WO2010034319A1 - Magnetite nanoparticles as a single dose treatment for iron deficiency anemia - Google Patents

Magnetite nanoparticles as a single dose treatment for iron deficiency anemia Download PDF

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Publication number
WO2010034319A1
WO2010034319A1 PCT/EG2008/000036 EG2008000036W WO2010034319A1 WO 2010034319 A1 WO2010034319 A1 WO 2010034319A1 EG 2008000036 W EG2008000036 W EG 2008000036W WO 2010034319 A1 WO2010034319 A1 WO 2010034319A1
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WIPO (PCT)
Prior art keywords
magnetite nanoparticles
vitamin
ida
dose
treatment
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PCT/EG2008/000036
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French (fr)
Inventor
Taher Ahmed Salah El-Din
Mona Bakr Mohamed
Hossam Mohamed Kamel
Mahmoud Abdel Kader
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Innovative Research And Development Co. (Inrad)
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Priority to PCT/EG2008/000036 priority Critical patent/WO2010034319A1/en
Publication of WO2010034319A1 publication Critical patent/WO2010034319A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/26Iron; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51Nanocapsules; Nanoparticles
    • A61K9/5107Excipients; Inactive ingredients
    • A61K9/5123Organic compounds, e.g. fats, sugars
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06Antianaemics

Abstract

In this patent, we introduce magnetite nanoparticles coated with vitamin C as a new modality for treatment of Iron deficiency Anemia (IDA). Animal trials studies reveal that a single dose of Magnetite nanoparticles capped with Vitamin C is sufficient to cure IDA either administrated Intra- Peritoneal (IP) or oral. Within only 10 days, administration of a single dose increases the Hemoglobin concentration (Hb) from 7 g/dL to 14 g/dL and RBCs counts from 3.2x106/mm3 up till 6.5x106/mm3. Moreover, the hematological studies of the bone-marrow gives strong evidence that the used magnetite nanoparticles capped with Vitamin C stimulate erythropoiesis, where the myeloid-erythroid ratio (M/E) decreases from 1.3 till 0.3, without any apparent toxicity and it dose not affect haemostasis. This is conclusive prove of the high efficiency of magnetite nanoparticles capped with Vitamin C as a new drug for treatment of IDA.

Description

Magnetite Nanoparticles as a Single Dose Treatment for Iron Deficiency Anemia
Technical field :
Pharmacy Background Art :
Iron is a component of proteins required for crucial cellular processes being iron containing proteins involved in oxygen transport, ATP production, DNA synthesis, and other physiological processes [1-3]. Its deficiency causing a disease called Iron deficiency anemia, which is a reduction in the oxygen- carrying capacity of red blood cells that results in a variety of symptoms, including dyspnea, headaches, light-headedness, short breath and fatigue . Therefore, anemia has been associated with reduced health-related quality of life and its treatment is essential to improve our health and performance. Iron deficiency anaemia (IDA) is the most common disease involving about 1/3 of the global population and it is directly associated with nutrition. According to the World Health Organization, 46% of the world's 5- to 14- year-old children are anaemic, the great majority resident in developing countries[4]. In the Third World, 56% of pregnant women are anaemic and 38 % of the total women are anaemic. Even in countries such as USA, which is the most developed, about 7.8 million of women and about 700,000 of growing children have problems of iron deficiency [5,6]. In Egypt, statistics shows that above 70% of people are anemic and most of the patients are women and children.
The medical community believes that the iron deficiency, with or without anemia, can easily be corrected with the administration of oral iron. It is not unusual, however, to encounter patients with persistent anemia and iron deficiency, who claim to have been on oral iron for months! Oral iron is not well-tolerated by all patients; it has gastrointestinal side-effects (constipation or diarrhoea, nausea)-, and patients do not adhere to it as they should(7). Furthermore, even with good compliance, iron absorption is not always adequate. It had been reported recently that the presence of Cysteine and Vitamin C increase the absorption of iron in the body [8] When body iron stores are depleted (low-serum iron, serum ferritin and transferrin saturation), erythropoiesis becomes iron restricted, as reflected by a low mean corpuscular volume and mean corpuscular haemoglobin, an increase in the percentage of hypochromic red cells and a low haemoglobin (Hb) content of reticulocytes [9]. Administration of oral iron can correct the anaemia, provided time is not a limitation, and significant doses (200 mg) can be tolerated. Following the administration of oral iron, it takes 2-3 weeks for the Hb to start rising, 2 months for it to return to normal levels and 6 months for iron stores to be repleted; with intravenous iron Hb starts rising in 1 week, the percentage of responding patients is higher and iron stores are repleted [10]. Boosting iron stores is an advantage, particularly for patients receiving erythropoiesis stimulating agents (ESAs) [11].
There are now three iron products that are safe for intravenous administration: iron saccharate, iron gluconate and low molecular weight iron dextran. The best gives rise in the Hb level after one week, and It comes back to the normal level after a month of treatment through twice weekly intravenous administration doses.
We discovered that magnetite nanoparticles capped with ascorbic acid (vitamin C) can be used as single dose drug for anemia treatment and it raises the RBCs and HB level to their normal values within 10 days.
Magnetite (Fe3O4) is a mixed iron oxide (FeO-Fe2O3) with an inverse spinel crystal structure. In the inverse spinel structure, half of the Fe+3 ions are tetrahedrally coordinated and the other half of the Fe+3 ions and all of the Fe+2 ions are octahedrally coordinated. Each octahedral site has six nearest neighbor O-2 ions arranged on the corners of an octahedron, while each tetrahedral site has four nearest neighbor O-2 atoms arranged on the corners of a tetrahedron.
Magnetite nanoparticles (MNPs) can be prepared in a number of ways, the most common of which is the chcriiicz! cc- precipitation of Fe salts with the addition of a hydroxide base. These methods allow the preparation of magnetic nanoparticles in a simple rather way with a careful control in size and shape and thus are very appropriate for their use in biomedical applications. Uniform particles are usually prepared via homogeneous precipitation reactions, a process that involves the separation of the nudeation and growth of the nuclei.
We prepared magnetite nanoparticles capped with ascorbic acid (Vitamin C). We discovered that magnetite nanoparticles coated with Vitamin C increases the hemoglobin level and also increases the formation of RBCs. Animal experiments have been carried out to ensure the efficiency of magnetite nanoparticles capped with Vitamin C in anemia treatment. Hemoglobin levels have been decreased in the mammals to be less than 7, then a single dose of our proposed drug is given to the mammals either IP or orally. Within 10 days, the hemoglobin level and RBCs increased to normal levels. The used magnetite nanoparticles stimulate erythropoiesis without any apparent toxicity and it dose not affect haemostasis
Disclosure of Invention :
Methodology:
Part I: Magnetite nanoparticles
- Preparation of biocompatible magnetite nanoparticles (Fe3O4) using vitamin C as a capping material
- The prepared MNP have an average size of 5 nm as shown from the transmission electron microscope (TEM) images in Figure 1.
- Quantitative determinations of the iron content of the prepared stock solution of the MNP using inductivity coupled plasma (ICP) preparation of serial concentrations of magnetite nanoparticles , 10 ppm, 30 ppm and 60 ppm to be used as treatment doses.
Part II: Animal Experimental Design
- Five weeks old Albino rats of the Wisconsin Holtzman strain, weighing 150-160 g, were divided into four groups according to mode of drug administration as follows:
-2 - Intra peritoneal (IP) group, oral groLfp; positive control group and negative control group.
Both of IP and oral groups were subdivided into three groups according to dose used for treatment, 10 ppm , 30 ppm, 60 ppm. The following diagram summarizes the experimental design.
Figure imgf000005_0001
- All methods used in this study were done according to the NIH guidelines.
- The aim of this experiment is to study the effect of the prepared MNP as a drug for treatment of iron deficiency anemia (IDA) as mentioned previously. So the examined rats have to acquire IDA disease, for doing this four successive blood samples were withdrawn during four days from all groups except the negative control one.
- The Hemoglobin (Hb) and RBCs count of the IP, oral and positive control groups were measured and taken as a base at the start time where the mean values of these groups were about 7.5 g for Hb and 3.5 x 106 / mm3 for RBCs.
- This means that all groups acquired IDA except the negative control group. - 10 ppm, 30 ppm ' and 60 ppm 'i?5?zz were administered intra peritoneal at the abdomen cavity of the rats in the IP group and orally through gastric tube into the stomach of the rats in the oral group.
- The positive and negative control groups were not given any doses of the drug..
Bone marrow Smear:
- The rats were sacrificed at the end thirty days and their femurs were the source of bone marrow for examination of myeloid erythroid ratio (M/E)
The bones were dissected and the marrow removed then mixed with a drop of serum of the same animal species. A smear was prepared by spreading a drop of the resulting suspension on clean dry slides to form a thin bone marrow film.
The films were stained with Leishman stain and examined microscopically. (Hoffbrand and Pettit., 1992)
- During the studying period, any clinical signs were carefully observed.
1- Hematological analysis:
- Hematological tests were done to estimate Hb and RBCs count of all groups at three time intervals, after ten, twenty and thirty days of the drug administration.
- Also, other hematological parameters such as leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets and hematocrit were measured using an autoanalyser.
2- Serum biochemical analysis:
- Blood samples were collected at the start (base line) and at the end of each period. The serum biochemical analysis was carried out to determine; total protein, albumin, bilirubin, AST, ALT, glucose, cholesterol, triglycerides, urea, creatinine, uric acid.
-ς- 3- Histopatholoqical analysis:
- The brain, liver, lungs, kidneys, heart and spleen were removed and subsequently processed for histopathological examination.
Results:
1. Our prepared Magnetite nanoparticles did not induce any abnormal clinical signs in the laboratory animals.
2. Did not cause any adverse effects on growth because no statistically significant differences in the body weight gain was found compared to the control group.
3. The serum biochemical analysis indicated that, there was no alteration in blood chemistry compared to control .
4. Hematological Parameters indicated, no significant change in leukocytes, differential or platelet count compared to control group.
5. The most significant sign that was observed through this study, is the marked increase in hemoglobin levels. Where the mean Hb concentration was about 7.5 g/dl before treatment and increased to 13 g/dl within the first 10 days of the treatment.
6. Also the mean RBCs count was 3.5 xlO6/mm3 before magnetite nanoparticles administration and 30 days after administration the mean RBCs count was 8.5 xlO6/mm3.
7. The histopathological examination indicated that, mild inflammatory cells infiltrated mainly the liver & kidneys due to immune response. This was observed in the acute phase 14 days after injection. The inflammatory reaction decreased after 28 days during the subacute phase and completely recovered at the end of chronic phase , 90 days after injection
Conclusion:
- The treatment of the prepared magnetite nanoparticles did not induce any apparent toxicity.
-4- - The marked efficiency of the prepared magnetite nanoparticles in increasing Hb and RBCs significantly .This being an effective treatment for IDA.
Brief Description of Drawings :
Fie IwA: TEM images of the magnetite particles capped with Ascorbic acid. Hie sample is monodispersed with average size of about 4 nm.
BONE MARROW SMEARS FROM THE FEMUR OF RATS
GROUP OF RATS NEGATIVE CONTROL :
Fig LB.There was no alteration observed and the normal
Myeloid (M) and erythroid (E) precursor and the M/E ratio « 1 :
1. (H&EX160)
GROUP OF RATS KEPT AS POSITIVE CONTROL
(EXPERIMENTALLY ANEMICl:
Fig 2.A&B.Pepletion was observed in the erythroid precursors and the M/E ratio »3:l(H&Ex 160)
GROUP OF RATS TREATED BY lQppm :
Fie 3A&B& 4A&B Active dividing megakaryocytes and elevated erythroid precursors with M/E ratio * 1.5 :1. ( H & E x 160)
GROUP OF RATS TREATED BY 3Qppm :
(Fiα.5&61 : There was obvious number of megakaryocytes associated with increase in the erythroid precursos and erythroid islands with M/E ratio «1:2. (H&Ex 160)
GROUP OF RATS TREATED BY βOppm :
Fie 7&8: Multiple numbers of erythroid precursors and erythroid islands as well as increased megakaryocytes were observed and the M/E ratio «1:3. (H&Ex 160)

Claims

Claims
• A novel drug for Iron deficiency Anemia (IDA) treatment based on Biocompatible Magnetite Nanoparticles capped with Ascorbic acid.
• The method according to claim I5 provide a single dose of magnetite nanoparticles for IDA treated orally or (intraproteinial / intramuscular)
• The used magnetite nanoparticles stimulate the erythropoiesis without any apparent toxicity and it dose not affect haemostasis.
-S -
PCT/EG2008/000036 2008-09-29 2008-09-29 Magnetite nanoparticles as a single dose treatment for iron deficiency anemia WO2010034319A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012092305A3 (en) * 2010-12-27 2012-11-01 Incube Labs, Llc Nanonized iron compositions and methods of use thereof
WO2014135170A1 (en) * 2013-03-06 2014-09-12 Nanotech For Photoelectronics Research Novel formula of iron based nanocomposites for rapid and efficient treatment of iron deficiency anemia
WO2015102289A1 (en) * 2013-12-30 2015-07-09 한화케미칼 주식회사 Pharmaceutical composition for preventing or treating iron deficiency, comprising iron oxide nanoparticles
EP2965754A1 (en) * 2014-07-11 2016-01-13 MegaPro Biomedical Co., Ltd. Method of treating iron deficiency
US10258647B2 (en) 2015-09-01 2019-04-16 Particle Dynamics International, Llc Iron-polysaccharide complexes and methods for the preparation thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007116951A1 (en) * 2006-03-30 2007-10-18 Fujifilm Corporation Drug-immobilized inorganic nanoparticle
WO2008034675A1 (en) * 2006-09-22 2008-03-27 Consejo Superior De Investigaciones Cientificas Systems containing magnetic nanoparticles and polymers, such as nanocomposites and ferrofluids, and applications thereof
JP2008156440A (en) * 2006-12-22 2008-07-10 Tokyo Univ Of Science Antioxidant, skin cosmetic containing the same, medicine for external use, and food and drink

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007116951A1 (en) * 2006-03-30 2007-10-18 Fujifilm Corporation Drug-immobilized inorganic nanoparticle
WO2008034675A1 (en) * 2006-09-22 2008-03-27 Consejo Superior De Investigaciones Cientificas Systems containing magnetic nanoparticles and polymers, such as nanocomposites and ferrofluids, and applications thereof
JP2008156440A (en) * 2006-12-22 2008-07-10 Tokyo Univ Of Science Antioxidant, skin cosmetic containing the same, medicine for external use, and food and drink

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012092305A3 (en) * 2010-12-27 2012-11-01 Incube Labs, Llc Nanonized iron compositions and methods of use thereof
JP2016511261A (en) * 2013-03-06 2016-04-14 ナノテク フォー フォトエレクトロニクス リサーチNanotech For Photoelectronics Research A novel formulation of iron-based nanocomposites for rapid and effective treatment of iron deficiency anemia
WO2014135170A1 (en) * 2013-03-06 2014-09-12 Nanotech For Photoelectronics Research Novel formula of iron based nanocomposites for rapid and efficient treatment of iron deficiency anemia
CN105101957A (en) * 2013-03-06 2015-11-25 光电子纳米技术研究所 Novel formula of iron based nanocomposites for rapid and efficient treatment of iron deficiency anemia
WO2015102289A1 (en) * 2013-12-30 2015-07-09 한화케미칼 주식회사 Pharmaceutical composition for preventing or treating iron deficiency, comprising iron oxide nanoparticles
CN105848661A (en) * 2013-12-30 2016-08-10 韩化石油化学株式会社 Pharmaceutical composition for preventing or treating iron deficiency, comprising iron oxide nanoparticles
WO2016004894A1 (en) * 2014-07-11 2016-01-14 Megapro Biomedical Co., Ltd Method of treating iron deficiency
EP2965754A1 (en) * 2014-07-11 2016-01-13 MegaPro Biomedical Co., Ltd. Method of treating iron deficiency
US9492399B2 (en) 2014-07-11 2016-11-15 Megapro Biomedical Co., Ltd. Method of treating iron deficiency
CN107073035A (en) * 2014-07-11 2017-08-18 巨生生医股份有限公司 The method for treating asiderosis
CN107073035B (en) * 2014-07-11 2020-08-28 巨生生医股份有限公司 Method of treating iron deficiency
US10258647B2 (en) 2015-09-01 2019-04-16 Particle Dynamics International, Llc Iron-polysaccharide complexes and methods for the preparation thereof
US10682375B2 (en) 2015-09-01 2020-06-16 Particle Dynamics International, Llc Iron-polysaccharide complexes and methods for the preparation thereof
US11154570B2 (en) 2015-09-01 2021-10-26 Particle Dynamics International, LLC. Iron-polysaccharide complexes and methods for the preparation thereof

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