US007754702B2
`
`(12) United States Patent
`Helenek et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,754,702 B2
`Jul. 13, 2010
`
`(54) METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF IRON
`
`(75) Inventors: Mary Jane Helenek, Brookville, NY
`(US); Marc L. Tokars, Douglassville,
`PA (US); Richard P. Lawrence,
`Calverton, NY (US)
`
`(73) Assignee: Luitpold Pharmaceuticals, Inc.,
`Shirley, NY (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 403 days.
`
`(21) Appl.N0.: 11/620,986
`
`(22) Filed:
`
`Jan. 8, 2007
`
`(65)
`
`Prior Publication Data
`
`US 2007/0161600 A1
`
`Jul. 12,2007
`
`Related US. Application Data
`
`(60) Provisional application No. 60/757,119, ?led on Jan.
`6, 2006.
`
`(51) Int. Cl.
`(2006.01)
`A61K 31/715
`(2006.01)
`A61K 31/716
`(52) US. Cl. .................... .. 514/54; 556/146; 536/123.1;
`536/123.12; 536/123.13
`(58) Field of Classi?cation Search ................. .. 514/53,
`514/54; 556/146
`See application ?le for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,624,668 A *
`6,599,498 B1
`6,960,571 B2
`2004/0180849 A1*
`
`4/1997
`7/2003
`11/2005
`9/2004
`
`Lawrence et al. ...... .. 424/7817
`Groman et al.
`Helenek et al.
`
`Helenek et al. ............. .. 514/53
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`WO
`
`9711711
`2004037865
`2007023154
`
`4/1997
`5/2004
`3/2007
`
`OTHER PUBLICATIONS
`
`So?c et al. J. Neural Transm, 1988, 74, p. 199-205.*
`Sipe et al. Brain Iron Metabolism and Neurodegenerative Disorders,
`2002, 24(2-3), p. 188-196.*
`Cisar et al. Journal of Experimental Medicine, 1975, 142, p. 435
`459*
`Macdougall. Nephrol. Dial. Transplant, 2000, 15, p. 1743-1745.*
`Andersson, NSE. British Medical Journal, 1961, p. 275-279.*
`Fielding, J. British Medical Journal, 1961, p. 279-283.*
`
`Newnham et al. Internal Medicine Journal, 2006, 36(10), p. 672
`674*
`Haines et al. Internal Medicine Journal, 2009, 39, p. 252-255.*
`Nissenson et al. Kidney International, 2003, 64(Supplement 87), p.
`$64-$71 .*
`Bailie GR, et al., Hypersensitivity reactions and deaths associated
`With intravenous iron preparations, Nephrol. Dial. Transplant, 2005,
`pp. 1443-1449, vol. 20(7).
`Beshara S, et al., Pharmacokinetics and red cell utilization of 52Fe/
`59Fe-labelled iron polymaltose in anaemic patients using positron
`emission tomography, Br. J. Haematol., 2003, pp. 853-859, vol.
`120(5).
`Fishbane S, Safety in iron management, Am. J. Kidney Dis., 2003,
`pp. 19-26, vol. 41(5 Suppl).
`Geisser P, et al ., Structure/histotoxicity relationship of parenteral iron
`preparations, Arzneimittelforschung, 1992, pp. 1439-1452, vol.
`42(12).
`Kudasheva DS, et al., Structure of carbohydrate-bound polynuclear
`iron oxyhydroxide nanoparticles in parenteral formulations, J. Inorg.
`Biochem., 2004, pp. 1757-1769, vol. 98(11).
`Landry R, et al., Pharmacokinetic study of ferumoxytol: a new iron
`replacement therapy in normal subjects and hemodialysis patients,
`Am. J. Nephrol., 2005, pp. 400-410, vol. 25(4).
`NKF-IQDOQI Clinical Practice Guidelines for Anemia of Chronic
`Kidney Disease: update 2000, Am. J. Kidney Dis., 2001, pp. S182
`S238, vol. 37(1 Suppl 1).
`SpinoWitZ BS, et al., The safety and ef?cacy of ferumoxytol therapy
`in anemic chronic kidney disease patients, Kidney Int., 2005, pp.
`1801-1807, vol. 68(4).
`Van Wyck DB, et al., Making sense: a scienti?c approach to intrave
`nous iron therapy, J. Am. Soc. Nephrol., 2004, pp. S91-S92, vol. 15
`Suppl 2.
`Van Wyck DB, Labile iron: manifestations and clinical implications,
`J. Am. Soc. Nephrol., 2004, pp. S107-S111, vol. 15 Suppl 2.
`European Search Report issued Oct. 21, 2009 in connection With
`related European Application No. 077163095.
`
`* cited by examiner
`
`Primary ExamineriShaojia Anna Jiang
`Assistant ExamineriJonathan S Lau
`(74) Attorney, Agent, or FirmiSonnenschein Nath &
`Rosenthal LLP
`
`(57)
`
`ABSTRACT
`
`The present invention generally relates to treatment of iron
`related conditions With iron carbohydrate complexes. One
`aspect of the invention is a method of treatment of iron-related
`conditions With a single unit dosage of at least about 0.6
`grams of elemental iron via an iron carbohydrate complex.
`The method generally employs iron carbohydrate complexes
`With nearly neutral pH, physiological osmolarity, and stable
`and non-immunogenic carbohydrate components so as to
`rapidly administer high single unit doses of iron intrave
`nously to patients in need thereof.
`
`57 Claims, 2 Drawing Sheets
`
`Pharmacosmos, Exh. 1039, p. 1
`
`

`
`US. Patent
`
`Jul. 13, 2010
`
`Sheet 1 of2
`
`US 7,754,702 B2
`
`FIGURE 1
`
`FIG. 1A
`
`FIG. 15
`
`0.50
`
`0
`
`0.25
`
`0.50
`
`0.75
`
`1.00
`
`Pharmacosmos, Exh. 1039, p. 2
`
`

`
`US. Patent
`
`Jul. 13, 2010
`
`Sheet 2 of2
`
`US 7,754,702 B2
`
`FIGURE 2
`
`glc glucose
`
`---- hydrogen bond
`
`Pharmacosmos, Exh. 1039, p. 3
`
`

`
`US 7,754,702 B2
`
`1
`METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF IRON
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims priority from US. Provisional
`Application Ser. No. 60/757,119 ?led on Jan. 6, 2006, Which
`is incorporated herein by reference in its entirety.
`
`FIELD OF THE INVENTION
`
`The present invention generally relates to treatment of
`iron-related conditions With iron carbohydrate complexes.
`
`BACKGROUND
`
`2
`high molecular mass substances produce more allergic reac
`tions than the corresponding loW molecular mass substances.
`Geisser et al. (1992) Arzneimillelforschung 42: 1439-1452.
`Ferumoxytol is a neWer parenteral iron formulation but
`limited information is available as to its ef?cacy and admin
`istration. See e.g., Landry et al. (2005) Am J Nephrol 25,
`400-410, 408; and SpinoWitZ et al. (2005) Kidney Intl 68,
`1801-1807; US. Pat. No. 6,599,498.
`Various pharmacokinetic studies suggest that doses of iron
`complexes higher than 200 mg of iron are generally unsuit
`able and that the conventional therapy model prescribes
`repeated applications of loWer doses over several days. See
`Geisser et al., (1992) Arzneimillelforschung 42: 1439-1452.
`For example, to achieve iron repletion under current therapy
`models, a total dose of 1 g typically requires 5 to 10 sessions
`over an extended period of time. These delivery modes incur
`signi?cant expense for supplies such as tubing and infusate,
`costly nursing time, multiple administrations, and patient
`inconvenience.
`
`SUMMARY OF THE INVENTION
`
`Among the various aspects of the present invention is the
`provision of a method of treatment of iron-associated dis
`eases, disorders, or conditions With iron formulations.
`Brie?y, therefore, the present invention is directed to use of
`iron carbohydrate complexes that can be administered
`parenterally at relatively high single unit dosages, thereby
`providing a safe and e?icient means for delivery of a total
`dose of iron in feWer sessions over the course of therapeutic
`treatment.
`The present teachings include methods of treating a dis
`ease, disorder, or condition characterized by iron de?ciency
`or dysfunctional iron metabolism through the administration
`of at least 0.6 grams of elemental iron via a single unit dosage
`of an iron carbohydrate complex to a subject that is in need of
`such therapy.
`In various embodiments, the method treats anemia. In
`some embodiments, the anemia is an iron de?ciency anemia,
`such as that associated With chronic blood loss; acute blood
`loss; pregnancy; childbirth; childhood development; psycho
`motor and cognitive development in children; breath holding
`spells; heavy uterine bleeding; menstruation; chronic recur
`rent hemoptysis; idiopathic pulmonary siderosis; chronic
`internal bleeding; gastrointestinal bleeding; parasitic infec
`tions; chronic kidney disease; dialysis; surgery or acute
`trauma; and chronic ingestion of alcohol, chronic ingestion of
`salicylates, chronic ingestion of steroids; chronic ingestion of
`non-steroidial anti-in?ammatory agents, or chronic ingestion
`of erythropoiesis stimulating agents. In some aspects, the
`anemia is anemia of chronic disease, such as rheumatoid
`arthritis; cancer; Hodgkins leukemia; non-Hodgkins leuke
`mia; cancer chemotherapy; in?ammatory boWel disease;
`ulcerative colitis thyroiditis; hepatitis; systemic lupus erythe
`matosus; polymyalgia rheumatica; scleroder'ma; mixed con
`nective tissue disease; Soj gren’s syndrome; congestive heart
`failure/cardiomyopathy; or idiopathic geriatric anemia. In
`some embodiments, the anemia is due to impaired iron
`absorption or poor nutrition, such as anemia associated With
`Crohn’s Disease; gastric surgery; ingestion of drug products
`that inhibit iron absorption; and chronic use of calcium. In
`various embodiments, the method treats restless leg syn
`drome; blood donation; Parkinson’s disease; hair loss; or
`attention de?cit disorder.
`In various embodiments, the single dosage unit of elemen
`tal iron is betWeen at least about 0.6 grams and 2.5 grams. In
`some embodiments, the single dosage unit of elemental iron
`
`Parenteral iron therapy is knoWn to be effective in a variety
`of diseases and conditions including, but not limited to,
`severe iron de?ciency, iron de?ciency anemia, problems of
`intestinal iron absorption, intestinal iron intolerance, cases
`Where regular intake of an oral iron preparation is not guar
`anteed, iron de?ciency Where there is no response to oral
`therapy (e.g., dialysis patients), and situations Where iron
`stores are scarcely or not at all formed but Would be important
`for further therapy (e. g., in combination With erythropoietin).
`Geisser et al., ArZneimittelforschung (1992) 42(12), 1439
`1452. There exist various commercially available parenteral
`iron formulations. But many currently available parenteral
`iron drugs, While purportedly effective at repleting iron
`stores, have health risks and dosage limitations associated
`With their use.
`Currently available parenteral iron formulations approved
`for use in the US. include iron dextran (e.g., InF ed, Dexfer
`rum), sodium ferric gluconate complex in sucrose (Ferrlecit),
`and iron sucrose (Venofer). Although serious and life-threat
`ening reactions occur most frequently With iron dextran, they
`are also knoWn to occur With other parenteral iron products. In
`addition, non-life threatening reactions such as arthralgia,
`back pain, hypotension, fever, myalgia, pruritus, vertigo, and
`vomiting also occur. These reactions, While not life-threaten
`ing, often preclude further dosing and therefore iron reple
`tion.
`Iron dextran, the ?rst parenteral iron product available in
`the United States (US), has been associated With an incidence
`of anaphylactoid-type reactions (i.e., dyspnea, Wheezing,
`chest pain, hypotension, urticaria, angioedema). See gener
`ally Fishbane, Am J Kidney Dis (2003) 41 (5Suppl), 18-26;
`Landry et al. (2005) Am J Nephrol 25, 400-410, 407. This
`high incidence of anaphylactoid reactions is believed to be
`caused by the formation of antibodies to the dextran moiety.
`Other parenteral iron products (e.g., iron sucrose and iron
`gluconate) do not contain the dextran moiety, and the inci
`dence of anaphylaxis With these products is markedly loWer.
`Fishbane, Am J Kidney Dis (2003) 41(5Suppl), 18-26; Gei
`sser et al., ArZneimittelforschung (1992) 42(12), 1439-52.
`HoWever, the physical characteristics of, for example, iron
`gluconate and iron sucrose lead to dosage and administration
`rate limitations. Negative characteristics include high pH,
`high osmolarity, loW dosage limits (e.g., maximum 500 mg
`iron once per Week, not exceeding 7 mg iron/ kg body Weight),
`and the long duration of administration (e.g., 100 mg iron
`over at least 5 minutes as an injection; 500 mg iron over at
`least 3.5 hours as a drip infusion). Furthermore, injectable
`
`20
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`25
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`30
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`35
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`40
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`45
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`50
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`60
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`65
`
`Pharmacosmos, Exh. 1039, p. 4
`
`

`
`US 7,754,702 B2
`
`3
`is at least about 0.7 grams; at least about 0.8 grams; at least
`about 0.9 grams; at least about 1.0 grams; at least about 1.1
`grams; at least about 1.2 grams; at least about 1.3 grams; at
`least about 1.4 grams; at least about 1.5 grams; at least about
`1.6 grams; at least about 1.7 grams; at least about 1.8 grams;
`at least about 1.9 grams; at least about 2.0 grams; at least
`about 2.1 grams; at least about 2.2 grams; at least about 2.3
`grams; at least about 2.4 grams; or at least about 2.5 grams.
`In various embodiments, the single dosage unit of elemen
`tal iron is administered in about 15 minutes or less. In some
`embodiments, the single dosage unit of elemental iron is
`administered in about 10 minutes or less, about 5 minutes or
`less, or about 2 minutes or less.
`In various embodiments, the subject does not experience a
`signi?cant adverse reaction to the single dosage unit admin
`istration.
`In various embodiments, the iron carbohydrate complex
`has a pH betWeen about 5.0 to about 7.0; physiological osmo
`larity; an iron core siZe no greater than about 9 nm; a mean
`diameter particle siZe no greater than about 35 nm; a blood
`half-life of betWeen about 10 hours to about 20 hours; a
`substantially non-immunogenic carbohydrate component;
`and substantially no cross reactivity With anti-dextran anti
`bodies.
`In various embodiments, the iron carbohydrate complex
`contains about 24% to about 32% elemental iron; contains
`about 25% to about 50% carbohydrate; has a molecular
`Weight of about 90,000 daltons to about 800,000 daltons, or
`some combination thereof.
`In various embodiments, the iron carbohydrate complex is
`an iron monosaccharide complex, an iron disaccharide com
`plex, or an iron polysaccharide complex. In some embodi
`ments, the iron carbohydrate complex is iron carboxymaltose
`complex, iron mannitol complex, iron polyisomaltose com
`plex, ironpolymaltose complex, iron gluconate complex, iron
`sorbitol complex, or an iron hydrogenated dextran complex.
`In some embodiments, the iron carbohydrate complex is an
`iron polyglucose sorbitol carboxymethyl ether complex. In
`some preferred embodiments, the iron carboxymaltose com
`plex contains about 24% to about 32% elemental iron, about
`25% to about 50% carbohydrate, and is about 100,000 daltons
`to about 350,000 daltons. In some preferred embodiments,
`the iron carboxymaltose complex is obtained from an aque
`ous solution of iron (III) salt and an aqueous solution of the
`oxidation product of one or more maltodextrins using an
`aqueous hypochlorite solution at a pH value Within the alka
`line range, Wherein, When one maltodextrin is applied, its
`dextrose equivalent lies betWeen 5 and 20, and When a mix
`ture of several maltodextrins is applied, the dextrose equiva
`lent lies betWeen 5 and 20 and the dextrose equivalent of each
`individual maltodextrin contained in the mixture lies betWeen
`2 and 20. In some preferred embodiments, the iron carboxy
`maltose complex has a chemical formula of [FeOx(OH)y
`(H2O)Z]n[{(C6H1OO5)m(C6H12O7)}Z]k$ Where n is about 103,
`m is about 8, l is about 11, and k is about 4; contains about
`28% elemental iron; and has a molecular Weight of about
`150,000 Da. In some preferred embodiments, the iron car
`boxymaltose complex is polynuclear iron (III)-hydroxide
`4(R)-(poly-(1Q4)-O-0t-glucopyranosyl)-oxy-2(R),3(S),5
`(R),6-tetrahydroxy-hexanoate.
`In various embodiments, the iron carbohydrate complex
`comprises an iron core With a mean iron core siZe of no
`greater than about 9 nm. In some embodiments, the mean iron
`core siZe is at least about 1 nm but no greater than about 9 nm;
`at least about 3 nm but no greater than about 7 nm; or at least
`about 4 nm but not greater than about 5 nm.
`
`20
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`
`4
`In various embodiments, the mean siZe of a particle of the
`iron carbohydrate complex is no greater than about 35 nm. In
`some embodiments, the particle mean siZe is no greater than
`about 30 nm. In some embodiments, the particle mean siZe is
`no greater than about 25 nm. In some embodiments, the
`particle mean siZe is no greater than about 20 nm; no greater
`than about 15 nm; no greater than about 10 nm; or at least
`about 6 nm but no greater than about 7 nm.
`In various embodiments, the iron carbohydrate complex is
`administered parenterally, for example intravenously or intra
`muscularly. In some embodiments, the iron carbohydrate
`complex is intravenously infused. In certain embodiments,
`the single unit dose of iron carbohydrate complex is intrave
`nously infused at a concentration of about 1000 mg elemental
`iron in about 200 ml to about 300 ml of diluent, for example,
`about 250 ml of diluent or about 215 ml of diluent. In some
`embodiments, the iron carbohydrate complex is intrave
`nously injected as a bolus. In certain embodiments, the iron
`carbohydrate complex is intravenously injected as a bolus at
`a concentration of about 1000 mg elemental iron in about 200
`ml to about 300 ml of diluent, for example, about 250 ml of
`diluent or about 215 ml of diluent. In some embodiments, the
`iron carbohydrate complex is intramuscularly infused at a
`concentration of about 1000 mg elemental iron in about 200
`ml to about 300 ml of diluent, for example, about 250 ml of
`diluent or about 215 ml of diluent. In some embodiments, the
`iron carbohydrate complex is intramuscularly infused at a
`concentration of about 500 mg elemental iron in less than
`about 10 ml diluent.
`In various embodiments, the method also includes a second
`administration of the iron carbohydrate complex upon recur
`rence of at least one symptom of the treated disease, disorder,
`or condition.
`In various embodiments, the method also includes a second
`administration of the iron carbohydrate complex after 1 day to
`12 months after the ?rst administration.
`In a preferred embodiment, the method of treating a dis
`ease, disorder, or condition characterized by iron de?ciency
`or dysfunctional iron metabolism comprises intravenously
`administering to a subject in need thereof an iron carboxy
`maltose complex in a single dosage unit of at least about 1000
`mg of elemental iron in about 200 ml to about 300 ml of
`diluent in about 5 minutes or less; Wherein the iron carboxy
`maltose complex comprises an iron core With a mean iron
`core siZe of at least about 1 nm but no greater than about 9 nm;
`mean siZe of a particle of the iron carboxymaltose complex is
`no greater than about 35 nm; and the iron carboxymaltose
`complex is administered intravenously infused or intrave
`nously injected at a concentration of about 1000 mg elemen
`tal iron in about 200 ml to about 300 ml of diluent. In some
`these embodiments, the iron carboxymaltose complex is
`polynuclear iron (III)-hydroxide 4(R)-(poly-(1—>4)-O-0t
`glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hex
`anoate. In some these embodiments, the iron carboxymaltose
`complex is obtained from an aqueous solution of iron (III) salt
`and an aqueous solution of the oxidation product of one or
`more maltodextrins using an aqueous hypochlorite solution at
`a pH value Within the alkaline range, Wherein, When one
`maltodextrin is applied, its dextrose equivalent lies betWeen
`about 5 and about 20, and When a mixture of several malto
`dextrins is applied, the dextrose equivalent lies betWeen about
`5 and about 20 and the dextrose equivalent of each individual
`maltodextrin contained in the mixture lies betWeen about 2
`and about 20.
`
`Pharmacosmos, Exh. 1039, p. 5
`
`

`
`US 7,754,702 B2
`
`5
`Other objects and features Will be in part apparent and in
`part pointed out hereinafter.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Those of skill in the art Will understand that the drawings,
`described below, are for illustrative purposes only. The draW
`ings are not intended to limit the scope of the present teach
`ings in any Way.
`FIG. 1 is a series of electron micrographs that depict the
`particle siZe of three iron carbohydrate complexes. FIG. 1A is
`an electron micrograph depicting the particle siZe of Dexfer
`rum (an iron dextran). FIG. 1B is an electron micrograph
`depicting the particle siZe of Venofer (an iron sucrose). FIG.
`1C is an electron micrograph depicting the particle siZe of
`polynuclear iron (III)-hydroxide 4(R)-(poly-(lQ4)-O-0t
`glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hex
`anoate (“VIT-45”, an iron carboxymaltose complex).
`FIG. 2 is a schematic representation of an exemplary iron
`carboxymaltose complex.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The present invention makes use of iron carbohydrate com
`plexes that can be administered parenterally at relatively high
`single unit dosages for the therapeutic treatment of a variety
`of iron-associated diseases, disorders, or conditions. Gener
`ally, states indicative of a need for therapy With high single
`unit dosages of iron carbohydrate complexes include, but are
`not limited to iron de?ciency anemia, anemia of chronic
`disease, and states characterized by dysfunctional iron
`metabolism. Ef?cacious treatment of these, and other, dis
`eases and conditions With parenteral iron formulations (sup
`plied at loWer single unit do sages than those described herein)
`is generally knoWn in the art. See e. g., Van Wyck et al. (2004)
`J Am Soc Nephrol 15, S9l-S92. The present invention is
`directed to use of iron carbohydrate complexes that can be
`administered parenterally at relatively high single unit dos
`ages, thereby providing a safe and e?icient means for delivery
`of a total dose of iron in feWer sessions over the course of
`therapeutic treatment.
`Iron de?ciency anemia is associated With, for example,
`chronic blood loss; acute blood loss; pregnancy; childbirth;
`childhood development; psychomotor and cognitive develop
`ment in children; breath holding spells; heavy uterine bleed
`ing; menstruation; chronic recurrent hemoptysis; idiopathic
`pulmonary siderosis; chronic internal bleeding; gastrointes
`tinal bleeding; parasitic infections; chronic kidney disease;
`dialysis; surgery or acute trauma; and chronic ingestion of
`alcohol, chronic ingestion of salicylates, chronic ingestion of
`steroids; chronic ingestion of non-steroidial anti-in?amma
`tory agents, or chronic ingestion of erythropoiesis stimulating
`agents.
`Anemia of chronic disease is associated With, for example,
`rheumatoid arthritis; cancer; Hodgkins leukemia; non
`Hodgkins leukemia; cancer chemotherapy; in?ammatory
`boWel disease; ulcerative colitis thyroiditis; hepatitis; sys
`temic lupus erythematosus; polymyalgia rheumatica; sclero
`derma; mixed connective tissue disease; Sojgren’ s syndrome;
`congestive heart failure/cardiomyopathy; and idiopathic geri
`atric anemia.
`Anemia is also associated With, for example, Crohn’s Dis
`ease; gastric surgery; ingestion of drug products that inhibit
`iron absorption; and chronic use of calcium.
`States characterized by dysfunctional iron metabolism and
`treatable With the single unit dosages of iron carbohydrate
`complexes described herein include, but are not limited to,
`
`20
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`50
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`65
`
`6
`restless leg syndrome; blood donation; Parkinson’s disease;
`hair loss; and attention de?cit disorder.
`Again, each of the above listed states, diseases, disorders,
`and conditions, as Well as others, can bene?t from the treat
`ment methodologies described herein. Generally, treating a
`state, disease, disorder, or condition includes preventing or
`delaying the appearance of clinical symptoms in a mammal
`that may be afflicted With or predisposed to the state, disease,
`disorder, or condition but does not yet experience or display
`clinical or subclinical symptoms thereof. Treating can also
`include inhibiting the state, disease, disorder, or condition,
`e.g., arresting or reducing the development of the disease or at
`least one clinical or subclinical symptom thereof. Further
`more, treating can include relieving the disease, e. g., causing
`regression of the state, disease, disorder, or condition or at
`least one of its clinical or subclinical symptoms.
`The bene?t to a subject to be treated is either statistically
`signi?cant or at least perceptible to the patient or to the
`physician. Measures of e?icacy of iron replacement therapy
`are generally based on measurement of iron-related param
`eters in blood. The aim of treatment is usually to return both
`Hb and iron stores to normal levels. Thus, e?icacy of iron
`replacement therapy can be interpreted in terms of the ability
`to normalise Hb levels and iron stores. The effectiveness of
`treatment With one or more single unit doses of iron carbo
`hydrate complex, as described herein, can be demonstrated,
`for example, by improvements in ferritin and transferrin satu
`ration, and in raising hemoglobin levels in anemic patients.
`Iron stores can be assessed by interpreting serum ferritin
`levels. TfS is frequently used, in addition, to diagnose abso
`lute or functional iron de?ciencies. In patients With iron de?
`ciency, serum transferrin is elevated and Will decrease follow
`ing successful iron treatment.
`Admimstration
`Methods of treatment of various diseases, disorders, or
`conditions With iron complex compositions comprise the
`administration of the complex in single unit dosages of at
`least 0.6 grams of elemental iron to about at least 2.5 grams of
`elemental iron. Administration of single unit dosages can be,
`for example, over pre-determined time intervals or in
`response to the appearance and/or reappearance of symp
`toms. For example, the iron carbohydrate complex can be
`re-administered upon recurrence of at least one symptom of
`the disease or disorder. As another example, the iron carbo
`hydrate complex can be re-administered at some time period
`after the initial administration (e.g., after 4 days to 12
`months).
`Any route of delivery of the single unit dose of iron carbo
`hydrate complex is acceptable so long as iron from the iron
`complex is released such that symptoms are treated. The
`single unit dose of iron carbohydrate complex can be admin
`istered parenterally, for example intravenously or intramus
`cularly. Intravenous administration can be delivered as a
`bolus or preferably as an infusion. For example, the single
`unit dose of iron carbohydrate complex can be intravenously
`infused at a concentration of about 1000 mg elemental iron in
`about 200 ml to about 300 ml of diluent, preferably about 215
`ml of diluent or about 250 ml of diluent. The iron carbohy
`drate complex can be intravenously injected as a bolus. For
`example, the iron carbohydrate complex can be intravenously
`injected as a bolus at a concentration of about 1000 mg
`elemental iron in about 200 ml to about 300 ml of diluent,
`preferably about 215 ml of diluent or about 250 ml of diluent.
`The iron carbohydrate complex can be intramuscularly
`infused at a concentration of, for example, about 1000 mg
`elemental iron in about 200 ml to about 300 ml of diluent,
`preferably, about 250 ml of diluent or about 215 ml of diluent.
`
`Pharmacosmos, Exh. 1039, p. 6
`
`

`
`US 7,754,702 B2
`
`7
`If applied as an infusion, the iron carbohydrate complex can
`be diluted With sterile saline (e.g., polynuclear iron (lll)
`hydroxide 4(R)-(poly-(1Q4)-O-0t-glucopyranosyl)-oxy-2
`(R),3(S),5(R),6-tetrahydroxy-hexanoate (“VlT-45”) 0.9%
`mN NaCl or 500 mg iron in up to 250 mL NaCl). The iron
`carbohydrate complex can be intravenously injected as a
`bolus Without dilution. As an example, the iron carbohydrate
`complex can be intramuscularly injected at a concentration of
`about 500 mg elemental iron in less than about 10 ml diluent,
`preferably about 5 ml.
`Generally, total iron dosage Will depend on the iron de?cit
`of the patient. One skilled in the art can tailor the total iron
`dose required for a subject While avoiding iron overload, as
`overdosing With respect to the total required amount of iron
`has to be avoided, as is the case for all iron preparations.
`The total iron dosage can be delivered as a single unit
`dosage or a series of single unit dosages. An appropriate
`single unit dosage level Will generally be at least 0.6 grams of
`elemental iron, particularly at least 0.7 grams; at least 0.8
`grams; at least 0.9 grams; at least 1.0 grams; at least 1.1
`grams; at least 1.2 grams; at least 1.3 grams; at least 1.4
`grams; at least 1.5 grams; at least 1.6 grams; at least 1.7
`grams; at least 1.8 grams; at least 1.9 grams; at least 2.0
`grams; at least 2.1 grams; at least 2.2 grams; at least 2.3
`grams; at least 2.4 grams; or at least 2.5 grams. For example,
`a single unit dosage is at least 1.0 grams of elemental iron. As
`another example, a single unit dosage is at least 1.5 grams of
`elemental iron. As a further example, a single unit dosage is at
`least 2.0 grams of elemental iron. In yet another example, a
`single unit dosage is at least 2.5 grams of elemental iron.
`An appropriate single unit dosage level can also be deter
`mined on the basis of patient Weight. For example, an appro
`priate single unit dosage level Will generally be at least 9 mg
`of elemental ironper kg body Weight, particularly at least 10.5
`mg/kg, at least 12 mg/kg, at least 13.5 mg/kg, at least 15
`mg/kg, at least 16.5 mg/kg, at least 18 mg/kg, at least 19.5
`mg/kg, at least 21 mg/kg, at least 22.5 mg/kg, at least 24
`mg/kg, at least 25.5 mg/kg, at least 27 mg/kg, at least 28.5
`mg/kg, at least 30 mg/kg, at least 31.5 mg/kg, at least 33
`mg/kg, at least 34.5 mg/kg, at least 36 mg/kg, or at least 37.5
`mg/kg.
`Preferably, a single unit dosage can be administered in 15
`minutes or less. For example, the single unit dosage can be
`administered in 14 minutes or less, 13 minutes or less, 12
`minutes or less, 11 minutes or less, 10 minutes or less, 9
`minutes or less, 8 minutes or less, 7 minutes or less, 6 minutes
`or less, 5 minutes or less, 4 minutes or less, 3 minutes or less,
`or 2 minutes or less.
`Administration of iron can occur as a one-time delivery of
`a single unit dose or over a course of treatment involving
`delivery of multiple single unit doses. Multiple single unit
`doses can be administered, for example, over pre-determined
`time intervals or in response to the appearance and reappear
`ance of symptoms. The frequency of dosing depends on the
`disease or disorder being treated, the response of each indi
`vidual patient, and the administered amount of elemental
`iron. An appropriate regime of dosing adequate to alloW the
`body to absorb the iron from the bloodstream can be, for
`example, a course of therapy once every day to once every
`eighteen months.
`Such consecutive single unit dosing can be designed to
`deliver a relatively high total dosage of iron over a relatively
`loW period of time. For example, a single unit dose (e. g., 1000
`mg) can be administered every 24 hours. As illustration, a
`total dose of2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg
`of elemental iron can be delivered via consecutive daily single
`unit doses of about 600 mg to about 1000 mg of elemental
`
`40
`
`45
`
`20
`
`25
`
`30
`
`35
`
`50
`
`55
`
`60
`
`65
`
`8
`iron. Given that a single unit dose of 1000 mg can be intra
`venously introduced into a patient in a concentrated form
`over, for example, tWo minutes, such administrative protocol
`provides a practitioner and patient With an effective, e?icient,
`and safe means to deliver elemental iron.
`As another example, a single unit dose can be administered
`every 3-4 days.As a further example, a single unit dose can be
`administered once per Week. Alternatively, the single unit
`doses of iron complex may be administered ad hoc, that is, as
`symptoms reappear, as long as safety precautions are
`regarded as practiced by medical professionals.
`It Will be understood, hoWever, that the speci?c dose and
`frequency of administration for any particular patient may be
`varied and depends upon a variety of factors, including the
`activity of the employed iron complex, the metabolic stability
`and length of action of that complex, the age, body Weight,
`general health, sex, diet, mode and time of administration,
`rate of excretion, drug combination, the severity and nature of
`the particular condition, and the host undergoing therapy.
`The folloWing provides but a feW examples of treatment
`protocols for various diseases or disorders.
`Iron carbohydrate complex can be given as a single unit
`dose for the treatment of Restless Leg Syndrome. For
`example, 1000 mg of elemental iron from an iron carboxy
`maltose (e.g., polynuclear iron (lll)-hydroxide 4(R)-(poly
`(1 a4)-O-0t-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahy
`droxy-hexanoate) can be intravenously injected as a single
`dose (e.g., 1.5-5 mg iron/ml in normal saline) to a subject
`suffering from Restless Leg Syndrome. A single intravenous
`treatment can provide relief of symptoms for an extended
`