RU2179401C1 - Beta-carotene-based biologically active additive and method to obtain microemulsion - Google Patents

Abstract

FIELD: medicine, food industry, agriculture. SUBSTANCE: the method suggests to apply beta-carotene-based biologically active additive which also includes alphatocopherol acetate, zinc ascorbinate and a pharmacologically acceptable filler (vegetable oil or emulsifier, stabilizer and water). The method is also suggested to obtain microemulsion of above-mentioned additive which consists of beta-carotene homogenization in preheated emulsifier at the presence of antioxidant and stabilizer with subsequent mixing the obtained solution with water (heated to 50 C, not higher) which was additionally introduced with zinc ascorbinate. EFFECT: increased assortment of beta-carotene-based biologically active additives due to enhanced bioavailability of active components, restored zinc deficiency, improved betacarotene uptake. 2 cl, 1 dwg, 1 tbl, 7 ex

Description

 The invention relates to the field of medicine, food and agricultural industry.

 The deterioration of the ecological and social conditions of life has led to the depletion of the body of such valuable vital substances for the living organism as vitamins, micro and macrocells. The main tendency to replenish these components is the design of biologically active additives that increase the body's resistance and have a certain focus, which are either included in the composition of food products, feeds, drinks, or are used independently or in combination in various technological forms (Problems associated with patent protection biologically active food additives (I.Pavlyuchenko, Budantseva, I.Pitryanas, A.Ulyanova, Intellect, property 4, 2000). Known vitamin aids for increasing natural resistance are based either on the activity of one active component or on a complex of active components. For example, the dietary supplement of Patent 2076704 contains carotenoids in vegetable oil. The replacement of vitamin A in known drugs with beta-carotene allows you to save all the positive properties of vitamin A, eliminate the risk of toxic effects with prolonged use and overdose, for example, teratogenicity (RF patent 2076704, 04/10/97).

 The use of beta-carotene as a vitamin A derivative in a vitamin supplement for the treatment of avitaminosis in birds in combination with antioxidants in the form of alpha-tocopherol acetate in the presence of butyloxyanisole and dimethyl sulfoxide based on vegetable oil improves the stability of beta-carotene and vitamins. The additive is obtained by mixing the active components and butyloxyanisole with edible sunflower oil (application RU 93008967/14, BI 11/96).

 However, studies have shown that simply administering beta-carotene in the presence of antioxidants is not enough. To enhance the absorption of vitamin A, the presence of Zn ion is necessary, which ensures the transport of vitamin A through the intestinal mucosa through a zinc-containing protein. Therefore, they began to strive for the joint use of this synergistic pair.

So, there is a well-known feed additive to corn feed containing mineral, vitamin and protein components in the form of heat-treated soy, fodder yeast, oilcake, fruits and berries, lysine feed concentrate, vitamins A, D, E, B ₂ , beta-carotene, zinc, manganese, copper, cobalt, edible salt, precipitate, limestone, dry coffee slurry, fodder grains from phytophora and fodder lignin (patent RU 2050145, 10.12.95). In the same direction, a premix for lactating cows is known, which includes a biologically active additive in the form of a mixture of microbial carotene, feed lysine, lactonin, copper sulfate, zinc sulfate, manganese sulfate, cobalt chloride, amino iodine, ammonium phosphate, sodium chloride, phyludine and coniferous flour (patent RU 1503732, 05.23.91).

 The disadvantage of the considered compositions is the narrow focus of the preparations (specifically for agriculture), the introduction of trace elements in the form of inorganic salts, which dramatically reduces the bioavailability and unpredictability of the behavior of such a complex multicomponent system in acidic and alkaline environments in the presence of gastrointestinal enzymes.

 The introduction of micro and macro elements in the form of an organic salt increases their bioavailability. For example, a vitamin-feed additive is known, which is obtained by treating the mother liquor of ascorbic acid with ferrous sulfate, cobalt sulfate, zinc sulfate, followed by application to wheat bran (Temporary instruction on the use of vitamin-mineral feed additives based on ascorbic acid in animal husbandry and poultry farming (in order wide industrial experience in 1999-2001) .V. Seliverstov, Deputy Head of the Department of Veterinary Medicine, approved on December 28, 1999).

 The pharmacological properties of the additive are due to the trace elements in its composition in an easily digestible nutrient form in the presence of ascorbic acid. The degree of assimilation of beta-carotene and trace elements is also affected by the aggregate state of the administered supplement. It is shown that the introduction of a biologically active additive in the form of a microemulsion is preferable.

 In this direction, a biologically active additive is known - BETAVITON (water-soluble), selected as a prototype for the claimed composition with a beta-carotene content of at least 2%, including the antioxidant alpha-tocopherol acetate 0.5%, an ascorbate-containing component in the form of ascorbic acid 0.25% and a pharmacologically applicable excipient.

 When using the additive in experiments on chickens, it was found that, along with an increase in resistance in the yolks of chicken eggs, the content of carotenoids increases by 10.3%, vitamin A by 30.4% (the Guide to the use of Betaviton-beta-carotene water-soluble was developed by LLP (AVG -LTD) St. Petersburg, agreed with the chief medical officer MSC-24 of the Federal Administration for Biomedical and Experimental Problems of the Russian Federation V.T. Lyamin July 31, 1998, Moscow, approved by the Technical Director of BELVITAMINY OJSC , 1998).

 With all the positive results achieved by the prototype, the disadvantages include incomplete absorption of beta-carotene (vitamin A), which is due to a deficiency of the trace element zinc in the diets of animals and birds in many regions of the Russian Federation related to biogeochemical regions characterized by zinc deficiency.

 As a prototype for the method, a method for producing beta-carotene microemulsion is selected, which includes homogenizing beta-carotene in a preheated emulsifier in the presence of an antioxidant, followed by mixing the resulting solution with water (patent RU 2077529, 04/20/97).

 The objective of the invention is to expand the range of dietary supplements based on beta-carotene by designing a composition with increased digestibility of beta-carotene, including in regions with a deficiency of zinc, and the development of a method for producing a microemulsion of this additive.

Technical results are:
- increase the bioavailability of the active components of the additive;
- prevention of zinc deficiency;
- increased absorption of beta-carotene;
- achievement of bio-coordination result during assimilation;
- providing the possibility of obtaining a zinc-containing microemulsion based on beta-carotene.

 The solution of the above problem and the achievement of technical results in relation to the composition became possible due to the fact that in the well-known biologically active additive based on beta-carotene, including active components: beta-carotene, antioxidant alpha-tocopherol acetate, ascorbate-containing component and a pharmacologically acceptable excipient, as ascorbate component additive includes a biologically available organic salt in the form of zinc ascorbate in the following ratio, wt. %: beta-carotene 1-3, alpha-tocopherol acetate 0.5-0.9, zinc ascorbate 1.9-2.5 and, as a pharmacologically acceptable excipient, includes an excipient in the form of either vegetable oil or a mixture of emulsifier, stabilizer and water.

 The functional activity of zinc ascorbate introduced into the composition is due to the formation of a structure with a chelate bond participating in all metabolic processes.

 The obtained biologically active additive combines the positive properties of the prototype, namely it has storage stability due to the use of beta-carotene as a retinol derivative, which has a stabilizing effect on the composition and expands its spectrum of action. Beta-carotene prevents the danger of an overdose of vitamin A, since the process of converting beta-carotene to vitamin A is strictly regulated by the activity of the enzyme carotenoid-15-15-dioxygenase and occurs with a deficiency of vitamin A in the blood, and the latter regulates the absorption of zinc by the body. The combined introduction of synergists - zinc and vitamin A - allows you to achieve a bio-coordination result of assimilation. Presumably, the prolongation of the absorption process is achieved due to the inclusion of zinc ion in the composition in the form of a bioavailable salt with a lower dissociation coefficient compared to the inorganic salt, which leads to a gradual release of zinc. Moreover, the rate of zinc release is comparable to the rate of the biochemical reaction of its binding to protein with the formation of a zinc-containing protein complex, without which the body cannot absorb beta-carotene and vitamin A. Moreover, a large intestine area is included in the absorption process, due to which it is more biologically used active components of the additive.

 The presence of an antioxidant, such as alpha-tocopherol acetate, enhances the antioxidant effect of beta-carotene, protects it from destruction, preventing the development of free radical processes.

 The resulting composition has a novelty and significant difference compared to analogues that determine the technical level through the use of a pair of synergists vitamin A-zinc (in a bioavailable form) in the presence of an antioxidant, provides the formation of the digestive tract ecosystem and can be used for a long time as a mass prophylactic adaptogenic agent in environmentally unfavorable areas and regions characterized by zinc deficiency. Unlike multicomponent analogs, including an inorganic zinc salt, the proposed composition is introduced already in the form of an organic structure, characterized by formed internal bonds, ensuring the normal course of metabolic processes.

 The choice of a pharmacologically acceptable excipient or vegetable oil, or a mixture consisting of an emulsifier, stabilizer and water, depends on the prevailing culture of the drug, i.e. either in the form of a familiar oil solution, or in the form of a water-soluble microemulsion that reflects a new direction.

 As a prototype for the preparation of a microemulsion of the claimed preparation, patent 2077523 was selected (patent RU 2077529, 04.20.97).

The solution of the problem and the achievement of the technical result regarding the method became possible due to the fact that in the known method for producing microemulsion, including the homogenization of beta-carotene in a pre-heated emulsifier in the presence of an antioxidant and stabilizer, followed by mixing the resulting solution with water, the water is pre-heated to a temperature before the mixing operation not higher than 50 ^o C and add to it with stirring additional zinc ascorbate in the following ratio of components, wt.%: beta-caro tin 1-3, antioxidant 0.5-0.9, zinc ascorbate 1.9-2.5, emulsifier 19, stabilizer 0.002, water - up to 100. Exceeding temperatures above 50 ^o C entails a loss of zinc ascorbate.

 The proposed method allows to obtain a stable water-soluble microemulsion of fat-soluble beta-carotene and transfer the drug to the category of water-dispersed, which is important in modern production and corresponds to current trends.

 The invention is illustrated in the drawing, which schematically shows a method for producing a microemulsion, and a table in which, for clarity, the data of examples are summarized.

The method is as follows. An emulsifier is loaded from a collection tank 1 into a measuring container 2, tween-80 is used as it in the presence of a stabilizer - butyloxyanisole. From the measuring tank 2, the emulsifier is fed into the reactor 3, equipped with a heat exchanger 4 and a stirrer 5, heated, crystalline beta-carotene is added from the container 6 and dissolved. Alpha-tocopherol acetate, used as an antioxidant, is charged from tank 7 and the mixture is homogenized with stirring for 10 minutes. In parallel, in a reactor 8 equipped with a stirrer 9 and a heat exchanger 10, water is heated to a temperature not exceeding 50 ^° C, zinc ascorbate is loaded from the tank 11 with stirring, after which the beta-carotene emulsion and the prepared zinc ascorbate solution are mixed. The resulting preparation is filtered through a filter 12 and sent to the packaging.

 Example 1

Prepare a microemulsion of a biologically active additive by the present method with a ratio of components, wt.%:
Beta Carotene - 1
Antioxidant (alpha-tocopherol acetate) - 0.5
Zinc ascorbate - 1.9
Emulsifier (twin-80) - 19
Stabilizer (butyloxyanisole) - 0.002
Water - Up to 100
which corresponds to the minimum values of the components within the claimed limits.

 Determination of the bioavailability and effectiveness of the additive was carried out on control groups of laying hens, while in the study group the claimed preparation was added daily to drink during 10 days according to the instructions for use.

 At the end of the experiment, the liver of the bird was examined for the accumulation of carotene, zinc, and vitamin A.

The following results were obtained for the claimed composition:
Carotene, mcg / g - 18.9
Vitamin A, mcg / g - 151.3
Zinc, mg / kg - 17.7
The resulting emulsion is stable and does not separate during storage.
Example 2

Prepare a microemulsion of a biologically active additive by the present method with a ratio of components, wt.%:
Beta Carotene - 2.0
Antioxidant (alpha-tocopherol acetate) - 0.7
Zinc ascorbate - 2.2
Emulsifier (twin-80) - 19
Stabilizer (butyloxyanisole) - 0.002
Water - Up to 100
which corresponds to the average values of the components within the claimed limits.

When determining the bioavailability and effectiveness of the additive analogously to example 1 it was found that in the liver of the bird contained:
Carotene, mcg / g - 27.4
Vitamin A, mcg / g - 219.5
Zinc, mg / kg - 22.1
The resulting emulsion is stable and does not delaminate during storage.

 Example 3

Prepare a microemulsion of a biologically active additive by the present method with a ratio of components, wt.%:
Beta Carotene - 3
Antioxidant (alpha-tocopherol acetate) - 0.9
Zinc ascorbate - 2.5
Emulsifier (twin-80) - 19
Stabilizer (butyloxyanisole) - 0.002
Water - Up to 100
which corresponds to the maximum value of the components within the claimed limits.

When determining the bioavailability and effectiveness of the additive analogously to example 1 it was found that in the liver of the bird contained:
Carotene, mcg / g - 38.7
Vitamin A, mcg / g - 315.4
Zinc, mg / kg - 49.0
The resulting emulsion is stable and does not delaminate during storage.

 Example 4

Prepare a microemulsion of a biologically active additive by the present method with a ratio of components, wt.%:
Beta Carotene - 0.5
Antioxidant (alpha-tocopherol acetate) - 0.4
Zinc ascorbate - 1.0
Emulsifier (twin-80) - 19
Stabilizer (butyloxyanisole) - 0.002
Water - Up to 100
which corresponds to prohibitive minimum values within the claimed limits.

When determining the bioavailability and effectiveness of the additive analogously to example 1 it was found that in the liver of the bird contained:
Carotene, mcg / g - 9.6
Vitamin A, mcg / g - 93.1
Zinc, mg / kg - 13.2
The resulting emulsion is stable and does not delaminate during storage.

 Example 5

Prepare a microemulsion of a biologically active additive by the present method with a ratio of components, wt.%:
Beta Carotene - 3.5
Antioxidant (alpha-tocopherol acetate) - 1.2
Zinc ascorbate - 3.0
Emulsifier (twin-80) - 19
Stabilizer (butyloxyanisole) - 0.002
Water - Up to 100
which corresponds to the prohibitive maximum declared values of the components relative to the claimed limits.

When determining the bioavailability and effectiveness of the additive analogously to example 1 it was found that in the liver of the bird contained:
Carotene, mcg / g - 39.9
Vitamin A, mcg / g - 328.9
Zinc, mg / kg - 60.7
The resulting microemulsion is stable and does not delaminate during storage.

 Example 6

 Prepare an oil solution of the inventive biologically active additives with the composition of the active components according to example 2, which corresponds to the average values of the components within the claimed limits. As a filler used purified vegetable oil.

"When determining the bioavailability and effectiveness of the additive analogously to example 1 it was found that in the liver of the bird contained:
Carotene, mcg / g - 19.1
Vitamin A, mcg / g - 310.6
Zinc, mg / kg - 30.8
Example 7

 The prototype is BETAVITON dietary supplement.

A Betaviton microemulsion is prepared at a ratio of components, wt.%:
Beta Carotene - 2.0
Antioxidant (alpha-tocopherol acetate) - 0.5
Ascorbic acid - 0.25
Emulsifier (twin-80) - 19
Stabilizer (butyloxyanisole) - 0.002
Water - Up to 100
When determining the bioavailability and effectiveness of the additive analogously to example 1 it was found that in the liver of a bird contains:
Analysis results 7
Carotene, mcg / g - 10.5
Vitamin A, mcg / g - 120.1
Zinc, mg / kg - 9.6
As can be seen from examples 2 and 7, the claimed composition allows to achieve better absorption compared with the prototype carotene by 38.3%, vitamin A by 38.08%, zinc by 43.44%.

 Examples 1 and 3 show the industrial applicability of a dietary supplement within the claimed limits. Reducing the number of components below the declared limits (example 4) reduces the effectiveness of the impact; an increase in the number of components above the stated limits is not economically feasible (example 5). Examples 1 and 3 also showed the possibility of obtaining a stable active microemulsion of the claimed additives, not inferior in properties to the microemulsion of the prototype, using a pharmacologically acceptable excipient in the form of an emulsion, stabilizer, water, which shows the industrial applicability of the claimed method.

 Thus, the invention has an inventive step and is industrially applicable. Using the proposed combination of essential features both in the first and in the second paragraphs of the formula, it is possible to provide a bio-coordination result during assimilation, prevent zinc deficiency, increase the absorption of beta-carotene, increase the bioavailability of the active components of the additive, and also provide the possibility of releasing a zinc-containing emulsion.

Claims (1)

1. A beta-carotene-based dietary supplement comprising active ingredients: beta-carotene, antioxidant alpha-tocopherol acetate, an ascorbate-containing component and a pharmacologically acceptable excipient, characterized in that it contains a biologically assimilable organic zinc ascorbate salt as an ascorbate component, and as a pharmacologically acceptable excipient, or vegetable oil, or an emulsifier, stabilizer and water in the following ratio, wt. %:
Beta Carotene - 1 - 3
Alpha-Tocopherol Acetate - 0.5 - 0.9
Organic Zinc Ascorbate Salt - 1.9 - 2.5
Pharmacologically acceptable excipient (vegetable oil or emulsifier, stabilizer, water) - The rest is up to 100%
2. A method of obtaining a microemulsion of a beta-carotene-based dietary supplement, comprising homogenizing beta-carotene in a preheated emulsifier in the presence of an antioxidant and stabilizer, followed by mixing the resulting solution with water, characterized in that the latter is preheated before mixing the homogenized mixture with water temperature not higher than 40-50 ^o C and add to it with stirring additional zinc ascorbate in the following ratio of components, wt. %:
Beta Carotene - 1 - 3
Antioxidant - 0.5 - 0.9
Zinc ascorbate - 1.9 - 2.5
Emulsifier - 19.0
Stabilizer - 0.002
Water - Up to 100

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