Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
1999-12-28
2001-10-16
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S001110, C424S001650, C424S009300, C424S009400, C556S030000
Reexamination Certificate
active
06303101
ABSTRACT:
The present invention relates to the use in diagnostic imaging, in particular X-ray, MRI, ultrasound and scintigrapny, of contrast agents comprising bismuth clusters and/or organic bismuth compounds, and to contrast media containing such bismuth compounds. Another aspect of the present invention is the use of the bismuth compounds in therapy, in particular as antiulcer agents.
All diagnostic imaging is based on the achievement of different signal levels from different structures within the body. Thus in X-ray imaging, for example, for a given body structure to be visible in the image the X-ray attenuation by that structure must differ from that of the surrounding tissues. The difference in signal between the body structure and its surroundings is frequently termed contrast and much effort has been devoted to means of enhancing contrast in diagnostic imaging since the greater the contrast between a body structure and its surroundings the higher the quality of the images and the greater their value to the physician performing the diagnosis. Moreover, the greater the contrast the smaller the body structures that may be visualized in the imaging procedure, i.e. increased contrast can lead to increased spatial resolution.
The diagnostic quality of images is strongly dependent on the inherent noise level in the imaging procedure—the ratio of the contrast level to the noise level can thus be seen to represent an effective diagnostic quality factor for diagnostic images.
Achieving improvement in such a diagnostic quality factor has long been and still remains an important goal. In techniques such as X-ray and ultrasound, one approach to improve the diagnostic quality factor has been to introduce contrast enhancing materials, contrast agents, into the body region being imaged.
Thus in X-ray, for instance, early examples of contrast agents were insoluble inorganic barium salts which enhanced X-ray attenuation in the body zones into which they distributed. More recently the field of X-ray contrast agents has been dominated by soluble iodine containing compounds such as those markedet by Nycomed AS under the trade names Omnipaque® and Visipaue®.
Much recent work on X-ray contrast agents has concentrated on aminopolycarboxylic acid (APCA) chelates of heavy metal ions and, recognising that effective imaging of many body sites requires localization at the body sites in question of relatively high concentrations of the metal ions, there have been suggestions that polychelants, that is substances possessing more than one separate chelant moiety, might be used to achieve this.
Various bismuth compounds have been suggested in the prior art as X-ray absorbing agents. Other prior art documents focus on the use of metal chelates in diagnostic imaging, mainly in MRI. In addition, bismuth compounds have a long history in therapeutic medicine specially in treatment of gastrointestinal diseases such as ulcers. Although antiulcer agents such as the H
2
-antagonists cimetidine and ranitidine, and more recently proton pump inhibitors such as omeprazole, have been developed, there is still medical use of bismuth compounds in ulcer treatment.
The most frequently used bismuth compounds as gastrointestinal drugs today are bismuth subnitrate and bismuth subsalicylate. Bismuth subnitrate or bismuth hydroxide nitrate oxide (Bi
5
O(OH)
9
(NO
3
)
4
is prepared by hydrolysis of bismuth nitrate and is practically insoluable in water. It is usually used as a suspension (milk of bismuth). Bismuth subnitrate is also used topically in lotions and ointments. Bismuth subsalicylate or basic bismuth salicylate (C
7
H
5
BiO
4
) is also practically insoluble in water and is administered as a suspension or in the form of tablets. Products containing bismuth subsalicylate are used against indigestion, nausea and diarrhea. As an antidiarmheal agent it shows good activity against Salmonella with less activity versus
E. coli.
Several bismuth compounds are known to be biologically active and have been suggested as active ingredients in various drug formulations. Organobismuth compounds can be used as antibacterial agents, for example against infections caused by highly resistant gram-negative bacteria (U.S. Pat. No. 3,466,366 of M&T Chem Inc); a protein-type bismuth complex is suggested for treatment of inflammation and infections in the gastrointestinal system in U.S. Pat. No. 4,153,685 (Schering Corp); bismuthyl prostanoate derivatives for ulcer control are suggested in BE 809388 (Aries R); phenylbismuth bis(2-pyridinethiol) 1-oxide as an antibacterial and antifungal agent is disclosed in U.S. Pat. No. 3,824,307 (Procter & Gamble Co); an antiinflammatory and antiulcer bismuth composition containing a mixture of trivalent bismuth, water-soluble protein, an organic acid anion and an alkali in ZA 8107456 (Schering Corp); bismuth subsalicylate in combination with other agents in a synergistic formulation for diarrhoea treatment in U.S. Pat. No. 4,588,589 (Richardson Vicks); treatment of non-ulcer dyspepsia associated with
Campylobacter pyloridis
infection with bismuth salts such as tripotassium dicitrato-bismuthate in WO 89/03219 (Borody T. J.); organo-bismuth compounds useful as anti-coccidium agents for poultry, and as insecticides in J63225391 (Nitto Kasei and Shionogi); pharmaceutical compositions for treatment of gastrointestinal disorders associated with
Campylobacter pylori
infections comprising a pharmaceutically acceptable bismuth compound and first and second antibiotic or antimicrobial agents in EP 439453 (Capability Services et al.); salts formed between rantidine and bismuth carboxylic acid complexes for treatment of gastrointestinal disorders in U.S. Pat. No. 5,008,256 (Glaxo); further salts formed between an H
2
-receptor antagonist and a complex of bismuth with a carboxylic acid with activity against gastrointestinal conditions and aginst
Campylobacter pylori
in U.S. Pat. No. 5,273,984 (Glaxo); a suspension for oral administration comprising a bismuth containing pharmaceutical agent, benzoic acid and sorbic acid, polymer and water for use against various gastrointestinal disorders in U.S. Pat. No. 5,013,560 (Procter & Gamble); furan derivatives with bismuth carboxylic acid complexes for treatment of various gastrointestinal disorders including activity against
Heliobacter pylori
infections in WO 92/01457 (Evans B. K. et al.); salts of ranitidine with a bismuth carboxylate complex and alkali salt for treatment of various gastrointestinal disorders in GB 2248185 (Glaxo); and ranitidine bismuth citrate and non-steroidal anti-inflammatory drugs for the treatment of inflammation diseases in GB 2262036 (Glaxo).
Finally, WO 95/06053 discloses certain substituted triphenyl bismuth compounds as X-ray contrast agents.
We have now found that certain bismuth compounds give particularly effective contrast enhancement when used as contrast agents. Some of these compounds also can be used in the treatment of various gastrointestinal disorders.
Thus, one aspect of this invention is a diagnostic imaging contrast medium comprising a covalent non-cluster type bismuth compound. Such medium may be used for contrast enhancement in diagnostic imaging, in particular x-ray, MRI, ultrasound imaging and scintigraphy.
For X-ray or ultrasound imaging it is preferred that the compounds comprise two or more heavy atoms where at least one of the heavy atoms is bismuth. For the sake of clarity, the word “heavy atom” means a bromine atom or an atom with atomic number higher than 49.
For MRI the compounds would comprises bismuth and one or more MR active atoms. For the sake of clarity, the words “MR active atom” means an atom that directly or indirectly affects the MR signal. Typical MR active atoms include for example manganese, gadolinium, dysprosium, iron and fluorine.
The invention provides for example diagnostic imaging contrast media comprising a physiologically tolerable molecule of anyu of formulae I-IV,
where the groups R
1
-R
5
may be the same or different and are defined as any croup forming a hydrolyticaliy stable bond to bism
Almen Torsten
Berg Arne
Droege Michael
Golman Klaes
Klaveness Jo
Fish & Richardson P.C.
Jones Dameron L.
Nycomed Imaging AS
LandOfFree
Bismuth compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Bismuth compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bismuth compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2565924