I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US008895612B2
`
`c12) United States Patent
`Helenek et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,895,612 B2
`*Nov. 25, 2014
`
`(54) METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF IRON
`
`(71) Applicant: Luitpold Pharmaceuticals, Inc.,
`Shirley, NY (US)
`
`(72)
`
`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 ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 14/100,717
`
`(22)
`
`Filed:
`
`Dec. 9, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2014/0099381 Al
`
`Apr. 10, 2014
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 13/847,254, filed on
`Mar. 19, 2013, which is a continuation of application
`No. 12/787,283, filed on May 25, 2010, now Pat. No.
`8,431,549, which is a continuation of application No.
`11/620,986, filed on Jan. 8, 2007, now Pat. No.
`7,754,702.
`
`(60) Provisional application No. 60/757,119, filed on Jan.
`6, 2006.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 311295
`A61K 3117016
`A61K 311715
`A61K 311721
`C07H 23100
`(52) U.S. Cl.
`CPC .............. C07H 23100 (2013.01); A61K 311715
`(2013.01); A61K 311721 (2013.01)
`USPC ................. 514/502; 514/53; 514/54; 514/58;
`514/59
`
`( 58) Field of Classification Search
`USPC .................................. 514/53, 54, 58, 59, 502
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
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`
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`200410180849 Al *
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`112011 Groman et al.
`12/2003 Groman et al.
`912004 Helenek et al.
`
`514/53
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`FOREIGN PATENT DOCUMENTS
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`KR
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`
`2493806
`10-2005-0070014
`W097/11711
`WO 2004037865 Al *
`WO 2007/023154
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`512004
`7 /2005
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`.............. C08B 31118
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`OTHER PUBLICATIONS
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`Australian Office Action dated Sep. 15, 2011 in related Australian
`Application No. AU2007205167 filed Jan. 8, 2007, 3 pages.
`Bailie et al., Hypersensitivity reactions and deaths associated with
`intravenous iron preparations, Nephrol Dial Transplant, 2005, pp.
`1443-1449, vol. 20.
`Beshara et al., Pharmacokinetics and red cell utilization of 52F e/59Fe(cid:173)
`labelled iron polymaltose in anaemic patients using positron emis(cid:173)
`sion tomography, Br J of Haematol, 2003, pp. 853-859, vol. 120.
`Canadian Office Action dated Jan. 4, 2013 in related Canadian Appli(cid:173)
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`cation No. CN 200780002006 filed Jan. 8, 2007, English translation,
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`Cisar et al., Binding Properties oflmmunoglobulin Combining Sites
`Specific for Terminal or Nonterminal Antigenic Determinants in
`Dextran, J Exp. Med,1975, pp. 435-459, vol. 142.
`Eschbach et al., NKF-K/DOQI clinical practice guidelines for ane(cid:173)
`mia of chronic kidney disease: update 2000, Am J Kidney Dis, 2001,
`pp. Sl82-S238, vol. 37 (Supp 1).
`
`(Continued)
`
`Primary Examiner - Layla Bland
`Assistant Examiner -
`Jonathan S Lau
`(74) Attorney, Agent, or Firm - Dentons US LLP
`
`(57)
`
`ABSTRACT
`
`The present invention generally relates to treatment of iron(cid:173)
`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(cid:173)
`nously to patients in need thereof.
`
`20 Claims, 2 Drawing Sheets
`
`Pharmacosmos, Exh. 1001, p. 1
`
`

`
`US 8,895,612 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`European Supplementary Search Report issued Oct. 21, 2009 in
`related European Application No. EP 07716309.5, 9 pages.
`European Official Communication dated May 10, 2011 in related
`European Application No. EP 07716309 .5 filed Jan. 8, 2007, 6 pages.
`European Official Communication dated Jun. 4, 2012 in related Euro(cid:173)
`pean Application No. EP 07716309.5 filed Jan. 8, 2007, 5 pages.
`European Office Action dated Jul. 5, 2013 in related European Appli(cid:173)
`cation No. EP 07716309.5 filed on Jan. 8, 2007, 5 pages.
`European Search Report dated Jul. 8, 2013 in related European Appli(cid:173)
`cation No. EP 13166988.9 filed May 8, 2013, 8 pages.
`Fielding, Intravenous iron-dextrin in iron-deficiency anaemia, Brit(cid:173)
`ish Medical Journal, 1961, pp. 279-283, vol. 2.
`Fishbane, Safety in iron management, Am J Kidney Dis, 2003, Sl8-
`S26, vol. 41, No. 6 (Suppl 5).
`Geisser et al., Structure/histotoxicity relationship of parenteral iron
`preparations, Drug Research, 1992, pp. 1439-1452, vol. 42, No. 12.
`Haines et al., Delayed adverse reactions to total-dose intravenous
`iron polymaltose, Internal Medicine Journal, 2009, pp. 252-255, vol.
`39.
`International Search Report and Written Opinion dated Sep. 12, 2007
`in related PCT Application No. PCT/US07/00176 filed Jan. 8, 2007,
`6 pages.
`Korean Office Action (in Korean and English) dated May 28, 2013 in
`related Application No. 10-2008-701-6352 filed Jul. 4, 2008, 13
`pages.
`
`Kudasheva et al., Structure of carbohydrate-bound polynuclear iron
`oxyhydroxide nanoparticles in parenteral formulations, Journal of
`Inorganic Biochemistry, 2004, pp. 1757-1769, vol. 98.
`Landry 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.
`MacDougall, Intravenous administration of iron in epoetin-treated
`haemodialysis patients-which drugs, which regimen?, Nephrol
`Dial Transplant, 2000, pp. 1743-1745, vol. 15.
`Marchasin et al., The Treatment of Iron-Deficiency Anemia with
`Intravenous Iron Dextran, Blood, 1964, pp. 354-358, vol. 23, No. 3.
`Newnham et al., Safety of iron polymaltose given as a total dose iron
`infusion, Internal Medicine Journal, 2006, pp. 672-674, vol. 36, No.
`10.
`Nissenson et al., Controversies in iron management, Kidney Interna(cid:173)
`tional, 2003, pp. S64-S71, vol. 64 (Supp 87).
`Sipe et al., Brain iron metabolism and neurodegenerative disorders,
`Dev Neurosci, 2002, pp. 188-196, vol. 24, No. 2-3.
`Sofie et al., Increased iron (III) and total iron content in post mortem
`substantia nigra ofparkinsonian brain, J. Neural Transm, 1988, pp.
`199-205, vol. 74.
`Spinowitz et al., The safety and efficacy of ferumoxytol therapy in
`anemic chronic kidney disease patients, Kidney International, 2005,
`pp. 1801-1807, vol. 68.
`Van Wyck et al., Making sense: a scientific approach to intravenous
`iron therapy, J Am Soc Nephrol, 2004, pp. S91-S92, vol. 15 (Supp.2).
`Van Wyck, Labile iron: manifestations and clinical implications, J
`Am Soc Nephrol, 2004, pp. Sl07-Sl 11, vol. 15 (Supp. 2).
`* cited by examiner
`
`Pharmacosmos, Exh. 1001, p. 2
`
`

`
`U.S. Patent
`
`Nov. 25, 2014
`
`Sheet 1of2
`
`US 8,895,612 B2
`
`FIGURE 1
`
`FIG. 18
`
`FIG.1A
`
`FIG. 1C
`
`Pharmacosmos, Exh. 1001, p. 3
`
`

`
`U.S. Patent
`
`Nov. 25, 2014
`
`Sheet 2of2
`
`US 8,895,612 B2
`
`FIGURE 2
`
`~ Fe3
`
`+
`
`OH(cid:173)
`@ 02-
`
`• H20
`glc glucose
`
`hydrogen bond
`
`OH
`
`OH
`
`OH
`
`HO
`
`o
`
`Ho-(;;;}
`
`! Ho,,_'(;:J
`
`:::.;,)~:
`
`.,,,&.,.. .. ':':::::':'_,
`
`~---····:;;;.
`
`* HO~H01,,,,,,
`
`OH
`
`(glc)n
`
`0
`
`OH
`
`OH
`
`Pharmacosmos, Exh. 1001, p. 4
`
`

`
`US 8,895,612 B2
`
`1
`METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF IRON
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a Continuation Application that claims
`priority to U.S. Non-Provisional application Ser. No. 13/847,
`254, filed 19 Mar. 2013; U.S. Non-Provisional application
`Ser. No. 12/787,283, filed 25 May 2010, issued as U.S. Pat.
`No. 8,431,549 on 30 Apr. 2013: and U.S. Non-Provisional
`application Ser. No. 11/620,986, filed 8 Jan. 2007, issued as
`U.S. Pat. No. 7,754,702on13 Jul. 2010, both of which claim
`priority to U.S. Provisional Application Ser. No. 601757,119,
`filed 6 Jan. 2006, each of which is incorporated herein by 15
`reference in their entireties.
`
`FIELD OF THE INVENTION
`
`2
`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
`high molecular mass substances produce more allergic reac(cid:173)
`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(cid:173)
`lO 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(cid:173)
`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
`.
`.
`mconvemence.
`
`SUMMARY OF THE INVENTION
`
`The present invention generally relates to treatment of 20
`iron-related conditions with iron carbohydrate complexes.
`
`BACKGROUND
`
`Parenteral iron therapy is known to be effective in a variety 25
`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(cid:173)
`anteed, iron deficiency where there is no response to oral 30
`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 35
`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(cid:173)
`rum), sodium ferric gluconate complex in sucrose (Ferrlecit),
`and iron sucrose (Venofer). Although serious and life-threat(cid:173)
`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(cid:173)
`ing, often preclude further dosing and therefore iron reple(cid:173)
`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(cid:173)
`ally Fishbane, Am J Kidney Dis (2003) 41(5 Suppl), 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(cid:173)
`dence of anaphylaxis with these products is markedly lower.
`Fishbane, Am J Kidney Dis (2003) 41(5 Suppl), 18-26: Gei(cid:173)
`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
`
`Among the various aspects of the present invention is the
`provision of a method of treatment of iron-associated dis(cid:173)
`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(cid:173)
`ease, disorder, or condition characterized by iron deficiency
`40 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
`45 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(cid:173)
`motor and cognitive development in children; breath holding
`spells; heavy uterine bleeding; menstruation; chronic recur-
`50 rent hemoptysis; idiopathic pulmonary siderosis; chronic
`internal bleeding; gastrointestinal bleeding; parasitic infec(cid:173)
`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
`55 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(cid:173)
`mia; cancer chemotherapy; inflammatory bowel disease;
`60 ulcerative colitis thyroiditis; hepatitis; systemic lupus erythe(cid:173)
`matosus; polymyalgia rheumatica; scleroderma; mixed con(cid:173)
`nective tissue disease; Sojgren's syndrome; congestive heart
`failure/cardiomyopathy; or idiopathic geriatric anemia. In
`some embodiments, the anemia is due to impaired iron
`65 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
`
`Pharmacosmos, Exh. 1001, p. 5
`
`

`
`US 8,895,612 B2
`
`3
`various embodiments, the method treats restless leg syn(cid:173)
`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
`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. 15
`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(cid:173)
`istration.
`In various embodiments, the iron carbohydrate complex
`has a pH between about 5.0 to about 7.0: physiological osmo- 25
`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- 30
`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(cid:173)
`plex, or an iron polysaccharide complex. In some embodi(cid:173)
`ments, the iron carbohydrate complex is iron carboxymaltose 40
`complex, iron mannitol complex, iron polyisomaltose com(cid:173)
`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 45
`some preferred embodiments, the iron carboxymaltose com(cid:173)
`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- 50
`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(cid:173)
`line range, wherein, when one maltodextrin is applied, its
`dextrose equivalent lies between 5 and 20, and when a mix- 55
`ture of several maltodextrins is applied, the dextrose equiva(cid:173)
`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(cid:173)
`maltose complex has a chemical formula of [FeOx(OH)y
`[ {(C6H 100 5)m (C 6H 120 7)}zh, where n is about 103,
`(H20)2
`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(cid:173)
`boxymaltose complex is polynuclear iron (III)-hydroxide
`4(R)-(poly-(1 ~4)-0-a-glucopyranosyl)-oxy-2(R),3(S),5
`(R),6-tetrahydroxy-hexanoate.
`
`4
`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.
`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
`10 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(cid:173)
`muscularly. In some embodiments, the iron carbohydrate
`complex is intravenously infused. In certain embodiments,
`the single unit dose of iron carbohydrate complex is intrave-
`20 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
`35 about 10 ml diluent.
`In various embodiments, the method also includes a second
`administration of the iron carbohydrate complex upon recur(cid:173)
`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(cid:173)
`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(cid:173)
`maltose complex comprises an iron core with a mean iron
`core size of at least about 1 nm but no greaterthan 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(cid:173)
`nously injected at a concentration of about 1000 mg elemen(cid:173)
`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)-0-a­
`glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hex-
`60 anoate. In some these embodiments, the iron carboxymaltose
`complex is obtained from an aqueous solution ofiron (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
`65 maltodextrin is applied, its dextrose equivalent lies between
`about 5 and about 20, and when a mixture of several malto(cid:173)
`dextrins is applied, the dextrose equivalent lies between about
`
`]
`
`Pharmacosmos, Exh. 1001, p. 6
`
`

`
`US 8,895,612 B2
`
`5
`5 and about 20 and the dextrose equivalent of each individual
`maltodextrin contained in the mixture lies between about 2
`and about 20.
`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(cid:173)
`ings are not intended to limit the scope of the present teach(cid:173)
`ings in any way.
`FIG. 1 is a series of electron micrographs that depict the
`particle size of three iron carbohydrate complexes. FIG. lA is
`an electron micrograph depicting the particle size of Dexfer(cid:173)
`rum (an iron dextran). FIG. lB is an electron micrograph
`depicting the particle size ofVenofer (an iron sucrose). FIG.
`lC is an electron micrograph depicting the particle size of
`polynuclear iron (III)-hydroxide 4(R)-(poly-(1 ~4)-0-a­
`glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hex(cid:173)
`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 ofiron carbohydrate com(cid:173)
`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- 30
`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- 35
`eases and conditions with parenteral iron formulations (sup(cid:173)
`plied at lower single unit dosages than those described herein)
`is generally known in the art. See e.g., Van Wyck et al. (2004)
`J Am Soc Nephrol 15, S91-S92. The present invention is
`directed to use of iron carbohydrate complexes that can be 40
`administered parenterally at relatively high single unit dos(cid:173)
`ages, thereby providing a safe and efficient means for delivery
`of a total dose of iron in fewer sessions over the course of
`therapeutic treatment.
`Iron deficiency anemia is associated with, for example, 45
`chronic blood loss; acute blood loss; pregnancy; childbirth;
`childhood development; psychomotor and cognitive develop(cid:173)
`ment in children; breath holding spells; heavy uterine bleed(cid:173)
`ing; menstruation; chronic recurrent hemoptysis; idiopathic
`pulmonary siderosis; chronic internal bleeding; gastrointes- 50
`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(cid:173)
`tory agents, or chronic ingestion of erythropoiesis stimulating 55
`agents.
`Anemia of chronic disease is associated with, for example,
`rheumatoid arthritis; cancer; Hodgkins leukemia; non(cid:173)
`Hodgkins leukemia; cancer chemotherapy; inflammatory
`bowel disease; ulcerative colitis thyroiditis; hepatitis; sys- 60
`temic lupus erythematosus; polymyalgia rheumatica; sclero(cid:173)
`derma; mixed connective tissue disease; Sojgren' s syndrome;
`congestive heart failure/cardiomyopathy; and idiopathic geri(cid:173)
`atric anemia.
`Anemia is also associated with, for example, Crohn' s Dis(cid:173)
`ease; gastric surgery; ingestion of drug products that inhibit
`iron absorption; and chronic use of calcium.
`
`20
`
`6
`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,
`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(cid:173)
`ment methodologies described herein. Generally, treating a
`state, disease, disorder, or condition includes preventing or
`10 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,
`15 e.g., arresting or reducing the development of the disease or at
`least one clinical or subclinical symptom thereof. Further(cid:173)
`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(cid:173)
`eters in blood. The aim of treatment is usually to return both
`25 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(cid:173)
`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(cid:173)
`lute or functional iron deficiencies. In patients with iron defi(cid:173)
`ciency, serum transferrin is elevated and will decrease follow(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`istered parenterally, for example intravenously or intramus(cid:173)
`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
`65 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
`
`Pharmacosmos, Exh. 1001, p. 7
`
`

`
`US 8,895,612 B2
`
`7
`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.
`If applied as an infusion, the iron carbohydrate complex can
`be diluted with sterile saline (e.g., polynuclear iron (III)(cid:173)
`hydroxide
`4(R)-(poly-(1 ~4)-0-a-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 10
`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 15
`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 20
`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 25
`grams; at least 1.8 grams; at l