RU2800675C1 - Method of producing micellated solutions in powder form - Google Patents

Abstract

FIELD: pharmaceutical and food industries.

SUBSTANCE: group of inventions relates to a method of obtaining micellized solutions in powder form and powdered micellar form for food additives. A method of obtaining a powdered micelle form, including the initial preparation of a liquid micelle form and subsequent conversion of this form into a powder form, while the liquid micelle form is obtained by introducing an active substance in an amount of not more than 30 wt.% into an excess of a surfactant (surfactant) in an amount of more than 70 wt .% with a hydrophilic-lipophilic balance (HLB) value of more than 9 at a temperature of 60÷65°C with further heating up to 85÷87°C with constant stirring, subsequent exposure until the solution is transparent and homogeneous and cooled to room temperature, and the powder form is obtained by mixing the resulting liquid form with a sorbent in the ratio of micellar solution from 1 to 60 wt.% and sorbent from 40 to 99 wt.% by initially mixing the sorbent, then gradually adding the liquid form to it with constant stirring, and after the complete addition of the liquid form, increasing the mixing speed until the components are completely distributed to obtain the finished product. Powdered micelle form for food supplement obtained as described above containing micelles and silicon dioxide at a ratio of 56 wt.% of micelles to 44 wt.% of sorbent.

EFFECT: group of inventions described above makes it possible to preserve the structures of micelles when converting the product into a powder form, while maintaining its increased bioavailability.

6 cl, 2 dwg, 2 tbl, 5 ex

Description

The invention relates to a technology for the production of micellized solutions in powder form, in particular, the production of powdered micellized curcumin.

Micellar solutions in powder form are a new category of products that allow micellized solutions to significantly expand the possibilities and applications while maintaining increased bioavailability. The advantages of the new form are: the possibility of using in products in which liquids are not used for technological reasons; creation of formulations that combine micellated substances and substances that are not amenable to micellization, as well as the absence of foreign flavors in the product. The latter property removes the organoleptic limitations associated with the appearance of a bitter taste in the product when a liquid micelle form is introduced into it. All this opens up the possibility of using powdered micellar solutions by end users in everyday life.

The micellization technology itself is a unique way of encapsulating substances in a micelle ranging in size from 5 to 40 nm. The structure of such a micelle repeats the structure of a physiological micelle, which is formed in the human body during the digestion process and is responsible for the absorption of nutrients. The advantage of the technology lies in the fact that micelles allow the active substance to remain inside itself under various environmental influences, under mechanical action in the process of further food production, under chemical action in the gastrointestinal tract, while the structure of the active substance itself does not change. Micellar products, depending on the active substance used, can be used in various fields: in the food industry, in the cosmetics industry, in the animal feed industry, and also in the pharmaceutical industry. On the basis of micellization technology, antioxidants, dyes, preservatives and flavor extracts are produced to provide a technological effect in food products. In addition, micelles are used to enrich food products with various biologically active substances, as well as in the production of dietary supplements for food.

From the foregoing, it is clear that with such a wide range of applications, a micellar product is required to be in a form that is convenient for use in various food products, production technologies and the use of various equipment. Typically, the finished micellar product is a viscous liquid that can be dissolved in water or oil. In some cases, this is enough for the micellized product to be used in the production of the final product without changing the existing technological process or equipment. However, there are many products for which the use of a liquid form is not possible or not feasible. In such cases, micronized powder forms of various active substances are usually used, which are also absorbed better than the original form of the substance, but the particle size in them is in the range of several microns, which means that the bioavailability will be lower than that of the micellized form. As an example of a product for which the use of a powdered form would be relevant, we can cite the production of dietary supplements for food in soft gelatin capsules. The technology for the production of such capsules requires very strict adherence to the production schedule, as well as the use of expensive equipment, while there is always a risk of capsule leakage, which leads to a large percentage of rejects and product losses. At the same time, the production of hard gelatin capsules is a simpler process with a lower percentage of wastage, however, this requires a powder form of the active substance that will be suitable for filling capsules.

Another example would be the use of the dry form of a micellar product for food fortification, both in the industrial production of these foods and directly by the end consumer. For the consumer, the micellized powder can be added to drinks, cereals, dairy products, and the like. immediately before eating them. The main advantage of the powder form, in addition to ease of use, is the absence of foreign tastes from surfactants that are part of the micelles. Due to the powder form, such a product can be used in dosages ten times higher than in the liquid micellar form without compromising the taste. This is especially important when it is required to use a dosage of the product in the amount of 0.2-0.5% in order to obtain an effective dose of the active substance. At the same time, the liquid micelle form can cause the appearance of bitterness already in an amount of more than 0.04%. Moreover, the consumer can individually adjust the dosage depending on their needs.

Another advantage of the micellar powder form is that it can be combined with other powdered substances. This option is possible if the complex effect of several active substances on the human body has a synergistic effect or they complement each other, while one of the substances can be micellized, while the other is not. In this case, it is convenient to obtain a powder mixture in which at least one of the active substances will be in the form of micelles.

The mixture in the form of a powder can be used as a content for hard gelatin capsules, as part of a tablet form, used to prepare fortified drinks, directly added to food, etc.

In view of the foregoing, the problem solved in the creation of the claimed invention was to develop such a method for obtaining a powdered form of a micelle solution, which would include micelles with an active substance, which would retain an increased bioavailability to a degree commensurate with the liquid form. The technical result achieved in solving this problem is to preserve the structure of micelles when the product is converted into powder form and, accordingly, to maintain its increased bioavailability, as well as to expand the scope of micellar products due to the possibility of their use in those areas where it was previously was difficult or impossible due to the liquid consistency for technological reasons.

To achieve the stated result, a method is proposed for obtaining micelles in powder form, including the initial preparation of a liquid micellized form and subsequent transfer of such a form to powder, while the liquid micellized form is obtained by introducing the active substance in an amount of not more than 30 wt.% into an excess of a surfactant (surfactant ) in an amount of more than 70 wt.% with a hydrophilic-lipophilic balance (HLB) value of more than 9 at a temperature of 60÷65°C with further heating to 85÷87°C with constant stirring, subsequent exposure until the solution is transparent and homogeneous and cooled to room temperature, and obtaining a powder form is carried out by mixing the resulting liquid form with a sorbent in the ratio of micellar solution from 1 to 60 wt.% and sorbent from 40 to 99 wt.% by initially mixing the sorbent, then gradually adding to it with constant stirring liquid form, and after the complete addition of the liquid form - increasing the stirring speed until the components are completely distributed to obtain the finished product.

The surfactant can be selected from the group including polysorbate 20, polysorbate 80, polyethylene glycol and/or its derivatives, sucrose and fatty acid esters, or mixtures thereof, and silicon dioxide or microcrystalline cellulose (MCC) can be used as a sorption agent.

To achieve the desired result, it is also proposed to obtain a micellar solution in powder form obtained according to the claimed method, containing micelles, for example, micelles of curcumin, and silicon dioxide at a ratio of 56 wt.% micelles to 44 wt.% sorbent substance.

The invention is illustrated in figure 1, which shows the distribution of particle sizes in liquid and powder micellar forms, and figure 2, which shows the change in the concentration of curcuminoids in the blood.

In general, the production of the powder micellar form according to the claimed invention occurs in two stages. At the first stage, a liquid micellar form is obtained. In general, such a solution is obtained by introducing the active substance into an excess of surfactant of more than 80% with an HLB value of more than 9 at an elevated temperature and further heating with constant stirring. At room temperature, the finished product is a clear viscous liquid that can be diluted with water without becoming cloudy, which is achieved by the formation of micelles smaller than the wavelength of light. The particle size ranges from 5 to 40 nm, depending on the formulation used, which is important for the stability of the micellar solution and increasing the bioavailability of the active substance. Examples of surfactants used are polysorbate 20, polysorbate 80, polyethylene glycol and its derivatives, sucrose fatty acid esters, and mixtures thereof.

At the second stage, it is transferred from liquid to powder form by mixing with sorbent substances. To do this, the prescription amount of the sorbent is placed in a container and the mixing process is started using a submersible mixer. At this time, the micellar product is gradually introduced, after which the stirrer speed is increased in order to achieve a complete and even distribution of the product in the mixture. The most suitable sorption substances are silicon dioxide and microcrystalline cellulose (MCC). These substances are approved and safe for use in the food industry, have no taste and smell, and also have a large number of modifications suitable for use with various substances. For a specialist, however, it is obvious that the selection of a specific sorption substance is carried out on the basis of various names of micellar products, their composition and the required final concentration of the substance.

Example 1 Preparation of a liquid micellar form: 93 g of polysorbate 80 is heated to a temperature of 60-65°C. When the specified temperature is reached, 7 g of curcumin are added to the polysorbate and heated with constant stirring until a temperature of 85-87°C is reached. Maintain the mixture at this temperature until the product becomes transparent and homogeneous. After that, the micellized solution can be cooled to room temperature.

Preparation of the micellar powder form: 88 g of ^Aeroperl® 300 silica (manufactured by Evonik, Germany) is placed in a 0.5 liter container and mixing is started with a submersible mixer at 1000 rpm. Gradually, 112 g of micellized curcumin solution is added to the sorbent and then the stirrer speed is increased to 6000 rpm. The output is a friable yellow powder that does not form lumps and is suitable for use in the production of hard gelatin capsules.

Example 2 Preparation of a liquid micelle form of vitamin D: 89 g of polysorbate 80 is heated to a temperature of 60-65°C. When the specified temperature is reached, 11 g of vitamin D with a concentration of 1.0 million IU/g is added to the polysorbate and heated with constant stirring until a temperature of 85-87°C is reached. Maintain the mixture at this temperature until the product becomes transparent and homogeneous. After that, the micellized solution can be cooled to room temperature.

Preparation of the micellar powder form: 90 g of HDK® N20 silica (manufactured by Wacker Chemie AG, Germany) are placed in a 0.5 liter container and mixing is started with a submersible mixer at 1000 rpm. Gradually, 10 g of micellized vitamin D solution is added to the sorbent and then the stirrer speed is increased to 6000 rpm. At the output we get a friable white powder.

EXAMPLE 3 Preparation of a liquid micelle form of vitamin C: Prepare 27 g of a 50% aqueous solution of ascorbic acid with slight heating to 60°C. Next, 30 g of glycerin is added to the resulting solution with constant stirring, and the mixture is again heated to 60°C. When the specified temperature is reached, 43 g of polysorbate 20 are added and, as before, with constant stirring, heated to 85-87°C. Maintain the mixture at this temperature until the product becomes transparent and homogeneous. After that, the micellized solution can be cooled to room temperature.

Preparation of micellar powder form: 70 g of PROSOLV® SMCC HD90 silica (manufactured by JRS PHARMA GmbH & Co., Germany) is placed in a 0.5 liter container and mixing is started with a submersible mixer at a speed of 1000 rpm. Gradually, 30 g of a micellar solution of vitamin C is added to the sorbent, and then the stirrer speed is increased to 6000 rpm. At the output we get a friable white powder.

Example 4 Preparation of a liquid micellar form: 95 g of polysorbate 80 is heated to a temperature of 60-65°C. When the specified temperature is reached, 5 g of curcumin are added to the polysorbate and heated with constant stirring until a temperature of 85-87°C is reached. Maintain the mixture at this temperature until the product becomes transparent and homogeneous. After that, the micellized solution can be cooled to room temperature.

Preparation of the micellar powder form: 100 g of ^Aeroperl® 300 silica (manufactured by Evonik, Germany) is placed in a 0.5 liter container and mixing is started with a submersible mixer at a speed of 1000 rpm. Gradually, 100 g of micellar curcumin solution is added to the sorbent and then the stirrer speed is increased to 6000 rpm. When producing a large amount of product in an industrial plant, the number of revolutions of the agitator will depend on its design and the capabilities of the equipment.

After obtaining a crumbly powder of uniform yellow color, 200 g of hydrolyzed collagen powder and 5 g of vitamin C are added to the product. Mixing is continued until a homogeneous consistency is obtained.

Example 5 10 g of dry green tea extract containing 50% epigallocatechin gallate was mixed with 22 g of fatty acid triglycerides at room temperature. The resulting mixture is dosed into 67 g of polysorbate 80 (E433), heated to 27°C, and heated to a temperature not exceeding 87°C with constant stirring. After reaching this temperature, 1 g of glycerol is added to the product and heated again to a temperature not exceeding 87°C. After obtaining a homogeneous product, begin cooling to a temperature below 60°C.

In a separate container, 30 g of polysorbate 20 and 54 g of polysorbate 80 are mixed, and heated to 60°C with constant stirring. After reaching the indicated temperature, 5 g of green tea extract, prepared as described above, is added. Next contribute 11 g of a 10% oil solution of astaxanthin and with constant stirring heated to 87°C and immediately cooled to a temperature below 60°C. In this way, a liquid micelle form of astaxanthin is obtained, additionally stabilized with green tea to protect astaxanthin from oxidation.

To prepare a powdered micelle form of astaxanthin: 150 g of Aeroperl ^® 300 silicon dioxide (manufactured by Evonik, Germany) is placed in a 0.5 liter container and mixing is started using a submersible mixer at a speed of 1000 rpm. Gradually, 20 g of a micellar solution of astaxanthin is added to the sorbent, and then the stirrer speed is increased to 6000 rpm. When producing a large amount of product in an industrial plant, the number of revolutions of the agitator will depend on its design and the capabilities of the equipment. After obtaining a homogeneous orange powder, 100 g of D-glucosamine is added to the container and mixing is continued until a homogeneous consistency is obtained.

In order to confirm the retention of the micelle structure of the active substance in the powder micelle form, an experiment was carried out comparing particle sizes and particle distribution in solutions obtained from the liquid micelle and powder micelle form of the present invention. In the laboratory, according to example No. 1, both forms of micellized curcumin and their aqueous solutions were prepared in 1000-fold dilution. Particle size measurements were carried out with a NANO-flex II particle size analyzer using the dynamic light scattering (DLS) method. Figure 1 shows graphs for comparing the distribution of particles in the analyzed samples, showing the distribution of the powder form in the boundaries similar to the liquid form, and the distribution of particles in solutions are shown in table 1.

Table 1.

Index Liquid micelle form Powdered micelle form Diameter of the maximum number of particles in solution, nm 8.3 8.9 Q50, nm (diameter of 50% particles in solution) 7.7 8.4 Q10, nm (diameter of 10% particles in solution) 7.0 8.8 Q90, nm (diameter of 90% particles in solution) 7.1 10.8

The obtained values prove the retention of micellar particles when transferred from liquid to powder form, while since the particles retain their size, their increased bioavailability is also maintained, which is confirmed by the results of the following experiment.

The bioavailability trial involved two groups of 3 participants. Volunteers received a single dose of 500 mg of curcuminoids in the form of hard gelatin capsules. The first group took capsules with curcumin in native form, the second - with powdered micellized curcumin obtained according to the claimed invention.

The content of curcuminoids in the blood was determined at 7 time points (before administration, after 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours) and analyzed by HPLC/MS/MS.

Based on the results obtained, pharmacokinetic parameters were calculated (table 2 and figure 2), which showed a significant increase in the bioavailability of the powder micellar form.

Table 2.

Parameter Dimension Native form of curcumin Powdered micelle form Meaning Meaning T _1/2 h - 10.17 _Tmax h 8 1 _Cmax ng/ml 34.26 2696.03 AUC _0-t ng/ml*h 181.13 9954.94 AUC _0-∞ ng/ml*h - 19071.74 MRT _0-∞ h - 12.45

T _1/2 - half-life; _Cmax - maximum concentration; _Tmax - time to reach maximum concentration; AUC _0-t - the area under the pharmacokinetic curve "concentration-time" from zero to the extreme point; AUC _0-∞ - the area under the pharmacokinetic curve "concentration-time" from zero to infinity; MRT _0-t - the average retention time of the active substance in the blood from 0 point to the extreme point.

Claims (6)

1. A method for obtaining a powdered micelle form, including the initial preparation of a liquid micelle form and subsequent conversion of such a form into a powder form, while the liquid micelle form is obtained by introducing an active substance in an amount of not more than 30 wt.% into an excess of a surfactant (surfactant) in an amount of more than 70 wt.% with a hydrophilic-lipophilic balance (HLB) value of more than 9 at a temperature of 60÷65°C with further heating to 85÷87°C with constant stirring, subsequent exposure until the solution is transparent and homogeneous and cooled to room temperature, and obtaining a powdered form is carried out by mixing the resulting liquid form with a sorbent in the ratio of micellar solution from 1 to 60 wt.% and sorbent from 40 to 99 wt.% by initially mixing the sorbent, then gradually adding the liquid form to it with constant stirring, and after the complete addition of the liquid form, increase the mixing speed until the components are completely distributed to obtain the finished product. 2. The method according to claim 1, in which the surfactant is selected from the group including polysorbate 20, polysorbate 80, polyethylene glycol and/or its derivatives, esters of sucrose and fatty acids, or mixtures thereof. 3. The method according to claim 1 or 2, in which silicon dioxide or microcrystalline cellulose (MCC) is used as a sorption substance. 4. The method according to any one of claims 1 to 3, wherein the active substance is selected from the group consisting of curcumin, vitamin D, vitamin C, astaxanthin. 5. Powdered micelle form for food supplement, obtained by the method according to any one of claims 1 to 4, containing micelles and silicon dioxide at a ratio of 56 wt.% micelles to 44 wt.% sorbent. 6. Powder form according to claim 5, in which micelles are used as micelles selected from the group including curcumin, vitamin D, vitamin C, astaxanthin.