Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2000-03-08
2003-07-29
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009350, C424S493000, C514S054000, C514S059000
Reexamination Certificate
active
06599498
ABSTRACT:
TECHNICAL FIELD
The field relates to compositions which are carboxymethyl reduced polysaccharides, and methods for use as plasma extenders and for coating iron oxide particles, and compositions comprised of superparamagnetic and non-superparamagnetic iron oxides coated with a reduced polysaccharide or derivatized reduced polysaccharide, and methods for use as MRI contrast agents and hematinics.
BACKGROUND
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 developed and adopted in clinical practice. These are: low molecular weight gadolinium complexes such as Magnavist®; and colloidal iron oxides. 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 if sterilized by autoclaving; narrow range of organ uptake for purposes of imaging; 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
low molecular weight
colloidal
contrast agent
gadolinium
iron oxides
Low production costs:
Yes
No
efficient synthesis
Autoclavable without
Yes
No
excipients
T1 agent
Yes
Sometimes
T2 agent
No
Yes
Non toxic at vast excess
Yes
No
Imaging vascular
No
No
compartment at early phase
(as a bolus administration)
and at a late stage
(equilibrium phase)
Multiple administration in
No
No
single examination
Image of multiple target
Yes
Sometimes
organs
Bolus injection
Yes
No
Low volume of injection
No
No
Iron source for anemia
No
Yes
SUMMARY
An 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 polysaccharide 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.
Another preferred embodiment of the invention is a method of providing an iron oxide complex for administration 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 caboxyalkylation, for example, wherein the carboxyalkylation is a carboxymethylation. The term “derivatizing” and related terms (e.g. derivatives, derivatized, derivatization, etc) refer to the conventional sense of functionalization at the reactive sites of the composition. 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
−1
. 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 superparamagnetic.
In yet another embodiment, the invention provides a method of formulating an iron oxide complex coated with a reduced polysaccharide. This composition is for pharmacological use and the composition has decreased toxicity in comparison to an analogous iron oxide complex coated with native polysaccharide. The method of formulating such an iron oxide complex comprises: producing a reduced polysaccharide iron oxide complex, and sterilizing the complex by autoclaving. The formulation provides 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. The reduced polysaccharide iron oxide complex has such decreased toxicity. In a further aspect of the method, the iron oxide is superparamagnetic.
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 an analogous iron oxide complex coated with native derivatized polysaccharide. The method of formulating such an iron oxide complex comprises: producing a reduced derivatized polysaccharide iron oxide complex; and sterilizing the complex by autoclaving. According to this method, producing the complex can include derivatizing a reduced polysaccharide by carboxyalkylation, for example, wherein the carboxyalkylation 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
−1
. 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 superparamagnetic.
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 diminishment with T2 sequences. A further aspect of the embodiment 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.
Another embodiment of the invention provides a reduced polysaccharide iron oxide complex for use as an intravenous iron supplement.
Another embodiment of the invention provides a reduced derivatized polysaccharide iron oxide complex for use as an intravenous iron supplement.
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 comprising: 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.
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 embod
Bengele Howard
Frigo Timothy B.
Groman Ernest V.
Lewis Jerome M.
Paul Kenneth G.
Advanced Magnetics Inc.
Bromberg & Sunstein LLP
Padmanabhan Sreeni
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