WO2021137780A1 - Préparation d'une composition de comprimé pelliculé comprenant du fer hémique pour une carence en fer - Google Patents

Préparation d'une composition de comprimé pelliculé comprenant du fer hémique pour une carence en fer Download PDF

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Publication number
WO2021137780A1
WO2021137780A1 PCT/TR2020/050050 TR2020050050W WO2021137780A1 WO 2021137780 A1 WO2021137780 A1 WO 2021137780A1 TR 2020050050 W TR2020050050 W TR 2020050050W WO 2021137780 A1 WO2021137780 A1 WO 2021137780A1
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WO
WIPO (PCT)
Prior art keywords
iron
ferric
ferrous
composition according
heme
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Application number
PCT/TR2020/050050
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English (en)
Inventor
Hatice Öncel
Yılmaz ÇAPAN
Onur PINARBAŞLI
Feriştah BİLGİN
Nagehan SARRAÇOĞLU
Original Assignee
İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş. filed Critical İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş.
Publication of WO2021137780A1 publication Critical patent/WO2021137780A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Definitions

  • the present invention relates to formulate a film tablet composition comprising heme iron for treating iron defiency with optimization of film coating properties.
  • the composition comprising heme iron can be combined with one or more other iron sources (ionic iron and/or liposomal iron).
  • Vitamin and mineral preparations are commonly administered to treat specific medical conditions or as general nutritional supplements.
  • Micronutrients are elements or compounds which are present in foods in small or trace amounts and include vitamins, minerals, or other elements. In as much as the human body does not synthesize many compounds which are essential to the human body, these specific vitamins and minerals can be obtained from only two sources: food and supplements.
  • Iron is an essential mineral that is naturally present in many foods, added to some food products, and available as a dietary supplement. It is the most abundant trace element in humans; also it is structurally essential to the formation of haemoglobin and myoglobin, and imperative in oxygen transport, energy production, and DNA synthesis. Iron is also necessary for growth, development, normal cellular functioning, and synthesis of some hormones and connective tissue.
  • the average iron content in healthy human body is around 40 mg/kg body weight for women and 50 mg/kg for men. Approximately 30 mg/kg of iron is present within red cells as haemoglobin, with 4 mg/kg as myoglobin in muscle tissue and 2 mg/kg as iron containing enzymes in cells. The remainder is held in reserve as storage iron in the form of ferritin or haemosiderin predominantly in the liver, spleen and bone marrow. In absolute terms, the quantity of storage iron is usually 0.2 g, the actual amount present at any one time depending on the balance between dietary intake and physiological requirements. Under normal circumstances, ferritin predominates as the principal form of tissue in the liver and spleen.
  • Iron deficiency can lead to the development of a form of anemia, resulting in lower than normal levels of hemoglobin, the molecule in red blood cells responsible for transporting oxygen. Symptoms of iron deficiency include fatigue; shortness of breath; palpitations or rapid heartbeat; dizziness or lightheadedness; pallor; weakness; frequent infections; headache; cold extremities; restless leg syndrome; poor appetite in children or altered appetite for nonedible substances such as ice or dirt; and in women of reproductive age, altered menstrual cycles (very light or very heavy). Not surprisingly, therefore, iron deficiency anemia independently increases morbidity and mortality.
  • heme iron a small fraction of total dietary iron derived from haemoglobin and myoglobin from animal sources
  • non -heme (elemental, inorganic) iron available in abundance from vegetable sources and used in the fortification of commercially available foods.
  • the heme iron may be either in the ferrous (Fe 2+ ) or ferric state (Fe 3+ ) and is coordinated with the 4 pyrrole nitrogens.
  • iron from heme iron is bioavailable and absorbed to a significantly higher extent than iron from non-heme sources.
  • the bioavailability of iron from heme iron sources may be 2- to 7-fold higher than that of iron from non-heme sources.
  • the recommended daily dose of heme iron (blood peptonates) amounts to 2 g heme iron (blood peptonates) which is equivalent to 20 mg of elemental iron.
  • iron is absorbed as either a heme iron (an intact metalloporphyrin ring), or non heme iron (ionic iron).
  • Non-heme iron is found in plant sources include dried beans, peas and lentils and some fruits and vegetables.
  • Fleme iron which is principally found in animal sources include meat, fish and poultry.
  • Fleme iron is isolated from animal sources with maximal human intestinal absorption. It is not associated with common side effects of elemental (non-heme) iron supplementation such as constipation, nausea, and gastrointestinal upset.
  • Fleme iron is more readily and effectively absorbed than non-heme iron and, thus, provides a significantly greater dietary source of iron than non-heme iron.
  • iron deficiency is the most common known form of nutritional deficiency amongst humans.
  • Iron deficiency anaemia a microcytic anaemia with haemoglobin concentrations below normal
  • Iron deficiency anaemia is the most common nutritional deficiency disorder, being found in all countries of the world. Subjects at greatest risk are those with high iron requirements owing to growth (infants, children, pregnant women) or high losses (women with high menstrual losses), or those with impaired absorption, e.g. in the presence of infection/ inflammation.
  • iron deficiency causes developmental delays and behavioral disturbances; and in pregnant women, it increases the risk for a preterm delivery and delivering a low-birthweight baby.
  • iron supplements are typically prescribed in doses containing between 40 mg and 150 mg of elemental iron per day, wherein a higher dosage of iron results in greater overall absorption.
  • a high dose of iron as a supplement cause distressing side effects, such as nausea, diarrhea, constipation and/or cramping; thus, resulting in patient non-compliance with the prescribed supplement regimen.
  • Iron supplements can be delivered intramuscularly, intravenously, or orally. According to studies oral administration is preferred due to its convenience.
  • Frykman et al. (1994) gave to 49 healthy volunteers a supplement containing a mixture of heme iron obtained from pig hemoglobin containing 1.2 mg of iron and 8 mg of ferrous fumarate, compared with a control group (45 healthy subjects) who were given a supplement containing 60 mg of iron as ferrous fumarate only. After two months of supplementation, less iron was required in the heme iron-supplemented group to maintain blood iron levels and the number of patients reporting side effects such as stomach ache, constipation, nausea or diarrhea during supplementation was significantly reduced.
  • heme iron has no side effects associated with its consumption and that it does not cause nausea, gastric irritation, vomiting or diarrhea. Also, it is indicated that administration of heme iron (blood peptonates) either alone in capsules, pills, or combined with food, does not cause the characteristic side effects of non-heme iron intake (i.e. nausea, stomach irritation, vomiting or diarrhoea).
  • heme iron is a favoured source of iron because it is absorbed more efficiently than non-heme iron.
  • Ferric pyrophosphate is the usual form of iron used for liposomal iron delivery. According to clinical studies conducted by Blanco-Rojo et al. (2011), Plesea-Condratovici et al. (2012) and Parisi et al. (2012), it is suggested that, ferric pyrophosphate in liposomal iron delivery is safe for treatment of iron deficiency.
  • Liposomes are unilamellar vesicles and are nano-sized particles. Lipid bilayer provides stability and may release the contents gradually. Gradual release may help in better absorption of liposomal contents.
  • supplements comprising one or more heme iron and/or ionic iron and/or liposomal iron or some combinations of these are required for essential metabolic functions.
  • Deficiency states of iron are common clinical conditions. Clinically, they present with not only disordered haematopoiesis, but also widespread effects in other organs that can precede the appearance of haematological abnormalities.
  • the iron supplements may further comprise one or more vitamin, mineral, or some combinations of these, including, without limitation folic acid, vitamin A, vitamin B (all series, including B3, B6, B12), vitamin C, vitamin D, vitamin E, calcium, magnesium, or the like. It has further become recognized that various life -stage groups of the human population require different quantities and types of vitamins and minerals to prevent or alleviate diseases, as well as to maintain general good health.
  • the composition which is intended to be developed for the treatment of iron deficiency comprising heme iron provides a solution to the problem of peeling for the film coating of the tablet.
  • the present invention relates to formulate a pharmaceutical film coated tablet composition comprising heme iron, wherein the film coating comprises combination of copovidone, synthetic polymer of glucose like polydextrose, and a cellulose derivative selected from hydroxypropyl me hylcellulose, hydroxypropyl cellulose, ethyl cellulose and macrocrystalline cellulose.
  • the pharmaceutical film coated tablet composition comprising heme iron may be comprised only heme iron or heme iron combined with other iron sources, wherein the film coating comprises combination of copovidone, synthetic polymer of glucose like polydextrose, and a cellulose derivative selected from hydroxypropyl methylceiluiose, hydroxypropyl cellulose, ethyl cellulose and microcrystalline cellulose.
  • the pharmaceutical film coated tablet composition comprising heme iron may be comprised heme iron combined with ionic iron as a different iron source, wherein the film coating comprises combination of copovidone, synthetic polymer of glucose like polydextrose, and a cellulose derivative selected from hydroxypropyl methylceiluiose, hydroxypropyl cellulose, ethyl cellulose and microcrystalline cellulose.
  • the pharmaceutical film coated tablet composition comprising heme iron may be comprised heme iron combined with liposomal iron as a different iron source, wherein the film coating comprises combination of copovidone, synthetic polymer of glucose like polydextrose, and a cellulose derivative selected from hydroxypropyl methylceiluiose, hydroxypropyl cellulose, ethyl cellulose and microcrystalline cellulose.
  • the pharmaceutical tablet composition comprising heme iron may further comprise one or more vitamin, mineral, or some combinations of these, including, without limitation folic acid, vitamin A, vitamin B (all series, including B3, B6, B12), vitamin C, vitamin D, vitamin E, calcium, magnesium, or the like, wherein the film coating comprises combination of copovidone, synthetic polymer of glucose like polydextrose, and a cellulose derivative selected from hydroxypropyl methylceiluiose, hydroxypropyl cellulose, ethyl cellulose and microcrystalline cellulose.
  • composition of the present invention may comprise any combination of the following ingredients: heme iron in an amount equivalent to 6.0mg - lO.Omg of elemental iron, ionic iron in an amount equivalent to 4.0mg - 12.0mg of elemental iron, liposomal iron in an amount equivalent to 4.0mg - 12.0mg of elemental iron and/or one or more vitamin, mineral, or some combinations of these within the limits, wherein the film coating comprises combination of copovidone, synthetic polymer of glucose like polydextrose, and a cellulose derivative selected from hydroxypropyl methylceiluiose, hydroxypropyl cellulose, ethyl cellulose and microcrystalline cellulose.
  • Iron is present in the human body in the form of ferric (Fe +3 ) or ferrous (Fe +2 ), two oxidation states.
  • the ionic irons of the present invention are preferably in the form of soluble iron salts, but may further include, without limitation, slightly soluble iron salts, insoluble iron salts, carbonyl irons, and blends, mixtures or combinations thereof.
  • the selected soluble iron salt(s) may include, without limitation, ferrous sulfate, ferrous gluconate, ferrous fumarate, ferric hypophosphite, ferric albuminate, ferric chloride, ferric citrate, ferric oxide saccharated, ferric ammonium citrate, ferrous chloride, ferrous iodide, ferrous lactate, ferric trisglycinate, ferrous bisglycinate, ferric nitrate, ferrous hydroxide saccharate, ferric sulfate, ferric gluconate, ferric aspartate, ferrous sulfate heptahydrate, ferrous phosphate, ferric ascorbate, ferrous formate, ferrous acetate, ferrous malate, ferrous glutamate, ferrous cholinisocitrate, ferroglycine sulfate, ferric oxide hydrate, ferric pyrophosphate soluble, ferric hydroxide saccharate, ferric manganese saccharate, ferric sub
  • liposomal iron is a preparation of ferric pyrophosphate carried within a phospholipidic membrane.
  • the present composition may further selectively comprise one or more vitamin and/or mineral; including, without limitation, folic acid, vitamin A, vitamin B (all series, including B3, B6, B12), vitamin C, vitamin D, vitamin E, calcium, magnesium, or the like.
  • vitamin and/or mineral including, without limitation, folic acid, vitamin A, vitamin B (all series, including B3, B6, B12), vitamin C, vitamin D, vitamin E, calcium, magnesium, or the like.
  • Vitamin B12 refers to all forms of cobalamin including, without limitation, hydroxocobalamin, cyanocobalamin and methylcobalamin. It is a cobalt-containing vitamin that is synthesized by microorganisms and exists in different chemical forms in foods of animal origin, including milk, cheese and eggs, as well as artificially fortified foods. It is necessary for overall metabolism, the function of the nervous system, metabolism of folic acid, and the production of red blood cells. Therefore, vitamin B12 deficiency (quantitative or functional) leads to an accumulation of homocysteine and methylmalonic acid (MMA) in plasma.
  • MMA methylmalonic acid
  • Folate an essential micronutrient, is a critical cofactor in one-carbon metabolism.
  • Low folate status may be caused by low dietary intake, poor absorption of ingested folate and alteration of folate metabolism due to genetic defects or drug interactions.
  • External supplementation of folate may occur as folic acid, folinic acid or 5-methyltetrahydrofolate (5-MTHF).
  • Folic acid (vitamin B9) is essential in the production of red blood cells, the production of hormones, and the synthesis of DNA. Folic acid co-enzymes play a crucial role in one carbon metabolism, principally as acceptors and donors of one-carbon units.
  • the various compositions of the present invention may include one or more forms of the foregoing vitamins and / or minerals in any amount and in any combination with the selected heme iron and/or the selected ionic iron salt and/or liposomal iron.
  • Film coating is the process whereby a tablet is surrounded by a thin layer of polymeric material or non-polymeric material.
  • peeling problems were encountered in coatings containing both HPMC based coating material and PVA based coating material at low/high temperature. The peeling problem gives an orange peel effect and a general uneveness in color as well as pin holes in the film layer.
  • coating problem was solved in order to provide a smooth tablet.
  • the problem solved by using the film coating comprising combination of copovidone, a synthetic polymer of glucose like polydextrose, and a cellulose derivative selected from hydroxypropyl methyicellulose, hydroxypropyl cellulose, ethyl cellulose and microcrystalline cellulose.
  • the advantages of the invention is providing a good flat non-tacky tablets which lessens the incidence of tablet-to-tablet picking, thereby avoiding the orange peel effect of uneven color distribution.
  • Film coating is a complex process having different factors affecting the film properties like type and concentration of film forming agents.
  • copovidone is selected as its superior properties. It has good plasticity and elasticity properties and at the same time the films it creates are also less tacky. On the other hand, copovidone usually absorbs too much water, it is therefore recommended to combine it with less hygroscopic substances such as cellulose derivatives, shellac, polyvinyl alcohol, polyethylene glycol (e.g. macrogol 6000) or sucrose.
  • film coating agents comprising copovidone, a synthetic polymer of glucose like polydextrose, and a cellulose derivative like hydroxypropyl methyicellulose, hydroxypropyl cellulose, ethyl cellulose and microcrystalline cellulose has many advantages like providing ability to use low temperature of coating, a smoother appearance and also increasing sprayability and film elasticity.
  • inventive film coating agent may contain further suitable excipients such as, but not limited, glidants, pigments, surfactants or other coating auxiliaries.
  • compositions of this invention are detailed below with examples. Flowever, pharmaceutical compounds of this invention are not restricted to the following examples. Example 1.
  • Component dose (%w/w)
  • a tablet composition was prepared with proper amounts of ingredients and excipients given above. Following completion of the blend process, compressed into tablets with using suitable tooling. The produced tablets are film coated with the combination of film coating agents comprising copovidone, a synthetic polymer of glucose like polydextrose, and a cellulose derivative like hydroxypropyl methylcellulose.
  • Tablets are prepared using the above amounts of the active ingredient and excipients as set out in Example 1 and the film is coated in the same way.
  • Stability Studies The stability of a drug product is an important factor in the manufacture of safe and effective pharmaceutical products. Stability issues can be caused by environmental factors such as humidity, temperature and the like.
  • the physical and chemical stability may be tested in conventional manner, e.g. the dietary supplement tablets may be tested as such by measurement of appearance, water content, assay, and microbiological tests.
  • stability was assessed under three different storage conditions (25 °C ⁇ 2°C, 30°C ⁇ 2°C and 40°C ⁇ 2°C) in temperature -programmable control cabinets.
  • RH relative Humidity
  • 25°C ⁇ 2°C / 60% ⁇ 5% RH represents ambient condition and carries out up to 24 months
  • RH represents intermediate condition and carries out up to 12 months
  • RH represents accelerated conditions and carries out up to 6 months.
  • the tablets of the invention were found stable at three different conditions, in conventional packaging, e.g. sealed PVC/PVdC/Alu or P VC/PE/P VdC/Alu blister.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une formulation de comprimé enrobé d'un film pharmaceutique utilisée comme traitement d'une carence en fer afin d'optimiser un procédé de revêtement de film comprenant du fer hémique seul ou du fer hémique en combinaison avec une ou plusieurs autres sources de fer. L'invention concerne également un procédé pour la préparation desdites compositions pharmaceutiques et leurs utilisations associées.
PCT/TR2020/050050 2019-12-30 2020-01-27 Préparation d'une composition de comprimé pelliculé comprenant du fer hémique pour une carence en fer WO2021137780A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201922566 2019-12-30
TR2019/22566 2019-12-30

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WO2021137780A1 true WO2021137780A1 (fr) 2021-07-08

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115997835A (zh) * 2022-12-27 2023-04-25 河南佳禾康生物食品科技有限公司 一种阿胶血红素铁组合物及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4752479A (en) * 1986-05-27 1988-06-21 Ciba-Geigy Corporaton Multi vitamin and mineral dietary supplement with controlled release bioavailable iron
WO2009062993A1 (fr) * 2007-11-16 2009-05-22 Vifor (International) Ag Compositions pharmaceutiques
US7585527B2 (en) * 2005-09-19 2009-09-08 Bala Venkataraman Composition and method for treating iron deficiency anemia
CN102335193A (zh) * 2011-10-10 2012-02-01 河北师范大学 铁脂质体的应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4752479A (en) * 1986-05-27 1988-06-21 Ciba-Geigy Corporaton Multi vitamin and mineral dietary supplement with controlled release bioavailable iron
US7585527B2 (en) * 2005-09-19 2009-09-08 Bala Venkataraman Composition and method for treating iron deficiency anemia
WO2009062993A1 (fr) * 2007-11-16 2009-05-22 Vifor (International) Ag Compositions pharmaceutiques
CN102335193A (zh) * 2011-10-10 2012-02-01 河北师范大学 铁脂质体的应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115997835A (zh) * 2022-12-27 2023-04-25 河南佳禾康生物食品科技有限公司 一种阿胶血红素铁组合物及其制备方法

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