Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Reexamination Certificate
2001-03-05
2004-04-27
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
C424S009400
Reexamination Certificate
active
06726896
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of rendering an image of an organ, in particular a colon, in a manner suitable for detecting colon cancer using methods such as CT Colography, and to compositions suitable for use in these methods.
BACKGROUND
In western-style communities, colorectal cancer is the third most common form of cancer and has the second highest death rate. Over 80% of colorectal cancers originate as a polyp, which, unless there has been a family history of colon cancer, tend not to develop until the patient reaches 50 years of age. Removal of the polyp will terminate the risk of cancer originating at that site. The development from polyp to cancer is slow, usually requiring about ten years. Because of these factors, adequate screening of the “at-risk” population for colorectal cancer will have a major effect on prevention.
Techniques exist at present that can locate colonic polyps with high accuracy. Amongst the most widely used method of detection is radiological examination. However, radiological examinations of soft-tissues, such as the colon, are limited by their poor X-ray absorption characteristics. Without artificial enhancement, such tissues are poorly imaged, and a contrast agent, which strongly interacts with X-rays, such as barium sulfate, is required.
The most commonly employed radiological technique is the double contrast barium enema. This requires a strictly regulated diet, together with the administration of extremely potent laxative products, for up to 48 hours prior to the examination to produce the so-called “fully prepared colon”. Barium sulfate is then placed in the patient's rectum and colon via the anus prior to radiological examination. The barium enema examination typically carries some stigma, is uncomfortable, and word of mouth accounts usually ensure that a patient presenting for the first time already has an extensive knowledge of the unpleasantness that lies in store.
Colonoscopy is a popular, if more expensive, alternative to the barium enema but which still requires a strict dietary and laxative regime similar to the barium enema to produce the fully prepared colon. Colonoscopy requires that the patient be heavily sedated during the procedure as it is substantially more uncomfortable and invasive than a barium enema. It also entails substantially more expense to the community, and inconvenience to the patient, who may require hospitalisation. Colonoscopy also has a fairly high risk of patient injury about 1 in 7000 patients suffering a perforation of the colon and about 1 in 50,000 dying from the procedure as a result of complications to the perforation or adverse reactions to the anaesthetic.
An alternative diagnostic technique has been introduced that is far less problematic for the patient and should increase the likelihood of acceptance by the general public. This technique has a variety of names, including Virtual Colonoscopy, Virtual Colography, CT Colography and CT Colonography. It requires the patient to undergo a CT scan of the abdomen. Subsequent image reconstruction allows examination of the colon in order to detect polyps. This technique has only become possible with the recent arrival of helical CT scanners, in which the data acquisition takes place in a continuous process (unlike previous scanners which acquired data in consecutive slices), together with high performance work stations capable of rapidly rendering 3D-views into useful medical information.
A number of trials have confirmed the feasibility of CT Colography as an accurate screening technique for colon cancer. However, this too has similar drawbacks to the other methods which may prevent it being widely used as a preventative tool against colon cancer.
Under normal circumstances the colon is heavily loaded with stool (faeces) at various stages of development. Faeces often has the same size and appearance as polyps in a CT scan, and in practical terms they are generally indistinguishable from each other.
Thus, to be effective, CT Colography requires patients to have a fully prepared colon by submitting to the same rigorous diet and laxative program used for Colonoscopy. Thus, while some of the discomfort and inconvenience of the previous procedures have been avoided, the requirement for a prepared colon has not minimised patient discomfort to the point that it will obtain high acceptance by the “at risk” population group.
The degree of discomfort and inconvenience of all the investigative techniques available to check for colonic polyps means that very much less than 10% of the “at risk” population have these examinations even once in their life, let alone at the five yearly frequencies advocated by various studies.
The above discussion of prior art is not to be construed as an admission with regard to the common general knowledge in Australia.
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or at least to provide a useful alternative.
DISCLOSURE OF THE INVENTION
According to a first aspect the invention provides a stool marker formulation for oral administration and suitable for use in CT Colography including a material adapted to provide marked stool, said marked stool having a modified response to radiation relative to unmarked stool.
Normally, the modified response to radiation is to render stool opaque to radiation.
In preferred embodiments, the material to render stool opaque to radiation is water insoluble, and most preferably is barium sulfate. However, other materials can be used, for example iodine compounds. Iodinated materials can be used provided these have been rendered into an insoluble form that passes through the gastrointestinal tract without being dissolved or metabolised. Suitable iodine compounds include for example: Iopanoic acid; Dionosil (propylidone); Hytrast, a mixture of Iopydol and Iopydone; Lipiodol; Iodipin; Iodochloral; Iophendylate; Ethiodol and other Iodinated vegetable oils or any polymeric material containing organically bound iodine atoms in sufficient quantity to achieve radio opacity.
Alternatively, the materials to render stool opaque to radiation can include finely divided particles of metals, metal oxides and metallic salts, for example bismuth, iron, platinum, gold, strontium and the like.
The stool marker formulation is ideally administered in an amount effective to differentiate stool from non-stool without rendering density or movement induced artefacts in the CT rendering of the stool. Thus, when barium sulfate is administered as the material to render stool opaque to radiation in liquid form, it does not exceed 3% wt per volume of the formulation. When the preferred dosage sizes of 200-250 mL are used, the absolute dosage of barium sulfate accordingly preferably does not exceed 6-7.5 g. A dosage of about 5 g has been found to be particularly useful. Liquid formulations containing barium sulfate in an amount of as low as 0.5 wt per volume (total around 1 g barium sulfate) may also be used. Employing too low a quantity of marker will of course prevent effective differentiation between marked and non-marked stool.
In an alternative but equally preferred embodiment, the barium sulfate may be administered in a solid form, to achieve the same total dosage and to provide marked stool. A solid dosage form of 5 g has been found particularly useful.
In highly preferred the stool marker formulations of the present invention, the material to render stool opaque to radiation is destabilised to ensure that the resistance to flocculation is minimised. Preferably, this destabilisation takes place by limiting the amount of ionic dispersants in the formulation and/or by the addition of flocculants.
It is also advantageous if the tendency for agglomeration of the individual active particles of the material to render stool opaque to radiation is inhibited before administration to the patient. This inhibition may takes place for instance by ensuring that the particles are separated during preparation of the formulation or prior t
Hartley Michael G.
Weingarten, Schurgin, Gagenbin & Lebovici LLP
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