Encapsulated gas or partial vacuum CT contrast material

Abstract

To provide encapsulated gas or partial vacuum particle contrast media for use in CT imaging.SOLUTION: In an exemplary embodiment, the invention provides an enteric contrast medium formulation. An exemplary formulation comprises (a) an enteric contrast medium comprising encapsulated gas or partial vacuum particles suspended in water. Exemplary encapsulated gas or partial vacuum particles have a specific gravity between 0.2 and 1.5. In various embodiments, the encapsulated gas or partial vacuum particles are suspended in aqueous media by an agent compatible with enteric administration of the formulation to a subject in need of such administration. In an exemplary embodiment, the contrast material is incorporated into a pharmaceutically acceptable carrier in which the material is suspended homogeneously. In an exemplary embodiment, the encapsulated gas or partial vacuum particles comprise 5% or more of the weight of the contrast material formulation.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 149,815, filed April 20, 2015, the entirety of which is incorporated herein by reference for all purposes.

[0002]

[0002] Funded research and development This invention was made with Government support under Grant Nos. EB013816 and TR000004 awarded by the National Institutes of Health. The U.S. Government has certain rights in this invention. [Background technology]

[0003]

[0003] The use of contrast materials for medical CT imaging is essential for many clinical scenarios, especially in the abdomen and pelvis, where the numerous internal organs and blood vessels present a very complex anatomy. Enteric contrast agents can be given by mouth or via a tube into the intestine to distend it and improve its visualization.

[0004]

[0004] Contrast materials for the intestine can be "positive" and give a signal substantially higher than water (e.g., >60 Hounsfield Units, or HU). These agents utilize materials with high x-ray attenuation properties. Alternatively, contrast materials for the intestine can be "neutral" and give a signal similar to that of water or soft tissue (e.g., CT numbers between -20 HU and 60 HU). Contrast materials for the intestine can also be "negative" and give a signal lower than that of water (e.g., CT numbers less than -20 HU), and these agents utilize materials with low x-ray attenuation properties.

[0005]

[0005] All commercial positive CT contrast materials are based on iodine or barium, and because the other atoms in these agents are similar to the atoms of the body's soft tissues and water, the difference in x-ray attenuation between the positive agents and the body's soft tissues is due mostly or entirely to the iodine or barium.

[0006]

[0006] There is no dispute that positive intestinal CT contrast agents, which mark the intestinal lumen with a bright signal on CT imaging, are of high value for detecting extraintestinal fluid collections and masses (which can resemble non-staining intestine on CT reading in a wide range of diseases).

[0007]

[0007] Despite the value of positive enteric contrast, bright enteric contrast material paradoxically obscures the CT findings of intravenous contrast for some of the most devastating diseases, including: 1) trauma (leakage of contrast material may be equivocal as to whether it is from a vascular hemorrhagic origin vs. an enteric luminal origin); 2) intestinal ischemia and infarction (the nonenhancing bowel wall may be obscured by bright intraluminal enteric contrast material); 3) intestinal inflammation (hyperenhancement of the bowel wall by IV contrast is the most reliable feature of active disease); 4) intestinal hemorrhage (extravasation of iodized contrast into the bowel or enhancing tumor is masked by the presence of enteric contrast); and 5) three-dimensional image reconstruction of the blood vessels.

[0008] Another problem with currently available positive clinical contrast materials is their inability to be distinguished from one another or from other radiopaque structures (such as metal debris, calcifications, surgical staple lines or implants during CT imaging). Even with dual-energy CT (DECT) or multi-energy CT or spectral CT (now an increasingly widespread clinical technique that allows material differentiation of imaged voxels based on the known 80:140 kVp CT number ratios of the individual materials), iodine and barium-based contrast materials are not easily distinguished from one another because their 80:140 kVp CT number ratios are virtually identical. This limitation causes clinical errors and delays. For example, a CT scan enhanced with positive enteric barium contrast and intravenous iodine contrast showing leakage of contrast into the peritoneum may be ambiguous as to whether the leakage is due to hemorrhage (iodine), bowel perforation (barium), or urinary tract injury (excreted iodine), each of which is a clinical emergency but requires entirely different management. To resolve such ambiguity, a repeat scan may be necessary at the expense of time and lost opportunity for treatment. Repeat CT scans also result in additional radiation dose. Increased public concern about CT radiation dose led to a 2011 NIH summit focused on reducing CT dose. CT scanners capable of multienergy or spectral imaging are under development, but even with improved capabilities, these new CT technologies probably cannot easily distinguish between barium-based contrast materials and iodized ones.

[0009]

[0009] Further limitations of current positive intestinal CT contrast materials are toxicity and complications. Barium-based agents can cause severe, potentially fatal, peritonitis or worsen infection at the site of leakage, converting partial ileus to complete ileus. Iodized agents can cause severe, even fatal, pneumonia if inadvertently aspirated, and can also cause life-threatening allergic-type reactions, and this concern has limited their use to 1% of patients known to have a previous reaction. This is probably related in part to the hyperosmolar nature of these agents. Additionally, some of these agents are brown in color and have a bad taste. Some patients (up to 1-3%) have reactions to iodized contrast materials.

[0010]

[0010] "Neutral" enteric CT contrast materials are useful for CT imaging. Examples of neutral enteric contrast materials are water, milk, or liquids containing non-absorbable carbohydrates (such as sorbitol or methylcellulose) with or without only minimal amounts of iodine or barium (e.g., VoLumen®). Neutral enteric CT contrast agents are commonly used to distend the intestinal lumen and allow intravenous contrast material to clearly show the relative hypervascularity or hypovascularity of the intestinal wall that would be obscured by positive enteric contrast material. Because the signal from neutral agents resembles the signal of natural soft tissue or water, they may not be as diagnostically certain as positive enteric contrast agents for intestinal leakage, extraluminal fluid collection, intraperitoneal abscess, or hematoma.

[0011]

[0011] "Negative" enteric contrast agents are not commonly used, but have a CT value of less than -20 HU. Examples of these low X-ray attenuation contrast materials are hydrocarbon oils (such as peanut oil or vegetable oil), perfluorocarbons, and gases (such as insufflated air or carbon dioxide, or chemically produced carbon dioxide). Negative enteric contrast agents can provide excellent visualization of the bowel wall and bowel wall enhancement when given with intravenous contrast. The most commonly used negative enteric agent is carbon dioxide for gastric or colonic distension. However, small bowel use of available negative agents is not well tolerated. Although negative enteric contrast materials can resemble naturally occurring fat in CT, detection of disease at CT is largely dependent on identifying abnormal amounts of fat in the bowel. Gaseous enteric contrast agents (gas insufflated into or produced in the bowel lumen) may not be as useful as positive enteric contrast materials for visualization of intestinal leakage. Even with dual-energy CT, the signal of available negative agents cannot be distinguished from that of naturally occurring fat or abnormal gas collections. No practical nonbulking, nonoil-based negative contrast agents that can be delivered in liquid form are currently available.

[0012] A further limitation of intestinal gas or gas-generating agents as a contrast agent is that intestinal gas causes more motion artifacts in CT than intestinal liquid (FIGS. 2 and 19).

[0013]

[0013] Encapsulated gas contrast materials have been previously described for ultrasound and MRI (usually perfluorocarbons). Encapsulated gas contrast materials have also been investigated for CT (e.g. MRX80, based on perfluorocarbons). Partial vacuum agents have not been investigated as contrast materials for CT.

[0014]

[0014] Modern dual-energy CT images and spectral CT images can be reconstructed as virtual monochromatic energy images (images that simulate what the CT scan image would look like if it were obtained with monochromatic energy x-rays of any given x-ray energy (such as energies selected from 40-140 keV)). In these virtual monochromatic energy images, iodized and barium contrast materials appear highly positive at low keV settings (40-70 keV) and at higher keV settings (140 keV), the signal gradually decreases such that the iodized and barium contrast materials signal fades to that of water or soft tissue (approximately -20-50 HU). In other words, barium and iodine can act as positive contrast agents at low keV and neutral contrast agents at higher keV. However, the signals from iodized and barium agents remain indistinguishable from each other, either in dual-energy CT or with virtual monochromatic energy images, which greatly negates the advantage of being able to convert the positive CT signals of contrast materials into neutral CT signals.Similarly, the signals of available neutral agents resemble the signals of water, and the signals of available negative contrast agents resemble the signals of fat or gas in dual-energy CT and cannot be meaningfully converted into other color signals by dual-energy CT or spectral CT.

[0015]

[0015] Commercially available enteric CT contrast materials cannot simultaneously act as positive, neutral, and negative contrast agents, even with dual-energy CT.

[0016]

[0016] There are several clinical scenarios that would improve CT diagnosis through the use of one type (positive, neutral or negative) enteric contrast medium that can also be converted by post-processing of the image to show one or more of the other types of signals (positive, neutral or negative) on CT. For example, in suspected bowel ischemia, a neutral or negative enteric contrast medium would be useful to find either hyperenhancement or hypoenhancement of the bowel wall to detect inflammation or ischemia, respectively. In this same scenario, a positive contrast medium would allow the identification of bowel perforation, abscess and fistula. Since no commercial enteric agent can be both positive and negative, the imaging physician must choose one or the other agent, knowing that with any available CT protocol, some findings may be revealed, while other important findings may be obscured, and therefore CT scans are suboptimal.

[0017]

[0017] The development of safe clinical enteric contrast materials that can be used simultaneously with, but are distinct from, iodized and barium agents or other contrast agents under development (such as those based on heavy metals such as tungsten, ytterbium or tantalum) will change CT imaging for millions of patients with a wide range of diseases. Different "color" contrast agents can be injected into multiple body compartments and interrogated simultaneously, allowing a single CT, DECT or multi-energy CT examination to provide timely, high-resolution, perfectly registered anatomical images of each system for rapid and confident diagnosis. This capability will transform our ability to rapidly and accurately evaluate multiple organ damage from trauma, invasive tumors, surgical complications, and inflammatory diseases. Applicant's prior patents show that low atomic number (Z<30) contrast agents or silicon-based polymer agents can provide positive CT signals that can be distinguished from iodine-based and barium-based contrast agents in DECT.

[0018]

[0018] The development of a safe clinical enteric CT contrast material that can be digitally manipulated to appear as negative, neutral, or positive contrast material under the control of the interpreting physician would provide powerful diagnostic capabilities and eliminate guesswork and protocol errors as well as diagnostic errors. Reduction in errors would result in more rapid diagnoses and reduced need for additional workup. Physicians would no longer need to weigh the advantages and disadvantages of administering neutral or negative vs. positive enteric contrast material for a given clinical scenario.

[0019]

[0019] Non-iodized positive contrast materials that have been tested for use with CT imaging include a wide range of high atomic number (Z) elements: tungsten, tantalum, ytterbium, bismuth, lanthanide elements (such as gadolinium) and gold, among others [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]. Silicone-based low atomic number contrast agents have recently been invented by the applicant's group.

[0020]

[0020] Dual-energy CT is a relatively new technology; practical DECT scanners have been available for only the past 8 years.

[0021]

[0021] In clinical CT imaging, the CT number of water is defined as 0 HU, while the CT number of room air / vacuum is defined as -1000 HU, regardless of the kVp setting. The CT numbers of non-fatty soft tissues are generally in the range of 10-60 HU.

[0022]

[0022] Examples of materials with lower X-ray attenuation than non-fatty soft tissue include fats and oils, which have CT numbers in the range of -20 to -150 HU when imaged at 120 kVp. Furthermore, the CT numbers of gases are generally less than -500 HU due to the very low physical density of gases.

[0023]

[0023] Examples of materials with higher X-ray attenuation than non-fatty soft tissue include solid or liquid phase materials with an effective Z higher than 8. These materials include the positive contrast materials mentioned above.

[0024]

[0024] In dual-energy CT, positive enteric contrast material, which has a CT number ratio of 80:140 kVp that is substantially different from iodized contrast material or other positive intravascular contrast material, can be digitally subtracted from the CT image to provide an image similar to a CT scan obtained with intravascular contrast material alone. However, this signal separation may introduce some image artifacts and noise that may cause diagnostic ambiguity or confusion. It is currently very difficult to highlight neutral or negative enteric contrast material in conventional CT because the signals of such agents cannot be reliably distinguished from the signals of water, liquid, fat or gas that may be present in normal or diseased tissue, respectively. Summary of the Invention

[0025]

[0025] The present invention solves these and other problems by providing encapsulated gas or partial vacuum particles that are safe and effective as contrast materials suitable for human use during CT imaging, including dual energy CT and spectral CT. In an exemplary embodiment, the contrast material contains particles that are encapsulated gas or vacuum, the shell is comprised primarily of silicon dioxide, silicon-containing rubber, ceramic, or other inert, insoluble material, and the formulation is comprised of the encapsulated gas or vacuum particles suspended in a water or oil medium. In various embodiments, additives are added to the shell, coat the shell, contained within the lumen of the shell, or added to the suspension medium to modify the overall 80:140 kVp CT number ratio of the contrast material. In various embodiments, the present invention provides the benefits of negative, neutral, and positive enteric contrast agents in CT, without any deficiencies in judgment for these types of enteric contrast media. In various embodiments, the present invention may appear as a negative contrast material in conventional CT, but the contrast material signal can be converted to a stronger negative, neutral, or positive signal in dual energy or spectral CT imaging. Alternatively, in various embodiments, the present invention may appear as a positive contrast material in conventional CT, but the contrast material signal can be converted to a negative or neutral signal in DECT or spectral CT imaging. Alternatively, in various embodiments, the present invention may appear as a neutral contrast material in conventional CT, but the contrast material signal can be converted to a negative or positive signal in DECT or spectral CT imaging. Advantages of a positive enteric contrast signal include superior identification of intestinal leaks, detection of extraluminal collections (such as abscesses), detection of abdominopelvic tumors and masses, assessment of intestinal transit time, assessment of intestinal obstruction transition points, and superior assessment of bowel wall thickening. Inadequacies of positive enteric contrast include obscuring crucial findings of bowel wall ischemia or bowel inflammation when intravascular contrast material is given concomitantly, obscuring the abdominopelvic vessels, preventing 3D reconstruction of CT angiograms, obscuring the origin of extravasated contrast material, and obscuring active intraluminal gastrointestinal bleeding.Advantages of negative or neutral enteric contrast include superior assessment of bowel wall hyperenhancement or hypoenhancement; superior assessment of intraluminal mass enhancement; noninterference with three-dimensional reconstruction of CT angiograms; and lower radiation dose when CT scans are obtained with automatic exposure control due to the lower x-ray attenuation of negative agents on CT scout images. Disadvantages of neutral or negative enteric contrast include reduced ability to detect bowel leaks or extraluminal fluid collections, abscesses, injury to fat, or hematomas.

[0026] In CT imaging, the materials of the present invention can give lower or higher CT numbers than those produced by water and non-fatty soft tissues (range, -20 to 60 Hounsfield Units or HU). The combination of low and high x-ray attenuation materials in substantial proportions makes it possible to modify the x-ray attenuation of the new materials such that 1) the new x-ray attenuation is significantly different from the attenuation of other body or medically relevant materials in CT images, and 2) the new x-ray attenuation in different x-ray energy spectra is significantly different from the attenuation of other medically relevant materials in dual energy CT or spectral CT images.

[0027]

[0027] For example, gas and vacuum can produce a low CT signal of approximately -1000HU, while silicon dioxide produces a high CT signal of approximately 550HU in a 50% w / w suspension in water. Gas and vacuum within the silicon dioxide encapsulated gas and vacuum particles allows the extremely negative CT numbers of gas and vacuum to dramatically reduce the overall CT number produced by the overall particle across all CT kVp settings. This reduction in CT number can be used to substantially alter the ratio of low kVp CT number to high kVp CT number of the material to a level that is significantly different from the CT number ratio of iodine contrast material and barium contrast material or other materials naturally occurring in the human body. For example, the 80:140 kVp CT number ratio of silicon dioxide, gas and vacuum (approximately 1.3, 1.0 and 1.0, respectively) can be changed to 0.3, which is substantially different from the CT number ratio of soft tissue (1.0) or iodine contrast material (1.7) or barium contrast material (1.7). In another embodiment, the 80:140 kVp ratio of iodine contrast material or barium contrast material can be changed to be higher than 2.4 when encapsulated gas and vacuum particles are mixed with iodine material or barium material in a suspension medium. In another embodiment, the 80:140 kVp number ratio of iodine contrast material or barium contrast material can be reduced to less than 0.6 when iodine or barium is diluted and mixed with a relatively large amount of encapsulated gas and vacuum particles.

[0028]

[0028] Advantages of certain glass encapsulation shells (such as borosilicate glasses) include inertness, low solubility, stability, high strength, and very low coefficient of thermal expansion. These properties allow the encapsulated gas or partial vacuum to remain stable over a wide range of physiological pH and temperature.

[0029]

[0029] Enteral agents for CT are generally safer than injectables for several reasons: 1) Enteral agents require substantially lower doses and concentrations of material than intravascular agents. A typical intravenous iodized agent administration requires up to 150 mL of 350 mg iodine / mL contrast agent (52 gram dose) for an abdominal CT scan. A typical oral dose is only 800 mL of 10 mg iodine / mL contrast agent (8 gram total iodine dose); 2) contrast material is poorly absorbed through the intestinal wall into the blood vessels; 3) viscosity and osmolality are minimal concerns with enteral contrast material; 4) nephrotoxicity seen with all intravascular agents is unlikely to occur with enteral agents; 5) anaphylactoid and immune reactions are probably much less likely with enteral administration than with intravascular administration.

[0030]

[0030] Of note, in addition to the safety of the enteral formulation and efficacy for CT imaging, other aspects including physical uniformity, storage stability, flow ability (and thus potentially high but acceptable viscosity), and even oral taste are considered in order to optimize the final enteral contrast formulation to meet practical clinical use.

[0031]

[0031] Furthermore, the encapsulated gas or partial vacuum particle enteric contrast agent of the present invention provides the advantage of allowing for simultaneous administration of enteric agents and separate intravascular agents or other body compartment agents that can be easily identified by DECT or multi-energy CT. Since the agents are imaged as they are simultaneously present in the body, in one embodiment, essentially perfect registration of images of the contrasted regions is provided when signals are extracted from each agent. The resulting well-registered images provide better information for diagnostic evaluation than if each contrast material were delivered and imaged independently and separate CT scans were performed. Furthermore, in an exemplary embodiment, the radiation dose is less than half that of two separate scans (with each contrast agent). In various embodiments, the media and formulations of the present invention facilitate repeat CT scanning and reduce ambiguity caused by oral contrast agents based on different materials previously delivered. In various embodiments, multiple enteric agents (including encapsulated gas or partial vacuum particles and other enteric agents) are simultaneously present during CT imaging.

[0032] The formulations and methods of the present invention also offer the advantage of reduced radiation dose to the patient due to reduced need for repeat / follow-up imaging scans.

[0033]

[0033] In an exemplary embodiment, the use of the present invention reduces CT radiation dose compared to the use of currently available positive enteric contrast materials, since less CT tube current is required to generate sufficient x-ray flux to achieve diagnostic levels of image noise when the intestinal contents are less radiopaque (e.g., neutral or negative CT numbers). For example, the automatic exposure control in CT can determine the required x-ray tube current based on the x-ray density of the subject in the scout view.

[0034]

[0034] In an exemplary embodiment, the present invention provides an agent that can be better separated from both iodized or barium contrast agents and from soft tissue or water in dual-energy CT than other previously described contrast materials due to the very high 80:140 kVp CT number ratio of greater than 2.4 in various embodiments of the present invention, or the very low 80:140 kVp CT number ratio (e.g., less than 0.5).

[0035] In an exemplary embodiment, the present invention provides particles of encapsulated gas or partial vacuum in water suspension that are enteric contrast medium formulations. An exemplary formulation includes an enteric contrast medium that includes encapsulated gas or vacuum within a shell material to form small particles. The material is formulated in a pharma- ceutically acceptable aqueous or oil-based vehicle in which the particles are suspended. In an exemplary embodiment, the shell material of the particles of the present invention contains silicon, and the material is a silicon-based polymer. In an exemplary embodiment, the shell material contains silicon, and the material is in the form of glass (such as borosilicate). In an exemplary embodiment, the shell material is a polymer plastic, rubber, wax, ceramic, or resin. In an exemplary embodiment, the shell material contains or is coated with an additional high atomic number material with z between 40 and 84. In an exemplary embodiment, the vehicle contains a material that exhibits high x-ray attenuation (such as a material containing barium or iodine), thereby modifying the CT number and the ratio of low to high CT numbers of the resulting contrast agent.

[0036]

[0036] In an exemplary embodiment, the present invention provides a contrast medium formulation that can be delivered into the digestive system and other body cavities, which may be natural (such as the vagina or bladder) or surgically created (such as a neobladder), or into artificial medical devices (such as tubes, catheters, pouches, reservoirs, or pumps).

[0037]

[0037] Additional exemplary advantages, objects and embodiments of the present invention are set forth in the description that follows.

[0038]

[0038] The intestinal contrast agent of the present invention is substantially different from the microbubble contrast agents used in ultrasound imaging. Microbubbles in ultrasound are gaseous microbubbles, usually perfluorocarbon or nitrogen gas, and are surface-coated with materials such as albumin, carbohydrates, lipids, or biocompatible polymers that allow ultrasound to cause the bubbles to expand and contract, thereby amplifying the signal in ultrasound imaging. The average size of ultrasound contrast agent microbubbles is usually in the range of 2-6 microns, with a typical concentration level of about 10 million microbubbles per mL. It is therefore calculated that less than 1% of the volume of a microbubble-type ultrasound contrast agent is gas-filled or hollow, and such a small volume fraction of gas or void space does not produce a sufficiently large signal to be useful during CT or X-ray imaging. Two recent reviews are presented here. 1)Ultrasound microbubble contrast agents: Fundamentals and application to gene and drug delivery by Ferrara, Katherine; Pollard, Rachel; Borden, Mark. Book Series: ANNUAL REVIEW OF BIOMEDICAL ENGINEERING Volume: 9 Pages: 415-447 Published in 2007; 2)Microbubbles in medical imaging: current applications and future directions by Lindner, JR. NATURE REVIEWS DRUG DISCOVERY, Volume: 3 Issue: 6 Pages: 527-532 Published in June 2004.

[0039]

[0039] The intestinal CT contrast material of the present invention is substantially different from previous perfluorocarbon oral contrast materials proposed for CT and MR and X-ray imaging. These previous agents include liquid perfluorocarbons, which may be emulsified or unemulsified; the perfluorocarbons may be brominated or unebrominated. In these previous agents, the perfluorocarbons expand into gas at body temperature, which may generate a negative contrast signal and further intestinal distension. A drawback of perfluorocarbon agents is that they may be difficult to administer, and their distension characteristics raise safety concerns when administered to diseased intestinal segments (U.S. Patent Nos. 5,205,290; 4,951,673; Spilde et al., "Evaluation of an Experimental Low-Attenuation Gastrointestinal Contrast Agent for CT Imaging of Intestinal Ischemia in an Animal Model". Acad.Radiol.1999;6:94-101). Brominated perfluorocarbons have been described as CT contrast agents and can produce positive CT number signals.

[0040]

[0040] Other embodiments, objects and advantages of the present invention will become apparent from the following detailed description. [Brief description of the drawings]

[0041] [Figure 1]

[0041] Computer simulation of 80:140 kVp CT number ratios (black to white greyscale, top, within black outlined boxes) for individual atoms with atomic numbers (Z, bottom) ranging from 1 to 100. The simulation was based on the expected CT x-ray tube output spectrum of a typical clinical CT scanner and the x-ray attenuation coefficients of individual elements from the National Institute of Standards and Technology. The simulation accurately predicts that conventional iodine-based and barium-based CT contrast agents (I and Ba, respectively) have a high 80:140 kVp CT number ratio of approximately 1.7, calcium-based materials (such as bone) have an intermediate 80:140 kVp CT number ratio of just above 1.4, and silica (SiO2) has an intermediate 80:140 kVp CT number ratio of about 1.27. However, clearly, this atom-based model did not predict that the material would have a very high 80:140 kVp CT number ratio of more than 1.8 or less than 0.9 or negative numbers (top, grayscale gradient, outside the box outlined in black). The applicant's previous finding (WO2015 / 024025A1) that silicon-based polymers (illustratively polydimethylsiloxane (PDMS)) have such high 80:140 kVp CT number ratios (2.6-2.8) was not initially predicted by itself. Similarly, the applicant's finding that encapsulated gas or partial vacuum particles could provide a wide range of 80:140 kVp CT number ratios less than 0.8 (including negative or well above 2.0 ratios, which exceed the range predicted by the original computer simulations) was also not predicted. [Diagram 2]

[0042] Transverse (left image) and coronal (right image) CT images show motion artifacts around gas-filled bowel (black intraperitoneal structures) but not around fluid-filled bowel (small arrows). Gas within the bowel lumen is highly negative (-950 to -1005 HU) in the CT number, which can cause artifacts that can be bright signals (large arrows) and dark signals (arrowheads) around the bowel. [Diagram 3]

[0043] Tuning the CT numbers of borosilicate encapsulated gas and partial vacuum microsphere suspensions by the addition of heavy metals. A) Heavy metal addition to aqueous suspensions: CT numbers of aqueous suspensions of borosilicate encapsulated gas and partial vacuum microsphere particles (specific gravity 0.6 g / mL) with and without added high X-ray attenuation material (0.1% iodine in aqueous medium) are shown. The combination of the two materials results in a new contrast agent with much higher CT numbers at low virtual monochromatic energy keV and a steeper slope of signal loss from low to high keV. This new contrast material provides a strongly negative CT signal when the virtual monochromatic energy keV is higher than 75 and a strongly positive CT signal when the virtual monochromatic energy keV is lower than 55. The borosilicate microsphere suspension alone does not provide as high a signal as the combined iodine and borosilicate microsphere formulation. Addition of large amounts of iodine or barium to the formulation allows for upward tuning of the CT number signal at lower monochromatic energy keV levels (not shown). B) Heavy metal addition into the particles. The CT numbers of two 20% wt / wt aqueous suspensions (specific gravity 0.50 g / mL) of different borosilicate encapsulated gas and partial vacuum microsphere particles, one with 0.5% barium incorporated into the shell material and the other without, are shown. Again, the addition of barium preferentially causes an increase in the measured CT number in the CT image range of lower virtual monochromatic energy keV. In this example, the CT number for the barium-doped microsphere suspension becomes positive at 40 keV while remaining strongly negative at keV higher than 60 keV. Different results can be obtained with different types and amounts of heavy metals (not shown). [Figure 4]

[0044] Conventional CT scans of vials of different materials imaged at 80 kVp (left side) and 140 kVp (right side image). 1 = 18 micron hollow silica microspheres of iM30K, 30% w / w with iohexol at 15 mg I / mL in water; 2 = Pepto-bismol® bismuth salicylate; 3 = iodine in water (15 mg I / mL iohexol); 4 = 18 micron hollow silica microspheres of iM30K at 40% w / w in water; 5 = barium at 1% w / w and iM30K at 30% w / w with sorbitol and water; 6 = 2% BaSO4 (Readi-Cat2®) (containing sorbitol in water); 7 = 30 micron silica microspheres of S60HD at 40% w / w in water; 8 = 2% barium sulfate in water. The partially suspended hollow silica microspheres (#4 and 7) are not as radiopaque as water at 80 and 140 kVp, and even have a lower signal at 140 kVp than at 80 kVp. Layering of water (which is physically denser than the hollow silica microspheres) is seen at the bottom of both of these vials. A small amount of high x-ray attenuation material (representing non-hollow borosilica) is at the bottom of the S60HD vial. In vial #1, iohexol is uniformly dissolved in water, which layers at the bottom of the vial. The iodine and barium contrast materials (#3, 6, and 8) each show a reduced signal from 80 to 140 kVp. Tubes with hollow silica microspheres mixed with iodine (1) and barium (5) show a very substantial relative drop in CT signal from 80 to 140 kVp. The ratio of CT numbers at 80:140 kVp for the iodine-silica microsphere mixture was 2.8 and for the barium-silica microspheres was 4.1. The bismuth material (Pepto-bismol®) shows relatively little change in CT number between 80 and 140 kVp. [Diagram 5]

[0045] Dual energy CT scans of different materials reconstructed with virtual monochromatic energies of 40 keV (left) and 140 keV (right images). 1 = 18 micron hollow silica microspheres of iM30K, 30% w / w with iohexol at 15 mg I / mL in water; 2 = Pepto-bismol® bismuth salicylate; 3 = iodine in water (15 mg I / mL iohexol); 4 = 18 micron hollow silica microspheres of iM30K at 40% w / w in water; 5 = barium at 1% w / w and iM30K at 30% w / w with sorbitol and water; 6 = BaSO4 (Readi-Cat2®) at 2% (containing sorbitol in water); 7 = 30 micron silica microspheres of S60HD at 40% w / w in water; 8 = barium sulfate at 2% in water. Partially suspended hollow silica microspheres (#4 and 7) show signal loss from 40 keV, resulting in a very low signal at 140 keV. A layering of water (heavier than silica microspheres) is seen at the bottom of these tubes. In vial #1, iohexol is dissolved uniformly in water, which layers at the bottom of the vial. Iodine and barium contrast materials (#3, 6 and 8) each show a reduced signal from 40 keV to 140 keV, such that the signal is similar to that of water at 140 keV. Tubes with silica microspheres mixed with iodine (1) and barium (5) show a substantial drop in CT signal on the 140 keV image, such that the CT number is less than -100 HU on the 140 keV image reconstruction. The bismuth material (Pepto-bismol®) shows a relatively small change in CT number between 40 and 140 keV. [Figure 6]

[0046] Contrast materials imaged with dual-energy CT with virtual monochromatic energy image reconstruction at 40, 70, and 140 keV. 1=water; 2=0.1% iodine solution; 3=0.1% barium suspension; 4=borosilicate hollow microspheres 30% w / w in water; 5=0.1% iodine solution with 30% w / w borosilicate hollow microspheres in water; 6=0.1% iodine solution with 30% w / w borosilicate hollow microspheres in water. Water does not change much in CT numbers across monochromatic energy reconstructions. Iodine and barium in water show slightly higher CT numbers at low keV than at high keV. Borosilicate hollow microspheres in water show positive signal at low keV and negative signal at high keV reconstruction. When 1% iodine or 1% barium is added to the mixture of borosilicate hollow microspheres, the CT number increases substantially at low keV. [Figure 7]

[0047] The CT number values ​​correspond to the images of the contrast material in FIG. [Figure 8]

[0048] A 3.8 kg rabbit imaged with dual-energy CT with 300 mL of intestinal 30% wt / wt borosilicate hollow microspheres and intravenous iodized contrast. Bowel wall enhancement (e.g., in the rabbit cecum (arrowhead)) is well observed at 140 kVp (left image) showing intravenous iodized contrast, but small hematomas (thin arrows) and free fluid (large arrow) are not well observed. Two-material discrimination with a threshold of -50 HU was performed to extract the signal from the intestinal contrast, which was then inverted and doubled to produce the positive signal seen in the oral contrast image (center image). Note that this image shows no signal from soft tissue, fat, and iodized contrast. The oral contrast signal was then added to the 140 kVp image to generate a composite image. Here, the hematoma (thin arrow, right image) and free fluid (large arrow) are more clearly presented. As in any image with positive enteric contrast, the enhancement of the bowel wall by the intravenous contrast material is obscured in the bowel segment containing the positive contrast material signal. If only conventional iodized and barium agents were utilized, separation of the signals from the enteric and intravenous contrast agents in this example would not be obtainable. [Figure 9]

[0049] A 3.9 kg rabbit imaged with dual-energy CT with 300 mL of intestinal 30% wt / wt borosilicate hollow microspheres doped with a small amount of barium sulfate and intravenous iodized contrast agent. The intestinal lumen signal can be made strongly positive (left image) by using a low virtual monochromatic image (40 keV), neutral (middle image) by using a medium virtual monochromatic image (65 keV), or negative (right image) by observing with a high virtual monochromatic image (100 keV). Note that the fluid in the bladder (bottom of image) and soft tissues such as the liver (top of image) do not change signal substantially across different virtual monochromatic energy keVs. [Figure 10]

[0050] Examples of previously patented or disclosed agents with high 80:140 kVp CT number ratios created by combining high x-ray attenuation materials (such as iodized or silicon-containing compounds) with hydrocarbons. While high 80:140 kVp CT number ratios can be achieved by conventional methods, the encapsulated gaseous materials of the present invention provide a wider range of possible 80:140 kVp CT number ratios, including ratios less than 0.9 (see FIG. 11). Note: By definition, water has a CT number of approximately 0 HU at all kVp settings. [Figure 11]

[0051] An embodiment in which a high x-ray attenuation material is mixed with a gas or partial vacuum to produce a material with a 80:140 kVp CT number ratio well beyond the range of 1.0 to 1.8. When a substantial amount of gas is combined with a high x-ray attenuation material, the CT number of the material and the 80:140 kVp CT number ratio can be substantially changed. [Figure 12]

[0052] Table of CT numbers for virtual monoenergetic dual-energy or spectral CT image reconstructions (e.g., low x-ray attenuating material (gas / vacuum), high x-ray attenuating material, and particles of gas or partial vacuum encapsulated by a high x-ray attenuating material shell). By definition, the CT number of pure water is set as 0 HU for all virtual monoenergetic image reconstructions. [Figure 13]

[0053] Table of CT numbers for example high x-ray attenuation materials, encapsulated gas or partial vacuum particle formulations, and further addition of other high x-ray attenuation materials to the formulations at different kVp tube potential settings, and dual energy CT virtual monochromatic energy CT settings. Note: The CT number of the gas / vacuum in these cases is approximately -1000 HU. [Figure 14]

[0054] Table of potential benefits of encapsulated gas or partial vacuum particulate contrast materials compared to commercial previously described enteric CT contrast agents. [Figure 15]

[0055] The hollow microsphere-based contrast materials show similar CT numbers and 80:140 kVp CT number ratios when scanned on General Electric (GE) and Siemens CT scanners. The CT numbers were measured at 80, 100, 120 and 140 kVp CT tube potentials on a commercial clinical dual-energy CT scanner. For General Electric, the scanner was a 750HD. For Siemens, the scanner was a Somatom Definition. Readi-cat® contrast material contains 2.1% w / v barium sulfate in aqueous suspension. The borosilicate hollow microspheres are a 3M product (iM30K). The preferred high and low 80 / 140 kVp CT number ratios of these exemplary contrast material formulations of the present invention were similar when imaged on two commercial dual-energy CT scanners from different CT scanner manufacturers. [Figure 16]

[0056] An exemplary hollow borosilicate glass microsphere (e.g., iM30K from 3M Inc) is shown in this schematic. The exemplary microsphere has a density of 0.60 g / cm3 and an average diameter of 18 microns. In comparison, the density of bulk borosilicate glass is 2.4 g / cm3. Approximately 75% of the volume of the borosilicate glass microsphere is hollow (gas-filled or partial vacuum shown in gray). The shell material (black) has an average thickness of about 10% of the radius of the microsphere and is approximately 0.9 microns thick. Small defects of trapped gas and partial vacuum may be present in the shell material. In an exemplary embodiment of the invention, a suspending agent is used to maintain hollow microspheres in an aqueous formulation to produce a useful enteric contrast material with a preferred CT number for use with single energy spectral CT and a preferred CT number ratio of 80 / 140 kVp for use with dual energy or spectral CT, in the presence or absence of additional high Z contrast agents (iodine or barium materials). The shell may or may not have small defects therein. The overall particle may have a primary hollow space or may be subdivided by septa of shell material. [Figure 17]

[0057] Example of encapsulated gas or partial vacuum particles in 30% w / w suspension in water with corresponding CT numbers at 80 kVp and 140 kVp. A significantly wide range of CT numbers and a wide range of 80:140 kVp CT number ratios are achieved depending on shell composition and thickness. [Figure 18]

[0058] Coronal dual-energy CT images of a rat with intravenous iodized contrast material (black arrowhead) and an exemplary bowel preparation of the present invention (white arrow). The bowel preparation is 30% w / w encapsulated gas and partial vacuum borosilicate microspheres (iM30K, 3M) with 2.5% w / w iodine (iohexol, General Electric Healthcare) suspended using sorbitol and methylcellulose. The 60 keV image is a virtual monochromatic image obtained from a CT scanner. Three-material decomposition was performed using the 40 keV and 140 keV virtual monochromatic images as source data to produce an iodine contrast image, an oral contrast image, and a water image. The iodine image shows a positive signal from the iodine contrast without the signal of the bowel agent. The oral contrast image shows a positive signal of the bowel agent without the signal of the intravenous agent. The water image simulates an unenhanced CT scan without either agent. [Figure 19]

[0059] Dual energy CT image of a cross section of intestinal necrosis in a rabbit abdomen imaged with intravenous iodized contrast material and an exemplary bowel preparation of the present invention. The anterior bowel was necrosed by percutaneous microwave ablation (ablation for 12 minutes at 65 watts using a 17g P15 antenna, Certus 140 generator, NeuWave, Madison, WI). The bowel contrast preparation is 30% w / w encapsulated gas and partial vacuum borosilicate microspheres (iM30K, 3M) suspended using 0.3% xanthan gum in water. The 140 kVp image (left image) shows normal bowel wall enhancement with intravenous contrast for the left and right abdominal bowels. The bowel lumen (asterisk) is filled with negative contrast material measuring -60 HU, which is similar to the signal of retroperitoneal fat measuring -80 HU in this example. In the anterior mid-abdominal area, reduced bowel wall enhancement is observed (arrows), suggesting necrosis. The 40 keV virtual monoenergetic image (right image) more clearly shows that the anterior mid-intestinal wall is not enhanced by intravenous contrast. The absence of bowel wall enhancement confirms bowel wall necrosis in these bowel segments. In contrast, the left and right abdominal bowels show normal bright intravenous contrast enhancement at 40 keV. The signal of the bowel luminal contrast material is 45 HU at 40 keV. In contrast, the retroperitoneal fat is approximately -150 HU on this 40 keV image. In other words, even though the bowel contrast material and the retroperitoneal fat have similar HU values ​​at 140 kVp, the two materials are shown to be different on the 40 keV image of the dual-energy CT. Of note, even though the bowel contrast material has a negative signal, no substantial artifact is seen around the bowel filled with this negative contrast material. However, bright artifact is seen adjacent to the gas-filled segments of bowel (thin arrows). The relative absence of intestinal gas image artifacts is an advantage of the negative enteric contrast agents of the present invention over the advantages of non-encapsulated gas negative enteric contrast agents (see FIG. 2). [Figure 20]

[0060] Improved sensitivity for abdominal disease at CT and dual-energy CT with encapsulated gas and partially evacuated borosilicate microsphere enteric contrast material compared to commercially available enteric contrast agents. Three enteric contrast agents were compared in a rabbit model of abdominal disease imaged with intravenous iodine contrast-enhanced CT: a positive contrast agent, 2% w / w barium sulfate (ReadiCat2, Bracco); a neutral contrast agent, sorbitol solution (VoLumen, Bracco); and a negative contrast agent, hollow encapsulated gas and partially evacuated borosilicate microspheres ("hollow", iM30K, 3M). The negative contrast encapsulated gas and partially evacuated agent was also post-processed with dual-energy CT ("hollow DECT") to produce additional images with positive and neutral appearance of enteric contrast signal. Rabbits were implanted with a 2 cm hematoma or subjected to focal microwave ablation to generate areas of intestinal ischemia or hyperemia. Lesions were confirmed pathologically by gross and microscopic examination. Six radiologists reviewed each set of images on a DICOM viewer to detect abdominal lesions. Sensitivity for hematomas was almost perfect when positive barium or negative midjejunal contrast was used (with or without DECT postprocessing), but only 57% for neutral agents. Conversely, reader sensitivity for intestinal ischemia or hyperemia was only 26 and 17%, respectively, for positive barium contrast, but 82 and 73%, respectively, for neutral sorbitol contrast, and even higher for negative midjejunal contrast. The addition of DECT postprocessing improved the sensitivity even further for the detection of intestinal ischemia and hyperemia. The specificities of the different enteric contrast agents for each type of abdominal lesion were all above 94%. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] I. Introduction

[0061] An important issue with current enteric contrast agents for CT is that each type (positive, negative and neutral) reliably identifies only the important subset of anatomy required for various CT diagnoses. Positive enteric contrast materials can mark the bowel lumen with a bright signal that allows differentiation of the bowel from fluid collections and diseased non-intestinal tissue, but this positive signal cannot be distinguished from the positive signal from intravenous contrast materials. Neutral enteric contrast materials allow visualization of the bowel wall enhancement by positive intravenous contrast agents at CT, but resemble soft tissue and fluid. No negative enteric contrast agents described so far have been approved by the FDA. Although these negative enteric contrast agents adequately show all of the above anatomy and the signal of positive intravenous contrast agents, they may cause unwanted side effects, may be inconvenient to administer, and may cause artifacts at CT.

[0043]

[0062] In any type of clinical CT, some degree of separation of contrast material from other contrast materials and soft tissues can be obtained by the use of CT number thresholds. For example, CT numbers >80 HU are unlikely to be produced by normal soft tissues, and CT numbers <-20 HU are unlikely to be produced by normal soft tissues other than fat. Positive contrast material that gives a CT number higher than 80 HU is easily identified as non-soft tissue material. Similarly, negative contrast material that is less than -20 HU can be reliably identified as non-soft tissue material, with the exception that fat may give a similar CT number. Notably, fat is a pathological process that is rarely considered in the intestinal lumen.

[0044]

[0063] Alternatively, in dual-energy or spectral CT, materials can be identified based on their relative attenuation of low energy x-rays vs. high energy x-rays. Dual-energy CT and spectral CT are increasingly common capabilities in modern scanners. Current dual-energy technology allows for simultaneous imaging of a patient with x-rays of two or more different energy spectra, such as provided by two or more different tube potentials (such as 80 and 140 kVp, or alternatively 100 and 140 kVp). Dual-energy CT and spectral CT imaging can also be obtained using other methods, including sandwich detectors, split-beam x-rays filtered by different materials, or photon counting, which quantifies or classifies the energy of x-rays observed by the detector. Materials in the body are identified based on the ratio of their low tube potential CT number to their high tube potential CT number (e.g., 80:140 kVp CT number ratio), which is related to the atomic numbers of the atoms in the materials and their physical density. Simulations of CT number ratios for clinical CT scanners show that iodine and barium exhibit a high 80:140 kVp CT number ratio of approximately 1.7, with CT numbers measured in Hounsfield units (HU), which is close to the maximum predicted for a given element on the periodic table for current clinical scanners. Materials with more widely differing ratios are more clearly discriminated by DECT, and thus iodine and barium can be discriminated quite well from water or most soft tissues (which have 80:140 kVp CT number ratios of approximately 1.0). Signals from materials with intermediate 80:140 kVp CT number ratios (1.25-1.45) can be more or less discriminated from signals of iodized or barium contrast material in addition to both water or most soft tissues by the use of two-material, three-material, or multi-material discrimination algorithms. Signals from materials with very high or very low 80:140 kVp CT number ratios (>2.1 or <0.6, respectively) are better separated from the signals of soft tissue and iodized contrast material.The enteric contrast agents of the present invention can be tailored to have these very high or very low or even negative 80:140 kVp CT number ratios.

[0045]

[0064] In single energy spectral CT, the signal from a particular one of the positive enteric contrast materials of the present invention may be difficult to distinguish from the signal of a positive intravenous iodized contrast agent or other heavy atom contrast agent. However, in dual energy or spectral CT, the 80:140 kVp CT number ratio of the positive enteric contrast material of the present invention can be selected to be substantially different (e.g., >2.1 or <0.9) from the ratio of an iodized contrast agent (1.7-1.8) or other heavy atom contrast agent (0.9-1.3), so that the signal from the positive enteric contrast material of the present invention is easily distinguished from the iodized intravenous contrast material.

[0046]

[0065] In single energy spectral CT, the signal from certain of the neutral enteric contrast materials of the present invention is easily distinguished from intravenous positive contrast material, but may be difficult to distinguish from water, biological fluids, or soft tissue, as with currently available neutral enteric agents. However, in dual energy or spectral CT, the CT number ratio of 80:140 kVp can be selected to be less than 1.0 or greater than 1.8, such that it is substantially different from the ratios of water, soft tissue, or iodine contrast material (about 1.0, about 1.0, and about 1.7-1.8, respectively), so that the signal from the neutral enteric contrast material of the present invention can be easily distinguished from water, biological fluids, or soft tissue.

[0047]

[0066] In single energy spectral CT, the signal from the negative enteric contrast material of the present invention is difficult to distinguish from fat, but is distinguishable from all other tissues and intravenous contrast agents. However, in dual energy CT or spectral CT, the CT number ratio of 80:140 kVp can be selected to be less than 1.0 or higher than 1.5, so as to be substantially different from the ratio of fat (about 1.2), so that the signal from the negative enteric contrast material of the present invention can be easily distinguished from fat.

[0048]

[0067] Encapsulated gas or partially evacuated organic polymer particles have been previously described as contrast materials for CT (e.g., encapsulated fluorocarbons capable of producing positive or negative signals on CT and negative signals on MR images) (U.S. Pat. No. 5,205,290). However, there has been no prior description of encapsulated gas or partially evacuated microparticles in which the shell material is selected to contribute substantially (e.g., at least about 30 HU) to the CT number (Hounsfield units) itself. Similarly, there has been no prior description of encapsulated gas or partially evacuated microparticles in which the shell material is selected to provide a substantial CT number difference when the microparticle formulation is imaged at low vs. high x-ray tube potentials (e.g., 80 kVp vs. 140 kVp). Although encapsulated gas particles have been described as contrast agents for ultrasound, these agents do not exhibit a CT number ratio at 80:140 kVp that is similar to the water signal on CT and substantially different from that of water and soft tissue.

[0049]

[0068] Historically, positive contrast agents for CT have predominantly used a single highly X-ray attenuating element (such as iodine in iodized contrast agents or barium in barium sulfate agents) as the reporter atom that generates the contrast agent's signal. The addition of gas or partial vacuum to highly X-ray attenuating materials to modify the signal of the resulting material for use with CT (including dual energy CT or spectral CT) has not been previously described. In various embodiments, the present invention utilizes gas or partial vacuum to modify the signal of the overall present contrast agent formulation to improve its value as a contrast agent for CT and dual energy CT or spectral CT.

[0050]

[0069] Historically, gas-based CT contrast agents did not utilize other elements to modify the gas signal in CT. Gas-filled microsphere contrast agents (including fluorocarbon contrast agents) did not utilize shell materials to substantially change the CT number of the encapsulated gas, and did not utilize shell materials to substantially change the 80:140 kVp CT number ratio of the encapsulated gas. In various embodiments, the present invention utilizes other non-gaseous atoms and molecules to modify the signal produced by gases and vacuum in CT, improving their value as contrast agents for CT and dual energy CT or spectral CT.

[0051]

[0070] The present invention, in various embodiments, provides contrast agents for CT with one or both of the following properties: 1) a CT signal (CT number) that is substantially different from critical soft tissue or intravenous contrast agents; and 2) a ratio of low kVp to high kVp CT numbers that is substantially different from critical soft tissue, fat, or intravenous contrast agents.

[0052] II. Definition

[0071] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and laboratory procedures in organic chemistry, pharmaceutical formulation, and medical imaging are those well known and commonly used in the art.

[0053]

[0072] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., at least one) of the grammatical object of the article. As an example, "an element" means one element or more than one element. Contrast agents with iodine, barium, or other atoms with a Z higher than 40 are exemplary "high Z" materials.

[0054]

[0073] A "disease" is a state in the health of an animal in which the animal is unable to maintain homeostasis and then the animal's health continues to deteriorate if the disease is not remitted.

[0055]

[0074] "Concurrent" administration refers to the use of an imaging agent in conjunction with a medical imaging procedure performed on a subject. As will be understood by one of skill in the art, concurrent administration of an imaging agent to a subject includes administration during or before the medical imaging procedure is performed such that the imaging agent is visible in a medical image of the subject.

[0056]

[0075] "Half-life" or "t 1 / 2The term "half-life", as used herein in the context of administering the enteric contrast medium of the present invention to a patient, is defined as the time required for the intestinal concentration of a drug in a patient to decrease by a factor of two. There may be more than one half-life associated with a contrast medium, depending on multiple clearance mechanisms, redistribution, and other mechanisms well known in the art. Further explanation of "half-life" is found in Pharmaceutical Biotechnology (1997, DFA Crommelin and RD Sindelar, eds., Harwood Publishers, Amsterdam, pp101-120).

[0057]

[0076] "Enteric contrast medium formulation", as used herein, unless otherwise indicated, means a pharma- ceutically acceptable liquid or paste formulation for administration to a subject, which comprises at least one enteric contrast medium, with or without a pharma- ceutically acceptable excipient for suspending the at least one medium, and which is prepared by dissolving, emulsifying, or suspending an enteric contrast medium as described herein in a pharma- ceutically acceptable vehicle, e.g., in the form of a powder, emulsion, or mash, prior to use for administration to a subject. Preferably, the suspending medium is water.

[0058]

[0077] The term "residence time," as used herein in the context of administering an enteric contrast medium to a patient, is defined as the average time that an enteric contrast medium remains in the patient's body after administration.

[0059]

[0078] The term "dual-energy CT or spectral CT" refers to a CT image in which a detector records an x-ray flux that is at least two different x-ray spectra. The x-ray spectra can be generated prior to the x-rays passing through the object being imaged, such as by different x-ray sources set at different tube potentials, different x-ray sources filtered by different materials, or a given x-ray source being switched between different tube potentials. Alternatively, the x-ray spectra can be separated after passing through the object being imaged, such as by the use of a multi-layer detector array or by a photon-counting detector.

[0060]

[0079] As used herein, "pharmaceutically acceptable carrier" includes any material that when combined with the conjugate retains the activity of the conjugate activity and is non-reactive with the subject's immune system. Examples include, but are not limited to, any of the standard pharmaceutical carriers, such as phosphate buffered saline solution, water, emulsions (such as oil / water emulsions), and various types of wetting agents. Other carriers may also include sterile solutions. Typically, such carriers contain excipients such as starch, milk, sugar, sorbitol, methylcellulose, certain types of clay, gelatin, stearic acid or its salts, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols, or other known excipients. Such carriers may also include flavors, textures, and colorants or other ingredients. Compositions containing such carriers are formulated by well-known conventional methods.

[0061]

[0080] As used herein, "administering" means orally, as a suppository, by topical contact, rectally, intravenously, intraperitoneally, intramuscularly, intralesionally, intranasally or subcutaneously, intrathecally, or by infusion into a surgically created pouch or surgically placed catheter or device, or by implantation of a slow release device (e.g., a mini-osmotic pump) into a subject.

[0062]

[0081] The term "enteric contrast medium" as used herein is understood to mean a dry or non-suspended component or mixture of components comprising at least one X-ray absorbing substance and, optionally, at least one pharma- ceutically acceptable excipient (which itself may contain other components, such as, for example, flavorings, antioxidants, wetting agents, emulsifiers, etc.). The "dry suspension mixture" may then be dissolved or suspended in a suspension medium to form the enteric contrast medium formulation of the present invention. The terms "suspending medium" and "pharma-ceutically acceptable excipient" as used herein refer to the medium in which the component(s) of the enteric contrast medium are emulsified or suspended.

[0063]

[0082] The terms "coating" and "coated" as used herein are understood to include coatings that are biocompatible in environments having acidic or neutral or basic pH values.

[0064]

[0083] The terms "particle" and "particles" as used herein refer to any shape of free-flowing material larger than about 1 nm, such as crystals, beads (smooth, round or spherical particles), pellets, spheres, and granules. Particles can be hollow bubbles or contain multiple internal cavities. Exemplary specific sizes for particles include about 1 nm to about 500 microns (e.g., 1 micron to about 100 microns), encompassing each single diameter value and each diameter range within the larger range across all endpoints; in various embodiments, the particles are larger than about 5 microns. Further useful particle sizes include, for example, about 5 microns to about 100 microns (e.g., about 20 microns to about 70 microns). Particles can contain gas or partial vacuum. Particles can be solid.

[0065]

[0084] The term "suspending agent" as used herein refers to any convenient agent known in the art used to form and / or maintain the suspension of a solid in a liquid (e.g., aqueous or oily). Exemplary suspending agents are selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, alginates, with sodium carboxymethylcellulose, including xantham gum, being preferred. Suspending agents can be used in any useful amount. Exemplary useful amounts are within the range of about 0 to about 20% by weight for powder formulations and about 0 to about 10% by weight for oral suspensions.

[0066]

[0085] In the context of the present invention, "stable" refers to a suspension that does not significantly separate into its components as different phases or layers between the time of preparation of the suspension and administration to a subject in an imaging study.

[0067]

[0086] The term "encapsulated gas or partial vacuum" as used herein refers to a gas or vacuum that is confined and highly restricted from communication with the outside environment, such that a minimal amount of gas or vacuum is released from the confined space during the expected residence time of biological use. The encapsulated gas may be at a pressure lower than, equal to, or higher than the ambient atmospheric pressure or suspending fluid vehicle.

[0068]

[0087] The term "high x-ray attenuation" as used herein refers to materials that produce higher CT numbers than water and non-fatty soft tissue in single-energy spectral CT imaging.

[0069]

[0088] The term "low x-ray attenuation" as used herein refers to materials that produce lower CT numbers than water and non-fatty soft tissue in single-energy spectral CT imaging.

[0070]

[0089] "Unpleasant and / or bitter taste" as used herein means that a majority of human patients judge the contained enteric contrast medium to have an unpleasant and / or bitter and / or extremely bitter taste after ingestion.

[0071]

[0090] With reference to the ability of the shell material of the particles in the contrast media of the present invention to affect the CT number, the term "substantially" refers to the following: Exemplary shell materials contribute substantially to the CT number of the contrast medium and / or the body cavity in which the contrast medium is present when the CT image is acquired. Contributing "substantially" refers to an addition of at least about 30 HU to the CT number of the contrast medium and / or the body cavity in which the contrast medium is present when the CT image is acquired. In various embodiments, the shell material contributes at least about 50 HU, at least about 100 HU, at least about 150 HU, or at least about 200 HU to the CT number. In exemplary embodiments, the shell material contributes more to the CT number than an equivalent amount of organic polymer at the same density would contribute under the same imaging conditions. In various embodiments, the shell material contributes at least about 10% more, at least about 25% more, at least about 50% more, at least about 75% more, or at least about 100% more HU units to the CT number than an equivalent amount of organic polymer at the same density would contribute under the same imaging conditions.

[0072]

[0091] Current clinical CT scanners can generate different X-ray spectra for imaging. The energy spectrum depends primarily on the scanner tube potential (kVp) setting of the machine (typically ranging from 80 to 140 kVp), and the X-ray filters, which can be made from different metals (e.g., tin, aluminum, copper, gold, etc.). These kVp settings result in the CT scanner generating X-rays with a spectrum of energies, with the maximum energy X-rays being 80 keV at a tube potential setting of 80 kVp and 140 keV at 140 kVp. For a given monochromatic energy X-ray energy passing through a known material, the degree of X-ray attenuation is defined by the Beer-Lambert law and is proportional to a) the density of the atom, b) the distance the X-ray passes through the material, and c) the X-ray attenuation coefficient for that particular atom or material at that particular X-ray energy. Since the x-ray spectrum is relatively constant at any given kVp setting for a given scanner, the ratio of x-ray attenuation at 80 kVp vs 140 kVp, as measured in Hounsfield Units (HU), can be determined for any given material. Generally, iodine and barium have 80:140 kVp CT number ratios of approximately 1.7 to 1.8. Water by definition has an 80:140 kVp CT number ratio of 1.0, since water is defined as having 0 HU for any given x-ray spectrum in CT. Elements of the periodic table have 80:140 kVp CT number ratios ranging from approximately 0.9 to 1.8. Materials with more widely dispersed 80:140 kVp CT number ratios are more easily differentiated with dual-energy CT or spectral CT. Other methods of obtaining dual-energy CT include the selection of different tube potential settings (eg, 70, 100 and 120 kVp), giving results similar to 80 kVp and 140 kVp dual-energy CT.Alternative methods for obtaining dual-energy or multi-energy CT are that the x-ray spectrum can be modified to obtain higher separation of the energy spectrum (e.g., by applying a tin or gold filter to one of the kVp setting tubes) or other methods can be utilized to quantify the absorption of x-rays of different energies (e.g., sandwich detectors, where the top layer(s) of the x-ray detector and filter detect and block lower energy x-rays, thereby modifying the x-ray spectrum to which the lower layer(s) are exposed; photon counting detectors, where detected x-rays are classified according to energy). The use of these other methods is still limited in distinguishing iodized materials from barium-based materials, and materials with atoms of widely different atomic numbers can be better distinguished.

[0073]

[0092] A virtual monochromatic energy CT image is an image reconstruction obtained from dual-energy or spectral CT data, whereby the x-ray absorption of each voxel of the image at a given monochromatic energy x-ray energy is an estimate. One way to achieve a virtual monochromatic energy CT image is to assume that the imaged object is entirely composed of two materials (such as iodine and water) and perform two-material decomposition based on the dual-energy or spectral CT data to determine the relative x-ray attenuation due to iodine and water for each voxel of the image. The virtual monochromatic energy CT image can then be back-extrapolated for any monochromatic energy x-ray energy by using reference x-ray attenuation coefficients corresponding to iodine and water (such as can be found at the National Institutes of Standards and Technology) to determine the CT number at the x-ray energy corresponding to each voxel of the image. In this manner, a virtual monochromatic energy image can be obtained for a wide range of keV (such as 40 keV or 140 keV, or any energy between, above or below these thresholds). The virtual monochromatic energy image can be filtered to reduce noise and improve image quality. The virtual monochromatic energy image can also be obtained by multi-material decomposition or photon counting techniques.

[0074] III. Exemplary Embodiments A. Composition

[0093] In various embodiments, the present invention provides an enteric or non-vascular contrast agent that can be easily distinguished from body tissues and available CT contrast materials on the market or previously described in CT imaging. The use of encapsulated gas or partial vacuum particles can produce contrast agents with or without high X-ray attenuation materials (such as iodine or barium) that have a relative CT number signal that is significantly different from body tissues or traditional iodized CT contrast materials and barium CT contrast materials. As an example, the gas or vacuum can be encapsulated by any biocompatible material, including organic and inorganic polymers, and glass. Exemplary materials include silicon-based materials (e.g., SiO2, e.g., glass), ceramics, plastics, or other shell materials. In various embodiments, the encapsulation material is used to modify the overall particle X-ray attenuation, thereby producing new contrast material formulations with useful X-ray attenuation properties. As an example, such encapsulated gas or partial vacuum particle contrast materials can be easily differentiated from conventional iodized and barium CT contrast materials, as well as from soft tissue and water, in conventional CT. The use of dual-energy or spectral CT allows even further differentiation of these contrast agents from commercial iodized and barium contrast agents, as well as from fat, soft tissue and water. For example, in high-energy virtual monochromatic energy CT images (such as 120 keV), the material can show a negative contrast agent signal, and in low-energy virtual monochromatic energy CT images (such as 40 keV), the material can show a neutral or positive contrast agent signal. The agents of the present invention allow the development of a new class of contrast materials with tunable CT numbers and ratios of low kVp CT numbers to high kVp CT numbers that can be separated from each other, as well as from existing contrast agents and naturally occurring body tissues.

[0075]

[0094] In various embodiments, the shells of the particles of the contrast media of the present invention are formed from inorganic materials (e.g., silica, alumina, ceramics). Exemplary particle shells contain more inorganic atoms by weight than organic atoms. Exemplary particle shells are formed from materials other than organic polymers. Exemplary particles are not formed from polymers or copolymers prepared from acrylic acid, methacrylic acid, ethylenimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate (HEMA), lactic acid, glycolic acid, ε-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkyl acrylates, siloxanes, dimethylsiloxanes, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzylstyrene, sodium styrene sulfonate, sodium 2-sulfoxyethyl methacrylate, vinylpyridine, aminoethyl methacrylate, 2-methacryloyloxy-trimethylammonium chloride, and polyvinylidene. In various embodiments, the shell of the particles of the invention is formed from a material other than a multifunctional crosslinking monomer (such as N,N'-methylenebisacrylamide, ethylene glycol dimethacrylate, 2,2'-(p-phenylenedioxy)diethyl dimethacrylate, divinylbenzene, triallylamine, and methylene bis-(4-phenyl-isocyanate), or combinations thereof). Exemplary shells of the particles of the invention include materials other than polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polylactic acid, poly-ε-caprolactone), epoxy resins, poly(ethylene oxide), poly(ethylene glycol), and polyamide (nylon).Further exemplary particle shells of the particles of the present invention include materials other than copolymers including the following: polyvinylidene-polyacrylonitrile, polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and polystyrene-polyacrylonitrile. In an exemplary embodiment, the shells of the particles of the contrast media of the present invention are formed from materials other than the copolymer polyvinylidene-polyacrylonitrile.

[0076]

[0095] In various embodiments, the particles have a specific gravity of about 0.05 g / cm 3 In various embodiments, the specific density of the particles of the contrast media of the present invention is at least about 0.1, at least about 0.3, at least about 0.5, at least about 0.7, at least about 1, at least about 1.5, or at least about 2 g / cm. 3 In various embodiments, the specific gravity of the particles of the contrast media of the present invention is at least that of water.

[0077]

[0096] Exemplary particles of the present invention are at least partially evacuated, hi various embodiments, the interior space of the particle has a pressure of about 1 atmosphere or less (e.g., less than about 0.8 atm, less than about 0.6 atm, less than about 0.3 atm, or less than about 0.1 atm).

[0078]

[0097] In various embodiments, the interior space of the particle is at least partially filled with a gas, as discussed herein. When the interior of the particle is at least partially filled with a gas other than air, the gas is preferably not a hydrocarbon, a fluorocarbon, or a hydrofluorocarbon. In various embodiments, the gas is an elemental gas. In various embodiments, the gas is other than carbon dioxide, oxygen, nitrogen, xenon, argon, neon, helium, air, or a combination thereof.

[0079]

[0098] The exemplary particles of the present invention are not considered to be "low density" particles. By low density, it is meant that the particles of the media of the present invention have an internal void (hollow) volume that is at least about 75% of the total volume of the particle. Low density also refers to particles that have a void volume of at least about 80% (e.g., at least about 85%, e.g., at least about 90%) of the total volume of the particle. The exemplary particles in the media of the present invention include a void volume that is less than 75% (e.g., less than 70%, less than 65%, less than 60%, less than 50%, or less than about 30%) of the total volume of the particle.

[0080]

[0099] In operation, the particles of the contrast media of the present invention have distinctive properties as compared to other particulate contrast media. For example, the particles generally have a higher specific gravity than the contents of the lumen of the gastrointestinal tract or other body cavity, so that the various particles of the contrast media do not decrease the density of the contents of the lumen of the gastrointestinal tract or other body cavity. In various embodiments, the particles of the media increase the density of the contents of the lumen of the gastrointestinal tract or other body cavity.

[0081]

[0100] Exemplary contrast media of the present invention do not reduce the CT number of the lumen of the gastrointestinal tract or other body cavities or do not significantly reduce the CT number in a CT image. Exemplary particles of contrast media reduce the CT number of the lumen to at least about -30 HU. Exemplary particles provide a reduction in HU to between about -30 HU and about -150 HU, sufficient to mark the interior of the intestine or other body cavities.

[0082]

[0101] Exemplary enteric contrast media of the present invention substantially reduce the CT number to less than 100 HU per 10% volume of the enteric contrast medium formulation by volume of aqueous suspension, such that to achieve a CT number of -100 HU, at least 12.5% ​​or more of the total volume of the formulation must be enteric contrast medium, and to achieve a CT number of -200 HU, at least 25% or more of the total volume of the formulation must be enteric contrast medium. In other embodiments of the present invention, the enteric contrast media of the present invention can also increase the CT number of the enteric contrast medium formulation.

[0083]

[0102] The contrast agents of the present invention may provide improved CT applications with one or more of the following benefits: 1) The intestinal lumen or non-vascular structures contrasted by the contrast materials of the present invention can be more easily distinguished from soft tissues than those contrasted by currently available CT contrast materials. 2) the bowel or non-vascular structures are contrasted by the contrast materials of the present invention and can be distinguished from vascular structures or soft tissues that are contrasted by CT contrast materials currently available for CT imaging; 3) The intestine or non-vascular structures can be stained with the contrast agents of the present invention for CT imaging based on the CT signal with single-energy spectral CT, or by the ratio of relative low-energy x-ray attenuation to high-energy x-ray attenuation with dual-energy or spectral CT, without interfering with the assessment of contrast material-related wall enhancement within the vasculature of the structure (intestinal wall, bladder wall, other walls, including associated disease such as inflammation or neoplasia).

[0084]

[0103] In various embodiments, the present invention provides enteral contrast agents based on encapsulated gas or partial vacuum particles. In various embodiments, the contrast agent can be selected to provide a negative, neutral, or positive signal in single energy spectral CT. In various embodiments, the contrast agent can be selected to have a very high CT number ratio from low kVp images to high kVp images (such as a CT number ratio of 80:140 kVp greater than about 2.1, and may even be higher than about 2.7), or about 1.25 to about 1.5; or less than about 0.6; or less than 0.0, depending on the relative number and type of particles or other different atoms incorporated into the suspension medium. In various embodiments, the contrast agent formulation includes iodized or barium materials to modify the CT number for use with single energy spectral CT and the CT number ratio of 80:140 kVp for use with dual energy or spectral CT.

[0085]

[0104] The benefits of the agents of the present invention are a result of the agents' novel X-ray imaging properties. In CT scans, conventional positive CT contrast materials all produce similar signals, and they all cause increased X-ray attenuation (positive contrast) when present, and cannot be distinguished except by context. The materials of the present invention have significantly different relative low-energy to high-energy X-ray attenuation ratios in dual-energy CT or spectral CT, and are therefore easily distinguished from other positive contrast agents using dual-energy CT or spectral CT. For example, iodized CT contrast agents or barium-based CT contrast agents have 80:140 kVp CT number ratios of about 1.7 to about 1.8. In computer simulations, elements of the periodic table have been shown to have 80:140 kVp CT number ratios of about 0.9 to about 1.8. Notably, the 80:140 kVp CT number ratio of water is 1.0 by definition. In the simulations, the iodine-based and barium-based materials had the highest theoretical 80:140 kVp CT number ratios of all elements on the periodic table. It was not predicted that the materials could have substantially higher 80:140 kVp CT number ratios than iodine and barium, or that the drugs could have substantially lower 80:140 kVp CT number ratios than water. Figure 1.

[0086]

[0105] Therefore, it is indeed surprising that in vitro experiments have shown that materials with 80:140 kVp CT number ratios substantially lower than about 0.9 or higher than about 1.8 can exist or be produced. The concentrations of two contrast materials with significantly different CT number ratios from low to high x-ray energy spectra are much more accurately quantified with dual energy CT compared to contrast materials with CT number ratios from low to high x-ray energy spectra that are more similar to each other when in a mixed solution. For example, the concentrations of iodine-based and barium-based agents could not be very accurately quantified. The present invention of composite low and high x-ray attenuation material particles provides an outstanding difference in 80:140 kVp CT number ratios compared to soft tissue, water, and any compound iodized / barium contrast materials previously described in the literature, including those in our prior patent applications. In other words, these agents are more readily distinguishable from other contrast agents and soft tissues than other experimental or conventionally available agents. Members of the microparticle or microsphere family (with or without a biocompatible shell or coating) are known to be of minimal and acceptable toxicity for use as enteric contrast materials.

[0087]

[0106] Thus, in an exemplary embodiment, the present invention provides an enteric contrast medium formulation that is formulated for enteral administration to a subject simultaneously with a medical imaging procedure performed on the subject's abdomen.The exemplary formulation includes an enteric contrast medium that includes a suspension of at least one encapsulated gas or partially evacuated particle, an aqueous or oil-based component, and a suspending agent.The suspending agent maintains at least one encapsulated gas or partially evacuated particle in aqueous or oil suspension as a pharma-ceutically acceptable enteric contrast material.Another exemplary formulation includes an enteric contrast medium that includes at least one encapsulated gas or partially evacuated particle that incorporates a radiopaque material (such as iodine, barium, tungsten, tantalum, bismuth, or ytterbium within the particle or in an aqueous or oil suspension medium).

[0088]

[0107] In an exemplary embodiment, the present invention provides an enteric contrast medium and its formulation that is readily distinguishable from other currently available contrast materials in single-energy and dual-energy or spectral CT images. The present invention is illustrated by reference to an enteric contrast medium formulation. An exemplary formulation includes an enteric contrast medium that includes a suspension of at least one encapsulated gas or partial vacuum particle, an aqueous or oil component, and a suspending agent. The suspending agent maintains the at least one encapsulated gas or partial vacuum particle in aqueous or oil suspension with the aqueous or oil component being a pharma-ceutically acceptable aqueous or oil vehicle. In various embodiments, the particles are coated with a material that is compatible with enteral administration of the formulation to a subject in need of such administration.

[0089]

[0108] Exemplary encapsulation materials for the encapsulated gas or partial vacuum particles of the present invention can be glass, gel, resin, ceramic, metal, or rubber, or a plurality of these materials.

[0090]

[0109] In an exemplary embodiment, the encapsulation material for the gas or partial vacuum of the particles is glass. Exemplary glasses for use in the present invention are those containing silicon dioxide (e.g., silicon dioxide blended with additives such as potash (potassium oxide), soda (sodium carbonate or oxide), sodium oxide, lime (calcium oxide), boron trioxide, boric acid, magnesia, alumina, iron oxide, or other oxides). In an exemplary embodiment, the glass shell of the hollow microspheres contains silicon oxide as a base or core member, with other chemical components in the above glasses (mainly oxides) being present in minor amounts for purposes of melting improvement, processing, and property modification, as found in the current art of the glass industry. In an exemplary embodiment, the borosilicate glass shell is composed of about 80% silica, about 13% boron oxide, about 4% sodium oxide, and about 2-3% aluminum oxide.

[0091]

[0110] In various embodiments, the particles are formed from a shell material that defines an internal space. Exemplary shell materials contribute at least about 30 HU to the CT number of the contrast medium and / or the body cavity in which the contrast medium is present when the CT image is acquired. In various embodiments, the shell material contributes at least about 50 HU, at least about 100 HU, at least about 150 HU, or at least about 200 HU to the CT number. In exemplary embodiments, the shell material contributes more to the CT number than an equivalent amount of organic polymer at the same density would contribute under the same imaging conditions. In various embodiments, the shell material contributes at least about 10% more, at least about 25% more, at least about 50% more, at least about 75% more, or at least about 100% more HU units to the CT number than an equivalent amount of organic polymer at the same density would contribute under the same imaging conditions.

[0092]

[0111] In an exemplary embodiment, the specific gravity of the glass microparticles is 0.45 g / mL. The specific gravity of glass is approximately 2.3 g / mL, so then approximately 20% of the volume of the microparticles is glass and 80% is gas / partial vacuum. When this exemplary particulate material is formulated in a formulation at 20% weight / weight, the encapsulated gas or partial vacuum microparticles make up approximately 35% of the volume of the formulation, where the gas and partial vacuum parts make up 28% of the volume of the formulation, and the glass makes up 7% of the volume of the formulation. In CT images, the gas and partial vacuum are -1000 HU at all kVp, solid glass is approximately 1241 HU at 80 kVp and 1041 HU at 140 kVp, and water is 0 HU at all kVp by definition. Thus, in this exemplary formulation, the gas and partial vacuum fraction contributes 28% x (-1000 HU at all kVp) = -280 HU, water contributes 0 HU (by definition), glass contributes 7% x (1332 HU at 80 kVp) = 93 HU and 7% x (1031 HU at 140 kVp) = 72 HU, resulting in a formulation with an overall CT number of -187 HU at 80 kVp and -208 HU at 140 kVp. In a practical example of physical reduction, a 20% w / w formulation of 0.45 g / mL borosilicate glass hollow microspheres in water showed -103 HU at 80 kVp and -151 HU at 140 kVp. The slight discrepancy in HU values ​​was likely due to differences in the composition of the actual borosilicate glass used in the hollow microspheres of the example compared to the glass used in the calculations.

[0093]

[0112] In an exemplary embodiment, the encapsulated gas of the particles is a sulfur-containing gas or oxygen or carbon dioxide. In various embodiments, the gas is sulfur dioxide or sulfite.

[0094]

[0113] In an exemplary embodiment, the partial vacuum encapsulated by the particles is between 0.01 and 1.0 atmospheres.

[0095]

[0114] In an exemplary embodiment, the pressure of the gas inside the particle is equal to or greater than atmospheric pressure and there is no partial vacuum.

[0096]

[0115] In an exemplary embodiment, the encapsulated gas or partial vacuum particles have an average specific gravity of about 0.2 to about 1.6 g / cc. In an exemplary embodiment, the encapsulated gas or partial vacuum particles have an average specific gravity of about 0.1 to 1.0 g / cc. In an exemplary embodiment, the encapsulated gas or partial vacuum particles have an average specific gravity of about 0.3 to about 0.6 g / cc.

[0097]

[0116] Exemplary encapsulated gas or partial vacuum particles for use in the formulations of the present invention include borosilicate microspheres having a specific gravity similar to that of water (e.g., about 0.3 to about 1.5 g / cc), with preferred specific gravities being about 0.4 to about 1.4 g / cc.

[0098]

[0117] One or more encapsulated gas or partial vacuum particles may be used together.

[0099]

[0118] Any useful suspending agent or combination of suspending agents can be utilized in the formulations of the present invention. In various embodiments, the suspending agent is thixotropic, forming a gel-like medium at rest but a liquid upon agitation.

[0100]

[0119] In an exemplary embodiment, the enteric contrast medium is formulated into a pharma- ceutically acceptable carrier in which particles of encapsulated gas or partial vacuum are suspended.

[0101]

[0120] In various embodiments, the encapsulant contains a highly radiopaque material, such as barium or iodine. In various embodiments, the encapsulant contains a heavy atomic number element, such as tungsten, tantalum, ytterbium, gold, or bismuth.

[0102]

[0121] In various embodiments, the radiopaque material (such as iodine, barium, tungsten, tantalum, ytterbium, gold, or bismuth) is present in the contrast medium either as separate suspended particles or as dissolved material in an aqueous or oil-based vehicle.

[0103]

[0122] In an exemplary embodiment, the encapsulated gas or partial vacuum particles are coated to provide useful properties for the contrast material, such as improved suspension in a medium, increased specific gravity, or altered x-ray attenuation when imaged with low or high x-ray energy spectra.

[0104]

[0123] In an exemplary embodiment, the coating comprises an organic molecule with 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 comprises an organic molecule with a molecular weight of less than about 3 kd, less than about 2 kd, or less than about 1.5 kd, which is a member selected from organic acids (or alcohols, amines) and derivatives or analogs thereof, oligosaccharides, and combinations thereof.

[0105]

[0124] In an exemplary embodiment, the coating is a protein (eg, albumin).

[0106]

[0125] In various embodiments, the particles of the present invention are coated with a biocompatible coating.Suitable coatings are known in the art, and it is within the ability of the skilled artisan to select a suitable coating for a particular formulation and / or application.See, for example, Yeh BM, Fu Y, Desai T, WO2014145509A1.

[0107]

[0126] The suspension phase of the formulation of the present invention can include particles of any useful size. Exemplary specific sizes for particles include about 1 nm to about 500 microns (e.g., 1 micron to about 100 microns), including each single diameter value and each diameter range within the larger range across all endpoints; in various embodiments, the particles are larger than about 5 microns. Further useful particle sizes include, for example, about 5 microns to about 100 microns (e.g., about 20 microns to about 70 microns).

[0108]

[0127] The formulations of the present invention may include a single enteric contrast medium or two or more enteric contrast media. The media may be present in similar or different concentrations according to any useful concentration measurement. Exemplary embodiments include different concentrations of one or more particles or soluble agents, each of which contributes substantially to the X-ray attenuation compared to the X-ray attenuation of water in the overall contrast formulation. Thus, in various embodiments, between about 5% (w / w, expressed as a weight percent, e.g., about 5 grams of contrast agent particles in about 100 grams of total contrast formulation) and 90% (w / w) of the weight of the formulation are the particles. In exemplary embodiments, the formulation includes between about 10% (w / w) and about 50% (w / w) of particles.

[0109]

[0128] In an exemplary embodiment, the invention provides a formulation comprising at least about 5% (eg, at least about 20%) of said encapsulated gas or partial vacuum particles.

[0110]

[0129] The formulations of the present invention comprise a population of encapsulated gas or partial vacuum particles of the present invention suspended in a pharma- ceutically acceptable vehicle. The vehicle may contain other useful components. For example, in some embodiments, the vehicle may comprise an aqueous medium, which may further comprise an additive to provide a secondary property to the formulation (e.g., retarding dehydration of the formulation in the intestine, providing flavor, stabilizing the suspension, promoting fluidity of the suspension, thickening the suspension, providing pH buffering, and combinations thereof).

[0111]

[0130] The formulations of the 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 of -200 HU in a 120 kVp CT image. In another exemplary embodiment, the enteric contrast medium has a CT number ratio of 80:140 kVp of about 0.8 or less. Formulations with exemplary useful values ​​for this ratio include formulations with a CT number ratio of 80:140 kVp of about 0.1 to about 0.8 (e.g., about 0.3 to about 0.5, e.g., about 0.5 to 0.7). Other formulations with exemplary useful values ​​for this ratio include formulations with a CT number ratio of 80:140 kVp of about 2.1 to 6.0 (e.g., about 2.3 to 2.7, e.g., about 2.7 to 3.5). This amount can be readily determined for any contrast medium of the invention by one of skill in the art.

[0112]

[0131] In an exemplary embodiment, the invention provides an enteric contrast medium formulation, the enteric contrast medium having an 80:140 kVp CT number ratio of greater than about 2.1. In an exemplary embodiment, the invention provides an enteric contrast medium formulation, the enteric contrast medium having an 80:140 kVp CT number ratio of about 1.5 to 2.1. In an exemplary embodiment, the invention provides an enteric contrast medium formulation, the enteric contrast medium having an 80:140 kVp CT number ratio of less than about 1.5.

[0113]

[0132] 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 can be soluble or insoluble in a pharma- ceutically acceptable vehicle. When the second contrast medium is a particulate drug, the second contrast medium can comprise different atoms in the particulate core, different coating, be of different diameter, etc., compared to the first contrast medium. The second contrast medium can also be one or more of iodized contrast medium, Ba-based contrast medium, Gd-based contrast medium, Bi-based contrast medium, W-based contrast medium, Mg-based contrast medium, Ta-based contrast medium, Yb-based contrast medium, or other Si-based contrast medium.

[0114]

[0133] In an exemplary embodiment, the second contrast medium is an iodized contrast material (eg, iohexol, iodixanol, diatrizoate, iopamidol).

[0115]

[0134] In an exemplary embodiment, the second contrast medium is a barium-based contrast material (eg, barium sulfate).

[0116]

[0135] Within the scope of the present invention, the formulations are designed for administration of a single dosage. These unit dosage forms contain a sufficient amount of the formulations of the present invention to provide detectable imaging in the subject to which they are administered. In an exemplary embodiment, the unit dosage formulation includes a container that holds sufficient enteric contrast medium to enhance the diagnostic image of the subject to which the unit dosage is administered in a diagnostically meaningful manner. The container can be a vial, an infusion bag, or other suitable container. The enteric contrast medium can be in the form of a preformulated liquid, concentrate, or powder. In an exemplary embodiment, the subject weighs about 70 kg. In an exemplary embodiment, the image is measured through the subject's abdomen, the subject's pelvis, or a combination thereof.

[0117]

[0136] In various embodiments, the unit dosage formulation contains about 800 to about 1500 mL of contrast medium per adult human dose, which can be divided into smaller containers of a size such as 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.

[0118]

[0137] Any of the formulations described herein can be formulated and utilized for administration via any of a variety of routes. Exemplary routes of administration include oral, rectal, intravaginal, intravascular, intraspinal, intravesical, and the like.

[0119]

[0138] Highly concentrated encapsulated gas or partial vacuum particle contrast materials have not been described as contrast materials for use with CT. In exemplary embodiments, the encapsulated gas or partial vacuum particles in the formulation are highly concentrated (e.g., about 50-500 mg / g, e.g., about 100-500 mg / g, e.g., about 150-300 mg / g). In exemplary embodiments, the particles comprise about 5% (w / w)-90% (w / w) (e.g., about 5% (w / w)-60% (w / w)) of the formulation.

[0120]

[0139] In various embodiments, the enteric contrast medium of the present invention and preferably its formulations exhibit chemical stability over a wide pH range (e.g., from about 1.5 to about 10). The stomach exposes the intestinal contents to a low pH of 1.5, and the bile and small intestine can expose the intestinal contents to a high pH of up to 10. 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 materials occurs in the gastrointestinal tract, or if the degradation products are potentially toxic.

[0121]

[0140] In various embodiments, the present invention provides a method for determining whether or not a particular particle of an encapsulated gas or partial vacuum has a sufficiently long t to allow for the completion of an imaging experiment with a concentration that remains high enough within the region of interest. 1 / 2 In various embodiments, the present invention provides enteric contrast media and formulations that have an in vivo residence time that is short enough to essentially allow all of the administered encapsulated gas or partial vacuum particles to be cleared from the subject's body before being altered (metabolized, hydrolyzed, oxidized, etc.) by the subject's body.

[0122]

[0141] In various embodiments, the formulation has a small intestinal transit time of less than 12 hours in normal subjects. In an exemplary embodiment, the formulation contains sorbitol, polyethylene glycol, or both to accelerate the intestinal transit time.

[0123]

[0142] In an exemplary embodiment, the invention provides an enteral contrast medium that dissolves slowly, such that the majority of the administered encapsulated gas or partial vacuum particles are expelled via the gastrointestinal tract before being modified by the subject's body, and the dissolved or modified portions are excreted via the urinary tract.

[0124]

[0143] The pharmaceutical formulations of the present invention may optionally contain excipients and other ingredients, such as one or more sweeteners, flavorings and / or additional taste modifiers to mask bitter or unpleasant tastes, suspending agents, glidants, antioxidants, preservatives and other conventional excipients as needed.

[0125]

[0144] The suspensions of the present invention may optionally contain one or more antioxidants, taste modifiers, if necessary, sweeteners, glidants, suspending agents and preservatives.

[0126]

[0145] As will be appreciated, the above-mentioned optional ingredients may be added to the powder formulations of the present invention or the oral suspensions of the present invention.

[0127]

[0146] Antioxidants suitable for use herein include any convenient agent known in the art for this purpose (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.

[0128]

[0147] Antioxidants may be used in amounts that protect the formulation from oxidation, as will be apparent to one of skill in the art.

[0129]

[0148] The sweetener used in the formulations of the present invention may be any convenient agent known in the art for this purpose and may be selected from any compatible group of sweeteners, including natural sweeteners such as sucrose, fructose, dextrose, xylitol, sorbitol or mannitol, as well as artificial sweeteners such as aspartame, acesulfame K and sucrolose. Xylitol and aspartame are preferred sweeteners.

[0130]

[0149] Flavors and flavor modifiers or taste modifiers can also be used to further improve taste and can be any convenient agent known in the art for this purpose, including, but not limited to, orange flavor, vanilla flavor, licorice flavor, orange vanilla flavor, creme de mint, cherry flavor, cherry vanilla flavor, berry mix flavor, passion fruit flavor, pear flavor, strawberry flavor, mandarin orange flavor, bubble gum flavor, tropical punch flavor, juice blend for grape, grape flavor, artificial grape flavor, grape bubble gum flavor, tutti frutti flavor, citrus flavor, lemon flavor, chocolate flavor, coffee flavor, and combinations thereof.

[0131]

[0150] The suspending agent may be any convenient agent known in the art for this purpose and may be selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, alginates, and sodium carboxymethylcellulose, with xanthan gum being preferred.Suspending agents may be used in amounts ranging from about 0 to about 20% by weight for powder formulations and from about 0 to about 10% by weight for oral suspensions.

[0132]

[0151] The preservative may be any convenient agent known in the art for this purpose and may be selected from the group consisting of any compound compatible with the drug active (methyl and propylparaben, benzoic acid, sodium benzoate, potassium sorbate, etc.), with methylparaben being preferred.

[0133]

[0152] The present invention also provides kits for use in clinical and / or research settings. An exemplary kit includes: (a) a first vial containing an enteric contrast medium of the present invention; (b) a second vial containing a suspension; and (c) instructions for using and / or formulating the enteric contrast medium as a suspension. 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.

[0134]

[0153] The contrast medium contained in the second vial can be soluble or insoluble in a pharma-ceutically acceptable vehicle.When the second contrast medium is a particulate drug, the second contrast medium can have a different atom in the particulate core, a different coating, a different encapsulation material, contain a different gas, be a different diameter, etc., compared to the first contrast medium.The second contrast medium can also be one or more of iodized contrast medium, Ba-based contrast medium, Gd-based contrast medium, W-based contrast medium, Bi-based contrast medium, Yb-based contrast medium, Si-based contrast medium, or Ta-based contrast medium.

[0135]

[0154] B. Method The present invention also provides a method of obtaining and enhancing clinically meaningful CT images from a subject to which the formulation of the present invention is administered, utilizing the formulation of the present invention. Thus, in an exemplary embodiment, the present invention provides a method of obtaining contrast-enhanced CT projection data of a subject, which is then reconstructed into a CT image. The method includes administering a diagnostically effective amount of the enteric contrast medium formulation of the present invention to the subject; obtaining CT projection data of the subject, which is then reconstructed into a CT image. In various embodiments, the enteric contrast medium has a CT number ratio of 80:140 kVp of less than about 0.8 in the image in a DECT imaging study. In various embodiments, the enteric contrast medium has a CT number ratio of 80:140 kVp of greater than about 2.0 in the image in a DECT imaging study.

[0136]

[0155] In an exemplary embodiment, the present invention provides contrast-enhanced CT images of a subject through a region of the subject in which an enteric contrast medium of the present invention is distributed.

[0137]

[0156] The images of the present invention and those obtained by the methods of the present invention utilize the contrast media of the present invention. The images are obtained through any section of the subject's body. In an exemplary method, the images are through the abdomen and / or pelvis of the subject.

[0138]

[0157] The present invention also provides methods for post-processing CT projection data, CT images, or both to digitally separate CT signals produced by the enteric contrast medium of the present invention from CT signals produced by soft tissues, body fluids, or other contrast media. In various embodiments, two-material decomposition, three-material decomposition, multi-material decomposition, or virtual monochromatic energy images, and combinations thereof, are used to separate dual-energy CT or spectral CT signals produced by the enteric contrast material of the present invention from CT signals produced by other contrast media or body tissues based on relative differences in x-ray attenuation in low vs. high x-ray energy spectra. In various embodiments, signal strength (such as a threshold signal) is also considered in the material decomposition method to aid in separating CT signals produced by the contrast medium of the present invention from CT signals produced by other imaged materials. In an exemplary embodiment of the present invention, post-processing of the material decomposition images produces a new CT image where the CT signals from the contrast material of the present invention are highlighted or subtracted from the CT signals produced by other contrast materials or body tissues. In an exemplary embodiment of the invention, post-processing of the material decomposition image produces a new CT image where CT signals from contrast materials other than the contrast agents of the invention are highlighted or subtracted from CT signals produced by the contrast materials of the invention or body tissues.

[0139]

[0158] One of the advantages of the contrast medium and formulation of the present invention is that it is compatible with the administration of one or more additional contrast agents via any desired route. In various embodiments, the method further comprises administering to the subject a second contrast medium different from the enteric contrast medium of the present invention. In various embodiments, the second contrast medium is administered via a route selected from intravascular administration, enteral administration, anal administration, and administration into a different body cavity, whether natural (e.g., vagina, bladder), caused by injury (e.g., fistula, abscess, sinus tract), surgically created (e.g., neobladder, ileal pouch), or artificial (e.g., medical device such as catheter, reservoir, tube, or pump). Multiple contrast materials can be administered to different body compartments. In an exemplary embodiment, the second contrast medium is an iodine or barium-based medium, and the third contrast medium is a tantalum, bismuth, ytterbium, gadolinium, or tungsten-based contrast medium. In an exemplary embodiment, the second or third contrast medium is an embodiment of the contrast medium of the present invention.

[0140]

[0159] In an exemplary embodiment, the contrast agents of the present invention are used simultaneously with and differentiated from iodized and barium agents or other contrast agents under development (such as those based on heavy metals such as tungsten, ytterbium, bismuth, or tantalum). One or more body compartments are injected and, in cases of two or more body compartments, simultaneously interrogated for single DECT or multi-energy CT examination, providing timely, high-resolution, fully registered anatomical images of each system for rapid and confident diagnosis. The method of the present invention provides a means to accurately assess multi-organ damage from trauma, tumors, surgical complications, and inflammatory diseases.

[0141]

[0160] In an exemplary embodiment, the first and second contrast media are distinguishable from one another in an image set encompassing the region in which the first and second contrast media are distributed. An exemplary second contrast medium is an iodized contrast medium.

[0142]

[0161] The second contrast medium may be soluble or insoluble in a pharma- ceutically acceptable vehicle. When the second contrast medium is a particulate drug, the second contrast medium may comprise different atoms in the particulate core, a different coating, be of a different diameter, etc., compared to the first contrast agent. The second contrast medium may also be one or more of an iodized contrast medium, a Ba-based contrast medium, a Gd-based contrast medium, a W-based contrast medium, a Si-based contrast medium, a Mg-based contrast medium, a Yb-based contrast medium, a Bi-based contrast medium, or a Ta-based contrast medium.

[0143]

[0162] In an exemplary embodiment, the second contrast medium is an iodine-based or barium-based medium.

[0144]

[0163] In an exemplary embodiment, the second contrast medium is a silicon-based medium.

[0145]

[0164] The present invention provides a method for improving CT diagnosis through the use of one type (positive, neutral or negative) enteric contrast medium, which can also be converted by post-processing of images to show one or more of other types of signals (positive, neutral or negative) in CT.For example, in suspected bowel ischemia, neutral or negative enteric contrast medium is useful for finding either hyperenhancement or hypoenhancement of the bowel wall, which detects inflammation or ischemia, respectively.In another exemplary method, positive contrast medium allows identification of bowel perforation, abscess and fistula.

[0146]

[0165] The development of a safe clinical enteric CT contrast material that can be digitally manipulated to appear as negative, neutral, or positive contrast material under the control of the interpreting physician would provide powerful diagnostic capabilities and eliminate guesswork and protocol errors as well as diagnostic errors. Reduction in errors would result in more rapid diagnoses and reduced need for additional workup. Physicians would no longer need to weigh the advantages and disadvantages of administering neutral or negative vs. positive enteric contrast material for a given clinical scenario.

[0147]

[0166] The following examples are provided to illustrate exemplary embodiments of the invention, but do not define or limit its scope.

[0148] Working Example

[0167] Example 1 Encapsulated gas or partial vacuum microparticles are common, commercially available, and can be produced by many techniques well known to those skilled in the art. A general range of methods utilizes a "blowing agent," which is a substance that can release gas when heated to high temperatures. An example of the production of encapsulated gas or partial vacuum microparticles is to heat a shell material (in the form of a glass or ceramic frit, powder, or solution) and a blowing agent to a temperature sufficient to melt the shell material, then cause gas release from the blowing agent to produce hollow microparticles, which are then cooled. For example, the heating temperature can range from 800 to 1500 degrees Celsius, depending on the needs of the shell material variations, to create different types of encapsulated gas or partial vacuum microparticles. Another process is to heat a porous glass or ceramic material to melt it slightly and seal the surface so that the gas or partial vacuum is retained inside the particle. A partial vacuum in a heating chamber can be utilized by the above methods to adjust the fraction and physical properties of the resulting encapsulated gas or partial vacuum microparticles in the product. Gravity, with or without updrafts or downdrafts, can be used to modify the residence time of the particles in the heated zone, thereby affecting the diameter and specific gravity of the resulting encapsulated gas or partial vacuum microparticles. Further selection of microparticle subpopulations can be obtained by a number of mechanical means based on physical properties (such as diameter or specific gravity).

[0149]

[0168] Due to safety considerations of enteric CT contrast agents, the microparticle shell materials (such as silica, borosilicate, or glass) are selected to be biologically safe and inert (e.g., those materials free of toxic levels of elements such as lead, cadmium, and the like).

[0150]

[0169] Example 2 Stable suspensions of encapsulated gas or partially evacuated microparticles in aqueous solutions can be obtained by the use of suspending agents. For example, the use of 0.2-0.5% xanthan gum was used to suspend 10-50% wt / wt of iM30K (3M) encapsulated gas or partially evacuated particles in water. The resulting particle suspensions remained uniform on CT imaging for over 7 months. Slight increases in CT numbers at all kVp settings were observed in the suspensions after the first 2 months. These slight increases in CT numbers did not substantially alter the ability of the formulation to separate from water, soft tissue, or conventional iodized or barium contrast materials on dual energy CT imaging. The viscosity of the suspensions ranged from 50 to 2400 g / cm-sec.

[0151]

[0170] Stable suspensions of encapsulated gas or partial vacuum microparticles in aqueous solutions with dissolved iodized iohexol or suspended barium sulfate were made using 0.2-0.5% xanthan gum. The suspensions contained 30% wt / wt iM30K, 0.1%-2% wt / wt iodine, or 0.1%-2% wt / wt barium. The iodine-containing suspensions remained homogeneous on CT imaging for more than 8 months after formulation. Slight increases in CT numbers at all kVp settings were observed in the suspensions after the first 2 months. These slight increases in CT numbers did not substantially alter the ability of the formulations to separate from water, soft tissue, or conventional iodized or barium contrast materials on dual-energy CT imaging. The viscosities of the suspensions ranged from 50-1000 g / cm-sec.

[0152]

[0171] In vivo imaging experiments in rabbits, rats, and mice have demonstrated that the encapsulated gas or partial vacuum particle contrast agents of the present invention provide simultaneous positive, neutral, and negative enteric contrast in a single DECT scan. Figures 8, 9, 18, and 19.

[0153]

[0172] The present invention has been illustrated by 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 may be devised by those skilled in the art without departing from the true spirit and scope of the present invention. The appended claims should be construed to include all such embodiments and equivalent variations.

[0154]

[0173] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated by reference in their entirety.

Claims

1. 1. A pharmaceutical formulation of a stable suspension of a first enteric CT imaging contrast agent, comprising: a stable aqueous suspension of the first enteric CT imaging contrast agent, the first CT imaging contrast agent comprising a plurality of hollow particles comprising an inorganic glass shell encapsulating a partial vacuum or gas within an interior space; the first enteric CT imaging contrast agent is stably suspended in a sterile, pharmaceutically acceptable aqueous suspension medium compatible with enteral administration of the pharmaceutical formulation to a subject concurrently with CT imaging of a region of the subject containing the first enteric CT imaging contrast agent; the pharmaceutical formulation comprises about 5% (w / w) of the first enteric CT imaging contrast agent; the sterile, pharmaceutically acceptable aqueous suspension medium comprises up to about 10% of a suspending agent that stabilizes the suspension of the first enteric CT imaging contrast agent; The stable pharmaceutical formulation is characterized in that the transit time through the small intestine when administered to a subject through the intestine is less than 12 hours.

2. wherein the unit dosage per enteral administration is sufficient to provide detectable contrast in CT imaging in a subject to whom the unit dosage is administered; 10. The stable pharmaceutical formulation of claim 1 in a unit dosage format, wherein the unit dosage is in a container suitable for enteral administration of the contrast agent to the subject concurrently with acquisition of a CT image of the subject.

3. 3. The unit dosage format of claim 2, wherein said unit dosage of said formulation is from about 800 mL to about 1500 mL of said formulation.

4. 2. The stable pharmaceutical formulation of claim 1, wherein the suspending agent is selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, alginate, and sodium carboxymethylcellulose.

5. 2. The stable pharmaceutical formulation of claim 1, wherein the suspending agent is xanthan gum and is present in the formulation in an amount up to about 10% (w / w) of the formulation.

6. 6. The stable pharmaceutical formulation of claim 5, wherein the suspending agent is xanthan gum and is present in the stable pharmaceutical formulation in an amount of 0.2% to 0.5%.

7. 10. The stable pharmaceutical formulation of claim 1, wherein the hollow particles have an internal void that is at least about 75% of the total volume of the particle.

8. 10. The stable pharmaceutical formulation of claim 1, wherein the hollow particles have a specific gravity of about 0.4 g / cc to about 1.4 g / cc.

9. 10. The stable pharmaceutical formulation of claim 1, further comprising a second CT imaging contrast agent different from the first enteric CT imaging contrast agent.

10. 10. The stable pharmaceutical formulation of claim 9, wherein the second CT imaging contrast agent is selected from barium, tungsten, tantalum, ytterbium, gold, bismuth, iodinated contrast agents, and combinations thereof.

11. 10. The stable pharmaceutical formulation of claim 1, further comprising one or more additives that retard dehydration in the intestine, provide flavor, and combinations thereof.

12. The stable pharmaceutical formulation of claim 1, which is distributed in the intestine of a subject after enteral administration to the subject.

13. 4. The stable pharmaceutical formulation of claim 3, wherein the unit dosage is distributed in the intestine of the subject after enteral administration to the subject.

14. 13. The stable pharmaceutical formulation of claim 12, wherein the subject is located within a CT scanner.

15. 10. The stable pharmaceutical formulation of claim 1, wherein the stable pharmaceutical formulation is packaged in a kit having instructions for using the stable pharmaceutical formulation of the first enteric CT imaging contrast agent.

16. 2. The stable pharmaceutical formulation of claim 1, wherein the first enteric CT imaging contrast agent is the only contrast agent within the stable pharmaceutical formulation.

17. CT images obtained through a region of the subject selected from the abdomen, the pelvis, and combinations thereof; The image is a CT image showing contrast within the intestinal lumen from a first contrast medium comprising a plurality of hollow microparticles comprising an inorganic glass shell encapsulating a partial vacuum or gas within an internal void.

18. 18. The CT image of claim 17, wherein the CT image is acquired using dual-energy CT, multi-energy CT, or spectral CT.

19. 19. The CT image of claim 18, wherein the image is a virtual monochromatic energy image.

20. 18. The CT image of claim 17, wherein the 80:140 kVp CT number of the first contrast agent in the image is greater than about 2.1 and less than about 0.

6.

21. 18. The CT image of claim 17, wherein the inorganic glass shell contributes at least about 30 Hounsfield Units (HU) to the CT number of the first contrast agent or to the CT number of a body cavity into which the first contrast agent is distributed during acquisition of the image.

22. 20. The CT image of claim 17, further showing contrast from a second contrast agent different from the first contrast agent.

23. 18. The CT image of claim 17, wherein the first contrast agent and the second contrast agent are distinguishable from each other in the image.

24. 18. The CT image of claim 17, wherein the contrast from the first contrast agent is selected from negative contrast, neutral contrast, and positive contrast.

25. 18. The CT image of claim 17, wherein the image is formed using post-processing to convert negative contrast from the first contrast agent to neutral or positive contrast.

26. 1. A stable aqueous pharmaceutical suspension of a single enteric CT imaging contrast agent in a single dosage form for administration to a subject concurrently with a CT imaging procedure being performed on a region of the subject, wherein at least a portion of the single dosage of the CT imaging contrast agent is distributed in the region of the subject; the single-dosage administration form comprising a container containing a sufficient amount of the single enteric CT imaging contrast agent to provide detectable contrast enhancement in a CT image of the subject obtained during the CT imaging procedure for the region of the subject in which at least a portion of the single dose of the CT imaging contrast agent is distributed; The pharmaceutical suspension comprises: at least about 20% (w / w) of said single enteric CT imaging contrast agent, said single CT imaging contrast agent comprising a plurality of hollow microparticles comprising an inorganic glass shell encapsulating a partial vacuum or gas within an internal void; a sterile, pharmaceutically acceptable suspension medium comprising a suspending agent that stabilizes the suspension of the single enteric CT imaging contrast agent, the suspension medium being compatible with enteral administration of the single dosage form to the subject concurrently with the CT imaging procedure; The single-dose administration form is a stable aqueous pharmaceutical suspension characterized in that it has an intestinal transit time through the small intestine of less than 12 hours when administered intestinally to the subject.

Images