Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
2000-09-29
2002-09-10
Moezie, Minna (Department: 1617)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S009600, C424S009700, C424S009420, C548S579000
Reexamination Certificate
active
06447749
ABSTRACT:
The invention relates to the field of galenical formulations, which are used in particular as contrast media for the visualization of lymph nodes. The invention relates to the subject that is characterized in the claims, namely new galenical formulations that contain perfluoroalkyl-containing dye molecules and other perfluoroalkyl-containing substances.
Malignant tumors metastasize heaped in regional lymph nodes, whereby several lymph node stations can also be involved. Thus, lymph node metastases are found in about 50-69% of all patients with malignant tumors (Elke, Lymphographie [Lymphography], in: Frommhold, Stender, Thurn (eds.), Radiologische Diagnostik in Klinik und Praxis [Radiological Diagnosis in Clinical Studies and Practice], Volume IV, Thieme Verlag Stuttgart, 7th Ed., 434-496, 1984). The diagnosis of a metastatic attack of lymph nodes is of great importance with respect to the therapy and prognosis of malignant diseases. With the modern imaging methods (CT, US, and MRT), lymphogenous metastasis sites of malignant tumors are detected only inadequately, since in most cases, only the size and the shape of the lymph node can be used as a diagnostic criterion. Thus, small metastases in non-enlarged lymph nodes (<2 cm) are not distinguished from lymph node hyperplasias without a malignant attack (Steinkamp et al., Sonographie und Kernspintomographie: Differentialdiagnostik von reaktiver Lymphknotenvergrböberung und Lymphknotenmetastasen am Hals [Sonography and Nuclear Spin Tomography: Differential Diagnosis of Reactive Lymph Node Enlargement and Lymph Node Metastases on the Neck], Radiol. Diagn. 33: 158, 1992).
It would be desirable to distinguish between lymph nodes with metastatic attack and hyperplastic lymph nodes with the aid of specific contrast media. In this case, the contrast medium could be adminisitered intravasally or interstitially/intracutaneously (see above Siefert, H. M. et al., Lymphology 13, 150-157, 1980). The interstitial/intracutaneous administration has the advantage that the substance is transported directly from the scattering focus (e.g., primary tumor) by the corresponding lymph tract into the potentially related regional lymph node stations. Likewise, a high concentration of the contrast medium in the lymph nodes can be achieved with a low dose. Such markers that are to be administered interstitially were mainly used in the nuclear-medicine evaluation (with use of radioactive particles, such as, e.g.,
198
Au-colloid). Nuclear-medicine methods have only a very inadequate spatial resolution, however, in contrast to nuclear spin tomography with its high spatial resolution in the range of fractions of a millimeter. The direct x-ray-lymphography (injection of an oily contrast medium suspension in a prepared lymph vessel) is an invasive method that is used very rarely and that can visualize only a few lymph outflow stations. Fluorescence-labeled dextrans are also used experimentally in animal experiments to be able to observe the lymph outflow after their interstitial administration. All commonly used markers for the visualization of lymph tracts and lymph nodes after interstitial/intracutaneous administration have in common the fact that they are substances with a particulate nature (“particulates,” e.g., emulsions and nanocrystal suspensions) or large polymers (see above, WO 90/14846). The previously described preparations have proven to be of value, however, based on their inadequate local and systemic compatibility as well as their small lymph passageway, which produces an inadequate diagnostic efficiency, in most cases unsuitable for indirect lymphography.
There is generally a greet need, therefore, for lymph-specific contrast media with suitable pharmaceutical and pharmacological properties. In the pharmaceutical properties, focus is placed first on the highest possible contrast medium concentration and an adequate stability. In the case of the pharmacological properties, and in addition to a diagnostically relevant lymph concentration that is as uniform as possible over several (or in the case of intravenous administration over all) lymph stations, focus is placed mainly on a quick and complete excretion of the contrast medium to avoid an unnecessary load of the entire organism. Moreover, corresponding preparations must have at their disposal an adequate local and acute compatibility.
With respect to the application in radiological practice and in addition to as simple an application as possible of corresponding preparations, the quick “start-up” of the preparations is of central importance. Thus, if at all possible, it should be possible to perform imaging within a few hours after the administration of the contrast media.
Contrast media that are suitable for the visualization of lymph nodes in nuclear spin tomography are described in German Laid-Open Specification DE 196 03 033. There, perfluoroalkyl-containing metal complexes are disclosed, which are preferably used as lymphographic agents (see FIG. 1 of DE 196 03 033). Similar metal complexes that are suitable especially as blood-pool agents are described in German Laid-Open Specification DE 197 29 013.
A process for in-vivo diagnosis with use of NIR radiation is described in International Application WO 96/17628. Such diagnostic processes are at present under development. The contrast media that are described in this document are not suitable for visualizing the lymph nodes. There is therefore a need for suitable lymph-specific contrast media for these new diagnostic processes.
The object of this invention is therefore to make available new galenical formulations that are suitable as contrast media especially for the visualization of lymph nodes in the above-mentioned new diagnostic processes, and that meet the above-mentioned pharmaceutical and pharmacological requirements.
This object is achieved by the galenical formulations of this invention.
The new galenical formulations contain perfluoroalkyl-containing dye molecules, which can be used as contrast media in near-infrared diagnosis. The dyes satisfy certain photophysical and chemical requirements. They have high absorption coefficients and high fluorescence quantum yields to produce an effective signal even at the lowest tissue concentrations. The absorption maxima overlap a wide spectral range in a freely selectable manner. For detection in lower tissue layers (several centimeters under the surface), the spectral range between 600 and 900 nm is essential, while absorption wavelengths of 400 to 600 nm are sufficient for surface detection. The dyes further have a high chemical stability and photostability. When using light for fluorescence stimulation, the essential problem is the limited penetration depth of the light, which lies in the submillimeter range in the VIS but can be in the centimeter range in the NIR. With respect to the penetration depth, detection processes in surface tissue diseases, as well as soft tissues, are unproblematic. Since a considerable number of tissue changes (e.g., breast tumors, skin tumors, lymph node changes) are located on the surface, optical diagnostic processes in addition to the conventional methods are offered to perform a tissue differentiation based on different absorption and fluorescence patterns. In this case, the pronounced diffusion of light, which obtains increasing influence with growing tissue thickness, reduces both the resolution and the contrast of an optical image. Dyes that are used as so-called optical contrast media and are concentrated in the tissues that are to be detected can result in principle in an increase of the diagnostic value of optical detection processes, in which they increase the absorption of the tissue and provide an additional measurement signal with the dye-specific fluorescence, which can be detected arbitrarily often in front of a low tissue background with high sensitivity.
Preferred are dyes from the following classes:
Polymethine dyes, such as, e.g., cyanine dyes, squarilium dyes, croconium dyes, oxonol dyes, merocyanine
Becker Andreas
Licha Kai
Platzek Johannes
Riefke Bjoern
Millen White Zelano & Branigan P.C.
Moezie Minna
Schering Aktiengesellschaft
Wells Lauren Q.
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