I lllll llllllll II llllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US 20060116349Al
`
`c19) United States
`c12) Patent Application Publication
`Helenek et al.
`
`c10) Pub. No.: US 2006/0116349 Al
`Jun. 1, 2006
`(43) Pub. Date:
`
`(54) METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF IRON FOR THE
`TREATMENT OF RESTLESS LEG
`SYNDROME
`
`(75)
`
`Inventors: Mary Jane Helenek, Brookville, NY
`(US); Marc L. Tokars, Douglassville,
`PA (US); Richard P. Lawrence,
`Calverton, NY (US)
`
`Correspondence Address:
`SONNENSCHEIN NATH & ROSENTHAL LLP
`P.O. BOX 061080
`WACKER DRIVE STATION, SEARS TOWER
`CHICAGO, IL 60606-1080 (US)
`
`(22) Filed:
`
`Oct. 31, 2005
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. 10/389,228,
`filed on Mar. 14, 2003, now Pat. No. 6,960,571.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 311737
`(2006.01)
`A61K 311724
`(52) U.S. Cl. ................................................. 514/54; 514/58
`
`(57)
`
`ABSTRACT
`
`(73) Assignee: Luitpold Pharmaceuticals, Inc.
`
`(21) Appl. No.:
`
`111263,510
`
`The invention is directed to methods of treating Restless Leg
`Syndrome by administering iron complexes with specificed
`iron release rates or specified iron core size.
`
`Pharmacosmos, Exh. 1064, p. 1
`
`

`
`Patent Application Publication
`
`Jun. 1, 2006 Sheet 1 of 2
`
`US 2006/0116349 Al
`
`FIGURE 1
`
`400
`
`300
`
`=o -Cl
`:1. -
`
`c:
`0
`.!::: 200
`"O
`c:
`:J
`0
`.0 c:
`:::>
`
`100
`
`G
`
`s
`
`I
`D
`
`Cmax (ref)
`
`100 mg
`
`• 125 mg
`•
`• 100 mg
`• 100 mg
`
`0
`
`0
`
`2000
`
`4000
`
`6000
`
`8000
`
`Added iron (µg/dl)
`
`Pharmacosmos, Exh. 1064, p. 2
`
`

`
`Patent Application Publication
`
`Jun. 1, 2006 Sheet 2 of 2
`
`US 2006/0116349 Al
`
`Dexferrum
`
`Venofer
`
`0
`
`0.25
`
`0.50
`
`0.75
`
`0
`
`0.25
`
`0.50
`
`0.75
`
`Fig. 2A
`
`Vit-45
`
`""
`
`1.00
`
`Fig. 2B
`
`Fig. 2C
`
`Pharmacosmos, Exh. 1064, p. 3
`
`

`
`US 2006/0116349 Al
`
`Jun. 1, 2006
`
`1
`
`METHODS AND COMPOSITIONS FOR
`ADMINISTRATION OF IRON FOR THE
`TREATMENT OF RESTLESS LEG SYNDROME
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This is a continuation-in-part of co-pending U.S.
`patent application Ser. No. 10/389,228, filed Mar. 14, 2003.
`The above reference is incorporated herein by reference in
`its entirety.
`
`BACKGROUND
`
`[0002] Restless Legs Syndrome
`
`[0003] Victims seriously afflicted with Restless Leg Syn(cid:173)
`drome (RLS; also known as Ekbom's syndrome), are vir(cid:173)
`tually unable to remain seated or even to stand still. Activi(cid:173)
`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(cid:173)
`mances, become difficult if not impossible. Tortured by these
`sensations which become more severe at night, RLS patients
`find sleep to be virtually impossible, adding to the dimin(cid:173)
`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(cid:173)
`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(cid:173)
`while-awake (DWA) (Herring et al. 1986) or more com(cid:173)
`monly, periodic limb movements while awake (PLMW).
`
`[0004] 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(cid:173)
`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 2001 a). 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 define RLS), periodic limb
`movement disorder (PLMD; a sleep disorder) and nocturnal
`(or sleep) myoclonus (Allen and Earley 2001a).
`[0005]
`Iron and Dopamine Concentrations are Intertwined
`Factors in RLS.
`[0006] Lack of iron and reduced dopamine synthesis in the
`brain are important factors in RLS (Ekbom 1960, Nord(cid:173)
`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 hydroxy lase, 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, Herring et al., 1999, Montplaisir et
`al. 1991).
`[0007] Because iron is a co-factor for tyrosine hydroxy lase
`in dopamine synthesis, dopamine is reduced. When chela(cid:173)
`tors (substances that make iron physiologically unavailable)
`are administered to rats having excessive brain iron, they
`were effective in reducing dopamine and dopamine turnover
`(Ward et al. 1995). Studies in iron-deficient animals have
`also demonstrated decreases in dopamine receptors (Ben(cid:173)
`Shachar et al. 1985, Ward et al. 1995), dopamine transporter
`function and density, and 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 fluid
`(CFS) ferritin (an important iron storage protein) and three(cid:173)
`fold more CSF transferrin (iron transport blood protein),
`despite normal serum levels of ferritin and transferrin in
`both RLS and controls (Earley et al. 2000). Iron concentra(cid:173)
`tions vary throughout the brain, the site of dopamine syn(cid:173)
`thesis; RLS patients have less iron in the substantia nigra and
`in the putamen parts of the brain (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
`
`Parkinson
`
`Pergolide w/
`levodopa!carbidopa
`Prarnipexole
`Narcotic analgesics
`
`Clonazepam
`Triazolarn
`Gabapentin
`
`Parkinson
`
`Parkinson
`Pain control
`
`Epilepsy
`Insomnia
`Epilepsy
`
`Carbarnazepine
`
`Epilepsy
`
`dyskinesia (inability to control movements), nausea,
`hallucinations
`dyskinesia, nausea, hallucinations, rhinitis (mucous
`membrane inflammation), 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 (llilable to coordinate
`muscular movement)
`fetal malformation, rash, hyponatremia (blood sodium
`deficiency), hepatotoxicity, blood disorders, ataxia, gastro(cid:173)
`intestinal problems, sexual dysfunction, toxicity
`
`% affected3
`
`4-17
`
`7-62
`
`9-28
`none reported
`
`6-37
`1-14
`11-19
`
`1-33
`
`Pharmacosmos, Exh. 1064, p. 4
`
`

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`US 2006/0116349 Al
`
`Jun. 1, 2006
`
`2
`
`Medication
`
`Clonidine
`
`intravenous iron dextran
`
`TABLE I-continued
`
`Side effects of current treatments for Restless Legs Syndrome (RLS) 1
`
`Disease2
`
`Side effects
`
`reduced blood pressure, dermatitis, systemic side effects (dry
`mouth, somnolence, dizziness, headache)
`anaphylaxis, possibility resulting in death
`
`Hypertension
`
`iron deficiencies
`(Fishbane et al. 1996)
`and random sampling
`(Hamstra et al. 1980)
`
`% a:ffected3
`
`8-89
`
`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.
`2 Studies were performed on patients suffering from the indicated disease, not RLS, with the indicated drug.
`3 As reported in the studies referenced within (Chesson AL et al. 1999). See Chesson et al. 1999 for more information. The percent (&)
`range is derived from the reported percentages for each side effect; thus in the first example, 12-1 7% suffered from dyskinesia, 6% from
`nausea and 4% from hallucinations; the reported range is 4--17%.
`
`[0008] Treating RLS
`[0009] Current treatments for RLS are varied and plagued
`with undesirable side effects (see Table 1). Therapies have
`included the administration of dopamine agonists (sub(cid:173)
`stances that prod the production of dopamine), other dopam(cid:173)
`inergic agents, benzodiazepines, opiates and anti-convul(cid:173)
`sants. In cases where RLS results from a secondary
`condition, such as pregnancy, end-stage renal disease, eryth(cid:173)
`ropoietin (EPO) treatment and iron deficiency, 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.
`[0010] 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, Herring et
`al. 1999). Despite changes in their treatment regimes,
`15-20% of patients find that all medications are inadequate
`because of adverse effects and limited treatment benefit
`(Earley and Allen 1996).
`[0011] 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(cid:173)
`tion is simple and inexpensive. In fact, RLS patients with
`serum iron deficiency respond dramatically to oral iron
`supplements (Ekbom 1960, O'Keeffe et al. 1994). However,
`in RLS patients with normal_serum ferritin levels, the
`benefits 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 benefits
`(O'Keeffe et al. 1994). This approach to raise body stores of
`iron is ineffective because the gut controls iron absorption,
`responding not to dopamine synthesis cues, but to serum
`iron levels (Conrad et al. 1999). To increase body stores of
`iron when serum ferritin levels are normal, unacceptably
`high oral doses for months would need to be administered,
`or methods that bypass gut regulation would need to be used.
`[0012]
`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 dextrose 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(cid:173)
`can Regent Laboratories, Inc.; Shirley, N.Y.) and those
`outlined in (Andreasen and Christensen 2001); 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 significant 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(cid:173)
`ening condition; just less than 50% of those suffering
`anaphylaxis die.
`
`SUMMARY OF THE INVENTION
`[0013] Among the various aspects of the present invention
`is the provision of a method of treating Restless Leg
`Syndrome (RLS). Briefly, therefore, the present invention is
`directed to treating RLS with an iron carbohydrate complex
`of particular iron release rate and/or iron core size. Thus, the
`methods described herein provide for the safe and eflicica(cid:173)
`cious delivery of iron to subjects in need thereof as well as
`allowing thorough tissue distribution, faster labile iron
`release, and increased in vitro donation of iron to transferrin.
`
`[0014] The present teachings include methods for treating
`Restless Leg Syndrome that involve the administration of an
`iron complex to a patient suffering from RLS. The iron
`complex can be selected from an iron carbohydrate, an iron
`aminoglycan, or an iron polymer. The iron release rate of the
`iron complex used in this aspect of the invention is at least
`115 µg/dl at a concentration of at least 2,000 µg/dl.
`
`[0015]
`In accordance with a further aspect, RLS is treated
`by administering an iron complex of particular iron core size
`to a patient suffering from RLS. The iron complex can be
`selected from an iron carbohydrate, an iron aminoglycan, or
`an iron polymer. The iron core size of the iron complex used
`in this aspect is no greater than 9 nm.
`
`[0016] Yet another aspect provides kits, comprising an
`iron complex having an iron core size no greater than 9 nm
`(in solution or lyophilized), a syringe, and a syringe needle.
`The kit may also include instructions for use.
`[0017] Other objects and features will be in part apparent
`and in part pointed out hereinafter.
`
`Pharmacosmos, Exh. 1064, p. 5
`
`

`
`US 2006/0116349 Al
`
`Jun. 1, 2006
`
`3
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0018] Those of skill in the art will understand that the
`drawings, described below, are for illustrative purposes only.
`The drawings are not intended to limit the scope of the
`present teachings in any way.
`
`[0019] FIG. 1 shows the change in serum transferrin(cid:173)
`bound iron (li. iron) of the intravenous injection preparations
`for ferric gluconate (also known as sodium ferric gluconate,
`iron gluconate complex (in sucrose) or Ferriecit®; Watson
`Pharma, Inc.; Corona, Calif.), iron sucrose (Venofer® (iron
`sucrose injection USP); American Regent Laboratories, Inc.;
`Shirley, N.Y.), iron dextran (INFeD®; Watson Pharma, Inc.),
`and another iron dextran (Dexferrum®; American Regent
`Laboratories, Inc.) as related to the amount of added iron.
`x-axis, added elemental iron (µg/dl); y-axis, li. iron (µg/dl).
`
`[0020] FIG. 2 is a series of electron micrographs that
`depict the particle size of three iron carbohydrate complexes.
`FIG. 2A is an electron micrograph depicting the particle size
`ofDexferrum (Iron Dextran). FIG. 2B is an electron micro(cid:173)
`graph depicting the particle size of Venofer (Iron Sucrose).
`FIG. 2C is an electron micrograph depicting the particle size
`of Vit -45 (Iron Carboxymaltose ).
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0021] 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, but
`at a lower dosage. These iron complexes avoid the risks of
`anaphylactic shock associated with IDI when administered
`intravenously and, because of the higher release rate, dosage
`can be lowered.
`
`[0022] An example of such an iron complex is Venofer®,
`an iron sucrose complex that has an incidence of anaphy(cid:173)
`lactoid 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.
`
`[0023]
`
`Iron Compositions for the Treatment of RLS
`
`[0024]
`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(cid:173)
`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)).
`
`[0025] Examples of iron carbohydrate complexes include
`iron simple saccharide complexes, iron oligosaccharide
`complexes, and iron polysaccharide complexes, such as:
`iron carboxymaltose, iron sucrose, iron polyisomaltose (iron
`dextran), iron polymaltose (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(cid:173)
`sorbitol-citric acid complex and iron sucrose-gluconic acid
`complex), and mixtures thereof.
`
`[0026] 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.
`
`[0027] Examples of iron polymer complexes include iron
`hyluronic acid complex, iron protein complexes, and mix(cid:173)
`tures thereof. Iron protein complexes include ferritin, trans(cid:173)
`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 filtra(cid:173)
`tion.
`
`[0028] One preferred iron complex
`iron sucrose
`is
`(Venofer®). This composition also avoids toxicity issues
`that are associated with smaller sugars, especially glucon(cid:173)
`ates, which have high iron release rates. Iron sucrose com(cid:173)
`positions balance these toxicity issues with optimal iron
`release rates.
`
`[0029] Determining Iron Complex Iron Release Rates
`(Esposito, 2002)
`
`[0030] 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 µg/dl. In the
`present invention, the iron complex must have a release rate
`of at least 115 µg/dl at a concentration of at least 2000 µg/dl;
`including 2000, 3000, 3500, 5000, and 10,000 µg/dl. Pref(cid:173)
`erably, at least 120 µg/dl, more preferably, at least 140 µg/dl.
`Two tests can be implemented to determine iron release
`rates, that by Esposito et al. (2000) and by Jacobs et al.
`(1990).
`
`[0031]
`
`"Chelator Test" (Esposito et al. 2000)
`
`[0032] The release rate of a candidate iron complex is the
`ability of the candidate complex to donate iron to apotrans(cid:173)
`ferrin or to an iron chelator, such as desferrioxamine. To
`detect such transfer, the probes fluorescein-transferrin (FI(cid:173)
`Tf) and fluorescein-desferrioxamine (FI-DFO) can be used,
`which undergo quenching upon binding to iron (Breuer and
`Cabantchik 2001). In short, the method involves mobiliza(cid:173)
`tion of iron from serum with 10 mM oxalate and its transfer
`to the metallosensor fluoresceinated apotransferrin (FI-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 fluorescence signal of fluo(cid:173)
`resceinated apotransferrin. Fluorescence may be measured
`using, for example, 96-well plates and a plate reader oper(cid:173)
`ating at 485/538 nm excitation/emission filter pair (gain=
`25).
`
`[0033]
`
`"Alumina Colunm Test" (Jacobs et al. 1990)
`
`[0034]
`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 final iron concentration determined using a chemistry
`analyzer, such as a Hitachi 717 chemistry analyzer. Fer(cid:173)
`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 clarifies
`
`Pharmacosmos, Exh. 1064, p. 6
`
`

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`US 2006/0116349 Al
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`Jun. 1, 2006
`
`4
`
`lipemic samples, buffers lower the pH to <2.0 to free iron as
`Fe3 + from transferrin, ascorbate reduces Fe3 + to Fe2+, and
`ferrozine reacts with Fe2
`+ to form a colored complex mea(cid:173)
`sured spectophotometrically at 560 nm. From this result the
`value of a control (blank) sample is subtracted from the
`experimental sample readings, and the result are recorded as
`the ll Tf-bound iron (µg/dl).
`
`[0035] Pharmaceutical Compositions
`
`[0036]
`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(cid:173)
`ervation, or to optimize a particular method of delivery.
`
`[0037] A "pharmaceutically acceptable carrier" includes
`any and all solvents, dispersion media, coatings, antibacte(cid:173)
`rial and anti-fungal agents, isotonic and absorption delaying
`agents, and the like, compatible with pharmaceutical admin(cid:173)
`istration (Gennaro 2000). Preferred examples of such carri(cid:173)
`ers or diluents include, but are not limited to, water, saline,
`Finger's solutions and dextrose solution. Supplementary
`active compounds can also be incorporated into the com(cid:173)
`positions. For intravenous administration, Venofer® is pref(cid:173)
`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
`
`[0038] General Considerations
`
`[0039] An iron complex composition of the invention for
`administration is formulated to be compatible with the
`intended route of administration, such as intravenous injec(cid:173)
`tion. Solutions and suspensions used for parenteral, intrad(cid:173)
`ermal or subcutaneous application can include a sterile
`diluent, such as water for injection, saline solution, poly(cid:173)
`ethylene glycols, glycerine, propylene glycol or other syn(cid:173)
`thetic solvents; antibacterial agents such as benzyl alcohol or
`methyl parabens; antioxidants such as ascorbic acid or
`sodium bisulfite; buffers such as acetates, citrates or phos(cid:173)
`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(cid:173)
`ide. Preparations can be enclosed in ampules, disposable
`syringes or multiple dose vials made of glass or plastic.
`
`[0040] 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(cid:173)
`PHOR EL™ (BASF; Parsippany, N.J.) or phosphate buff(cid:173)
`ered saline (PBS). The composition must be sterile and
`should be fluid 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,
`polyolo (such as glycerol, propylene glycol, and liquid
`polyethylene glycol), and other compatible, suitable mix(cid:173)
`tures. Various antibacterial and anti-fungal agents, for
`example, parabens, chlorobutanol, phenol, ascorbic acid,
`and thimerosal, can contain microorganism contamination.
`Isotonic agents such as sugars, polyalcohols, such as mani(cid:173)
`tol, sorbitol, and sodium chloride can be included in the
`
`that can delay absorption
`compos1t10n. Compositions
`include agents such as aluminum monostearate and gelatin.
`
`[0041] 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(cid:173)
`dients as required, followed by sterilization. Methods of
`preparation of sterile solids for the preparation of sterile
`injectable solutions include vacuum drying and freeze(cid:173)
`drying to yield a solid containing the iron complex and any
`other desired ingredient.
`
`[0042] Systemic Administration
`
`[0043] Systemic administration can be transmucosal or
`transdermal. For transmucosal or transdermal administra(cid:173)
`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(cid:173)
`tories can be used for transmucosal administration. For
`transdermal administration, the active compounds are for(cid:173)
`mulated into ointments, salves, gels, or creams.
`
`[0044] Carriers
`
`[0045] 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(cid:173)
`gradable or biocompatible polymers can be used, such as
`ethylene vinyl acetate, polyanhydrides, polyglycolic acid,
`collagen, polyorthoesters, and polylactic acid. Such materi(cid:173)
`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.
`
`[0046] Kits for Pharmaceutical Compositions
`
`[0047]
`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(cid:173)
`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(cid:173)
`out losing the activity of the components.
`
`[0048] Kits may also include reagents in separate contain(cid:173)
`ers that facilitate the execution of a specific test, such as
`diagnostic tests.
`
`[0049] Containers or Vessels
`
`[0050] 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(cid:173)
`bonate, polystyrene, etc., ceramic, metal or any other mate(cid:173)
`rial typically employed to hold reagents. Other examples of
`suitable containers include bottles that are 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, flasks, bottles, syringes,
`etc. Containers may have a sterile access port, such as a
`bottle having a stopper that can be pierced by a hypodermic
`
`Pharmacosmos, Exh. 1064, p. 7
`
`

`
`US 2006/0116349 Al
`
`Jun. 1, 2006
`
`5
`
`injection needle. Other containers may have two compart(cid:173)
`ments that are separated by a readily removable membrane
`that, upon removal, permits the components to mix. Remov(cid:173)
`able membranes may be glass, plastic, rubber, etc.
`
`[0051]
`
`Instructional Materials
`
`[0052] Kits may also be supplied with instructional mate(cid:173)
`rials. Instructions may be printed on paper or other substrate,
`and/or may be supplied on an electronic-readable medium,
`such as a floppy disc, CD-ROM, DVD-ROM, mini-disc,
`SACD, Zip disc, videotape, audio tape, etc. Detailed instruc(cid:173)
`tions may not be physically associated with the kit; instead,
`a user may be directed to an internet web site specified by
`the manufacturer or distributor of the kit, or supplied as
`electronic mail.
`
`[0053] Methods for the Treatment ofRLS with Iron Com(cid:173)
`plex Compositions
`
`[0054] Methods of treatment of RLS with iron complex
`compositions having greater iron release rates than 115 µg/dl
`and/or core size no greater than 9 nm comprise the admin(cid:173)
`istration of the complex, either as doses administered over
`pre-determined time intervals or in response to the appear(cid:173)
`ance and reappearance ofRLS symptoms. In general, dosage
`depends on the route of administration. The preferred route
`of administration is intravenous infusion; however, certain
`iron compounds may be administered 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 intravenously) such that RLS symp(cid:173)
`toms are treated.
`
`[0055] An appropriate dosage level will generally be about
`0.1 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, 1100.0, 1200.0, 1300.0, 1400.0, 1500.0,
`1600.0, 1700.0, 1800.0, 1900.0, 2000.0, 2100.0, 2200.0,
`2300.0, 2400.0 or 2500.0 milligrams of elemental iron to the
`maximal tolerated dose (MTD) per administration. For
`example, the dosage level can be about 0.1 to about 1000 mg
`per dose; or about 100 mg to about 500 mg per dose.
`Alternatively, the dosage level can be, for example, about
`1800 mg to about 1900 mg. The compounds may be
`administered on various regimes (see Example 3).
`
`[0056] 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(cid:173)
`ration, CSF and serum iron values, MRI measures of brain
`iron and full clinical evaluations with sleep and immobili(cid:173)
`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.
`[0057] 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, five,
`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.
`It will be understood, however, that the specific
`[0058]
`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 co