Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
1999-11-30
2003-06-10
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009320, C424S009300, C424S009100, C424S001110, C424S646000, C514S006900, C514S054000, C514S059000, C514S060000
Reexamination Certificate
active
06576221
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to iron-containing nanoparticles having a modular structure, their production, and their use for diagnostic and therapeutic purposes.
BACKGROUND OF THE INVENTION
Substances that show maximum magnetization even at a low field strength (high saturation magnetization) but no remanence after the external magnetic field is switched off, as the thermal energy counteracts the permanent alignment of spontaneously magnetized Weiss' domains, are called superparamagnetic substances. This category includes iron-containing crystals that are developed as parenteral MR contrast materials. A characteristic property of said substances is their strong impact on proton relaxation times and thus their great efficacy as a contrast medium in this diagnostic procedure. In medical diagnostics, the focus of examining superparamagnetic substances was placed on iron oxides having a “magnetite-like” crystal structure of the kind found in magnetite or maghemite (spinel, inverse spinel).
The superparamagnetic iron oxides to be used as MR contrast materials have similar properties in that they strongly influence proton relaxation in their close range (high relaxivity), and that they are particles having a “magnetite-like” crystal structure.
A great number of methods have been described for the production of iron-containing crystals (iron oxides) having superparamagnetic properties. These methods can be classified according to various aspects. Two basic methods to produce superparamagnetic crystals can be distinguished between: sintering at high temperatures and subsequent mechanical comminution, or wet chemical synthesis in solution. Up Lo now, only those particles that were produced by wet synthesis have been investigated for medical applications, while the sintering method has been described for the manufacture of iron oxides for technological (sound carriers, paint pigments and toners) and biotechnological applications such as the magnetic separating method [Schostek S, Beer A; DE 3,729,697 A1; Borelli N F, Luderer A A, Panzarino J N; U.S. Pat. No. 4,323,056; Osamu I, Takeshi H, Toshihiro M et al.; JP 60,260,463 A2]. Wet chemical synthesis can be subcategorized. There is “two-pot synthesis”, which first produces an iron-containing core (iron oxide) to which a stabilizer is added to ensure the physical and galenic quality. The production of an iron core using ion exchangers is a variant of “two-pot synthesis”. With “single-pot synthesis”, the iron oxides are produced in the presence of the stabilizer which already coats the cores during nucleation and precipitation of the iron salts, thereby preventing aggregation and sedimentation of the nanocrystals.
Apart from distinguishing “two-pot” and “single-pot” methods according to the processes involved, there is another distinction based on the type of solvent used, namely between aqueous (Hasegawa M, Hokukoku S; U.S. Pat. No. 4,101,435; Fuji Rebio K. K.; JP 59,195,1611 and non-aqueous methods [Porath J, Mats L; EP 179,039 A2; Shigeo A, Mikio K, Toshikatzu M; J. Mater. Chem. 2(3); 277-280; 1992; Norio H, Saturo O; JP 05,026,879 A2].
Particles that were produced in a “two-pot” process using non-aqueous solvents are mainly used in engineering. Magnetic iron oxides for use as contrast materials in human diagnostics require an aqueous dispersing agent for medical and toxicological reasons. A special place is held in this categorization by those particles that were produced in a non-aqueous solvent but can be stable when disersed in an aqueous medium after production. Such particles are currently used, in general, in ex-vivo diagnostics, e.g. in magnetic separation engineering [Chagnon M S, Groman E V, Josephson L, et al.; U.S. Pat. No. 4,554,088] but have also been proposed for in-vivo diagnostics [Pilgrimm H; U.S. Pat. No. 5,160,725].
Particles produced in a “two-pot” process were mainly used in the early experimental examinations up to the mid-1980s, while today's tests involving iron oxides are described only for materials produced by a “single-pot synthesis”. The “single-pot” method has been generally accepted for the production of superparamagnetic iron-containing oxides for human diagnostic applications as they are superior to those produced by a “two-pot” method from the point of view of their physical and chemical quality as well as pharmaceutical/galenic stability.
Pharmaceutically stable suspensions/solutions of particles produced in aqueous media according to the “single-pot method” may be subdivided into iron oxides of different sizes. Biotechnological applications were proposed for particles in the micrometer range [Schröder U, Mosbach K; WO 83/01738 or Schröder U; WO 83/03426], and their application even claimed in in-vivo diagnostics and therapy [Widder K J, Senyei A E; U.S. Pat. No. 4,247,406 or Jacobsen T. Klaveness J; WO 85/04330]. For approaches in medical diagnostics, however, particles in the nanometer range are the main ones described today. This range may also be subdivided according to the preferred use into “large” (overall diameter ca. >50 nm) and “small” (overall diameter ca. <50 nm) particles. MR diagnostics of the liver and the spleen is the main field of application, as particles of this size are rapidly and nearly completely taken up by the macrophages of these organs [Kresse M, Pfefferer D, Lawaczeck R; EP 516,252 A2 or Groman E V, Josephson L; U.S. Pat. No. 4,770,183]. Furthermore, proposals were made for uses as reinforcing substances in clinical hyperthermia [Hasegawa M, Hirose K, Hokukoku S, et al.; WO 92/22586 A1 and Gordon R T; U.S. Pat. No. 4,731,239].
Nearly all the particles currently proposed for medical applications are iron oxides that were produced in the presence of dextran as the stabilizing substance [Bacic G, Niesmann M R, Magin R L et al.; SMRM—Book of abstracts 328; 1987; Ohgushi M, Nagayama K, Wada A et al.; J. Magnetic Resonance 29; 599-601; 1978; Pouliquen D, Le Jeune J J, Perdrisot R et al.; Magnetic Resonance Imaging 9; 275-283; 1991 or Ferrucci J T and Stark D D; AJR 155; 311-325; 1990] but the use of other polysaccharides has also been described, for example, for arabinogalactan [Josephson L, Groman E V, Menz E et al; Magnetic Resonance Imaging 8; 616-637; 1990], starch [Fahlvik A K, Holtz E, Schröder U et al; Invest. Radiol. 25; 793-797; 1990], glycosaminoglycans [Pfefferer D, Schimpfky C, Lawaczeck R; SMRM—Book of abstracts 773; 1993], or proteins [Widder D J, Grief W L, Widder K J et al.; AJR 148; 399-404; 1987].
The exact conditions for synthesis such as those involving iron salts, temperature, coating polymer (stabilizer), titration rate, alkali selection, purification, etc. affect the chemical and physical properties of the products and, therefore, their pharmaceutical and galenic quality as well as medical value.
An important step in the development leading to an effective use in specific applications was made by Weissleder and Papisov [Weissleder R; Papisov M I; Reviews of Magnetic Resonance in Medicine 4; 1-20; 1992] who were able to show that the “targetability” of the magnetic iron oxides is reciprocally proportional to particle size. A problem in this respect is the fact that efficacy (MR effect) decreases with smaller particle sizes. The production of particularly small magnetic iron oxides without any fractionating stages has recently been described [Hasegawa M, Ito Y, Yamada H, et al.; JP 4,227,792]. Experiments on “functional imaging” were reported for particularly small particles called MIONs. The dextran coating of said particles (magnetic labels) were oxidized using periodate and then coupled with specific molecules (antimyosin; polyclonal antibody) [Weissleder R, Lee A S, Khaw B A et al.; Radiology 182; 381-385; 1992, or Weissleder R, Lee A S, Fishman A et al.; Radiology 181; 245-249; 1991].
A special course is taken by Menz et al. [Menz ET, Rothenberg J M, Groman
Ebert Wolfgang
Elste Volker
Gaida Josef
Herrmann Anja
Jukl Monika
Institut fur Diagnostikforschung GmbH
Jones Dameron L.
Millen White Zelano & Branigan P.C.
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