Molecular sieve-enclosed transition and rare earth metal ions as

Details Molecular sieve-enclosed transition and rare earth metal ions as Molecular sieve-enclosed transition and rare earth metal ions as

1993-05-27

1995-07-04

Hollinden, Gary E.

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Magnetic imaging agent

436173, 436 932, 424684, 514836, 514974, 4233281, A61B 5055

Patent

active

054298148

DESCRIPTION:

BRIEF SUMMARY
The invention relates to contrast or imaging agents useful in vivo for studies and diagnosis of the gastrointestinal tract. The agents are molecular sieve materials enclosing a paramagnetic ion such as trivalent gadolinium. The loaded molecular sieves are particularly suitable for oral administration and function well as magnetic resonance imaging contrast or image brightening agents in the upper gastrointestinal tract.
The availability of sophisticated methods such as MRI and CT has contributed to the increased use of imaging technology in therapy and diagnostic studies. Gastrointestinal tract imaging is a particular area of interest because currently used imaging agents generally provide poor imaging, resulting in visualization of little more than gross blockages or anatomical abnormalities.
Barium sulfate and paramagnetic iron oxide are agents traditionally used for gastrointestinal studies. The latter material has become popular because of the paramagnetic properties of Fe.sub.2 O.sub.3 which is suited for MRI studies, but it has many disadvantages. These include black bowel, side effects of diarrhea and, from an important analytical standpoint, the presence of artifacts arising from clumping. When paramagnetic iron concentrates, it may become ferromagnetic, drastically altering its imaging properties. Even when images are obtained, the signal is black, making it difficult to distinguish imaged from nonimaged areas.
The development of imaging contrast agents, particularly for gastrointestinal tract studies has been slow. Historically, the most popular agent has been superparamagnetic iron oxide for magnetic imaging, due to its nonbiodegradability. Although good contrast effects have been achieved in some MR studies in the small bowel, increasing occurrence of blurring and "metal" artifacts in the distal part of the bowel has been recorded (Lonnemark et al., 1989). In other studies with superparamagnetic iron oxide, good resolution of the head and tail of the pancreas, anterior margins of the kidneys and para-aortic region has been shown in human patients. However, there are undesirable side effects such as episodes of diarrhea in some patients (Hahn et al., 1990).
Magnetic imaging is particularly useful for the study and diagnosis of tumors or inflammatory abdominal diseases. Paramagnetic species represented by gadolinium seem to be potentially agents for these studies, the metal itself cannot be used in humans because of its toxic properties. Nevertheless, diethylenetriamine penta-acetic acid (DTPA) complexes of trivalent gadolinium have less toxicity than the uncomplexed salt and have been tested in human patients. Opacification of the gastrointestinal tract has been reported, but less than 60% of the magnetic resonance scans showed improved delineation of abdominal pathologies. Furthermore, nearly 40% of the patients reported diarrhea and meteorism (Claussen et al., 1989).
Encapsulation of solid paramagnetic complexes in sulfonated ion-exchange resins for use in abdominal imaging has been suggested. It has been speculated that such encapsulation in acid-stable materials would prevent significant demetallation which otherwise occurs in the stomach when image contrasting agents are orally administered for gastrointestinal tract imaging (Braybrook and Hall, 1989).
Superparamagnetic iron oxide has been coated onto a polymer carrier matrix and evaluated as an oral contrast medium for MRI. Generally good images were obtained in the region of the small bowel, except the duodenum, but the useful concentration range appeared to be fairly narrow since some concentrations caused an artifact in the stomach after ingestion of the agent (Lonnemark et al., 1989).
There is clearly a need for orally effective, well-tolerated agents that can be used in humans for imaging studies. In particular, an MRI imaging agent applicable to gastrointestinal tract studies would be useful for visualizing the anatomy of the intestinal tract and particularly to differentiate normal and pathological states, such as tumors. An effecti

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