(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2003/0232084A1
`(43) Pub. Date:
`Dec. 18, 2003
`Groman et al.
`
`US 2003O232084A1
`
`(54) POLYOL AND POLYETHER IRON OXIDE
`COMPLEXES AS PHARMACOLOGICAL
`AND/OR MRI CONTRASTAGENTS
`(76) Inventors: Ernest V. Groman, Brookline, MA
`(US); Kenneth G. Paul, Holliston, MA
`(US); Timothy B. Frigo, Waltham, MA
`(US); Howard Bengele, Canton, MA
`(US); Jerome M. Lewis, Newton, MA
`(US)
`Correspondence Address:
`Barbara J. Carter
`Bromberg & Sunstein LLP
`125 Summer Street
`Boston, MA 02110-1618 (US)
`(21) Appl. No.:
`10/410,527
`(22) Filed:
`Apr. 9, 2003
`Related U.S. Application Data
`(63) Continuation-in-part of application No. 09/521,264,
`filed on Mar. 8, 2000, now Pat. No. 6,599,498.
`
`(60) Provisional application No. 60/128,579, filed on Apr.
`9, 1999.
`
`Publication Classification
`
`(51) Int. Cl. ............................. A61K 33/26; A61K 9/14
`(52) U.S. Cl. ............................................ 424/486; 424/646
`
`(57)
`
`ABSTRACT
`
`Pharmacological compositions, and methods for administra
`tion, of the type employing an iron oxide complex with a
`polyol or polyether. The methods of administration may
`comprise parenteral administration of an effective dose of
`the complex formulated in a biocompatible liquid delivered
`at a rate of from about 1 mL/sec to less than 1 mL/min and
`wherein upon administration the complex provides minimal
`detectable free iron in a Subject, and minimal incidence of
`anaphylaxis. The pharmacological compositions are of the
`type employing a polyol or polyether iron oxide complex,
`which, upon parenteral administration to a Subject, are
`Substantially immunosilent, provide minimal anaphylaxis
`and minimal free iron, and undergo minimal dissolution in
`WVO.
`
`IPR2019-01142
`Pharmacosmos v. American Regent
`Petitioner Ex. 1003 - Page 1
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`

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`Patent Application Publication Dec. 18, 2003 Sheet 1 of 13
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`US 2003/0232084 A1
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`Percent of Cross-Reactivity to ol-Dextran for C-7228 versus INFeD'Usin g ELISA
`
`ELISA Results. Using Rat Serum Raised to Dextran-BSA
`
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`Figure 1
`
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`Petitioner Ex. 1003 - Page 2
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`Patent Application Publication Dec. 18, 2003 Sheet 2 of 13
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`US 2003/0232084 A1
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`Patent Application Publication Dec. 18, 2003 Sheet 3 of 13
`
`US 2003/0232084 A1
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`Patent Application Publication Dec. 18, 2003. Sheet 4 of 13
`Figure 4
`
`US 2003/0232084 A1
`
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`IPR2019-01142
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`Petitioner Ex. 1003 - Page 5
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`Patent Application Publication Dec. 18, 2003 Sheet 5 of 13
`
`US 2003/0232084 A1
`
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`IPR2019-01142
`Pharmacosmosv. American Regent
`Petitioner Ex. 1003 - Page 6
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`IPR2019-01142
`Pharmacosmos v. American Regent
`Petitioner Ex. 1003 - Page 6
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`
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`

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`Patent Application Publication Dec. 18, 2003 Sheet 6 of 13
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`US 2003/0232084 A1
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`Patent Application Publication Dec. 18, 2003 Sheet 7 of 13
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`US 2003/0232084 A1
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`Figure 7A
`
`
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`Patent Application Publication Dec. 18, 2003. Sheet 8 of 13
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`US 2003/0232084 A1
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`Figure 7B
`
`
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`Post Contras
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`Patent Application Publication Dec. 18, 2003 Sheet 9 of 13
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`US 2003/0232084 A1
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`Figure 8A
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`
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`Patent Application Publication Dec. 18, 2003. Sheet 10 of 13
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`US 2003/0232084 A1
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`Figure 8B
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`
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`IPR2019-01142
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`

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`Patent Application Publication Dec. 18, 2003. Sheet 11 of 13
`Figure 9A
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`US 2003/0232084 A1
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`
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`Patent Application Publication Dec. 18, 2003 Sheet 12 of 13
`Figure 9B
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`US 2003/0232084A1
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`
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`Patent Application Publication Dec. 18, 2003. Sheet 13 of 13
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`US 2003/0232084 A1
`
`Figure 10
`
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`
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`IPR2019-01142
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`US 2003/0232084 A1
`
`Dec. 18, 2003
`
`POLYOLAND POLYETHER IRON OXDE
`COMPLEXES AS PHARMACOLOGICAL AND/OR
`MR CONTRASTAGENTS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`0001. This application is a continuation-in-part applica
`tion from U.S. patent application Ser. No. 09/521,264, filed
`Mar. 8, 2000 which in turn claims the benefit of Provisional
`Application No. 60/128,579, filed in the United States Patent
`and Trademark Office on Apr. 9, 1999, both of which are
`hereby incorporated by reference herein.
`
`TECHNICAL FIELD AND BACKGROUND ART
`0002 The field relates to complexes of polyols and
`polyethers with iron oxides including a reduced polysaccha
`ride or derivatized reduced polysaccharide, and methods for
`administering as pharmacological and/or MRI contrast
`agents.
`
`BACKGROUND
`0003. Since the invention of magnetic resonance imaging
`(MRI), a parallel technology of injectable chemicals called
`contrast agents has developed. Contrast agents play an
`important role in the practice of medicine in that they help
`produce more useful MRI images for diagnostic purposes. In
`particular, two classes of imaging agents have been devel
`oped and adopted in clinical practice. These are: low
`molecular Weight gadolinium complexes. Such as Mag
`navist(R); and colloidal iron oxides such as Feridex I.V.OE) and
`Combidex(R). Neither of these two types of agents is ideal.
`Problems encountered with these agents are shown in Table
`1, and include: expense of components, inefficiency of
`Synthesis, loss of coating during terminal Sterilization (auto
`claving); narrow range of organ uptake for purposes of
`imaging, toxic side-effects, restriction of use to either first
`pass or equilibrium dosing, and others that are described
`herein. Agents that overcome these problems, and that
`combine the properties of these two types of contrast agents,
`are highly desirable.
`
`TABLE 1.
`
`Comparison of ideal properties of MRI contrast agents with properties of
`low molecular weight gadolinium based contrast agents and colloidal iron
`oxides.
`
`Properties of an ideal
`contrast agent
`
`low molecular weight
`gadolinium
`
`colloidal iron
`Oxides
`
`Low production costs:
`efficient synthesis
`Autoclavable without
`excipients
`T1 agent
`T2 agent
`Non toxic
`Imaging vascular
`compartment at early phase
`(as a bolus administration)
`and at a late stage
`(equilibrium phase)
`Multiple administration in
`single examination
`Image of multiple target
`Organs
`Bolus injection
`
`Yes
`
`Yes
`
`Yes
`No
`Yes
`No
`
`No
`
`Yes
`
`Yes
`
`No
`
`No
`
`Sometimes
`Yes
`No
`No
`
`No
`
`Sometimes
`
`No
`
`TABLE 1-continued
`
`Comparison of ideal properties of MRI contrast agents with properties of
`low molecular weight gadolinium based contrast agents and colloidal iron
`oxides.
`
`Properties of an ideal
`contrast agent
`
`low molecular weight
`gadolinium
`
`colloidal iron
`oxides
`
`Low volume of injection
`Iron source for anemia
`
`No
`No
`
`No
`Yes
`
`SUMMARY OF THE INVENTION
`0004. An embodiment in accordance with the presently
`claimed invention includes an improved method for admin
`istration of a pharmacological composition of the type
`employing an iron oxide complex with a polyol or polyether,
`wherein the improvement comprises administering parenter
`ally an effective dose of an iron oxide complex with a polyol
`or polyether, the complex formulated in a biocompatible
`liquid So that upon administration the complex provides
`minimal detectable free iron in a Subject and minimal
`incidence of anaphylaxis, and effecting Such administration
`at a rate Substantially greater than 1 mL/min or alternatively,
`the administration may be at a rate of about 1 mL/sec.
`0005 We have found it possible to formulate complexes
`having the properties described above. Whereas prior art
`complexes of dextran and iron oxide can be made that have
`minimal detectable free iron, and other complexes of iron
`oxide may have minimal incidence of anaphylaxis, no prior
`art complexes of iron oxide have both properties. We have
`Surprisingly found a way of providing a complex of modi
`fied polyols or polyethers with iron oxide that have both
`properties. We have found, for example, that a polysaccha
`ride Such as dextran, when reduced and carboxyalkylated,
`can be complexed with iron oxide to produce a composition
`that continues (like dextran iron oxide) to have minimal
`detectable free iron in a Subject, while (unlike dextran iron
`oxide) also having minimal incidence of anaphylaxis.
`0006 Another embodiment of the present invention
`includes an improved method for administration of a phar
`macological composition of the type employing an autocla
`vable reduced carboxyalkylated polysaccharide iron oxide
`complex with a polyol or polyether, wherein the improve
`ment comprises administering parenterally an effective dose
`of an iron oxide complex, the complex formulated in a
`biocompatible liquid So that upon administration the com
`pleX provides minimal detectable free iron in a Subject, and
`minimal incidence of anaphylaxis, and effecting Such
`administration at a rate Substantially greater than 1 mL/min
`or alternatively, a rate of about 1 mL/sec.
`0007. A particular embodiment of the presently claimed
`invention includes an improved method for administration
`of a pharmacological composition of the type employing an
`iron oxide complex with a polyol or polyether, wherein the
`improvement comprises parenteral administration of the
`complex to provide minimal detectable free iron in a Subject
`as measured by a catalytic bleomycin assay and minimal
`incidence of anaphylaxis.
`0008 Another particular embodiment includes an
`improved method for administration of a pharmacological
`
`IPR2019-01142
`Pharmacosmos v. American Regent
`Petitioner Ex. 1003 - Page 15
`
`

`

`US 2003/0232084 A1
`
`Dec. 18, 2003
`
`composition of the type employing an iron oxide complex
`with a polyol, for example dextran, or polyether, for example
`polyethylene glycol, wherein the improvement further com
`prises parenteral administration of the complex to provide
`minimal dissolution of the complex in a human Subject
`measured as a function of transferrin Saturation in Vivo.
`0009 Still another particular embodiment provides an
`improved method for administration of a pharmacological
`composition of the type employing an iron oxide complex
`with a polyol or polyether, wherein the improvement further
`comprises parenteral administration of the complex to pro
`vide the polyol or polyether complex as an immunosilent
`complex in a human Subject.
`0.010 Another particular embodiment in accordance with
`the present invention includes an improved pharmacological
`composition of the type employing an iron oxide complex
`with a polyol or polyether, wherein the improvement com
`prises formulating a polyol or polyether complexation with
`iron oxide to provide upon administration to a Subject
`minimal detectable free iron in the Subject as measured by
`a catalytic bleomycin assay and minimal incidence of ana
`phylaxis.
`0.011
`Yet another embodiment in accordance with the
`present invention is an improved pharmacological compo
`Sition of the type employing an iron oxide complex with a
`polyol or polyether, wherein the improvement comprises
`formulating a polyol or polyether complex with the iron
`oxide to provide upon administration to a Subject minimal
`dissolution of the complex in the Subject, measured as a
`function of transferrin Saturation in Vivo.
`0012. Other embodiments include an improved pharma
`cological composition of the type employing an iron oxide
`complex with a polyol or polyether, wherein the improve
`ment comprises formulating a polyol or polyether complex
`ation with iron oxide to provide upon administration to a
`Subject the iron oxide complex as an immunosilent complex
`in a human Subject.
`0013 Another embodiment in accordance with the
`present invention includes an improved method for admin
`istration of a pharmacological composition of the type
`employing an iron oxide complex with a polyol or polyether,
`wherein the improvement comprises parenteral administra
`tion of an effective dose of the complex formulated in a
`biocompatible liquid delivered at a rate Substantially greater
`than 1 mL/min and wherein upon administration the com
`pleX provides minimal detectable free iron in a Subject, and
`minimal incidence of anaphylaxis, or alternatively, the com
`pleX is delivered at a rate of about 1 mL/Sec. More particu
`larly, the improved method may utilize an assay for deter
`mining minimal detectable free iron wherein the assay is any
`assay known in the art for measuring free iron concentration,
`including a BDI assay, atomic absorption SpectroScopy, a %
`transferrin Saturation assay, a % dialysis assay, and a bac
`terial growth assay. Still more particularly, the assay for
`determining minimal incidence of anaphylaxis is an ELISA
`asSay.
`In other embodiments in accordance with the
`0.014.
`invention includes an improved method for administering a
`pharmacological composition of the type employing an iron
`oxide complex with a polyol or polyether, wherein the
`improvement comprises parenteral administration of an
`
`effective dose of the complex formulated in a biocompatible
`liquid delivered at a rate Substantially greater than 1
`mL/min, or alternatively at about 1 mL/Sec, and wherein
`upon administration the complex provides minimal detect
`able free iron in a Subject and minimal incidence of ana
`phylaxis, and wherein the free iron concentration is deter
`mined using a BDI assay, and is less than about 750 nM, or
`less than about 0.04 ug/mL, or less than about 0.1% of the
`effective dose of iron oxide, depending upon how the
`BDI-detected free iron measurement is reported. In alterna
`tive embodiments, the free iron concentration is determined
`using atomic absorption spectroscopy, and is less than about
`1 ppm or less than about 0.04 ug/mL, or less than about 0.1%
`of the effective dose of the iron oxide, depending upon how
`the atomic absorption-detected free iron measurement is
`reported; or, the free iron concentration is determined using
`a iron dialyzed % assay, and the dialyzed-determined free
`iron percent is less than about 1%.
`0015 Yet another embodiment of the present invention
`includes an improved method for administration of a phar
`macological composition of the type employing an iron
`oxide complex with a polyol or polyether, wherein the
`improvement comprises parenteral administration of an
`effective dose of the complex formulated in a biocompatible
`liquid delivered at a rate Substantially greater than 1
`mL/min, or alternatively at a rate of about 1 mL/Sec, and
`wherein upon administration the complex provides minimal
`detectable free iron in a Subject and minimal incidence of
`anaphylaxis, and wherein the improvement further com
`prises parenteral administration of the complex to provide
`minimal dissolution of the complex in a human Subject.
`More particularly, in alternative embodiment, the minimal
`dissolution of the complex is determined using a % trans
`ferrin Saturation assay; and more particularly, the minimal
`dissolution of the complex determined by a % transferrin
`saturation assay is less than about 95% saturation for a total
`dose from about 1 mg/kg of body weight to about 4 mg/kg
`of body weight, up to a total Single dose of about 500 mg to
`about 600. An alternative embodiment further comprises
`parenteral administration of the complex to provide the iron
`oxide complex as a Substantially immunosilent complex in
`a human Subject. In Such embodiments, Verification of
`administration that provides a complex that is Substantially
`immunosilent in a human complex may be determined by a
`guinea pig anaphylaxis test.
`0016 Other embodiments in accordance with the present
`invention include an improved pharmacological composi
`tion of the type employing an iron oxide complex with a
`polyol or polyether, wherein the improvement comprises a
`polyol or polyether iron oxide complex composition pre
`pared at concentrations of between about 1 mg/kg of body
`weight to about 4 mg/kg of body weight in a total Volume of
`biocompatible liquid from about 1 mL to about 15 mL and
`for a total single dose from about 50 mg to about 600 mg,
`wherein the pharmacological composition is capable of
`being parenterally administered to a Subject at a rate Sub
`Stantially greater than 1 mL/min, or alternatively at a rate of
`about 1 mL/Sec, and wherein the iron oxide complex pro
`vides upon administration minimal detectable free iron in
`the Subject and minimal incidence of anaphylaxis. More
`particularly, the improved pharmacological composition
`may further comprise an iron oxide complex having minimal
`free iron concentration in the Subject. Determination of
`minimal free iron can be measured using any Standard assay
`
`IPR2019-01142
`Pharmacosmos v. American Regent
`Petitioner Ex. 1003 - Page 16
`
`

`

`US 2003/0232084 A1
`
`Dec. 18, 2003
`
`for measuring free iron known in the art, including a BDI
`assay, atomic absorption spectroscopy, a % transferrin Satu
`ration assay, a % dialysis assay, or a bacterial growth assay.
`Alternatively, the improved pharmacological composition
`may further comprise an iron oxide complex that undergoes
`minimal dissolution in a human Subject upon administration
`to the subject. Other alternatives envision that the improved
`pharmacological composition may further comprise an iron
`oxide complex that undergoes minimal dissolution upon
`administration in a human Subject. Minimal dissolution may
`be determined using a % transferrin Saturation assay. Alter
`natively, the improved pharmacological composition may
`further comprise an iron oxide complex that is Substantially
`immunosilent upon administration in a human Subject, and
`particularly, the improved pharmacological composition
`may further comprise an iron oxide complex that is Sub
`Stantially immunosilent in a human Subject as determined by
`a guinea pig anaphylaxis test.
`0.017. Yet another embodiment in accordance with the
`present invention includes a method of treating a Subject
`with an iron oxide complex to a Subject in need thereof, the
`method comprising parenterally administering the complex
`formulated in a pharmaceutically acceptable formulation in
`a biocompatible liquid, effecting administration at a rate
`Substantially greater than 1 mL/min, and providing an effec
`tive dose in the range of about 1 mg/kg of body weight to
`about 4 mg/kg of body weight in a total Volume of biocom
`patible liquid of between about 1 mL and 15 mL so that
`minimal free iron and minimal anaphylaxis occurs. More
`particularly, the method may comprise effecting administra
`tion at a rate of between about 180 u/sec and about 1
`mL/min. Still more particularly, the administration of the
`iron oxide complex provides minimal dissolution of the
`complex in the Subject and may further provide a Substan
`tially immunosilent complex to the Subject. More particu
`larly, a guinea pig test may be used to determine that the
`complex administered in the above method for treating is
`Substantially immunosilent to the Subject.
`0.018. Another embodiment of the invention includes a
`method of treating a Subject with an autoclavable reduced
`carboxyalkylated polyol, for example dextran, iron oxide
`complex having at least 750 but less than 1500 umole of
`carboxyalkyl groups per gram of polyol to a Subject, the
`method comprising parenterally administering the complex
`formulated in a pharmaceutically acceptable formulation in
`a biocompatible liquid, effecting administration at a rate
`Substantially greater than 1 mL/min, and providing an effec
`tive dose in the range of about 1 mg/kg of body weight to
`about 4 mg/kg of body weight in a total Volume of biocom
`patible liquid of between about 1 mL and 15 mL so that
`minimal free iron and minimal anaphylaxis occurs.
`0.019
`Yet another embodiment includes an improved
`pharmacological composition of the type employing an
`autoclavable carboxyalkylated polyether iron oxide com
`plex, for example polyethylene glycol, wherein the improve
`ment comprises a carboxyalkylated iron oxide complex
`composition having at least 250 umole but less than 1500
`tumole of carboxyalkyl groups per gram of polyether, pre
`pared at concentrations of between about 1 mg/kg of body
`weight to about 4 mg/kg of body weight in a total Volume of
`biocompatible liquid from about 1 mL to about 15 mL and
`for a total single dose from about 50 mg to about 600 mg,
`wherein the pharmacological composition is capable of
`
`being parenterally administered to a Subject at a rate Sub
`Stantially greater than 1 mL/min and wherein the iron oxide
`complex provides upon administration minimal detectable
`free iron in the Subject and minimal incidence of anaphy
`laxis.
`0020. Another embodiment of the invention is a method
`of providing an iron oxide complex for administration to a
`mammal Subject, the method comprising: producing a
`reduced polysaccharide iron oxide complex, and Sterilizing
`the complex by autoclaving. In general, the reduced polysac
`charide is a reduced polymer of glucose. An example of a
`reduced polymer of glucose is a reduced dextran. The
`reduced polysaccharide is produced through reaction of a
`polysaccharide with a reagent Selected from the group
`consisting of a borohydride Salt or hydrogen in the presence
`of a hydrogenation catalyst. In a further aspect of the
`method, the iron oxide is Superparamagnetic.
`0021 Another particular embodiment of the invention is
`a method of providing an iron oxide complex for adminis
`tration to a mammalian Subject, the method comprising:
`producing a derivatized reduced polysaccharide iron oxide
`complex, and Sterilizing the complex by autoclaving.
`According to this method, producing the complex can
`include derivatizing a reduced polysaccharide by formation
`of, for example, ethers, amides, esters, and amines at the
`hydroxyl positions of the polysaccharide. In a particular
`embodiment, the derivative formed is an ether of the
`polysaccharide, more particularly a carboxyalkyl ether of
`the polysaccharide, and more particularly, a carboxymethyl
`ether of the polysaccharide. Further according to this
`method, the reduced polysaccharide can be a reduced dex
`tran. The derivatized, reduced polysaccharide can be iso
`lated as the Sodium Salt and does not contain an infrared
`absorption peak in the region of 1650-1800 cm. In one
`aspect of the method, producing the derivatized reduced
`polysaccharide is achieved at a temperature of less than
`approximately 50° C. In another aspect of the method,
`producing the derivatized reduced polysaccharide is
`achieved at a temperature of less than approximately 40 C.
`In a further aspect of the method, the iron oxide is Super
`paramagnetic.
`0022. In yet another embodiment, the invention provides
`a method of formulating an iron oxide complex coated with
`a reduced polysaccharide. This composition is for pharma
`cological use and the composition has decreased toxicity in
`comparison to a formulation of an iron oxide complex
`coated with the non-reduced polysaccharide. The method of
`formulating Such an iron oxide complex comprises: produc
`ing a reduced polysaccharide iron oxide complex, and
`Sterilizing the complex by autoclaving. The formulation
`provides a polysaccharide which was produced by reacting
`the polysaccharide with one of a reducing agent Selected
`from the group consisting of a borohydride Salt or hydrogen
`in the presence of an hydrogenation catalyst, wherein the
`reduced polysaccharide iron oxide complex So made has
`Such decreased toxicity. In a further aspect of the method,
`the iron oxide is Superparamagnetic.
`0023. In yet another embodiment, the invention provides
`a method of formulating an iron oxide complex coated with
`a reduced derivatized polysaccharide. This composition is
`for pharmacological use and the composition has decreased
`toxicity in comparison to a formulation of an iron oxide
`
`IPR2019-01142
`Pharmacosmos v. American Regent
`Petitioner Ex. 1003 - Page 17
`
`

`

`US 2003/0232084 A1
`
`Dec. 18, 2003
`
`complex coated with the non-reduced derivatized polysac
`charide. The method of formulating Such an iron oxide
`complex comprises: producing a reduced derivatized
`polysaccharide iron oxide complex; and Sterilizing the com
`plex by autoclaving. According to this method, producing
`the complex can include derivatizing a reduced polysaccha
`ride by carboxyalkylation, for example, wherein the car
`boxyalkylation is a carboxymethylation. Further according
`to this method, the reduced polysaccharide can be a reduced
`dextran. The derivatized, reduced polysaccharide can be
`isolated as the Sodium Salt and does not contain an infrared
`absorption peak in the region of 1650-1800 cm. In one
`aspect of the method, producing the derivatized reduced
`polysaccharide is achieved at a temperature of less than
`approximately 50° C. In another aspect of the method,
`producing the derivatized reduced polysaccharide is
`achieved at a temperature of less than approximately 40 C.
`In a further aspect of the method, the iron oxide is Super
`paramagnetic.
`0024. Another embodiment of the invention provides a
`reduced derivatized polysaccharide iron oxide complex with
`T1 and T2 relaxation properties to allow contrast agent
`Signal enhancement with T1 Sequences and Signal dimin
`ishment with T2 sequences. A further aspect of the embodi
`ment is that the reduced derivatized polysaccharide iron
`oxide can be administered multiple times for Sequential
`imaging in a Single examination. Yet another aspect of the
`agent is that it can be used to image multiple organ Systems
`including the vascular System, liver, Spleen, bone marrow,
`and lymph nodes.
`0.025. Another embodiment of the invention provides a
`reduced polysaccharide iron oxide complex for use as an
`intravenous iron Supplement.
`0026. Another embodiment of the invention provides a
`reduced derivatized polysaccharide iron oxide complex for
`use as an intravenous iron Supplement.
`0027. In yet a further embodiment, the invention provides
`an improved method of administering to a mammalian
`Subject an autoclaved reduced polysaccharide iron oxide
`complex. The improved method of administration compris
`ing: injection of an autoclaved reduced polysaccharide iron
`oxide complex in a volume of 15 mL or less. In another
`aspect of the embodiment the injected Volume is injected as
`a bolus. In a further aspect of the method, the iron oxide is
`Superparamagnetic. In a further aspect of the embodiment
`the injected Volume provides improved image quality.
`0028. In yet a further embodiment, the invention provides
`an improved method of administering to a mammalian
`Subject an autoclaved derivatized reduced polysaccharide
`iron oxide complex, the improved method of administration
`comprising: injection of an autoclaved reduced derivatized
`polysaccharide iron oxide complex in a volume of 15 mL or
`leSS. In another aspect of the embodiment the injected
`Volume is injected as a bolus. In a further aspect of the
`method, the iron oxide is Superparamagnetic. In a further
`aspect of the embodiment the injected Volume provides
`improved image quality.
`0029. An embodiment of the invention provides an
`improved method of administering to a mammalian Subject
`a reduced polysaccharide iron complex to a mammalian
`Subject wherein the improvement comprises administration
`
`of a reduced polysaccharide in formulation to provide
`reduced toxicity relative to administration of a non-reduced
`polysaccharide. In a further aspect of the embodiment, the
`iron oxide is Superparamagnetic.
`0030. An embodiment of the invention provides an
`improved method of administering to a mammalian Subject
`a reduced derivatized polysaccharide iron complex in a
`manner that the composition provides reduced toxicity,
`wherein the improvement comprises utilizing a reduced
`derivatized polysaccharide in formulation of the composi
`tion. In a further aspect of the embodiment, the iron oxide is
`Superparamagnetic.
`0031. An embodiment of the invention provides a
`reduced polysaccharide iron oxide complex, wherein the
`reduced polysaccharide is derivatized, for example, the
`reduced derivatized polysaccharide is a carboxyalkyl
`polysaccharide. The carboxyalkyl is Selected from the group
`consisting of carboxymethyl, carboxyethyl and carboxypro
`pyl. Further, the reduced polysaccharide can be a reduced
`dextran, for example, the reduced dextran can be a reduced
`carboxymethyl dextran. A further aspect of this embodiment
`of the invention is that the level of derivatization of the
`reduced dextran is at least 750 tumole but less than 1500
`tumole of carboxyl groups per gram of polysaccharide
`wherein Said composition has reduced toxicity relative to
`composition with respect to lower levels of derivatization.
`0032. An embodiment of the invention provides a
`reduced polysaccharide iron oxide complex, Such complex
`being stable at a temperature of at least approximately 100
`C. In a preferred embodiment, Such complex is stable at a
`temperature of approximately 121 C. In an even more
`preferred aspect of the reduced polysaccharide iron oxide
`complex, Such complex is stable at a temperature of at least
`121 C. for a time sufficient to sterilize the complex. In a
`further aspect of the embodiment, the iron oxide is Super
`paramagnetic.
`0033. An embodiment of the invention provides a
`reduced derivatized polysaccharide iron oxide complex,
`Such complex being Stable at a temperature of at least
`approximately 100° C. In a preferred embodiment, such
`complex is stable at a temperature of approximately 121 C.
`In an even more preferred aspect of the reduced polysac
`charide iron oxide complex, Such complex is stable at a
`temperature of at least 121 C. for a time sufficient to
`Sterilize the complex. In a further aspect of the embodiment,
`the iron oxide is Superparamagnetic.
`0034. A particular embodiment of the invention is a
`method of formulating for pharmacological use a reduced
`polysaccharide iron oxide complex having increased pH
`Stability in comparison to the corresponding native dextran
`iron oxide, the method comprising: providing dextran, and
`reacting the dextran with a borohydride Salt or hydrogen in
`the presence of an hydrogenation catalyst, reacting the
`reduced dextran with iron Salts to provide a formulation
`having a Stable pH.
`0035) A particular embodiment of the invention is a
`method of formulating for pharmacological use a reduced
`derivatized polysaccharide iron oxide complex having
`increased pH Stability in comparison to the corresponding
`native dextran iron oxide, the method comprising: providing
`dextran; and reacting the dextran with a borohydride Salt or
`
`IPR2019-01142
`Pharmacosmos v. American Regent
`Petitioner Ex. 1003 - Page 18
`
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`US 2003/0232084 A1
`
`Dec. 18, 2003
`
`hydrogen in the presence of an hydrogenation catalyst,
`reacting the reduced dextran with iron Salts to provide a
`formulation having a stable pH.
`0036). In another embodiment, the invention provides a
`method of formulating a reduced derivatized dextran com
`position for pharmacological use wherein the composition
`has decreased toxicity in comparison to native dextran,
`comprising: producing a reduced derivatized polysaccha
`ride; and Sterilizing the product by autoclaving. According
`to this method, the reduced polysaccharide is obtained by
`reacting the native polysaccharide with one of Several reduc
`ing agents Selected from the group consisting of a borohy
`dride Salt or hydrogen in the presence of a hydrogenation
`catalyst. In a preferred aspect of the emb