Method for producing a composition of metallic micronutrient chelate complexes

Abstract

The invention relates to the medical and food industry. What is proposed is a method for producing a composition of metallic micronutrient chelate complexes. According to the invention, a 5-20% aqueous solution of micellar casein has added thereto a solution of a chloride of one or more metallic micronutrients with a concentration of 40-50%, wherein the ratio of the mass of the protein to the mass of the salt is 5:1 - 3:1. The mixture is then held for 40-120 minutes at a temperature of 30-60°С and a рН of 7.5-9.4 under agitation, with the given pH value being continuously controlled and maintained by titration. The resulting aqueous micellar casein chelate solution is then purified of residual inorganic salts by microfiltration and diafiltration with sublimation or spray drying. The dried micellar casein-based chelates are mixed, in an amount that satisfies the daily micronutrient requirement, with a pharmaceutically acceptable carrier. The following are used as metallic micronutrients: calcium, magnesium, zinc, copper, iron, manganese, chromium and cobalt. The concentration of micronutrients in the resulting composition is 0.01-100 mg of micronutrients per gram of the composition. Not less than 90% of the micronutrients are chemically bound to the micellar casein. The invention is directed toward increasing the effectiveness of a composition of metallic micronutrient chelate complexes by virtue of particle size uniformity.

Description

[0001] NAME OF INVENTION

[0002] Method for obtaining a composition of chelate complexes of metals and microelements

[0003] AREA OF TECHNOLOGY

[0004] The invention relates to the medical and food industries, namely to a composition for the prevention of disorders and optimization of mineral metabolism, containing microelements in the form of chelates based on micellar casein as an active substance.

[0005] PRIOR ART

[0006] Food complexes based on liquid protein hydrolysates are known, enriched with microelements such as phosphates, potassium, manganese, copper, calcium, magnesium, copper, calcium, magnesium, iron, cobalt, zinc, or amino acids - methionine or lysine (WO 00 / 4984, A23J 3 / 00).

[0007] A chelated food complex is known, obtained using the endothermic low-temperature synthesis of chelate compounds of macro- and microelements with protein hydrolysates through the interaction of hydrolyzed protein with a macro- or microelement in an inorganic salt at a pH of 7.0-7.4, resulting in the formation of a chelate compound that is easily absorbed and assimilated through the gastrointestinal tract (WO 87 / 02867, A 23 J 3 / 00). Calcium, magnesium, iron, zinc, copper, vanadium, cobalt, manganese, chromium, selenium, germanium, or lithium can be used as microelements.

[0008] A disadvantage of the invention is the possible presence in its composition of a significant amount of inorganic salts of macro- and microelements not associated with organic components, which reduces their absorption and increases the risk of side effects in case of possible overdoses.

[0009] The closest analogue of the claimed technical solution is a chelate food complex based on a milk protein hydrolysate (mainly whey milk protein hydrolysate or whole milk protein or casein hydrolysate) and microelement salts (mainly zinc chloride, copper chloride, manganese chloride, chromium chloride, cobalt chloride), containing microelements in the concentration range of 1-30 mg / g, of which at least 90% are in organic form (patent RU 2243677).

[0010] The disadvantage of this composition is that the wide range of high-molecular compounds, especially in the composition of the “enzymatic hydrolysate of whey proteins and casein” (as stated in the above-mentioned patent), is a heterogeneous material that is extremely difficult to standardize for the subsequent production of a homogeneous and standardized product capable of supplying microelements to the body of humans and animals.

[0011] It seems more appropriate to use standardized proteins in their native form, such as micellar casein, as a basis for creating chelates.

[0012] In the production of micellar caseins, ultrafiltration membranes are used, the pore size of which ensures the retention of almost all milk proteins, with the maximum removal of non-protein components. By using membranes of different sizes, it is possible to obtain micellar caseins with specified physicochemical properties, such as solubility, fat and moisture retention, emulsification, and also perform a number of technological functions in food systems (Kumar P, Sharma N, Ranjan R, Kumar S, Bhat ZF, Jeong DK. Perspective of membrane technology in dairy industry: A review. Asian-Australasian Journal of Animal Science. 2013;26(9): 1347-1358. https: / / doi.org / 10.5713 / ajas.2013.13082).

[0013] DISCLOSURE OF THE INVENTION

[0014] Therefore, the task of creating a composition for the prevention and optimization of mineral metabolism, containing a chelate complex of increased effectiveness, is highly relevant.

[0015] In the course of the conducted research, the set task was solved by creating a composition for the prevention of disorders and optimization of mineral metabolism, including standardized protein and microelements bound in chelate complexes, while the composition contains micellar casein as a protein, the concentration of microelements is 0.01-100 mg of microelements per gram of the composition, of which at least 90% of the microelements are chemically bound with micellar casein, in combination with a pharmaceutically acceptable carrier.

[0016] It is preferable that the composition includes calcium, magnesium, iron, zinc, copper, manganese, chromium, and cobalt as microelements.

[0017] It is preferable that the composition is made in the form of capsules, tablets, powder, solutions, or is part of vitamin-mineral complexes.

[0018] A new technical result of using the proposed composition is an increase in its effectiveness due to an increased level of standardization, in particular the uniformity of particle size, which allows for the effective use of the proposed composition for the prevention of disorders and the optimization of mineral metabolism.

[0019] The technical result achieved by the proposed composition is due to its new properties discovered during research.

[0020] The micellar casein used in the proposed composition surpasses rennet casein and all types of animal and plant protein mixtures—egg albumin, milk or whey proteins, hemoglobin, soy protein, yeast proteins, and hydrolysates of these proteins—in its physicochemical properties. This is because micellar casein molecules are uniform in size and have nearly 100% solubility.

[0021] Table 1. Some physicochemical properties of proteins, including the micellar casein fraction (according to our own research).

[0022] The high efficiency of micellar casein-based micronutrient chelates is due to their homogeneity and preservation of native properties. Micellar casein has a solubility close to 100% and preserves the protein's native properties, enabling "soft chelation" at solution pH values ​​that preserve the protein's native structure. Preservation of the protein's native structure is also ensured by the selected reagent concentration ranges and the order of their addition, which helps avoid the effects of extreme concentrations of highly active substances on the protein. Table 2 shows the solubility of micellar casein-based chelates and their particle sizes. Table 2. Solubility of micellar casein-based chelates and chelate particle sizes (based on our own research).

[0023] Due to the listed advantages, the compositions of chelate complexes based on micellar casein show high efficiency in preventing disorders and optimizing mineral metabolism, which was demonstrated in our experiment.

[0024] EMBODIMENTS OF THE INVENTION

[0025] The claimed composition is obtained as follows.

[0026] Chelate complexes are produced from micellar casein obtained from milk by microfiltration and soluble salts of trace metals (calcium, magnesium, zinc, copper, iron, manganese, chromium, cobalt).

[0027] A solution of a metal or several metal chloride with a concentration of 40-50% is added to a 5-20% aqueous solution of micellar casein at a protein to salt mass ratio of 5:1 -3:1, then the mixture is kept for 40-120 minutes at a temperature of 30-60°C and a pH of 7.5-9.4 with stirring and continuous monitoring and maintenance of the set pH value by titration, then the resulting aqueous solution of micellar casein chelates is purified from the remaining inorganic salts by microfiltration and diafiltration with sublimation or spray drying.

[0028] The described technological process results in chelated complexes in which at least 90% of the trace element is bound to the peptide structures of micellar casein. The concentration of trace elements in the product is determined by atomic absorption spectrometry. The total trace element content in the product ranges from 1-10% and depends on the synthesis conditions. The finished product is a homogeneous, finely dispersed powder ranging from light beige to light brown in color, or blue for copper complexes. It has a slightly bitter taste and a faint, specific odor. It is readily soluble in water and virtually insoluble in organic solvents.

[0029] Dried micellar casein-based chelates, in quantities sufficient to meet the daily micronutrient requirement, are mixed with suitable carriers. The resulting mixture is either packaged as a powder, or tableted and packaged, or placed in capsules (such as hard gelatin capsules for medical use and packaged), or dissolved in water and bottled.

[0030] Below are examples of the production of the proposed composition in the form of vitamin-mineral complexes.

[0031] Example 1. Composition of calcium-magnesium chelate based on micellar casein.

[0032] Dried calcium-magnesium chelate (10% calcium, 5% magnesium) based on micellar casein in an amount of 5,000 mg is added to bars containing additional proteins, carbohydrates, and fats as fillers, as well as premixes of vitamins and minerals. The resulting composition, weighing 10-50 g, contains 500 mg of calcium and 250 mg of magnesium, of which at least 450 mg of calcium and 225 mg of magnesium (90%) are chemically bound to micellar casein.

[0033] Example 2. Multimineral composition containing chelates of iron, zinc, copper, cobalt, chromium, manganese based on micellar casein.

[0034] Dried iron chelate (iron content 4%) based on micellar casein in the amount of 250 mg, dried zinc chelate (zinc content 5%) based on micellar casein in the amount of 100 mg, dried copper chelate (copper content 3%) based on micellar casein in the amount of 50 mg, dried manganese chelate (manganese content 4%) in the amount of 50 mg, dried cobalt chelate based on micellar casein (cobalt content 1%) in the amount of 10 mg, dried chromium chelate based on micellar casein (chromium content 1%) in the amount of 25 mg, mixed with carriers, as well as premixes of vitamins and mineral components and packaged in the form of capsules, tablets.

[0035] The resulting composition, weighing 0.9-2 g, contains 10 mg iron, 5 mg zinc, 1.5 mg copper, 2 mg manganese, 50 μg cobalt, and 25 μg chromium. 90% of each trace element is chemically bound to micellar casein.

[0036] Example 3. A magnesium chelate composition based on micellar casein. Dried magnesium chelate based on micellar casein in an amount of 10 g (3% magnesium) is mixed with premixes of vitamins, minerals, and flavorings, using sucrose as a carrier. The resulting product is used as a powder for beverage preparation.

[0037] The resulting composition weighing 15-25 g contains 300 mg of magnesium, of which at least 270 mg of magnesium (90%) is chemically bound to micellar casein.

[0038] Below are examples of the compositions of these compounds. The drug form is available as lozenges (example 2).

[0039] Tablet weight: 1000 mg

[0040] Compound:

[0041] Dried iron chelate (iron content 4%) based on micellar casein in the amount of 250 mg, dried zinc chelate (zinc content 5%) based on micellar casein in the amount of 100 mg, dried copper chelate (copper content 3%) based on micellar casein in the amount of 50 mg, dried manganese chelate (manganese content 4%) in the amount of 50 mg, dried cobalt chelate based on micellar casein (cobalt content 1%) in the amount of 10 mg, dried chromium chelate based on micellar casein (chromium content 1%) in the amount of 25 mg, cholecalpiferol concentrate - 3 mcg, sorbitol 450 mg, magnesium stearate -10 mg.

[0042] Powder, in sticks, weight 18 g (example 3)

[0043] Ingredients: sucrose - 6-17.6 g, edible salt - 0.1-0.28 g, vitamin C - 15-43 mg, vitamin B3 - 3-8 mg, vitamin E - 2-6 mg, vitamin B5 - 1-3 mg, vitamin B6 - 0.01-0.61 mg, vitamin B2 - 0.01-0.61 mg, vitamin B1 - 0.01-0.6 mg, vitamin B9 - 0.1 mg, vitamin B12 - 0.001 mg, dried magnesium chelate (magnesium content 3%) - 1000 mg, flavoring - 0.1-0.2 g.

[0044] Example 4.

[0045] This differs from example 2 in that the dried calcium-magnesium chelate is used to prepare an active feed additive that also contains cholecalciferol concentrate, mixing it with sucrose and / or starch. The resulting powder is packaged in stick packs.

[0046] The method for preventing disorders and optimizing mineral metabolism is based on the use of the compositions presented in Examples 1-4. It is advisable to take the compositions 1-3 times daily for 3-12 weeks.

[0047] To demonstrate the efficacy of micellar casein-based chelates, biological experiments were conducted in accordance with the recommendations of MUK 2.3.2.721 "Determining the Safety and Efficacy of Dietary Supplements." The experiment was conducted on male Wistar rats weighing 200 g, with n = 9-10 rats in each group.

[0048] Experimental model of osteoporosis.

[0049] Osteoporosis was modeled by daily administration of 1 mg of prednisolone through a tube for 4 weeks.

[0050] On the 29th day, the animals were decapitated under chloroform anesthesia, blood serum was obtained, and the femur bones and lumbar vertebrae were isolated for further biochemical analysis.

[0051] To study the effectiveness of the composition in the prevention and treatment of experimental osteoporosis, the animals were divided into 4 groups. The group of intact animals included rats that did not receive any drugs. The control group included animals that were administered prednisolone according to the above-mentioned method for 28 days. Animals of the two experimental groups consumed a composition (example 1) daily with food, consisting of: dried calcium-magnesium chelate - 1500 mg, cholecalciferol concentrate - 3 μg, sorbitol - 450 mg, magnesium stearate - 10 mg, distributed so that the daily dose of each animal contained Ca - 0.03 g, Mg - 0.02 g, vitamin D - 0.0002 mg. Rats of the first experimental group consumed the supplement for 28 days simultaneously with the administration of prednisolone (first experimental group). Rats in the second experimental group consumed the supplement for 28 days after 4 weeks of prednisolone administration.

[0052] Methods of experimental research.

[0053] The determination of calcium-phosphorus metabolism indicators was assessed based on the level of concentration of total calcium and inorganic phosphorus in the blood serum, as well as the level of their excretion in the urine per day.

[0054] Calcium and phosphorus were determined spectrophotometrically using the Calcium-Novo and Phosphorus-Novo reagent kits and methods, respectively. Measurements were performed on a Shimadzu UV-1601 spectrophotometer. 1-cm-thick quartz cuvettes were used for the measurements. Calcium was determined at a wavelength of 650 nm, and phosphorus at 340 nm.

[0055] Dry combustion was used to analyze the calcium and magnesium content of bones. The amount of calcium and magnesium salts in bones was determined using a Kapel-205 capillary electrophoresis system.

[0056] Statistical processing of the results of biochemical and biomechanical studies was carried out using the analysis of variance method.

[0057] Results of the experimental study:

[0058] Disturbances in calcium-phosphorus metabolism, primarily affecting bone tissue and serum, are known to play a role in the pathogenesis of glucocorticoid-induced osteoporosis. Our studies showed that the control group of animals treated with glucocorticoids for 28 days experienced a significant decrease in serum calcium levels.

[0059] Table 3. Calcium and phosphorus content (in mmol / l) in the blood serum of experimental animals.

[0060] Note: p < 0.01 (mean error).

[0061] Administration of a composition containing significant amounts of calcium, magnesium, and vitamin D revealed a clear normalizing effect. Serum calcium levels were normal and consistent with those in intact animals.

[0062] Note: p < 0.01 (mean error)

[0063] The results of the study of calcium and magnesium in bone tissue are presented in Table 4.

[0064] Table 4. Calcium and magnesium content (in meq / 100 ml) in the femur of experimental animals.

[0065] Administration of prednisolone for 4 weeks caused a decrease in the content of both calcium and magnesium in bone tissue by more than 15%. Concomitant administration of the composition during prednisolone administration completely abolished the effect of the glucocorticoid (Experimental Group 1), as did administration of the composition for 28 days after modeling osteoporosis (Experimental Group 2).

[0066] Research results show that compositions containing microelement chelates based on micellar casein are effective in preventing disorders and optimizing mineral metabolism.

Claims

Invention formula A method for producing a composition of chelate complexes of metals and microelements, characterized in that a solution of a chloride of a metal microelement or several metal microelements with a concentration of 40-50% is added to a 5-20% aqueous solution of micellar casein at a protein to salt mass ratio of 5: 1-3: 1, then the mixture is kept for 40-120 minutes at a temperature of 30-60 ° C and a pH of 7.5 -9.4 with stirring and with continuous monitoring and maintaining a given pH value by titration, then the resulting aqueous solution of micellar casein chelates is purified from the remaining inorganic salts by microfiltration and diafiltration with sublimation or spray drying, dried chelates based on micellar casein in an amount that provides the daily requirement for microelements are mixed with a pharmaceutically acceptable carrier, and calcium, magnesium, zinc, copper, iron, manganese, chromium, cobalt are used as microelement metals,wherein the concentration of microelements in the resulting composition is 0.01-100 mg of microelements per gram of composition, of which at least 90% of the microelements are chemically bound to micellar casein.

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