USOO8431549B2
`
`(12) United States Patent
`Helenek et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8431,549 B2
`*Apr. 30, 2013
`
`(54) METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF RON
`
`(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)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 47 days.
`This patent is Subject to a terminal dis
`claimer.
`
`(*) Notice:
`
`(21) Appl. No.: 12/787.283
`(22) Filed:
`May 25, 2010
`
`(65)
`
`Prior Publication Data
`US 2010/0266644 A1
`Oct. 21, 2010
`
`Related U.S. Application Data
`(63) Continuation of application No. 1 1/620.986, filed on
`Jan. 8, 2007, now Pat. No. 7,754,702.
`(60) Provisional application No. 60/757,119, filed on Jan.
`6, 2006.
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A6 IK3I/72
`A6 IK3I/78
`A 6LX3L/295
`(52) U.S. Cl.
`USPC ................ 514/58: 514/54: 514/502:536/113
`(58) Field of Classification Search .................... 514/54,
`514/58, 502
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`3,100,202 A * 8, 1963 Muller et al. ................. 536,113
`5,624,668 A
`4/1997 Lawrence et al.
`6,599.498 B1
`7/2003 Groman et al.
`6,960,571 B2 11/2005 Helenek et al.
`7,612,109 B2 11/2009 Geisser et al.
`2004/0180849 A1
`9, 2004 Helenek et al.
`
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`971 1711
`4f1997
`2004037865
`5, 2004
`2007023154
`3, 2007
`
`OTHER PUBLICATIONS
`Hamstra et al. JAMA, 1980, 243(17), p. 1726-1731.*
`Australian Office Action dated Sep. 15, 2011 in related Application
`No. AU2007205167 filed Jan. 8, 2007, 3 pages.
`Chinese Office Action dated Apr. 30, 2010 in related Application No.
`CN200780002006 filed Jan. 8, 2007, English translation, 7 pages.
`European Official Communication dated Oct. 5, 2011 in related
`Application No. EP077163093.5 filed Jan. 8, 2007, 6 pages.
`
`International Search Report and Written Opinion dated Sep. 12, 2007
`in related PCT Application No. PCT/US07/00176 filed Jan. 8, 2007,
`6 pages.
`Andersson, "Clinical investigations on a new intramuscular
`haematinic', British Medical Journal, 1961, 275-279.
`Bailie et al., “HyperSensitivity reactions and deaths associated with
`intravenous iron preparations”, Nephrol Dial Transplant, 2005,
`20:1443-1449.
`Beshara et al., “Pharmacokinetics and red cell utilization of 52Fef
`59Fe-labelled iron polymaltose in anaemic patients using positron
`emission tomography', Br J of Haematol, 2003, 120:853-859.
`Cisar et al., “Binding properties of immunoglobulin combining sites
`specific for terminal or nonterminal antigenic determinants in
`dextran”, J Exp Med, 1975, 142:435-459.
`Eschbach et al., “NKF-K/DOQI clinical practice guidelines for ane
`mia of chronic kidney disease: update 2000'. Am J Kidney Dis, 2001,
`37(1 Supp. 1):S182-238.
`European Search Report issued Oct. 21, 2009, in the related applica
`tion EP 07716309.5.
`Fielding, “Intravenous iron-dextrin in iron-deficiency anaemia',
`British Medical Journal, 1961, 279-283.
`Fishbane, "Safety in iron management'. Am J Kidney Dis, 2003,
`41(6 Suppl 5):S18-S26.
`Geisser et al., “Structure/histotoxicity relationship of parenteral iron
`preparations'. Drug Research, 1992, 42 (12): 1439-1452.
`Haines et al., “Delayed adverse reactions to total-dose intravenous
`iron polymaltose'. Internal Medicine Journal, 2009, 39:252-255.
`Kudasheva et al., “Structure of carbohydrate-bound polynuclear iron
`Oxyhydroxide nanoparticles in parenteral formulations'. Journal of
`Inorganic Biochemistry, 2004, 98: 1757-1769.
`Landry et al., "Pharmacokinetic study of ferumoxytol: a new iron
`replacement therapy in normal Subjects and hemodialysis patients'.
`Am J Nephrol, 2005, 25:400-410.
`MacDougall, “Intravenous administration of iron in epoetin-treated
`haemodialysis patients—which drugs, which regimen?'. Nephrol
`Dial Transplant, 2000, 15:1743-1745.
`Newnham et al., “Safety of iron polymaltose given as a total dose iron
`infusion'. Internal Medicine Journal, 2006, 36 (10):672-674.
`Nissenson et al., “Controversies in iron management'. Kidney Inter
`national, 2003, 64(Supplement 87):S64-S71.
`Sipe et al., "Brain iron metabolism and neurodegenerative disorders'.
`Dev Neurosci, 2002, 24(2-3): 188-196.
`Sofic et al., “Increased iron(III) and total iron content in post mortem
`Substantia nigra of parkinsonian brain'. J. Neural Transm, 1988,
`T4:199-205.
`Spinowitz et al., “The safety and efficacy offerumoxytol therapy in
`anemic chronic kidney disease patients'. Kidney International, 2005,
`68:1801-1807.
`
`(Continued)
`Primary Examiner — Shaojia Anna Jiang
`Assistant Examiner — Jonathan S Lau
`(74) Attorney, Agent, or Firm — SNR Denton US 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.
`
`23 Claims, 2 Drawing Sheets
`
`IPR2019-01142
`Pharamacosmos v. American Regent
`Petitioner Ex. 1001 - Page 1
`
`

`

`US 8431549 B2
`Page 2
`
`OTHER PUBLICATIONS
`Van Wycket al., “Making sense: a scientific approach to intravenous
`iron therapy”, JAm Soc Nephrol. 2004, 15 (Suppl 2):S91-S92.
`Van Wyck, "Labile iron: manifestations and clinical implications', J
`Am Soc Nephrol, 2004, 15(Suppl 2):S107-S111.
`
`European Official Communication dated Jun. 4, 2012 in related
`Application No. EP 07716309.5 filed Jan. 8, 2007, 5 pages.
`European Official Communication dated Jun. 4, 2012 in related
`Application No. EP 07716309.5 filed Jan. 8, 2007, 4 pages.
`
`* cited by examiner
`
`IPR2019-01142
`Pharamacosmos v. American Regent
`Petitioner Ex. 1001 - Page 2
`
`

`

`U.S. Patent
`
`Apr. 30, 2013
`
`Sheet 1 of 2
`
`US 8431,549 B2
`
`FIGURE 1
`
`..
`
`35
`
`-BS
`
`25
`
`st
`
`FG. A
`
`FG. B
`
`
`
`FG. C
`
`IPR2019-01142
`Pharamacosmos v. American Regent
`Petitioner Ex. 1001 - Page 3
`
`

`

`U.S. Patent
`
`Apr. 30, 2013
`
`Sheet 2 of 2
`
`US 8431,549 B2
`
`FGURE 2
`
`
`
`gic glucose
`---- hydrogen bond
`
`IPR2019-01142
`Pharamacosmos v. American Regent
`Petitioner Ex. 1001 - Page 4
`
`

`

`1.
`METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF RON
`
`US 8,431,549 B2
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a Continuation Application that claims
`priority to U.S. Non-Provisional application Ser. No. 1 1/620.
`986, filed on Jan. 8, 2007, which in turn claims priority from
`U.S. Provisional Application Ser. No. 60/757,119, filed on
`Jan. 6, 2006, each of which is incorporated herein by refer
`ence in its entirety.
`
`FIELD OF THE INVENTION
`
`The present invention generally relates to treatment of
`iron-related conditions with iron carbohydrate complexes.
`
`10
`
`15
`
`BACKGROUND
`
`Parenteral iron therapy is known to be effective in a variety
`of diseases and conditions including, but not limited to,
`severe iron deficiency, iron deficiency anemia, problems of
`intestinal iron absorption, intestinal iron intolerance, cases
`where regular intake of an oral iron preparation is not guar
`anteed, iron deficiency 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 U.S. include iron dextran (e.g., InFed, 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 knownto occur with other parenteral ironproducts. 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 first 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
`
`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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`55
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`60
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`65
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`2
`high molecular mass Substances produce more allergic reac
`tions than the corresponding low molecular mass Substances.
`Geisser et al. (1992) Arzneimittelforschung 42: 1439-1452.
`Ferumoxytol is a newer parenteral iron formulation but
`limited information is available as to its efficacy 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; U.S. 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) Arzneimittelforschung 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
`significant 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.
`Briefly, 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 efficient 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 deficiency
`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 deficiency 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-inflammatory 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; inflammatory bowel disease;
`ulcerative colitis thyroiditis; hepatitis; systemic lupus erythe
`matosus; polymyalgia rheumatica; Scleroderma; mixed con
`nective tissue disease; Solgren'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 deficit 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
`
`IPR2019-01142
`Pharamacosmos v. American Regent
`Petitioner Ex. 1001 - Page 5
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`

`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
`significant 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 mm; a mean
`diameter particle size no greater than about 35 nmi; 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
`35
`plex, iron polymaltose 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
`40
`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
`50
`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 Fe0, (OH),
`(H2O), {(CHOs), (CH2O7), where n is about 103.
`m is about 8, 1 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-(1->4)-O-O-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 mm. In some embodiments, the mean iron
`core size is at least about 1 nm but no greater than about 9 mm:
`at least about 3 nm but no greater than about 7 mm; or at least
`about 4 nm but not greater than about 5 nm.
`
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`US 8,431,549 B2
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`10
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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 nmi; no greater
`than about 15 nmi; 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 first administration.
`In a preferred embodiment, the method of treating a dis
`ease, disorder, or condition characterized by iron deficiency
`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 mm:
`mean size of a particle of the iron carboxymaltose complex is
`no greater than about 35 nmi; 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-O-
`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.
`
`IPR2019-01142
`Pharamacosmos v. American Regent
`Petitioner Ex. 1001 - Page 6
`
`

`

`US 8,431,549 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-(1->4)-O-O-
`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.
`
`10
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`15
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`6
`restless leg syndrome; blood donation; Parkinson's disease;
`hair loss; and attention deficit disorder.
`Again, each of the above listed States, diseases, disorders,
`and conditions, as well as others, can benefit 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 benefit to a subject to be treated is either statistically
`significant or at least perceptible to the patient or to the
`physician. Measures of efficacy 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, efficacy 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. T?S is frequently used, in addition, to diagnose abso
`lute or functional iron deficiencies. In patients with iron defi
`ciency, serum transferrin is elevated and will decrease follow
`ing Successful iron treatment.
`Administration
`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.
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`The present invention makes use of iron carbohydrate com
`plexes that can be administered parenterally at relatively high
`25
`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 deficiency anemia, anemia of chronic
`disease, and states characterized by dysfunctional iron
`metabolism. Efficacious treatment of these, and other, dis
`eases and conditions with parenteral iron formulations (Sup
`plied at lower single unit dosages than those described herein)
`is generally known in the art. See e.g., Van Wycket al. (2004)
`J Am Soc Nephrol 15, S91-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 efficient means for delivery
`of a total dose of iron in fewer sessions over the course of
`40
`therapeutic treatment.
`Iron deficiency 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-inflamma
`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; inflammatory
`bowel disease; ulcerative colitis thyroiditis; hepatitis; sys
`temic lupus erythematosus; polymyalgia rheumatica; Sclero
`derma; mixed connective tissue disease; Soigren'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,
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`IPR2019-01142
`Pharamacosmos v. American Regent
`Petitioner Ex. 1001 - Page 7
`
`

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`7
`If applied as an infusion, the iron carbohydrate complex can
`be diluted with sterile saline (e.g., polynuclear iron (III)-
`hydroxide 4(R)-(poly-(1->4)-O-O-glucopyranosyl)-oxy-2
`(R).3(S),5(R),6-tetrahydroxy-hexanoate (“VIT-45") 0.9%
`m/V 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 deficit
`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
`ofelemental iron per 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
`m