Iron delivery method for treating iron-deficiency anemia

Abstract

The inventions relate to medicine and pharmaceutics and can be used in the treatment of iron-deficiency anemia. A method for producing a composition of water-soluble readily absorbable bivalent iron includes dissolving an organic reducing compound in water and adding a source of iron(II), wherein the molar ratio of the organic reducing compound to the iron(II) source is from approximately 3:1 to 10:1. A composition of water-soluble readily absorbable bivalent iron is produced using the claimed method, and a hermetically sealed ampoule is used in a method for delivering said composition. The result is the fast and effective treatment of iron-deficiency anemia in patients.

Description

[0001] A METHOD OF DELIVERY OF IRON FOR THE TREATMENT OF IRON DEFICIENCY ANEMIA

[0002] The group of inventions relates to medicine and pharmaceuticals and can be used in the treatment of iron deficiency anemia.

[0003] Iron is the most abundant trace element in the human body. Iron is critical for oxygen transport, erythropoiesis, and plays a significant role in many biological processes, including the synthesis of (deoxy)ribonucleic acids (DNA, RNA), amino acids, collagen, steroids, various neurotransmitters, and proteins involved in electron transport, mitochondrial respiration, cell proliferation, differentiation, and regulation of gene expression, as well as in the functioning of the immune system, detoxification processes, and drug metabolism [1, 2].

[0004] Iron homeostasis is controlled primarily by dietary iron intake, intestinal absorption, and recycling mechanisms [2]. Iron deficiency, or sideropenia, is a condition in which total body iron stores are insufficient to maintain normal metabolic functions [3]. Iron deficiency is the most common nutrient deficiency worldwide and a leading cause of anemia in approximately 2 billion people [4]. According to the Global Burden of Disease Study, which assessed 87 risk factors in 204 countries and territories from 1990 to 2019, the global prevalence of iron deficiency was 14.4% and 28.5 million disability-adjusted life years (DALYs) were lost worldwide in 2019 [5]. It should be noted that in this study, iron deficiency in the absence of anemia was not taken into account, and only insufficient intake of elemental iron from food was considered as the cause of the deficiency.Therefore, the global prevalence of iron deficiency without anemia remains unclear, although the proposed figure is at least twice the prevalence of iron deficiency anemia (IDA) [6].

[0005] The concept of iron deficiency is quite heterogeneous, including cases of both absolute and functional deficiency, with or without anemia, with or without clinical symptoms. In the absence of anemia, iron deficiency is associated with clinical signs and symptoms, including fatigue, dizziness, impaired physical performance, and decreased work productivity [4]. Iron deficiency can be caused by physiological, pathological, environmental, medicinal, genetic, or erythropoietic causes [4]. Iron deficiency can be due to insufficient iron intake, excessive iron loss (i.e., blood), or excessive iron utilization.

[0006] Given the global problem of iron deficiency and the high prevalence of IDA, the fight against anemia is currently a global health priority: the World Health Organization (WHO) aims to reduce the prevalence of anemia in women of reproductive age by 50% by 2025 [7].

[0007] Most of the iron in the body is contained in the hemoglobin of red blood cells, and most of the remaining iron is contained in myoglobin and enzymes [1, 8]. Almost all metabolically active iron is in a protein-bound state; free iron ions can be present in extremely low concentrations [9]. The main iron depots are the liver, spleen, and bone marrow

[0010] . In this case, the protein ferritin plays a special role in iron deposition, the functions of which include the accumulation and storage of iron reserves (ferritin contains up to 4500 Fe ions 2+). Under physiological conditions, the amount of ferritin is comparable to the amount of iron in the body (the more ferritin, the more iron)

[0010] , normally its level in the blood serum is 30 300 μg / l (an increase of >300 μg / l indicates iron overload, cell destruction and inflammation).

[0008] Transferrin protein and transferrin receptors play an important role in iron transport; 0.1–3.2% of the total amount of iron in the body, contained in plasma, binds to transferrin, and in this form, iron can enter the tissues through binding to the transferrin receptor [8]. Transferrin is synthesized in hepatocytes, and the less iron in the body, the more transferrin is synthesized; normally, its level is 2–3 g / l

[0010] .

[0009] Plasma iron levels are tightly regulated. Under normal physiological conditions, no more than 0.05% (2.5 mg) of the total iron is lost daily [9]. It should be noted that 2030 mg of iron are required daily for effective erythropoiesis. Replenishment occurs from iron absorbed by macrophages in the spleen and liver from aging red blood cells (approximately 2030 mg daily; iron recycling mechanism), while a much smaller amount (1^-2 mg per day) is absorbed from food in the duodenum, where iron absorption by the body is homeostatically regulated and is possible only in the divalent state (Fe 2+ ), since trivalent iron (Fe 3+ ) is practically not absorbed [10, 11].

[0010] Most of the nonheme iron ingested with food enters the gastrointestinal tract in the trivalent form. However, Fe 3+, is essentially non-bioavailable and therefore must first be converted to ferrous iron before absorption. There are many food components that can restore Fe 3+ to Fe 2+ , including ascorbic acid and amino acids such as cysteine ​​and histidine. It is believed that the action of these dietary reducing agents occurs in the acidic environment of the gastric lumen. Indeed, the significant requirement for an acidic environment for iron absorption is confirmed by the fact that achlorhydria is usually associated with iron deficiency anemia. However, it should not be forgotten that food brings a sufficient amount of atmospheric oxygen into the stomach, which helps maintain iron in the trivalent state. At the same time, a significant portion of the iron reaching the duodenal enterocytes in the trivalent state can still be reduced to Fe 2+ due to the endogenous restorative activity of cells.

[0011] Several studies have shown that the brush border of intestinal enterocytes and cultured intestinal cells possesses iron reductase enzymatic activity.

[0012] After this, divalent iron can be transported into enterocytes by the transporter protein DMT-1 (Divalent Metal Transporter 1).

[0012] Prior art

[0013] The most common method for preventing and treating iron deficiency disorders (IDD) is oral iron supplementation. The recommended dose for treating IDD in adolescents and adults is 120 mg per day

[0013] . Many experts recommend a dose of up to 200 mg per day.

[0014] This dose is two orders of magnitude greater (a hundredfold) than the aforementioned amount of iron absorbed from food (1-2 mg per day). It should be remembered that this is in addition to the amount of iron the patient already receives from food. It is not surprising that with such doses, many patients suffer from side effects from iron supplements. The most common side effects are gastrointestinal, such as nausea / vomiting, constipation or diarrhea, flatulence, a metallic taste, tooth staining, or a feeling of discomfort in the epigastric region [15,16].

[0014] The closest analogue of the inventions is natural mineral water from springs in Karelia at the Martial Waters resort, where mineral waters of rare composition and record iron content (up to 100 mg / liter) are available. The waters are weakly mineralized (0.2 - 1.0 g / liter) and contain hydrocarbonate-sulfate magnesium and calcium. The iron content ranges from 20 to 100 mg / liter. For many years, these waters have been successfully used for drinking treatment of IDA (iron deficiency anemia).

[0017] One glass (200 ml) of such water can contain from 4 to 20 mg of easily digestible divalent iron. The main problem with using this mineral water is that it must be consumed immediately and directly at the source, as the divalent iron it contains is quickly oxidized by atmospheric oxygen to form an insoluble precipitate of trivalent iron hydroxide, making the water quickly unfit for consumption.

[0015] The technical problem solved by this invention is the development of a low-dose, easily absorbable iron preparation that does not cause side effects, yet still satisfies the iron needs of patients with iron deficiency.

[0016] The technical result of the group of inventions consists in the rapid (within one to two weeks) and effective treatment of iron deficiency anemia in patients due to a significant increase in the level of iron, ferritin and hemoglobin by ensuring the delivery of a minimally sufficient amount of water-soluble, easily digestible divalent iron to intestinal enterocytes, which promotes rapid absorption of iron, bypassing the stage of reduction by reductase on the apical surface of enterocytes.

[0017] The technical result is achieved by the proposed method for obtaining a composition of water-soluble, easily digestible divalent iron, which includes dissolving a reducing organic compound in water and adding a source of iron (II) to obtain a composition of water-soluble, easily digestible divalent iron.

[0018] In this case, the reducing organic compound is selected from glucose, sucrose, ascorbic acid, malic acid, citric acid, malonic acid or any mixture thereof, the reducing organic compound is preferably selected from ascorbic and / or citric acid.

[0019] Preferably, the iron (II) source is selected from the group consisting of anhydrous iron (II) sulfate, iron (II) sulfate hexahydrate, and ammonium iron (II) sulfate hexahydrate.

[0020] Preferably, the molar ratio of organic acid to iron(II) source is from about 1:3 to 1:10.

[0021] The claimed technical result is also achieved by a composition of water-soluble, easily digestible divalent iron obtained by the said method for (delivering divalent iron to intestinal enterocytes / preventing and treating iron deficiency conditions), containing a reducing organic compound and a source of iron (II), taken in a molar ratio of approximately 1:3 to 1:10, and water.

[0022] In this case, it is preferable to select the reducing organic compound from glucose, sucrose, ascorbic acid, malic acid, citric acid, malonic acid or any mixture thereof, and the reducing organic compound from ascorbic and / or citric acid.

[0023] Preferably, the iron (II) source is selected from the group consisting of anhydrous iron (II) sulfate, iron (II) sulfate hexahydrate, and ammonium iron (II) sulfate hexahydrate.

[0024] In addition, the claimed technical result is achieved through the use of a hermetically sealed ampoule for use in the method (delivery of divalent iron to intestinal enterocytes / prevention and treatment of iron deficiency conditions) containing the above composition.

[0025] The stated result is achieved through the use of the said composition for the delivery of divalent iron to intestinal enterocytes / prevention and treatment of iron deficiency conditions.

[0026] The claimed result is achieved through a method of delivering divalent iron to intestinal enterocytes / prevention and treatment of iron deficiency conditions, including the use of the claimed composition.

[0027] Preferably, the method comprises dissolving the composition, contained in a hermetically sealed ampoule, in drinking water to 50-300 ml, preferably to 50-200 ml.

[0028] Preferably, the dissolved composition is taken on an empty stomach or 3-4 hours after eating.

[0029] Implementation of the invention

[0030] Below is a more detailed description of the claimed group of inventions, which does not limit the scope of the invention's claims, but demonstrates the possibility of implementing the entire group with the achievement of the claimed technical result.

[0031] First, an aqueous solution is prepared by dissolving the reducing organic compound in water and adding an iron (II) source to obtain a water-soluble, readily available divalent iron composition.

[0032] Below we present possible options with indication of quantitative components for the preparation of this solution using various reducing organic compounds.

[0033] 1. Dissolve 345 mg (1.8 mmol) of citric acid in 200 ml of pure water. Then add and dissolve 27 mg (0.18 mmol) of anhydrous iron(II) sulfate. Place this solution in a hermetically sealed container. Take the solution on an empty stomach or 3-4 hours after meals.

[0034] 2. Dissolve 159 mg (0.9 mmol) of ascorbic acid in 100 ml of pure water, then add and dissolve 47 mg (0.18 mmol) of iron(II) sulfate hexahydrate. Place this solution in a hermetically sealed container. Take the solution on an empty stomach or 3-4 hours after meals.

[0035] 3. Dissolve 345 mg (1.8 mmol) of citric acid in 200 ml of pure water, then add and dissolve 70 mg (0.18 mmol) of Mohr's salt (ammonium iron (II) sulfate hexahydrate) to this solution. Place this solution in a hermetically sealed container. Take the solution on an empty stomach or 3-4 hours after meals. 4. Dissolve 7 g (39.8 mmol) of citric acid and 1.9 g (9.9 mmol) of ascorbic acid in 1 l of pure water, then add 7 g (17.8 mmol) of Mohr's salt (ammonium iron (II) sulfate hexahydrate) to this solution and dissolve. Pour this solution and seal it in 10 ml ampoules. Sterilize the ampoules before storage. When using, the contents of one ampoule are diluted with drinking water to 50-200 ml and taken on an empty stomach or 3-4 hours after a meal.

[0036] 5. Dissolve 159 mg (0.9 mmol) of ascorbic acid and 1000 mg of glucose in 100 ml of pure water. Then add and dissolve 47 mg (0.18 mmol) of iron (II) sulfate hexahydrate. Place this solution in a hermetically sealed container. Take the solution on an empty stomach or 3-4 hours after meals.

[0037] 6. Dissolve 105 mg (0.9 mmol) of fumaric acid and 1000 mg of glucose in 100 ml of pure water. Then add and dissolve 47 mg (0.18 mmol) of iron(II) sulfate hexahydrate. Place this solution in a hermetically sealed container. Take the solution on an empty stomach or 3-4 hours after meals.

[0038] 7. Dissolve 121 mg (0.9 mmol) of malic acid and 1000 mg of glucose in 100 ml of pure water. Then add and dissolve 47 mg (0.18 mmol) of iron(II) sulfate hexahydrate. Place this solution in a hermetically sealed container. Take the solution on an empty stomach or 3-4 hours after meals.

[0039] 8. Dissolve 106 mg (0.9 mmol) of succinic acid and 1000 mg of glucose in 100 ml of pure water. Then add and dissolve 47 mg (0.18 mmol) of iron(II) sulfate hexahydrate. Place this solution in a hermetically sealed container. Take the solution on an empty stomach or 3-4 hours after meals.

[0040] An aqueous solution containing 10 to 200 mg of ferrous iron and a fifty-fold stoichiometric excess of one or more of the above-mentioned reducing organic compounds is drunk by a patient suffering from ID / IDA on an empty stomach before eating, or 3-4 hours after eating, once or twice a day in a volume of 50 to 300 ml, preferably 50 to 200 ml.

[0041] Since the patient's stomach is practically empty at this point, the solution moves rapidly from the lower esophageal sphincter along the lesser curvature of the stomach through the gastric canal (Canalis gastricus)

[0018] into the pyloric region of the stomach. Then, due to the natural peristalsis of the stomach, a significant portion of the solution passes through the pylorus (Sphincter pylorus) into the duodenum. Due to the accelerated passage of the solution through the gastric canal (Canalis gastricus), exposure to the active environment of the stomach is significantly reduced, primarily with the oxygen it contains, which is capable of oxidizing iron to the trivalent state. The above-mentioned reducing organic substances contained in the solution, of course, also contribute to the preservation of iron in the divalent state. Then, already in the intestine, rapid absorption of the divalent iron contained in the solution occurs, bypassing the stage of reduction by reductase on the apical surface of enterocytes.

[0042] Due to the above-described action, patients quickly (within one to two weeks) experience a significant increase in the levels of iron, ferritin and hemoglobin.

[0043] Clinical examples

[0044] Example 1.

[0045] Patient 3. 74 years old. History of type II diabetes mellitus, coronary heart disease.

[0046] Blood tests revealed hemoglobin 96 g / L, ferritin 8 μg / L. Iron deficiency anemia (IDA) stage I. She took 50 ml of an aqueous solution containing 10 mg of iron (II) and 345 mg (1.8 mmol) of citric acid, previously dissolved in 200 ml of water, on an empty stomach. She took the resulting solution once a day for 14 days.

[0047] After 14 days, blood test: hemoglobin 120 g / l, ferritin 27 mcg / l.

[0048] Example 2,

[0049] Patient V., 78 years old. History of stage IV colon cancer.

[0050] Blood tests revealed hemoglobin 83 g / L, ferritin 4 μg / L. Iron deficiency anemia (IDA) stage II. She took 300 ml of an aqueous solution containing 200 mg of iron (II) and 159 mg (0.9 mmol) of ascorbic acid, previously dissolved in 100 ml of water, on an empty stomach. She took the resulting solution twice a day for 14 days.

[0051] After 14 days, blood test: hemoglobin 97 g / l, ferritin 11 mcg / l.

[0052] A repeat course of 14 days was prescribed.

[0053] After 14 days: hemoglobin 123 g / l, ferritin 26 mcg / l

[0054] The indicators are normal

[0055] Example 3,

[0056] Patient A, 26 years old

[0057] History of heavy menstruation, dysfunctional uterine bleeding.

[0058] Hemoglobin 107 g / l

[0059] Ferritin 17 mcg / L

[0060] Taking an aqueous solution on an empty stomach or 3-4 hours after a meal: 159 mg (0.9 mmol) of ascorbic acid and 1000 mg of glucose are dissolved in 100 ml of pure water, then 47 mg (0.18 mmol) of iron (II) sulfate hexahydrate are added and dissolved in this solution. One course of 1 ampoule twice a day, morning and evening. After 14 days: hemoglobin 127 g / l, ferritin 40 mcg / l. Indicators are normal.

[0061] Example 4,

[0062] Patient K., 13 years old. His medical history shows that he is healthy and has shown active growth over the past year.

[0063] Hemoglobin 100 g / l

[0064] Ferritin 14 mcg / L

[0065] Taking an aqueous solution on an empty stomach or 3-4 hours after a meal: dissolve 121 mg (0.9 mmol) of malic acid and 1000 mg of glucose in 100 ml of pure water, then add and dissolve 47 mg (0.18 mmol) of iron (II) sulfate hexahydrate. One course of treatment: 1 ampoule twice daily, morning and evening. After 14 days: hemoglobin 130 g / L, ferritin 34 mcg / L. Values ​​are normal.

[0066] References

[0067] 1. Yiannikourides A, Latunde-Dada GO. A Short Review of Iron Metabolism and Pathophysiology of Iron Disorders. Medicines. 2019;6(3):85. https: / / doi.org / 10.3390 / medicines6030085

[0068] 2. Moustarah F, Mohiuddin SS. Dietary Iron. [Updated 2022 Apr 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. Accessed November 4, 2022. https: / / www.ncbi.nlm.nih.gov / books / NBK540969

[0069] 3. Hanif N, Anwer F. Chronic Iron Deficiency. [Updated 2022 Sept 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. Accessed November 04, 2022. https: / / www.ncbi.nlm.nih.gov / books / NBK560876

[0070] 4. WHO guideline on use of ferritin concentrations to assess iron status in individuals and populations. Geneva: World Health Organization; 2020. Accessed November 04, 2022. https: / / www.who.int / publications / i / item / 9789240000124

[0071] 5. GBD 2019 Risk Factors Collaborators. Global burden of 87 risk factors in 204 countries and territories, 1990-2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1223-1249. https: / / doi.org / 10.1016 / S0140-6736(20)30752-2

[0072] 6. Camaschella C. Iron deficiency. Blood. 2019;133(l):30-39. https: / / doi.org / 10.1182 / blood-2018-05-815944

[0073] 7. World Health Organization. Global nutrition targets 2025: policy brief series (WHO / NMH / NHD / 14.2). Geneva: World Health Organization; 2014. Accessed November 04, 2022. https: / / www.who.int / publications / i / item / WHO-NMH-NHD- 14.2

[0074] 8. Conway D, Henderson MA. Iron metabolism. Anaesthesia and Intensive Care Medicine. 2019;20(3): 175-177. https: / / doi.Org / 10.1016 / i.mpaic.2019.01.003

[0075] 8

[0076] SUBSTITUTE SHEET (RULE 26) 9. National Hematological Society. Iron Overload: Diagnosis and Treatment. National Clinical Guidelines (approved at the VI Congress of Russian Hematologists). 2018. Link active on 04.11.22. National Hematological Society. Iron Overload: Diagnosis and Treatment. National Clinical Guidelines (approved at the VI Congress of Russian Hematologists). 2018. Accessed November 04, 2022. (In Russ.). https: / / npngo.ru / uploads / media document / 289 / d4dc2f81 -4968-4ab0-883a0d26027f8e46.pdf

[0077] 10. Volchkova NS, Subkhankulova SF. Diagnosis and management of anemia in clinical practice and its association with cardiovascular pathology. International Journal of the Heart and Vascular Diseases. 2022;10(34):44-53. Volchkova NS, Subkhankulova SF. Diagnosis and management of anemia in clinical practice and its association with cardiovascular pathology. International Journal of the Heart and Vascular Diseases. 2022;10(34):44-53. (In Russ.).

[0078] 11. Nemeth E, Ganz T. Hepcidin-Ferroportin Interaction Controls Systemic Iron

[0079] Homeostasis. International Journal of Molecular Sciences. 2021;22(12): 6493. https: / / doi.org / 10.3390 / iims22126493

[0080] 12. Sharp P, Srai SK. The molecular mechanisms involved in intestinal iron absorption.

[0081] World J Gastroenterol 2007; 13(35): 4716-4724. https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC4611193 /

[0082] 13. WHO, UNICEF, UNU. IDA: prevention, assessment and control: report of joint WHO / UNICEF / UNU consultation. - Geneva: WHO, 1998.

[0083] 14. Stoffel NU, von Siebenthal HK, Moretti D, Zimmermann MB. Oral iron supplementation in iron-deficient women: How much and how often? Mol Aspects Med. 2020 Oct;75: 100865. Epub 2020 Jul 7. PMID: 32650997. https: / / doi.Org / 10.1016 / i.mam.2020.100865

[0084] 15. Tolkien Z, Stecher L, Mander AP, Pereira DI, Powell JJ. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One. 2015 Feb 20;10(2):e0117383. doi: 10.1371 / journal.pone.Ol 17383. PMID: 25700159; PMCID: PMC4336293.

[0085] 16. Cancelo-Hidalgo MJ, Castelo-Branco C, Palacios S, Haya-Palazuelos J, Ciria-Recasens M, Manasanch J, Perez-Edo E. Tolerability of different oral iron supplements: a systematic review. Curr Med Res Opin. 2013 Apr;29(4):291-303. doi: 10.1185 / 03007995.2012.761599. Epub 2013 Feb 6. PMID: 23252877.

[0086] 17. "List of Russian resorts with justification for their uniqueness based on natural healing factors. Methodological guidelines." List of the Ministry of Health of the Russian Federation dated 22.12.1999 No. 99 / 228

[0087] 18. G. Jefferson, J Anat Physiol. 1915 Jan; 49(Pt 2): 165-181 https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC1289022 /

[0088] SUBSTITUTE SHEET (RULE 26)

Claims

CLAUSES OF THE INVENTION 1. A method for producing a composition of water-soluble, easily digestible divalent iron, comprising dissolving a reducing organic compound in water and adding a source of iron (II) to produce a composition of water-soluble, easily digestible divalent iron.

2. The method according to claim 1, wherein the reducing organic compound is selected from glucose, sucrose, ascorbic acid, malic acid, citric acid, malonic acid, or any mixture thereof.

3. The method according to i.1, wherein the reducing organic compound is preferably selected from ascorbic and / or citric acid.

4. The method according to any one of paragraphs 1-3, wherein the source of iron (II) is selected from the group consisting of anhydrous iron (II) sulfate, iron (II) sulfate hexahydrate, and ammonium iron (II) sulfate hexahydrate.

5. The method according to paragraphs 1-4, wherein the molar ratio of organic acid to iron(II) source is from approximately 1:3 to 1:

10.

6. A water-soluble, easily digestible divalent iron composition obtained by the method according to paragraphs 1-4, for delivering divalent iron to intestinal enterocytes / preventing and treating iron deficiency conditions, containing a reducing organic compound and an iron (II) source taken in a molar ratio of approximately 1:3 to 1:10, and water.

7. The composition according to claim 5, wherein the reducing organic compound is selected from glucose, sucrose, ascorbic acid, malic acid, citric acid, malonic acid, or any mixture thereof.

8. The composition according to any one of claims 6 or 7, wherein the reducing organic compound is preferably selected from ascorbic and / or citric acid.

9. The composition according to any one of paragraphs 6-8, wherein the iron (II) source is selected from the group consisting of anhydrous iron (II) sulfate, iron (II) sulfate hexahydrate, and ammonium iron (II) sulfate hexahydrate.

10. A hermetically sealed ampoule for use in a method for delivering divalent iron to intestinal enterocytes / preventing and treating iron deficiency conditions, containing a composition according to any one of paragraphs 6-9.

11. Use of the composition according to paragraphs 6-9 for the delivery of divalent iron to intestinal enterocytes / prevention and treatment of iron deficiency conditions. 10 SUBSTITUTE SHEET (RULE 26)