(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0180849 A1
`(43) Pub. Date:
`Sep. 16, 2004
`Helenek et al.
`
`US 20040180849A1
`
`(54) METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF IRON FOR THE
`TREATMENT OF RESTLESS LEG
`SYNDROME
`
`(76) Inventors: Mary Jane Helenek, Brookville, NY
`(US); Ralf A. Lange, Amagansett, NY
`(US); Fred B. Oldham, West Chester,
`PA (US); Marc L. Tokars,
`Douglassville, PA (US)
`
`(21) Appl. No.:
`
`10/389,228
`
`(22) Filed:
`
`Mar. 14, 2003
`
`Publication Classi?cation
`
`(51) Int. Cl.7 .................. .. A61K 31/7012; A61K 31/555
`(52) US. Cl. ............................................ .. 514/53; 514/184
`
`(57)
`
`ABSTRACT
`
`Correspondence Address:
`SONNENSCHEIN NATH & ROSENTHAL LLP
`PO. BOX 061080
`WACKER DRIVE STATION, SEARS TOWER
`CHICAGO, IL 60606-1080 (US)
`
`A method of treating Restless Leg Syndrome, includes
`administering to a subject an iron complex having an iron
`release rate greater than IDI. The iron release rate is deter
`mined at a concentration of at least 2,000 tag/d1.
`
`Pharmacosmos, Exh. 1007, p. 1
`
`

`

`Patent Application Publication Sep. 16, 2004
`
`US 2004/0180849 A1
`
`Fig.1
`
`400 -h
`
`c 300 1‘
`‘O
`a
`a
`8
`g 200 #-
`:5 g
`:3
`
`100 "
`
`gr
`
`G
`
`S
`
`i
`
`0
`
`Cmax (re?
`O 125 mg
`Q 100 mg
`0 100 mg
`
`g 100 mg
`
`0 dr
`
`0
`
`0 .0
`i
`2000
`
`i
`4000
`
`i
`6000
`
`i
`8000
`
`Added iron (pg/di)
`
`Pharmacosmos, Exh. 1007, p. 2
`
`

`

`US 2004/0180849 A1
`
`Sep. 16, 2004
`
`METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF IRON FOR THE
`TREATMENT OF RESTLESS LEG SYNDROME
`
`BACKGROUND
`
`[0001] Restless Legs Syndrome
`[0002] Victims seriously afflicted With Restless Leg Syn
`drome (RLS; also known as Ekbom’s syndrome), are vir
`tually unable to remain seated or even to stand still. Activi
`ties that require maintaining motor rest and limited cognitive
`stimulation, such as transportation (car, plane, train, etc.) or
`attending longer meetings, lectures, movies or other perfor
`mances, become dif?cult if not impossible. Tortured by these
`sensations Which become more severe at night, RLS patients
`?nd sleep to be virtually impossible, adding to the dimin
`ishing 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 com
`monly, periodic limb movements While aWake (PLMW).
`[0003] 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 sensa
`tions; (3) When at rest, symptoms return or Worsen; and (4)
`marked circadian variation in occurrence or severity of RLS
`symptoms; 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).
`
`[0004] Iron and Dopamine Concentrations are IntertWined
`Factors in RLS
`
`[0005] Lack of iron and reduced dopamine synthesis in the
`brain are important factors in RLS (Ekbom 1960, Nord
`lander 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).
`[0006] Because iron is a co-factor for tyrosine hydroxylase
`in dopamine synthesis, dopamine is reduced. When chela
`tors (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
`dopamine and dopamine turnover (Ward et al. 1995). Stud
`ies 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 recep
`tor 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 concentra
`tions 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
`
`Parkinson
`Parkinson
`
`Parkinson
`Pain control
`
`Epilepsy
`Insomnia
`Epilepsy
`
`Carbamazepine
`
`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
`
`Pharmacosmos, Exh. 1007, p. 3
`
`

`

`US 2004/0180849 A1
`
`Sep. 16, 2004
`
`TABLE 1-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%.
`
`[0007] Treating RLS
`[0008] Current treatments for RLS are varied and plagued
`With undesirable side effects (see Table 1). Therapies have
`included the administration of dopamine agonists (sub
`stances 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.
`[0009] 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).
`[0010] 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 administra
`tion is simple and inexpensive. In fact, RLS patients With
`iron de?ciency respond dramatically to oral iron supple
`ments (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
`ferritin 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 absorp
`tion, 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 admin
`istration.
`
`[0011] Intravenous administration of iron circumvents the
`problems 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® (Ameri
`can Regent Inc., Shirley, NY.) (referred to collectively 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 threatening condi
`tion; just less than 50% or those suffering anaphylaxis die.
`
`SUMMARY
`[0012] In a ?rst aspect, the present invention is a method
`of treating Restless Leg Syndrome, comprising administer
`ing 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.
`
`[0013] 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.
`
`[0014] 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.
`
`[0015] In a fourth aspect, the present invention is a kit,
`comprising 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
`[0016] FIG. 1 shoWs the change in serum transferrin
`bound iron (A iron) of the intravenous injection preparations
`
`Pharmacosmos, Exh. 1007, p. 4
`
`

`

`US 2004/0180849 A1
`
`Sep. 16, 2004
`
`for ferric gluconate (also known as sodium ferric gluconate
`complex in sucrose or Ferrlecitg; Watson Pharma, Inc.;
`Corona, Calif.), iron sucrose (Venofer® (iron sucrose injec
`tion USP); American Regent Inc.; Shirley, NY), iron dex
`tran (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).
`
`DETAILED DESCRIPTION
`
`[0017] 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.
`
`[0018] 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.
`
`[0019] Iron Compositions for the Treatment of RLS
`
`[0020] Iron complexes are compounds Which contain iron
`in (II) or (III) oxidation state, complexed With an organic
`compound. These include iron polymer complexes, iron
`carbohydrate complexes, and iron aminoglycosan com
`plexes. These complexes are commercially available, or
`have Well knoWn syntheses (see, for example, (Andreasen
`and Christensen 2001, Andreasen and Christensen 2001,
`Geisser et al. 1992, Groman and Josephson 1990, Groman et
`al. 1989)).
`[0021] 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.
`
`[0022] Examples of iron aminoglycosan complexes
`include iron chondroitin sulfate, iron dermatin sulfate, iron
`keratan sulfate, Which may be further complexed With other
`compounds and mixtures thereof.
`
`[0023] Examples of iron polymer complexes include iron
`hyaluronic acid complex, iron protein complexes, and mix
`tures thereof. Iron protein complexes include ferritin, trans
`ferritin, 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.
`
`[0024] 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.
`
`[0025] Determining Iron Complex Iron Release Rates
`
`[0026] 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 695-1135 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. Pref
`erably, at least 120 pg/dl, more preferably, at least 140 pg/dl.
`TWo tests can be implemented to determine iron release
`rates, that by Esposito et al. (2000) and by Jacobs et al.
`(1990).
`[0027] “Chelator Test” (Esposito et al 2000)
`
`[0028] The release rate of a candidate iron complex is the
`ability of the candidate complex to donate iron to apotrans
`ferrin or to an iron chelator, such as desferrioxamine. To
`detect such transfer, the probes ?uorescein-transferrin (Fl
`Tf) and ?uoresceindesferrioxamine (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).
`[0029]
`[0030] 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).
`
`“Alumina Column Test” (Jacobs et al. 1990)
`
`[0031] Pharmaceutical Compositions
`
`[0032] 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, pres
`ervation, or to optimiZe a particular method of delivery.
`
`Pharmacosmos, Exh. 1007, p. 5
`
`

`

`US 2004/0180849 A1
`
`Sep. 16, 2004
`
`[0033] A “pharmaceutically acceptable carrier” includes
`any and all solvents, dispersion media, coatings, antibacte
`rial and anti-fungal agents, isotonic and absorption delaying
`agents, and the like, compatible With pharmaceutical admin
`istration (Gennaro 2000). Preferred examples of such carri
`ers or diluents include, but are not limited to, Water, saline,
`Ringer’s Lactate solutions and dextrose solution. Supple
`mentary active compounds can also be incorporated into the
`compositions. For intravenous administration, Venofer® is
`preferably 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
`
`[0034] General Considerations
`
`[0035] A iron complex composition of the invention for
`administration is formulated to be compatible With the
`intended route of administration, such as intravenous injec
`tion. Solutions and suspensions used for parenteral, intrad
`ermal or subcutaneous application can include a sterile
`diluent, such as Water for injection, saline solution, poly
`ethylene glycols, glycerine, propylene glycol or other syn
`thetic solvents; antibacterial agents such as benZyl alcohol or
`methylparabens; antioxidants such as ascorbic acid or
`sodium bisul?te; buffers such as acetates, citrates or phos
`phates, 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 hydrox
`ide. Preparations can be enclosed in ampules, disposable
`syringes or multiple dose vials made of glass or plastic.
`[0036] 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.
`
`[0037] Sterile injectable solutions can be prepared by
`incorporating an iron complex in the required amount in an
`appropriate solvent With a single or combination of ingre
`dients 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.
`[0038] Systemic Administration
`
`[0039] Systemic administration can be transmucosal or
`transdermal. For transmucosal or transdermal administra
`
`tion, penetrants that can permeate the target barrier(s) are
`selected. Transmucosal penetrants include, detergents, bile
`salts, and fusidic acid derivatives. Nasal sprays or supposi
`tories can be used for transmucosal administration. For
`transdermal administration, the active compounds are for
`mulated into ointments, salves, gels, or creams.
`[0040] Carriers
`[0041] 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.
`[0042] Kits for Pharmaceutical Compositions
`[0043] 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 pack
`aged 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.
`[0044] Kits may also include reagents in separate contain
`ers that facilitate the execution of a speci?c test, such as
`diagnostic tests.
`
`[0045] Containers or Vessels
`
`[0046] The reagents included in kits can be supplied in
`containers of any sort such that the life of the different
`components are preserved and are not adsorbed or altered by
`the materials of the container. For example, sealed glass
`ampules or vials may contain lyophiliZed iron complex or
`buffer that have been packaged under a neutral non-reacting
`gas, such as nitrogen. Ampules may consist of any suitable
`material, such as glass, organic polymers, such as polycar
`bonate, polystyrene, etc., ceramic, metal or any other mate
`rial typically employed to hold reagents. Other examples of
`suitable containers include bottles that arc fabricated from
`similar substances as ampules, and envelopes that consist of
`foil-lined interiors, such as aluminum or an alloy. Other
`containers include test tubes, vials, ?asks, bottles, syringes,
`etc. Containers may have a sterile access port, such as a
`bottle having a stopper that can be pierced by a hypodermic
`injection needle. Other containers may have tWo compart
`ments that are separated by a readily removable membrane
`that, upon removal, permits the components to mix. Remov
`able membranes may be glass, plastic, rubber, etc.
`[0047]
`[0048] Kits may also be supplied With instructional mate
`rials. Instructions may be printed on paper or other substrate,
`and/or may be supplied on an electronic-readable medium,
`such as a ?oppy disc, CD-ROM, DVD-ROM, mini-disc,
`SACD, Zip disc, videotape, audio tape, etc. Detailed instruc
`tions may not be physically associated With the kit; instead,
`a user may be directed to an internet Web site speci?ed by
`the manufacturer or distributor of the kit, or supplied as
`electronic mail.
`
`Instructional Materials
`
`Pharmacosmos, Exh. 1007, p. 6
`
`

`

`US 2004/0180849 A1
`
`Sep. 16, 2004
`
`[0049] Methods for the Treatment of RLS With Compo
`sitions Having Greater Iron Release Rates than IDI
`
`[0050] Methods of treatment of RLS With iron complex
`compositions having greater iron release rates than IDI
`comprise the administration of the complex, either as doses
`administered over pre-determined time intervals or in
`response to the appearance and reappearance of RLS symp
`toms. In general, dosage depends on the route of adminis
`tration. The preferred route of administration is intravenous
`infusion; hoWever, certain iron compounds may be admin
`istered intramuscularly such as iron dextran. HoWever, any
`route is acceptable as long as iron from the iron complex is
`quickly released (more quickly than IDI administered intra
`venously) such that RLS symptoms are treated.
`[0051] An appropriate dosage level Will generally be about
`10 mg to 1000 mg of elemental iron per dose, Which can be
`administered in single or multiple doses, particularly at least
`1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0,
`200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0,
`900.0, 1000.0, and 2000.0 milligrams of elemental iron, and
`furthermore up to the maximal tolerated dose (MTD) per
`administration. Preferably, the dosage level Will be about 0.1
`to about 1000 mg per dose; most preferably about 100 mg
`to about 500 mg per dose. The compounds may be admin
`istered on various regimes (see Example 3).
`[0052] For example, a 1000 mg of elemental iron of an
`injectable intravenous iron sucrose complex (Venofer®) is
`given as a single dose (as a 1.5-5 mg iron/ml in normal
`saline) to RLS patients. A single intravenous treatment Will
`provide relief of symptoms for an extended period of time,
`approximately tWo to tWelve months (Nordlander 1953),
`although relief may be granted for shorter or longer periods.
`If desired, post-infusion changes in CNS iron status can be
`monitored using measurements of CSF ferritin (and other
`iron-related proteins) and of brain iron stores using MRI.
`Post-infusion changes in RLS are assessed using standard
`subjective (e.g., patient diary, rating scale) and objective
`(e.g., P50, SIT, Leg Activity Meters) measures of clinical
`status. If desired, to better evaluate RLS symptom amelio
`ration, CSF and serum iron values, MRI measures of brain
`iron and full clinical evaluations With sleep and immobili
`Zation tests are obtained prior to treatment, approximately
`tWo Weeks after treatment, and again tWelve months later or
`When symptoms return. Clinical ratings, Leg Activity Meter
`recordings and serum ferritin are obtained monthly after
`treatment. CSF ferritin changes can also be used to assess
`symptom dissipation. More details are provided in Example
`2 and the references cited therein.
`
`[0053] The frequency of dosing depends on the response
`of each individual patient and the administered amount of
`elemental iron. An appropriate regime of dosing Will be once
`every Week to once every eighteen months, more preferably
`once every tWo to tWelve months, or any interval betWeen,
`such as once every tWo months and one day, three, four, ?ve,
`six, seven, eight, nine, ten and eleven months. Alternatively,
`the iron complexes may be administered ad hoc, that is, as
`symptoms reappear, as long as safety precautions are
`regarded as practiced by medical professionals.
`
`[0054] It Will be understood, hoWever, that the speci?c
`dose and frequency of administration for any particular
`patient may be varied and depends upon a variety of factors,
`including the activity of the employed iron complex, the
`
`metabolic stability and length of action of that complex, the
`age, body Weight, general health, sex, diet, mode and time
`of administration, rate of excretion, drug combination, the
`severity of the particular condition, and the host undergoing
`therapy.
`
`EXAMPLES
`
`[0055] The folloWing examples are provided to illustrate
`the invention. Those skilled in the art can readily make
`insigni?cant variations in the compositions and methods of
`this invention. The examples are not meant to limit the
`invention in any Way.
`
`Example 1
`
`Iron Release Rates
`
`[0056] Intravenous iron agents donate iron to transferrin
`indirectly through prior intracellular uptake, processing and
`controlled release. HoWever, evidence that many adverse
`reactions to intravenous iron agents are dose-related, dose
`limiting and vary by class of agent support the hypothesis
`that direct donation may also occur. Intravenous iron admin
`istration at suf?cient doses may transiently over-saturate
`iron binding capacity, and that agents may vary in their
`potential to donate iron directly.
`[0057] The ability of candidate iron complexes (intrave
`nous injection preparations for ferric gluconate (also knoWn
`as sodium ferric gluconate complex in sucrose, Ferrlecit®)),
`iron sucrose (iron sucrose injection USP, Venofer®) and
`both available formulations of iron dextran (INFeD® and
`Dexferrum®) to donate iron to transferrin in serum in vitro
`Was assayed. A series of dilutions of the iron agents Were
`added to fresh serum, passed over an alumina column to
`remove iron-sugar complexes, and the resulting elutant
`assayed for transferrin-bound iron.
`
`[0058] This assay reliably excludes both iron agent and
`inorganic iron from interfering With the colorimetric assay
`of transferrin-bound iron in serum (Jacobs and Alexander
`1990).
`[0059] Parenteral Iron Formulations
`[0060] Ferric gluconate complex in sucrose, Ferrlecit®,
`12.5 mg/ml in 5 ml ampules (Watson Pharmaceuticals, Inc,
`Corona, Calif.), iron sucrose (iron sucrose injection USP,
`Venofer®, 20 mg/ml in 5 ml vials; American Regent Inc.,
`Shirley, NY.) and tWo formulations of iron dextran
`(INFeD®; Watson Pharmaceuticals, Inc, Corona, Calif.; and
`Dexferrum®; American Regent Inc., Shirley, NY; both 100
`mg/ml in 2 ml vials) Were used.
`[0061] For each experiment, all agents at all experimental
`concentrations Were examined on the same day. For each
`concentration of iron agent, an equimolar stock solution Was
`prepared on the day of use, using successive dilutions
`(E 1:10) in 0.9% NaCl.
`[0062] Experimental Iron