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WO2001000204A1 - Methode et composition pharmaceutique pour l'administration parenterale de fer - Google Patents

Methode et composition pharmaceutique pour l'administration parenterale de fer Download PDF

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WO2001000204A1
WO2001000204A1 PCT/US2000/017311 US0017311W WO0100204A1 WO 2001000204 A1 WO2001000204 A1 WO 2001000204A1 US 0017311 W US0017311 W US 0017311W WO 0100204 A1 WO0100204 A1 WO 0100204A1
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iron
dialysate
dialysis
patients
compound
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Ajay Gupta
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    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • 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
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1654—Dialysates therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/28—Peritoneal dialysis ; Other peritoneal treatment, e.g. oxygenation
    • A61M1/287—Dialysates therefor

Definitions

  • the invention relates to methods and compositions for the therapeutic delivery of iron to patients in need of iron supplementation.
  • Iron deficiency is the most common nutritional problem worldwide, causing iron deficiency anemia in 500-600 million people (Cook, Skikne & Baynes, 1994; DeMaeyer & Adiels-Tegman, 1985). Iron deficiency is associated with prematurity and low birth weight during pregnancy, defects in cognitive and psychomotor development during childhood, and impaired work capacity in adulthood (Basta, Soekirman, Karyadi & Scrimshaw, 1979; Lieberman, Ryan, Monson & Schoenbaum, 1988; Lozoff, Jimenez & Wolf, 1991 ; Ohira et al., 1979; Oski & Honig, 1978; Oski, Honig, Helu & Howanitz, 1983).
  • Oral iron supplementation programs have failed primarily due to patient noncompliance and gastrointestinal adverse effects (Schultink, van der Ree, Matulessi & Gross, 1993).
  • iron has been administered parenterally for more than one hundred years (Stockman, 1893).
  • Patients that may benefit from parenteral iron may have iron deficiency from diverse causes including a) nutritional deficiency; or b) blood loss secondary to cancer, gastrointestinal ulceration, gynecological causes, extracorporeal blood loss in hemodialysis patients, or worm (e.g. hookworm) infestation.
  • Simple iron salts are considered too toxic for parenteral administration, since ionization of these compounds liberates free iron, and iron is a transition element capable of catalyzing free radical generation and lipid peroxidation (Brown, Moore, Reynafarje & Smith, 1950; Minotti & Aust, 1992).
  • Fe(ll) is the most reactive form leading to the production of highly reactive hydroxyl radicals by the Fenton reaction, or alkoxyl and peroxyl radicals from the breakdown of lipid peroxides (reviewed by Gutteridge and Halliwell, 1990).
  • colloidal iron compounds that are polynuclear ferric hydroxide carbohydrate complexes, are currently in use for parenteral administration of iron. These compounds are characterized by a complex structure in which a core of ferric iron lies surrounded by a complex carbohydrate structure, so that iron core is shielded from coming in direct contact with plasma or cells. Examples of these compounds include iron dextran, polymaltose, gluconate, saccharate and chondroitin sulfate.
  • polynuclear iron complexes have very low intravenous acute toxicity (LD 50 > 200 - 2,500 mg Fe/kg), compared to soluble iron salts (10 - 20 mg Fe/kg), attributed to their low ionic iron content, since most of the iron is present as Fe(lll) that is bound strongly to the carbohydrate moiety (Geisser, Baer & Schaub, 1992).
  • colloidal iron compounds are also associated with serious side effects including hypotension and anaphylactoid reactions (Goldberg, 1958). The toxicity of these compounds may be secondary to liberation of free iron due to chemical interactions in plasma (Goldberg, 1958), or due to the presence of free iron in the pharmaceutical preparation.
  • iron dextran preparation Imferon®
  • iron dextran preparation Imferon®
  • Cox and coworkers have found that 1-2% of iron present in fresh ampules of Imferon® is ferrous iron, present as an extremely weak ferrous-dextran complex (Cox, King & Reynolds, 1965). Presumably, depolymerization of iron-dextran complex releases free dextran molecules (Mol. Wt. ⁇ 6000 Dalton, ⁇ 33 glucose units) and ionic iron.
  • iron dextran complex In the anesthetized cat, infusion of iron dextran complex (Imferon®) produces a hypotensive response that exhibits a rough correlation with its ferrous iron content and can be abolished by reducing the speed of infusion, while ferric iron produces a smaller transient depressor response followed by a more sustained presser response (Coxetal., 1965; Goldberg, 1958). That redox active iron is released by colloidal iron compounds in the circulation is further evidenced by the rise in plasma total peroxide and malondialdehyde concentrations within ten minutes following infusion of 100 mg iron sucrose complex (Roob et al., 1998).
  • the free radical generation and lipid peroxidation catalyzed by free iron may also play a role in the pathogenesis of a variety of chronic diseases such as inflammation, ischemia, atherosclerosis, cancer, heart disease, and stroke. Recent evidence suggests an increase in cardiovascular and infectious mortality in the US maintenance dialysis patients receiving higher doses of iron dextran intravenously (Collins, Ebben, Ma & Xia, 1998).
  • the carbohydrate complex such as the dextran moiety, released by depolymerization of colloidal iron compounds may also be immunogenic, thereby stimulating formation of circulating antibodies. Circulating anti-dextran antibodies in patients administered repeated doses of iron dextran have also been implicated in anaphylactoid reactions (Cox et al., 1965).
  • colloidal iron complexes when introduced directly into the circulation, are unable to efficiently donate their iron to apotransferrin, to form transferrin.
  • transferrin shall be used to refer to both the precursor form of the protein which lacks iron, and the iron bound form.
  • These colloidal iron complexes are ideally deposited in the reticuloendothelial system (RES) after parenteral administration, processed in the RES, and then iron is released into the circulation where it binds to apotransferrin and is transported to the target tissues.
  • Iron-dextran complex INFeD
  • INFeD Iron-dextran complex
  • the rate at which iron is donated to transferrin by an iron compound is highly dependent on the nature of the iron compound. If the compound is not able to efficiently donate iron to transferrin, the complex or the iron present in it may bind nonspecifically to a variety of plasma proteins, including albumin. It is this fraction that is rapidly taken up by tissues nonspecifically and causes toxic reactions.
  • the LD 50 for monomeric iron compounds such as ferrous gluconate and sulfate is only about 11 mg Fe/kg body weight in white mice, compared with more than 2500 mg Fe/kg body weight for polynuclear iron-carbohydrate complexes, after intravenous administration (Geisser et al., 1992).
  • monomeric iron compounds monomeric iron salts, complexes and chelates
  • polymeric iron complexes such as iron dextran or iron gluconate
  • monomeric iron compounds such as ferrous sulfate, iron ascorbate, ferrous gluconate, and ferric citrate
  • Dialysis is required to maintain homeostasis in patients with end stage kidney failure. Dialysis is defined as the movement of solute and water through a semipermeable membrane which separates the patient's blood from the dialysate solution.
  • the semipermeable membrane can either be the peritoneal membrane in peritoneal dialysis patients or an artificial dialyzer membrane in hemodialysis patients.
  • Erythropoietin therapy functions by stimulating red cell production and thereby iron utilization.
  • transfusions are avoided in most chronic dialysis patients. Blood tests and gastrointestinal bleeding further contribute to loss of iron. Therefore, accelerated iron utilization coupled with small but unavoidable loss of extra corporeal blood with hemodialysis and increased gastrointestinal losses of iron lead to iron deficiency in almost all patients on long term maintenance dialysis.
  • iron deficiency has become a major problem in the dialysis patients treated with erythropoietin.
  • transferrin saturation ratio of serum iron to total iron binding capacity
  • serum ferritin ratio of serum iron to total iron binding capacity
  • iron deficiency is the most common cause of erythropoietin resistance (Kleiner, et al., 1995). Uremic patients suffering from absolute or functional iron deficiency require lower doses of erythropoietin if they receive effective iron supplementation. Based on these considerations, Van Wyck, etal., (1989) have suggested that all renal patients with low to normal iron stores should prophylactically receive iron. Iron supplementation is accomplished most conveniently by the oral administration of iron one to three times a day.
  • iron is available for intravenous administration as iron dextran, iron saccharate and iron gluconate.
  • iron dextran is approved for intravenous use and is widely used for this purpose in dialysis patients.
  • intravenous iron therapy has several advantages over oral administration. Intravenous therapy overcomes both compliance problems and the low gastrointestinal tolerance often observed in patients on oral therapy. Schaefer and Schaefer (1992) reported a 47% reduction in erythropoietin dose when intravenous iron was given to iron deficient hemodialysis patients previously treated with oral iron. On the other hand, intravenous iron therapy with compounds presently in use does have risks and disadvantages. Anaphylactoid reactions have been reported in patients (Hamstra et al., 1980; Kumpf et al., 1990). Therefore, a test dose must be administered when parenteral iron therapy is first prescribed.
  • Intravenous iron therapy can also cause hypotension, and loin and epigastric pain during dialysis which may be severe enough to stop the treatment. Further, the intravenous drug is expensive and requires pharmacy and nursing time for administration. With intravenous iron therapy, serum iron, transferrin and ferritin ievels must be regularly monitored to estimate the need for iron and to measure a response to the therapy. Finally, there is also a concern about potential iron overload with intravenous therapy, since the risk of infection and possibly cancer are increased in patients with iron overload (Weinberg, 1984). Recent evidence further suggests a 35% higher risk for cause-specific infectious deaths in US Medicare ESRD patients given intravenous iron frequently (Collins et at., 1997).
  • colloidal iron compounds or iron in its mineral form are not soluble in aqueous solutions and therefore not suitable for addition to the dialysate.
  • iron is known to be toxic when administered parenterally in its mineral form. The toxic effects may arise from precipitation of iron in the blood, producing multiple pulmonary and sometimes systemic emboli. Symptoms resembling that of fat embolism occur. Irritation of the gastrointestinal tract gives rise to diarrhea and vomiting. Also, depression of the central nervous system can lead to coma and death (Heath et al., 1982).
  • Pyrophosphate has also been shown to enhance iron transfer from transferrin to ferritin (Konopka et al., 1980). It also promotes iron exchange between transferrin molecules (Morgan, 1977). It further facilitates delivery of iron to isolated rat liver mitochondria (Nilson et al., 1984). Ferric pyrophosphate has been used for iron fortification of food and for oral treatment of iron deficiency anemia (Javaid et al., 1991).
  • Ferric pyrophosphate has also been used for supplying iron to eukaryotic and bacterial cells, grown in culture (Byrd et al., 1991). Toxic effects of ferric pyrophosphate have been studied by Maurer and coworkers in an animal model (1990). This study showed an LD 50 slightly higher than 320 mg of ferric pyrophosphate per kilogram or approximately 30 milligrams of iron per kilogram body weight. The effective dose for replacing iron losses in hemodialysis patients is estimated to be 0.2 to 0.3 milligrams iron per kilogram body weight per dialysis session. Therefore, the safety factor (ratio of LD 50 to effective dose) is over 100.
  • stannous pyrophosphate Another metal pyrophosphate complex, stannous pyrophosphate has been reported to cause hypocalcemia and immediate toxic effects. Since ferric ion forms a stronger complex to pyrophosphate than do stannous ion, or calcium ion (Harken et al., 1981 ; Sillen et al., 1964), hypocalcemia is not a known side affect of ferric pyrophosphate administration.
  • physico-chemical criteria and methods are described for the successful selection of monomeric Fe (III) compounds that are suitable for parenteral administration.
  • Clinical trial of one such compound (soluble ferric pyrophosphate) in dialysis patients is described.
  • Clinical scenarios and methods of administration of these compounds to patients by the intravenous, intramuscular, subcutaneous and transdermal routes or by addition to dialysate in dialysis patients are described.
  • parenteral is described.
  • other novel approaches that may be used to mitigate the iron toxicity are described.
  • the invention is a pharmaceutical composition
  • the iron compound comprises one or more iron atoms bound to one or more ligands, which iron compound: (a) is suitable for parenteral administration to mammals, for the treatment of iron deficiency;
  • a method of treating iron deficiency in a mammal comprises parenterally administering to the mammal an effective amount of the aforesaid non-toxic, monomeric iron compound.
  • a method of iron administration to a dialysis patient comprising administering to the patient through a hemodialysis solution or peritoneal dialysis solution an effective amount of a non-toxic, monomeric iron compound comprising one or more iron (III) atoms bound to one or more ligands, which iron compound:
  • (h) is water-soluble; wherein the iron compound is infused into the circulation of the patient during dialysis by diffusion across a semipermeable membrane.
  • the iron concentration in the dialysate may range from about
  • the iron concentration in the dialysate may range from about 1 to about 500 ⁇ g per deciliter.
  • a dialysate concentrate containing the iron compound is also contemplated.
  • the iron concentration in a hemodialysate concentrate will range from about 0.3 to about 35 mg/L.
  • the iron compound is ferric pyrophosphate.
  • the compound is other than ferric pyrophosphate, such as hydroxamate or a hydroxypyridinone. Any of the compositions of the invention may optionally comprise one or more antioxidants.
  • iron is preferably delivered to the circulation of the mammal at a rate such that the iron binding capacity of transferrin in the body of the mammal is not exceeded by the delivered iron. Most preferably, iron is delivered to the circulation of the mammal at a rate such that 80% of the iron binding capacity of transferrin in the body of the mammal is not exceeded by the delivered iron.
  • the optional antioxidant is administered proximal in time to the administration of the iron compound.
  • the antioxidant may be administered simultaneously with the iron compound, or shortly before or after the iron compound.
  • the antioxidant is combined with the iron compound in the same formulation.
  • FIGURE 1 is a pair of graphs showing serum iron versus time and iron per TIBC (percent) versus time.
  • FIGURE 2 is a graph showing serum iron per total iron binding capacity (TIBC) (percent).
  • FIGURE 3 is a graph showing the study design and concentration of iron in the dialysate over the study period.
  • FIGURE 4 is a graph of group whole blood hemoglobin average over the study period.
  • FIGURE 5 is a graph of the group reticulocyte hemoglobin average amount over the study period.
  • FIGURE 6 is a graph of the group predialysis serum iron level average over the study period.
  • FIGURE 7 is a graph of the group increment in average serum iron with dialysis over the study period.
  • FIGURE 8 is a graph of the group predialysis total iron binding capacity average over the study period.
  • FIGURE 9 is a graph of the group predialysis transferrin saturation (TSAT) average over the study period.
  • FIGURE 10 is a graph of the group postdialysis transferrin saturation (TSAT) average over the study period.
  • FIGURE 11 is a graph of the group average change in transferrin saturation (TSAT) during dialysis over the study period.
  • FIGURE 12 is a graph of the group average percentage change in mean transferrin saturation (TSAT) with dialysis over the study period.
  • FIGURE 13 is a graph of the group predialysis ferritin average over the study period.
  • FIGURE 14 is a graph of the group erythropoietin dose per treatment average over the study period.
  • FIGURE 15 is a graph of the group weekly dose of intravenous iron (Infed®) average over the study period.
  • FIGURE 16 is a graph showing the serum iron in rabbits undergoing acute peritoneal dialysis with a dialysis solution that contains ferric pyrophosphate.
  • FIGURE 17 is a graph showing total iron binding capacity (TIBC) in rabbits during peritoneal dialysis.
  • FIGURE 18 is a graph showing the transferrin saturation (serum Fe TIBC, %) in rabbits undergoing acute peritoneal dialysis with a dialysis solution that contains ferric pyrophosphate.
  • FIGURE 19 is a graph of serum iron ( ⁇ g/dL) and transferrin saturation (TSAT%) as a function of time in a human hemodialysis patient receiving ferric pyrophosphate via the dialysate.
  • monomeric iron compounds are administered safely and effectively by parenteral administration for the prevention or treatment of iron deficiency in a mammal.
  • monomeric is meant a compound which is not an oligomer or polymer.
  • the iron compound is mononuclear, as opposed to polynuclear.
  • iron compound is meant not only simple salts of iron, but also all other associations of iron atoms with other atoms or molecules, e.g., complexes or chelates of iron.
  • the compound may be organic or inorganic in nature.
  • the compound is composed of iron atoms and another atom or chemical group which may be an anion (as in the case of an iron salt) or a chelate or other ligand, which is typically organic in nature.
  • ligand shall be used herein to mean all such atoms and chemical groups which may form an iron compound as defined above.
  • the successful prediction of bioiogical activity, safety and efficacy for a given iron compound depends on an understanding of its function in biological systems and the ability to relate these functions to simple physicochemical properties of the iron compound measured in vitro.
  • the iron compounds utilized in the practice of the invention are characterized by the hereinafter-described properties.
  • the iron compound utilized in the practice of the present invention may reside in the iron (II) (ferrous) or iron (III) oxidation state, but are preferably in the iron (III) state at the time of administration into the mammal.
  • the iron compound must be able to donate its iron rapidly to transferrin.
  • Transferrin is the major carrier of iron in mammalian systems and is responsible for iron transport to the target tissue.
  • Fe(lll) acetohydroxamate is an example of an iron compound which is able to rapidly donate its iron to transferrin.
  • the iron compound should thus be able to donate a substantial portion of its iron content directly to transferrin under physiological conditions.
  • substantially portion is meant at least about 50% of the iron content of the iron compound.
  • the iron compound should not induce significant binding of the contained iron to proteins other than transferrin, or to other ligands found in body fluids, under physiological conditions.
  • significant binding with respect to the amount of iron binding to liqands other than transferrin is meant the proportion of a therapeutic iron dose that when it complexes to other ligands or proteins produces clinically significant side effects.
  • the ligand should not significantly complex with other metal ions present in body fluids such as calcium, magnesium, zinc and copper.
  • significantly complex is meant that the ligand induces a more than about 10% reduction in the serum concentration of the aforesaid other metal ions, under physiological conditions.
  • the ligand comprising the iron compound should be strongly complexed to the iron atom, preferably Fe(lll), such that when the iron compound is administered in therapeutic doses it does not release a clinically significant amount of free iron to the patient's body fluids, under physiological conditions.
  • a clinically significant amount is meant an amount of free iron which would result in significant oxidant stress to the patient, or any other side-effects as hereinafter discussed.
  • the iron compound is characterized by a log of conditional stability constant (as hereinafter described) of at least 6 in a physiological electrolyte solution.
  • the iron compound and the ligand should be biocompatible and safe for administration to humans or animals, particularly administration by the parenteral route.
  • Ferric pyrophosphate is an example of such a compound.
  • the iron compound has a molecularweight of less than about 30,000 daltons for intravenous administration.
  • the molecular weight should be preferably less than about 12,000 daltons, more preferably less than about 10,000 daltons.
  • Acetohydroxamate is an example of such a ligand.
  • the monomeric iron compounds that are highly stable, possess iron which is not available for transfer to transferrin, can be considered similar to the polynuclear iron-carbohydrate complexes. Such compounds are not believed suitable for parenteral administration, and it is not the purpose of this invention to make these compounds available for parenteral use. However, it should be noted that such highly stable compounds may be very desirable for oral administration because local release of free ionic iron in the gastrointestinal tract by iron salts is primarily responsible for the oxidant damage, inflammation, ulceration and clinical gastrointestinal toxicity. Stability of these compounds will prevent dissociation and release of free iron. Furthermore, even though iron in these compounds may not be available for transfer to transferrin directly, the processing of these compounds in the intestinal mucosal cells may make this iron bioavailable.
  • the monomeric iron compound is ferric pyrophosphate.
  • the compound is other than ferric pyrophosphate.
  • parenteral administration of iron compounds according to the present invention delivers the compounds directly into the circulation when administered intravenously or via the dialysate, and into the interstitial fluid when transdermal, subcutaneous or intramuscular routes are used.
  • a suitable solution to test the stability of candidate iron compounds consists of about 140 mM sodium, 4 mM potassium, 1.2 mM calcium, 0.9 mM magnesium, 1.5 micromolar zinc, 1.6 micromolar copper, 100 mM chloride, 1 mM lactate and 1 mM inorganic phosphorus, and has a pH of about 7.4.
  • the state of aggregation is determined to ensure that the compound is monomeric. This can be determined by testing the magnetic moments of a solution of the compound acco.ding to known procedures (Brown et al., 1978).
  • the kinetics of iron transfer from the monomeric iron compound to transferrin can be tested by mixing the iron compound with transferrin in vitro, and measuring the change in the transferrin absorption spectra using spectrophotometric techniques or nuclear magnetic resonance techniques as described by Brown and coworkers (Brown etal., 1978).
  • Stability may be further determined with resort to the calculation of the conditional stability constant ( ⁇ ') of the candidate compounds under physiological conditions.
  • Inverse values of dissociation (instability) constants are stability constants ( ⁇ or K stab ). These constants are available from the literature for a large number of iron compoun ⁇ s, having been determined under non-physiologic conditions, often at extremes of pH and in the absence of any other competing ligands. However, when other competing ions are present, common side reactions as those caused by hydrogen ions, hydroxide ions, buffering substances, masking agents and disturbing metal ions occur. Therefore, the term 'conditional stability constant' was coined to stress that 'constant' is not constant but depends on experimental conditions.
  • Conditions "C” in Table 2 represent physiological conditions. The value of ⁇ ' under conditions “C” is herein defined as the "conditional stability constant" for a compound.
  • Conditions A (competing equilibria only involve H + and OH " ): Fe not complexed to L present as ⁇ Fe n+ + Fe(OH) x m+ ⁇ ; L not complexed to Fe present as ⁇ L 0_ + LH P" + LH 2 q" + etc ⁇
  • Conditions B (competing equilibria involve HJ OH " . NaJ KJ Mg 2 J Ca 2+ . Cu 2+ . and
  • Fe not complexed to L present as ⁇ Fe" + + Fe(OH) x m+ + FeY ⁇ where Y lactate (1 mM), phosphate (1 mM) and Cl " (100 mM);
  • the iron compounds of this invention are highly stable and largely undissociated under physiologic conditions, so that when introduced directly into the body fluids there is minimal dissociation of the compound before iron can be donated to transferrin. Consequently, there is minimal and clinically insignificant liberation of free iron.
  • these compounds have high conditional stability constants, where the log of the constant is greater than at least 6.0 or 7.0. Fe(ll) compounds are unlikely to meet this criteria. In fact only a few Fe(lll) compounds meet this criteria as shown in Table 2.
  • conditional stability constant of iron for the ligand in the preferred monomeric iron compounds is high, and the iron (preferably ferric) is complexed to the ligand tightly such that there is no significant complexation of the ligand by the other metal cations present in body fluids.
  • the monomeric compounds used in the practice of the invention are characterized by a log of conditional stability constant greater than 6.0. Therefore, the compounds of this invention include, for example, Fe(lll) complexed to acetohydroxamate and other hydroxamates; pyrophosphate; hydroxypyridinones; and derivatives of these compounds.
  • a “hydroxamate” is meant any compound which contains the hydroxamate group.
  • hydroxypyridinone any compound containing the hydroxypyridinone group.
  • the conditional stability constant of dimethyl hydroxypyridinone (DMPH) could not be determined since the data for DMPH binding to sodium, potassium, magnesium, calcium, copper and zinc is not available.
  • DMPH dimethyl hydroxypyridinone
  • the chemical structure and the high conditional stability constant when competing equilibria only involve hydrogen and hydroxyl ions suggests the suitability of this compound for the purposes of the invention.
  • Compounds of this invention also include other known or yet to be discovered compounds with log ⁇ ' values greater than 6.0.
  • chelators of iron that function as natural siderophores or are their synthetic derivatives, may be suitable for parenteral administration, since the siderophores have a high and specific affinity for Fe(lll).
  • Siderophore-Fe(lll) complexes are involved in microbial iron transport.
  • siderophores see P. Singleton and D. Sainsbury, Dictionary of Microbiology and Moivcular Biology, 2d ed., John Wiley & Sons, New York, NY, 1987, pp 806-807, incorporated herein by reference.
  • siderophores comprise low-molecular weight ferric iron-chelating compounds which are synthesized and exported by most organisms for the sequestration and uptake of iron.
  • the two main structural classes of siderophores are the catecholamides and the hydroxa mates.
  • the following is a practical method to determine the generation of free iron and complexation of other metal cations when an iron compound is administered parenterally.
  • a physiologic amount of iron(lll) compound is added to a solution containing transferrin (such as plasma).
  • transferrin such as plasma
  • the amount of free iron generated is determined.
  • the decrease in the serum concentration of uncomplexed or free metal ions of calcium, magnesium, zinc, etc. is also determined.
  • a plasma solution containing transferrin and an iron compound of interest, ferric pyrophosphate was subjected to ultra-filtration to separate iron that is free in the plasma from the iron bound to transferrin.
  • 3.5 liters of human plasma was subjected to hemodialysis in vitro using a F-80 polysulfone, high flux dialyzer and a Fresenius-H hemodialysis machine.
  • the plasma was dialyzed against bicarbonate dialysate containing 12 mcg/dl of iron, as ferric pyrophosphate.
  • the dialysate flow rate was 800 ml/min, while the plasma flow rate was maintained at 300 ml/min.
  • Plasma samples were taken prior to starting dialysis (pre-dialysis) and after 4 hours of hemodialysis (post-dialysis). These samples were subjected to ultrafiltration using an Amicon ultrafiltration membrane with a 10,000 molecular weight cut-off, thereby allowing free iron and its low molecular weight chelates, but not transferrin to go through the pores. Iron concentration was determined in the plasma samples and the samples of the ultrafiltrate using an atomic absorption assay. The pre-dialysis iron concentrations in the plasma and ultrafiltrate were 0.400 and 0.0118 mg/L, respectively. The post-dialysis iron concentrations in the plasma and ultrafiltrate were 1.110 and 0.0020 mg/L, respectively.
  • ferric pyrophosphate when ferric pyrophosphate was infused into the plasma by dialysis, there was nearly a three fold increase in the concentration of serum iron, and plasma iron exceeded the iron binding capacity of plasma. However, there was no increase in the concentration of free iron or low molecular weight iron chelates in the ultrafiltrate of the plasma, suggesting that iron in ferric pyrophosphate binds to plasma proteins and is not present as free iron. This method may be used to screen the presence of free iron and low molecular weight iron chelates, when iron compounds are administered parenterally.
  • plasma containing a variety of proteins can be substituted by a physiological salt solution to which physiologic concentrations of the protein transferrin have been added.
  • bleomycin detectable im ⁇ free iron present in the body fluids can be quantitated by the bleomycin binding assay; such iron is referred to as "bleomycin detectable im ⁇ " (Banyai et al., 1998). Therefore animal or human trials of the candidate iron compounds can use bleomycin detectable iron as a measure of free iron generated in the body fluids when the compound is administered.
  • a monomeric iron compound is infused via the dialysate in patients with renal failure.
  • Dialysis patients are those patients undergoing hemodialysis or peritoneal dialysis for renal failure. Long-term dialysis therapy for treatment of end stage renal failure is referred to as "maintenance dialysis". Patients on maintenance hemodialysis have been estimated to lose about 2 to 3 grams of iron per year, corresponding to approximately 6 ml per day (2 liters per year) blood loss from all sources (Eschbach et al., 1977). These patients generally receive hemodialysis three times per week.
  • a dialysis solution (dialysate) for hemodialysis can be generated using a variety of different methods and different dialysis machines.
  • dialysate is mixed either from salts or liquid concentrates and water.
  • dialysate continuously by mixing liquid or solid concentrates with water.
  • dialysates There are two types of dialysates - acetate based and bicarbonate-based.
  • Acetate dialysate is often prepared from a 35-fold concentrated solution.
  • Bicarbonate dialysate must be produced form at least two concentrates.
  • a first concentrate contains sodium bicarbonate; a second concentrate contains calcium and magnesium salts.
  • the other constituents of the bicarbonate-based dialysate can be put in either concentrate.
  • the most common system uses a 1 -molar sodium bicarbonate concentrate and a so called "acid- concentrate" that contains sodium, potassium, calcium, and magnesium chloride as well as some acetic acid to adjust dialysate pH to about 7.3.
  • Acid concentrates are diluted about 35-45 fold in the preparation of the dialysate.
  • a system for continuous production of a saturated bicarbonate concentrate that is subsequently diluted with water to produce dialysate utilizes a cartridge filled with bicarbonate powder. Water percolates through the cartridge and the liquid exiting this cartridge at the bottom is a saturated bicarbonate solution.
  • Alternative technical solutions using the same principle utilize bags instead of cartridges. The percolation principle can be applied to other salts including the iron compounds of this invention.
  • the compatibility of a monomeric iron compound with a dialysate or dialysate concentrate can be easily tested by determining solubility and stability of the compound when the two are mixed together, using standard laboratory techniques.
  • the molecular weight of the monomeric iron compound should be small enough to allow efficient diffusion across the dialysis membranes during hemodialysis and peritoneal dialysis.
  • Fe (III) pyrophosphate, Fe (III) hydroxamates and Fe (III) hydroxypyridinones satisfy this requirement.
  • a specific example of a hemodialysis system is the Fresenius system. In the Fresenius system, the ratio of acid:bicarbonate:water:total is 1 : 1.23:32.77:35.
  • one part of the concentrated bicarbonate solution is mixed with 27.5 parts of the other (acid + water), to make the final dialysate.
  • purified water is pumped from the purified water source into a large tank.
  • Fresenius supplies sodium bicarbonate powder packaged in plastic bags and the contents of each bag are mixed with purified water in the tank, to make 25 gallons (94.6 liters) of bicarbonate solution.
  • the concentrated solution is run into plastic receptacles. The concentrate is prepared within 24 hours of its use.
  • the monomeric iron compound administered via dialysate is ferric pyrophosphate ("FePyP").
  • Ferric pyrophosphate (Fe 4 P 6 0 21 ) has a molecular weight of 745.2. It is a nonahydrate with yellowish-green crystals. It has been used as a catalyst, in fireproofing synthetic fibers and in corrosion preventing pigments.
  • Ferric pyrophosphate is freely soluble in the bicarbonate concentrate. It may be added in a dry or solution form to the dialysis concentrate.
  • Dialysate iron concentration can be increased by adding different amounts of FePyP to the bicarbonate concentrate (Table 3).
  • Ferric pyrophosphate may be added to the dialysate concentrate either in its crystalline form or as an aqueous solution.
  • plasma (3.5 liters) was dialyzed in vitro using an F-80 dialyzer with the plasma flow rate set at 300 ml/min. and the dialysate flow rate 800 ml/min.
  • Ferric pyrophosphate (420 mg) was added to 20 liters of bicarbonate concentrate and intermittently stirred for one hour prior to the dialysis. This was a clear solution with a light greenish yellow tinge.
  • the final dialysate was a clear, colorless solution, with 5 ⁇ g/dl iron content, as measured by a calorimetric assay.
  • Physiological saline solution was added to the plasma every minute at regular intervals to compensate for obligate ultrafiltration, and to keep the plasma volume constant. Serum Fe and TIBC were measured at frequent intervals. There was a progressive increase in serum iron concentration (A), and transferrin saturation (B), as shown in Figure 1.
  • Dialysis is defined as the movement of solute and water through a semipermeable membrane (the dialyzer) which separates the patient's blood from a cleansing solution (the dialysate).
  • Diffusive transport is the movement of solutes across the membrane, and is dependent on the concentration gradient between plasma water and dialysate;
  • Convective transport is the bulk flow of solute through the dialyzer in the direction of hydrostatic pressure difference;
  • Osmosis is the passage of solvent (water) across the membrane in the direction of the osmotic concentration gradient;
  • Ultrafiltration is the movement of solute free water along the hydrostatic pressure gradient across the membrane.
  • the patient's plasma tends to equilibrate with the dialysate solution overtime.
  • the composition of the dialysate permits one to remove, balance or even infuse solutes from and into the patient.
  • the electrochemical concentration gradient is the driving force that allows the passive diffusion and equilibration between the dialysate and the patient's blood compartment.
  • the process of dialysis can be accomplished by using an artificial kidney (hemodialysis and hemofiltration) or patient's abdomen (peritoneal dialysis).
  • a synthetic or semi-synthetic semipermeable membrane made of either cellulose acetate, cupraphane, polyacrylonitrile, polymethyl methacrylate, or polysulfone, is used.
  • a constant flow of blood on one side of the membrane and dialysate on the other allows removal of waste products.
  • An artificial kidney can be used to perform hemodialysis, during which diffusion is the major mechanism for solute removal.
  • hemofiltration also called hemodiafiltration and diafiltration relies on ultrafiltration and convective transport rather than diffusion to move solutes across a high porosity semipermeable membrane.
  • hemodialysis is used to include all dialysis techniques (e.g. hemofiltration) that require an extracorporeal blood circuit and an artificial membrane.
  • peritoneal dialysis uses patient's peritoneal membrane to exchange solutes and fluid with the blood compartment. Therefore, peritoneal dialysis is the treatment of uremia by the application of kinetic transport of water-soluble metabolites by the force of diffusion and the transport of water by the force of osmosis across the peritoneum.
  • the peritoneum is the largest serous membrane of the body (approximately 2m 2 in an adult). It lines the inside of the abdominal wall (parietal peritoneum) and the viscera (visceral peritoneum). The space between the parietal and visceral portions of the membrane is called the "peritoneal cavity".
  • Aqueous solutions infused into the cavity contact the blood vascular space through the capillary network in the peritoneal membrane.
  • the solution infused into the peritoneal cavity tends to equilibrate with plasma water over time and it is removed at the end of one exchange after partial or complete equilibration.
  • the composition of the dialysate permits to remove, balance or even infuse solutes from and into the patient.
  • the electrochemical concentration gradient is the driving force that allows the passive diffusion and equilibration between the dialysate and blood compartment.
  • Dialysis solutions (hemodialysis or peritoneal dialysis) of the present invention are characterized by an added monomeric iron compound, having a molecular weight less than about 12,000 daltons, preferably having a molecular weight of less than 5000 daltons.
  • the ferric compound should be 1) soluble in dialysis solutions in ⁇ equate concentrations; 2) efficiently transfer from the dialysate to the blood compartment; 3) bind to transferrin in the plasma and be available for use by tissue; 4) be well tolerated without any short or long term side effects; and 5) be economical.
  • Ferric pyrophosphate possess all the above characteristics and therefore is the preferred iron compound for use with the present invention, though other soluble ferric compounds may also be used, as discussed above.
  • hemodialysis machines utilize an automated proportioning system to mix salts in deionized water in specific proportions to generate the final dialysate solution.
  • the dialysate concentrates are usually supplied by the manufacturer either as a solution ready to use or as a premixed powder that is added to purified water in large reservoirs.
  • the concentrates are pumped into a chamber in the dialysis machine where they are mixed with purified water to make the final dialysate solution.
  • the ionic composition of the final dialysate solution for hemodialysis is as follows: Na + 132-145 mmol/L, K + 0-4.0 mmol/L, Cr 99- 112 mmol/L, Ca ++ 1.0 - 2.0 mmol/L, Mg +2 0.25-0.75 mmol/L, glucose 0-5.5 mmol/L.
  • the correction of metabolic acidosis is one of the fundamental goals of dialysis. In dialysis, the process of H + removal from the blood is mainly achieved by the flux of alkaline equivalents from the dialysate into the blood, thereby replacing physiological buffers normally utilized in the chemical process of buffering.
  • acetate or bicarbonate containing dialysate In dialysis practice, base transfer across the dialysis membrane is achieved by using acetate or bicarbonate containing dialysate.
  • the dialysate contains 27-35 mmol/L of bicarbonate and 2.5-10 mmol/L of acetate.
  • the dialysate In acetate dialysis the dialysate is devoid of bicarbonate and contains 31-45 mmol/L of acetate.
  • Ferric pyrophosphate in particular is compatible with both acetate and bicarbonate based hemodialysis solutions.
  • the peritoneal dialysis fluid usually contains Na + 132-135 mmol/L,
  • Ferric pyrophosphate in particular is soluble and compatible with peritoneal dialysis solutions.
  • a suitable monomeric iron compound e.g., ferric pyrophosphate, is either added directly to peritoneal dialysis solutions, or to the concentrate for hemodialysis.
  • the compound has to be added at a proportionally higher concentration in the concentrate.
  • 2 to 25 ⁇ g of the ferric iron (e.g., as ferric pyrophosphate) per deciliter of the hemodialysis solution is used for hemodialysis. Accordingly, 4 to 50 milligrams of iron are infused into the patient during a two to five hour hemodialysis session.
  • ferric iron e.g., as ferric pyrophosphate
  • 4 to 50 milligrams of iron are infused into the patient during a two to five hour hemodialysis session.
  • hemodialysis patients number 230-250,000 in the United States and about one million worldwide. The majority of these patients require erythropoietin therapy to maintain hemoglobin in the target range of 10-12 gm/dL.
  • dialysate iron therapy is able to maintain iron balance in the majority of hemodialysis patients without a need for oral or intravenous iron supplementation. In a minority of patients receiving dialysate iron therapy, the requirement for intravenous iron is significantly reduced but not completely eliminated.
  • the present invention provides pharmaceutical composition of a soluble, noncolloidal ferric compound that can be added to dialysis solutions to meet the iron supplementation or therapeutic needs of dialysis patients.
  • a soluble, noncolloidal ferric compound that can be added to dialysis solutions to meet the iron supplementation or therapeutic needs of dialysis patients.
  • some dialysis patients may still need oral or intravenous iron supplements.
  • monomeric iron may be delivered intravenously, such as by continuous infusion.
  • Transferrin is responsible for conveying iron between sites of iron storage and utilization. It has a molecular weight of 77,000 and contains two metal-binding sites per molecule and also binds one bicarbonate anion per metal atom. The metal-binding sites are equivalent in their affinity for iron but apparently not identical in biological activity. The rate at which an iron is donated to transferrin by an iron compound is highly dependent on the nature of the iron compound.
  • Free iron should not accumulate in the circulating blood, since it is toxic. Iron bound loosely to plasma proteins other than transferrin is also toxic. Therefore, iron in plasma and other body fluids should not exceed the iron binding capacity of transferrin; over-saturation of transferrin should be avoided. The rate of infusion of the monomeric iron compound should thus be slow enough to avoid transferrin over-saturation.
  • a stable access to the circulation is desirable, so that the total amount of iron needed by the patient can be infused over a period of hours to days. The following are non-limiting choices for intravenous access that may be used for slow intravenous infusion of monomeric iron compound according to the practice of the present invention:
  • the iron compound may be administered by ordinary peripheral or central venous cannulas in hospitalized patients or patients visiting an outpatient clinic.
  • the iron compound may be administered by an infusion pump such as the type presently used for home infusion of dobutamine or insulin.
  • the iron compound may be administered by an indwelling catheter that may or may not be tunneled in the subcutaneous tissue.
  • the catheter may comprise, for example, a Quinton, Hickman, or Groshong catheter as used for chemotherapy in cancer patients and for hemodialysis in end-stage kidney failure patients.
  • the iron compound may also be administered by other means of dialysis access such as an arteriovenous shunt; the shunt is accessed by insertion of needles for the purposes of dis /sis.
  • the monomeric iron compound may be infused into the extra-corporeal circuit directly as described later in this application.
  • the monomeric compound is administered in the form of a sterile solution when administered by the intravenous, subcutaneous, intramuscular or intra-peritoneal route. This is in contrast to administration via a hemodialysis solution, which must be clean but not necessarily sterile.
  • the monomeric iron compound as exemplified by ferric pyrophosphate, may be freely soluble in warm water and compatible in any physiologically acceptable aqueous solution such as physiological salt solution (saline, or Ringer's lactate) or isotonic dextrose solution.
  • physiological salt solution saline, or Ringer's lactate
  • isotonic dextrose solution Such solutions can be supplied as pre-mixed, ready to use formulations or formulated easily in a hospital pharmacy, outpatient pharmacy, or at a patients bedside by mixing the said iron compound, in a solid or liquid phase to an appropriate diluting fluid such as dextrose or salt solution.
  • the solvent may be a sterile solution containing salt, dextrose or just pure water.
  • the monomeric iron compound can be infused even in non-aqueous solvents or suspension fluids, as long as the suspension, colloid or solution is stable and suitable for parenteral administration.
  • the rate of iron compound infusion should be such that transferrin saturation is not exceeded. It may be advisable to restrict the infusion rate whereby the percentage saturation of plasma iron binding capacity (transferrin saturation) is 80% or less.
  • infusion of the monomeric iron compound can continue for days to weeks.
  • continuous or intermittent infusions may be given for days to weeks if a stable access is available, such as an indwelling catheter for chemotherapy in cancer patients.
  • the monomeric iron compound may be administered at a rate that equals the uptake and utilization of iron by tissues, such as the erythron.
  • the efficiency of administration can be improved by a short bolus infusion to raise transferrin saturation (TSAT) from a baseline level to about 80% in a few minutes, followed by infusion at a slower rate to maintain transferrin saturation at this high level for the duration of the infusion.
  • TSAT transferrin saturation
  • the amount of iron compound required to raise the transferrin saturation from baseline to peak can be calculated.
  • an estimated plasma volume of 4000 ml, plasma iron binding capacity of 250 mcg/dl or 2.5 mg/liter the total iron binding capacity of plasma is about 10 mg.
  • the total iron binding capacity of transferrin present in plasma and interstitial compartment is about 20 mg iron. If the baseline transferrin saturation is 15% and iron administration is needed to raise the target transferrin saturation to 75%, a 60% increase in TSAT is desired. A 60% increase in total iron binding capacity of 20 mg equals 20 x 0.6 mg or 12 mg iron. Therefore, the patient would need 12 mg iron, as the said iron compound, to raise his transferrin saturation from 15% to 75% over a short period of time.
  • the maintenance rate for iron infusion is a function of the rate of tissue iron uptake.
  • the rate of iron uptake by the tissues may be measured according to the procedure set forth in Example 6, wherein ferric pyrophosphate was infused in a patient with kidney failure receiving hemodialysis via the dialysate. Blood samples are taken before starting dialysis, at the end of dialysis and for an hour after dialysis had been completed. The decline in the serum iron concentration and transferrin saturation (TSAT) is determined at these time points. Based on the patients estimated plasma volume, plasma iron binding capacity, and the measured decline in transferrin saturation over one hour, the amount of iron (delivered as ferric pyrophosphate) taken up by the target tissues per hour is determined.
  • the rate of exit of the monomeric iron compound from circulation and therefore the rate at which the compound should be infused to maintain the desired transferrin saturation, can be estimated by measuring the rate of decline of serum iron levels after an infusion of the iron compound.
  • a hypothetical patient has a measured transferrin saturation of 75% after infusion of 12 mg iron and the transferrin saturation declines to 50%, 1 hour after the infusion.
  • a 25% decline in TSAT when the total iron binding capacity of the patient is 20 mg, suggests a tissue-uptake of 5 mg iron over an hour. Therefore infusion of 5 mg iron (or about 50 mg ferric pyrophosphate) to such a patient would be expected to maintain TSAT at the desired sub-maximal level.
  • monomeric iron may be delivered subcutaneously, such as by a continuous release implant formulation containing the monomeric iron compound.
  • a polymeric depot containing the iron compound utilizes two mechanisms for the release of iron. The first involves leaching of iron compound at or near the surface, essentially a diffusion/dissolution controlled event. The second involves bio-degradation of the polymer as it comes in contact with body fluids and release of iron compound from the interior of the depot.
  • the depot formulation is selected to provide a consistent, gradual release profile. Slow release of iron from the depot will obviate the need for regular administration of oral iron in an iron deficient patient, and compliance with iron supplementation will be improved.
  • monomeric iron may be delivered transdermally.
  • An appropriate monomeric iron-containing formulation may be applied to the skin of the patient as a paste, with or without an occlusive dressing.
  • the iron compound may be contained in an appropriate transdermal device or "patch". Iron is absorbed through the skin over prolonged periods of time, thereby obviating the need for oral iron.
  • Lipophilic substances have a tendency to sorb into the dense horny layer of the epidermis, that may provide a reservoir for slow release of medication.
  • the horny layer is a considerable obstacle that even lipophilic substances can only penetrate slowly. Consequently the release of the drug such as an iron compound into the circulation is inhibited.
  • the serum level of iron will be flat and low, or plateau-like, in contrast to the development of high serum levels, after an intravenous or oral bolus.
  • the dense horny layer with its reservoir capacity, therefore provides for a steady-state release of iron which avoids "roller coaster" drug delivery and its effects.
  • the penetration rate, or flux, of the various candidate iron compounds can be tested by application of equivalent amounts of iron and measuring the serum iron levels.
  • anti-oxidants are administered as an adjunct to iron administration, in orderto reduce oxidant stress and/or endothelial dysfunction.
  • the toxicity of simple iron salts or the polymeric iron complexes is secondary to liberation of free iron due to chemical interactions in plasma or infusion of free iron that is present in such preparations.
  • Bleomycin- detectable free iron can be found in serum after the parenteral administration of colloidal iron (Banyai et al., 1998).
  • the pathophysiologic effects are different depending on the molecular species of free iron, Fe(ll) or Fe(lll).
  • Fe(ll) is the most reactive form leading to the production of highly reactive hydroxyl radicals by the Fenton reaction, or alkoxyl and peroxyl radicals from the breakdown of lipid peroxides (reviewed by Gutteridge and Halliwell, 1990). That redox active iron is released by colloidal iron compounds in the circulation is further evidenced by the rise in plasma total peroxide and malondialdehyde concentrations within ten minutes following infusion of colloidal iron (Roob et al., 1998). In the anesthetized cat Fe(ll) produces a hypotensive response which may be attributable to the oxidant stress.
  • the free radical generation and lipid peroxidation catalyzed by free iron may also play a role in the pathogenesis of a variety of chronic diseases such as inflammation, ischemia, atherosclerosis, cancer, heart disease, and stroke.
  • Fe(lll) produces a smaller transient depressor response followed by a more sustained pressor response (Cox et al., 1965; Goldberg, 1958). The pressor response suggests that Fe(lll) may induce endothelial dysfunction and interfere with the nitric oxide pathway.
  • patients receiving monomeric iron compound may also receive one or more antioxidants to mitigate endothelial dysfunction and oxidant stress.
  • patients receive vitamin C, 1000 mg (range: 100 - 1 ,500 mg) and vitamin E, 800 IU (range: 100 to 1500 IU), prior to, at the time of, or immediately after the administration of iron.
  • Other antioxidants may be substituted.
  • the antioxidants(s) are preferably administered at the same time as the iron compound.
  • a pharmaceutical composition that combines a therapeutic dose of iron (not daily recommended allowance as dietary supplement) with antioxidants is comprised of about 25 to 1500 mg of iron, in the form of a monomeric or polymeric iron complex, chelate or compound, about 100 to 10,000 units of vitamin E, and about 50 to 10,000 mg of vitamin C, or any other suitable antioxidants.
  • This pharmaceutical composition may be suitable for oral or p ⁇ rsnteral use based on the vehicles or solvents used, liquid or solid phase and sterility of the dosage form.
  • FePyP Ferric pyrophosphate
  • M.W. 745.2, CAS 10058-44-3 Ferric pyrophosphate
  • FePyP is a greenish yellow, crystalline compound that is known to have a solubility of 50 mg per ml in warm water (Catalog no. P 626; Sigma Chemical Co., St. Louis, Missouri). Initially, a small amount of FePyP crystals were added to the acid (pH, 2.49) and basic (pH, 7.81) concentrates and a bicarbonate dialysate (pH, 7.15). FePyP dissolved readily in the bicarbonate dialysate and the bicarbonate concentrate, forming a yellow-orange solution.
  • Plasma was obtained from a uremic patient undergoing plasma exchange therapy for Goodpastures syndrome. Citrated plasma was stored at-20°C in plastic bags. In three separate experiments, plasma was dialyzed against dialysates with different concentration of Fe, prepared by adding variable amounts of FePyP to the bicarbonate concentrate. Dialyzers with a polysulfone membrane (Fresenius, USA) were used. When the volume of plasma being dialyzed was less than 1000 ml, a small dialyzer (F-4, Fresenius) with small blood volume (65 ml) and surface area (0.8 sq. meter) was used at a plasma flow rate of 100 ml/min.
  • F-4 Fresenius
  • a F-80 dialyzer with a priming volume of 120 ml and a surface area of 1.8 sq. meter was used at a plasma flow rate of 300 ml/min. Heparin (500 units per hour) was infused to prevent clotting in the circuit. Serum was drawn at regular intervals during the experiment and serum iron (Fe), total iron binding capacity (TIBC) and transferrin saturation (Fe/TIBC x 100) were measured by a calorimetric assay. The obligate ultrafiltration of fluid during hemodialysis was compensated by an infusion of 0.9% saline. The iron parameters were corrected for net ultrafiltration by expressing the results as transferrin saturation.
  • the hourly increase in plasma iron concentration was 23, 23, 35 and 45 ⁇ g/dl, and the net increase in iron concentration was 140 ⁇ g/dl over the course of the experiment. Therefore, 5 mg iron (or -50 mg FePyP) was infused into 3.5 liters of plasma, using a dialysate with 5 ⁇ g iron per dl.
  • ferric pyrophosphate can be added to the bicarbonate concentrate, to attain iron concentrations of 2-70 ⁇ g/dl in the final dialysate to meet various levels of Fe deficiency in patients. Hemodialysis with iron containing dialysate does result in transfer of iron to the blood compartment. In these in vitro experiments, maximum iron transfer cannot be obtained since transferrin is confined to a closed system.
  • dialysate iron To determine a safe and effective dose of dialysate iron, a cohort of chronic hemodialysis patients were dialyzed with ferric pyrophosphate containing dialysate, while contemporaneous controls received regular doses of intravenous iron, in an open label, phase l/ll clinical trial. All subjects in the study were receiving maintenance hemodialysis for end stage kidney failure, and requiring erythropoietin and intravenous iron to maintain hemoglobin in the 10-12 gm/dl range. After obtaining an informed consent, patients were enrolled and oral iron was discontinued. All patients received maintenance intravenous iron (50-100 mg every 1 -2 weeks) during a 4 week long pre-treatment phase.
  • the doses of intravenous iron dextran were adjusted based on the serum ferritin and transferrin saturation. Throughout the study, all patients were eligible to receive variable maintenance doses (0, 25, 50 or 100 mg) of supplemental IV iron dextran (INFeD ® , Schein Pharmaceuticals Inc., NJ) once a week during hemodialysis in order to maintain predialysis TSAT > 20% and ferritin > 100 ⁇ g/L.
  • variable maintenance doses (0, 25, 50 or 100 mg) of supplemental IV iron dextran (INFeD ® , Schein Pharmaceuticals Inc., NJ) once a week during hemodialysis in order to maintain predialysis TSAT > 20% and ferritin > 100 ⁇ g/L.
  • NKF-DOQI National Kidney Foundation-Dialysis Outcomes Quality Initiative
  • NKF-DOQI guidelines do not recommend continuation of oral iron supplements in chronic hemodialysis patients on maintenance intravenous iron. This was the basis why the control group was maintained on regular doses of intravenous iron, while oral iron was discontinued. This being the standard of care, the subjects on maintenance intravenous iron (IV-Fe Group) served as the control against the experimental group receiving dialysate iron therapy (Dialysate-Fe Group).
  • the study population was randomly selected from all patients undergoing maintenance hemodialysis at Clara Ford Dialysis unit. Patients who met the inclusion and exclusion criteria, as described below, were eligible for entry into the pre-treatment phase of the study only after the nature and purpose of the protocol had been explained to them and after they had voluntarily granted written informed consent to participate.
  • a random number generator was used to generate a list of 24 numbers. Odd and even numbers were assigned A or B designation respectively.
  • a list of 23 patients was created based on the order in which consent was obtained for participation in the study. Patients were assigned to groups A or B based on their order in the list. Twenty-two patients entered the Treatment Phase. One patient in the dialysate iron group elected to withdraw from the study due to lack of interest on the first day of the treatment phase. The remaining twenty-one patients completed the study.
  • Ferric pyrophosphate complexed with sodium citrate is soluble in aqueous solutions (ferric pyrophosphate soluble, Mallinckrodt Inc., St. Louis, Missouri). Soluble ferric pyrophosphate was dissolved in purified water and this solution was added to a freshly prepared bicarbonate concentrate solution. Dialysate solutions containing the desired concentration of soluble ferric pyrophosphate were generated by the addition of an appropriately higher concentration of the compound to the bicarbonate concentrate. A stable and clear dialysate solution containing up to 71 ⁇ g/dl iron as ferric pyrophosphate could be generated using this method. Bicarbonate concentrate solutions were used within 24 hours of preparation to avoid bacterial growth.
  • Iron parameters for detection of iron deficiency or toxicity
  • Liver function tests to detect hepatotoxicity
  • Nutritional parameters such as weight, albumin, cholesterol and triglycerides were measured to detect malnutrition.
  • Serum electrolytes • Serum calcium and inorganic phosphorus: to detect any potential hypocalcemia or hyperphosphaemia secondary to ferric pyrophosphate administration.
  • TSAT transferrin saturation
  • Retic Hgb reticulocyte hemoglobin
  • serum ferritin a measure of the tissue stores
  • the baseline period, labeled month 0 included data for the four weeks immediately prior to the start of the intervention. (There was some data available for some or all the fifth week prior to the intervention, but data from this week is omitted from the formal data analysis.)
  • Weeks 1 to 4 when the dialysate dose of 2 ⁇ g/dl was employed, are labeled month "1", weeks 5 to 8 labeled month "2", weeks 9 to 12 labeled month "3", weeks 13 to 16 labeled month "4", weeks 17 to 20 labeled month "5", and weeks 21 to 26 (or 27) are labeled month "6".
  • Treatment doses, serum ferritin and transferrin saturation were plotted over time for each patient in each group. The proportion of patients who achieved optimal iron status in each group were computed as well as the average time required for this. Average serum ferritin and transferrin saturation levels were computed for each group at each time point.
  • Retic-Hgb reticulocyte hemoglobin
  • the average weekly dose of intravenous iron was 59.6 mg in the IV-Fe group and 68.7 mg in the Dialysate-Fe group ( Figure 15).
  • the requirement for intravenous iron was significantly reduced with dialysate iron (p ⁇ 0.002 with 8-12 ⁇ g/dl dialysate iron).
  • the average weekly doses of intravenous iron were adjusted for baseline levels.
  • the average weekly dose of intravenous iron significantly declined from an average of 68.7 mg in month 0 to 8.9 mg in month 6 (p ⁇ 0.002).
  • the average weekly dose of intravenous iron in IV-Fe group did not change significantly from 68.7 mg in the baseline period to 56.2 mg in the 6th month (p>0.7).
  • month 6 only 2 out of the 10 patients receiving dialysate iron required additional intravenous iron supplements.
  • the baseline total iron binding capacity (TIBC, mean ⁇ S.D.) was 222.3 ⁇ 43.8 ⁇ g/dl in Dialysate-Fe group and 192.7 ⁇ 48.1 ⁇ g/dl in IV-Fe group, and the difference between the two groups was not significant (p>0.14) ( Figure 8).
  • Circulating transferrin increases in the presence of iron deficiency. However, based on reticulocyte hemoglobin and serum iron parameters, there was no difference in the iron status between the two groups. Transferrin can be suppressed in patients with reticuloendothelial block and anemic of chronic disease.
  • Serum ferritin is a marker for the tissue stores of iron. To ensure adequate supply of iron to the bone marrow, the recommended target range for serum ferritin in the dialysis patients receiving erythropoietin therapy is 100 - 500 ⁇ g/L.
  • the baseline serum ferritin was 154 ⁇ 120 ⁇ g/L in Dialysate-Fe group and 261 ⁇ 211 ⁇ g/L in the IV-Fe group (mean ⁇ S.D.), and the difference between the two groups was not statistically significant (Figure 13). There was no significant change in serum ferritin, in either group, during the course of the study.
  • the serum ferritin level in month 6 was 154 ⁇ 120 ⁇ g/L in Dialysate-Fe group and 261 ⁇ 211 ⁇ g/L in the IV-Fe group (mean ⁇ S.D.), and the difference between the 2 groups was not statistically significant (Figure 13).
  • dialysate iron did not have any significant effect on serum calcium or phosphate concentrations.
  • dialysate iron therapy is:
  • the requirements for intravenous iron may be reduced by about 80%;
  • PD patients are less prone to iron deficiency than hemodialysis patients.
  • PD patients lose blood through the gastrointestinal tract and from phlebotomy for laboratory tests.
  • iron utilization is increased in dialysis patients treated with erythropoietin. Consequently, iron deficiency is common in PD patients.
  • Iron supplementation in PD patients is commonly accomplished by the oral route, since intravenous access is not as readily available in PD patients.
  • peripheral intravenous access may be impossible to obtain in some patients when the veins have been thrombosed by venesection or cannulation. In this situation, intravenous iron infusion would necessitate cannulation of a central vein.
  • the dialysate was prepared by adding a sterile filtered ferric pyrophosphate solution to a 2 liter bag of peritoneal dialysis solution (4.25% Dianeal ® ).
  • the iron concentration in the final dialysate was 500 ⁇ g/dl.
  • Rabbits were sedated using a subcutaneous injection of 2 mg/kg acepromazine and 0.2 mg/kg butorphanol, and restrained on a board in a supine position. Blood was drawn for hemoglobin and iron studies. The skin over the abdominal wall was shaved, disinfected with betadine and anesthetized by instillation of 1% lidocaine. An I8g angiocath was advanced into the peritoneal cavity for infusion of dialysis solution. After 210 ml dialysate had been infused from a 2 liter bag, infusion was stopped, the angiocath was removed and the rabbit was returned to its cage. Blood samples were drawn for iron studies, 30 and 120 minutes after starting dialysis.
  • the rabbit was sedated as described previously and restrained in a prone upright position.
  • An 18g angiocath was reinserted into the peritoneal cavity and the dialysate was drained by gravity. After the dialysate had stopped draining, the angiocath was removed and the rabbit was returned to its cage.
  • Serum iron level was estimated by a calorimetric method, after separating iron from transferrin and then converting it into divalent iron.
  • the total iron binding capacity (TIBC) was measured using the modified method of Goodwin. The serum iron levels and transferrin saturation were compared at TIBC.
  • Iron deficient rabbits were dialyzed with a dialysis solution containing ferric pyrophosphate. Peritoneal exchanges were performed on study days
  • ferric pyrophosphate does not have any acute toxic effects on the peritoneal membrane.
  • Dialysis involves diffuse transport of molecules across a semipermeable membrane. For a molecule that is present on both sides of the membrane, there is transport in both directions but the net transport occurs along the concentration gradient. Free plasma iron is highly toxic and therefore, almost all circulating iron is bound to proteins and plasma concentration of free iron is negligible. Consequently, during dialysis there is no transfer of iron from the blood to the dialysate compartment. In fact, when ferric pyrophosphate is added to the dialysate, there is a one way transfer of iron to the blood compartment during dialysis. This resembles parenteral delivery by routes such as intravenous, intramuscular, subcutaneous, or transdermal. Therefore it is possible to administer ferric pyrophosphate, and other iron compounds, parenterally by these routes, both in dialysis and non-dialysis patients.
  • the average increment in serum iron concentration during a 3-4 hour dialysis session was about 140 ⁇ g/dl. Assuming a plasma volume of 3.5 liters, it can be estimated that the increment in circulating iron bound to transferrin was about 5.25 mg per dialysis session.
  • the extravascular space contains about as much transferrin as the intravascular space, and there is a free exchange of iron in between the two pools of transferrin. Therefore, it can be estimated that a total of about 10.5 mg iron (or about 105 mg ferric pyrophosphate) was transferred to the patient during a dialysis session.
  • ferric pyrophosphate and other suitable iron compounds, may be delivered by the dialysate route in hemodialysis
  • Example 4 peritoneal route in peritoneal dialysis patients (Example 3), or intravenous/subcutaneous/intramuscular/transdermal routes in dialysis or non-dialysis patients (Example 4).
  • the following example illustrates a method for measuring the rate of iron uptake by the tissues when an iron compound is infused.
  • Ferric pyrophosphate was infused in a patient with kidney failure receiving hemodialysis via the dialysate, at a dialysate iron concentration of 12 mcg/dl.
  • Blood samples were taken before starting dialysis, at the end of dialysis and for an hour after dialysis had been completed.
  • TSAT transferrin saturation
  • suitable maintenance infusion rate for the patient would be 3-5 mg of iron, or 30-50 mg of ferric pyrophosphate, per hour.
  • Dialysate iron therapy Infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int, 55, 891- 898.
  • Schaeffer R Schaefer L. The hypochromic red cell: A new parameter for monitoring or iron supplementation during r-hu Erythropoietin therapy. J Perinat Med 1995;23:83-88.
  • Schaeffer R Schaefer L. Management of iron substitution therapy during rHuErytbropoietin therapy in chronic renal failure patients. Erythropoiesis 1992;3:71-75.
  • Van Wyck DB Stivelman J, Ruiz J, Kirlin L, Katz M, Ogden D. Iron status in patients receiving erythropoietin for dialysis-associated anemia. Kidney /nM 989;3:712-716. Weinberg E. Iron withholding: a defense against infection and neoplasia. Physiol Rev 1984;64:65-102.

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Abstract

L'invention concerne des méthodes et des compositions pour l'administration parentérale de fer, y compris l'administration par des solutions d'hémodialyse ou de dialyse péritonéale pendant le processus de dialyse. Le fer se présente sous forme d'un composé de fer monomère non colloïdal adapté pour l'administration parentérale.
PCT/US2000/017311 1999-06-30 2000-06-23 Methode et composition pharmaceutique pour l'administration parenterale de fer Ceased WO2001000204A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1790356A1 (fr) * 2005-11-24 2007-05-30 Vifor (International) Ag Préparation contenant des complexes de fer(III) et des composés rédoxs
EP2016940A1 (fr) * 2007-07-20 2009-01-21 Rockwell Medical Technologies Inc. A Corporation of the state of Michigan Procédés de préparation et utilisation de compositions chélatées de citrate et pyrophosphate ferrique
WO2009062203A1 (fr) * 2007-11-09 2009-05-14 Biolink Life Sciences, Inc. Complément nutritionnel à base de fer
US20100272827A1 (en) * 2009-04-25 2010-10-28 Mir Imran Method for transdermal iontophoretic delivery of chelated agents
US8864699B2 (en) 1999-09-22 2014-10-21 Advanced Renal Technologies High citrate dialysate and uses thereof
US9161951B2 (en) 2005-12-23 2015-10-20 Ajay Gupta Parenteral nutrition composition containing iron
US9161980B2 (en) 2004-03-01 2015-10-20 Gambro Lundia Ab Medical solution, a method for producing said medical solution and use thereof
US9216247B2 (en) 1998-10-20 2015-12-22 Advanced Renal Technologies Buffered compositions for dialysis
EP2123270B2 (fr) † 2006-12-12 2016-06-15 Advanced Renal Technologies, Inc. Agent améliorant le métabolisme du fer
US9913806B2 (en) 2008-06-25 2018-03-13 Fe3 Medical, Inc. Patches and methods for the transdermal delivery of a therapeutically effective amount of iron
US10729721B2 (en) 2004-10-14 2020-08-04 Gambro Lundia Ab Dialysis solution, formulated and stored in two parts, comprising phosphate
EP4221723A4 (fr) * 2020-09-29 2024-11-06 LG Bionano, LLC Procédés de préparation de complexes à base de fer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5108767A (en) * 1991-06-10 1992-04-28 Abbott Laboratories Liquid nutritional product for persons receiving renal dialysis
US5906978A (en) * 1996-08-14 1999-05-25 Hemocleanse, Inc. Method for iron delivery to a patient by transfer from dialysate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5108767A (en) * 1991-06-10 1992-04-28 Abbott Laboratories Liquid nutritional product for persons receiving renal dialysis
US5906978A (en) * 1996-08-14 1999-05-25 Hemocleanse, Inc. Method for iron delivery to a patient by transfer from dialysate

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9216247B2 (en) 1998-10-20 2015-12-22 Advanced Renal Technologies Buffered compositions for dialysis
US8864699B2 (en) 1999-09-22 2014-10-21 Advanced Renal Technologies High citrate dialysate and uses thereof
US9161980B2 (en) 2004-03-01 2015-10-20 Gambro Lundia Ab Medical solution, a method for producing said medical solution and use thereof
US11285173B2 (en) 2004-10-14 2022-03-29 Gambro Lundia Ab Dialysis solution, formulated and stored in two parts, comprising phosphate
US10729722B2 (en) 2004-10-14 2020-08-04 Gambro Lundia Ab Dialysis solution, formulated and stored in two parts, comprising phosphate
US10729721B2 (en) 2004-10-14 2020-08-04 Gambro Lundia Ab Dialysis solution, formulated and stored in two parts, comprising phosphate
WO2007060038A3 (fr) * 2005-11-24 2008-05-08 Vifor Int Ag Preparation comprenant des composes complexes de fer (iii) et une ou plusieurs substances a activite redox
RU2394597C2 (ru) * 2005-11-24 2010-07-20 Вифор (Интернациональ) Аг Препарат, содержащий комплексные соединения железа (iii) и активное окислительно-восстановительное вещество
EP1790356A1 (fr) * 2005-11-24 2007-05-30 Vifor (International) Ag Préparation contenant des complexes de fer(III) et des composés rédoxs
US9161951B2 (en) 2005-12-23 2015-10-20 Ajay Gupta Parenteral nutrition composition containing iron
EP2123270B2 (fr) † 2006-12-12 2016-06-15 Advanced Renal Technologies, Inc. Agent améliorant le métabolisme du fer
US7816404B2 (en) 2007-07-20 2010-10-19 Rockwell Medical Technologies, Inc. Methods for the preparation and use of ferric pyrophosphate citrate chelate compositions
EP2016940A1 (fr) * 2007-07-20 2009-01-21 Rockwell Medical Technologies Inc. A Corporation of the state of Michigan Procédés de préparation et utilisation de compositions chélatées de citrate et pyrophosphate ferrique
WO2009062203A1 (fr) * 2007-11-09 2009-05-14 Biolink Life Sciences, Inc. Complément nutritionnel à base de fer
US9913806B2 (en) 2008-06-25 2018-03-13 Fe3 Medical, Inc. Patches and methods for the transdermal delivery of a therapeutically effective amount of iron
US10463629B2 (en) 2008-06-25 2019-11-05 Fe3 Medical, Inc. Patches and methods for the transdermal delivery of a therapeutically effective amount of iron
US8821945B2 (en) * 2009-04-25 2014-09-02 Fe3 Medical, Inc. Method for transdermal iontophoretic delivery of chelated agents
US9402904B2 (en) 2009-04-25 2016-08-02 Fe3 Medical, Inc. Method for transdermal iontophoretic delivery of chelated agents
US20100272827A1 (en) * 2009-04-25 2010-10-28 Mir Imran Method for transdermal iontophoretic delivery of chelated agents
EP4221723A4 (fr) * 2020-09-29 2024-11-06 LG Bionano, LLC Procédés de préparation de complexes à base de fer

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