Silicone based bowel CT contrast material

Abstract

To provide a silicone-based polymer contrast medium for use in a CT imaging.SOLUTION: According to an embodiment, the invention provides a bowel contrast medium formulation. An exemplary formulation comprises (a) a bowel contrast medium including a silicone-based polymer oil which is emulsified in water. An exemplary silicone-based polymer oil has viscosity of almost 50 eSt-100000 eSt. In various embodiments, the silicone-based polymer oil is emulsified using a vehicle or dispersion medium which is adapted for administration of a formulation to a target which requires enteric administration. In the embodiment, the contrast material is incorporated in a pharmaceutically acceptable vehicle in which, the material is emulsified in a presence of a surfactant. In the embodiment, the silicone-based polymer is included by 30% or more of weight of the contrast material formulation.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] Cross - Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 61 / 866,806, filed Aug. 16, 2013, which is hereby incorporated by reference in its entirety for all purposes under 35 USC119(e). Reference to which is hereby incorporated by reference in its entirety for all purposes under 35 USC119(e).

Background Art

[0002]

[0002] Computed tomography (CT) has superseded all other diagnostic tests for the evaluation of many common clinical programs such as emergency trauma triage, evaluation of abdominal pain, and evaluation of inflammatory or ischemic bowel. The development of contrast materials for CT imaging has revolutionized medical imaging, particularly in the abdomen and pelvis where the viscera show more overlapping structures. Despite the proven value of contrast materials for CT, no substantially improved clinical agents have been introduced in the past 20 years. All commercially available CT contrast materials are based on iodine (intravascular or enteral) or barium (enteral only).

[0003]

[0003] The basic limitation of current clinical CT contrast materials is that they cannot be distinguished from each other or from other radiopaque structures such as metal pieces, calcifications, surgical staple lines, or implants. Even in dual-energy CT (DECT) or multi-energy CT, a currently emerging clinical technique that can distinguish imaged voxels based on the known CT number ratios of individual substances at 80:140 kVp, iodine-based and barium-based contrast materials cannot be easily distinguished from each other because their CT number ratios at 80:140 kVp are substantially the same. This limitation causes clinical confusion and delays. For example, if a CT scan enhanced with an oral barium contrast agent and an intravenous iodine contrast agent shows leakage of the contrast agent into the peritoneal cavity, it may be ambiguous whether the leakage is due to bleeding (iodine), bowel perforation (barium), or urethral injury (excreted iodine), each of which is a clinical emergency but requires completely different management. Such ambiguity leads to confusion, delays, and medical errors. To resolve the ambiguity, the scan can be repeated at the expense of loss of time and reduced treatment opportunities. Repeating the CT scan also adds to the radiation dose. Due to the increasing public concern about CT radiation dose, the 2011 NIH summit focused on reducing CT dose. CT scanners capable of multi-energy or spectral imaging have been developed, but even with improved capabilities, these new CT technologies are unlikely to be able to easily distinguish iodine-based from conventional barium-based contrast materials.

[0004]

[0004] There is no room for debate that "positive" enteral CT contrast agents, which mark the intestinal lumen with a bright signal during CT imaging to detect extraintestinal fluid accumulation, intestinal perforation, and masses in a wide range of diseases, have high value. Tumors, abscesses, and hematomas similar to the intestine are well-known diagnostic pitfalls in CT interpretation. Despite the value of "positive" enteral contrast agents, bright enteral contrast materials paradoxically: 1) trauma where it is unclear whether the leakage of the contrast material is due to vascular bleeding or from the intestinal lumen; 2) intestinal ischemia and infarction where the unenhanced intestinal wall can be obscured by the bright intraluminal enteral contrast material; 3) inflammation of the intestine where hyperenhancement of the intestinal wall by IV contrast agent is the most reliable feature of active disease; 4) intestinal bleeding where spillage of iodinated contrast agent into the intestine or the highlighted tumor is masked by the presence of enteral contrast agent; and 5) obscure findings from intravenous contrast CT for the most severe among diseases such as CT angiography where enteral contrast agent limits three-dimensional reconstruction.

[0005]

[0005] Further limitations of current enteral CT contrast materials are toxicity and complications. Barium -based agents can cause severe, potentially fatal peritonitis at the leakage site, or exacerbate infections, and can convert partial intestinal obstruction to complete intestinal obstruction. Iodinated agents can cause severe and even fatal pneumonia if inadvertently aspirated, and can also cause life-threatening allergic-type reactions, and for this reason, their use is restricted to up to 1% of patients who have had a previous reaction. This may be related in part to the high osmotic pressure of some clinical CT agents. Furthermore, some of these agents are brown and taste bad. Some patients (up to 1 - 3%) react to iodinated contrast materials.

[0006]

[0006] "Neutral" enteric CT contrast materials, such as liquids containing non-absorbable carbohydrates such as sorbitol or methylcellulose that do not contain water, iodine, or barium, are similar to water or soft tissue in the CT signal and have CT numbers of -10 to 60 Hounsfield units in CT imaging. These agents are generally used to distend the bowel lumen and enable the intravenous contrast material to clearly show relatively high or low vascular distributions in the bowel wall that might otherwise be obscured by "positive" enteric contrast materials. Since the signal from these agents is similar to that of natural soft tissue or water, they are not as confident in diagnosing bowel leakage, extra-luminal fluid collections, intra-abdominal abscesses, or hematomas as "positive" enteric contrast agents.

[0007]

[0007] "Negative" enteric contrast agents, although not generally used, have CT numbers of less than -20 Hounsfield units. Hydrocarbon oils such as peanut oil or vegetable oil are used to provide "negative" enteric contrast materials, which can provide excellent delineation of the bowel wall and bowel wall enhancement when given with an intravenous contrast agent, but "negative" contrast agents are not well tolerated. Furthermore, "negative" and "neutral" contrast agents are each similar to natural liquid or fat, and thus, extra-luminal fluid collections outside the bowel or blood vessels are ambiguous with respect to whether the signal represents contrast material or liquid or fat. Therefore, "negative" and "neutral" contrast materials are not as useful as positive enteric contrast materials in depicting bowel leakage or extra-luminal fluid collections, abscesses, or hematomas.

[0008]

[0008] Dual-energy CT and spectral CT enable simultaneous or near-simultaneous imaging of a subject using X-ray spectra of two different energies, one having a higher overall energy and the other having a lower overall energy. Individual materials exhibit a unique ratio of X-ray attenuation in the low-energy versus high-energy X-ray spectra, and thus, using the difference in low-versus-high X-ray energy spectrum attenuation, it is possible to distinguish between individual materials in CT imaging. The X-ray spectrum is typically determined by the X-ray tube potential setting. For example, setting the tube potential to 80 kVp generates a low-energy X-ray spectrum, and setting it to 140 kVp generates a high-energy X-ray spectrum. The CT number ratio of 80:140 kVp is fixed for any individual material, independent of the material concentration. Thus, imaging of two materials with dual-energy CT where the X-ray tube potential is set to 80 and 140 kVp enables the discrimination of the two materials based on their known characteristic CT number ratio of 80:140 kVp. Substance discrimination can be performed on the CT projection data obtained by the detector before the reconstruction of the CT image or acquired from the reconstructed CT image.

[0009]

[0009] Also, current dual-energy and spectral CT images can be reconstructed as virtual monoenergetic images, which are images that simulate what the CT scan images would look like if they were obtained using monoenergetic X-rays of any given X-ray energy, such as an energy selected from 40 to 140 keV. In these virtual monoenergetic images, iodine and barium contrast materials appear highly "positive" at low keV settings (40 to 70 keV), and at high keV settings (140 keV), the signal of the iodine and barium contrast materials gradually decreases such that it approaches the standard baseline of water or soft tissue (about -10 to 50 Hounsfield units). In other words, barium and iodine can act as "positive" contrast agents at low keV and as "neutral" contrast agents at high keV. However, iodine and barium agents still cannot be distinguished from each other. Position). In other words, barium and iodine can act as "positive" contrast agents at low keV and as "neutral" contrast agents at high keV. However, iodine and barium agents still cannot be distinguished from each other.

[0010]

[0010] Is there, or has there previously been reported, an enteric CT contrast material that can function simultaneously as "positive", "neutral", and "negative" contrast agents?

[0011]

[0011] There are generally several clinical scenarios where CT diagnosis can be improved by using an enteric "positive" contrast agent that can be converted to a "negative" contrast medium by image post - processing. For example, in suspected bowel ischemia, "neutral" or "negative" bowel contrast agents can each help to detect hyper - or hypo - enhancement of the bowel wall to detect inflammation or ischemia. In this same scenario, "positive" contrast agents enable the identification of bowel perforation, abscess, and fistula. Imaging physicians who are aware that without using an enteric agent that can be both "positive" and "negative", certain findings are enhanced by any available CT protocol while other important findings can be obscured, must choose from among multiple agents, and thus the CT scan is sub - optimal.

[0012]

[0012] The development of a safe clinical enteric contrast material that can be used simultaneously with iodinated and barium agents or other agents in development, such as those based on heavy metals like tungsten or tantalum and can be distinguished from them, would immediately and dramatically transform dual - energy CT imaging of trauma patients and millions of Americans with a wide range of diseases. It would be possible to inject into multiple body compartments and simultaneously examine by dual - energy, spectral, or multi - energy CT examinations to obtain high - resolution, perfectly co - registered anatomical images timely for each system for rapid and confident diagnosis, transforming the ability of clinicians to rapidly and accurately assess multi - organ injury due to trauma, infiltrative tumors, surgical complications, and inflammatory diseases.

[0013]

[0013] The development of a safe clinical enteric CT contrast material that can be digitally manipulated to appear as a "positive," "neutral," or "negative" contrast material under the control of the interpreting physician provides powerful diagnostic capabilities and eliminates guesswork and protocol and diagnostic errors. The reduction in errors results in more rapid diagnosis and a reduction in the need for additional elaborate examinations. Physicians no longer need to weigh the benefits and drawbacks of giving a "neutral" or "negative" versus a "positive" enteric contrast material for a given clinical plan.

[0014]

[0014] Non-iodine materials that have been tested for use with CT imaging include tungsten, tantalum, bismuth, gold, gadolinium, yttrium, and other lanthanides and a wide range of other high atomic number (Z) elements (Yu S, Watson A. Metal-Based X-ray Contrast Media. Chem Rev. 1999; 99(9):2353-2378 and Mongan J, Rathnayake S, Fu Y, Wang R, Jones EF, Gao DW, Yeh BM. In vivo Differentiation of Complementary Contrast Media at Dual-Energy CT. Radiology. 2012;265(1): 267-272). High-Z elements attenuate more X-rays per mole than low-Z elements. Materials based on low atomic number elements with atomic numbers less than 30 have not received attention or research interest for CT or DECT contrast enhancement applications.

[0015]

[0015] With respect to image quality and usefulness, iodine-based enteric contrast materials cannot be easily distinguished from intravascular iodine agents by DECT except contextually. Barium-based enteric contrast materials cannot be easily distinguished from intravascular iodine agents by DECT except contextually. Spillage of barium from the intestine into surrounding tissues acts as an adjuvant and substantially worsens infections and abscesses It occurs. The spilled barium may exacerbate inflammation and cause granulation of tissues. Barium often aggregates in a coarse, non-uniform pattern (coating the intestinal wall), thereby causing imaging artifacts or obscuring the appearance of the intestine. Barium that has entered the tube (leaked from the damaged intestine and entered the bloodstream) may cause microthrombi in the lungs or liver and may remain for a long time. The barium suspension separates easily and often needs to be shaken immediately before ingestion. Barium agents leave a white, chalky residue in and around the mouth and on clothing.

[0016]

[0016] An oral / enteric contrast agent that does not interfere with intravenous contrast agents for enhanced / non-enhanced CT imaging of the intestinal wall will cause a paradigm shift in the approach to abdominal CT imaging and will dramatically improve abdominal imaging by DECT. Dual-energy CT is a relatively new technology, and it has been less than five years since practical DECT scanners became available. Currently, most radiologists use enteric contrast agents in routine abdominopelvic CT scans to distinguish the intestine from other intra-abdominal structures (free fluid, cystic collections, ovaries, tumors, etc.). However, positive enteric contrast agents obscure the vascular enhancement / non-enhancement of the intestinal wall, thereby reducing the effectiveness of CT for the evaluation of intestinal inflammation, tumors, ischemia, and other lesions. Also, it may be unclear whether the spilled contrast material came from the intestine, the blood vessels, or both. Currently, no practical contrast material that can complement iodine-based or barium-based contrast materials is available.

Summary of the Invention

[0017]

[0017] The present invention solves these and other existing problems by providing a safe and effective formulation containing a silicone polymer compound as an enteric CT (or DECT) contrast agent suitable for use in humans. In an exemplary embodiment, the silicone polymer is an oil (or other liquid immiscible with water), and the formulation is an oil-in-water emulsion. In various embodiments, the present invention provides the advantages of CT "positive" and "negative" enteric contrast agents without the pitfalls of any type of enteric contrast medium. The advantages of "positive" enteric contrast agents include excellent identification of enteric leakage, detection of extraluminal collections such as abscesses, detection of abdominopelvic tumors and masses, evaluation of intestinal transit time, identification of transition points of intestinal obstruction, and excellent evaluation of intestinal wall thickening. The pitfalls of "positive" enteric contrast agents include the toxicity of iodine or barium contrast materials (see below) or the obscurity of critically important findings of intestinal wall ischemia or intestinal inflammation when intravascular contrast materials are administered simultaneously, the obscurity of the vascular structures of the abdominopelvis, inhibition of 3D reconstruction of CT angiography, ambiguity regarding the origin of spilled contrast material, and the obscurity of ongoing luminal gastrointestinal bleeding. The advantages of "negative" and "neutral" enteric contrast materials include excellent evaluation of hyper- or hypo-enhancement of the intestinal wall; excellent evaluation of enhancement of intraluminal masses; non-interference with three-dimensional reconstruction of CT angiography; and lower radiation doses when acquiring CT scans using automatic exposure control due to the lower X-ray attenuation of "negative" agents on CT scout images. The pitfalls of "negative" enteric contrast agents include a reduced ability to detect enteric leakage or extraluminal fluid collections, abscesses, or hematomas.

[0018]

[0018] The use of agents containing low atomic number atoms has many advantages over the use of agents containing higher atomic number atoms: 1) much lower unit cost; 2) much lower toxicity; 3) many agents containing low atomic number atoms are already used in foods or over-the-counter drugs. Agents containing low atomic number atoms can replace agents with high atomic numbers for routine CT.

[0019]

[0019] Enteral drugs for CT are generally safer than injectable drugs for several reasons: 1) The doses and concentrations required for enteral imaging are substantially lower than those of intravascular drugs. The administration of a typical intravenous iodine agent for abdominal CT scans requires 150 mL of a 350 mg / mL iodine contrast agent (iodine dose of 52 g). A typical oral dose is only 800 mL of a 10 mg / mL iodine contrast agent (total iodine dose of 8 g). 2) The amount of contrast material absorbed into the vascular system through the intestinal wall is extremely small. 3) Concerns about the viscosity and osmotic pressure of enteral imaging materials are minimal. 4) The nephrotoxicity seen in all intravascular drugs is unlikely in enteral drugs. 5) The likelihood of anaphylaxis and immune reactions in the intestine is extremely low compared to intravascular contrast agent administration.

[0020]

[0020] Furthermore, the non-iodine, non-barium enteral drug of the present invention provides the advantage that when used in clinical CT, enteral imaging materials and separate intravascular or other in vivo compartment contrast materials can be simultaneously administered and easily distinguished from each other by dual-energy or spectral CT. Since the drugs are administered so that they are imaged when present in the body simultaneously, in one embodiment, images of the regions with enhanced contrast are essentially completely co-registered, and the information obtained for evaluation is more and more accurate than when each contrast material is delivered separately, imaged, and individual CT scans are performed. Furthermore, in one exemplary embodiment, the radiation dose is approximately half that of two individual scans. In various embodiments, the contrast media and formulations of the present invention facilitate the repetition of CT scans and reduce the ambiguity caused by oral contrast agents based on previously delivered different materials.

[0021]

[0021] The formulations and methods of the present invention also provide the advantage of reducing the radiation dose by reducing the need for repeat / follow-up scans.

[0022]

[0022] In an exemplary embodiment, the present invention provides a drug that can be separated by dual-energy CT from both iodine or barium contrast materials and soft tissue or water, better than any other previously described contrast material, due to a very high CT number ratio of 80:140 kVp greater than 2.5.

[0023]

[0023] In an exemplary embodiment, the present invention provides a contrast material that can be separated by dual-energy CT from heavy metal-based contrast materials better than any other previously described contrast material, due to the very high CT number ratio (greater than 2.5) of 80:140 kVp of the present invention. Heavy metal-based contrast materials under development generally include W, Ta, Yb, Bi, and Au-based agents having a CT number ratio of 80:140 kVp less than 1.3.

[0024]

[0024] In an exemplary embodiment, the present invention provides an oil-in-water emulsion that is an enteric contrast medium preparation. The exemplary preparation includes an enteric contrast medium containing oil droplets that are essentially insoluble in water and / or solid particles of a material made from a plurality of atoms having an atomic number in the range of 6 to 52. In an exemplary embodiment, the material, the droplets and / or the particles are emulsified in a pharmaceutically acceptable vehicle in which they are uniformly suspended with the aid of an emulsifier. In an exemplary embodiment, the atom that contributes most to X-ray attenuation is silicon, and the material is a silicon-based polymer.

[0025]

[0025] In an exemplary embodiment, the present invention provides a contrast medium preparation that can also be delivered to other body cavities, which may be natural such as the digestive system and vagina or bladder, or surgically created such as an artificial bladder, or artificial medical devices such as tubes, catheters, pouches, reservoirs, or pumps.

[0026]

[0026] Further exemplary advantages, objects, and embodiments of the present invention are explained by the following description.

Brief Description of the Drawings

[0027]

Figure 1

[0027] It is a diagram of a computer simulation of the CT number ratio at 80:140 kVp for individual atoms having atomic numbers in the range of 1 to 100. This simulation was based on the expected CT x-ray tube output spectrum of a clinical CT scanner and the x-ray attenuation coefficients of individual elements from the National Institute of Standards and Technology. This simulation accurately predicted that conventional iodine-based and barium-based CT contrast agents (I and Ba, respectively) have a high CT number ratio at 80:140 kVp of about 1.7, that calcium-based materials such as bone have an intermediate CT number ratio at 80:140 kVp just over 1.4, and that silica (SiO2) has an intermediate CT number ratio at 80:140 kVp of about 1.27. However, this model did not predict that any simple material would have a very high CT number ratio at 80:140 kVp greater than 2.5 or even greater than 1.8. As such, the finding that silicon-based polymers, such as polydimethylsiloxane (PDMS), have such high CT number ratios at 80:140 kVp (2.6 - 2.8) was not initially predicted.

Figure 2

[0028] Figure showing that a silicon-based polymer emulsion and a silicon-based polymer provide both "negative" and "positive" contrast in vitro. Vials of silica (SiO2), gadolinium chelate (Gd), iohexol (I), and 75% silicon-based polymer emulsion containing 1% Tween-20 emulsifier (SiE) in water and pure silicon-based polymer oil (SiO) were imaged using dual-energy CT and reconstructed as virtual monochromatic images at 40 keV, 70 keV, and 140 keV (row). SiO2 and Gd lose a little signal at CT numbers from 40 to 140 keV. Iohexol iodine contrast loses substantial signal at 40 to 140 keV. SiE and SiO show much signal loss at 40 to 140 keV and are very rare in that they show even lower negative CT numbers than that of water at 140 keV. The CT numbers of these agents are shown in Figure 8.

Figure 3

[0029] Figure showing that a silicon-based polymer enables simultaneous imaging with an intravenous contrast material, providing simultaneous "positive," "neutral," and "negative" enterography imaging of a subject in a single DECT scan with virtual monochromatic CT image reconstruction. A rat imaged with dual-energy CT using a silicon-based polymer enterography material and an intravascular iohexol iodine contrast material, with image reconstructions as simple virtual monochromatic 40 keV (left), 70 keV (center), and 90 keV (right) images. The intravascular contrast material loses some signal between 40 and 90 keV images, but still appears as a bright signal (arrow) on the 90 keV image. The silicon-based polymer enterography material (arrowhead) is prominently bright on the 40 keV image, a neutral signal (similar to muscle and water) on the 70 keV image, and a negative signal (much darker than water) on the 90 keV image. Enteric wall enhancement by the iodine angiographic material still clearly appears as a bright signal on the 90 keV image. This distinct discrimination of the two contrast materials aids in the combined use of two appropriately complementary contrast agents (e.g., an enteric silicon-based polymer and an intravenous iodine agent) and the use of different keV settings to discriminate between the two agents. Alternatively, more standard two-, three-, or multiple-substance discrimination methods can be used to identify the contrast materials (see Fig. 6).

Figure 4

[0030] Figure showing that a silicon-based polymer emulsion enables simultaneous imaging using an intravenous contrast material to provide simultaneous “positive” and “negative” enteric imaging of the intestinal tract in a single DECT scan. A rabbit imaged with a dual-energy CT using a silicon-based polymer emulsion enteric contrast material and an intra-vascular iohexol iodine contrast material, with image reconstructions as simple virtual monochromatic 40 keV (left) and 90 keV (right) images. The intra-vascular contrast material loses some signal between the 40 - 90 keV images, but still appears as a bright signal (arrowhead) even on the 90 keV image. The enteric contrast material of the silicon-based polymer emulsion (arrow) is prominently bright on the 40 keV image, but is a negative signal (darker than water) on the 90 keV image. Enteric wall enhancement by the angiographic material is clearly visible on the 90 keV image where the intestinal lumen is dark. Since barium and iodine cannot be discriminated by DECT or conventional CT, the ability to modulate the brightness of the intestinal lumen is not possible when using conventional CT or DECT scans imaged with conventional iodine or barium enteric contrast materials and conventional iodine intra-vascular contrast agents.

Figure 5

[0031] In CT enhanced with a non-intravascular contrast agent, a figure showing that a silicon-based polymer emulsion provides simultaneous "positive", "neutral", and "negative" enterography imaging of the intestinal tract in a single DECT scan. In this examination, no intravenous contrast agent was administered. A rabbit imaged with dual-energy CT using an intestinal silicon-based polymer emulsion, along with image reconstructions as simple virtual monochromatic 40 keV (left), 70 keV (center), and 140 keV (right) images. The intestinal contrast material of the silicon-based polymer emulsion (arrow) can be selected to be displayed as a bright positive signal (40 keV) image, a neutral signal (70 keV), or a very dark signal (140 keV) or any gray shade as desired by the reader through dynamic adjustment of the keV setting. This ability to modulate the brightness of the intestinal lumen is not possible when using conventional CT or DECT scans imaged with conventional iodine or barium enterography materials that can only show positive or neutral in signal intensity compared to water and soft tissue at best.

Figure 6

[0032] A figure showing a rabbit imaged with dual-energy CT using a silicon-based polymer intestinal contrast material and intravascular iohexol, along with digital three-material discrimination for differentiating the silicon-based polymer from the iohexol contrast material. The 40 keV virtual monochromatic image shows the intestinal wall that cannot be differentiated from intestinal lumen contrast (arrow, left image). The iodine map image (center) clearly shows the intestinal wall with digital removal of the silicon-based polymer contrast. Similarly, the map image of the silicon-based polymer (right) clearly shows the intestinal lumen (arrow) when the iodine contrast material is digitally removed. Blood vessels (arrowheads) are clearly depicted on the iodine map image (center), the enterography is digitally subtracted by material discrimination, and these blood vessels are more easily recognized compared to the 40 keV image (left).

Figure 7

[0033] It is a figure obtained by imaging a silicon-based polymer and a silicon-based polymer emulsion in a CT phantom. The silicon-based polymer emulsion has a very high and consistent CT number ratio value of 2.70 - 2.77 at 80:140 kVp and a CT number ratio value of 1.77 - 1.80 at 100:140 kVp. These values are much higher than those of iodine-based or barium-based agents that show a CT number ratio of approximately 1.7 - 1.76 at 80:140 kVp. The silicon-based polymer is from Fisher Scientific (silicone oil, catalog number S159) or Sigma-Aldrich, and the fluorinated silicon-based polymer is from Dow Corning (fluorosilicone oil, catalog number FS-1265). Note: All percentages regarding the formulation are weight / weight percentages (w / w%) except for 70% (v / v%) isopropyl alcohol.

Figure 8

[0034] It is a figure showing CT numbers in Hounsfield Unit (HU) derived from virtual monochromatic images from dual-energy CT scans of formulations containing a gadolinium chelate dilution solution, an iohexol solution, a silicon dioxide suspension, a pure silicon-based polymer oil, and a 75% emulsion of the silicon-based polymer oil. The silicon-based polymer was obtained from Fisher Scientific (catalog number S159). At 40 keV, the silicon-based polymer and the silicon-based polymer emulsion showed high CT numbers above 300 HU and were considered "positive contrast". At 140 keV, the silicon-based polymer and the silicon-based polymer emulsion showed negative CT numbers lower than -20 HU and were considered "negative contrast". Water (always 0 HU + / - 20 HU) and soft tissue are in the range of -10 HU to 60 HU, and substances in this range are called "neutral" in contrast. Iohexol, an iodine contrast agent, achieves positive contrast and neutral contrast in the low and high ranges of the virtual monochromatic CT image respectively, but it should be noted that it does not achieve values within the range of "negative" contrast materials. Values for human fat and olive / canola oil are shown for comparison. Representative corresponding images are shown in Figure 2.

Figure 9

[0035] It is a diagram showing a scheme of oil-in-water emulsion particles / droplets.

Figure 10

[0036] A list of surfactants and emulsifiers commonly used in the cosmetics, food, or pharmaceutical industries is referred to as an example of the emulsifier for use in the formulations of the present invention. The hydrophilic-lipophilic balance (HLB) value is a physicochemical parameter for evaluating the affinity between a surfactant molecule and water (or oil): the higher the HLB value, the higher the hydrophilicity and the lower the lipophilicity of the surfactant molecule. Generally, the HLB value ranges from 0 to 20. In various embodiments, a surfactant having an HLB of about 9 to about 18 is preferred for forming an oil-in-water (O / W) type emulsion of the silicon-based polymer during emulsification. Note: An exemplary stable oil-in-water (o / w) type emulsion is prepared using an emulsifier having an HLB value of 9 to 18.

Figure 11

[0037] It is a diagram showing a shell-hardened polysiloxane emulsion. A crosslinking group can be introduced near the hydrophilic region of the emulsifier molecule. First, the emulsification of the silicon-based polymer oil is carried out in water in the presence of such a crosslinkable surfactant; then, in a second step, i.e., the intramolecular crosslinking of many such groups (e.g., thiol groups) on the surface of the tiny droplets of the oil is applied. This crosslinking can further stabilize the emulsion particles by providing a "hardened" shell.

Figure 12

[0038] Figure showing high-dose intragastric forced administration of barium 2.1% w / v, 100% PDMS (silicone oil 350 cst from Sigma Aldrich), or 75% PDMS emulsion (silicone oil 350 cst from Sigma Aldrich emulsified in distilled water with 0.25% Tween 20) in Swiss-Webster mice in non-GLP tests. Each data point is the average of 3 mice. No obvious toxicity was seen in mice (left graph) after 4X dose on days 1 and 2 observed over a total of 19 days, or in mice (right graph) given 2X daily dose over 14 days and observed over a total of 17 days. No significant difference was seen in the growth curve trajectories of mice receiving silicone oil or silicone oil emulsion compared to control mice (barium sulfate 2.1% w / v) within each cohort. No gross visceral damage was seen in all mice at the time of sacrifice.

Figure 13

[0039] Figure showing that silicone-based contrast materials exhibit similar CT numbers and a CT number ratio of 80:140 kVp when scanned on General Electric (GE) and Siemens CT scanners. CT numbers were measured on a commercial clinical dual-energy CT scanner at CT tube potentials of 80, 100, 120, and 140 kVp. For General Electric, the scanner was 750HD. For Siemens, the scanner was Somatom Definition. The Readi-Cat™ contrast material contains 2.1% w / v barium sulfate in an aqueous suspension. The silicone oil is 350 cst from Sigma Aldrich. The 70% w / w silicone oil emulsion is prepared in distilled water with 0.25% Tween-20.

Figure 14

[0040] Figure showing that silicone oil and its aqueous (oil-in-water) emulsions exhibit a significantly higher and consistent CT number ratio of 80:140 kVp, regardless of the base viscosity of the silicone oil (measured in cSt). Cross-linked silicone rubber, fluorosilicone oil, and silicon dioxide exhibit lower 80:140 kVp CT number ratios but higher CT numbers.

Figure 15

[0041] Figure showing selected corresponding CT images for FIGS. 13 and 14. Diluted iodine contrast material (iohexol, 5 mg I / mL), 100% 350 cst silicone oil (Sigma Aldrich), a 75% emulsion of Sigma Aldrich 350 cSt silicone oil in water, and vials of water were scanned at X-ray tube settings of 80, 100, 120, and 140 kVp. The iodine contrast material exhibits a lower intensity signal (lower CT number) at higher kVp X-ray tube settings compared to lower settings. Silicone oil and silicone oil emulsions exhibit an even more substantial loss of signal at higher settings compared to lower kVp X-ray tube settings. Water does not change in CT number with varying kVp X-ray tube settings. Dual-energy CT can distinguish silicone-based contrast materials from iodine contrast materials due to a substantially higher relative decrease in the CT number of silicone oil as an increase in the kVp X-ray tube setting compared to what is seen with the use of iodine contrast material. Since water and soft tissue do not change in relative CT number at various kVp settings, both iodine contrast material and silicone-based contrast materials can be distinguished from water and soft tissue.

DETAILED DESCRIPTION OF THE INVENTION

[0028] I. Introduction

[0042] Dual energy and spectral CT are standard capabilities of modern scanners. With current dual energy technology, it is possible to simultaneously image a patient with X-rays of two or more different energy spectra, such as those generated by setting one X-ray tube potential to 80 kVp to generate one X-ray spectrum and then setting the other X-ray tube potential to 140 kVp to generate a second X-ray spectrum. Alternatively, the X-ray tube potential can be rapidly varied between a low kVp setting and a high kVp setting. The X-ray energy spectra from these tube potentials can be further modified to achieve better spectral separation by selectively filtering the low or high kVp X-ray beams, such as by using a tin filter on the high kVp X-ray beam. Dual energy and spectral CT imaging can also be acquired using other methods such as sandwich detectors or photon counting that quantify X-ray attenuation in different parts of the X-ray spectrum. Materials in the body are identified based on differences in their high and low tube potential CT number ratios (e.g., the CT number ratio of 80:140 kVp). This difference is related to the atomic number of the atoms in the material. Simulations of CT number ratios for clinical CT scanners have shown that iodine and barium exhibit a high 80:140 kVp CT number ratio of approximately 1.7, which is close to the maximum values predicted for current clinical scanners, along with the CT numbers measured in Hounsfield units. Materials with more widely different ratios are more clearly distinguishable by DECT, and thus iodine and barium can be very well distinguished from water or most soft tissues, which have a CT number ratio of 80:140 kVp of approximately 1.0. Materials with intermediate 80:140 kVp CT number ratios (1.25 - 1.45) can be somewhat distinguished from both water or most soft tissues and iodine or barium contrast materials by using a three-material discrimination algorithm. The best elements that can be incorporated into contrast materials to distinguish from iodine and barium were thought to have a low ratio close to 1.0 (corresponding to high atomic numbers, e.g., 71 - 83, or also to low atomic numbers, e.g., 3 - 20).Pairs of such contrast materials can be separated by a simple two - material discrimination algorithm, but these materials with a low 80:140 kVp CT number ratio cannot be easily separated from water and soft tissue even when using a three - material or multi - material discrimination algorithm.

[0029]

[0043] Materials imaged by dual - energy or spectral CT can be digitally separated by the low - energy to high - energy X - ray spectral CT number ratio (e.g., 80:140 kVp CT number ratio) of each material. Digital separation (“material discrimination”) can be performed on projection data (data from the detector before reconstruction of the CT image) or on the CT image. The simplest method for digital separation is two - material discrimination, where the signal from each voxel is proportionally assigned to one material or another based on the CT number ratio of the low - energy to high - energy X - ray spectrum. By this method, two images are generated: an image representing the signal assigned to one material and another image representing the signal assigned to the other material. Based on the assumption that the CT number ratio of the low - energy to high - energy X - ray spectrum of three materials and the sum of the fractional densities of the three materials is 1.0, a somewhat more complex three - material discrimination method can be used to separate the three materials. Multi - material discrimination can be obtained by repeatedly applying three - material or two - material discrimination, and the contributions of three or more materials to the CT signal can be solved. All of these methods are extrapolated images representing how an object imaged in various mono - chromatic X - ray CT scans would appear, assuming that the object consists entirely of the materials assumed by the material discrimination method. These can also be used to generate virtual mono - chromatic CT images. The discrimination method can be performed on the image (e.g., on CT images at 80 and 140 kVp), or on the projection - space CT data, which is the data received by the X - ray detector, with or without using post - processing and filtering, before reconstructing the CT image.

[0030]

[0044] Some high atomic number elements have a CT number ratio of 80:140 kVp close to 1.0 and are thus easily distinguishable from iodine and barium contrast materials in dual - energy CT by material discrimination algorithms. Such high atomic number elements include tantalum (Ta, Z = 73), tungsten (W, Z = 74), bismuth (Bi , Z = 83), ytterbium (Yb, Z = 70), and gold (Au, Z = 79), which are the least toxic heavy atoms. Since the CT number ratio of 80:140 kVp of such contrast materials is very similar to that of water and soft tissue, excellent or even outstanding separation between iodine and these agents can be obtained by commercially available iodine - to - soft - tissue density material discrimination from any CT scanner vendor, without the need to optimize contrast - specific software. The signals obtained from these agents are often, if not always, seen in the "water / soft - tissue" density map in two - material discrimination separation, but not in the iodine map. The negative aspects of these high - Z agents are: 1) their overall high cost, relatively limited availability on Earth, and concerns regarding patient safety; 2) in dual - energy or spectral CT, these agents cannot be easily distinguished from soft tissue or water because their CT number ratio of 80:140 kVp or high - Z agents is similar to that of soft tissue or water; and 3) their high X - ray attenuation coefficient compared to that of soft tissue, which results in formulations containing a substantial amount of these agents that appear as "positive" signal contrast materials regardless of the kVp setting or monochromatic keV image reconstruction.

[0031]

[0045] Elements with low Z numbers have not been widely investigated as reporter atoms for CT or X-ray contrast materials. In particular, silicon-based polymers have not been previously described as X-ray attenuating components of enteric CT or X-ray contrast materials. The present invention provides a safe formulation of silicon-based polymers that can serve as safe and effective materials for enteric contrast agents. These materials can be readily distinguished from conventional commercially available iodine and barium-based contrast materials using simple two-substance discrimination. Furthermore, some of these materials have a CT number ratio of greater than 2.5 at 80:140 kVp and can thus also be distinguished from water and soft tissue as well as iodine / barium-based contrast materials by using three-substance and multi-substance discrimination. Potentially, further advances in CT technology will enable a higher ability to distinguish between materials having different X-ray absorption ratios at different X-ray energy spectra.

[0032]

[0046] For medical diagnostic imaging, the X-ray attenuation coefficient of a contrast material, and thus the CT attenuation number at a fixed concentration, increases exponentially with the effective atomic number of the material (R. C. Murty, Effective atomic numbers of heterogeneous materials, Nature. 1965; 207, 398-399). The effective atomic number of a material depends on the reporter atom, which is the atom in the material that contributes most to the X-ray attenuation of the material during imaging. Historically, only reporter atoms with high atomic numbers, such as iodine (Z = 53) or barium (Z = 56), have been used as reporter atoms for "positive" contrast materials, which are contrast materials having a CT number substantially greater than that of water or soft tissue. High concentrations of low atomic number materials have not been described for use in CT as positive contrast materials. Furthermore, CT or X-ray contrast that provides both "positive" and "negative" signals depending on the image reconstruction technique has not been described. For the first time according to the present invention, an effective and low-cost enteric contrast medium based on silicon-based polymers for X-ray and CT imaging, including dual energy and spectral CT, and a formulation of this medium are provided. This contrast material can provide both "positive" and "negative" signals depending on the image reconstruction technique.

[0033]

[0047] The very high 80:140 kVp CT number ratios of some silicon-based polymers are not only significantly different from those of conventional iodine or barium contrast agents, but also significantly different from soft tissue, and allow for the digital separation of this new type of contrast material from both conventional contrast agents and soft tissue using 3-material or multi-material discrimination algorithms.

[0034] II. Definitions

[0048] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein as well as laboratory procedures in organic chemistry, pharmaceutical formulations, and medical imaging are well known and commonly employed in the art.

[0035]

[0049] As used herein, the articles “a” and “an,” refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Contrast agents that include iodine, barium, or other atoms having a Z greater than 52 are exemplary “high Z” materials.

[0036]

[0036]

[0050] The designation “high Z” material or “low Z” material is based on a comparison of the atomic number of the reporter atom with the atomic numbers of iodine (Z = 53) and barium (Z = 56), which are the reporter atoms most commonly used in current clinical contrast agents for CT and X-ray imaging.

[0037]

[0051] “Concurrent” administration refers to using a contrast agent in conjunction with a medical imaging procedure being performed on a subject. As will be understood by those skilled in the art, concurrent administration of a contrast agent to a subject includes administration during or prior to the performance of a medical imaging procedure such that the contrast agent is visible in the medical image of the subject.

[0038]

[0052] “Disease” is a state of health of an animal in which the animal is unable to maintain homeostasis and in which the animal's health deteriorates if the disease is not ameliorated.

[0039]

[0053] The term “half-life” or “t1 / 2” as used herein in the context of administering the enteric contrast medium of the present invention to a patient refers to the time It is defined as the necessary time. Depending on the multiple clearance mechanisms, redistribution, and other mechanisms well known in the art, there may be two or more half-lives associated with the contrast medium. Further explanations of "half-life" can be found in Pharmaceutical Biotechnology (1997, edited by DFA Crommelin and RD Sindelar, Harwood Publishers, Amsterdam, pages 101 - 120). As used herein in the context of administering an enteric contrast medium to a patient, the term "retention time" is defined as the average time that the enteric contrast medium remains in the patient's body after administration.

[0040]

[0054] As used herein, "pharmaceutically acceptable carrier" includes any material that, when combined with a conjugate, retains the activity of the conjugate activity and does not react with the immune system of the subject. Examples include, but are not limited to, any standard pharmaceutical carrier such as phosphate buffered saline solution, water, emulsions such as oil / water emulsions, and various types of wetting agents. Other carriers also include sterile solutions. Typically, these carriers contain excipients such as starch, milk, sugar, sorbitol, methylcellulose, certain clays, gelatin, stearic acid or its salts, magnesium stearate or calcium stearate, talc, vegetable fats or oils, gums, glycols, or other known excipients. Such carriers may also contain flavoring agents, textures, and coloring agents or other components. Compositions containing such carriers are formulated by well-known conventional methods.

[0041]

[0055] As used herein, "administering" means oral administration, administration as a suppository, topical contact, rectal, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or implantation of a surgically created pouch or surgically placed catheter or device, or a sustained release device, such as a mini osmotic pump, to a subject. and other means of administration, including, but not limited to,

[0042]

[0056] As used herein, the term "enterographic medium" is understood to mean a dry or non-suspended component or mixture of components that includes at least one X-ray absorbing substance and optionally at least one pharmaceutically acceptable excipient which may itself include other ingredients such as flavor masking agents, antioxidants, wetting agents, emulsifying agents, etc. Subsequently, the non-suspended mixture can be dissolved, emulsified, or suspended in a suspension medium to form the enterographic medium preparation of the present invention. As used herein, terms such as "suspension medium" and "pharmaceutically acceptable excipient" refer to a medium in which the components of the enterographic medium are emulsified or suspended.

[0043]

[0057] As used herein, "enterographic medium preparation" means a pharmaceutically acceptable liquid or paste preparation for administration to a subject, which, unless otherwise described, includes at least one enterographic medium and may or may not include at least one pharmaceutically acceptable excipient for suspending the medium, and is prepared by dissolving, emulsifying, or suspending the enterographic medium described herein, for example, in the form of a powder, emulsion, or mash, in a pharmaceutically acceptable vehicle prior to use for administration to the subject. Preferably, the suspension medium is water.

[0044]

[0058] As used herein, the terms "coating" and "coated" are understood to include coatings that are biocompatible in an environment having an acidic or neutral or basic pH value. Exemplary coatings are hardening (cross-linking) surfactants or commonly used surfactants (e.g., Tween 20) that encapsulate another component of the preparation of the present invention, such as a liquid silicone-based polymer.

[0045]

[0059] As used herein, the term "particle" (singular and plural) refers to any free-flowing substance of any shape greater than about 1 nm, such as crystals, beads (smooth, round or spherical particles), pellets, spheres, and granules.

[0046]

[0060] The term "droplet" refers to the form of a liquid immiscible with water in an oil-in-water emulsion.

[0047]

[0061] As used herein, the term "flavor masking" includes the enteric contrast media of the present invention having an unpleasant flavor, which are processed to be easy to take orally and / or do not substantially release in the mouth, but release, for example, in the stomach or the intestinal tract, any formulation or particle, or an oral pharmaceutical composition.

[0048]

[0062] As used herein, "unpleasant and / or bitter flavor" means that most human patients judge that the enteric contrast media contained have an unpleasant and / or bitter and / or extremely bitter flavor after ingestion.

[0049]

[0063] Current clinical CT scanners can generate various X-ray spectra for imaging. The energy spectrum mainly depends on the setting of the scanner tube potential (kVp) of the machine, and typically ranges from 80 to 140 kVp, but it may be set higher or lower. With these kVp settings, the CT scanner generates X-rays having an energy spectrum, and the X-rays with the maximum energy are 80 keV when the tube potential setting is 80 kVp and 140 keV when it is 140 kVp. The X-ray spectrum is modulated, for example, by passing the X-rays through a metal filter, such as aluminum, copper, or tin. ​This is possible. For any given monochromatic x-ray energy passing through a known material, the degree of x-ray attenuation is defined by Beer-Lambert's law and is proportional to a) the density of the atoms, b) the distance the x-rays travel through the material, and c) the x-ray attenuation coefficient for the particular atoms or material at that specific x-ray energy. Since the x-ray spectrum is relatively constant for any given kVp setting of a given scanner, for any given material, the ratio of x-ray attenuation at 80 kVp and 140 kVp can be determined when measured by Hounsfield Unit (HU). Generally, when imaged with a standard CT scanner using an aluminum or copper filter, the 80:140 kVp CT number ratio of iodine and barium is about 1.7 - 1.8, but when a tin filter is used for imaging at 140 kVp, a substantially larger 80:140 kVp CT attenuation ratio is obtained (A. N. Primak, J. C. Ramirez Giraldo, X. Liu, L. Yu, and C. H. McCollough. Improved dual-energy material discrimination for dual-source CT by means of additional spectral filtration. Med. Phys. 36(4), pp. 1359 - 1369. April 2009). Since the CT number of water is defined as 0 in Hounsfield units for any given x-ray spectrum in CT, by definition, the 80:140 kVp CT number ratio of water is 1.0. The elements of the periodic table have 80:140 kVp CT number ratios in the range of about 0.9 - 1.8. Materials with a more widely dispersed 80:140 kVp CT number ratio are more easily distinguishable in dual-energy or spectral CT. Other methods for obtaining dual-energy CT include the use of different tube potential settings (e.g., 100 kVp or 70 kVp rather than 80 kVp). Alternative methods for obtaining dual or multi-energy CT include modifying the x-ray spectrum to more widely separate the energy spectra (e.g., by applying a tin filter to the x-ray tube set at a high kVp), and also Alternatively, other methods can be used to quantify the absorption of X-rays of different energies (e.g., a sandwich detector in which the upper layer of the X-ray detector blocks low-energy X-rays, thereby modulating the spectrum of the X-rays irradiating the lower layer; a photon-counting detector). These other methods are still limited for discriminating iodine-based materials and barium-based materials and can better discriminate materials containing atoms with significantly different atomic numbers.

[0050]

[0064] A virtual monochromatic CT image is an image reconstruction obtained from dual-energy or spectral CT data in which the X-ray absorption of individual voxels of the image at a given monochromatic X-ray energy is an estimated value. One method for achieving a virtual monochromatic CT image is to assume that the imaged object is composed entirely of two materials such as iodine and water, perform a two-material discrimination based on the dual-energy or spectral CT data, and determine the relative X-ray attenuation due to iodine and water for each voxel of the image. The virtual monochromatic CT image can then be extrapolated back for any monochromatic X-ray energy by using the corresponding reference X-ray attenuation coefficients for iodine and water, such as those found in the National Institutes of Standards and Technology, to determine the CT number at the corresponding X-ray energy for each voxel of the image. In this manner, virtual monochromatic images can be obtained for various ranges of keV, such as 40 keV, 140 keV, 200 keV, or any value in between or otherwise. Similarly, three-material and multi-material discrimination can be used to extrapolate back the virtual monochromatic CT image.

[0051]

[0065] When a structure is specified by its conventional chemical formula with substituents written from left to right, the structure optionally includes chemically identical substituents as a result of writing the structure from right to left. For example, -CH2O- is optionally intended to be described as -OCH2-.

[0052]

[0066] The term "alkyl", by itself or as part of another substituent, unless otherwise described, may be straight-chain, branched-chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated, mono-unsaturated or poly-unsaturated, and may include divalent, trivalent and polyvalent radicals having the specified number of carbon atoms (i.e., C1-C , where C 10 means 1 to 10 carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers such as, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Unsaturated alkyl groups have one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. The term "alkyl" also means, unless otherwise described, optionally includes derivatives of alkyl, such as "heteroalkyl", defined in more detail below. An alkyl group limited to hydrocarbon groups is called a "homoalkyl". Exemplary alkyl groups include mono-unsaturated C 9~10 , oleoyl chain or di-unsaturated C 9~10 , 12~13 linoleyl chain.

[0053]

[0067] The term "alkylene", by itself or as part of another substituent, is not limited but means a divalent radical derived from an alkane, such as exemplified by -CH2CH2CH2CH2-, and further includes the groups described below as "heteroalkylene". Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, and those having 10 or fewer carbon atoms are preferred in the present invention. "Lower alkyl" or "lower alkylene" generally refers to a short-chain alkyl or alkylene group having 8 or fewer carbon atoms.

[0054]

[0068] The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional meanings and each refers to an alkyl group bonded to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

[0055]

[0069] The terms "aryloxy" and "heteroaryloxy" are used in their conventional meanings and each refers to an aryl or heteroaryl group bonded to the remainder of the molecule via an oxygen atom.

[0056]

[0070] The term "heteroalkyl", by itself or in combination with another term, unless otherwise specified, means a stable straight-chain, branched-chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the recited number of carbon atoms and at least one heteroatom selected from the group consisting of O, N, Si, and S, where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, S, and Si can be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. For example, up to two heteroatoms may be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene", by itself or as part of another substituent, unless otherwise limited, means a divalent radical derived from heteroalkyl, as exemplified by -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatoms may occupy one or both of the ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkylenamino, alkylenediamino, etc.). Further, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not included by the direction in which the formula of the linking group is written. For example, the formula -CO2R'- represents both -C(O)OR' and -OC(O)R'. or both (e.g., alkyleneoxy, alkylenedioxy, alkylenamino, alkylenediamino, etc.). Further, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not included by the direction in which the formula of the linking group is written. For example, the formula -CO2R'- represents both -C(O)OR' and -OC(O)R'.

[0057]

[0071] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, unless otherwise described, each represent cyclic forms of "alkyl" and "heteroalkyl", respectively. Further, for heterocycloalkyl, the heteroatom can occupy the position where the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Further exemplary cycloalkyl groups include steroids such as cholesterol and its derivatives. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

[0058]

[0072] The term "halo" or "halogen", by itself or as part of another substituent, unless otherwise described, means a fluorine, chlorine, bromine, or iodine atom. Further, terms such as "haloalkyl" are meant to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" is meant to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-cyclobutyl, 3-bromopropyl, and the like.

[0059]

[0073] Unless otherwise described, the term "aryl" means a polyunsaturated aromatic substituent which may be a single ring or multiple rings (preferably 1 to 3 rings) that are fused together or commonly linked. The term "heteroaryl" refers to an aryl substituent (or ring) containing 1 to 4 heteroatoms selected from N, O, P, S, Si and B, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. Exemplary heteroaryl groups are 6-membered azines such as pyridinyl, diazinyl and triazinyl. The heteroaryl group can be bonded to the rest of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Each substituent of the above aryl and heteroaryl ring systems is selected from the group of acceptable substituents described below.

[0060]

[0074] For the sake of brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes the aryl, heteroaryl and heteroarene rings defined above. Thus, the term "arylalkyl" includes an alkyl group in which the aryl group has an alkyl group (e.g., benzyl, phenethyl) in which a carbon atom (e.g., a methylene group) is replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.). It means including a radical bonded to, for example, a thioether, pyridylmethyl, etc.

[0061]

[0075] Each of the above terms (e.g., "alkyl", "heteroalkyl", "aryl", and "heteroaryl") means, optionally, including both the indicated species in substituted and unsubstituted forms. Exemplary substituents for these species are provided below.

[0062]

[0076] Substituents for alkyl and heteroalkyl radicals (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generally referred to as "alkyl group substituents", and they include, but are not limited to, one or more of a number in the range of 0 to (2m'+1) (where m' is the total number of carbon atoms of such a radical) of H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, -OR', =O, =NR', =N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -CN and NO2. R', R'', R''' and R'''' are each preferably independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, for example aryl substituted with 1 to 3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When the compounds of the present invention contain two or more R groups, each R group is independently selected such that when two or more of these groups are present, they are each R', R'', R''' and R'''' groups. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NR'R'' means, but is not limited to, including 1-pyrrolidinyl and 4-morpholinyl.From the above considerations regarding substituents, one of ordinary skill in the art would understand that the term "alkyl" means including groups such as carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.). These terms include groups that can be considered exemplary "alkyl group substituents" which are components of exemplary "substituted alkyl" and "substituted heteroalkyl" moieties.

[0063]

[0077] Similar to the substituents described for alkyl radicals, substituents for aryl, heteroaryl, and heteroarene groups are generally referred to as "aryl group substituents". Such substituents include, for example, a number in the range from 0 to the total number of open valences on the aromatic ring system, and include, but are not limited to, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, -OR’, =O, =NR’, =N-OR’, -NR’R’’, -SR’, -halogen, -SiR’R’’R’’’, -OC(O)R’, -C(O)R’, -CO2R’, -CONR’R’’, -OC(O)NR’R’’, -NR’’C(O)R’, -NR’-C(O)NR’’R’’’, -NR’’C(O)2R’, -NR-C(NR’R’’R’’’)=NR’’’’, -NR-C(NR’R’’)=NR’’’, -S(O)R’, -S(O)2R’, -S(O)2NR’R’’, -NRSO2R’, -CN and -NO2, -R’, -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, and are selected from groups bonded to the heteroaryl or heteroarene nucleus via a carbon or heteroatom (e.g., P, N, O, S, Si, or B). Each of the groups named above is bonded directly or via a heteroatom (e.g., P, N, O, S, Si, or B) to the heteroarene or heteroaryl nucleus, where R’, R’’, R’ ’’and R’’’’ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When the compound of the present invention contains more than one R group, for example, each of the R groups is independently selected as R’, R’’, R’’’ and R’’’’ groups when more than one of these groups are present.

[0064]

[0078] Two substituents on adjacent atoms of an aryl, heteroarene or heteroaryl ring can optionally be replaced with a substituent of the formula -T-C(O)-(CRR’) q -U- (wherein T and U are independently -NR, -O-, -CRR’- or a single bond, and q is an integer from 0 to 3). Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring can optionally be replaced with a substituent of the formula -A-(CH2) r -B- (wherein A and B are independently -CRR’-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR’- or a single bond, and r is an integer from 1 to 4). One of the single bonds of the newly formed ring can optionally be replaced with a double bond. Alternatively, two substituents on adjacent atoms of an aryl, heteroarene or heteroaryl ring can optionally be replaced with a substituent of the formula -(CRR’) s -X-(CR’’R’’’) d -(wherein s and d are independently integers from 0 to 3, and X is -O-, -NR’-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR’-). The substituents R, R’, R’’ and R’’’ are preferably independently selected from hydrogen or substituted or unsubstituted (C1-C6) alkyl. These terms encompass groups that can be considered exemplary “aryl group substituents” which are components of exemplary “substituted aryl”, “substituted heteroarene” and “substituted heteroaryl” moieties.

[0065]

[0079] As used herein, the term "acyl" describes a substituent containing a carbonyl residue C(O)R. Exemplary species for R include H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl.

[0066]

[0080] As used herein, the term "fused ring system" means at least two rings, each ring having at least two atoms in common with another ring. A "fused ring system" may include aromatic and non-aromatic rings. Examples of "fused ring systems" are naphthalene, indole, quinoline, chromene, and the like.

[0067]

[0081] As used herein, the term "heteroatom" includes oxygen (O), nitrogen (N), phosphorus (P), sulfur (S), silicon (Si), boron (B), and halides (F, Cl, Br, or I).

[0068]

[0082] The symbol "R" is a general shorthand representing a substituent selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl groups.

[0069] III. Embodiments A. Composition

[0083] In various embodiments, the present invention provides non-iodine intestinal / non-vascular CT contrast materials that can be readily distinguished from commercially available CT contrast materials on the market or as further described in the literature. These silicon polymer-based materials have significantly different relative X-ray attenuation at different kVp settings compared to conventional iodine / barium CT contrast materials and contrast materials based on heavy metals. The new silicon polymer-based contrast materials can be readily distinguished from conventional iodine and barium CT contrast materials as well as soft tissue and water in dual-energy CT, and this When dual-energy / spectral CT images are obtained, the agents of the present invention can be identified by commercially available or "in-house" dual-energy CT (DECT) / spectral CT software. In low-energy virtual monochromatic CT images, such as 40 keV, the material shows a "positive" contrast signal, and in high-energy virtual monochromatic CT images, such as 100 - 140 keV, the material can show a "negative" contrast signal. Thus, the agents of the present invention provide one or more of the following benefits: 1) The ability to opacify the intestinal tract or non-vascular structures and distinguish these structures from opacified vascular structures in CT; 2) The ability to easily distinguish the origin of the extravasated contrast material as being either vascular or non-vascular; 3) The ability to obtain CT images with enhanced contrast of vascular and non-vascular structures simultaneously / almost simultaneously, thereby enabling the complete simultaneous registration of further differences between these structures; and 4) The ability to opacify the intestinal tract / non-vascular structures using a contrast agent for CT without inhibiting the evaluation of wall enhancement of these structures (intestinal wall, bladder wall, other wall structures) from intravenous contrast agents. This enables the first access to a wide range of improved CT applications.

[0070]

[0084] In various embodiments, the present invention provides an intestinal contrast material based on a silicone polymer in the form of an oil or other non-water miscible liquid, gel, rubber, and resin. In various embodiments, the silicon-containing oil can be selected to have a very high ratio of CT attenuation at 80 to 140 kVp greater than 2.1, which may be even higher than 2.7 or as low as a ratio lower than 1.38, depending on the relative number of other different atoms incorporated in the oil, such as fluorine or heavy atoms.

[0071]

[0085] The benefits of the agents of the present invention are the result of new properties of the agents. In CT scans, all conventional CT contrast materials look the same. They all cause an increase in X-ray attenuation (positive contrast) when present and are indistinguishable except in context. When dual-energy CT is used, they can be identified if the materials have significantly different CT attenuation ratios at different tube potentials such as 80 vs 140 kVp. For example, the CT attenuation ratios of iodine- or barium-based CT contrast materials have a CT number ratio of 1.7 - 1.8 for 80:140 kVp. In computer simulations, contrast agents containing atoms with high (z = 70 - 82) or low (z < 20) atomic numbers as reporter atoms can have a CT number ratio of less than 1.35 for 80:140 kVp, and such agents have been shown to be theoretically complementary to iodine- or barium-based (z = 53 and 56 respectively) contrast agents. Notably, the CT number ratio of water for 80:140 kVp is 1.0 by definition. In simulations, iodine- and barium-based contrast materials had the highest theoretical 80:140 kVp CT number ratios of the elements on the periodic table. It was not predicted that any agent could have a substantially higher 80:140 kVp CT number ratio than iodine- or barium-based agents. Figure 1.

[0072]

[0086] Thus, it is actually quite surprising that in vitro experiments have shown that materials exist or can be made that have a CT number ratio for 80:140 kVp that is substantially higher than 1.8 and 2.7 or greater. In a mixed solution imaged using DECT, the concentrations of two contrast materials with significantly different 80:140 kVp CT number ratios are quantified much more accurately than contrast agents with more similar 80:140 kVp CT number ratios to each other. The concentrations of iodine- and barium-based agents cannot be quantified with high precision because their 80:140 kVp CT number ratios are nearly the same. The polysiloxane-based contrast materials of the present invention provide by far the greatest difference in CT number ratio for 80:140 kVp compared to soft tissue, water, and iodine / barium contrast materials of any compound previously described in the literature. In other words, these agents are more distinguishable from any other experimental agent or It is more easily distinguishable from other contrast agents and soft tissues than agents that are conventionally available. Also, these silicon-based polymer agents are known to have minimal toxicity and are of an acceptable toxicity level.

[0073]

[0087] Thus, in an exemplary embodiment, the present invention provides an enteric contrast medium formulation that is formulated for oral delivery to a subject before or simultaneously with a medical imaging procedure performed on the abdomen of the subject. Exemplary formulations include an enteric contrast medium comprising an emulsion or suspension of at least one silicon-based polymer, an aqueous component, and an emulsifier and / or encapsulant. The emulsifier maintains at least one silicon-based polymer in an oil-in-water emulsion containing the aqueous component, which is a pharmaceutically acceptable aqueous vehicle. Another exemplary formulation includes an enteric contrast medium comprising at least one liquid silicon-based polymer that does not contain an aqueous component.

[0074]

[0088] In an exemplary embodiment, the present invention provides an enteric contrast medium that is readily distinguishable from other currently available contrast materials, and formulations thereof. The present invention is illustrated by reference to enteric contrast medium formulations. Exemplary formulations include an enteric contrast medium comprising an emulsion or suspension of at least one silicon-based polymer, an aqueous component, and an emulsifier and / or encapsulant. The emulsifier maintains at least one silicon-based polymer in an oil-water suspension or emulsion containing the aqueous component, which is a pharmaceutically acceptable aqueous vehicle (FIG. 7). In various embodiments, the particles are coated with a material compatible with such administration of the formulation to a subject in need of enteral administration.

[0075]

[0089] In an exemplary embodiment, the silicon-based polymer is an oil represented by linear polysiloxane. Exemplary silicon-based polymers useful in the compositions of the present invention have the formula:

[0076]

Chemical Formula

[0077]

[0090] In an exemplary embodiment, R 1 and R 2 are independently selected from substituted or unsubstituted monovalent hydrocarbon groups having 1 to 30 carbons, or a hydroxyl group, or a siloxyl group. Examples of unsubstituted monovalent hydrocarbon groups include alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, and octadecyl; cycloalkyl groups such as cyclopentyl and cyclohexyl; aryl groups such as phenyl; and aralkyl groups such as 2-phenylethyl and 2-phenylpropyl. Substituted monovalent hydrocarbon groups are those obtained by substituting a hydrocarbon group with a functional group. Examples of functional groups include halogen, epoxy, amino, mercapto, acryloxy, methacryloxy, fatty acid ester, carboxyl, hydroxyl, alkoxy, and poly(alkylene oxide). Among them, methyl, ethyl, propyl, and / or phenyl are preferred, and an alkyl group of 50% or more in moles is particularly preferred.

[0078]

[0091] The molecular structure of the siloxane may have not only a linear structure but also a branched structure, and preferably has a linear structure. The organopolysiloxane useful in the present invention can be prepared by methods known to those skilled in the art. Specific examples include, but are not limited to, polyorganosiloxane, or "silicones" such as dimethyl silicone, phenylmethyl silicone, methylhydrogen silicone, alkyl aralkyl modified silicone, fluorine modified silicone, amino modified silicone, amino modified polyether modified silicone, and amide modified silicone.

[0079]

[0092] More useful silicon-based polymers include, but are not limited to, highly branched polysiloxanes, copolymers of two or more polysiloxanes optionally containing one or more types of substituents, copolymers between a polysiloxane and another polymer optionally containing one or more types of substituents, blends of more than one polysiloxane or one polysiloxane and another polymer (such as silicone rubber, silicone resin, etc.), and shell-curing polysiloxanes. Here, other polymers include, but are not limited to, polycarbonate, polyalkylene glycol, and polyurethane.

[0080]

[0093] Specific examples of the silicon-based polymers useful in the present invention include polysiloxanes such as methylpolysiloxane, highly polymerized methylpolysiloxane, dimethylpolysiloxane, methylphenylpolysiloxane, methylhydrogenpolysiloxane, methylcyclopolysiloxane, polyoxyethylene / methylpolysiloxane copolymer, crosslinked methylpolysiloxane, and crosslinked methylphenylpolysiloxane; modified silicones such as polyether-modified silicone, fatty acid-modified silicone, acrylic acid-modified silicone, fluorine-modified silicone, amino-modified silicone, and alkyl-modified silicone; and cyclic silicones such as decamethyltetrasiloxane, octamethylcyclotetrasiloxane, octamethylcyclopentasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane, and methylcyclopolysiloxane.

[0081]

[0094] One or more silicon-based polymers can be used together.

[0082]

[0095] Exemplary compounds and exemplary emulsions thereof are described in FIG. 7.

[0083]

[0096] The silicon-based polymer may be linear as an oil with varying viscosities, or crosslinked as a gel or resin or rubber, and may also be in the form of an emulsion derived from the oil state. The emulsion is preferably stable for storage at ambient temperature or lower. "Stable" in this context means that the emulsion does not significantly separate into its components as distinct phases between the production of the emulsion and its administration to the subject in the imaging test.

[0084]

[0097] Any useful surfactant or combination of surfactants can be used in the formulations of the present invention. Exemplary surfactants useful in the present invention are described in FIG. 10. In various embodiments, the surfactant cures, i.e., crosslinks, to form an outer shell around another component of the formulation, such as a silicon-based polymer. FIG. 11.

[0085]

[0098] Silicon-based polymers are known to those skilled in the art. Essentially any silicon-based polymer is useful in the method of the present invention. The preferred polymer is selected for its ability to absorb or attenuate X-rays and the significantly high CT number ratio of 80:140kVp, is essentially non-toxic at the dose useful for imaging experiments, is stable to physiological conditions, and is easily eliminated by the subject after imaging procedure.

[0086]

[0099] Exemplary silicon-based polymers useful in the formulations of the present invention may be of virtually any molecular weight, for example, polymers within the molecular weight range of about 0.4 kd to about 1,000 kd, e.g., about 1.5 kd to about 500 kd, e.g., about 2 kd to about 100 kd, e.g., about 1.5 kd to about 70 kd are useful in the present invention.

[0087]

[0100] In various embodiments, the degree of polymerization (DP) is from about 5 to about 14,000, or more. Preferably, it is about 20 to about 1,000.

[0088]

[0101] Exemplary silicon-based polymers useful in the formulations of the present invention include those having a specific gravity of water and Examples include silicon-based polymers having a similar specific gravity (eg, about 0.9 to about 1.1).

[0089]

[0102] In various embodiments, the silicon-based polymer has a melting point of about 0.5 cm at room temperature (25° C.). In various embodiments, the silicon-based polymer has a viscosity of about 5 cSt to about 100,000 cSt, for example, about 5 cSt to about 200 cSt, at room temperature. In various embodiments, the silicon-based polymer has a viscosity of about 200 cSt to about 600 cSt, at room temperature. In various embodiments, the silicon-based polymer has a viscosity of about 600 cSt to about 1200 cSt, at room temperature. In various embodiments, the silicon-based polymer has a viscosity of about 1200 cSt to about 100,000 cSt, at room temperature.

[0090]

[0103] Exemplary enteric contrast medium formulations of the present invention are liquid at room and / or body temperature. Includes one or more silicon-based polymers (eg, fluorosilicone polymers, branched silicon-based polymers, silicon-based polymer gels, and silicon-based polymer solids).

[0091]

[0104] In an exemplary embodiment, the contrast medium is a polymer emulsified or suspended in a It is formulated in a pharma-ceutically acceptable vehicle.

[0092]

[0105] In various embodiments, a polymer, e.g., a silicon-based polymer, is added to the formulation. It accounts for about 10% (w / w%) to 100% (w / w), preferably 50 to 90% (w / w%) of the weight of the composition.

[0093]

[0106] In various embodiments, the silicon-based polymer is cured. are known in the art. In an exemplary embodiment, the silicon-based polymer comprises a base material capable of undergoing addition curing. Exemplary forms of addition curing include low temperature cure (i.e., they cure at room temperature) and self-curing systems. In various embodiments, the cure is a catalyzed addition reaction resulting from hydrosilylation, which is the conversion of organohydrogenpolysiloxanes (polysiloxanes having organic groups and Si-H bonds) to polysiloxanes containing multiatomic bridging groups, generally unsaturated crosslinkers, and preferably (optionally substituted) alkenyl groups, particularly vinyl or allyl groups.

[0094]

[0107] In an exemplary embodiment, the curable silicone is a silicon-based polymer that does not cure. It forms an outer shell around the

[0095]

[0108] In various embodiments, the enteric contrast medium of the present invention optionally comprises a water-soluble polymer. It includes a coating containing a limmer. As will be recognized by those skilled in the art, suitable water-soluble polymers for the applications in the present invention include, but are not limited to, poly(alkylene oxide), poly(amino acid), poly(ester) polymer, polysaccharide, protein, polyvinylpyrrolidone, poly(vinyl) polymer, poly(ethyleneimine) polymer, poly(acrylic acid) polymer, poly(siloxane) polymer, PAMAM dendrimer and other dendrimers, and combinations thereof, as well as the water-soluble polymers discussed herein. are mentioned.

[0096]

[0109] Whether they are curable silicone-based polymers, water-soluble polymers or others, the coating polymers incorporated into the contrast media of the present invention can be of substantially any molecular weight. For example, polymers within the molecular weight range of about 0.4 kd to about 1,000 kd, such as about 1.5 kd to about 500 kd, such as about 2 kd to about 100 kd, such as about 3 kd to about 70 kd, are useful in the present invention.

[0097]

[0097]

[0110] In an exemplary embodiment, the coating contains organic molecules having a molecular weight of less than about 3 kd, less than about 2 kd or less than about 1.5 kd. In an exemplary embodiment, the coating contains organic molecules having a molecular weight of less than about 3 kd, less than about 2 kd or less than about 1.5 kd, which are members selected from organic acids (or alcohols, amines) and their derivatives or analogs, oligosaccharides and combinations thereof.

[0098]

[0111] In an exemplary embodiment, the coating is a protein, for example, albumin is.

[0099]

[0112] The suspension phase of the formulation of the present invention may contain droplets or particles of any useful size. Yes. Exemplary specific sizes for droplets and / or particles include from about 1 nm to about 500 microns, such as from 1 nm to about 500 microns, such as from 1 micron to about 100 microns, each encompassing a single diameter value and respective diameter ranges within a larger range across all evaluation items; in various embodiments, the droplets and / or particles are greater than about 50 microns. Further useful sizes for droplets and / or particles include, for example, from about 5 microns to about 50 microns, such as from about 30 microns to about 50 microns. The size of the emulsion particles can be adjusted by varying the surfactant / oil molar ratio, the temperature during emulsification, the duration and intensity of the emulsification process.

[0100]

[0113] The emulsion is a predominantly targeted formulation derived from polysiloxane oil However, the formulations of the present invention may take the form of any type of suspension, colloid, emulsion, or solution, such as an aqueous solution. When the formulation of the present invention is a mixture with a vehicle, the formulation is in a form selected from suspensions, colloids, emulsions, hydrogels and combinations thereof. The formulations of the present invention may contain a single enteric contrast medium or two or more enteric contrast media. The media may be present at similar concentrations according to any useful concentration scale. Exemplary embodiments include one or more elements at different concentrations in the contrast medium. Thus, in various embodiments, from about 10% (w / w, expressed as weight percent, e.g., about 10 grams of contrast agent compound contained in a total of about 100 grams of the total contrast agent formulation) to 100% (w / w) of the weight of the said formulation is the said droplets and / or particles. In an exemplary embodiment, the formulation contains from about 50% (w / w) to about 90% (w / w) of droplets and / or particles.

[0101]

[0114] In an exemplary embodiment, the present invention provides a formulation comprising at least about 30%, such as at least at least about 50% of said silicon-based polymer.

[0102]

[0115] The formulation of the present invention comprises droplets of the present invention suspended in a pharmaceutically acceptable vehicle and / or a population of particles. The vehicle includes any other useful ingredients. For example, in some embodiments, the vehicle comprises an aqueous medium, which imparts a second property to the formulation, such as delaying dehydration of the formulation in the intestinal tract, providing flavor, stabilizing the suspension, enhancing the fluidity of the suspension, concentrating the suspension, providing pH buffering, and combinations thereof.

[0103]

[0116] The formulations of the present invention are molecularly and functionally distinct and can be recognized by both characteristics. For example, in one embodiment, the enteric contrast medium has a CT number ratio value of 80:140 kVp of about 2.5 or more. Exemplary useful values for this ratio include formulations having a CT number ratio of 80:140 kVp of about 2.5 to about 2.9, such as about 2.5 to about 2.8, such as about 2.6 to about 2.9. Those skilled in the art can readily determine the value of this ratio for any contrast medium of the present invention.

[0104]

[0117] In various embodiments, the formulations of the present invention are imaged on a dual energy or spectral CT scanner. In various embodiments, the dual energy or spectral CT scanner used to image the formulations of the present invention uses different filters for low and high kVp imaging, such as metal filters, such as aluminum or copper filters for low kVp imaging and tin filters for high kVp imaging. The use of such selective filters allows for a higher spectral separation of the low and high kVp X-ray imaging beams and excellent material discrimination separation of the formulations of the present invention from conventional iodine or barium contrast materials as well as water and soft tissue.

[0105]

[0118] In an exemplary embodiment, the present invention provides that the enteric contrast medium has an 80:1 Provided is an enteric contrast medium preparation having a CT number ratio of 40 kVp. In an exemplary embodiment, the present invention provides an enteric contrast medium preparation in which the enteric contrast medium has a CT number ratio of 80:140 kVp of about 1.5 to 2.1. In an exemplary embodiment, the present invention provides an enteric contrast medium preparation in which the enteric contrast medium has a CT number ratio of 80:140 kVp of less than about 1.5.

[0106]

[0119] In an exemplary embodiment, the formulation of the present invention comprises a second contrast medium that is different from the first contrast medium. The second contrast medium may be soluble or insoluble in a pharmaceutically acceptable vehicle. When the second contrast medium is a particulate agent, the second contrast medium may contain different atoms in the particle core, and the different coatings may be, for example, of different diameters compared to the first contrast medium. The second contrast medium may also be one or more of an iodine-based, Ba-based, Gd-based, Bi-based, W-based, Mg-based, Ta-based, Yb-based, or other Si-based contrast media.

[0107]

[0120] In an exemplary embodiment, the second contrast medium component is not limited but is an iodine oil similar to examples such as Lipiodol.

[0108]

[0121] In an exemplary embodiment, the second contrast medium is an Mg-based medium, such as Mg( OH)2.

[0109]

[0122] Formulations designed for single-dose administration are also within the scope of the present invention. These units The dosage forms contain an amount of the formulation of the present invention sufficient to provide a detectable contrast in the subject to which they are administered. In an exemplary embodiment, a unit dosage formulation includes a container that holds a sufficient amount of a contrast medium to enhance the diagnostic image of a subject to whom the unit dosage has been administered in a diagnostically meaningful manner. This container may be a vial, an infusion bag, or any other suitable container. The contrast medium may be in the form of a pre-formulated liquid, concentrate, or powder. In an exemplary embodiment, the weight of the subject is about 70 kg. In an exemplary embodiment, the image is obtained through the abdomen of the subject, the pelvis of the subject, or a combination thereof.

[0110]

[0123] In various embodiments, the unit dosage formulation contains from about 800 to about 1200 mL of a contrast agent per human adult dose and can be divided into smaller containers such as those sized from about 300 to about 600 mL. In an exemplary embodiment, the enteric contrast medium formulation is a unit dosage formulation of about 50 to about 100 mL. In an exemplary embodiment, the enteric contrast medium formulation is a unit dosage formulation of about 100 mL to about 800 mL.

[0111]

[0124] Any of the formulations described herein can be formulated and used for administration by any of a variety of routes. Exemplary routes of administration include oral, rectal, intravaginal, intravascular, intrathecal, intravesical, intracatheter, and the like.

[0112]

[0125] High-concentration low atomic number materials are used in CT as positive contrast materials It is not described below. In an exemplary embodiment, the low-Z contrast material in the formulation is at a high concentration, and is, for example, about 100 to about 900 mg / g, for example, about 150 to about 500 mg / g, for example, about 200 to about 300 mg / g, in terms of atoms of an X-ray attenuating element ("key atom" or "reporter atom"). In an exemplary embodiment, the low atomic number material of the enteric contrast medium occupies about 30% (w / w) to 100% (w / w), for example, about 50% (w / w) to about 90% (w / w) of the formulation. The concentrations herein refer to those of the key element in the contrast material that contribute most to the sharing of X-ray attenuation (absorption / scattering), but do not necessarily have to be those of the element with the highest atomic number within the molecule. X-ray attenuation is a function of the product of the X-ray attenuation coefficient of the individual atoms with respect to the X-ray spectrum and the concentration of the atoms in the contrast agent formulation summed over the range of X-ray energies in the X-ray spectrum to be imaged.

[0113]

[0126] In various embodiments, the present invention provides a contrast medium formulation that is a unit dose formulation and it contains more than about 40 g of a silicon-based polymer. In an exemplary embodiment, the enteric contrast medium formulation is a unit dose formulation and it contains more than about 300 g of a silicon-based polymer.

[0114]

[0127] The low-Z material attenuates X-rays used in medical CT less than high-Z materials such as iodine, barium, gadolinium , or other atoms, so a higher molar concentration of the low-Z material is required to obtain X-ray attenuation as strong as that of high-Z materials in CT. Thus, in an exemplary embodiment, the present invention provides a formulation of an enteric contrast agent having a concentration of low-Z element higher than the concentration of high-Z element in a known enteric contrast medium formulation.

[0115]

[0128] The contrast material for imaging is extremely safe for a wide range of patients and disease states All patients, whether diseased or relatively healthy, would greatly benefit from imaging studies that offer less risk of injury and toxicity. In an exemplary embodiment, the present invention provides a good safety margin and is less expensive than the LD of conventional iodine and barium contrast agents. 50 Comparable to LD 50 provides greater than about 25 g / kg of enteric contrast medium.

[0116]

[0129] In various embodiments, the contrast medium of the present invention and preferably its formulations are They exhibit chemical stability over a wide pH range (e.g., from about 1.5 to about 9). The stomach can expose the intestinal contents to a pH as low as 1.5, while the bile and small intestine can expose the intestinal contents to a pH as high as 9. Physicochemical stability is an important component of safety and helps minimize the risk of reactions or adverse events. Adverse reactions can occur if excessive dissolution or degradation of the material occurs in the gastrointestinal tract or if the degradation products are potentially toxic.

[0117]

[0130] In various embodiments, the present invention provides a method for visualization in CT within a region of interest. A concentration of silicon-based polymer that remains high enough to allow imaging experiments to be completed with a long enough t 1 / 2 In various embodiments, the present invention provides contrast media and formulations of contrast media having a residence time in vivo that is also reasonably short for essentially all of the administered silicon-based polymer emulsion formulation to be cleared from the subject's body before being destabilized or altered by the subject's body. In various embodiments, the silicon-containing polymer is a biologically inert material with excellent biocompatibility.

[0118]

[0131] In various embodiments, the intestinal transit time of the formulation is 12 hours in normal subjects. In an exemplary embodiment, the formulation includes sorbitol, polyethylene glycol, or both to speed up intestinal transit time.

[0119]

[0132] In an exemplary embodiment, the present invention provides a contrast medium that is biologically inert and slowly dissolves in water such that most of the administered silicon-based polymer is removed by the digestive tract before being altered by the body of the subject, and the dissolved or altered portion is excreted through the urethra.

[0120]

[0133] In an exemplary embodiment, the present invention provides an enteric contrast medium having droplets or particles with a silicon-based polymer core. In various embodiments, the core is coated. The core can be coated with a polymer or small molecule discussed herein. In a preferred embodiment, the underlying core is essentially non-toxic.

[0121]

[0134] In an exemplary embodiment, the formulations of the present invention do not pose the risks associated with current homogeneous dispersions / formulations. For example, in current methods using current barium-based formulations, non-uniform dispersions can cause imaging artifacts that can be misinterpreted as abnormal findings or mask abnormal findings. Barium contrast agents tend to aggregate or coat the intestinal mucosa, which can cause imaging artifacts in CT.

[0122]

[0135] The pharmaceutical formulations of the present invention may optionally contain excipients and one or more sweetening agents, flavoring agents and / or additional flavoring agents that mask bitter or unpleasant flavors, suspending agents, flow promoters, antioxidants, preservatives and other conventional excipients and other ingredients as necessary.

[0123]

[0136] The suspensions of the present invention may optionally contain one or more antioxidants, and optionally flavoring agents, sweetening agents, flow promoters, suspending agents, and preservatives.

[0124]

[0137] As will be appreciated, the above optional components can be added to the powder formulations of the present invention and / or an oral emulsion or suspension of the present invention.

[0125]

[0138] Suitable antioxidants for use herein include any conventional agents known in the art suitable for this purpose, such as sodium metabisulfite, sodium bisulfite, cysteine hydrochloride, citric acid, succinic acid, ascorbic acid, sodium ascorbate, fumaric acid, tartaric acid, maleic acid, malic acid, EDTA, etc., with sodium metabisulfite or sodium bisulfite being preferred.

[0126]

[0139] The antioxidant can be used in an amount that protects the formulation from oxidation, as will be apparent to those skilled in the art.

[0127]

[0140] Sweeteners for use in the formulations of the present invention can be any conventional agents known in the art for this purpose, and can be selected from the group of any suitable sweeteners, including natural sweeteners such as sucrose, fructose, dextrose, xylitol, sorbitol, or mannitol, as well as artificial sweeteners such as aspartame, acesulfame, sucralose, etc. Xylitol and aspartame are preferred sweeteners.

[0128]

[0141] Additionally, flavoring agents and flavor improvers or taste modifiers can be used to further improve the flavor, and these can be any conventional agents known in the art for this purpose, including but not limited to orange flavor, apricot flavor, chocolate flavor, maple flavor, etc. Flavors, marshmallow flavor, vanilla flavor, licorice flavor, orange vanilla flavor, claimed mint flavor, mint flavor, cherry flavor, cherry vanilla flavor, berry mix flavor, passion fruit flavor, mandarin orange flavor, bubble gum flavor, tropical punch flavor, grape juice compound, grape flavor, artificial grape flavor, grape bubble gum flavor, tutti frutti flavor, and combinations thereof are included.

[0129]

[0142] The suspending agent may be any convenient agent known in the art for this purpose , and can be selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, alginate, and sodium carboxymethylcellulose, with sodium carboxymethylcellulose ("NaCMC") being preferred. The suspending agent can be used in an amount ranging from about 0 to about 20% by weight of the powder formulation and from about 0 to about 10% by weight of the oral suspension.

[0130]

[0143] The preservative may be any convenient agent known in the art for this purpose, and can be selected from the group consisting of any compound compatible with drug activity, such as methylparaben and propylparaben, benzoic acid, sodium benzoate, potassium sorbate, etc., with methylparaben being preferred.

[0131]

[0144] The present invention also provides a kit for use in clinical and / or research settings. Exemplary kits include (a) a first vial containing the enteric contrast medium of the present invention; (b) a second vial containing an emulsifier; and (c) instructions for using and / or formulating the enteric contrast medium as an emulsion. In various embodiments, the kit further includes another vial containing a second contrast medium; and instructions for administering and / or formulating the first and second enteric contrast media in a clinical or research setting.

[0132]

[0145] The contrast medium contained in the second vial is soluble in a pharma- ceutically acceptable vehicle. If the second contrast medium is a particulate agent, the second contrast medium may contain different atoms in the particle core, have a different coating, be of a different diameter, etc., relative to the first contrast medium. The second contrast medium may be one or more of an iodine-based, Ba-based, Gd-based, W-based, Bi-based, or Ta-based contrast medium.

[0133]

[0146] In various embodiments, the contrast medium is an activated particle of a siloxane polymer. Activated particles useful for forming the coated contrast media of the present invention are discussed herein. The discussion focuses, for clarity of illustration, on the preparation of particles that are activated and then modified ("coated") with a modifying group (e.g., a water-soluble polymer). In particular, the discussion focuses on the preparation of modified sugars that include a poly(ethylene glycol) moiety. Those skilled in the art will recognize that the methods described herein are broadly applicable to the preparation of activated particles and polymer conjugates thereof, and thus the discussion should not be construed as limiting the scope of the present invention.

[0134]

[0147] Generally, the particle and the modifying group are linked together through the use of reactive groups, are typically converted to new organic functional groups or non-reactive species by a ligation process. The types of reactive groups and reactions useful for practicing the present invention are generally well known in the art of bioconjugate chemistry. Currently preferred types of reactions available for activating particles are those that proceed under relatively mild conditions. These include, but are not limited to, nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions), and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reactions, Diels-Alder additions). These and other useful reactions are described in detail in, for example, Smith and March, ADV. ADVANCED ORGANIC CHEMISTRY, 5th Edition, John Wiley & Sons, New York, 2001; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, D.C., 1982.

[0135]

[0148] Useful reactive functional groups pendant from activated particles or modified groups include, but are not limited to, , (a) carboxyl groups and their various derivatives, such as, but not limited to, N-hydroxysuccinimide ester, N-hydroxybenzotriazole ester, acid halide, acylimidazole, thioester, p-nitrophenyl ester, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups convertible to, for example, esters, ethers, aldehydes, etc.; (c) haloalkyl groups where the halide can later be replaced by a nucleophilic group such as, for example, an amine, carboxylate anion, thiolate anion, carbanion, or alkoxide ion, thereby effecting a covalent bond of a new group at the functional group of the halogen atom; (d) dienophile groups capable of participating in Diels-Alder reactions, such as, for example, maleimide groups; (e) aldehyde or ketone groups where subsequent derivatization is possible, for example, by formation of carbonyl derivatives such as imines, hydrazones, semicarbazones or oximes, or by mechanisms such as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups which can subsequently be reacted with amines, for example, to form sulfonamides; (g) For example, a thiol group that can be converted to a disulfide or reacted with alkyl and acyl halides; (h) For example, an amine or sulfhydryl group that can be acylated, alkylated or oxidized; (i) For example, an alkene that can undergo cycloaddition, acylation, Michael addition, etc.; and (j) For example, an epoxide that can react with amines and hydroxyl compounds; may be mentioned.

[0136]

[0149] Reactive functional groups can be protected because they participate in the reaction due to the presence of protecting groups. Those skilled in the art understand how to protect specific functional groups so that they do not interfere with the selected set of reaction conditions. For examples of useful protecting groups, see, for example, Greene et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York, 1991.

[0137]

[0150] An exemplary route to modified and coated particles is shown in FIG. 9.

[0138]

[0151] The use of reactive derivatives of poly(ethylene glycol) (PEG) (or other polymers or coatings) to attach one or more modifying groups to the particles is within the scope of the present invention. The present invention is not limited by the identity of the reactive poly(ethylene glycol) analogs. Many activated derivatives of poly(ethylene glycol) are commercially available and are also in the literature. Suitable activated PEG derivatives for preparing substrates useful in the present invention Selecting and conjugating as appropriate are well within the ability of one of ordinary skill in the art. Abuchowski et al., Cancer Biochem. Biophys., 7:175-186 (1984); Abuchowski et al., J. Biol. Chem., 252:3582-3586 (1977); Jackson et al., Anal. Biochem., 165:114-127 (1987); Koide et al., Biochem Biophys. Res. Commun., 111:659-667 (1983)), tresylate (Nilsson et al., Methods Enzymol., 104: 56-69 (1984); Delgado et al., Biotechnol. Appl. Biochem., 12: 119-128 (1990 ), N-hydroxysuccinimide-derived active esters (Buckmann et al., Makromol. Chem., 182: 1379-1384 (1981); Joppich et al., Makromol. Chem., 180: 1381-1384 (1979); Abuchowski et al., Cancer Biochem. Biophys., 7: 175-186 (1984); Katre et al., Proc. Natl. Acad. Sci. U.S.A., 84: 1487-1491 (1987); Kitamura et al., Cancer Res., 51: 4310-4315 (1991); Boccu et al., Z. Naturforsch., 38C: 94-99 (1983), carbonate (Zalipsky et al. , POLY(ETHYLENE GLYCOL) CHEMISTRY: BIOTECHNICAL AND BIOMEDICAL APPLICATIONS, edited by Harris, Plenum Press, New York, 1992, pages 347 - 370; Zalipsky et al., Biotechnol. Appl. Biochem., 15: 100 - 114 (1992); Veronese et al., Appl. Biochem. Biotech., 11: 141 - 152 (1985)), imidazolyl formate (Beauchamp et al., Anal. Biochem., 131: 25 - 33 (1983); Berger et al., Blood, 71: 1641 - 1647 (1988)), 4 - dithiopyridine (Woghiren et al., Bioconjugate Chem., 4: 314 - 318 (1993)), isocyanate (Byun et al., ASAIO Journal, M649 - M - 653 (1992)) and epoxide (see U.S. Patent No. 4,806,595 (1989) issued to Noishiki et al.). Other linking groups include urethane bonds between amino groups and activated PEG. See Veronese et al., Appl. Biochem. Biotechnol., 11: 141 - 152 (1985).

[0139]

[0152] The particle coating of the present invention may contain one or more polymers. Polymer - based drug delivery systems are known in the art. For example, see Dunn et al., POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS, ACS Symposium Series, Volume 469, American Chemical Society, Washington, D.C. 1991. Those skilled in the art will recognize that substantially any known water - insoluble polymer is applicable to the contrast media of the present invention.

[0140]

[0153] Representative polymers include, but are not limited to, polyphosphazenes, Poly(vinyl alcohol), polyamide, polycarbonate, polyalkylene, polyacrylamide, polyalkylene glycol, polyalkylene oxide, polyalkylene terephthalate, polyvinyl ether, polyvinyl ester, polyvinyl halide, polyvinyl pyrrolidone, polyglycolide, polysiloxane, polyurethane, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, pluronics and polyvinyl phenol and their copolymers are included.

[0141]

[0154] Synthetically modified natural polymers useful in the contrast media of the present invention include, but are not limited to, alkyl cellulose, hydroxyalkyl cellulose, cellulose ether, cellulose ester, and nitrocellulose. Preferred members among a wide variety of synthetically modified natural polymers include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, h ydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, and polymers of acrylic acid esters and methacrylic acid esters and alginic acid.

[0142]

[0155] These and other polymers considered herein are Sigma C hemical Co. (St. Louis, MO.), Polysciences (Warrenton, PA.), Aldrich (Milwaukee, WI.), Fluka (Ronkonkoma, NY) and BioRad (Richmond, CA), etc., and can be easily obtained from vendors or synthesized using standard techniques from monomers obtained from these vendors or otherwise.

[0143]

[0156] In various embodiments, the particles or droplets are coated with one or more biodegradable or bioabsorbable polymers. Representative biodegradable polymers useful in the particles or droplets of the present invention include, but are not limited to, polylactide, polyglycolide and their copolymers, poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, their blends and copolymers.

[0144]

[0157] For the purposes of the present invention, the term "bioabsorbable molecule" includes regions that can be metabolized or broken down by the body, absorbed, and / or removed through normal excretory pathways. Such metabolic or breakdown products are preferably substantially non-toxic to the body. For the purposes of the present invention, the term "bioabsorbable molecule" includes regions that can be metabolized or broken down by the body, absorbed, and / or removed through normal excretory pathways. Such metabolic or breakdown products are preferably substantially non-toxic to the body.

[0145]

[0158] The bioabsorbable region may be hydrophobic or hydrophilic as long as the copolymer composition does not become water-soluble as a whole. Thus, the bioabsorbable region is preferably selected such that the polymer remains water-insoluble as a whole. Accordingly, the relative properties, i.e., the type of functional groups included, and the relative proportion of the bioabsorbable region to the hydrophilic region, are selected to ensure that the useful bioabsorbable composition remains water-insoluble. The bioabsorbable region may be hydrophobic or hydrophilic as long as the copolymer composition does not become water-soluble as a whole. Thus, the bioabsorbable region is preferably selected such that the polymer remains water-insoluble as a whole. Accordingly, the relative properties, i.e., the type of functional groups included, and the relative proportion of the bioabsorbable region to the hydrophilic region, are selected to ensure that the useful bioabsorbable composition remains water-insoluble.

[0146]

[0159] Exemplary absorbent polymers include, for example, synthetically produced absorbent block copolymers of poly(α-hydroxy-carboxylic acid) / poly(oxyalkylene) (see Cohn et al., U.S. Patent No. 4,826,945). These copolymers are water-soluble without crosslinking and thus the body can excrete the degraded block copolymer composition. See Younes et al., J Biomed. Mater. Res. 21:1301-1316 (1987); and Cohn et al., J Biomed. Mater. Res. 22:993-1009 (1988).

[0147]

[0160] Currently preferred bioabsorbable polymers include one or more components selected from poly(esters), poly (hydroxy acids), poly(lactones), poly(amides), poly(ester-amides), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(carbonates), poly(phosphazines), poly(phosphoesters), poly(thioesters), polysaccharides, and mixtures thereof. Even more preferably, the bioabsorbable polymer contains a poly(hydroxy) acid component. Among the poly(hydroxy) acids, polylactic acid, polyglycolic acid, polycaproic acid, polybutyric acid, polyvaleric acid, and their copolymers and mixtures are preferred.

[0148]

[0161] In various embodiments, the enteric contrast media formulation does not contain the amount of silicone-based polymer found in oral care formulations and / or is useful as an oral care formulation and / or. In various embodiments, the enteric contrast medium formulation does not contain the amount of silicon-based polymer found in formulations for preventing flatulence and / or is not useful as a formulation for preventing flatulence. In various embodiments, the formulation contains at least 10%, at least 30%, at least 50%, at least 70% or at least 100% more silicon-based polymer than that contained in oral care or formulations for preventing flatulence. In various embodiments, the silicon-based polymer is not adsorbed onto solid particles.

[0149] B. Method

[0162] The present invention also relates to a method for the preparation of the present invention for the clinical study of a subject to which the preparation of the present invention is administered. The present invention provides a method for acquiring and enhancing a clinically meaningful CT image. Thus, in an exemplary embodiment, the present invention provides a method for acquiring contrast-enhanced CT projection data of a subject and then reconstructing it into a CT image, the method comprising administering to the subject a diagnostically effective amount of said enteric contrast medium formulation of the present invention, and acquiring CT projection data of the subject and then reconstructing it into a CT image. In various embodiments, the enteric contrast medium has a CT number ratio of 80:140 kVp of greater than 2.0 in said image in a DECT imaging experiment.

[0150]

[0163] In an exemplary embodiment, the present invention provides a method for preparing a contrast medium of the present invention, comprising: A CT image of the object is provided that has contrast enhancement through the region of interest.

[0151]

[0164] The images of the present invention and images acquired by the methods of the present invention are The image may be taken through any part of the subject's body. In an exemplary method, the image is through the abdomen and / or pelvis of the subject.

[0152]

[0165] The present invention also provides a method for post-processing the CT projection data, the CT images, or both, to obtain the A method is provided for digitally separating a CT signal generated by an inventive contrast medium from a CT signal generated by soft tissue, body fluid, or another contrast medium. In various embodiments, two-material discrimination, three-material discrimination or multi-material discrimination, or virtual monochromatic images and combinations thereof are used to separate a CT signal generated by the contrast material of the present invention from a CT signal generated by another contrast medium or body tissue. In an exemplary embodiment of the present invention, post-processing of the material discrimination image either emphasizes the CT signal from the contrast material of the present invention or generates a new CT image subtracted from the CT signal generated by another contrast material or body tissue. In an exemplary embodiment of the present invention, post-processing of the material discrimination image either emphasizes the CT signal from a contrast material other than the contrast agent of the present invention or generates a new CT image subtracted from the CT signal generated by the contrast material or body tissue of the present invention.

[0153]

[0166] One advantage of the contrast media and formulations of the present invention is their compatibility with the administration of one or more additional contrast agents via any desired route. In various embodiments, the method further comprises the step of administering a second contrast medium different from the enteric contrast medium to the subject. In various embodiments, the second contrast medium is administered via a route selected from intravascular administration, enteral administration, rectal administration, and administration to various body cavities that are natural (e.g., vagina, bladder), injury-induced (e.g., fistula, abscess, sinus tract), surgically created (e.g., artificial bladder, ileal pouch), or artificial (e.g., medical devices such as catheters, reservoirs, tubes, or pumps). Multiple contrast materials can be administered to different body compartments. In an exemplary embodiment, the second contrast medium is an iodine-based or barium-based medium and the third contrast medium is a tantalum, bismuth, yttrium, gadolinium, or tungsten-based contrast medium.

[0154]

[0154]

[0167] In an exemplary embodiment, the first and second contrast agents are the first and second contrast agents. In an image set that includes regions where both the shadow medium and the contrast medium are distributed, they are distinguishable from each other. Exemplary A second contrast medium is an iodine contrast medium.

[0155]

[0168] The second contrast medium may be soluble or insoluble in a pharmaceutically acceptable vehicle. If the second contrast medium is a particulate agent, the second contrast medium may contain different atoms in the core of the particles, have different coatings, and have different diameters with respect to the first contrast agent. The second contrast medium may be one or more of iodine-based, Ba-based, Gd-based, W-based, Si-based, Mg-based, Yb-based, Bi-based, or Ta-based contrast media.

[0156]

[0169] In an exemplary embodiment, the second contrast medium is an iodine-based or barium-based medium. is.

[0157]

[0170] In an exemplary embodiment, the second contrast medium is a silica-based medium.

[0158]

[0171] The following examples are provided to illustrate exemplary embodiments of the present invention and do not define or limit the scope of the present invention. description.

Examples

[0159] Example 1

[0172] (Method 1) A 1% aqueous solution of surfactant Tween 20 (Sigma-Aldrich) was prepared by dissolving 50 mg of Tween-20 in 4.95 g of distilled water. To this clear solution (in a 50 ml centrifuge tube), 15.0 g of a silicon-based polymer (50 cSt at 25°C, Fisher Scientific) was added dropwise through a 20 ml syringe attached to a 23G needle while gently vortexing. After the addition was complete, the mixture was left at room temperature for 3 minutes. , Vortexed vigorously to obtain a 75 wt% oil-in-water (o / w) emulsion containing 0.25 wt% Tween 20 surfactant (Note: Small bubbles are inevitable under non-vacuum preparation conditions). This emulsion was measured and an average particle size of 60 μm was obtained on a Malvern 3000 ZetaSizer. This emulsion can be stably stored at room temperature for at least 3 months without phase separation. The CT scan demonstrated its homogeneity (excluding the presence of small bubbles).

[0160]

[0173] (Method 2) A 1 percent aqueous solution of surfactant Tween-20 (Sigma-Aldrich) was prepared by dissolving 50 mg of Tween 20 in 4.95 g of distilled water. To this clear solution (in a 50 ml round-bottom flask), 15.0 g of a silicone polymer (50 cSt, Fisher Scientific) was slowly added while stirring vigorously. After completion of the addition, the mixture was sonicated using a probe sonicator / homogenizer at room temperature for 5 minutes to obtain a 75 wt% oil-in-water (o / w) emulsion.

[0161]

[0174] Notably, larger laboratory-scale preparations (1 - 2 liter size) of the same formulation can be easily and rapidly carried out by vigorously mixing the aqueous phase (diluted aqueous Tween-20 solution) and the oil phase (silicone oil) using a high-speed mechanical stirrer (e.g., up to 2000 cpm) at room temperature for 5 - 30 min.

[0162]

[0175] Similarly, emulsions are prepared using silicone polymers with various viscosities (350 cSt and 1000 cSt from Sigma Aldrich, 100000 cSt from Dow Corning). If Method 1 is selected for small-scale preparation, a more viscous oil is added through a larger needle (e.g., a 19G needle).

[0163] Example 2

[0176] The procedure of Example 1 was carried out using Triton X-100.

[0164] Example 3

[0177] The procedure of Example 1 was repeated with the exception of Triton X-100 and fluorinated silicon-based polymers. -FS-1265 (viscosity 350 cSt, Dow Corning) was used.

[0165] Example 4

[0178] A range of silicon-based polymers were incorporated into CT phantoms and imaged. The isocratic polymers exhibited very high and consistent CT number ratios of 80:140 kVp and 100:140 kVp (Figure 7).

[0166] Example 5

[0179] In vivo imaging experiments in rats have demonstrated that the silicon-based polymer of the present invention It has been shown that silicon-based polymer-based contrast agents provide simultaneous positive, neutral and negative enteric contrast in a single DECT scan. Figure 3 shows the silicon-based polymer-based contrast agent of the present invention as a bright signal on a 40 keV virtual monochromatic image (left image, arrowhead), as a neutral signal similar to water on a 70 keV virtual monochromatic image (middle image, arrowhead), and as a negative signal similar to fat on a 90 keV virtual monochromatic image (right image, arrow). Intravascular iodine contrast material (arrow) remains a bright signal on all three images. These images were generated using CT scan projection data and used for two-material decomposition to reconstruct virtual monochromatic 40, 70 and 90 keV CT images.

[0167]

[0180] In vivo imaging experiments in rabbits demonstrated that the silicon-based polymer of the present invention A contrast agent based on [the silicon-based polymer of the present invention] has been shown to provide simultaneous positive, neutral, and negative enteric imaging in a single DECT scan. Figure 4 shows the contrast agent based on the silicon-based polymer of the present invention as a bright signal on a virtual monochromatic image at 40 keV (left image, arrow) and as a neutral to negative signal on a virtual monochromatic image at 90 keV (right image, arrow). On both images, the intravascular iodine contrast material (arrowhead) remains a bright signal. These images were generated using CT scan projection data, which was used for dual-material discrimination to reconstruct virtual monochromatic CT images at 40 and 90 keV.

[0168]

[0181] In vivo imaging experiments in rabbits showed that the contrast agent based on the silicon-based polymer of the present invention A contrast agent based on [the silicon-based polymer of the present invention] has been shown to provide simultaneous positive, neutral, and negative enteric imaging in a single DECT scan. Figure 5 shows the contrast agent based on the silicon-based polymer of the present invention as a bright signal on a virtual monochromatic image at 40 keV (left image, arrow), as a neutral signal similar to water on a virtual monochromatic image at 70 keV (center image, arrow), and as a negative signal similar to fat on a virtual monochromatic image at 140 keV (right image, arrow). The intestinal wall does not substantially change its signal across these different virtual monochromatic images. These images were generated using CT scan projection data, which was used for dual-material discrimination to reconstruct virtual monochromatic CT images at 40, 70, and 140 keV.

[0169]

[0182] In vivo imaging experiments in rabbits showed that the contrast agent based on the silicon-based polymer of the present invention It has been shown that a silicon-based contrast agent can be isolated from a second intravascular contrast material on a single DECT scan. Figure 6 shows the silicon-based polymer-based contrast agent of the present invention as a bright signal in the intestinal lumen on a virtual monochromatic image at 40 keV (left image, arrow), and the iodine intravascular contrast agent as a bright signal in the blood vessels (left image, arrowhead). The three-material discrimination image shows the silicon-based contrast material after subtraction of the iodine intravascular contrast material signal (right image), and the iodine contrast material after subtraction of the silicon-based intestinal contrast material (central image). For this illustration, the soft tissue signal was added back to the iodine and silicone oil images. The three-material discrimination in this example was performed on virtual monochromatic CT images at 40 and 140 keV, which showed better performance than the more well-known method of using CT images at 80 and 140 kVp for three-material discrimination, demonstrating the versatility of the contrast material of the present invention.

[0170]

[0183] The present invention has been described with reference to various exemplary embodiments and examples. As will be apparent to those skilled in the art, other embodiments and variations of the present invention can be devised by those skilled in the art without departing from the true spirit and scope of the present invention. The appended claims are to be construed to include all such embodiments and equivalent variations.

[0171]

[0184] Each and every patent, patent application, and publication cited herein is hereby incorporated by reference in its entirety.

Claims

1. An enteric contrast medium formulation that is formulated for oral delivery to a subject simultaneously with a medical imaging procedure performed on the subject's abdomen, the formulation comprising an oil-in-water emulsion or suspension containing an emulsion or suspension of at least one silicon-based polymer or copolymer material (e.g., polysiloxane), an aqueous vehicle component, and an emulsifier or dispersant that maintains the at least one silicon-based polymer in the aqueous vehicle that is a pharmaceutically acceptable aqueous vehicle, wherein the silicon-based polymer or copolymer material is a member selected from linear, branched, or cross-linked structures containing a silicon-based polymer component and polymer blends containing a silicon-based polymer or copolymer, and combinations thereof, the formulation comprising the enteric contrast medium.

2. An enteric contrast medium formulation that is formulated for oral delivery to a subject simultaneously with a medical imaging procedure performed on the subject's abdomen, the formulation comprising a silicon-based polymer.

3. An enteric contrast medium formulation that is formulated for use in X-ray imaging or computed tomography, the formulation comprising a silicon-based polymer.

4. The enteric contrast medium formulation according to any one of claims 1 to 3, which is a unit dose formulation containing a diagnostically effective amount of the enteric contrast medium.

5. The enteric contrast medium formulation according to any one of claims 1 to 4, which is a unit dose formulation of about 800 mL to about 1200 mL per adult human dose and can be divided into smaller containers such as containers with a volume of 400 mL to 500 mL.

6. The enteric contrast medium formulation according to any one of claims 1 to 5, which is a unit dose formulation with a volume of about 50 to about 100 mL.

7. The enteric contrast medium formulation according to any one of claims 1 to 6, which is a unit dose formulation with a volume of about 100 mL to about 800 mL.

8. The enteric contrast medium formulation according to any one of claims 1 to 7, wherein the silicon-based polymer is liquid at room temperature or body temperature (e.g., silicone oil, fluorosilicone polymer, branched silicone polymer, silicon-based polymer gel, and cross-linked silicon-based polymers such as silicon-based polymer solids).

9. The enteric contrast medium formulation according to any one of claims 1 to 8, which contains at least about 30% weight / weight (30 to 100% weight / weight percentage) of the silicon-based polymer.

10. ​ An enteric contrast medium preparation according to any one of claims 1 to 9, comprising at least about 60% by weight of said silicon-based polymer.

11. The enteric contrast medium preparation according to any one of claims 1 to 10, wherein the emulsifier and the dispersant have a hydrophilic-lipophilic balance (HLB) value of 0 to 20, preferably a HLB value of 9 to 18.

12. The enteric contrast medium preparation according to any one of claims 1 to 11, wherein the emulsifier is a Tween surfactant, for example, Tween-20.

13. The enteric contrast medium preparation according to any one of claims 1 to 12, which is not useful as an oral care preparation. preparation.

14. The enteric contrast medium preparation according to any one of claims 1 to 13, which is not useful for preventing flatulence.

15. The enteric contrast medium preparation according to any one of claims 1 to 14, which is a unit dose preparation and contains more than about 25 g, for example, 200 g to 2000 g of said silicon-based polymer.

16. The enteric contrast medium preparation according to any one of claims 1 to 15, wherein the silicon-based polymer is the main component of the emulsion particles / droplets and is not adsorbed on the solid particles.

17. The enteric contrast medium preparation according to any one of claims 1 to 16, wherein about 30% (w / w) to 100% (w / w) of the weight of the preparation is said silicon-based polymer.

18. The enteric contrast medium preparation according to any one of claims 1 to 17, wherein the emulsifier contains a water-soluble polymer.

19. The enteric contrast medium preparation according to any one of claims 1 to 18, wherein the emulsifier contains one or more poly(ethylene glycol) chains.

20. The enteric contrast medium preparation according to any one of claims 1 to 19, wherein the pharmaceutically acceptable vehicle further comprises additives (to delay dehydration of the preparation in the intestine), flavoring agents, sweetening agents, thickening agents, suspending agents, fluidizing agents, pH buffers, laxatives, osmotic pressure regulators, and combinations thereof.

21. The enteric contrast medium preparation according to any one of claims 1 to 20, wherein the enteric contrast medium has a CT number ratio of more than about 2.1 at 80:140 kVp.

22. The enteric contrast medium preparation according to any one of claims 1 to 21, wherein the enteric contrast medium has a CT number ratio of about 1.5 to 2.1 at 80:140 kVp.

23. The enteric contrast medium preparation according to any one of claims 1 to 22, wherein the enteric contrast medium has a CT number ratio of 80:140 kVp of less than about 1.

5.

24. The enteric contrast medium preparation according to any one of claims 1 to 23, wherein the silicon-based polymer has a specific gravity similar to that of water (for example, about 0.9 to about 1.1).

25. The enteric contrast medium preparation according to any one of claims 1 to 24, wherein the silicon-based polymer has a viscosity of about 0.5 cSt to about 200 cSt at room temperature.

26. The enteric contrast medium preparation according to any one of claims 1 to 25, wherein the silicon-based polymer has a viscosity of about 200 cSt to about 600 cSt at room temperature.

27. The enteric contrast medium preparation according to any one of claims 1 to 26, wherein the silicon-based polymer has a viscosity of about 600 cSt to about 1200 cSt at room temperature.

28. The enteric contrast medium preparation according to any one of claims 1 to 27, wherein the silicon-based polymer has a viscosity of 1200 cSt to 100,000 cSt at room temperature.

29. The enteric contrast medium preparation according to any one of claims 1 to 28, wherein the silicon-based polymer has a molecular weight of about 0.4 kDa to about 5 kDa.

30. The enteric contrast medium preparation according to any one of claims 1 to 29, wherein the silicon-based polymer has a molecular weight of about 5 kDa to about 50 kDa.

31. The enteric contrast medium preparation according to any one of claims 1 to 30, wherein the silicon-based polymer has a molecular weight of about 50 kDa to about 1000 kDa.

32. A method for obtaining projection data of X-ray or computed tomography or dual-energy computed tomography or spectral computed tomography in which the contrast of the subject is emphasized, the method comprising: administering to the subject a diagnostically effective amount of the enteric contrast medium preparation according to any one of claims 1 to 31; and obtaining the projection data of the subject.

33. The method according to claim 32, wherein the projection data of the X-ray or computed tomography or dual-energy computed tomography or spectral computed tomography is reconstructed into a computed tomography image.

34. The method according to claim 32 or 33, wherein the contrast agent is imaged using a dual-energy or spectral CT scanner that uses X-ray filters of different materials or thicknesses (including 0) that modify the energy spectrum of the X-ray beam. Examples of materials for filtering the energy spectrum of the X-ray beam include, but are not limited to, aluminum, copper, or tin.

35. The method according to any one of claims 32 to 34, wherein the projection data of the X-ray or computed tomography or dual-energy computed tomography or spectral computed tomography is used for two-material, three-material, or multi-material discrimination and reconstructed into a CT image.

36. The method according to any one of claims 32 to 35, wherein the computed tomography image is used for two-material, three-material, or multi-material discrimination and further CT images are reconstructed.

37. The method according to any one of claims 32 to 36, wherein the computed tomography image is used to identify the enteric contrast medium preparation from other materials in the abdomen.

38. The method according to any one of claims 32 to 37, wherein the image is an image of a region selected from the abdomen and pelvis of the subject.

39. The method further includes a step of administering to the subject a second contrast medium different from the enteric contrast medium, and the second contrast medium is administered by a route selected from oral administration, intrathecal administration, intravesical administration, enteral administration, anal administration, intracatheter administration, intra-device administration, intravascular administration, administration to a fistula, and administration to a surgically created pouch. The method according to any one of claims 32 to 38.

40. The method according to claim 39, wherein the second contrast medium is a member selected from iodine contrast media, Ba-based, Gd-based, W-based, Bi-based, Mg-based, Yb-based, and Ta-based contrast media, and silicon-based contrast media.

41. The enteric contrast medium and the second contrast medium are distinguishable from each other in the image based on their relative X-ray attenuation at different X-ray spectra. The method according to any one of claims 34 to 40.

42. The method according to any one of claims 32 to 41, wherein the enteric contrast medium has a CT number ratio of greater than about 2.1 at 80:140 kVp in the image.

43. A method of DECT or spectral CT, wherein the formulation of the present invention is imaged on a dual-energy or spectral CT scanner that uses different filters for imaging at low and high kVp, such as an aluminum or copper filter for low kVp images and a tin filter for high kVp imaging.

44. The enteric contrast agent is administered to the subject by delivery via (a) a natural cavity selected from the mouth, vagina, bladder, rectum, and urethra; (b) a surgically created space selected from an ileal pouch and an artificial bladder; (c) a space created by an injury selected from a fistula, a sinus tract, and an abscess; or (d) a medical device selected from a catheter, a tube, a reservoir, a pouch, and a pump, according to any one of claims 32 to 42.

45. (a) a first vial or set of vials containing an enteric contrast medium according to any one of claims 1 to 30; (b) a second vial containing a second contrast medium; and (c) instructions for formulating the enteric contrast medium with or without the second contrast medium, a kit comprising.

46. The method according to claim 32, comprising the step of diagnosing the subject.

47. The method according to claim 46, wherein the subject is diagnosed with an injury selected from malignant tumors, inflammation, infection, and ischemia, and combinations thereof.

48. The method according to claim 46, wherein the subject is evaluated for anatomical details including the intestine or tissue adjacent to the intestine.

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