(12) United States Patent
`Helenek et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,960,571 B2
`Nov. 1, 2005
`
`US006960571B2
`
`(54)
`
`(75)
`
`(73)
`
`METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF IRON FOR THE
`TREATMENT OF RESTLESS LEG
`SYNDROME
`
`Inventors? Mary Jane Helenek, Br00kViHe> NY
`(Us); Ralf A- Lange, Amagansett, NY
`(US); Fred B. Oldham, West Chester,
`PDA(U1S); Billarcpk' [TfSkarS’
`Oug assvl 6’
`(
`)
`Assignee: Luitpold Pharmaceuticals, Inc.,
`Shirley, NY (Us)
`
`(*)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`Pawnt is extended or adjusted under 35
`U-S~C~ 154(9) by 0 days-
`
`(21)
`(22)
`(65)
`
`(51)
`(52)
`
`(58)
`
`(56)
`
`Appl- N05 10/389’228
`Filed,
`Man 14’ 2003
`
`Pnor Pubhcatlon Data
`Us 2004/0180849 A1 Sep 16’ 2004
`
`Int. c1.7 ................. .. A61K 31/7012; A61K 31/555
`US. Cl. ....................... .. 514/53; 514/184; 514/483;
`514/365; 514/387; 514/547; 514/674; 514/23;
`514/58; 514/59; 514/502; 536/4.1; 424/489;
`424/733; 424/9
`Field Of Search ........................ .. 514/53, 184, 483,
`514/365, 367, 547, 674, 23, 58, 59, 502;
`536/4.1; 424/489, 733, 9
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,827,945 A
`5/1989 Groman et a1.
`5,248,492 A
`9/1993 G
`t
`l.
`5,700,832 A * 12/1997 Bzr1i)km:tnaI ............... .. 514/502
`6,611,707 B1 * 8/2003 PrausnitZ et a1. ........... .. 604/21
`
`FOREIGN PATENT DOCUMENTS
`
`WO 00/25821
`WO 01/74162
`
`5/2000
`10/2001
`
`OTHER PUBLICATIONS
`
`Earley et al. “Abnormalities in CSF concentrations of fer
`ritin and transferrin in restless legs syndrome.” Neurology,
`54, pp. 1698—1700, Apr. (2 of 2) 2000.*
`Allen et al., “MRI Measurement of Brain Iron in Patients
`With Restless Legs Syndrome,” Neurology, 2001, pp.
`263_265, VOL 56_
`Allen et al., “Augmentation of the Restless Legs Syndrome
`With Carbidopa/Levodopa,” Sleep, 1996, pp. 205—213, vol.
`19'
`Allen et al., “Restless Legs Syndrome: ARevieW of Clinical
`and Pathophysiologic Features,” J. Clin. Neurophysiol.,
`2001, PP- 128—147, VOL 18
`Allen et al., “Validation of the Johns Hopkins Restless Legs
`Severity Scale,” Sleep Medicine, 2001, pp. 239—242, vol. 2.
`Bailie et al., “Restless Legs Syndrome—Focus on Dopam
`inergic Agents,” Med Facts, 2001, vol. 3, 1 page, obtained
`from
`http://WWW.nephrologypharmacy.com/doWnloads/
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`Ben—Shachar et al., “Effect of Iron Chelators on Dopamine
`D2 Receptors,” J. Neurochem., 1985, pp. 999—1005, VOl. 45.
`Bonnet et al., “ASDA Report, Atlas and Scoring Rules,”
`Sleep, 1993, pp- 748—759, vol- 16
`Breuer et al., “A Fluorescence—Based One—Step Assay for
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`2001, pp. 194—202, vol. 299.
`'
`(Con?rmed)
`
`Primary Examiner—James O. Wilson
`Assistant Examiner—Devesh Khare
`(74) Attorney, Agent, or Firm—Sonnenschein Nath &
`Rosemhal LLP
`
`(57)
`
`ABSTRACT
`
`.
`.
`A method. of treanng. Restle§s Leg Syndrom‘?’ memes
`admlmstenng to a Sublect an “on Complex havmg an “on
`release rate greater than IDI. The iron release rate is deter
`mined at a concentration of at least 2,000 ng/dl.
`
`16 Claims, 1 Drawing Sheet
`
`400 —
`
`C 300 -
`g
`3
`5
`i 200 +
`2
`.2
`3
`
`100 F’
`
`g:
`
`0 -’
`
`O -O
`
`G
`
`S
`
`l
`
`D
`
`Cmax (ref)
`Q 125 mg
`Q 100 mg
`D 100 mg
`
`Q 100 mg
`
`2300
`
`4600
`Added iron (ug/dl)
`
`6600
`
`80100
`
`Luitpold Pharmaceuticals, Inc., Ex. 2039, P.1
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`US 6,960,571 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Chesson et al., “Practice Parameters for the Treatment of
`Restless Legs Syndrome and Periodic Limb Movement
`Disorder, An American Academy of Sleep Medicine Report,
`Standards of Practice Committee of the American Academy
`of Sleep Medicine,” Sleep, 1999, pp. 961—968, vol. 22.
`Conrad et al., “Iron Absorption and Transport,” Am. J. Med.
`Sci., 1999, pp. 213—229, vol. 318.
`Danielson et al., “Pharmacokinetics of Iron(IIIi—Hydroxide
`Sucrose Complex After a Single Intravenous Dose in
`Healthy Volunteers,” Arzneimittelforschung, 1996, pp.
`615—621, vol. 46.
`Davis et al., “A Randomized, Double—Blind Placebo—Con
`trolled Trial of Iron in Restless Legs Syndrome,” European
`Neurology, 2000, pp. 70—75, vol. 43.
`Earley et al., “Pergolide and Carbidopa/Levodopa Treatment
`of the Restless Legs Syndrome and Periodic Leg Move
`ments in Sleep in a Consecutive Series of Patients,” Sleep,
`1996, pp. 801—810, vol. 19.
`Earley et al., “Abnormalities in CFS Concentrations of
`Ferritin and Transferrin in Restless Legs Syndrome,” Neu
`rology, 2000, pp. 1698—1700, vol. 54.
`Earley et al., “Randomized, Double—Blind, Placebo—Con
`trolled Trial of Pergolide in Restless Legs Syndrome,”
`Neurology, 1998, pp. 1599—1602, vol. 51.
`Ekbom, “Restless Legs Syndrome,” Neurology, 1960, pp.
`868—873, vol. 10.
`Ekbom, “Restless Legs Syndrome,” Focus on Dopaminergic
`Agents, Med Facts, 2001, pp. 868—873, vol. 3.
`Erikson et al., “Iron De?ciency Alters Dopamine Trans
`porter Functioning in Rat Striatum,” J. Nutr., 2000, pp.
`2831—2837, vol. 130.
`Esposito et al., “Labile Iron in Parenteral Iron Formulations
`and its Potential for Generating Plasma Nontransferrin
`Bound Iron in Dialysis Patients,” Eur. J. Clin. Invest., 2002,
`pp. 42—49, vol. 32.
`Fishbane et al., “The Safety of Intravenous Iron Dextran in
`Hemodialysis Patients,” Am. J. Kidney Dis., 1996, pp.
`529—534, vol. 28.
`Geisser et al., “Structure/Histotoxicity Relationship of
`Parenteral Iron Preparations,” Arzneimittelforschung, 1992,
`pp. 1439—1452, vol. 42.
`Gelman et al., “MR Imaging of Human Brain at 3.0 T:
`Preliminary Report on Transverse Relaxation Rates and
`Relation to Estimated Iron Content,” Radiology, 1999, pp.
`759—767, vol. 210.
`Gorny et al., “Evaluation of the PAM—RL System for the
`Detection of Periodic Leg Movements During Sleep in the
`Lab and Home Environments,” Sleep, 1986, p. 183, vol. 21.
`Hamstra et al., “Intravenous Iron Dextran in Clinical Medi
`cine,” JAMA, 1980, pp. 1726—1731, vol. 243.
`Hening et al., “Dyskinesias While AWake and Periodic
`Movements in Sleep in Restless Legs Syndrome: Treatment
`With Opoids,” Neurology, 1986, pp. 1361—1366, vol. 36.
`Hening et al., “The Treatment of Restless Legs Syndrome
`and Periodic Limb Movement Disorder, An American Acad
`emy of Sleep Medicine RevieW,” Sleep, 1999, pp. 970—999,
`vol. 22.
`
`Jacobs et al., “Colorimetry and Constant—Potential Coulom
`etry Determinations of Transferrin—Bound Iron, Total Iron
`Binding Capacity, and Total Iron in Serum Containing
`Iron—Dextran, With Use of Sodium Dithionite and Alumina
`Columns,” Clin. Chem., 1990, pp. 1803—1807, vol. 36.
`Montplaisir et al., “Restless Legs Syndrome and periodic
`Movements in Sleep: Physiopathology and Treatment With
`L—dopa,” Clin. Neuropharmacol., 1986, pp. 456—463, vol. 9.
`Montplaisir et al., “Immobilization Tests and Periodic Leg
`Movements in Sleep for the Diagnosis of Restless Leg
`Syndrome,” Mov. Disord., 1998, pp. 324—329, vol. 13.
`Montplaisir et al, “Restless Legs Syndrome and Periodic
`Leg Movements in Sleep: The Primary Role of Dopamin
`ergic Mechanism,” Eur. Neurol., 1991, pp. 41—43, vol. 31.
`Nelson et al., “In vivo Dopamine Metabolism is Altered in
`Iron—De?cient Anemic Rats,” J. Nutr., 1997, pp. 2282—2288,
`vol. 127.
`Nordlander, “Therapy in Restless Legs,” Acta Medica Scan
`dinavica, 1953, pp. 453—457, vol. 145.
`O’Keeffe et al., “Iron Status and Restless Legs Syndrome in
`the Elderly,” Age Ageing, 1994, pp. 200—203, vol. 23 (and
`abstract only from http://ageing.oupjournals.org/cgi/con
`tent/abstract/23/200).
`Pelletier et al., “Sensory and Motor Components of the
`Restless Legs Syndrome,” Neurology, 1992, pp. 1663—1666,
`vol. 42.
`Pollmacher et al., “Periodic Leg Movements (PLM): Their
`Relationship to Sleep Stages,” Sleep, 1993, pp. 572—577,
`vol. 16.
`Silber et al., “Pergolide in the Management of Restless Legs
`Syndrome: An Extended Study,” Sleep, 1997, pp. 878—882,
`vol. 20.
`Simon, “Anemia,” http://WWW.healthandage.com/html/
`Welliconnected/pdf/doc57.pdf, 17 pages, 2003.
`Staedt et al., “Nocturnal Myoclonus Syndrome (Periodic
`Movements in Sleep) Related to Central Dopamine
`D2—Receptor Alteration,” Eur. Arch. Psychiatry Clin. Neu
`rosci., 1995, pp. 8—10, vol. 245.
`Sun et al., “Iron and the Restless Legs Syndrome,” Sleep,
`1998, pp. 381—387, vol. 21.
`Turj anski et al., “Striatal Dopaminergic Function in Restless
`Legs Syndrome: 18F—dopa and 11C—raclopride PET Stud
`ies,” Neurology, 1999, pp. 932—937, vol. 52.
`Ward et al., “Brain Iron in the Ferrocene—Loaded Rat: Its
`Chelation and In?uence on Dopamine Metabolism,” Bio
`chem. Pharmacol., 1995, pp. 1821—1826, vol. 49.
`RLS—QLI Restless Legs Syndrome—Quality of Life Instru
`ment; RLS—QLI @ RLS Foundation, May 1, 2002.
`SF—12 Health Survey, Protocol PPXAPD—0072—138, Final
`Jan. 22, 2002.
`
`* cited by examiner
`
`Luitpold Pharmaceuticals, Inc., Ex. 2039, P.2
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`U.S. Patent
`
`Nov. 1, 2005
`
`US 6,960,571 B2
`
`Fig. 1
`
`
`
`
`
`:23 C9. 2585
`
`4 3 2 1
`0 0 0 O
`
`O 0 O O 0
`A. .1 + w W0
`
`G SID
`
`rll/
`
`Drvgggg
`(mmmm
`C0000
`mzoom
`m1111
`500
`
`0 I0 0 6
`
`w .0
`?loo
`
`In
`
`m .AIO
`
`2
`
`M
`
`0 ‘I0 0 4
`Added iron (pg/(1|)
`
`Luitpold Pharmaceuticals, Inc., Ex. 2039, P.3
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`US 6,960,571 B2
`
`1
`METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF IRON FOR THE
`TREATMENT OF RESTLESS LEG
`SYNDROME
`
`BACKGROUND
`Restless Legs Syndrome
`Victims seriously afflicted with Restless Leg Syndrome
`(RLS; also known as Ekbom’s syndrome), are virtually
`unable to remain seated or even to stand still. Activities that
`require maintaining motor rest and limited cognitive
`stimulation, such as transportation (car, plane, train, etc.) or
`attending longer meetings, lectures, movies or other
`performances, become difficult if not impossible. Tortured
`by these sensations Which become more severe at night, RLS
`patients ?nd sleep to be virtually impossible, adding to the
`diminishing quality of their lives. The urge to move, Which
`increases over periods of rest, can be completely dissipated
`by movement, such as Walking. HoWever, once movement
`ceases, symptoms return With increased intensity. If an RLS
`patient is forced to lie still, symptoms Will continue to build
`like a loaded spring and, eventually, the legs Will involuntary
`move, relieving symptoms immediately. Rhythmic or semi
`rhythmic movements of the legs are observed if the patient
`attempts to remain laying doWn (Pollmacher and Schulz
`1993). These movements are referred to as dyskinesias
`While-aWake (DWA) (Hening et al. 1986) or more
`commonly, periodic limb movements While aWake
`(PLMW).
`Clinically, RLS is indicated When four diagnostic criteria
`are met: (1) a sensation of an urge to move the limbs (usually
`the legs); (2) motor restlessness to reduce sensations; (3)
`When at rest, symptoms return or Worsen; and (4) marked
`circadian variation in occurrence or severity of RLS symp
`toms; that is, symptoms Worsen in the evening and at night
`(Allen and Earley 2001a). First recognized by Willis in
`1685, RLS has been misunderstood and confused With
`periodic limb movements in sleep (PLMS; Which may be a
`part of RLS, but does not de?ne RLS), periodic limb
`movement disorder (PLMD; a sleep disorder) and nocturnal
`(or sleep) myoclonus (Allen and Earley 2001a).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`2
`Iron and Dopamine Concentrations are IntertWined Fac
`tors in RLS
`
`Lack of iron and reduced dopamine synthesis in the brain
`are important factors in RLS (Ekbom 1960, Nordlander
`1953). Dopamine is a neural transmitter synthesized in the
`brain that is essential for proper central nervous system
`(CNS) function. In the synthesis of dopamine, iron is a
`cofactor for the enzyme tyrosine hydroxylase, Which is the
`rate-limiting step in dopamine metabolism (Cooper et al.
`1991). Iron in the dopaminergic system appears to be an
`important component in RLS pathophysiology (Chesson AL
`et al. 1999, Ekbom 1960, Hening et al. 1999, Montplaisir et
`al. 1991).
`Because iron is a co-factor for tyrosine hydroxylase in
`dopamine synthesis, dopamine is reduced. When chelators
`(substances that bind metals such as iron, and make them
`physiologically unavailable) are administered to rats having
`excessive brain iron, they Were effective in reducing dopam
`ine and dopamine turnover (Ward et al. 1995). Studies in
`iron-de?cient animals have also demonstrated decreases in
`dopamine receptors (Ben-Shachar et al. 1985, Ward et al.
`1995), dopamine transporter function and receptor density
`With an elevation in extracellular dopamine (Erikson et al.
`2000, Nelson et al. 1997). These observations in rats are also
`observed in RLS patients. For example, a decrease in
`dopamine receptors has been observed in basal ganglia
`(Staedt et al. 1995, Turjanski et al. 1999). RLS patients have
`65% less cerebral spinal ?uid (CFS) ferritin (an important
`iron storage protein) and three-fold more CSF transferrin
`(iron transport protein in blood and body ?uids), despite
`normal serum levels of ferritin and transferrin in both RLS
`and controls (Earley et al. 2000). Iron concentrations vary
`throughout the brain; RLS patients have less iron in the
`substantia nigra and in the putamen parts of the brain, both
`sites of dopamine synthesis (Allen et al 2001). In general,
`decreased ferritin levels are indicative of RLS severity
`(O’Keeffe et al. 1994, Sun et al. 1998). These observations
`indicate that the ability of the brain to transport or store iron
`is abnormal in idiopathic RLS (RLS having no apparent
`cause)
`
`TABLE 1
`
`Side effects of current treatments for Restless Legs Syndrome (RLS)1
`
`Medication
`
`Disease2
`
`Side effects
`
`levodopa/carbidopa
`Pergolide W/
`levodopa/carbidopa
`Pramipexole
`Narcotic analgesics
`
`Clonazepam
`Triazolam
`Gabapentin
`
`Carbamazepine
`
`Parkinson
`Parkinson
`
`Parkinson
`Pain control
`
`Epilepsy
`Insomnia
`Epilepsy
`
`Epilepsy
`
`Clonidine
`
`Hypertension
`
`dyskinesia (inability to control movements), nausea, hallucinations
`dyskinesia, nausea, hallucinations, rhinitis (mucous membrane
`in?ammation), constipation, pain
`somnolence, insomnia, nausea, constipation, hallucinations
`respiratory depression, nausea, somnolence, pruritus (severe itching),
`constipation, urinary retention
`somnolence, depression, in-coordination
`drowsiness, dizziness, memory impairment
`fatigue, dizziness, somnolence, ataxia (unable to coordinate muscular
`movement)
`fetal malformation, rash, hyponatremia (blood sodium de?ciency),
`hepatotoxicity, blood disorders, ataxia, gastro-intestinal problems, sexual
`dysfunction, toxicity
`reduced blood pressure, dermatitis, systemic side effects (dry mouth,
`somnolence, dizziness, headache)
`
`% affected3
`
`4-17
`7-62
`
`9-28
`none reported
`
`6-37
`1-14
`11-19
`
`1-33
`
`8-89
`
`Luitpold Pharmaceuticals, Inc., Ex. 2039, P.4
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`US 6,960,571 B2
`
`TABLE l-continued
`
`Side effects of current treatments for Restless Legs Syndrome (RLS)1
`
`Medication
`
`Disease2
`
`Side effects
`
`intravenous iron dextran
`
`iron de?ciencies
`(Fishbane et al.
`1996) and
`random sampling
`(Hamstra et al.
`1980)
`
`anaphylaxis, possibility resulting in death
`
`% affected3
`
`0.3-1.7 (Fishbane
`et al. 1996,
`Hamstra et al.
`1980)
`
`1Table derived from (Chesson AL et al. 1999), except for intravenous iron dextran.
`2Studies were performed on patients suffering from the indicated disease, not RLS, with the indicated drug.
`3As reported in the studies referenced within (Chesson AL et al. 1999). See Chesson et al. 1999 for more information. The percent (8:)
`range is derived from the reported percentages for each side effect; thus in the ?rst example, 12-17% suffered from dyskinesia, 6% from
`nausea and 4% from hallucinations; the reported range is 4—17%.
`
`Treating RLS
`Current treatments for RLS are varied and plagued with
`undesirable side effects (see Table 1). Therapies have
`included the administration of dopamine agonists
`(substances that promote the production of dopamine), other
`dopaminergic agents, benZodiaZepines, opiates and anti
`convulsants. In cases where RLS results from a secondary
`condition, such as pregnancy, end-stage renal disease, eryth
`ropoietin (EPO) treatment and iron de?ciency, removing the
`condition, such as giving birth or treating with traditional
`iron supplementation, can reduce or eliminate symptoms in
`at least some cases (Allen and Earley 2001a). However, RLS
`resulting from non-secondary conditions “idiopathic” RLS),
`presents a greater treatment challenge.
`Dopaminergic agents such as levodopa generally provide
`effective initial treatment, but with continued use, tolerance
`and symptom augmentation occur in about 80% of RLS
`patients (Allen and Earley 1996); this complication is also
`common for dopamine agonists (Earley and Allen 1996,
`Silber et al 1997). The other alternatives, benZodiaZepines,
`opiates and anti-convulsants are not as uniformly effective
`as the dopamine agents (Chesson AL et al. 1999, Hening et
`al. 1999). Despite changes in ther treatment regimes,
`15—20% of patients ?nd that all medications are inadequate
`because of adverse effects and limited treatment bene?t
`(Earley and Allen 1996).
`Because of the link between iron and dopamine synthesis,
`iron administration would appear to be a simple and safe
`treatment to increase body iron stores. An obvious choice is
`oral administration of iron since such administration is
`simple and inexpensive. In fact, RLS patients with iron
`de?ciency respond dramatically to oral iron supplements
`(Ekbom 1960, O’Keeffe et al. 1994). However, in RLS
`patients with normal serum ferritin levels, the bene?ts of
`oral iron therapy decrease inversely to baseline serum fer
`ritin levels: the higher the ferritin at the time of initiating
`therapy, the less pronounced the bene?ts (O’Keeffe et al.
`1994). This approach to raise body stores of iron is ineffec
`tive because the intestinal epithelium controls iron
`absorption, responding not to dopamine synthesis cues, but
`to serum iron levels (Conrad et al. 1999). Therefore, oral
`doses of iron are ineffective, and not tolerated. To increase
`body stores of iron when serum ferritin levels are normal,
`methods that bypass intestinal epithelial regulation would
`need to be used. For example, in the anemia of chronic
`disease, iron absorption and transport is dramatically
`impaired and serium ferritin levels being elevated does not
`accurately re?ect stored iron levels in the body. Also in the
`anemia of chronic disease the only effective way to deliver
`adequate iron for erythropoiesis to a deprived system is by
`intervenus administration.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`Intravenous administration of iron circumvents the prob
`lems and ineffectiveness of orally-administered iron for
`those RLS patients with normal serum ferritin levels. In fact,
`intravenous administration of iron dextran solutions, such as
`INFeD® (Watson Pharma, Inc.; Corona, Calif. (having an
`average apparent molecular weight of 165,000 g/mole with
`a range of approximately:10%), and Dexferrum®
`(American Regent Inc., Shirley, NY.) (referred to collec
`tively as “IDI”) successfully treats RLS. However, the
`dosage is high—1000 mg/administration; or about two- to
`ten-fold more than the usual dose when used to treat other
`conditions. While IDI offers hope to some RLS patients, it
`also suffers from signi?cant disadvantages: not only is the
`dosage high, but also dextran causes anaphylaxis in about
`1.7% of the population (Fishbane et al. 1996), a life threat
`ening condition; just less than 50% or those suffering
`anaphylaxis die.
`
`SUMMARY
`
`In a ?rst aspect, the present invention is a method of
`treating Restless Leg Syndrome, comprising administering
`to a subject an iron complex having an iron release rate
`greater than IDI. The iron release rate is determined at a
`concentration of at least 2,000 pg/dl.
`In a second aspect, the present invention is a method of
`treating Restless Leg Syndrome, comprising administering
`to a subject an iron complex having an iron release rate of
`at least 115 pg/dl at a concentration of 3438 pg/dl by the
`alumina column test.
`In a third aspect, the present invention is a method of
`treating Restless Leg Syndrome, including administering
`IDI, the improvement comprising replacing IDI with an iron
`complex having a greater release rate than IDI.
`In a fourth aspect, the present invention is a kit, compris
`ing an iron complex composition having a release rate
`greater than IDI, a syringe, and a needle for the syringe. The
`iron release rate is determined at a concentration of at least
`2,000 pig/d1.
`DESCRIPTION OF THE FIGURES
`FIG. 1 shows the change in serum transferrin-bound iron
`(A iron) of the intravenous injection preparations for ferric
`gluconate (also known as sodium ferric gluconate complex
`in sucrose or Ferrlecit®; Watson Pharma, Inc.; Corona,
`Calif.), iron sucrose (Venofer® (iron sucrose injection USP);
`American Regent Inc.; Shirley, NY), iron dextran
`(INFeD®; Watson Pharma, Inc.), and another iron dextran
`(Dexferrum®; American Regent Inc.) as related to the
`amount of added iron. x-axis, added elemental iron (ug/dl);
`y-axis, A iron (ug/dl).
`
`Luitpold Pharmaceuticals, Inc., Ex. 2039, P.5
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`US 6,960,571 B2
`
`5
`DETAILED DESCRIPTION
`
`The present invention makes use of the discovery that an
`iron complex, having a higher release rate of iron than IDI,
`has the same effect for the treatment of RLS as IDI, at a
`loWer dosage. These iron complexes avoid the risks of
`anaphylaxis associated With IDI When administered intra
`venously due to antibodies against the dextran moiety not
`being present in other iron complexes and, because of the
`higher release rate, therapadic dosage can be loWered.
`An example of such an iron complex is Venofer® (iron
`sucrose injection USP), an iron sucrose complex that has an
`incidence of anaphylactoid reactions of 0.0046% (that is, 1
`out of 20,000 people; IDI has a rate of anaphylaxis of 1.7%,
`or almost 2 out of 100 people). HoWever, any iron complex
`that has a release rate greater than that of IDI is an effective
`RLS therapeutic.
`Iron Compositions for the Treatment of RLS
`Iron complexes are compounds Which contain iron in (II)
`or (III) oxidation state, complexed With an organic com
`pound. These include iron polymer complexes, iron carbo
`hydrate complexes, and iron aminoglycosan complexes.
`These complexes are commercially available, or have Well
`knoWn syntheses (see, for example, (Andreasen and Chris
`tensen 2001, Andreasen and Christensen 2001, Geisser et al.
`1992, Groman and Josephson 1990, Groman et al. 1989)).
`Examples of iron carbohydrate complexes include iron
`simple saccharide complexes, iron oligosaccharide
`complexes, and iron polysaccharide complexes, such as:
`iron sucrose, iron polyisomaltose (iron dextran), iron poly
`maltose (iron dextrin), iron gluconate, iron sorbital, iron
`hydrogenated dextran, Which may be further complexed
`With other compounds, such as sorbital, citric acid and
`gluconic acid (for example iron dextrin-sorbitol-citric acid
`complex and iron sucrose-gluconic acid complex), and mix
`tures thereof.
`Examples of iron aminoglycosan complexes include iron
`chondroitin sulfate, iron dermatin sulfate, iron keratan
`sulfate, Which may be further complexed With other com
`pounds and mixtures thereof.
`Examples of iron polymer complexes include iron hyalu
`ronic acid complex, iron protein complexes, and mixtures
`thereof. Iron protein complexes include ferritin, transferritin,
`as Well as ferritin or transferritin With amino acid
`substitutions, and mixtures thereof. Preferably, the iron
`complexes have a molecular mass of at least 30,000, more
`preferably of 30,000 to 100,000 as determined by HPLC/
`CPG (as described in Geisser et al 1992). Preferably, the iron
`complexes have a siZe of at most 0.1 micrometer, more
`preferably 0.035 to 0.1 micrometer, as determined by ?ltra
`tion.
`The most preferred iron complex is iron sucrose (iron
`sucrose injection USP, Venofer®). This composition also
`avoids toxicity issues that are associated With smaller
`sugars, especially gluconates, Which have high iron release
`rates. Iron sucrose compositions balance these toxicity
`issues With optimal iron release rates.
`Determining Iron Complex Iron Release Rates
`The methods of the invention take advantage of the
`discovery that iron complexes having higher release rates of
`iron than IDI can be effectively administered at loWer doses.
`IDI has an iron release rate of 69.5—113.5 pg/dl. In the
`present invention, the iron complex must have a release rate
`of at least 115 pg/dl at a concentration of at least 2000 pg/dl;
`including 2000, 3000, 3500, 5000, and 10,000 ug/dl.
`Preferably, at least 120 pg/dl, more preferably, at least 140
`
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`pg/dl. TWo tests can be implemented to determine iron
`release rates, that by Esposito et al. (2000) and by Jacobs et
`al. (1990).
`“Chelator Test” (Esposito et al 2000)
`The release rate of a candidate iron complex is the ability
`of the candidate complex to donate iron to apotransferrin or
`to an iron chelator, such as desferrioxamine. To detect such
`transfer, the probes ?uorescein-transferrin (F1-Tf) and
`?uorescein-desferrioxamine (Fl-DFO) can be used, Which
`undergo quenching upon binding to iron (Breuer and
`Cabantchik 2001). In short, the method involves mobiliZa
`tion of iron from serum With 10 mM oxalate and its transfer
`to the metallosensor ?uoresceinated apotransferrin (F1-aTf).
`Gallium is present in the assay to prevent the binding of
`labile plasma iron to the unlabelled apotransferrin in the
`sample. Labile plasma iron values are derived from the
`magnitude of quenching of the ?uorescence signal of ?uo
`resceinated apotransferrin. Fluorescence may be measured
`using, for example, 96-well plates and a plate reader oper
`ating at 485/538 nm excitation/emission ?lter pair (gain=
`25).
`“Alumina Column Test” (Jacobs et al. 1990)
`In this test, samples (serum and candidate iron
`composition) are passed over an alumina column to absorb
`organic and drug-bound iron, the elutants are then collected
`and reconstituted to a pre-selected volume (e.g., 1.5 ml), and
`the ?nal iron concentration determined using a chemistry
`analyZer, such as a Hitachi 717 chemistry analyZer. Fer
`roZine reagents are used, Which included detergent, buffers
`of citric acid and thiourea, ascorbate, and ferroZine. This test
`is a non-proteiniZing method in Which detergent clari?es
`lipemic samples, buffers loWer the pH to <2.0 to free iron as
`Fe3+ from transferrin, ascorbate reduces Fe3+ to Fez", and
`ferroZine reacts With Fe2+ to form a colored complex mea
`sured spectophotometrically at 560 nm. From this result the
`value of a control (blank) sample is subtracted from the
`experimental sample readings, and the results are recorded
`as the A Tf-bound iron (ug/dl).
`Pharmaceutical Compositions
`In many cases, the iron complex may be delivered as a
`simple composition comprising the iron complex and the
`buffer in Which it is dissolved. HoWever, other products may
`be added, if desired, to maximiZe iron delivery, preservation,
`or to optimiZe a particular method of delivery.
`A “pharmaceutically acceptable carrier” includes any and
`all solvents, dispersion media, coatings, antibacterial and
`anti-fungal agents, isotonic and absorption delaying agents,
`and the like, compatible With pharmaceutical administration
`(Gennaro 2000). Preferred examples of such carriers or
`diluents include, but are not limited to, Water, saline, Ring
`er’s Lactate solutions and dextrose solution. Supplementary
`active compounds can also be incorporated into the com
`positions. For intravenous administration, Venofer® is pref
`erably diluted in normal saline to approximately 2—5 mg/ml.
`The volume of the pharmaceutical solution is based on the
`safe volume for the individual patient, as determined by a
`medical professional
`General Considerations
`A iron complex composition of the invention for admin
`istration is formulated to be compatible With the intended
`route of administration, such as intravenous injection. Solu
`tions and suspensions used for parenteral, intradermal or
`subcutaneous application can include a sterile diluent, such
`as Water for injection, saline solution, polyethylene glycols,
`glycerine, propylene glycol or other synthetic solvents;
`antibacterial agents such as benZyl alcohol or methylpara
`
`Luitpold Pharmaceuticals, Inc., Ex. 2039, P.6
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`

`
`US 6,960,571 B2
`
`7
`bens; antioxidants such as ascorbic acid or sodium bisul?te;
`buffers such as acetates, citrates or phosphates, and agents
`for the adjustment of tonicity such as sodium chloride or
`dextrose. The pH can be adjusted With acids or bases, such
`as hydrochloric acid or sodium hydroxide. Preparations can
`be enclosed in ampules, disposable syringes or multiple dose
`vials made of glass or plastic.
`Pharmaceutical compositions suitable for injection
`include sterile aqueous solutions or dispersions for the
`extemporaneous preparation of sterile injectable solutions or
`dispersion. For intravenous administration, suitable carriers
`include physiological saline, bacteriostatic Water, CREMO
`PHOR ELTM (BASF; Parsippany, N] or phosphate buff
`ered saline (PBS). The composition must be sterile and
`should be ?uid so as to be administered using a syringe.
`Such compositions should be stable during manufacture and
`storage and must be preserved against contamination from
`microorganisms, such as bacteria and fungi. The carrier can
`be a dispersion medium containing, for example, Water,
`polyol (such as glycerol, propylene glycol, and liquid poly
`ethylene glycol), and other compatible, suitable mixtures.
`Various antibacterial and anti-fungal agents, for example,
`benZyl alcohol, parabens, chlorobutanol, phenol, ascorbic
`acid, and thimerosal, can contain microorganism contami
`nation. Isotonic agents such as sugars, polyalcohols, such as
`manitol, sorbitol, and sodium chloride can be included in the
`composition. Compositions that can delay absorption
`include agents such as aluminum monostearate and gelatin.
`Sterile injectable solutions can be prepared by incorpo
`rating an iron complex in the required amount in an appro
`priate solvent With a single or combination of ingredients as
`required, folloWed by steriliZation. Methods of preparation
`of sterile solids for the preparation of sterile injectable
`solutions include vacuum drying and freeZe-drying to yield
`a solid containing the iron complex and any other desired
`ingredient.
`Systemic Administration
`Systemic administration can be transmucosal or transder
`mal. For transmucosal or transdermal administration, pen
`etrants that can permeate the target barrier(s) are selected.
`Transmucosal penetrants include, detergents, bile salts, and
`fusidic acid derivatives. Nasal sprays or suppositories can be
`used for transmucosal administration. For transdermal
`administration, the active compounds are formulated into
`ointments, salves, gels, or creams.
`Carriers
`Active compounds may be prepared With carriers that
`protect the compound against rapid elimination from the
`body, such as a controlled release formulation, including
`implants and microencapsulated delivery systems. Biode
`gradable or biocompatible polymers can be used, such as
`ethylene vinyl acetate, polyanhydrides, polyglycolic acid,
`collagen, polyorthoesters, and polylactic acid. Such materi
`als can be obtained commercially from ALZA Corporation
`(Mountain VieW, Calif.) and NOVA Pharmaceuticals, Inc.
`(Lake Elsinore, Calif.), or prepared by one of skill in the art.
`Kits for Pharmaceutical Compositions
`Iron complex compositions can be included in a kit,
`container, pack or dispenser, together With instructions for
`administration. When the invention is supplied as a kit, the
`different components of the composition may be packaged
`in separate containers, such as ampules or vials, and
`admixed immediately before use. Such packaging of the
`components separately may permit long-term storage With
`out losing the activity of the components.
`Kits may also include reagents in separate containers that
`facilitate the execution of a speci?c test, such as diagnostic
`tests.
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`Containers or Vessels
`The reagents included in kits can be supplied in cont