Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
1995-02-28
2001-06-26
Dudash, Diana (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009320
Reexamination Certificate
active
06251366
ABSTRACT:
The present invention relates to the use of dispersions of magneto-ionic particles consisting essentially of superparamagnetic solid particles and at least one polyelectrolyte as dispersing substance in water for the preparation of an MRI contrast medium.
The MRI technique (magnetic resonance imaging) permits the imaging of organs or regions of tissue. This entails the protons contained therein, especially those in the water, changing their magnetic behavior on exposure to a strong external magnetic field, and these changes and the differences in the proton concentration being determined and imaged. Since, however, the relative differences between the chemical and magnetic environment of the water molecules in the different organs and tissue portions are usually very small, the difference in intensity of the signals to be measured is also normally low so that corresponding images show little contrast. The contrast, which reflects the difference in intensity of two adjacent regions of the investigated object in the form of color levels, can be defined by formula 1
C
=(
I
a
−I
b
)/(
I
a
+I
b
) (1)
where C is the contrast and I
a
and I
b
are the intensity of two adjacent image or volume elements.
In order, nevertheless, to obtain the information which is necessary for a diagnosis using the MRI technique, which is an investigation method with few drawbacks compared with the use of X-rays or radioactive isotopes, it is known to employ contrast media which are adsorbed selectively on the various tissue portions or organ regions and, in this way, cause a measurable change in the magnetic states of the water molecules surrounding them. Contrast media of this type which are already in use contain either para-, superpara- or ferromagnetic substances. The mode of action of these contrast media is based on the generation of additional magnetic interactions between the proton and the static magnetic field. In this case the relaxation times T
1
and T
2
of the protons, and the relaxation rates R
1
[s
−1
] and R
2
[s
−1
], which correspond to the spin-lattice and the spin-spin coupling respectively, are measured and differ according to the chemical and physical environment of the organ or tissue protons (medium). It is thus possible for the measured relaxation rates to be stated as totals, according to formulae 2 and 3
R
1
(total)=
R
1
(medium)+
R
1
(contrast medium) (2)
and
R
2
(total)=
R
2
(medium)+
R
2
(contrast medium) (3)
The relaxation rates R
1
and R
2
related to the effect per mole of ferrite in the contrast medium are called relaxivities r
1
and r
2
[s
−1
M
−1
], and formulae 2 and 3 become formulae 2a and 3a.
R
1
(total)=
R
1
(medium)+
c·r
1
(2a)
and
R
2
(total)=
R
2
(medium)+
c·r
2
(3a)
where c is the concentration of contrast medium in M. In order to minimize the amount of contrast medium necessary in diagnostic methods utilizing the MRI technique, it is evident from the formulae shown that the parameters r
1
and r
2
must be as large as possible.
The known MRI contrast media contain as magnetic materials those with either paramagnetic, superparamagnetic or ferromagnetic properties. Of these, the ferromagnetic media are generally impractical due to the large particle size of ferromagnetic particles. Many studies (eg. on the flow properties of water in capillaries) require non-settling extremely fine-grained magnetic contrast media. Thus the solid particle size should not be larger than 100 nm. The known paramagnetic contrast media are poor T
2
agents. It is the superparamagnetic contrast media which are of particular interest because, owing to their large effect both on T
1
and on T
2
of the magnetic nuclei, they have a marked effect on the image contrast (eg. U.S. Pat. Nos. 4,675,173, 5,055,288). These contrast media containing superparamagnetic colloids with a spin-spin and a spin-lattice relaxation which is higher than with ferromagnetic or paramagnetic colloids thus have higher R
1
and R
2
values and allow the concentration of the contrast medium to be lower in MRI investigations (Lee Josephson et al., Magnetic Resonance Imaging, Vol. 6, 647-653 (1988)).
Although they have enhanced r
1
and r
2
values the known superparamagnetic contrast media are still far from ideal because they have poorly balanced r
2
/r
1
ratios. Prior art contrast media have, for example, values of 8×10
3
M
−1
s
−1
for r
1
and of 4×10
5
M
−1
s
−1
for r
2
(WO 85/04330) or of 4×10
4
M
−1
s
−1
for r
1
and of 1.6×10
5
M
−1
s
−1
for r
2
(U.S. Pat. No. 4,827,945).
A high r
1
value is required in order to keep the dose of the contrast medium to a minimum. In addition, a high r
2
/r
1
ratio allows the contrast medium to be used for two purposes ie. as an effective positive and negative contrast medium.
The signal intensity I, is a complex function of the number of protons and of their relaxation rate. If R
1
is increased, I is increased too (positive action). If R
2
is increased I is decreased (negative action). Using conventional ultrafast imaging techniques it is possible to adjust the T
2
contribution (which is proportional to the r
2
parameter). Thus positive and negative intensity effects can be obtained provided r
2
is sufficiently high compared with r
1
.
Thus there is no fine particle (particle diameter<100 nm) contrast medium reported that has r
1
>10
5
M
−1
s
−1
and that additionally maintains a value of r
2
/r
1
greater than 7 (measured at 20 MHz, 37° C.). Therefore it is an object of the present invention to provide a formulation of superparamagnetic solid particles which is suitable for preparing dual purpose MRI contrast medium and which has, in particular, high relaxivities r
1
and r
2
and a high r
2
/r
1
ratio.
We have found that this object is achieved by using dispersions of magneto-ionic particles consisting essentially of superparamagnetic solid particles and at least one polyelectrolyte with a molecular weight of from 1,000 to 25,000 as dispersing substance in water, where the superparamagnetic solid particles have a primary particle size of from 7 to 50 nm and a specific surface area of from 30 to 130 m
2
/g and are present in the dispersions of magneto-ionic particles in the form of colloidal units with on average only one superparamagnetic solid particle enveloped by the polyelectrolyte with a molecular weight of from 1,000 to 25,000 and with a charge number greater than 5 as dispersing substance, to prepare MRI contrast media with relaxivities r
1
greater than 9×10
4
M
−1
s
−1
and a ratio of r
2
to r
1
of at least 7, measured at 20 MHz and 37° C. Thus r
2
will be greater than 6.3×10
5
M
−1
s
−1
. When measured at 10 kHz and 37° C., r
1
is greater than 5×10
4
M
−1
s
−1
and when measured at 4 MHz and 37° C. it is greater than 1.5×10
5
M
−1
s
−1
.
The superparamagnetic solid particles contained in the dispersions of magneto-ionic particles used according to the invention are those which have a BET specific surface area of from 30 to 130 m
2
/g, preferably from 80 to 110 m
2
/g. The specific surface area was in this case determined by the DIN 66 132 method using a Ströhlein areameter supplied by Ströhlein, Düsseldorf, by the one-point difference method of Haul and Dümbgen. The median particle size is from 7 to 50 nm and in particular from 7 to 25 nm. Preferred classes of substances are superparamagnetic iron oxides such as Fe
3
O
4
, &ggr;-Fe
2
O
3
, berthollides and, in particular, the cubic ferrites of the composition M
v
Mn
w
Zn
x
Fe
y
O
z
described in U.S. Pat. No. 4,810,401.
These magnetic particles or mixtures containing these particles are coated with polyelectrolytes. The polyelectrolytes bring about not only a suitable steric stabilization but also an increase in the surface charge of the solid
Anseau Michel Robert
Kormann Claudius
Muller Robert Nicolas Henry
BASF - Aktiengesellschaft
Dudash Diana
Hartley Michael G.
Keil & Weinkauf
LandOfFree
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