X-ray imaging is a well known and extremely valuable tool for the early detection and diagnosis of various disease states in the human body. The use of contrast agents for image enhancement in medical x-ray imaging procedures is widespread. An excellent background on contrast agents and media in medical imaging is provided by D. P. Swanson et al, Pharmaceuticals in Medical Imaging, 1990, MacMillan Publishing Company, the disclosure of which is hereby incorporated by reference in its entirety.
Briefly, in x-ray imaging, transmitted radiation is used to produce a radiograph based upon overall tissue attenuation characteristics. X-rays pass through various tissues and are attenuated by scattering, i.e., reflection or refraction or energy absorption. However, certain body organs, vessels and anatomical sites exhibit so little absorption of x-ray radiation that radiographs of these body portions are difficult to obtain. To overcome this problem, radiologists routinely introduce an x-ray absorbing medium containing a contrast agent into such body organs, vessels and anatomical sites.
Currently available X-ray contrast agents generally exhibit a lack of site directed delivery or compartmentalization. Consequently, large quantities of agent are normally required for imaging. It would be desirable to restrict the contrast agent to specific biological or anatomical compartments, such as the blood pool, liver, kidney or spleen. This would reduce the overall amount of agent which needs to be administered to achieve the desired contrast enhancement.
Maximum enhancement of major blood vessels takes place during the so-called vascular phase of contrast media kinetics which occurs within about the first two minutes following the intravascular infusion or bolus injection of the contrast media. This is because the plasma concentration of an intravascular contrast medium decreases rapidly as a result of vascular mixing, transcapillary diffusion of the medium from the circulation into the interstitial spaces and renal excretion. Consequently, imaging of blood vessels must take place within a narrow time window, typically within a few minutes after infusion or injection of the x-ray contrast agent. Currently, there is no commercially available x-ray contrast agent for imaging blood vessels which provides good contrast images of the vasculature for an extended period of time. Therefore, multiple injections are often required to visualize the vasculature adequately. Furthermore, arteriography, as currently practiced, typically requires percutaneous or surgical catheterization, fluoroscopic localization and multiple bolus arterial administrations to adequately visualize a given vascular region.
The need for improved visualization of the liver, kidney and spleen, particularly for early detection of metastases, has led to numerous attempts at developing a contrast medium for accumulation by the mononuclear phagocyte system (MPS). In Handbook of Experimental Pharmacology, Vol. 73, Radiocontrast Agents, Chapter 13, "Particulate Suspensions as Contrast Media", Violante and Fischer describe and analyze the problems and complexities involved in designing and formulating such a medium. Inasmuch as the MPS of the liver and spleen is known to trap particles by phagocytosis, contrast agents in particulate form, such as emulsions of iodinated oils, e.g., iodinated ethyl esters of poppy seed oil, and liposomes containing water soluble iodinated contrast agents have been proposed for liver and spleen visualization. However, emulsions tend to be unacceptably toxic when administered both intravenously and subcutaneously and liposomes tend to require unacceptably large amounts of lipid to achieve adequate contrast enhancement. The MPS or Kuppfer cells of the liver, to which liposomes and emulsions have been directed, constitute approximately 5 percent of the total cell population, the remainder being hepatocyte cells.
Submicron inorganic radioactive thorium dioxide particles have been used for liver visualization and have shown effective contrast enhancement in clinical testing. However, their use has been discontinued because of the extremely lengthy retention of the particles in the liver. This, in combination with the inherent radioactivity of thorium, has led to serious adverse side effects including neoplasm and fibrosis.
Violante et al, U.S. Pat. No. 4,826,689, disclose a method of making uniformly sized noncrystalline amorphous particles from water-insoluble organic compounds wherein the organic compound is dissolved in an organic solvent. In one embodiment, iodipamide ethyl ester is dissolved in dimethyl sulfoxide. However, solvent precipitation techniques such as described in U.S. Pat. No. 4,826,689 for preparing particles tend to provide solvent contaminated particles. Such solvents are often toxic and can be very difficult, if not impossible, to adequately remove to pharmaceutically acceptable levels for diagnostic imaging. Additionally, amorphous materials and formulations tend to exhibit unacceptably poor stability and/or short shelf-lives.
Motoyama et al, U.S. Pat. No. 4,540,602 disclose that a solid drug can be pulverized in an aqueous solution of a water-soluble high molecular substance, and that as a result of such wet grinding, the drug is formed into finely divided particles ranging from 0.5 .mu.m or less to 5 .mu.m in diameter. However, there is no suggestion that particles having an average particle size of less than about 400 nm can be obtained. Indeed, attempts to reproduce the wet grinding procedures described by Motoyama et al resulted in particles having an average particle size of much greater than 1 .mu.m.
PCT/EP90/00053 describes water insoluble iodinated carbonate esters reported to be useful as contrast agents for visualization of the liver and spleen. Particles of mean diameter on the order of 1.0 micron of the disclosed esters reportedly are taken up by the reticuloendothelial system of the liver and spleen. However, such particles are prepared by conventional mechanical crushing or spray drying techniques or by solvent precipitation techniques such as described in U.S. Pat. No. 4,826,689.
Currently, there is no completely satisfactory x-ray contrast agent in the market for liver and spleen imaging. Each contrast agent and/or composition proposed for liver and spleen imaging has some disadvantage.
It would be desirable to provide improved x-ray contrast compositions for imaging vessels, anatomical sites and body organs such as the liver and spleen. Moreover, it would be highly desirable to provide intravenously administered x-ray contrast compositions which demonstrate effective imaging of the blood pool for extended periods of time.