Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2000-11-20
2003-10-28
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009320, C424S009322, C424S490000
Reexamination Certificate
active
06638494
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention concerns super-paramagnetic particles with an increased R
1
relaxivity which can be used as diagnostics in NMR tomography and as a pharmacologically active substance. This invention also concerns a production process and the use of the new particles.
2. The Prior Art
European Patent No B 284,549 describes super-paramagnetic single-domain particles of iron oxide, mixed iron oxides or iron with a particle size in the range between 3 and 20 nanometers, having organic substances of the group consisting of polyalkylene glycols containing phosphate groups, diphosphate groups, polyphosphate groups, thiophosphate groups, phosphonate groups or thiophosphonate groups, nucleotides containing phosphate groups, their oligomers or polymers and phosphate group-containing carbohydrates chemically bound at their surface, optionally having additional binding sites.
German Patent No. DE-A-4,309,333 describes stable, degradable aggregates with a particle size in the range between 10 and 1000 nanometers with defined behaviour in the magnetic field, with the aggregates consisting of multiple small super-paramagnetic single-domain particles of iron oxide, mixed iron oxides or iron with a particle size in the range between 3 and 20 nanometers, having substances of the group of polyalkylene glycols containing phosphate groups, diphosphate groups, polyphosphate groups, thiophosphate groups, phosphonate groups or thiophosphonate groups, or having carbohydrates or phosphate group-containing nucleotides their oligomers or polymers chemically bound at their surface.
WO 96/03653 describes super-paramagnetic particles consisting of super-paramagnetic single-domain particles and aggregates of super-paramagnetic single-domain particles having organic substances bound at their surface. The super-paramagnetic particles are composed of a mixture of small super-paramagnetic single-domain particles with a particle size in the range between 3 and 50 nanometers and stable, degradable aggregates of small super-paramagnetic single-domain particles with a particle size in the range between 10 and 1000 nanometers and consist of iron hydroxide, iron oxide hydrate, iron oxide mixed iron oxides or iron having mono- and/or polyhydroxyl group-containing aromatic substances, polyglycerols, amino acid-containing substances, silicate group-containing substances of ortho-silicic acid and their condensation products and phosphate group-containing substances of ortho- or meta-phosphoric acid and their condensation products bound at their surface.
Super-paramagnetic single-domain particles with a particle size in the range between 3 and 50 nanometers can be produced according to the state of the art and used, for example, as contrast media for NMR tomography, with preferred particle diameters in the range of 5-20 nm. In the regions of the body where these particles have accumulated, they lead to a greater shortening of the 2-relaxation time, and to darkening of the signal. Therefore, one also speaks of “negative” NMR contrast media with super-paramagnetic single-domain particles. The T relaxation time is inversely proportional to the relaxivity R, so the relaxivity R increases as the T relaxation time is shortened. The T
2
relaxation time has a linear dependence on the particle diameter of the magnetic particles. The larger the particle diameter, the greater the shortening of the T
2
relaxation time and the lower the required particle concentration to achieve a “negative” contrast. The contrast medium demand is in the range of 10 to 20 mmol Fe/kg body mass, and thus is much lower in comparison with the “positive” NMR contract media based on gadolinium chelates used in the past.
The T
1
relaxation time of such “negative” contrast media is not shortened greatly, so that there is no mentionable signal amplification in the NMR tomography in the body regions where they have accumulated. There is little lightening of the signal in the tissue. For many applications, it would be advantageous to be able to use super-paramagnetic single-domain particles with an increased “positive” NMR contrast medium effect.
If T
1
-weighted NMR tomography is to be performed, then the ratio of the relaxivities R
2
/R
1
must be as small as possible, but at least smaller than 5.
The R
1
relaxivity cannot be changed much with a reduction in particle diameter, but the R
2
relaxivity can be reduced. With very small super-paramagnetic single-domain particles, the ratio of relaxivities R
2
/R
1
is reduced so greatly that T
1
-weighted NMR tomography can be performed. Since super-paramagnetic single-domain particles have an influence on signal intensity even in very low concentrations, they can be superior to the paramagnetic contrast media used in the past.
SUMMARY OF THE INVENTION
The object of the present invention is to develop very small super-paramagnetic single-domain particles which can be used as contrast media for T
1
-weighted NMR tomography, for example.
According to this invention, this can be achieved by super-paramagnetic single-domain particles with an increased R
1
relaxivity and with surface stabilizer substances, comprising particles of iron hydroxide, iron oxide hydrate, iron oxide, mixed iron oxides or iron with a particle size in the range between one and ten nanometers, with an average particle diameter d
50
of two to four nanometers, an increased R
1
relaxivity in the range of two to fifty, an R
2
/R
1
relaxivity ratio of less than five, and having stabilizer substances on their surface of aliphatic dicarboxylic acids, aliphatic polycarboxylic acids substitution products thereof and derivatives thereof. That stabilizer substances prevent aggregation and sedimentation of the particles in a gravitational field or a magnetic field. On the stabilized particles are optionally bound further stabilizer substances, tissue-specific binding substances, pharmacologically active substances, pharmacologically active cells, pharmacologically active chelating agents, cell fusion mediating substances or gene transfer mediating substances, as well as mixtures thereof.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The super-paramagnetic single-domain particles of the invention with an increased R
1
relaxivity have on its surface first stabilizer substances.
If the first stabilizing substances are aliphatic dicarboxylic acids they are preferably malic acid, tartaric acid, glucaric acid.
If the first stabilizing substances are aliphatic polycarboxylic acids they are preferably citric acid, cyclohexanetricarboxlic acid, cyclohexanehexacarboxylic acid, ethylenediaminetetraacetic acid or diethylenetriaminepentaacetic acid.
Substitution products of dicarboxylic or polycarboxylic acids are compounds with unchanged carboxyl groups but one or more replaced hydrogen atoms by alkyl groups, halogen atoms or other groups such as citramalic acid, 2-methylene malic acid, alpha-hydroxycitric acid, aspartic acid, glutamic acid, pteroglutamic acid (folic acid).
Derivatives of dicarboxylic or polycarboxylic acids are compounds produced by changing of the carboxyl group such as esters, acid chlorides, anhydrides, amides, hydroxamic acids, imido esters, e.g. preferred C
12
-C
18
fatty acid esters with one or more of the a.m. dicarboxylic or polycarboxylic acids such as citric acid stearyl ester.
Various possibilities of achieving the goal of the invention—very small superparamagnetic particles for e.g. T1-weighted tomography—have been found:
1. By reducing the magnetic susceptibility of the super-paramagnetic single-domain particles;
2. By reducing the particle diameter of the super-paramagnetic single-domain particles in the range of 1-10 nm, preferably in the range of 2-4 nm;
3. Through the choice of stabilizer substances, and
4. Through the thickness and the water content of the stabilizer substance layer.
The very small super-paramagnetic single-domain particles may consist of the following substances: iron hydroxide, iron oxide hydrate, &ggr;-Fe
2
O
3
, Fe
3
O
4
, the mixed iron oxides of
Collard & Roe P.C.
Hartley Michael G.
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