use in the production of food, preferably in the form of ethyl acetate, methyl acetate, butyl acetate, ethanol acetate, butanol acetate , particularly preferably ethyl acetate, allows the homogenization process to produce an emulsion with a narrow and small particle distribution (the vast majority with a diameter of less than 1 μm, preferably in the range of 0.1 to 1 μm), which ensures the formation of a dispersible formulation in the spray drying process turmeric extract containing curcuminoids with the desired physico-chemical properties.

THE ESSENCE OF THE INVENTION

Innovative research carried out by the creators has shown that the use of a combination of starch octanyl succinate and cellulose derivatives, in particular hydroxypropyl cellulose or hydroxypropyl methylcellulose, as a carrier for dissolved in an organic solvent approved for use in food production, which is ethyl acetate, methyl acetate, butyl acetate, ethanol, butanol , particularly preferably ethyl acetate, turmeric extract containing curcuminoids, allows to obtain an emulsion in the process of homogenization. In addition, the inventors have found that the addition of a polysaccharide solution, preferably a high viscosity cellulose derivative, particularly preferably carboxymethyl cellulose (CMC), preferably if the solvent is water, stabilizes the emulsion. The obtained emulsion is stable and characterized by a narrow and small distribution of particles with a diameter of less than 1 μm, with no sedimentation or creaming process observable to the naked eye, preferably for a period of not less than 12 months.

The combination of starch octanyl succinate with modified cellulose as a carrier for the turmeric extract dissolved in an organic solvent makes it possible to prepare the curcuma formulation according to the invention in the form of an emulsion with a narrow and small particle size distribution, even using only turbo-vortex homogenization. In order to obtain the curcuma formulation according to the invention in a dry form, most preferably as a powder, stabilization of the emulsion system is carried out during drying of the formulation.

EN 241 424 B1 curcumin in the form of an emulsion consisting in diluting the prepared emulsion in an aqueous solution of carboxymethyl cellulose (CMC) at a concentration of 0.001 to 1%, preferably 0.01 to 0.5%, preferably 0.10 to 0.20%, preferably 0.10 to 0.20%, preferably 0.1-1.4%, in a proportion of not less than 1:6, preferably in a proportion of about 1:8, and drying the thus stabilized emulsion to obtain a powder, e.g. by spray drying. Produced powder - the curcumin powder formulation is still characterized by a narrow and low particle distribution, and after reconstitution of the produced powder, a stable dispersion system is obtained due to prior stabilization by carboxymethyl cellulose.

Surprisingly, it turned out that it is possible to obtain particles of the dispersed phase for turmeric extract containing curcuminoids with the particle size of the dispersed phase particles below 1 μm, which makes it possible to obtain a system that is stable from the point of view of thermodynamics of emulsion systems. The lower diameter range of the obtained particles does not affect the stability of emulsion production, although obtaining the majority of particles in a certain range, preferably in the particle diameter range of 0.1-1 μm, facilitates the industrial processing of such a uniform product at a later stage. With such a small particle size of the dispersed phase for the extract prepared in this way, the sedimentation velocity calculated from the Stokes equation

V = [(2r ² g(pp-pf)]/(9n) will be low, which is what the final curcumin formulation of the invention provides.

More surprisingly, it turned out that the curcumin formulation according to the invention has a higher bioavailability, i.e. it is better absorbed by the body than known and commercially available preparations containing curcumin, as well as having a higher permeability through the intestinal cell layer. Unexpectedly, it turned out that the curcumin formulation according to the invention provides improved properties in the regulation of liver function, better activates the action of liver enzymes, especially enzymes from the group of dehydrogenases, including aldehyde dehydrogenase, and also shows greater activity in anti-inflammatory, anti-cancer and anti-depressant effects than known and available curcumin preparations .

The following explanations and general definitions refer to the descriptions of preferred embodiments of the invention that follow.

The present invention, as illustrated below, may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein.

When the term "comprising" or "including" is used in this specification and claims, it is not intended to exclude other elements. For purposes of the present invention, the term "consisting of" is considered a preferred embodiment of the term "comprising" including. When a group is defined below that includes at least a certain number of embodiments, this is also to be understood as disclosing a group that preferably consists only of those embodiments.

The terms "about" or "approximately" in the context of the present invention mean a range of accuracy that a person skilled in the art will understand to be sufficient to still provide the technical effect of a given feature. The term "typically" means a deviation from the indicated numerical value of ± 10%, preferably ± 5%.

Technical terms are used in accordance with their usual meaning. If a specific meaning is used, the meaning will be described in detail with respect to the context in which the term is used.

By stability is meant the formation of a dispersed system with a particle size of the dispersed phase < 1 μm. Stability is understood as the formation of a dispersion system, homogeneous to the naked eye without a visible process of creaming or sedimentation. The system is considered stable if, during 20 minutes of centrifugation at 5000 rpm, min ^-1 and at 25°C, the amount of sediment at the bottom of the tube does not exceed 30% of the starting weight of the powder formulation dispersed in water.

Dispersion means a system composed of at least two immiscible phases, at least one of which is a finely divided system (dispersed phase), dispersed in a second continuous phase (dispersing phase), called the dispersion medium.

Solubility means the ability of a solid substance to dissolve in the liquid phase and form a dispersion system creating a heterogeneous mixture.

The invention relates to a curcumin formulation in a dry form, preferably a water-soluble powder, giving a dispersion system whose dispersed phase is characterized by a particle size of < 1 μm. Additional features of the developed curcumin formulation:

PL 241 424 B1 • The formulation is made without the use of ethanol or other alcohols or ketones (e.g. acetone) • The formulation is neutral in taste, i.e. no sweet, sour and bitter-scorching taste, i.e. the characteristic taste of turmeric • The formulation is produced at low temperatures, which favorably affects the chemical stability of curcuminoids

The subject of the invention is a curcumin formulation in dry form, comprising:

- 0.1-45% w/w starch octenyl succinate,

- 0.01-20% w/w of a cellulose derivative in the form of hydroxypropylmethylcellulose, hydroxypropylcellulose or a mixture thereof;

- 0.01-20% w/w turmeric extract, wherein the turmeric extract comprises at least 90% w/w curcuminoids, including curcumin, demethoxycurcumin and bisdemethoxycurcumin;

- 0.1-10% w/w β-glucan,

- 10-70% w/w of a cellulose derivative with a viscosity > 5600 mPas selected from carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, ethyl methyl cellulose, cross-linked cellulose gum;

wherein at least 90% of the particles are less than 1 Pm in diameter, more preferably at least 95% of the particles are less than 1 Pm in diameter, more preferably at least 99% of the particles are less than 1 Pm in diameter;

wherein preferably at least 90%, more preferably at least 95%, more preferably at least 99% of the particles have a diameter in the range of 0.1 to 1 Pm.

The curcumin formulation in dry form preferably comprises

- starch octenyl succinate in an amount of 25-35% w/w, more preferably 2-32% w/w;

- hydroxypropylmethylcellulose, hydroxypropylcellulose or a mixture thereof in an amount of 5-15%, more preferably in an amount of 8-10%;

- turmeric extract in an amount of 5-15%, more preferably in an amount of 8-10%, wherein the turmeric extract contains at least 90% w/w curcuminoids, including curcumin, demethoxycurcumin and bisdemethoxycurcumin,

- β-glucan in an amount of 3-5% w/w, more preferably in an amount of 3.8-4.2% w/w;

- carboxymethyl cellulose in an amount of 30-60% w/w, more preferably in an amount of 48-52% w/w.

The invention also relates to a process for the preparation of a curcumin formulation in dry form, which comprises the following steps:

a) dissolving a turmeric extract containing at least 90% curcuminoids in a food grade organic solvent selected from ethyl acetate, methyl acetate, butyl acetate, ethanol, butanol or a mixture thereof, preferably the organic solvent is ethyl acetate;

b) the dissolved turmeric extract of step a) is added to the carrier solution which is a mixture of polymers comprising starch octenyl succinate and a cellulose derivative, wherein the cellulose derivative is hydroxypropylcellulose, hydroxypropylmethylcellulose, or a mixture thereof dissolved in water, wherein the mixture of hydroxypropylcellulose to hydroxypropylmethylcellulose is relative to 10:1;

wherein the carrier is prepared by mechanically mixing the polymers, which are then dissolved in water, in a weight ratio of 1:5 to 1:25, preferably 1:10, and mechanically mixed to dissolve and combine the polymers, preferably for at least 10 hours, more preferably 12 hours, wherein 0.1 to 30 g of starch octanyl succinate and 0.02 to 20 g of hydeoxypropyl cellulose or hydroxypropyl methyl cellulose or a mixture thereof are used in the preparation of the carrier, based quantitatively on the mixture produced in step a) prepared from 0.01 g to 3 g of turmeric extract dissolved in 0.19 ml to 60 ml of organic solvent; wherein the temperature of the carrier solution during the addition of the dissolved turmeric extract is from 5°C to 10°C; cooling is preferably used to maintain this temperature of the prepared mixture (the use of higher temperatures affects the viscosity of the continuous phase, which in turn contributes to obtaining an emulsion system with an unfavorable particle size distribution, i.e. with a diameter above 1 μm);

c) the mixture obtained in step b) is homogenized to obtain an emulsion, preferably at a temperature of about 5°C to about 10°C (the use of higher temperatures affects the viscosity

PL 241 424 B1, which consequently contributes to obtaining an emulsion system with an unfavorable particle size distribution, i.e. a diameter above 1 μm);

d) the emulsion obtained in step c) is diluted with an aqueous solution of β-glucan (this is a polymer that positively affects the stability of the dispersion system), at a concentration of 1-8% of low viscosity β-glucan in the range of 40-200 mPas, preferably from oats or barley or a mixture thereof and further briefly homogenized;

e) the emulsion obtained in step d) is stabilized by diluting with an aqueous solution of a cellulose derivative with a viscosity above 5600 mPas selected from carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, ethyl methyl cellulose, cross-linked cellulose gum, in a proportion of not less than 1:6, preferably not less than 1:8, with mechanical mixing, preferably the high viscosity cellulose derivative is carboxymethyl cellulose (CMC), preferably in a concentration of 0.01 to 0.%, more preferably in a concentration of 0.10 to 0.20, more preferably in a concentration from 0.1 to 1.4% (w/w); and

f) the stabilized emulsion of step e) is dried to obtain the curcumin formulation in a dry form, preferably drying is carried out using spray drying with an inlet temperature to the dryer in the range of 110-160°C, more preferably 150°C, and an outlet temperature not greater than 65°C, preferably not greater than 55°C;

wherein greater than 90%, preferably greater than 95%, preferably greater than 99% of the particles obtained have a diameter of less than about 1 Pm, more preferably at least 90%, more preferably at least 95% of the particles, more preferably at least 99% of the particles have a diameter in the range 0.1 to about 1 μm.

In a preferred method for preparing the curcumin formulation, the drying in step f) is carried out using spray drying with an inlet temperature to the dryer in the range of 110-160°C, more preferably about 150°C, and an outlet temperature of not more than 65°C, preferably not more than about 55°C. It has surprisingly been found that the use of low temperatures in the range of 2-20°C, preferably from about 5°C to about 15°C, more preferably from about 5°C to about 10°C, more preferably about 7°C, in step b) and c) has been found to be C or in a water bath, preferably an ice bath, allows the formation of an emulsion with the desired particle size range. Higher temperatures affect the viscosity of the continuous phase, which in turn contributes to obtaining an emulsion system with an unfavorable particle size distribution with a diameter above 1 μm.

Preferred embodiments of the process for making a curcumin formulation in dry form to obtain a stabilized emulsion having a narrow and fine particle distribution in the range of about 0.1 to about 1 µm in diameter without appreciable sedimentation or creaming use a carrier of starch octanyl succinate polymers and a cellulose derivative. The carrier is made of a mixture of starch octanyl succinate and a cellulose derivative, preferably with a viscosity in the range of 40-200 mPas, particularly preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, preferably in the proportion of 0.1 to 3 g of starch octanyl succinate (e.g. PURITY GUM 2000®) to 0.02 up to 20 g of hydroxypropyl cellulose or hydroxypropyl methyl cellulose, or a mixture thereof in the proportions 0:0 to 10:1. After mechanical mixing of the polymers, they are dissolved in a polar solvent, which is particularly preferably water, in a weight ratio of 1:5 to 1:25, preferably 1:10. The resulting mixture is mechanically stirred to dissolve and combine the polymers, preferably for proper dissolution and connection of the polymers, for not less than 10 h, preferably about 12 h.

Separately, a turmeric solution with a minimum content of 90% curcuminoids is prepared in a food grade organic solvent, preferably ethyl acetate. The solution is obtained by dissolving 0.01 to 3 g of turmeric extract (min. 90% curcuminoids) in a food grade organic solvent, preferably 0.19 to 60 ml of ethyl acetate. The dissolved curcuminoid extract is added to the polymer mixture (polymer ratio 2:3 w/w) and homogenized using e.g. a mechanical homogenizer. Homogenization can be carried out in various ways in a continuous manner, for example by gradually increasing the speed of rotation, but most preferably it is carried out in two stages, first producing a pre-emulsion and then carrying out the actual homogenization. The two-stage emulsion production is carried out, for example, at a rotational speed in the range of 5000 rpm. rpm ^-1 - 15000 rpm min ^-1 , preferably at a rotational speed of the working element of 10,000 rpm. min ^-1 until the pre-emulsion is produced. The entire mixture from the time the curcuminoids are introduced into the polymer mixture is cooled, for example in an ice water bath. The temperature of the polymer mixture at the time of introduction of the dissolved ethyl acetate extract preferably should not exceed about 10°C and preferably should not be lower than about 5°C. After the pre-emulsion has been prepared, it is subjected to treatment

EN 241 424 B1 using a homogenizer, preferably a turbo-vortex homogenizer, and process parameters in the range of 20,000-24,000 rpm. ^rpm , preferably 22,000 rpm. min ^-1 for 3 min., after this time water or an aqueous β-glucan solution is added, preferably a 1-8% aqueous β-glucan solution, preferably from low viscosity oats or barley (about 40-200 mPas) in an amount of 0.5 to 210 ml (1:0.25 w/w) and further homogenized, for example for 1 min. The emulsion thus prepared is immediately combined with a polysaccharide solution, preferably a high viscosity cellulose derivative, preferably a solution of 0.1-1.4% aqueous high viscosity carboxymethylcellulose (CMC) solution. This technological procedure enables the production of a stable formulation, i.e. one with a particle size distribution of the dispersed phase < 1 μm in diameter (for at least 90% of the particles, preferably for 95%, most preferably for more than 99% of the particles of the dispersed phase). The emulsion is diluted with water in a proportion of not less than 1:6, more preferably not less than 1:8, the whole is mechanically stirred using a stirrer, preferably a propeller stirrer, and the stabilized emulsion is dried, obtaining a curcumin formulation in a dry, preferably powder form. Drying can be carried out by a number of methods known in the art, but preferably spray drying is carried out using a dryer inlet temperature of 110-160°C, preferably 150°C, and an outlet temperature of not more than 65°C, preferably 55°C.

Also described is a curcumin formulation in dry form obtained by the process for preparing the curcumin formulation of the invention.

The formulation obtained in accordance with the above description is based only on ingredients approved for use in the food industry in accordance with EU law. At the same time, due to the use of only plant ingredients and the complete elimination of ethyl alcohol as a solvent from the production process, the formulation can be certified in accordance with the HALAL procedures, which, if used in food products intended for the markets of Muslim countries, enables their distribution due to the non-use ethyl alcohol as a solvent in the formulation preparation process. The formulation is characterized by an intense orange-yellow color that is natural for turmeric.

In contrast to the known turmeric formulations available on the market, the turmeric formulation according to the invention, the food products produced on its basis, as well as the emulsion produced from it, is characterized by a completely neutral taste - without the bitterness characteristic of turmeric extracts and without the typical sweetish aftertaste, for formulations using maltodextrin and/or maltose, which significantly increases the scope of its application in the food, pharmaceutical and dietary supplement industries. The formulation is stable in dry form and in the form of an aqueous solution, which enables its effective use in a wide range of food products.

The invention relates to a beverage concentrate comprising a curcumin formulation according to the invention. A preferred beverage concentrate of the invention further comprises at least one of: 0-28% w/w glycerol and/or xanthan gum, 0-5% w/w ascorbic acid; 0-5% w/w, citric acid; 0-80% w/w, glucose; vitamins selected from thiamine, niacin, pyridoxine, folic acid, riboflavin or a mixture thereof; preservatives selected from benzoic acid, sodium benzoate, potassium sorbate, or a mixture thereof.

Also described is a beverage concentrate which further comprises at least one of: a stabilizing and thickening agent at a concentration of 0-28% w/w, preferably glycerol and/or xanthan gum; antioxidant and acidity regulator 0-5% w/w, preferably ascorbic acid; acidity regulator 0-5% w/w, preferably citric acid; electrolyte and sweetener 0-80% w/w, preferably glucose; B vitamins, preferably selected from thiamine, niacin, pyridoxine, folic acid and riboflavin; preservatives, preferably benzoic acid, sodium benzoate, potassium sorbate, or a mixture thereof.

The invention also relates to a beverage comprising the curcumin formulation according to the invention. The preparation of a beverage by diluting the beverage concentrate according to the invention is also described. The preferred beverage is a fruit juice based beverage, water.

A preferred beverage is a functional liver support beverage, wherein the concentration of curcuminoids in the beverage is 0.01-0.1% w/w.

The invention also relates to a dietary supplement comprising a curcumin formulation according to the invention, preferably the supplement is consumed in a dose corresponding to an amount of 0.2 to 2.0 g of curcuminoids per kilogram of body weight of the subject.

A beneficial dietary supplement supports the work of the liver, and preferably activates the activity of liver enzymes, preferably enzymes from the group of dehydrogenases, preferably aldehyde dehydrogenase.

PL 241 424 B1

The preferred dietary supplement is in liquid form. A preferred dietary supplement is in liquid form and contains the formulation according to the invention in an amount giving curcuminoids at a concentration of 0.01-0.1% w/v, fruit juice concentrate 1-20% w/v, sweetener 2-10% w/v, stabilizing and thickening agent at a concentration of 2-10% w/v.

Also described is a pharmaceutical composition comprising the described curcumin formulation and a pharmaceutically acceptable additive.

Also described is a pharmaceutical composition comprising the described curcumin formulation for use as a medicament.

Preferably, the composition is for use as a medicament in the regulation of liver function activating the action of liver enzymes, preferably enzymes from the group of dehydrogenases, preferably aldehyde dehydrogenase.

What is extremely important due to the increased bioavailability, beverages/emulsions or compositions made based on the turmeric formulation of the invention do not require the addition of piperine, which was necessary to increase the bioavailability of turmeric formulations known in the art.

The inventors found that the formulation according to the invention can be successfully used to produce a stable concentrate containing from 5 to 20% of the formulation concentration and the final concentration of curcuminoids (from 0.1 to 2.0% w/w) being preferably 5 to 20 times concentrated concentrate for use in the production of beverages, especially functional beverages, in which the active substance is curcumin, especially beverages with the effect of activating the metabolism of acetaldehyde.

Due to the high stability, lack of modification of biological activity and increased bioavailability of curcuminoids, the formulation according to the invention can be used to produce functional dietary supplements or pharmaceutical preparations in which one of the active substances is curcumin. Preferably, such preparations include preparations with liver functions regulating activity, activating the activity of enzymes, including enzymes from the group of dehydrogenases, including aldehyde dehydrogenase, anti-inflammatory, anti-cancer and anti-depressant activity.

In a preferred example of application, the formulation is used to produce a functional drink as a dietary supplement supporting liver function, especially in terms of activating enzymes that break down acetaldehyde, preventing some negative aspects of alcohol consumption by lowering the concentration of acetaldehyde in the blood. In a preferred embodiment, the formulation is used at a concentration corresponding to a final curcuminoid concentration of 0.01-0.1% w/w.

Due to the increased bioavailability of curcumin in the form of the described formulation, the use of the formulation makes it possible to eliminate from the recipe of the functional drink concentrate and the functional drink substances supporting bioavailability, used in preparations available on the market, in the form of e.g. black pepper extract in the form of piperine (Preparations ReadyQ, alcorythm ®) adversely affecting the taste of the preparation due to its sharp and burning taste and irritating, and substances additionally inducing the activity of enzymes accelerating the decomposition of acetaldehyde, such as DHM (dihydromyricetin) (ReadyQ, Morning Recovery preparations).

The concentrate may also contain excipients in any combination including at least one of the following substances, such as:

- a stabilizing and thickening agent at a concentration of 0-28% w/w, preferably glycerol and/or xanthan gum,

- antioxidant and acidity regulator 0-5% w/w, preferably ascorbic acid,

- acidity regulator 0-5% w/w, preferably citric acid

- electrolyte and sweetener 0-80% w/w, preferably glucose.

The concentrate may also contain B vitamins (including thiamine, niacin, pyridoxine, folic acid and riboflavin) in concentrations for each vitamin not higher than twice the maximum reference intake dose, taking into account the stability surplus, multiplied by the concentration value of the concentrate.

The concentrate may contain preservatives in any combination including at least one of the substances listed below, such as, assuming that the total concentration of preservatives, after dilution of the concentrate to the target concentration, does not exceed 0.2% w/w, the concentrate may contain exemplary preservatives : benzoic acid 0-2% w/w, sodium benzoate 0-2% w/w, potassium sorbate 0-2% w/w, or a mixture thereof.

PL 241 424 B1

Due to the completely neutral taste, the use of excipients allowed in the food industry and bioavailability. The inventors have found that the use of the formulations according to the invention to produce beverages allows the technological problems arising from the state of the art to be avoided.

DESCRIPTION OF DRAWING FIGURES

For a better understanding of the invention, it is illustrated by non-limiting embodiments and the accompanying drawings, in which:

FIG. 1 shows the particle size distribution of the produced emulsion before spray drying; FIG. 2 shows the particle size distribution of a reconstituted powder containing 15% curcuminoids.

EXAMPLES

The following examples are provided solely for the purpose of illustrating the invention and explaining particular aspects thereof, not for the purpose of limiting it, and should not be construed as being in its entirety as defined by the appended claims. In the following examples, unless otherwise indicated, standard materials and methods used in the art were used or manufacturers' recommendations for specific materials and methods were followed.

Example 1

Preparation of a curcumin formulation in the form of a powder

6 g of starch octanyl succinate (e.g. PURITY GUM 2000®) and 2 g of hydroxypropyl methylcellulose (a cellulose derivative with a viscosity in the range of 40-200 mPas) were mixed. After mechanical mixing of the polymers, they were dissolved in a polar solvent, which was water, in the amount of 100 ml. The resulting mixture was mechanically mixed to dissolve and combine the polymers, the inventors surprisingly found that this occurs after not less than 10 h, preferably 12 h. 1.6 g of turmeric extract (min. 90% content of curcuminoids) was dissolved in 30 ml of ethyl acetate at boiling point this solvent. The dissolved curcuminoid extract was added immediately after dissolution to the mixture of polymers and homogenized using a mechanical homogenizer at the rotational speed of the working element of 10,000 ^rpm until a pre-emulsion was obtained, i.e. a homogeneous mixture assessed with the naked eye. The whole mixture, from the moment of introducing the curcuminoids to the mixture of polymers, was cooled in an ice water bath. The temperature was kept in the range of 5-10°C, preferably 7°C. After the pre-emulsion was prepared, it was subjected to proper homogenization using a turbo-vortex homogenizer and process parameters: ^22,000 rpm for 3 minutes, after which water or a 1.5% aqueous solution of low-viscosity oat or barley β-glucan (40 -200 mPas) in 50 ml and further homogenized for 1 min. The thus prepared emulsion was immediately combined with a 1% aqueous solution of high viscosity carboxymethyl cellulose (CMC) (>5600 mPas). The emulsion was diluted in 1L of the solution prepared in this way, with mechanical stirring using a propeller stirrer. For the emulsion solution, the percentage distribution of particle size in the test sample in individual size categories was determined. Results were obtained with a distribution similar to that of Example 2 (greater than 99% of the particles were in the size range of about 0.1 to about 1 μm).

The emulsion solution prepared in this way was subjected to conventional spray drying using a temperature at the inlet to the dryer of about 150°C, and at the outlet of about 55°C. For the obtained curcumin formulations in the form of powder after its dissolution, the size of the obtained particles and their size distribution were determined (Table 1, Fig. 2).

PL 241 424 B1

Table 1. Percentage distribution of particle size in the tested sample (powder after reconstitution), in individual size categories

no. Lower limit of the range (pm) Average particle size in the range (pm) % particles no. Lower limit of the range (pm) Average particle size in the range (pm) % particles no. Lower limit of the range (pm) Average particle size in the range (pm) % particles 1 0 0.025 0 23 1.24 1.34 0 45 35.56 38.495 0 2 0.05 0.055 0 24 1.44 1.56 0.07 46 41.43 44.85 0 3 0.06 0.065 0 25 1.68 1.815 0.31 47 48.27 52.25 0 4 0.07 0.075 0 26 1.95 2.115 0.43 48 56.23 60.87 0 5 0.08 0.085 0 27 2.28 2.465 0.43 49 65.51 70.915 0 6 0.09 0.1 0 28 2.65 2.87 0.36 50 76.32 82.615 0 7 0.11 0.12 0 29 3.09 3.345 0.28 51 88.91 96.245 0 8 0.13 0.14 0.01 thirty 3.6 3,895 0.2 52 103.58 112.125 0 9 0.15 0.16 0.07 31 4.19 4.535 0.13 53 120.67 130.625 0 10 0.17 0.135 0.51 32 4.88 5.285 0 54 140.58 152.175 0 11 0.2 0.215 2.39 33 5.69 6.16 0 55 163.77 177.285 0 12 0.23 0.25 7.71 34 6.63 7.175 0 56 190.8 206.54 0 13 0.27 0.29 15.99 35 7.72 8.36 0 57 222.28 240.615 0 14 0.31 0.335 21.02 36 9 9.74 0 58 258.95 280.315 0 15 0.36 0.39 19.72 37 10.48 11.345 0 59 301.68 326.57 0 16 0.42 0.455 15.52 38 12.21 13.215 0 60 351.46 380.455 0 17 0.49 0.535 9.77 39 14.22 15.395 0 61 409.45 443.23 0 18 0.58 0.625 4.02 40 16.57 17.94 0 62 477.01 516.36 0 19 0.67 0.725 1 41 19.31 20.9 0 63 555.71 601.56 0 twenty 0.78 0.845 0 42 22.49 24.345 0 64 647.41 700.82 0 21 0.91 0.985 0 43 26.2 28.365 0 65 754.23 816.45 0 22 1.06 1.15 0 44 30.53 33.045 0 66 878.67 878.67 0

It has surprisingly turned out that the formulation obtained as described above has a particularly favorable particle size distribution in the range of about 0.1 to about 1 [mu]m in diameter (greater than about 95% of the particles, preferably greater than 97%, preferably 100% of the particles), with curcuminoids in the range (from 0.01% to 15%), which increases its dispersion properties in the aqueous environment, enabling the preparation of emulsions with a high degree of homogeneity.

The quantitative and qualitative composition of the obtained dried (up to 5% moisture) formulation prepared according to the above example was as follows:

starch octanyl succinate 29.5% (w/w) hydroxypropyl methylcellulose (as a cellulose derivative) 9.8% (w/w) turmeric extract (min. 90% curcuminoids) 7.9% (w/w β-glucan 3.7 % (w/w) carboxymethylcellulose 49.1% (w/w);

with greater than 97% of the reconstituted particles having a size in the range of about 0.1 to about 1 µm.

The formulation was characterized by an intense orange-yellow color, was neutral in taste and easily dissolved in water to form a uniform suspension.

Example 2

Preparation of a curcumin formulation in the form of a powder

The formulation of the mixture was obtained as in example 1 with the difference that:

after mechanical mixing of the polymers, they were dissolved in a polar solvent, which was water, in the amount of 90 ml;

g of turmeric extract (min. 90% content of curcuminoids) was dissolved in a mixture of ethyl acetate and acetone in a ratio of 5:1 in the amount of 35 ml at the boiling point of the mixture.

The resulting mixture was mechanically mixed to dissolve and combine the polymers, not less than 10 h, preferably 12 h. The dissolved curcuminoid extract was added immediately after dissolution to the polymer mixture and homogenized using a mechanical homogenizer at the rotational speed of the working element ^of 10,000 rpm until - emulsion, i.e. obtaining a homogeneous mixture assessed with the naked eye. The whole mixture, from the moment of introducing the curcuminoids to the mixture of polymers, was cooled in an ice water bath. The temperature was kept in the range of 5-10°C, preferably around 7°C. For the curcumin formulations obtained in the form of emulsions, the size of the obtained particles and their size distribution were determined (Table 2, Fig. 1).

PL 241 424 B1

The inventors surprisingly found that the formulation obtained as described above has a particularly favorable particle size distribution in the range of from about 0.1 to about 1 µm in diameter (greater than about 95% of the particles, preferably 100% of the particles), with curcuminoid content in the range (from 0.01% to 20%), which increases its dispersion properties in an aqueous environment, enabling the preparation of emulsions with a high degree of homogeneity.

Table 2. Percentage distribution of particle size in the tested sample (emulsion), in individual size categories

no. Lower limit of the range (pm) Average particle size in the range (pm) % particles no. Lower limit of the range (pm) Average particle size in the range (pm) % particles no. Lower limit of the range (pm) Average particle size in the range (pm) % particles 1 0 0.025 0 23 1.24 1.34 0 45 35.56 38.495 0 2 0.05 0.055 0 24 1.44 1.56 0 46 41.43 44.85 0 3 0.06 0.065 0 25 1.68 1.815 0 47 48.27 52.25 0 4 0.07 0.075 0 26 1.95 2.115 0 48 56.23 60.87 0 5 0.08 0.085 0 27 2.28 2.465 0 49 65.51 70.915 0 6 0.09 0.1 0 28 2.65 2.87 0 50 76.32 82.615 0 7 0.11 0.12 0 29 3.09 3.345 0 51 88.91 96.245 0 8 0.13 0.14 0.02 thirty 3.6 3,895 0 52 103.58 112.125 0 9 0.15 0.16 0.11 31 4.19 4.535 0 53 120.67 130.625 0 10 0.17 0.185 0.57 32 4.88 5.285 0 54 140.58 152.175 0 11 0.2 0.215 2.26 33 5.69 6.16 0 55 163.77 177.285 0 12 0.23 0.25 6.53 34 6.63 7.175 0 56 190.8 206.54 0 13 0.27 0.29 12.97 35 7.72 8.36 0 57 222.28 240.615 0 14 0.31 0.335 17.42 36 9 9.74 0 58 258.95 280.315 0 15 0.36 0.39 17.9 37 10.48 11.345 0 59 301.68 326.57 0 16 0.42 0.455 16.65 38 12.21 13.215 0 60 351.46 380.455 0 17 0.49 0.535 13.67 39 14.22 15.395 0 61 409.45 443.23 0 18 0.58 0.625 8.53 40 16.57 17.94 0 62 477.01 516.36 0 19 0.67 0.725 3.38 41 19.31 20.9 0 63 555.71 601.56 0 twenty 0.78 0.845 0 42 22.49 24.345 0 64 647.41 700.82 0 21 0.91 0.985 0 43 26.2 28.365 0 65 754.23 816.45 0 22 1.06 1.15 0 44 30.53 33.045 0 66 878.67 878.67 0

The quantitative and qualitative composition of the obtained dried (up to 5% moisture) formulation prepared according to the above example was as follows:

starch octanyl succinate 28.9% w/w;

hydroxypropyl methylcellulose 9.6% w/w;

turmeric extract (min. 90% curcuminoids) 9.6% w/w β-glucan 3.6% w/w;

carboxymethylcellulose 48.3% w/w;

wherein for this emulsion composition, 100% of the particles had a particle size in the range of about 0.1 to about 1 µm.

For the obtained curcumin formulation in the form of powder, the size of the obtained particles and their size distribution after reconstitution were determined. More than 98% of the particles after reconstitution of the powder had a size in the range of about 0.1 to about 1 µm. Thus, results with a distribution similar to the results from example 1 were obtained.

The formulation was characterized by an intense orange-yellow color, was neutral in taste and easily dissolved in water, creating a uniform suspension.

Example 3

Preparation of a curcumin formulation in the form of a powder

The formulation of the mixture was obtained as in example 1 with the difference that:

after mechanical mixing of the polymers, they were dissolved in a polar solvent, which was water, in an amount of 90 ml;

the prepared emulsion solution was subjected to freeze drying using the following process parameters: drying pressure 0.5 mbar, shelf temperature program: from 0 to 2 h -20°C, 2-3 h 20°C, 3-1 8 h 20°C, 18- 19 h 40°C, 18-19 h pressure 0.2 mbar, 19-24 h 40°C - end of the process. For the curcumin emulsion and powder formulations obtained

After dissolving the powder, the size of the obtained particles and their size distribution were determined. Results with a distribution similar to those for examples 1 and 2 were obtained.

The inventors have surprisingly found that the formulation obtained as described above has a particularly favorable particle size distribution in the range of about 0.1 to about 1 μm in diameter (greater than about 95% of the particles, preferably 100% of the particles), with a content of curcuminoids in the range (from 0.01% to 20%), which increases its dispersion properties in an aqueous environment, enabling the preparation of emulsions with a high degree of homogeneity.

The quantitative and qualitative composition of the obtained dried (up to 5% moisture) formulation prepared according to the above example was as follows:

starch octanyl succinate 26.5% (w/w) hydroxypropyl methylcellulose 9.8% (w/w) turmeric extract (min. 90% curcuminoids) 16.4% (w/w) β-glucan 3.7% (w/w) w) carboxymethyl cellulose 43.6% (w/w) with more than 97% of the particles having a particle size in the range of about 0.1 to about 1 μm after reconstitution.

The formulation was characterized by an intense orange-yellow color, was neutral in taste and easily dissolved in water, creating a uniform suspension.

Example 4

Curcumin formulation aqueous solution

The curcumin powder formulation prepared according to Examples 1-3 was dissolved in water at certain concentrations and their physico-chemical properties were tested. Based on the obtained results, it was found that the formulations form a stable suspension in the aqueous environment, in the concentration range from 0.01% to 30% w/w. Preferably the concentration is 0.05-10.00%, particularly preferably 0.5%-1.5% (w/w). At the indicated concentrations, especially at the preferred concentrations, the formulation forms an optically homogeneous suspension, at room temperature after 24 hours, optically no visible precipitate was observed.

The aqueous solution of the formulation in the right concentrations is characterized by chemical stability (the study was carried out on the basis of the observation of color changes, indicating oxidation processes of the active substance and color changes in an acidic environment, in the pH range equal to or higher than 3.0 and less than 7.0, which makes it possible to use it in food production.

In aqueous solutions, the formulation remains stable for a period of min. 12 months, as shown in aging tests under accelerated aging conditions (according to ICH Q1A (R2) Stability testing of new drug substances and drug products - EDQM recommendations).

In order to confirm the stability of the suspension and determine the level of sedimentation, a study was carried out consisting in centrifugation of a suspension with a concentration of 0.5% curcuminoids in 15 ml of distilled water at a speed of 5000 rpm for 20 minutes at a temperature of 25°C in the REF 11778 rotor of the MPW380R centrifuge MPW.

Suspensions compared:

a) the test formulation of Examples 1-3

b) turmeric extract containing 95% curcuminoids

c) CAVACURMIN (Wacker Chemie AG) and CurQfen (Akay Group Ltd.) The suspensions were standardized to a total curcuminoid concentration of 0.5% w/w.

PL 241 424 B1

Table 3. Stability results for the developed formulation and similar formulations available on the market. P1, P2, P3 formulation prepared according to example 1,2,3, respectively.

Tested product sample concentration (volume of sample subjected to stability test 15 ml) concentration of curcuminoids in water suspension (15 ml) % of substance in the form of sediment after centrifugation at 50,000 rpm at 25°C and after 20 min The formulation according to the invention P1 (7.9% curcuminoids*) 949.33 mg in 15 ml of water 0.5% 20.4% P2 (9.6% curcuminoids*) 781.22 mg in 15 ml of water 0.5% 19.9% P3 (16.4% curcuminoids*) 457.3 mg in 15 ml of water 0.5% 19.5% CAVACURMIN® (16.4% curcuminoids*) 457.3 mg in 15 ml of water 0.5% 100% CurOfen® (47.1% curcuminoids*) 159.2 mg in 15 ml of water 0.5% 95% turmeric extract (% curcuminoids*) 81.5 mg in 15 ml of water 0.5% The extract floats on the surface of the water *Curcumin content this was measured spectrophotometrically at λ = 420nm. The solution in which

curcuminoids were extracted from the formulation and spectrophotometric measurements were made to water:acetone 30:70 v/v.

The results unequivocally indicate a greater suspension stability of the formulation according to the invention.

Example 5

Bioavailability of the aqueous suspension of the formulation

The inventors performed a bioavailability study of a suspension in water of the formulations of the invention. The study was conducted in vitro on a cellular model of absorption and penetration through the epithelial cell layer of the intestinal epithelium, using the Caco-2 cell line, according to the protocol described in: Frank, J., 2017. The study compared the bioavailability of turmeric extract, the tested formulation according to the invention and CAVACURMIN® (Wacker Chemie AG) and CurOfen® (Akay Group Ltd.) The bioavailability was tested on suspensions normalized for the final content of curcuminoids - concentration of 10 pg/ml.

Table 4 Absorption and permeability of curcuminoid formulations through Caco-2 cell monolayer over 60 min. P1, P2, P3 formulation prepared according to example 1,2,3, respectively.

Initial concentration of curcuminoids time (minutes) % of curcumin absorbed by cells % curcumin that penetrated the cell monolayer CurOufen® 10µg/ml 60 39.64% ±0.22% 0.66% ± 0.04% CAVACURMIN® 10µg/ml 60 21.61%±0.15% 0.00% ± 0.00% Formulation acc. invention P1 P2 P3 10µg/ml 60 42.57% ±1.21% 44.23% ±0.89% 43.62% ± 0.07% 0.63% ± 0.80% 0.72% ± 0.40% 0.67% ± 0.50%

The study clearly demonstrated the increased bioavailability of the formulations of the invention compared to CAVACURMIN® and CurOufen®. The formulation according to the invention is absorbed by cells at a level more than 2 times higher than that of Cavacurmin® and more than 10% higher than that of CurOfen® (in studies, CurOfen® has been shown to have 45

PL 241 424 B1 up to 270 times higher bioavailability than native turmeric extract - Kumar et al. 2016). At the same time, the formulation according to the invention shows 1.5% higher permeability through the cell monolayer than CurQfen®, measured over 60 minutes.

Example 6

Concentrate to be used in the production of functional drinks and dietary supplements using a formulation produced in accordance with one of the methods described in examples 1, 2 and 3.

A 5-fold concentrated concentrate containing:

formulation according to of the invention: 5% w/w prepared according to Example 1:

xanthan gum: 1.1% w/w;

glycerol: 26.5% w/w;

citric acid: 2.5% w/w;

sodium benzoate: 0.5% w/w;

potassium sorbate: 0.5% w/w;

glucose: 40% w/w;

water: up to 100% w/w.

The concentrate showed high stability, confirmed by pH and microbiological tests. No changes in pH, no growth of mesophilic bacteria, molds and yeasts were demonstrated during the storage period of up to 6 months. Neither the color of the concentrate nor its other organoleptic properties changed. To prepare the final drink, the concentrate should be diluted 1:4 (concentrate:liquid), preferably with water or reconstituted fruit juice from the concentrate, preferably tropical fruit juice, preferably mango, peach, orange juice or a mixture of these juices. Concentrates were similarly prepared using the formulation prepared according to Example 2 (using 7% w/w of the manufactured formulation) and Example 3 (using 10% w/w of the manufactured formulation).

Example 7

Functional drink

A functional drink supporting the work of the liver was produced, activating the action of liver enzymes, preferably enzymes from the group of dehydrogenases, preferably aldehyde dehydrogenase during alcohol consumption, a) 5-fold concentrated fruit juice concentrate (preferably lemon, grapefruit, mango, passion fruit, orange, peach, pineapple, especially orange) was mixed with the formulation prepared according to example 1 so that the final concentration of the formulation in the finished product was 0.01% w/v, the mixture was supplemented with water so as to obtain 1-fold the final concentration of the juice. b) 5-fold concentrated fruit juice concentrate (preferably lemon, grapefruit, mango, passion fruit, orange, peach, pineapple) was mixed with the formulation prepared according to example 1 so that the final concentration of the formulation in the finished product was 0.01% w/v, the mixture was supplemented with water to obtain a 1-fold final concentration of the juice, then a sweetener (glucose) was added to the mixture to the concentration in the final product of 4% and citric acid to the concentration in the final product of 0.4%, and then supplemented with water to obtain twice diluted fruit juice.

A functional juice drink can be consumed without restrictions as a fruit juice equivalent for diluting alcohol-based cocktails or drinking alcohol, in order to activate the metabolism of acetaldehyde, preferably enzymes from the group of dehydrogenases, preferably aldehyde dehydrogenase and reduce the effects of alcohol consumption resulting from acetaldehyde poisoning .

Example 8

Dietary supplement in the form of capsules

A dietary supplement in the form of capsules supporting the work of the liver was produced, activating the activity of liver enzymes, including enzymes from the group of dehydrogenases, especially aldehyde dehydrogenase, intended for use before or during alcohol consumption. The formulation prepared in accordance with example 1 was encapsulated in gel capsules approved for pharmaceutical use in doses of 500 mg of the substance according to the formulation. In an optional variant, the gel capsules, in addition to the formulation, contain the addition of adjuvants and fillers, preferably if the adjuvant is beta-glucan, in a dose of up to 100 mg, and the filler is cellulose. Preferably, the capsules will be made of a gel substance that dissolves in the intestinal environment

PL 241 424 B1, preferably if the substance is a polymer of plant, microbial or synthetic origin, meeting the criteria of HALAL and vegan certification. A single gel capsule is a single dose of the supplement to be taken 60 minutes before or during alcohol consumption for an adult weighing up to 85 kg. Taking capsules, especially before alcohol consumption, activates the action of liver enzymes, including enzymes from the group of dehydrogenases, increasing the tolerance of the person taking the curcumin formulation with increased bioavailability to the ethyl alcohol consumed by the individual.

Example 9

Dietary supplement in liquid form

A dietary supplement in a liquid form supporting the work of the liver, activating the action of liver enzymes, preferably enzymes from the group of dehydrogenases, preferably aldehyde dehydrogenase, to be taken before or during alcohol consumption, was produced.

Mango juice concentrate, mixed in a tank with a vortex mixer with water, glucose, glycerol, xanthan gum, citric acid, B vitamins, thiamine, niacin, pyridoxine, folic acid and riboflavin, preservatives sodium benzoate and potassium sorbate and a formulation made according to example 1 to a final concentration of curcuminoids of 0.1% w/v and natural flavor of passion fruit. After thorough mixing of the ingredients, the prepared liquid dietary supplement with a density of 1.02 g*cm3-1 was poured into 100 ml bottles, constituting a single dose of the supplement to be taken within 60 minutes before or during alcohol consumption for an adult body weight up to 85 kg.

The final concentrations of ingredients in the finished liquid dietary supplement were as follows:

- mango juice concentrate 6% w/v

- natural passion fruit flavor 0.001% w/v

- glucose 8% w/v

- xanthan gum 0.226% w/v

- glycerol (99.5%) 5.333% w/v

- citric acid 0.5% w/v

- potassium sorbate 0.1% w/v

- sodium benzoate 0.1% w/v

- niacin 0.0165% w/v

- thiamine 0.0029% w/v

- riboflavin 0.00132% w/v

- pyridoxine 0.023% w/v

- folic acid 0.000352% w/v

- formulation according to the invention according to example 1 to the final concentration of curcuminoids

0.1% w/v

A dietary supplement in liquid form is intended to be consumed immediately before or during alcohol consumption in the form of a single dose of 100 ml for an adult weighing up to 85 kg, as a preparation supporting the work of the liver, activating the activity of liver enzymes, preferably enzymes from the group of dehydrogenases, preferably aldehyde dehydrogenase to be taken before or during alcohol consumption. Taking a dietary supplement in liquid form, especially before drinking alcohol, activates the action of liver enzymes, including enzymes from the group of dehydrogenases, increasing the tolerance in a person taking the curcumin formulation according to the invention with increased bioavailability contained therein to the ethyl alcohol consumed by the individual.

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Claims (9)

PL 241 424 B1 Patent claims 1. A curcumin formulation in dry form, characterized in that it comprises - 0.1-45% w/w starch octenyl succinate, - 0.01-20% w/w of a cellulose derivative in the form of hydroxypropylmethylcellulose, hydroxypropylcellulose or a mixture thereof; - 0.01-20% w/w turmeric extract, wherein the turmeric extract comprises at least 90% w/w curcuminoids, including curcumin, demethoxycurcumin and bisdemethoxycurcumin; - 0.1-10% w/w β-glucan, - 10-70% w/w of a cellulose derivative with a viscosity > 5600 mPas selected from carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, ethyl methyl cellulose, cross-linked cellulose gum; wherein at least 90% of the particles are less than 1 Pm in diameter, more preferably at least 95% of the particles are less than 1 Pm in diameter, more preferably at least 99% of the particles are less than 1 Pm in diameter; wherein preferably at least 90%, more preferably at least 95%, more preferably at least 99% of the particles have a diameter in the range of 0.1 to 1 Pm. 2. A curcumin formulation in dry form according to claim 1, characterized in that it comprises - starch octenyl succinate in an amount of 25-35% w/w, more preferably 28-32% w/w; - hydroxypropylmethylcellulose, hydroxypropylcellulose or a mixture thereof in an amount of 5-15%, more preferably in an amount of 8-10%; - turmeric extract in an amount of 5-15%, more preferably in an amount of 8-10%, wherein the turmeric extract contains at least 90% w/w curcuminoids, including curcumin, demethoxycurcumin and bisdemethoxycurcumin, - β-glucan in an amount of 3-5% w/w, more preferably in an amount of 3.8-4.2% w/w; - carboxymethyl cellulose in an amount of 30-60% w/w, more preferably in an amount of 48-52% w/w. 3. A method for producing a curcumin formulation in dry form, which includes the following steps: a) dissolving a turmeric extract containing at least 90% curcuminoids in a food grade organic solvent selected from ethyl acetate, methyl acetate, butyl acetate, ethanol, butanol or a mixture thereof, preferably the organic solvent is ethyl acetate; b) the dissolved turmeric extract of step a) is added to the carrier solution which is a mixture of polymers comprising starch octenyl succinate and a cellulose derivative, wherein the cellulose derivative is hydroxypropylcellulose, hydroxypropylmethylcellulose, or a mixture thereof dissolved in water, wherein the mixture of hydroxypropylcellulose to hydroxypropylmethylcellulose is relative to 10:1; wherein the carrier is prepared by mechanically mixing the polymers, which are then dissolved in water, in a weight ratio of 1:5 to 1:25, preferably 1:10, and mechanically mixed to dissolve and combine the polymers, preferably for at least 10 hours, more preferably 12 hours, wherein 0.1 to 30 g of starch octanyl succinate and 0.02 to 20 g of hydeoxypropyl cellulose or hydroxypropyl methyl cellulose or a mixture thereof are used in the preparation of the carrier, based quantitatively on the mixture produced in step a) made with 0.01 g to 3 g of the extract from turmeric dissolved in 0.19 ml to 60 ml of an organic solvent; wherein the temperature of the carrier solution during the addition of the dissolved turmeric extract is between 5°C and 10°C, preferably cooling is used to maintain this temperature of the resulting mixture; c) homogenizing the mixture obtained in step b) into an emulsion by homogenizing at a temperature of 5°C to 10°C; d) the emulsion obtained in step c) is diluted with a 1-8% aqueous solution of β-glucan with a viscosity in the range of 40-200 mPas and then homogenized briefly; wherein the preferred β-glucan is oat or barley β-glucan or a mixture thereof; PL 241 424 B1 e) the emulsion obtained in step d) is stabilized by diluting with an aqueous solution of a cellulose derivative with a viscosity above 5600 mPas selected from carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, ethyl methyl cellulose, cross-linked cellulose gum, in a proportion of not less than 1:6, preferably not less than 1:8, with mechanical mixing, preferably the high viscosity cellulose derivative is carboxymethyl cellulose (CMC), preferably in a concentration of 0.01 to 0.%, more preferably in a concentration of 0.10 to 0.20%, more preferably in a concentration of 0.1 to 1.4% (w/w); and f) the stabilized emulsion of step e) is dried to obtain the curcumin formulation in a dry form, preferably drying is carried out using spray drying with an inlet temperature to the dryer in the range of 110-160°C, more preferably 150°C, and an outlet temperature not greater than 65°C, preferably not greater than 55°C; wherein more than 90% of the particles obtained have a diameter of less than 1 μm, preferably more than 95%, preferably more than 99% of the particles obtained have a diameter of less than 1 μm, more preferably at least 90%, more preferably at least 95% of the particles, more preferably at least 99% particles have a diameter in the range of 0.1 μm to 1 μm. 4. A beverage concentrate comprising a formulation as defined in claim 1. 1-2. 5. A beverage concentrate according to claim 4, further comprising at least one of: - 0-28% w/w glycerol and/or xanthan gum; - 0-5% w/w ascorbic acid; - 0-5% w/w, citric acid; - 0-80% w/w, glucose; - vitamins selected from thiamine, niacin, pyridoxine, folic acid, riboflavin or a mixture thereof; - preservatives selected from benzoic acid, sodium benzoate, potassium sorbate, or a mixture thereof. 6. A beverage comprising a formulation as defined in claims 1-2. 7. A beverage according to claim 6, characterized in that it is a functional beverage, wherein the concentration of curcuminoids in the beverage is 0.01-0.1% w/w. 8. A dietary supplement comprising a formulation as defined in claims 1-2. 9. Dietary supplement according to claim 8, characterized in that it is in liquid form.