RU2409375C1 - Method for preparing microelement drug based on iron-dextrin complex - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing a microelement drug on the basis of an iron-dextrin complex. The method includes the following stages: mixed water-soluble iron (III) salt and one or more water-soluble salts containing other microelements, e.g., cobalt, copper, zinc, manganese and selenite, and low-molecular dextrin are neutralised before sedimentation of iron (III) hydroxide, alkalised to pH 9-11, heated up to complete resolution and neutralised with an acid. Then, membrane ultrafiltration procedure is used to purify the prepared colloidal iron-dextrin complex with microelement atoms deposited in a polymeric covalent lattice of iron (III) oxide, and to concentrate it.

EFFECT: method allows preparing high-effective high iron fixation polymicroelement drug ensuring the best effect in treating iron-deficient conditions and promoting immune system resistance.

3 cl, 2 dwg, 3 ex

Description

The invention relates to the pharmaceutical industry and can be used to obtain multielement drugs.

Multivitamin-microelement preparations (Kvadevit, Komplivit, Vitrum, Centrum and others) are widely known, prepared on the basis of transition metal sulfates - iron, zinc, manganese, cobalt, copper, etc. However, the degree of assimilation of iron, as well as copper, cobalt and other multivalent metals from their ionic compounds is relatively low: usually it is 3-7% (occasionally and under a special diet - up to 15-17%), which is primarily due to the irreversible binding of these ions to extremely durable insoluble complexes by some cn cific components of food - phytin, polyphenolic compounds, oxalates, certain proteins, legumes, etc. Another important reason for the low bioavailability of metals from simple ionic compounds is the mutual competitive suppression of the absorption of various ions in the gastrointestinal tract (GIT): for example, typical calcium ion concentrations in food products reduce the bioavailability of iron ions by a factor of 2.5–4, and the presence of ions zinc interferes with the absorption of copper ions, etc.

In addition, in the small intestine, iron ions, in turn, precipitate a phosphate ion with the formation of insoluble iron phosphate: the danger of developing rickets of children in conditions of excessive iron consumption is generally known (which is usually associated with the specifics of the water supply of the population of a given area). Divalent iron ions quantitatively bind hydrogen sulfide, which is one of the main mediators of intestinal motility, the result may be a series of difficultly diagnosed intestinal disorders and dysbacterioses. Iron ions form a strong insoluble compound with selenite ion, preventing its absorption. Ionic iron compounds, when administered orally, sharply worsen the color of tooth enamel: while this factor does not seem to be too significant in animal husbandry, the presence of free Fe (II) or Fe (III) ions is still highly undesirable in vitamin-microelement compositions for medical purposes. Ions of iron and copper sharply exacerbate the course of diseases associated with erosion of the mucous membranes of the gastrointestinal tract.

The problem of chemical incompatibility of iodide ions with copper (II) and iron (III) ions is especially significant. During joint storage in the premix, iodide ions are oxidized by iron (III) ions to free iodine and are lost due to the high volatility of the latter. Bivalent copper (both during storage and in the digestive tract) converts iodide ion into biologically absolutely monovalent copper iodide: and since the molar ratio Cu / I in premixes is very high, under typical conditions, one can expect a complete or almost complete absence of assimilable iodine in food additives (not to mention the forced - for this reason) practice of a huge overdose of iodides, which is highly undesirable from the point of view of stability of the hormonal status of animals or humans).

Variable-valence metal ions catalyze the oxidation and oxidative polymerization of unsaturated organic compounds with atmospheric oxygen, which is reflected primarily in the preservation of vitamins in a premix or vitamin-microelement composition. If polyunsaturated fatty acids ("Vitamin F") can still be introduced into the diet in addition to premix, then fat-soluble vitamins (A, D, E) are its traditional components: transition metal ions that make up this multivitamin-multielement composition dramatically reduce the allowable time product storage (which is expressed in the “rancidity” of oils and a drop in analytically determined concentrations of fat-soluble vitamins, as well as vitamin C).

It should be noted that transition metals are introduced into the most modern polymicroelement preparations of Western manufacture not in the form of simple inorganic salts, but in the form of chelates - aminoates, i.e. complexes with amino acids (copper, iron), or gluconates (manganese, zinc). For example, there is a known method for producing such a microelement preparation, including obtaining an amino acid solution, adding copper and zinc oxides and manganese carbonate to it, adding sodium hydroxide to the solution, obtaining a filtrate, adding iron sulfate to the filtrate, mixing, adding potassium iodide and / or selenite sodium, and / or cobalt chloride, drying the mixture by spraying to obtain the amino acid chelate premix (see CN 101248839, publ. 27.08.2008).

However, this technique only partially mitigates the severity of the problem, since the degree of assimilation of metals in this case increases from 3-7% to only 15-20%, competitive mutual inhibition of ion absorption in the gastrointestinal tract is not eliminated, and the rate of oxidation of the iodide ion by copper ion, although decreases many times, remains noticeable.

A known method of producing trace elements by the interaction of an alkaline aqueous solution of disodium or dipotassium salt of ethylenediamine-N, N'-disuccinic acid with a calculated number of solutions of salts of transition metals - iron (III), copper (II), manganese (II), cobalt (II) and zinc (II) (see RF patents No. 2097045, 11/27/97, No. 2277800, 06/20/2006). In the synthesis of the drug using sodium or potassium alkali. As salts of trace elements, as a rule, their chloride or sulfate salts are used. In the resulting preparations, metals are also present in the form of ionic compounds (partially dissociated complexes), and they are characterized, although to a much lesser extent, by the above disadvantages. In addition, the molecules of complexon released during the biological assimilation of metal complexonate do not undergo any noticeable enzymatic transformation in mammalian organisms (found in the urine intact) and are able to form extremely strong complexes with other polyvalent ions in the blood plasma, changing their equilibrium concentration: it is known, for example, that in developed countries the use of iron complexonate and EDTA (ethylenediaminetetraacetic acid) as a source of iron for people not permitted in connection with the potential risk of expiring chelator intervention in the natural biological exchange of zinc ions and other trace elements.

In the case of the use of trace elements obtained by methods known previously, biologically necessary transition metals are introduced into the diet in the form of ionized mineral compounds. The use of a nonionic form of transition metal compounds would eliminate or smooth out these problems.

Closest to the proposed is a method for producing an iron-containing drug based on a nonionic compound, comprising mixing a soluble iron (III) salt with a low molecular weight dextran or dextrin, neutralizing the resulting mixture before the formation of an iron (III) hydroxide precipitate, alkalizing to pH 10.5-11 , 5 with stirring and heating, re-neutralizing the solution, filtering it and isolating the iron-containing complex by ultrafiltration on membranes with an exclusion limit of 10 kDa or more e (RU 2198665 C1, publ. 02.20.2003).

The objective of the invention is to provide a method for producing a highly effective multielement preparation with a higher degree of assimilation of iron.

The technical result of the invention is to provide an iron-containing preparation, additionally containing microelements, which provides better treatment results for iron deficiency conditions, and also contributes to a greater degree of stability of the immune system.

The technical result is achieved by the proposed method.

The proposed method for producing a microelement drug is that a mixture of a water-soluble iron (III) salt and one or more water-soluble salts containing other trace elements, with low molecular weight dextrin, is neutralized in an aqueous solution with stirring until the formation of a precipitate of iron (III) hydroxide, alkalized it to pH 9-11, the mixture is heated until the precipitate is completely dissolved, the solution is neutralized with acid, the resulting colloidal solution of the iron-dextrin complex is deposited and concentrated micronutrient atoms in the covalent polymer lattice of iron (III) oxide.

In this case, the desalination and concentration of the resulting complex is carried out by ultrafiltration of its colloidal solution on membranes with an exclusion limit of at least 10 kDa.

As one or more water-soluble salts containing other trace elements, use a salt or salts of the series: selenite (IV) and transition metal salts of cobalt (II), copper (II), zinc (II), manganese (II).

In this case, a non-ionic form of the preparation is obtained in the form of colloidal polymer oxide (highly dehydrated hydroxide) of iron with trace elements deposited in its lattice.

The essence of the invention is to obtain stable iron-dextrin complexes in which part of the iron ions forming the crystal lattice of the polymer (strongly dehydrated) Fe (III) hydroxide is replaced by heteroelements (cobalt, copper, zinc, manganese, selenium, etc.), and The stability of aqueous colloidal solutions of the obtained complexes is due to the chemical immobilization of low molecular weight dextrins on the surfaces of submicroparticles modified with hetero elements of polymer iron (III) hydroxide. The resulting solutions are characterized by low viscosity, high stability during storage, their use provides a significant increase in the degree of biological assimilation of these trace elements.

Due to the absence in the Russian Federation by the beginning of the 21st century of its own parenteral antianemic preparations for animals (with strict mandatory use of milk pigs), the authors developed a relatively simple and cheap technology for the synthesis and deep purification of colloidal iron-dextran particles using modern membrane technologies and a patented method adopted as the closest analogue (RU 2198665).

In the course of developing the conditions for the synthesis of inorganic oxide-hydroxide "nuclei" for iron-dextran nanoparticles, it was found that it is possible in principle to replace a very significant fraction of iron atoms in the polymer oxide lattice with atoms of other polyvalent elements - copper, cobalt, zinc, selenium, etc.: when compliance with appropriate technological procedures, such a replacement does not lead to a noticeable decrease in stability and deterioration of the rheological properties of the drug. This fact served as the basis for the development of an experimental series of preparations with a high content of selenium, copper and cobalt. We emphasize that the atoms of the above heteroelements are present in the solution in a nonionic state, being included as structural elements in the covalent lattice of the crystalline oxide (highly dehydrated hydroxide) of ferric iron: they do not exhibit chemical reactions typical of the ions of these elements and cannot be separated from nanoparticles by dialysis and ultrafiltration.

It has been experimentally shown that the introduction of even insignificant concentrations of trace elements (Cu, Co, Se) into the iron oxide matrix of colloidal iron-dextrin particles sharply increases the therapeutic antianemic effect of the drug. Thus, the deposition of atoms of trace elements in the covalent lattice of iron oxide seems to be an original and very promising technique.

In the proposed method for the synthesis of microelements of iron hydroxide nanoparticles modified with microelements (with molecular masses from 100 KDa to 350 KDa, depending on the process conditions), the simplest inorganic metal salts are used, the efficiency of biological assimilation of the mineral components of the nanoparticles is extremely high, and as a result of the bioconversion of particles into only the simplest inorganic ions enter the blood (in principle, non-xenobiotics); at the same time, the high load of the nanoparticles with heteroelements makes it possible to introduce a 3-4-week normal intake of this microelement once to the animal or person without much labor and risk.

A method of obtaining a microelement drug is given below.

A concentrated dextrin solution containing Fe (III), Co (II), Cu (II), Zn (II), Mn (II) chlorides and sodium selenite (the composition and proportions for each group of animals or humans were established in accordance with established recommendations) are neutralized while stirring with a concentrated soda solution until the formation of a precipitate, alkalize the mixture with a solution of sodium hydroxide to pH 9-11, heat it to the temperature of dissolution of the precipitate, the resulting red-brown solution is acidified with concentrated Hcl to pH 5.8-6.5. The concentration and desalination of the colloidal solution is carried out by ultrafiltration on membranes with an exclusion limit of more than 10 kDa.

The following are examples of syntheses for this method.

EXAMPLE 1

SYNTHESIS OF A IRON-DEXTRINE COLLOID ENRICHED BY MANGANIAN

To 220 ml of a solution containing 40 g of ferric chloride hexahydrate, 1.5 g of manganese chloride tetrahydrate was added with stirring 100 ml of a 25% aqueous solution of dextrin, then 120 ml of an 18% aqueous solution of anhydrous carbonate was slowly added at room temperature with stirring. sodium to obtain a thick mixture. Then, the resulting solution was made alkaline with a 40% sodium hydroxide solution to a pH of 11.2 and heated for 1 hour at 95-97 ° C (the precipitate was completely dissolved and a homogeneous red-brown solution formed). The solution was cooled, acidified with 20% hydrochloric acid to pH 6.5, filtered through paper and ultrafiltered on fiber membranes with an exclusion limit of 100 KDa: the solution was desalted to a residual NaCl concentration of 8 mg / ml and concentrated to an iron content of about 72-80 mg / ml.

The resulting colloidal preparation in an amount of 110 ml is stable during storage, characterized by a low relative viscosity (viscosity relative to water - 2.5) and does not oxidize iodide ion in a concentrated KI solution for 2 hours.

After mineralization of an aliquot of the drug by boiling with 2N HCl by atomic absorption spectrophotometry, the concentrations of iron and manganese were determined equal to 75 mg / ml and 3.9 mg / ml, respectively, and the ratio [Fe] / [Mn] = 19.2.

EXAMPLE 2

SYNTHESIS OF IRON-DEXTRINE COLLOID ENRICHED BY ZINC

To 220 ml of an aqueous solution containing 40 g of ferric hexahydrate, 4.2 g of anhydrous zinc chloride, 100 ml of a solution containing 30 g of dextrin was added with stirring. Then 130 ml of an 18% solution of anhydrous sodium carbonate were added with stirring until a thick brown mixture was obtained. The mixture was made alkaline with a 40% sodium hydroxide solution to a pH of 9.8, heated with stirring at 95-98 ° C for 1 hour. The homogeneous solution was filtered, acidified with 6 N hydrochloric acid to pH 6.7, and purified by ultrafiltration on a fiber membrane filter with an exclusion limit of 100 Kda. The solution was desalted to a residual NaCl concentration of 10 mg / ml and concentrated to an iron content close to 50 mg / ml. After mineralization of an aliquot of the sample with boiling hydrochloric acid, the concentration of metals in the colloidal solution was determined by atomic absorption spectrophotometry: [Fe] = 52 mg / ml, [Zn] = 12.4 mg / ml, ratio [Fe] / [Zn] = 4, 2.

EXAMPLE 3

SYNTHESIS OF IRON-DEXTRINE COLLOID ENRICHED WITH COPPER, COBALT AND SELENIUM

To 220 ml of an aqueous solution containing 40 g of ferric chloride hexahydrate, 1.80 g of copper chloride dihydrate, 0.51 g of cobalt chloride hexahydrate, 17.0 mg of sodium hydroselenite was added with stirring 100 ml of a solution containing 30 g of dextrin. Then 140 ml of an 18% solution of anhydrous sodium carbonate were added with stirring until a thick brown mixture formed. Then, the sample was made alkaline to pH 10.2, heated to 95-98 ° C, and stirred at this temperature for 1 hour. The solution was cooled, acidified with 6N hydrochloric acid to pH 6.5, filtered through paper and ultrafiltered on fiber membranes with an exclusion limit of 100 kDa. The solution was desalted to a residual NaCl concentration of 10 mg / ml, and its concentration to an iron content of 50 mg / ml. After mineralization of the sample by the above method, an analytical determination of the content of the mineral components of the mixture was carried out: the concentration ratio [Fe]: [Cu]: [Co]: [Se] = 100: 7.9: 1.7: 0.1.

A study was conducted of the comparative effectiveness of iron-containing preparations obtained by the method according to the patent of the Russian Federation 2198665 and the proposed method.

Figure 1 shows the dynamics of changes in hemoglobin in experimental animals.

Figure 2 - dynamics of changes in the average indicators of cellular immunity (CD4) in the treatment of experimental animals.

To determine the comparative effectiveness of iron-containing preparations, 3 randomized groups of rats in the amount of 18 animals were formed.

Using well-known methods of anemization in an acute experiment, it was possible to achieve moderate anemia in experimental animals in 6 weeks.

To carry out the correction of anemia, we used injectable iron-containing preparations “Bio-iron feed with microelements” (obtained by the proposed method) (contains microelements: Fe (III) - 50 mg / ml, Co - 0.2 mg / ml, Cu - 0.1 mg / ml, Se - 0.07 mg / ml) and "Bio-iron feed" (obtained by the method according to patent 2198665) (contains Fe (III) - 50 mg / ml) synthesized by A-BIO LLC (Russia). The synthesis of colloids was carried out from the following raw materials: crystalline ferric chloride hydrate of reactive purity (Krasnoperekopsky plant, Ukraine) and polysaccharides - Kurosan dextrin (Germany).

During the experiment, the experimental animals were divided into 3 groups as follows.

The FIRST group of rats received the bio-iron feed iron-polymer preparation at a dose of 0.25 ml / 100 g once a week, 2 weeks.

SECOND group of rats received iron-polymer preparation “Bio-iron feed with microelements” at a dose of 0.25 ml / 100 g once a week for 2 weeks.

The THIRD group of rats was a control, animals of this group of treatment did not receive.

When analyzing the dynamics of red blood indices in experimental rats during treatment, a positive trend was observed in most groups compared with the control. Most clearly, the dynamics of changes in red blood during the treatment of experimental animals can be displayed in the form of a diagram of changes in hemoglobin indicators, which significantly differed in the groups during treatment (see figure 1).

The preparation “Bio-iron feed with microelements” (group 2) has a stimulating effect on hemoglobin indicators, as well as the preparation “Bio-iron feed” (without trace elements - group 1), however, the effectiveness of the second at the end of treatment was significantly higher compared to end results in group 1.

This fact can be explained by the presence in the polymer complex “Bio-iron feed with trace elements” in addition to iron, a number of trace elements that could show a synergistic stimulating effect on hematopoiesis.

The analysis of the dynamics of changes in cellular immunity during treatment is shown in the diagram (see figure 2). As can be seen, in all groups of experimental animals during treatment there was a statistically significant decrease in T4DM compared with the rise of T-helpers noted at 4-6 weeks of anemia.

Only with the help of the preparation “Bio-iron feed with microelements” did we manage to slow down the progressive decrease in T4DM to a certain extent, and the drug had a stabilizing effect on the number of T-helpers.

Findings:

1. The use in oral form of polymaltose (dextrin) compounds of polymer iron hydroxide with trace elements Co, Cu, Se included in the iron-dextrin polymer lattice provides significantly better treatment results for iron deficiency states in comparison with the same compound of polymer iron hydroxide without trace elements.

2. Also, the advantage of a polymer with trace elements was observed with a decrease in cellular immunity during treatment. The polymer with trace elements to a greater extent contributes to the stability of the immune system, exerting a stabilizing effect on the number of T-helpers.

Claims (3)

1. A method of obtaining a microelement drug, which consists in the fact that a mixture of a water-soluble salt of iron (III) and one or more water-soluble salts containing other trace elements, with low molecular weight dextrin, is neutralized in an aqueous solution with stirring until the formation of a precipitate of iron hydroxide (III) , alkalize it to pH 9-11, heat the mixture to completely dissolve the precipitate, neutralize the solution with acid, purify and concentrate the resulting colloidal solution of the iron-dextrin complex with deposited in the polymer covalent lattice of iron (III) oxide by trace elements atoms. 2. The method according to claim 1, characterized in that the purification of the obtained complex is carried out by ultrafiltration on membranes with an exclusion limit of at least 10 kDa. 3. The method according to claim 1, characterized in that as one or more water-soluble salts containing other trace elements, use a salt or salts of the series: selenite (IV) and transition metal salts of cobalt (II), copper (II), zinc (II), manganese (II).

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