Polaratherm trivalent iron as a means for the treatment of iron deficiency anemia and pharmaceutical composition based on it

 

(57) Abstract:

The invention relates to medicine. Proposed polaratherm ferric exhibiting therapeutic properties for iron-deficiency anemia, and pharmaceutical composition based on it. Polaratherm trivalent iron increases hemoglobin in the blood with minimal side effects. 2 S. and 1 C.p. f-crystals, 2 tab.

The present invention relates to medicine, in particular for enteral forms of iron preparations (ISP) may find application in the manufacture of medicaments for the treatment of iron deficiency anemia (IDA) in children and adults.

Thus we will distinguish yourself means to treat IDA (substance) and pharmaceutical compositions (drug form) on the basis of them.

It is widely known use as a tool for the treatment of IDA inorganic salts of ferrous iron (Fe (II)), such as ferric sulfate FeSO4(Lopakhin C. K., Belousov Y. K. Moiseev, B. C. Clinical pharmacology with the international nomenclature of drugs. Medicine, 1988, ch. II). Sulphate of iron (II) is highly soluble in water, in the stomach is in the form of hydrated ion Fe(H2O)62+

Marked (Scheider W. Arzneim Forsch. Drug Res., 1987, 37 (1), N 12, p. 92-95) that preparations containing simple salts of iron (II), cause side effects and are poorly tolerated by patients. The toxicity of these drugs due to their ability to be absorbed, which leads to excess iron in the body, as well as oxidation ferraiolo, causing the formation of radicals, which are able to affect cell membrane.

It is also known (Lopakhin C. K., and others Clinical pharmacology with the international nomenclature of drugs. Medicine, 1988, ch. II) use as a tool for the treatment of IDA inorganic iron (III) salts, such as ferric chloride FeCl3. However ferraioli undergo hydrolysis at earlier stages of the journey through the digestive tract and the intestine are mostly in the form of hydroxides, poorly absorbed by the receptors of iron.

There are a large number of pharmaceutical compositions (dosage forms) on the basis of simple salts of iron (II), in particular sulfate, in which Raia, representing capsules containing 0,150 g of iron sulfate (II) many small granules, coated with layers of a polymeric material soluble in the digestive tract. The gradual release of iron sulfate was allowed to avoid high local concentrations, leading to intolerance (Jarry H., Rote M. D. Intern. Record Med., 1958, 171, R. 87-91).

Also known (Largiader A. Schweiz. Rundschau Med. (praxis), 1973, 62, R. 173-175) the pharmaceutical composition of tardyferon, including on one tablet of 0.08 g of iron in the form of sulphate of iron (II) and 0.08 g of mucoprotein, which is the macromolecular fraction of the intestinal mucosa of sheep; mucoprotein reduces the ability of iron (II) oxidation.

Also known (Israels, M. C. G. , Simmons, A. V. Lancef, 1967, No. 1, p. 1297-1299) a pharmaceutical composition comprising 0,105 g of iron sulfate (II) and 0.50 g of ascorbic acid (terrordome - 500), which increases the absorption of iron and is involved in the intracellular metabolism of iron-binding proteins.

Also known (U.S. patent N 3076747, NCI 424-147, 1963) a pharmaceutical composition comprising from 1 to 12 equivalents of succinic acid to 1 equivalent of iron in the form of sulphate of iron (II). Succinic acid increases the absorption of iron. The use of succinic acid as well as Scola is obtained in a known dosage forms, comes in a redox reaction; thus, the additives introduced in the pharmaceutical composition, reduce poor tolerance of salts of iron (II), but does not eliminate it altogether.

The closest to therapeutic effect to the proposed treatment for IDA is fumarate, iron (II) (perfumers), which is attributed formula

< / BR>
(GOS. register of medicines and products of medical appointment, M , 1994, S. 175).

Fumarate, iron (II) poorly soluble in water, but absorbed by the body. Anion fumaric acid has antihypoxant and antioxidant effect. This leads to the fact that perfumers better tolerated than inorganic salts of iron (II) and pharmaceutical compositions based on them. However, the anion fumaric acid does not reduce the ability of the cation Fe2+oxidation and prevents the formation of peroxy radicals that affect cell membrane.

In addition, the synthesis of perfumaria quite complicated and expensive (see application Czechoslovakia N 273239, MCI And 61 H 31/19, 1992).

The aim of the invention is to develop tools for the treatment of IDA, better wrapping of patients, and pharmaceutical compose of dumartheray ferric formula

< / BR>
or in short

Fe2(C4H2O4)2(OH)2(H2O)2(perfumeinside)

It is known that fumaric acid forms complex compounds with ions of transition metals (see , for example, Hsiou Ju et al. Acta crystallogr., C, 1989, 45, vol.5, 721-724; G. Smith et al. Z. Kristallogr., 1995, 210, vol.1, 44-48; Panyushkin Century. So, Archipenko H. B. Coordination chemistry, 1994, 20, vol. 10, S. 799, and others). However, the products of the interaction of ferric salts with fumaric acid still has not been studied, and as pharmaceutical agents were not used.

Synthesis of perfumethat shown in example 1.

Example 1. Getting ferritometer.

The 3-liter flat-bottomed flask equipped with a mechanical stirrer and thermometer, is placed 2500 ml of distilled water, in which dissolve 240 g of sodium hydroxide. In the sodium hydroxide solution is gradually fed 348 g of fumaric acid. Completeness neutralization test for pH, which should be equal to 7.

To the resulting solution fumarata sodium in small portions with stirring 541 g setevogo ferric chloride FeCl3(H2O)6. The precipitate of dumartheray iron (III) filter and mark the CSOs weight.

Received 367 g ramakrishnaiah powder, insoluble in water and organic solvents. In aqueous solutions of acids obtained powder is dissolved with the breakdown of complex compounds.

According to the quantitative analysis of the obtained compound contains 26,5 1,0% iron. Were also studied by infrared (IR) spectra of sediment (tablets with KBr) and compared with the IR spectra fumaric acid and fumarata sodium. The IR spectrum of the obtained compound has no absorption band, corresponding communication H-O group - COOH. Calculation of atomic distances showed that the anion fumaric acid may not be associated with both groups-COO-with one ion Fe3+without rearrangement of the anion of maleic acid. However, maleates toxic, and the compound obtained according to our data, non-toxic.

Thus, given the iron content, the data of IR spectroscopy and lack of toxicity, the formula obtained complex compounds is

< / BR>
Molecular weight 410, the estimated iron content in connection 27,4%.

The study of clinical effectiveness of dumartheray iron (III) was performed on the model IDA caused in animals nutritional factor, combined with the blood loss. The experimental the protein and devoid of iron. After 3 weeks the animals on this diet they were subjected to twice the estimated blood loss in the amount of 20 mg per 1 kg of body weight once a week under the supervision of hemoglobin (HB) and erythrocyte (er). The severity of iron deficiency anemia in animals was evaluated by reducing the concentration of HB and Ayr, on changing the system antipersonnel protection (SAPS) by reducing the content of vitamin E and catalase activity, as well as on the results of study of lipid peroxidation (LPO) and coefficient of antioxidant activity of blood serum. Indicators GENDER was determined by the increase in the content of malondialdehyde in erythrocytes and diene conjugates in the blood. The results are presented in table. 1.

By reducing the content of NR and er 40% started treatment of rats polaratherm iron (III), and to compare the fumarate iron (II) (Dutch drug perfumers) and iron sulfate (II). Fumarate iron in the form of aqueous suspensions, ferric sulfate in aqueous solution was injected into the animal in the stomach with the help of the probe in a volume of 0.5 ml per 100 g body weight. Dose GSP was 3 mg of iron per 1 kg of body weight, which corresponds to the maximum therapeutic dose for humans. The course of treatment was 3 weeks. At the end of treatment Opredelenie iron preparations makes it possible to quickly increase the hemoglobin content in the blood and replenish depleted in iron-deficiency anemia iron depot. In this action dumartheray iron (III) is not inferior to action fumarata iron (II) and comparable with him.

The study of the system antipersonnel protection showed that during the development of IDA activity of cytoplasmic catalase drops sharply. In the treatment JSP catalase activity in all cases increases not to the initial level, but in the treatment of polaratherm iron (III) it is significantly higher than that in the treatment of iron (II), even fumarate, iron (II).

The content of vitamin E in the blood of animals treated with iron supplementation, confirms the General picture of the state of the system antipersonnel protection obtained in evaluating the performance of the catalase activity of the blood. So, when treating polaratherm iron (III) content of vitamin E in the blood increased by more than 2 times, and exceeded the original value. In rats, which were treated with fumarate, iron (II), the content of vitamin E was significantly lower than in animals treated with polaratherm iron (III). The lowest rates in the experiments with sulphate of iron (II).

Research intensity of reactions of lipid peroxidation showed that the introduction of dumartheray iron (III) content of the final products FLOOR (level milonov the e diene conjugates (initial products FLOOR) was decreased in 3 times and reached values, recorded prior to the experiment. The ratio of antioxidant activity of serum from animals treated with polaratherm iron (III), also returned to the level of norms.

In the case of treatment with fumarate, iron (II) lipid peroxidation in erythrocytes and serum were decreased compared to the values registered with anemia, but the content was much higher than in the treatment polaratherm iron (III). In the treatment of iron sulfate (II), the performance is even worse - there have been only a tendency to decrease of LPO products.

Thus, the results of the experiment showed that the proposed tool, not yielding fumarate, iron (II) effectiveness in the treatment of IDA, has minimal side effects, usually leading to poor tolerability of the drug.

The goal set in the present invention, is achieved by the fact that the pharmaceutical composition comprising the agent for the treatment of iron deficiency anemia and a pharmaceutically acceptable carrier, contains as a means for the treatment of IDA polaratherm iron (III), General formula

< / BR>
the number 0,139-0,324 g per dosage unit.

Polaratherm iron (III) in the form of a powder, priemlemogo media you can use various substances, such as sugar and its substitutes, such as sucrose, glucose, sorbitol, mannitol, lactose, saccharin; high-molecular compounds such as methyl cellulose (MC), microcrystalline cellulose (MCC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), gelatin, starch, technological additives, sodium chloride and citric acid; apadravya substances, such as talc, stearic acid, stearates of magnesium and calcium, and many other substances used in the pharmaceutical industry, taken as a mixture or separately.

The pharmaceutical composition may be produced in the form of tablets weight 0,5225-0,5775 containing 0,139-0,324 g dumartheray iron (III) and 0,226-0,411 g of filler, in the form of granules enclosed in a gelatin capsule; in the form of granules, Packed in conventional pharmaceutical packaging. Obtaining a pharmaceutical composition in different species are represented in examples 2-4.

Example 2. Obtaining tablets containing polaratherm iron (III).

In the laboratory setting fluidized-bed capacity of 2 l was downloaded 460 g of milk sugar and 138 g of starch and at a temperature of 50oC was stirred for 2 min at a pressure of atomizing air 2 MPa. The stirred mixture of. the dratha iron (III) and apadravya ingredients: 70 g of starch, 33 g of talc and 11 g of calcium stearate. The mixture continued to stir for 1-2 min at 50oC. the resulting mixture tabletirujut laboratory tablet press RTM-12 into tablets with a diameter of 12 mm and a weight of about 0,550,

In table. 2 shows various formulations of tablets based podargidae iron (III) obtained in the manner described above (positions 1-55, PL. 2).

Example 3. Obtaining a granulate containing polaratherm iron (III).

In a laboratory mixer with a capacity of 10 l load 0,300 kg dumartheray iron 4,005 kg of icing sugar, stirred for 5 min and moisturize combined humidifier consisting of 1.0 kg 64% sugar syrup, 5.0 g of the aromatic essences of food, 50.0 g of citric acid for 10-15 minutes until a uniform distribution of moisture. Then the wet mixture is passed through the pellet mill for wet granulation diameter holes in the wall of the Cup 4-5 mm. Wet granulate is dried in a laboratory scale fluidized-bed at a temperature of 60oC for 20 minutes the Dried granulate is passed through a universal pellet mill with diameter holes on a grid of 1.5 mm

The resulting mixture was Packed in packages of paper with a polymer coating on a 5.0,

St, containing polaratherm iron (III).

In a laboratory mixer with a capacity of 1.0 l load 300 g dumartheray iron, 110 g of milk sugar, stirred for 5 min and moisturize 10% solution of gelatin in the amount of 400 g for 10-15 minutes until a uniform distribution of moisture. Then the wet mixture is passed through the pellet mill for wet granulation diameter holes in the wall of the Cup 4-5 mm. Wet granulate is dried at a temperature of 60oC for 30 minutes the Dried granulate is passed through a universal pellet mill with diameter holes on a grid of 1.5 mm

The resulting mixture is filled into hard gelatin capsules of 0.45 g

In table. 2 presents the different formulations of the contents of the capsules (position 62-72, PL. 2).

1. Polaratherm ferric formula

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2. Polaratherm ferric under item 1, with a therapeutic effect in iron deficiency anemia.

3. Pharmaceutical composition comprising the agent for the treatment of iron deficiency anemia and a pharmaceutically acceptable carrier, characterized in that as a means for the treatment of iron deficiency anemia composition contains polaratherm trivalent W

 

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