(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2008/0234226 A1
`Erichsen et al.
`(43) Pub. Date:
`Sep. 25, 2008
`
`US 20080234226Al
`
`(54) USE OF IRON(III) COMPLEX COMPOUNDS
`FOR THE PREPARATION OF A
`MEDICAMENT FOR 0RAL TREATMENT OF
`IRON DEFICIENCY STATES IN PATIENTS
`WITH CHRONIC INFLAMMATORY BOWEL
`DISEASE
`
`(86) PCT No.:
`
`PCT/EP2006/065532
`
`§ 371 (OX1),
`(2), (4) Date:
`
`Apr. 21, 2008
`
`(30)
`
`Foreign Application Priority Data
`
`(75) Inventors:
`
`Kari Erichsen, Bergen (NO); B0
`Damelson’ Herglswll (CH)
`
`(EP) ................................ .. 051077907
`Aug. 25, 2005
`Publication Classi?cation
`
`Correspondence Address:
`RANKIN, HILL & CLARK LLP
`925 EUCLID AVENUE, sUITE 700
`CLEVELAND, OH 44115-1405 (US)
`
`(73) Assignee:
`
`VIFOR (INTERNATIONAL) AG,
`St‘ Gallen (CH)
`
`(21) Appl. NO.I
`
`12/064,053
`
`(22) PCT Filed;
`
`Aug, 22, 2006
`
`(51) Int- Cl
`(2006-01)
`A61K 31/721
`(2006-01)
`A61P 1/00
`(52) us. Cl. ........................................................ .. 514/59
`
`ABSTRACT
`(57)
`The use of iron(lll) complex compounds With carbohydrates
`or derivatives thereof for the preparation of a medicament for
`oral treatment of iron de?ciency states in patients With
`chronic in?ammatory boWel disease, in particular Crohn’s
`disease and colitis ulcerosa, is disclosed.
`
`450-
`
`¥—"'_‘1
`
`.-..
`
`'
`
`h 400-
`:z}
`"6 3 5O -
`
`g: 3 O0 ""
`
`V- I
`
`g 1 .50."
`m 1 00
`
`Q-
`
`.50 *
`
`before after
`iron(||) sulfate
`
`iron(lll)-polymaltose
`complex
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2050, P. 1
`
`

`
`Patent Application Publication
`
`Sep. 25, 2008
`
`US 2008/0234226 A1
`
`Figure 1
`
`)
`
`.%
`
`
`
`
`
`Plasma MDA (nmoI/L
`
`l
`
`I g
`
`.....\ N
`
`before after
`iron?i) sulfate
`
`iron(Hl)-p0iyma|tose
`complex
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2050, P. 2
`
`

`
`US 2008/0234226 A1
`
`Sep.25,2008
`
`USE OF IRON(III) COMPLEX COMPOUNDS
`FOR THE PREPARATION OF A
`MEDICAMENT FOR ORAL TREATMENT OF
`IRON DEFICIENCY STATES IN PATIENTS
`WITH CHRONIC INFLAMMATORY BOWEL
`DISEASE
`
`[0001] The present invention relates to novel therapeutic
`uses of iron(III) complex compounds With carbohydrates or
`derivatives thereof, in particular With dextrins or oxidation
`products of dextrins, namely for the preparation of medica
`ments for treatment of iron de?ciency states in patients With
`chronic in?ammatory boWel diseases, in particular Crohn’s
`disease and/or colitis ulcerosa.
`[0002] Iron de?ciency is the most frequent trace element
`de?ciency WorldWide. Approx. 2 billion people WorldWide
`suffer from iron de?ciency or iron de?ciency anaemia (E. M.
`DeMaeyer, “Preventing and controlling iron de?ciency
`anaemia through primary health care”, World Health Organi
`Zation, Geneva, 1989, ISBN 92 4 154249 7).
`[0003] WO 95/35113 discloses the use ofiron(III) oxide as
`an active compound for treatment of immunoinsu?ciency
`diseases, in particular AIDS.
`[0004] DE 1467980 discloses therapeutically usable iron
`injection preparations and processes for their preparation.
`[0005] US. Pat. No. 3,076,798 discloses processes for the
`preparation of iron(III)-polymaltose complex compounds
`Which are suitable for parenteral administration.
`[0006] WO 04/037865 discloses the use of iron-carbohy
`drate complexes for treatment or prophylaxis of iron de?
`ciency states.
`[0007] WO 03/087164 discloses iron complex compounds
`With hydrogenated dextrins for treatment or prophylaxis of
`iron de?ciency states.
`[0008] WO 02/46241 discloses iron(III)-pullulan complex
`compounds and their use for treatment or prophylaxis of iron
`de?ciency states.
`[0009] WO 99/48533 discloses iron-dextran compounds
`for treatment of iron de?ciency anaemia, Which comprise
`hydrogenated dextran having a particular molecular Weight of
`approx. 1,000 Dalton.
`[0010] I. Maslovski, American Journal of Hematology,
`April 2005, vol. 78, no. 4, p. 261 -264 discloses the activity of
`Ferrlecit®, an iron(III)-gluconate complex in sucrose having
`a molecular Weight of 350,000, or Venofer®, an iron(lll)
`sucrose complex, for intravenous treatment of anaemic
`patients suffering from chronic in?ammatory boWel disease.
`[0011] G. Bodemar et al., Scandinavian Journal of Gastro
`enterology, May 2004, vol. 39, p. 454-458 describes iron(III)
`sucrose compounds for intravenous treatment of anaemia in
`patients With Crohn’s disease and ulcerative colitis.
`[0012] DE-A-102 49 552 describes iron(III) complex com
`pounds With maltodextrins and the (particularly preferably
`parenteral) use thereof for treatment of anaemia.
`[0013] CH-A-694 197 describes iron(III)-polymaltose
`compounds for treatment of anaemia, but Without giving indi
`cations of actions in the gastrointestinal tract or on IBD or
`Crohn’s disease.
`[0014] Iron sulfate is knoWn to cause relatively frequently
`unpleasant dose-dependent side reactions, such as gas
`trointestinal disorders or a discoloration of the teeth. Iron
`from iron salt compounds is subject to passive diffusion of
`free iron ions. The iron can enter the circulation and as a result
`
`cause side reactions or an iron poisoning. Accordingly, the
`LD50 value in White mice of 230 mg iron/kg is relatively loW.
`[0015] The use of iron-dextran is disclosed in Oski et al.
`“Effect of Iron Therapy on Behavior Performance in Nonane
`mic, Iron-De?cient Infants”, PEDIATRICS 1983; volume 71 ;
`877-880. Parenteral use of iron-dextran is disadvantageous
`because a dextran-induced anaphylactic shock may occur.
`[0016] In?ammatory boWel diseases (IBD) include a group
`of diseases of the gastrointestinal tract Which are character
`iZed by intestinal in?ammation and a chronic course With
`constant relapses. IBD has traditionally been characteriZed
`either as colitis ulcerosa or as Crohn’s disease, based on
`clinical, radiological, endoscopic and histological criteria.
`Although the aetiology of IBD still requires de?nition, recent
`clinical and experimental studies suggest that the trigger and
`the pathogenesis of these diseases are multifactorial, and that
`interactions betWeen genetic, environmental and immune
`factors are involved.
`[0017] In?ammatory boWel diseases are not spread uni
`formly throughout the World. There is a clear tendency
`toWards an increased occurrence in developed countries com
`pared With less developed countries. The occurrence of IBD
`in Europe is approx. 390 cases per 100,000 people. Extrapo
`lation of these ?gures to the European population of approx.
`580 million gives an estimated number of 2.2 million people
`affected by IBD (Loftus EV, Jr., Gastroenterology 2004, 126,
`11504-1517). Colitis ulcerosa and Crohn’s disease are diag
`nosed most frequently in older adolescents and young adults,
`but can occur at any age.
`[0018] Colitis ulcerosa is a disease of the mucous mem
`brane Which conventionally affects the rectum and then
`extends into the adjacent areas, so that all or part of the colon
`is affected. The spread is continuous, Without areas of unaf
`fected mucous membrane remaining. The main symptoms of
`colitis ulcerosa are violent diarrhea, rectal bleeding, mucous
`discharge and cramp-like abdominal pain. The severity of the
`symptoms correlates With the extent of the disease.
`[0019] Crohn’s disease can affect any region of the gas
`trointestinal tract from the mouth to the anus, but most fre
`quently relates to the small intestine and/or the colon. The
`in?ammation is transmural and segmental, normal areas
`existing betWeen the areas of diseased intestine. Conse
`quences of the in?ammation include ?stulation on other loops
`of the intestine, the urinary bladder, the vagina or the perianal
`skin, abdominal or perianal abscesses and narroWing of the
`intestine. The location and the course of the disease in?uence
`the clinical manifestations. The most frequent symptoms are
`diarrhea, cramp-like abdominal pain, fever, anorexia and
`Weight loss.
`[0020] Extraintestinal manifestations of colitis ulcerosa
`and Crohn’s disease can relate to multiple organ systems,
`such as eyes, skin and joints, and equally gastrointestinal
`organs, including the liver and gallbladder.
`[0021] Treatment comprises administration of anti-in?am
`matory agents and under certain circumstances antibiotics,
`and a change in diet. An operation may occasionally be nec
`essary. Psychotherapy is furthermore often undertaken, on
`the one hand for the management of stress, Which is also a
`triggering factor, and on the other hand for treatment of
`depression, Which often arises as a consequence of the
`chronic ever-recurring symptoms (see eg Pschyrembel, Kli
`nisches Worterbuch, 256th edition, de Gruyter, p. 302/303, p.
`443; http://familydoctor.org or http://WWW.mayoclinic.com).
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2050, P. 3
`
`

`
`US 2008/0234226 A1
`
`Sep.25,2008
`
`[0022] Iron de?ciency often occurs as a complication in
`patients With chronic in?ammatory bowel disease. Chronic
`intestinal bleeding can lead to more iron being lost than is
`taken in through food. Conventional oral iron preparations, in
`general iron(ll) salts, often cause severe gastrointestinal side
`effects, Which leads to a poor patient compliance. Oral iron
`therapy can intensify the lesions of the intestinal tissue by
`catalysis of the formation of reactive oxygen species. Since
`free iron is a potent catalyst of the formation of reactive
`oxygen species, oral iron(ll) therapy can even be harmful for
`patients With chronic in?ammatory boWel disease. Oral iron
`(11) preparations are poorly absorbed and lead to high faecal
`iron concentrations, and a signi?cant content of the faecal
`iron is available for the catalytic activity. If iron comes into
`contact With the in?amed intestinal mucosa, it can increase
`the production of reactive oxygen species and as a result
`intensify tissue damage. It is therefore particularly important
`for patients With chronic in?ammatory boWel disease to have
`available readily tolerated iron preparations.
`[0023] lron(lll)-polymaltose complex contains iron in a
`nonionic form, Which is less toxic. FeWer side effects occur on
`administration of compounds of this type, and patient com
`pliance is improved compared With iron(ll) sulfate (Jacobs,
`R, Wood, L., Bird, A R., Hematol. 2000, 5:77-83). HoWever,
`there is not yet any experience or reports of the use of iron
`(lll)-polymaltose complex in patients With chronic in?am
`matory boWel disease.
`[0024] The inventors therefore had the object of discover
`ing readily tolerated iron compounds Which are suitable for
`treatment of iron de?ciency states in patients With chronic
`in?ammatory boWel disease.
`[0025] They Were able to demonstrate in a study that iron
`(Ill) complex compounds With carbohydrates, in particular
`With polymaltose (maltodextrin), are tolerated in particular
`and have a high patient compliance. In this study, it Was
`surprising that under treatment With the iron(lll) complexes
`no oxidative stress occurred, in contrast to treatment With
`iron(ll) sulfate, under Which a signi?cant increase in plasma
`malondialdehyde (MDA), a lipid peroxidation marker, Was
`observed.
`[0026] Oxidative stress, in particular lipid peroxidation, is
`associated With an increased risk of suffering from cardiac
`infarction, cancer and atherosclerosis. Oxidative modi?ca
`tion of loW-density lipoprotein (LDL) is held responsible for
`atherogenesis (see references given in Tuomainen et al.,
`Nutrition Research, vol. 19, no. 8, pp. 1121-1132, 1999).
`[0027] lron(lll)-polymaltose complex compounds indeed
`lead to only a sloW increase in the ferritin level, but are used
`more ef?ciently for haemoglobin synthesis (T.-P. Tuomainen
`et al., loc. cit., p. 1127). The inventors have provided the
`present invention on the basis of these results.
`[0028] The present invention therefore provides the use of
`iron(lll) complex compounds With carbohydrates or deriva
`tives thereof for the preparation of a medicament for treat
`ment of iron de?ciency states in patients With chronic in?am
`matory boWel disease.
`[0029] According to the invention, iron de?ciency state is
`understood as meaning a state in Which haemoglobin, iron
`and ferritin levels in the plasma are reduced and transferrin is
`increased, Which leads to a reduced transferrin saturation.
`[0030] The state to be treated according to the invention
`includes iron de?ciency anaemia and iron de?ciency Without
`anaemia. The classi?cation can be made, for example, by the
`haemoglobin value and the value for the transferrin saturation
`
`(%). Reference values for haemoglobin, determined by ?oW
`cytometry or the photometric cyanohaemoglobin method,
`and reference values for iron, ferritin and transferrin are
`listed, for example, in the reference bank of the charity Insti
`tut ?ir LaboratoriumsmediZin und Pathobiochemie (http://
`WWW.charite.de/ilp/routine/parameter.html) and in Thomas,
`L., Labor und Diagnose, TH Book Verlagsgesellschaft,
`Frankfurt/ Main 1998. Transferrin saturationis as a rule >16%
`in patients Without iron de?ciency. The normal values are
`given in Table 111 Which folloWs beloW.
`[0031] According to M. Wick, W. Pinggera, P. Lehmann,
`EisenstoffWechseliDiagno stik und Therapien der Anamien,
`4th exp. ed., Springer Verlag Vienna 1998, all forms of iron
`de?ciency can be detected by clinical chemistry. In this con
`text, a reduced ferritin concentration is in general accompa
`nied by an increased transferrin in compensation and a loWer
`transferrin saturation.
`[0032] Chronic in?ammatory boWel disease (IBD) is
`understood as meaning a chronic in?ammation of the diges
`tive tract, in particular Crohn’s disease and colitis ulcerosa.
`[0033] lron(lll) complex compounds With carbohydrates
`Which can be used according to the invention preferably
`include those in Which carbohydrates are chosen from the
`group consisting of dextrans and derivatives thereof, dextrins
`and derivatives thereof as Well as pullulan, oligomers and/or
`derivatives thereof. The derivatives mentioned include, in
`particular, the hydrogenated derivatives. lron(lll) complex
`compounds With dextrins or oxidation products thereof are
`particularly preferred. Examples of the preparation of the
`iron(lll) complex compounds according to the invention are
`to be found, for example, in the abovementioned patent speci
`?cations DE 14679800, WO 04037865 A1, US. Pat. No.
`3,076,798, WO 03/087164 and WO 02/46241, the disclosure
`content of Which, in particular in respect of the preparation
`processes, is to be included here in its full scope. The term
`“dextrins”, Which are preferably used according to the inven
`tion, is a collective name for various loWer and higher poly
`mers of D-glucose units Which are formed on incomplete
`hydrolysis of starch. Dextrins can furthermore be prepared by
`polymeriZation of sugars (e.g. WO 02083739 A2, US
`20030044513 A1, US. Pat. No. 3,766,165). Dextrins include
`maltodextrins and polymaltoses, Which are prepared by enZy
`matic cleavage of, for example, maiZe starch or potato starch
`With alpha-amylase and Which are characterized by the
`degree of hydrolysis, expressed by the DE value (dextrose
`equivalent). According to the invention, polymaltose can also
`be obtained by acid hydrolysis of starches, in particular dex
`trins. The preparation of the iron(lll) complex compounds
`Which can be used according to the invention is in general
`carried out by reaction of iron(ll) or -(III) salts, in particular
`iron(lll) chloride, With the dextrins, in particular polymal
`tose, or oxidation products of the dextrins in aqueous alkaline
`solution (pH>7) and subsequent Working up. The preparation
`is also achieved in a Weakly acid pH range. HoWever, alkaline
`pH values of, for example, >10 are preferred.
`[0034] The pH is preferably increased sloWly or gradually,
`and this can be effected, for example, by ?rst adding a Weak
`base, for example up to a pH of about 3; further neutraliZation
`can then be carried out With a stronger base. Possible Weak
`bases are, for example, alkali metal or alkaline earth metal
`carbonates or bicarbonates, such as sodium and potassium
`carbonate or bicarbonate, or ammonia. Strong bases are, for
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2050, P. 4
`
`

`
`US 2008/0234226 A1
`
`Sep.25,2008
`
`example, alkali metal or alkaline earth metal hydroxides,
`such as sodium, potassium, calcium or magnesium hydrox
`ide.
`[0035] The reaction can be promoted by heating. For
`example, temperatures of the order of 150 C. up to the boiling
`temperature can be used. It is preferable to increase the tem
`perature gradually. Thus, for example, the mixture can be ?rst
`heated to about 15 to 70° C. and the temperature can be
`gradually increased up to the boiling point.
`[0036] The reaction times are, for example, of the order of
`15 minutes to several hours, eg 20 minutes to 4 hours, for
`example 25 to 70 minutes, eg 30 to 60 minutes.
`[0037] When the reaction has taken place, the solution
`obtained can be cooled, for example, to room temperature and
`optionally diluted and optionally ?ltered. After the cooling,
`the pH can be adjusted to the neural point or slightly beloW
`this, for example to values of 5 to 7, by addition of acid or
`base. Bases Which can be used are, for example, those men
`tioned above for the reaction. Acids include, for example,
`hydrochloric acid and sulfuric acid. The solutions obtained
`are puri?ed and can be used directly for the preparation of
`medicaments. However, it is also possible to isolate the iron
`(III) complexes from the solution, for example by precipita
`tion With an alcohol, such as an alkanol, for example ethanol.
`The isolation can also be carried out by spray drying. The
`puri?cation can be carried out in the conventional manner, in
`particular for removal of salts. This can be carried out eg by
`reverse osmosis, it being possible for such a reverse osmosis
`to be carried out e.g. before the spray drying or before the
`direct use in medicaments.
`[0038] The iron(III) complexes obtained have, for example,
`an iron content of 10 to 40% Wt./Wt., in particular 20 to 35%
`Wt./Wt. They are in general readily Water-soluble. Neutral
`aqueous solutions having an iron content of, for example, 1%
`Wt./vol. to 20% Wt./vol. can be prepared therefrom. These
`solutions can be steriliZed by means of heat.
`[0039] Reference may be made to Us. Pat. No. 3,076,798
`in respect of the preparation of iron(III)-polymaltose com
`plex compounds.
`[0040] In a preferred embodiment of the invention, an iron
`(III) hydroxide-polymaltose complex compound is used. This
`iron(III)-polymaltose complex compound preferably has a
`molecular Weight in the range from 20,000 to 500,000, and in
`a preferred embodiment 30,000 to 80,000 Dalton (determined
`by means of gel permeation chromatography, for example as
`described by Geisser et al. in ArZneim. Forsch/Drug Res.
`42(11), 121439-1452 (1992), paragraph 2.2.5.). A particu
`larly preferred iron(III) hydroxide-polymaltose complex
`compound is the commercially obtainable Maltofer® from
`Vifor AG, SWitZerland. In a further preferred embodiment, an
`iron(III) complex compound With an oxidation product of one
`or more maltodextrins is used. This is obtainable, for
`example, from an aqueous iron(III) salt solution and an aque
`ous solution of the product of the oxidation of one or more
`maltodextrins With an aqueous hypochlorite solution at a pH
`in the alkaline range, Wherein if one maltodextrin is employed
`the dextrose equivalent thereof is 5 to 37 and if a mixture of
`several maltodextrins is employed the dextrose equivalent of
`the mixture is 5 to 37 and the dextrose equivalent of the
`individual maltodextrins involved in the mixture is 2 to 40.
`The Weight-average molecular Weight MW of the complexes
`obtained in this Way is, for example, 30 kDa to 500 kDa,
`preferably 80 to 350 kDa, particularly preferably up to 300
`kDa (determined by means of gel permeation chromatogra
`
`phy, for example as described by Geisser et al. in ArZneim.
`Forsch/Drug Res. 42(11), 121439-1452 (1992), paragraph
`2.2.5.). Reference may be made, for example, to WO
`2004037865 A1 in this respect, the disclosure content of
`Which is to be included in its full scope in the present Appli
`cation.
`[0041] Reference may be made to WO 03/087164 in
`respect of the preparation of iron complex compounds With
`hydrogenated dextrins.
`[0042] Reference may be made to WO 02/46241 in respect
`of the preparation of iron(III)-pullulan complex compounds.
`[0043] The iron(III) hydroxide complex compounds used
`according to the invention are preferably administered orally.
`In principle, hoWever, they can also be administered parenter
`ally, such as intravenously, and also intramuscularly. The oral
`daily dose is, for example, betWeen 10 and 500 mg iron/day of
`use. The dose can be taken by the patient Without question
`over a period of several months until the iron status has
`improved, Which is re?ected by the haemoglobin value, the
`transferrin saturation and the ferritin value. The oral admin
`istration is preferably in the form of a tablet, a capsule, an
`aqueous solution or emulsion, as granules, a capsule, a gel or
`as a sachet. The use of solutions or emulsions is particularly
`preferred for children, in the form of syrups or juices, drops,
`etc. For this, the iron(III) hydroxide-dextrin complex com
`pounds can be brought into the suitable administration form
`With conventional pharmaceutical carrier or auxiliary sub
`stances. Conventional binders or lubricants, diluents, disinte
`grating agents, etc. can be used for this.
`[0044] The use according to the invention can be effected
`on children, adolescents and adults suffering from chronic
`in?ammatory boWel diseases, preferably on adults.
`[0045] The use according to the invention proceeds in par
`ticular by means of improvement in the iron, haemoglobin,
`ferritin and transferrin values, Whereby the clinical disease
`activity indices of the boWel condition, abdominal pain and
`nausea are not impaired by the treatment according to the
`invention.
`
`BRIEF DESCRIPTION OF THE FIGURE
`
`[0046] FIG. 1 is a diagram Which shoWs the plasma MDA
`levels measured in the example before and after treatment
`With iron(II) sulfate or iron(III)-polymaltose complex. The
`effect of iron(II) sulfate and iron(III)-polymaltose complex
`on the plasma level of malondialdehyde (MDA) in patients
`With chronic in?ammatory boWel disease is shoWn. The
`results are expressed as the mean :SEM. p values are given
`for paired comparisons.
`[0047] The invention is explained and demonstrated in its
`mode of action by the folloWing example.
`
`Example
`Patients
`
`[0048] 41 patients With chronic in?ammatory boWel dis
`ease (colitis ulcerosa or Crohn’s disease in the active or qui
`escent state) and iron de?ciency (de?ned by the mean cor
`puscular volume (MCV)<80 ? or s-ferritin<15 ug/l or
`s-soluble transferrin receptor >1.54 mg/l) Were divided into
`tWo groups in accordance With the randomization principle.
`Patients Who had received an iron therapy or blood transfu
`sions during the 6 Weeks before the study Was conducted, an
`aZathioprine treatment starting less than tWo months before
`the start of the study or an in?iximab treatment, Were suffer
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2050, P. 5
`
`

`
`US 2008/0234226 A1
`
`Sep.25,2008
`
`ing from cobalamin or folic acid de?ciency, cancer or kidney
`diseases or Were pregnant Were excluded. Analysis of the
`blood, urine and stool and the clinical evaluation of the dis
`ease Were carried out on day 1 and 15.
`
`Medication
`
`[0049] The treatment Was carried out in group 1 With iron
`(II) sulfate (Nycoplus Ferro-Retard®, Nycomed Pharma AS,
`Norway) With one table (100 mg) (corresponding to 100 mg
`Fe“) in the morning and one tablet (100 mg) in the evening
`betWeen meals for 14 days, and in group 2 With iron(III)
`polymaltose complex (Maltofer Filmtabletten®, Vifor Inter
`national AG, SWitZerland) With tWo tablets (200 mg in total)
`(corresponding to 200 mg Fe(III)) once daily in the morning
`during a meal for 14 days. The tablets Were taken in accor
`dance With the manufacturer’s recommendations. Patient
`compliance Was de?ned as the consumption of the tablets
`handed out, 80% being regarded as satisfactory.
`
`Laboratory Studies
`[0050] Blood samples Were taken, after fasting during the
`night, on the morning of day 1 and day 15.
`[0051] The plasma malondialdehyde (MDA), plasma ami
`nothiophenols, plasma vitamins A, E and C and plasma beta
`carotene Were determined by high-performance liquid chro
`matography (HPLC) as described in the literature (Svardal, A
`M., Manssor, M A., Ueland, P M., Anal. Biochem. 1990;
`184:338-346; Vaagenes, H., Muna, Z A., Madsen, L., Berge,
`R K., Lipids 1998; 33: 1 131-1 137).
`[0052] Routine laboratory analyses included determination
`of blood haemoglobin, the blood reticulocyte count, deterrni
`nation of the mean corpuscular volume (MCV), the mean
`corpuscular haemoglobin (MCH) and the mean corpuscular
`haemoglobin concentration (MCHC), a blood erythrocyte
`count, blood leukocyte count and blood platelet count, deter
`mination of the reticulocyte haemoglobin (CHr), the hypo
`chromic red cell count (HYPO), determination of serum fer
`ritin and serum iron, determination of the serum total iron
`binding capacity, the serum soluble transferrin receptor and
`the serum C-reactive protein (S-CRP), measurement of the
`blood erythrocyte sedimentation rate (B-ESR) and deterrni
`nation of serum protein and serum albumin.
`[0053] Urine samples Were collected on the morning of day
`1 and day 15 and analysed for creatinine. Butyl-hydroxy
`toluene (BHT) Was added to 2 ml urine to a ?nal concentra
`tion of 20 mM. The samples Were then stored at —800 C. until
`analysed for urine 8-isoprostaglandin F20‘ (8-iso-PGF20L). The
`analysis Was carried out by gas chromatography/mass spec
`trometry in accordance with the method of NourooZ-Zadeh et
`al. (NourooZ-Zadeh J., Gopaul N K., BarroW S., Mallet A I.,
`Anggard E E., J. Chromatogr. B. Biomed. Appl. 1995; 667:
`199-208), but Was modi?ed in respect of the urine matrix by
`omitting the initial hydrolysis step and using the stationary
`phase protocol of Lee et al. (Lee C Y., Jenner A M., HalliWell
`B., Biochem. Biophys. Res. Commun. 2004; 320:696-702).
`
`on 5 parameters: general Well-being, abdominal pain, stool
`frequency, abdominal mass and extraintestinal complica
`tions. The maximum score is 25 and scores of 25 indicate
`active Crohn’s disease.
`In patients With colitis ulcerosa, the “Simple Clini
`[0055]
`cal Colitis Activity Index” Was recorded (Walmsley, R S.,
`Ayres, RC., Pounder, RE.,Allan, RN., Gut 1998; 43; 29-32).
`The Simple Clinical Colitis Activity Index is based on 6
`parameters: general Well-being, stool frequency during the
`day and during the night, urgency of defecation, blood in the
`stool and extraintestinal complications. The maximum score
`is 20 and values of 24 indicate active colitis ulcerosa.
`The Harvey-Bradshaw Simple Index and the Simple
`[0056]
`Clinical Colitis Activity Index are the same in respect of
`structure and the clinical signi?cance of a given change in the
`scores. In order to alloW the results of patients With Crohn’s
`disease and colitis ulcerosa to be considered together, the
`activity scores Were calculated as the actual score divided by
`the maximum score.
`[0057] All the patients completed the particular Crohn’s
`Disease Activity Index (CDAI) diary card (Best, W R., Beck
`tel, J M., Singleton, J W., Kern, F. Jr., Gastroenterology 1976;
`70:439-444) in the Week before the start of the iron therapy
`and during the tWo Weeks of iron therapy. The CDAI diary
`card comprises daily recording of general Well-being,
`abdominal pain and the number of liquid or very soft stools.
`The total of seven daily records gives a score for each symp
`tom. The higher the score, the more the patient is adversely
`affected. The medicament Was administered during the study
`for 14 days and the mean for the tWo Weeks is therefore used
`for the analysis. The patients also documented the occurrence
`of nausea before and during the iron therapy.
`[0058]
`Patients Who discontinued treatment With the medi
`cament because of a deterioration in the symptoms Were
`included in the analysis of the clinical disease activity and the
`symptom scores. Their disease activity scores Were increased
`by tWo points, and the symptom scores Were increased by one
`point per day.
`
`Aim and Results
`
`[0059] The primary aim of the study Was a comparison of
`the action of oral iron(II) sulfate and oral iron(III)-polymal
`tose complex on markers for oxidative tissue damage. The
`primary results Were plasma MDA and urine iso-PGFZOL. The
`second aim Was comparison of the action of the tWo iron
`formulations on the clinical disease activity and speci?c
`symptoms. The treatment time Was too short for a study of the
`clinical effectiveness on the elimination of iron de?ciency.
`
`Clinical Disease Activity
`
`Statistical Analysis
`
`[0054] The status of the clinical disease Was recorded
`before (day 1) and after (day 15) the iron therapy. The clinical
`disease activity Was evaluated in patients With Crohn’s dis
`ease With the “Harvey-Bradshaw Simple Index of Crohn’s
`Disease Activity” (Harvey, R F., BradshaW, J M., Lancet,
`1980; 1:514). The Harvey-Bradshaw Simple Index is based
`
`[0060] The differences Within and betWeen the groups Were
`evaluated using the paired and non-paired Student t test, and
`the mean of the differences and the 95% con?dence interval
`are stated. The values Were analysed using the Wilcoxon test
`for pair differences, and the median and range are stated. The
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2050, P. 6
`
`

`
`US 2008/0234226 A1
`
`Sep.25,2008
`
`comparison of ratios Was evaluated With the Fisher Exact test.
`P values of less than 0.05 are considered to be statistically
`signi?cant. The data Were analysed using the GraphPad Prism
`4 for WindoWs statistics software package (GraphPad Soft
`Ware, Inc., San Diego, USA).
`
`Results
`
`41 patients (Table 1) Were divided in accordance
`[0061]
`With the randomization principle for treatment either With
`iron(ll) sulfate (n:21) or With iron(lll)-polymaltose complex
`(n:20). 37 patients completed the study in accordance With
`the protocol. In these patients, counting of the tablets resulted
`in a comparable compliance in the patients treated With iron
`(11) sulfate (100% (82-100)) and With iron(lll)-polymaltose
`complex (100% (86-100)). Three patients (1 Crohn’s disease,
`2 colitis ulcerosa) discontinued the intake of iron(ll) sulfate
`after 1, 4 and days respectively, and one patient (Crohn’s
`disease) discontinued the treatment With iron(lll)-polymal
`tose complex after 1 day. They all suffered from intolerable
`boWel movements, abdominal pain and nausea. These
`patients Were excluded from the analysis of the laboratory
`values, but are included in the analysis of the clinical disease
`activity and the symptom scores.
`
`Markers for Oxidative Stress
`
`[0062] Treatment With iron(ll) sulfate clearly increased the
`plasma MDA values by 95 nmol/l (Cl 18 to 171; p:0.018)
`(FIG. 1) and increased the urine iso-PGFZa values by 194
`pg/mg creatinine (Cl 58 to 447; p:0.12). Treatment With
`iron(lll)-polymaltose complex did not signi?cantly change
`the plasma MDA (p:0.16) (FIG. 1) or urine iso-PGFM (p:0.
`56) (Table II). The plasma vitamins A, C and E, beta-carotene,
`glutathione, cysteine, cysteinyl-glycine and homocysteine
`Were unchanged after both treatments (Table II). On compari
`son of the treatment With iron(ll) sulfate and iron(lll)-poly
`maltose complex, the changes (before-after) in the plasma
`MDA (p:0.08) and urine iso-PGFZa (p:0.28) do not differ
`signi?cantly. HoWever, the mean plasma MDA values of the
`tWo groups Were signi?cantly different after the particular
`treatment (p:0.007), higher MDA values occurring in the
`iron(ll) sulfate group (Table 11). None of the urine or plasma
`parameters correlated With the clinical activity index.
`
`Clinical Disease Activity and Symptoms
`
`[0063] The scores of the clinical disease activity are given
`in Table III. Neither the treatment With iron(ll) sulfate (p:0.
`45) nor the treatment With iron(lll)-polymaltose complex
`(p:0.80) substantially changed the clinical disease activity
`indice