Iron bis-glycinate chelate used in oral therapy of anaemia in patients with celiacia

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology and enterology, and concerns treating anaemia in the patients with celiacia. That is ensured by an oral administration of iron bis-glycinate chelate in the form of an effervescent tablet, semi-solid or liquid dosage form in the range of doses of 5 to 200 mg a day that corresponds to 1 to 40 mg of an iron ion.

EFFECT: invention provides treating anaemia in the patients suffering celiacia by the effective absorption of orally administered iron bis-glycinate chelate.

11 cl, 3 tbl, 11 ex

 

The invention relates to bisglycinate-iron chelate for use in the treatment of anemia in patients with celiac disease.

Background of the invention

Celiac disease is a disease of small intestine with immune-mediated pathogenesis, characterized permanent intolerance to protein fractions of wheat, rye, barley and oats. In genetically predisposed subjects such intolerance causes damage to the mucous membrane, which, in turn, leads to atrophy of the small intestine (Farhad Zamaniet al., Gluten sensitive enteropathy in patients with iron deficiency = MKD anemia of unknown origin.World J. Gastroenterol.2008,14(48), 7381-7385).

Celiac disease affects both adults and children.

In fact, celiac disease is one of the most common causes of malabsorption, especially in childhood, when it is considered as one of the chronic diseases that can slow the growth.

In General, the clinical manifestations of the specified diseases vary greatly, and the only evaluation is partly the extent of the lesion of the small intestine (Fernando Bermejoet al., A guide to diagnosis of iron deficiency = MKD and iron deficiency = MKD anemia in digestive diseases.World J. Gastroenterol.2009,15(37), 4638-4643).

For this reason, the disease is expressed very heterogeneous, varying from forms with severe syndrome of malabsorption to virtually asymptomatic the ORM.

In this regard, it should be noted that celiac disease causes modification of both the quantity and forms of intestinal villi, through which is the absorption of exogenous and/or nutrients.

Celiac disease has a variety of symptoms, and each of them has varying degrees of severity of a subject with celiac disease (Jason W. Harperet al., Anemia in celiac disease is is multifactorial in etiology.Am. J. Hematol.2007,82, 996-1000).

Some clinical manifestations or symptoms present in patients with celiac disease of varying severity, include: weight loss, fatigue, nausea, vomiting, changes in blood clotting, osteopathy with bone pain, excessive mucus formation, mainly in the language, and neurological disorders of the peripheral nervous system (Farhad Zamaniet al., Gluten sensitive enteropathy in patients with iron deficiency = MKD anemia of unknown origin.World J. Gastroenterol.2008,14(48), 7381-7385; Freeman H.et al., Coeliac disease.Best. Pract. Res. Clin. Gastroent.2002,16(1), 37-49).

Another obvious symptom of celiac disease is diarrhea, the pathogenesis is multifactorial.

One of the causes of diarrhea is malabsorption of food, leading to increased besprosvetnoe content of feces, which due to its high osmotic ability have a greater amount of relatively physiological conditions. Another reason that causes diarrhea, the two who is poor digestion. In fact, in patients with celiac disease may experience a decrease in secretion of cholecystokinin and secretin, which leads to nerazdelenny proteins and lipids.

In addition, one of the most essential features that are common to about 50% of patients with celiac disease, is sideropenic anemia observed reduction in hemoglobin, ferritin and serum iron in the blood in geochronological test.

It is known that patients with celiac disease specified anemia cannot be treated with oral therapies based on compounds containing iron ions in the form of salts, complexes or other substances, split at the gastrointestinal level. In fact, according to literature data oral treatment with compounds containing iron, does not cause increase of hemoglobin/iron in the blood of patients with celiac disease (Fernandez-Banareset al., A short review of malabsorption and anemia.World J. Gastroenterol.2009,15(37), 4644-4652). Still consolidated treatment of anemia in patients with celiac disease consists of parenteral administration, particularly intravenous, iron salts, such as, for example, gluconate, therapeutic cycles repeated every 4 or 6 months depending on the severity of the anemia. Until now, this method of introduction was possible to obtain a therapeutic effect, required the patients with this pathology. To date oral treatment on the basis of iron salts was considered suitable only as a Supplement at the stage of maintaining the level of hemoglobin in the blood after parenteral treatment.

Parenteral route of administration often do not like patients, and especially its disadvantage is that it requires the participation of medical personnel and medical institutions or the hospitalization of the patient for monitoring of possible anaphylactic reactions.

Therefore desperately need to find a therapeutic solution for the treatment of anemia in patients with celiac disease, which can improve patients ' adherence to treatment.

Description of the invention

It has been unexpectedly found that bisglycinate-chelate iron, administered orally to patients with celiac disease, significantly increases the level of hemoglobin, ferritin and serum iron in the blood, and, therefore, can be effectively used in the treatment of anemia.

This compound and its structural formula (I) below, are widely known (Ashmed S. D. The chemistry of ferrous bis-glycinate chelate.Arch. Latino Am. De Nutr.,2001,51(1), 7-12; Atkins, P. W., Berau J. A. 1992 General Chemistry, 2nd ed. Scientific American Books, W. H. Freeman, New York; Coplinet al., Tolerability of iron: a comparison of bis-glycino iron II and ferrous sulfate.Clinical Therapeutics,vol. 13, n.5, 606-612, 1991).

Bisglycinate-chelate iron performance, which provides a fairly soluble chelate, different Central metal atom, Fe(II), tetracoordinated two chelating agents (glycine) and corresponding to the following structural formula (I):

Donor-acceptor interaction of the nitrogen atom contributes to the stabilization energy of the orbitals of the Central metal atom and the geometry of the binding agent, forming a five-membered ring.

This compound is also known because of its portability, security and high bioavailability (Jeppsen R. B. Toxicology and safety of Ferrochel and other iron amino acid chelates.Arch. Latino Am. De Nutr.,2001,51(1), 26-34; Opinion if the Scientific Panel on Food Additives, Flawourings, Processing Aids and materials in Contact with Food on a request from the Commission related to Ferrous bisglycinate as a source of iron for use in the manufacturing of foods and in food supplements.EFSA Journal,2006,299, 1-17).

From literature data it is known that such a chelate complex has a higher relative bioavailability of mineral salts, such as, for example, ferric sulfate, because it is absorbed in an unmodified form of the intestinal mucosa and, thus, is not subjected to any modification in the gastro-intestinal system (Pineda O.et al., Effectiveness of iron amino acid chelate on the treatment of iron deficiency = MKD anaemia in adolescents.Journal of appl. Nutr., Vol. 46, Numbers 1-2, 1994; Pineda O., Effectiveness of treatment of iron-deficiency = MKD anaemia in infants and young children with ferrous bis-glycinate chelate,Nutrition,2001,17(5), 381-384).

The stability of the connection, which proves the fact is, the product is hydrolyzed at different pH values gastrointestinal Department, and low molecular weight (204 Dalton) provide maximum absorption after oral administration (DeWayne H. A., The absorption and metabolism of iron amino acid chelate.Arch. Latino Am. De Nutr.,2001,51(1), 7-12; Marchetti, M.et al., Comparison of the rates of vitaminic degradation when mixed with metal sulphates or metal amino acid chelates,J. Food Comp. Anal.,2000, 13, 875-884).

Thus, the present invention is bisglycinate-iron chelate for use in the treatment of anemia in patients with celiac disease.

According to the present invention, the term "patient with celiac disease" is used to indicate the person as an adult subject, and child, and the term "child" ("children") refers to the population from birth to eighteen years.

The term "anemia" according to the present invention includes: sideropenic anemia, aplastic anemia, vitamin and/or folate-deficiency anemia (such as, for example, pernicious anemia, anemia of chronic diseases (such as AIDS, cancer or hepatitis and hemolytic anemia.

Based on the results of therapeutic efficacy, embodied in the present invention (in the following examples and experimental part) obtained in the treatment of bisglycinate-iron chelate suffering from anemia patients with celiac disease, can is about to conclude, what physico-chemical characteristics of bisglycinate iron, such as low molecular weight and lack of electric charge, serve as a positive factor in relation to the suction modified through the villi of the intestine observed in most patients with celiac disease.

Unlike conventional take oral iron salts bisglycinate iron is not divided into iron ion in the range of pH values between 3 and 10.

In contrast, conventional take oral iron salts, for example, sulfate, ferrous iron, break down at the level of the gastrointestinal tract on the iron ion and the corresponding anion. Fe++with a positive charge, is poorly absorbed altered intestinal villi.

It is preferable to use bisglycinate iron according to the invention for oral treatment sideropenic anemia in patients with celiac disease.

Sideropenic anemia is a form of anemia characterized by a noticeable decrease of hemoglobin in the bloodstream caused by the deficiency.

Therefore, the use of bisglycinate oral iron for treatment of this type of anemia is particularly preferred that bisglycinate iron according to the present invention can be considered as the drug of choice for use in patients with sideropenic anemia, even permanent, and/or gluten-free diets.

In particular, bisglycinate iron of the present invention, i.e., in tablets, preferably in effervescent tablets, or in semi-solid or liquid form, it is easier absorbed altered intestinal villi in a patient with celiac disease relative to other standard pharmaceutical forms.

Therefore, bisglycinate iron of the present invention is administered orally, preferably as part of a solid, semi-solid or liquid form, with the specified solid form selected from tablets, granules, microgranules or capsules, and the said semi-solid or liquid form selected from the suspension or solution.

Bisglycinate iron according to the invention can be introduced into the composition together with at least one sweetener and/or flavoring. Preferably, the ratio between the specified at least one sweetener and/or flavoring and bisglycinate iron according to the invention was about 0,56 by weight.

Specified, at least one sweetener and/or flavoring according to the invention can preferably be selected from Acesulfame K, Sucralose, sorbitol, sucrose, fructose, orange flavor, lemon flavor, tangerine flavor, caramel flavor, or a mixture thereof.

More specifically, bisglycinate iron of the present invention, prepact the tion, introduced into the composition together with a mixture containing Acesulfame K, Sucralose, sorbitol and flavor, and the weight ratio of Acesulfame K:Sucralose:sorbitol:the flavor is approximately 1:0,30-0,50:0,12-0,24;3,0-3,4, accordingly, preferably about 1:0.40 to:0,18:3,20 by weight.

According to the invention bisglycinate iron optionally, you can enter into the composition together with optional physiologically acceptable excipients and/or additives.

According to the invention of the pill, granulate and micro-granulate can be coated not coated and/or to provide a sparkling form, preferably effervescent tablet.

The term "effervescent" of the present invention is used to specify the form, is capable of producing carbon dioxide upon contact with water and/or buccal use, in the presence of saliva.

To obtain sparkling form according to the invention, it is preferable to use di, tri-carboxylic acids or their mixture.

More preferably the effervescent composition of the invention prepared using the dihydrate and monohydrate sodium citrate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, citric acid, tartaric acid, adipic acid, sodium dihydrophosphate, alginic acid, hydroxycarbonate magnesium or mixtures thereof.

In particular, in oral solid forms bi is glycinate iron according to the invention is contained in the number, ranging from 5 to 200 mg bisglycinate iron (corresponding to from 1 to 40 mg of Fe ion), preferably from 10 to 100 mg (i.e., corresponding to from 2 to 20 mg of Fe ion).

Preferably in the fizzy tablet bisglycinate iron is contained in a quantity equal to about 70 mg (i.e., corresponding to about 14 mg iron ion).

The preferred embodiment of the invention includes the introduction of bisglycinate iron two effervescent tablets per day, containing about 70 mg bisglycinate iron (i.e., 14 mg iron ion), within twenty days.

An additional variant embodiment of the invention includes the introduction of bisglycinate iron two effervescent tablets per day, containing about 70 mg bisglycinate iron (i.e., 14 mg iron ion), within twenty days, one effervescent tablet daily containing 70 mg of bisglycinate iron (i.e., 14 mg iron ion), for an additional forty days ("treatment cycle").

Each therapeutic cycle according to the invention can be repeated every 3-4 months for about one year.

Another variant embodiment of the invention includes the introduction of bisglycinate iron two effervescent tablets per day, containing about 70 mg bisglycinate iron (i.e., 14 mg iron ion), within twenty days, one effervescent tablet daily containing 70 mg of bisglycinate is Eliza (i.e., 14 mg iron ion), for an additional forty days ("treatment cycle") and maintenance therapy for two effervescent tablets per day, containing about 70 mg bisglycinate iron (i.e., 14 mg iron ion), within twenty days (the"maintenance therapy").

Supportive therapy according to the invention can be repeated every three months for a total period of time of about one year. The term "supportive therapy" according to the invention are used to indicate the continuation of therapy with a possible increase of the values of hemoglobin, ferritin, and serum iron.

In semi-solid and liquid forms bisglycinate iron according to the invention is contained in an amount of from 1 to 10 g/100 ml solution/suspension (corresponding to from 2 to 20 mg of Fe ion per ml), preferably about 5 g/100 ml solution/suspension (corresponds to 10 mg of Fe ion per ml).

These semi-solid or liquid form according to the invention, it is preferable to introduce children, preferably in the form of an aqueous solution.

Thus, an additional variant embodiment of the invention includes the introduction of bisglycinate iron children in aqueous solution with a pipette calibrated to 0.5 ml, 0.75 ml and 1 ml, allowing to adapt the dosage according to the age, weight of the subject and possibly severity of celiac disease.

According to an additional variant of implementation of the invented what I bisglycinate iron according to the invention can be entered together with one or more additional active ingredients.

Additional active ingredients of the present invention can preferably be selected from vitamins and/or mineral salts.

These vitamins can preferably be selected from vitamin B9 (folic acid), vitamin B12 and/or vitamin B6.

These mineral salts can preferably be selected from salts of potassium, magnesium, iodine, zinc.

Bisglycinate iron according to the present invention can be entered as monotherapy or after conventional therapy as oral and parenteral.

The following examples are intended for better understanding of the invention, it is not limiting in any way.

Example 1: composition of the fizzy tablets

The active ingredientmg tablet
Bisglycinate iron70 mg (equivalent to 14 mg Fe ion)
Excipients for sipacate
Citric acid433
Sodium bicarbonate307
Sweeteners
Acesulfame K 25
Sucralose10
Sorbitol4,5
Flavor
Orange flavor80

The ratio of Acesulfame K:Sucralose:sorbitol:flavouring in effervescent tablet of example 1 is 1:0,4:0,18:3,20.

the pH of the solution, prepared by dissolving effervescent tablets of example 1 from 150 mg of water is 4.7.

Examples 2-5: composition in aqueous solution

Table a
COMPONENTThe SOLUTION L1The SOLUTION L2The SOLUTION L3The SOLUTION L4
Bisglycinate iron5.0 g5.0 g5.0 g5.0 g
Fructose38,5 g38,5 g--
Sorbitol30,8 g 30,8 g30,8 g30,8 g
Citric acid1.5 g1.5 g1.5 g1.5 g
Caramel flavoring1.4 g-1,4-
Tangerine flavor-3.0 g-3.0 g
Sucrose--38,5 g38,5 g
Acesulfame K---0.5 g
Waterto 100 mlto 100 mlto 100 mlto 100 ml
pH4,144,174,144,16

Experimental part

a)Comparison eff is aktivnosti between bisglycinate iron, introduced orally to the invention, and standard treatment in patients with celiac disease

In this experiment included 12 subjects with celiac disease, have sideropenic anemia diagnosed by hemoglobin (Hb), ferritin, and iron (serum iron), obtained using geochronological test.

The celiac disease was diagnosed on clinical manifestations and the histological studies of the intestinal mucosa.

All patients initially received treatment with ferrous sulfate oral (1 tablet of ferrous sulfate of iron, corresponding to 105 mg iron ion) for 40 days and/or ferrous gluconate sodium using intravenous injection for various periods of time in accordance with the severity of anemia.

Both methods of treatment were suspended because they were ineffective and/or poorly tolerated.

In examples 6-10 specified clinical data of some patients with celiac disease who were treated with conventional iron salts as with oral (p. O.), and using intravenous (i.v.) introduction. In all patients the diagnosis of celiac disease was established in the result of the biopsy and serological tests. During traditional therapy diet of these patients were controlled and directed gluten-free food As demonstrated by the above examples 6-11, the following, regardless of treatment and diet hemoglobin, ferritin and serum iron was relatively low.

Then these patients received treatment with bisglycinate iron according to the invention, included in the effervescent tablet of example 1.

For the evaluation considered the hemoglobin (Hb) (table 1), ferritin (table 2) and serum iron (table 3) for each treated patient after conventional therapy (oral and/or intravenous), and after oral administration of the present invention (effervescent tablets).

therapeutic cycle corresponded to the treatment within 20 days two effervescent tablets per day, containing 14 mg of Fe ion in the tablet, then one effervescent tablet per day, containing 14 mg of Fe ion in the tablet within the next 40 days.

Subsequent maintenance therapy consistent with the treatment for 20 days in two effervescent tablets per day, containing 14 mg of Fe ion in the tablet, every 3 months for approximately one year.

During treatment, patients claimed to prefer oral treatment relative to parenteral treatment.

The product did not reveal any notable side effects.

Hemoglobin, ferritin and serum iron in the blood of the definition is whether after the first cycle of treatment, and treatment continued repetitive cycles according to the previously mentioned methods.

As can be seen from the values shown in tables 1-3, bisglycinate iron significantly increased hemoglobin, ferritin and serum iron after one therapeutic cycle.

Therefore, the obtained experimental data show the effectiveness of oral therapy using bisglycinate iron according to the invention in the treatment of anemia in patients with celiac disease, a condition in which up to the present time, all of the input oral compounds were ineffective.

Example 6

Patient I - woman

Previous methods of treatment

TypeThe treatmentDurationThe reason for the cancellation
Ferric sulfate, R. O.4 yearsA few days from time to timeGastrointestinal intolerance and the resulting poor efficiency
Ferrous gluconate sodium, i.v. (trivalent Fe)3 years15/18-day cycles every 3-4 months with 1-2 capsules a day in 250 ml NaCl The occurrence of allergies (skin rashes)

At the beginning of therapy with ferrous sulfate with the help of oral administration, the patient had the following characteristics:

HbSerum ironFerritinThe duration of treatment
Baseline10,2413240 days
The final indicators11,14838

The treatment cycle was completed, but there was epigastralgia and intestinal disorders.

After another round with the input oral ferrous sulfate were discontinued due to gastrointestinal intolerance, the patient performed oral treatment polymaltose iron.

HbSerum ironFerritinThe duration of treatment
10,6382920 days
The final indicators10,84325

Cycle therapy had been completed, and the treatment was well tolerated.

During therapy with several cycles of oral input polymaltose iron, alternating with cycles of oral input ferrous sulphate, indicators Hb maintained at a level between 9 and 10 g/DL with the emergence of metrorrhagia and reduced Hb to 7.7.

Beginning treatment with trivalent iron, i.v.

HbSerum ironFerritinThe duration of treatment
Baseline7,719<520 days
The final indicators9,84830-

The treatment cycle was completed with a dosage of 1 USD a day for 10 days, for the eat 2 capsules a day.

The patient continued intravenous ferric cycles every three/four months, supporting indicators Hb between 11 and 13. After appearance of rash on the skin after infusion of ferric treatment was cancelled.

Example 7

Patient II - woman

Previous methods of treatment

TypeThe time of treatment (years)DurationThe reason for the cancellation
Ferric sulfate, R. O.5 years, several attemptsA few daysGastrointestinal intolerance
Ferrous gluconate sodium, i.v. (trivalent Fe)2 years, two cycles of 10 vials10 days in different periodsLack of effectiveness due to inadequate dosage

At the beginning of therapy oral input ferric sulfate patient had the following characteristics:

HbSerum ironFerritin The duration of treatment
Baselinethe 11.655418/10 days
The final indicators12,36845

40-day treatment cycle has not been completed due to the occurrence of strong epigastralgia in a few days.

Next, the patient is orally introduced other formulations with iron with the following results:

HbSerum ironFerritinThe duration of treatment
Baseline11,04729A few days
The final indicators11,55633

40-day treatment cycle has not been completed due to the occurrence of strong epigastralgia in a few days. Indicators Hb support is of n at approximately 11 g/DL.

Beginning treatment with ferric intravenous:

HbSerum ironFerritinThe duration of treatment
Baseline10,41821A few days
The final indicators10,84933

The treatment cycle was not completed due to fear of infusion needle and difficulties of working with the patient.

Example 8

Patient III - man, vegetarian

Previous methods of treatment

TypeThe time of treatment (years)DurationThe reason for the cancellation
Ferric sulfate, R. O.5 yearsA one-month cycle, from time to timeLack of effectiveness
Never have introduced-Has not been obtained consent of a patient for intravenous

At the beginning of therapy oral input ferric sulfate patient had the following characteristics:

HbSerum ironFerritinThe duration of treatment
Baseline9,1321940 days
The final indicators103827

The treatment cycle was completed with the emergence of strong epigastralgia and intestinal disorders.

The patient has never acknowledged the presence of the disease, did not take the appropriate dose of iron and did not follow a clear diet.

Example 9

Patient IV - woman

Previous methods of treatment

TypeThe time of treatment (years) DurationThe reason for the cancellation
Ferric sulfate, R. O.Never taken--
Ferrous gluconate sodium, i.v. (trivalent Fe)3 years15/20-day cycles with 1 ampoule i.v.Lack of efficiency first, and then the resulting intolerance

The patient had never received oral ferrous sulfate iron due to severe gastrointestinal disorders (gastric ulcer syndrome and increased irritability of the colon).

Beginning treatment with ferric intravenous:

HbSerum ironFerritinThe duration of treatment
Baselinethe 9.7392120 days
The final indicators10,654 42

The treatment cycle was completed with a dosage of 1 USD a day for 10 days, then 2 capsules a day.

The patient continued intravenous iron cycles every three/four months with indicators about Hb 11 g/DL. The treatment was cancelled due to the occurrence of skin rashes and asthma attack after the iron infusion with intravenous administration.

Example 10

Patient V - woman

Previous methods of treatment

TypeThe time of treatment (years)DurationThe reason for the cancellation
Ferric sulfate, R. O.-Several attempts at 30/40 daysLack of effectiveness and the occurrence of gastrointestinal disorders
Ferrous gluconate sodium, i.v. (trivalent Fe)Only one cycleA few daysThe treatment was cancelled due to allergies

After a few cycles of treatment with oral input sulphate ferrous iron patient had the following characteristics:

HbSerum ironFerritinThe duration of treatment
Baseline8,422<540 days
The final indicatorsthe 9.74621

Due to gastro-intestinal disorders observed in patients, was tested therapy with intravenous iron. It was cancelled after three infusions due to allergic reactions.

Example 11

Patient VI - man

Previous methods of treatment

TypeThe time of treatment (years)DurationThe reason for the cancellation
Ferric sulfate, R. O.1 yearA few daysGastrointestinal disorders (diarrhoea)
Ferrous gluconate sodium, i.v. (trivalent Fe) 2 years3 cycles of 20 days with 1 ampoule i.v. in 250 ml of physiological solutionThe emergence of intolerance on the third cycle (phlebopathy)

Therapy introduced by oral ferrous sulfate iron was cancelled due to the occurrence after a few days of profuse diarrhoea. Beginning therapy with intravenous iron.

HbSerum ironFerritinThe duration of treatment
Baseline10,2413520 days
The final indicators12,64881

The emergence of phlebopathy in the course after the third infusion of therapeutic cycle.

Conclusion

Thus, as proved in the above examples and tables, only oral therapy with bisglycinate-chelate iron in the present the invention gave a significant increase of the studied blood parameters (serum iron, ferritin, hemoglobin) suffering from anemia patients with celiac disease and eliminate side effects (gastro-intestinal and other) arising as a result of consuming traditional iron salts with both oral and intravenous administration.

When conducting therapy with bisglycinate-iron chelate of the present invention, it can be assumed (on the basis of known data) better portability of the product, but such a significant effectiveness was completely unexpected.

1. Application bisglycinate-chelate iron in oral treatment of anemia in patients with celiac disease in the form of effervescent tablets, semi-solid or liquid form.

2. Application bisglycinate-chelate iron under item 1, where this tablet contains a number, ranging from 1 mg to 40 mg of Fe ion, preferably from 2 to 20 mg of Fe ion.

3. Application bisglycinate-chelate iron on p. 2, where this tablet contains a number equal to approximately 14 mg Fe ion.

4. Application bisglycinate-chelate iron under item 1, characterized in that it introduced two effervescent tablets per day, containing about 14 mg Fe ion on the pill, within twenty days.

5. Application bisglycinate-chelate iron under item 1, characterized in that it introduced two effervescent tablets per day, containing about 14 mg Fe ion on the tablet for on alzati days and one effervescent tablet containing 14 mg of Fe ion, for an additional forty days.

6. Application bisglycinate-chelate iron under item 1, characterized in that the semi-solid or liquid form selected from the suspension or solution.

7. Application bisglycinate-chelate iron on p. 6, where this semi-solid or liquid form contains a number ranging from 6 to 12 mg Fe ion/ml, preferably about 10 mg of Fe ion/ml

8. Application bisglycinate-chelate iron according to any one of paragraphs.1-3 and 6-7, wherein the specified bisglycinate-chelate of iron introduced into the composition together with at least one sweetener and/or flavoring.

9. Application bisglycinate-chelate iron on PP.1-7, distinguish fact that bisglycinate-iron chelate is administered together with at least one additional effective ingredient.

10. Application bisglycinate-chelate iron under item 8, characterized in that the specified bisglycinate-iron chelate is administered together with at least one additional effective ingredient.

11. Application bisglycinate-chelate iron on p. 1, wherein the anemia is sideropenic anemia.



 

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SUBSTANCE: invention relates to casein succinylate of iron (III) wherein iron content varies from 4.5 wt % to 7 wt %, water solubility exceeds 92% while phosphorus-to-nitrogen ratio exceeds 5 wt %.

EFFECT: additionally, invention relates to production of iron (III) and to pharmaceutical composition containing casein succinylate of iron (III).

17 cl, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to benzoimidazole derivatives of formula (I), as well as to their enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts, where n equals from 2 to 4, each of R1 substituents is independently selected from H, halogen, -C1-4alkyl, -C1-4pergaloalkyl, trifluoro-C1-4alkoxy, -NO2, -CN, CO2H, -OC1-4alkyl, -SC1-4alkyl, -S(C1-4alkyl)-Rc, -S(O)2(C1-4alkyl)-Rc, -S(O)-C1-4alkyl, -SO2-C1-4alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2-NH-Rc, -O-Rc, -CH2-O-Rc, -C(O)NH-Rc, -NRaRb, benzyloxy, phenyl, optionally substituted with one-two Rd, cyanobiphenyl-4-ylmethylsulpfanyl, cyanobiphenyl-4-ylmethanesulphonyl, or -S-(CH2)2-morpholine and two adjacent groups R1 can bind with formation of an aromatic 5-6-membered ring, optionally substituted with one methyl group or two atoms of halogen, optionally containing one or two S or N; Ra and Rb each independently represents C1-4alkyl, -C(O)C1-4alkyl, -C(O)-Rc, -C(O)CH2-Re, C1-4alkyl-Re, -SO2-Rc, -SO2-C1-4alkyl, phenyl, benzyl; or Ra and Rb together with a nitrogen atom, which they are bound with, form a monocyclic 5-6- membered heterocycloalkyl ring, optionally containing one heteroatom, selected from O; Rc represents -C3-8cycloalkyl, phenyl, optionally substituted with one-two Rd, benzyl, optionally substituted with one-three Rd; morpholine; Rd independently represents halogen, -OH, -C1-4alkyl or -C1-4perhalogenalkyl, trifluorine C1-4alcoxy, -OC1-4alkyl, or -O-benzyl optionally substituted with halogen, Re represents -C6heterocycloalkyl, optionally containing one or two of O or N atoms, optionally substituted with a methyl group; R2 and R3 both represent H, -CF3 or C1-3alkyl; each of Z represents a C or N atom, on condition that simultaneously not more than two Z represent N. The invention also relates to particular compounds, a pharmaceutical composition, based on formula (I) compound or a particular said compound, a method of treating diseases, mediated by propyl hydroxylase activity.

EFFECT: novel derivatives of benzimidazole, possessing an inhibiting activity with respect to PHD are obtained.

11 cl, 1 tbl, 186 ex

FIELD: biotechnologies.

SUBSTANCE: in a compound of formula ,

X means N or CH, R1 means hydrogen or cyano, R2 means saturated 4-7-membered residue of heterocyclyl, which is bound through a nitrogen atom that contains 1 to 2 heteroatoms chosen from N and O. Besides, heterocyclyl residue can be replaced with one substituent chosen from a group consisting of C3-C6-cycloalkyl, or with 1-4 fluorine atoms. The invention also refers to a method for obtaining compounds and to a medicine on their basis.

EFFECT: compounds can be used for production of a medicine suitable for being used in a method of treatment or prophylaxis of cardiovascular diseases, cardiac insufficiency, anemia, chronic diseases of kidneys and kidney failure.

16 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and aims at the simultaneous control of coccidiosis and iron deficiency. The compound comprises triazinones of formulas (I) or (II) wherein R1 means CF3-SO2- or CF3-S-, R2 means CH3, each R4, R5 and R6 means Cl (chlorine) or pharmaceutically acceptable salts thereof, and iron compounds (3+) specified in a group consisting of: multinucleated complex iron (III) and polysaccharide compounds and ammonium-iron (III) citrate. What is also declared is using the above compounds for producing drug preparations.

EFFECT: using the declared group of inventions is effective for the simultaneous control of coccidiosis and iron deficiency; it is accompanied by no adverse phenomena; the compound ingredients have no negative effects on each other; and their biological activity preserves.

17 cl, 15 tbl, 7 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to production of peptide derivative mimetic of EPO, with the formula: R1-R2-(CH2)n1-R3-(CH2)n2-R4-R5 (I) and its pharmaceutical salts, where R1, R5 are selected from cyclic peptides with sequences SEQ ID NO:5, 6, 7 and 8; n1, n2 represent integer numbers independently selected from 0-10; R2, R4 are selected from -CO or -CH2; R3 is selected from O, S, CH2, N(CH2)n3NHR6, NCO(CH2)n4NHR6, CHOCONH(CH2)n5NHR6, CHSCON(CH2)n5NHR6 or CHNHCON(CH2)n5NHR6; where n3 represents an integer number selected from 1-10, n4 is an integer number selected from 2-10, n5 represents an integer number selected from 2-10, R6 is selected from H or derivatives of metoxyethylene glycol. The produced peptide or its pharmaceutically acceptable salt is used within a pharmaceutical composition for treatment of disorders characterised with EPO deficit, low or defective population of erythrocytes.

EFFECT: invention makes it possible to produce an agonist of EPO receptor having higher biological activity compared to existing EPO mimetics.

15 cl, 2 dwg, 5 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to veterinary science and aims at treating and preventing alimentary anaemia in young pigs. A preparation contains an iron dextran complex, nanosized and zero-valent selenium (Se0), vitamin E, vitamin B12 and water in the following proportions, wt %: iron dextran complex 0.0001-80.0, selenium (Se0) 0.0001-5.0, vitamin E 0.0001-20.0, vitamin B12 0.0001-10.0, water for injections - the rest.

EFFECT: using the declared method provides compensating iron deficiency in young pigs, improving animal's growth and development, increasing total immunity and rapid adaptation to the varying ambient environment.

4 tbl, 4 ex, 4 dwg

FIELD: veterinary medicine.

SUBSTANCE: method of normalisation of the thrombin time duration in newborn calves with iron deficiency anemia consists in the fact that ferroglukin 150 mg (2 ml) intramuscularly is prescribed to newborn calves with iron deficiency anemia, twice with the interval of 4 days, cresacyne 5 mg/kg per day, including it in the scheme of watering for 4 days, starting simultaneously with the first injection of ferroglukin and gamavit intramuscularly once a day in the morning of 0.05 ml/kg for 4 days, starting simultaneously with ferroglukin and cresacyne.

EFFECT: acceleration of normalisation of thrombin time duration, enables to reduce the risk of vascular complications in newborn calves with iron deficiency anemia, to revitalise the herd, to reduce mortality, to maintain the volume and quality of the meat and dairy products obtained from animals.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a method for drug encapsulation by non-solvent addition; the method is characterised by the fact that the above drug is presented by ferrocene, while a coating is carrageenan precipitated from a butanol solution by adding ethanol as a non-solvent and water at room temperature.

EFFECT: invention provides simplifying and accelerating the microencapsulation process, reducing the microencapsulation loss (higher weight yield).

2 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science, namely to clinical pharmacology and veterinary therapy. The method consists in administering the complex iron-dextran preparation Ferranimal-75M intramuscularly on the 5th day of calf's life in a dose of 3 ml in a combination with an intramuscular injection of the preparation Hydropeptone in a dose of 10 ml. Ferranimal-75M is injected 10 days later in a dose of 2 ml in a combination with an injection of Hyropeptone 5 ml intramuscularly in different points.

EFFECT: method provides higher antioxidative activity of calf's blood serum, reduced pro-oxidant action of iron and incorporated radionuclides, as well as higher iron accessibility in treating and preventing iron-deficiency anaemia in calves exposed to the chronic incorporated radiation.

FIELD: veterinary medicine.

SUBSTANCE: ferroglyukin is administered to new-born calves with iron deficiency anaemia at a dose of 150 mg (2 ml) intramuscularly, twice with an interval of 4 days. Crezacyne 5 mg/kg per day is included in the watering scheme for 4 days, starting simultaneously with the first injection of ferroglyukin. Gamavit is administered intramuscularly once a day in the morning at a dose of 0.05 ml/kg for 4 days, starting simultaneously with ferroglyukin and crezacyne.

EFFECT: method enables to normalise consistently the platelet activity in new-born calves with iron deficiency anaemia during a short period of exposure, transferring it to the level typical of healthy calves, after 4 days of treatment, and to provide long-term maintenance of platelet haemostasis in the optimal mode of operation, eliminating the risk of thrombotic complications in animals and contributing to their normal growth and development.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel derivative of ferrocene 1-(1,1,1,3,3,3-hexafluoro-2-ferrocenylprop-2-yl)-imidazole of formula

which shows an antitumour activity. Also claimed is a method of its obtaining (versions).

EFFECT: invention makes it possible to obtain the novel derivative of ferrocene, which can be applied in medicine for chemotherapy of oncologic diseases.

4 cl, 1 dwg, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a metal-salen complex derivative. The complex is represented as A-B-C, where A is the metal-salen complex, B is a bond zone, including at least one disulphide bond; and C is a functional molecule, consisting of at least one of enzymes, antibodies, antigens, peptides, amino acids, oliginucleotides, proteins, nucleic acids and medication molecules. The bond zone (B) includes a molecule of a cross-linking agent to form a cross-linking between the said metal-salen complex (A) and the said functional molecule (C). The said metal-salen complex (A) and the said molecule of the cross-linking agent are bound together via at least one disulphide bond; and the said molecule of the cross-linking agent and the said functional molecule (C) are bound together via at least one disulphide bond. The zone of the disulphide bond (B) results from the formation of a bond between a SH group, introduced as a substituent into the said metal-salen complex, and the SH group of the said functional molecule (C), or results from the formation of a bond between the SH group of the said metal-salen complex (A) or the said functional molecule (C) and the SH group of the cross-linking agent molecule. Also claimed is a method of obtaining the metal-salen complex derivative.

EFFECT: invention makes it possible to obtain the derivative of a metal-salen complex, characterised by an excellent output and stability.

3 cl, 2 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to binuclear form of dinitrosyl iron complex with ethyl ether of glutathione (DNIC-EEG) of the formula [(EEGS)2Fe2(NO)4] with the structural formula: , where R-S represents ethyl ether of glutathione containing a thiol group. The invention also relates to a composition for reducing functional disorders of myocardium subjected to hypoxia-reoxygenation which contains binuclear form of dinitrosyl iron complex with ethyl ether of glutathione (DNIC EEG) as defined above and a pharmaceutically acceptable carrier. Also the use of DNIC-EEG is disclosed as antihypoxic agent.

EFFECT: reduction of hypoxic contracture, arrhythmias intensity and improvement of recovery of contractile function of the heart after reoxygenation.

3 cl, 1 tbl, 16 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely therapeutic dentistry and may be used for treating destructive forms of chronic periodontitis. That is ensured by administering a therapeutic preparation into a root canal. A sonic phoresis of the therapeutic preparation Beresh plus drops is preceded by coating the skin surrounding a causative tooth with a therapeutic mixture containing the preparation Beresh plus drops, 10% calcium gluconate and Vaseline oil. Thereafter, an emitter is used to process the area. The sonic phoresis is followed by a root canal obturation with calcium hydroxide. That is combined with administering ascorbic acid in a daily dose of 50-100 mg and the preparation Beresh plus drops 1 drop per 2 kg of body weight a day orally. The therapeutic course is 5-8 procedures.

EFFECT: invention enables arresting the inflammatory process in the aggressive lesion, reducing the number of complications and aggravations ensured by accelerating the repair processes in the apical aggressive lesion.

2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and aims at the simultaneous control of coccidiosis and iron deficiency. The compound comprises triazinones of formulas (I) or (II) wherein R1 means CF3-SO2- or CF3-S-, R2 means CH3, each R4, R5 and R6 means Cl (chlorine) or pharmaceutically acceptable salts thereof, and iron compounds (3+) specified in a group consisting of: multinucleated complex iron (III) and polysaccharide compounds and ammonium-iron (III) citrate. What is also declared is using the above compounds for producing drug preparations.

EFFECT: using the declared group of inventions is effective for the simultaneous control of coccidiosis and iron deficiency; it is accompanied by no adverse phenomena; the compound ingredients have no negative effects on each other; and their biological activity preserves.

17 cl, 15 tbl, 7 ex

FIELD: pharmaceutical engineering; medical engineering.

SUBSTANCE: method involves carrying out nuclear magnetic resonance tomography of human or animal blood circulation system containing chelating ion complexes of bivalent and valence three paramagnetic metals of (I)X-L-Y formula, where X is the polyamide carbonyl ligand residue and Y is the gallic acid derivative, .

EFFECT: high accuracy of diagnosis.

28 cl

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