Encapsulated gas or partially 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 of U.S. Provisional Application No. 62 / 149,815, filed on April 20, 2015, under 35 U.S.C. 119(e), the entire contents of which are hereby incorporated herein by reference for all purposes.

[0002]

[0002] Federally Sponsored Research and Development This invention was made with government support under Grant Nos. EB013816 and TR000004 awarded by the National Institutes of Health. The United States Government has certain rights in this invention.

Background Art

[0003]

[0003] The use of contrast materials for medical CT imaging is essential for many clinical scenarios, particularly in the abdomen and pelvis, where numerous internal organs and blood vessels exhibit highly complex anatomy. Enteral contrast agents can be administered into the intestine orally or via a tube to distend the intestine and improve its visualization.

[0004]

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

[0005]

[0005] All commercial positive CT contrast materials are based on iodine or barium. Since other atoms in these agents are similar to those in the soft tissues of the body and water, the difference in X-ray attenuation between the positive agent and the soft tissues of the body is largely or entirely due to the iodine or barium.

[0006]

[0006] There is no disagreement that positive intestinal CT contrast agents, which mark the intestinal lumen with a bright signal in CT imaging, are of great value for detecting extraintestinal fluid accumulation and masses (which may resemble the intestine that does not show up on CT in a wide range of diseases).

[0007]

[0007] Despite the value of positive intestinal contrast agents, bright intestinal contrast material paradoxically obscures CT findings of intravenous contrast agents for some of the most destructive diseases, which include: 1) trauma (the leakage of contrast material may be ambiguous as to whether it originates from vascular bleeding or intestinal lumen); 2) intestinal ischemia and infarction (the unenhanced intestinal wall may be obscured by bright intraluminal intestinal contrast material); 3) intestinal inflammation (hyperenhancement of the intestinal wall by IV contrast agent is the most reliable feature of active disease); 4) intestinal bleeding (extraluminal spillage of iodized contrast agent into the intestine or enhanced tumor is masked by the presence of the intestinal contrast agent); and 5) reconstruction of three-dimensional images of blood vessels.

[0008]

[0008] Another problem with currently available positive clinical contrast materials is that they cannot be distinguished from each other or from other radiopaque structures (such as metal fragments, calcifications, surgical staple lines, or implants when CT imaging). Even with dual-energy CT (DECT), multi-energy CT, or spectral CT (a clinical technique that is now becoming increasingly widespread, allowing for material discrimination of imaged voxels based on the known 80:140 kVp CT ratio of individual materials), iodine and barium-based contrast materials are not easily distinguishable from each other because their 80:140 kVp CT ratios are substantially the same. This limitation leads to clinical errors and delays. For example, CT scans enhanced with positive barium and intravenous iodine contrast agents, indicating leakage of contrast agent into the peritoneum, can be ambiguous as to whether the leakage is due to bleeding (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, it may be necessary to repeat the scan at the expense of time and treatment opportunities. Repeating CT scans also results in additional radiation dose. Growing public concern regarding CT radiation dose led to the 2011 NIH Summit, which focused on reducing CT doses. While CT scanners capable of multi-energy or spectral imaging are under development, even with improved capabilities, these new CT technologies may not be able to easily distinguish between barium-based and iodized contrast materials.

[0009]

[0009] Further limitations on current positive intestinal CT contrast materials are toxicity and complications. Barium-based agents can cause severe, potentially fatal peritonitis or exacerbate infection at the site of leakage, potentially converting partial intestinal obstruction into complete intestinal obstruction. Iodized agents can cause severe, even fatal, pneumonia if inadvertently inhaled, and can also trigger life-threatening allergic reactions, for which their use is limited to up to 1% of patients with a known prior reaction. This is likely partly related to the hyperosmolarity of these agents. In addition, some of these agents are brown and have a bad taste. A small number of patients (up to 1-3%) have a reaction to iodized contrast materials.

[0010]

[0010] "Neutral" intestinal CT contrast materials are beneficial for CT imaging. Examples of neutral intestinal contrast materials are water, milk, or liquids containing non-absorbable carbohydrates (such as sorbitol or methylcellulose) with or without small amounts of iodine or barium (e.g., VoLumen®). Neutral intestinal CT contrast agents are commonly used to distend the intestinal lumen, allowing intravenous contrast materials to clearly show relative vascularization over- or under-vascularization of the intestinal wall, which would be obscured with positive intestinal contrast materials. Because the signal from neutral agents is similar to the signal from natural soft tissue or water, they may not be as reliable in diagnosing intestinal leakage, extraluminal fluid accumulation, intra-abdominal abscesses, or hematomas as positive intestinal contrast agents.

[0011]

[0011] "Negative" bowel contrast agents are not commonly used but have CT values ​​of less than -20 HU. Examples of these low-radiation-attenuating contrast materials include 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 bowel contrast agents can provide excellent visualization of the intestinal wall and intestinal wall enhancement when administered with intravenous contrast agents. The most commonly used negative bowel agents are carbon dioxide for gastric or colonic dilation. However, the small intestinal use of available negative agents is not well tolerated. Negative bowel contrast materials may resemble naturally occurring fats in CT, but disease detection in CT does not depend much on identifying abnormal amounts of fat in the intestines. Gaseous bowel contrast agents (the gas is insufflated into the intestinal lumen or produced in the intestinal lumen) may not be as useful as positive bowel contrast materials for visualizing bowel leakage. Even with dual-energy CT, the signals from available negative contrast agents cannot be distinguished from signals of naturally occurring fat or abnormal gas accumulations. A practical, non-expanding, non-oil-based negative contrast agent that can be delivered in liquid form is not currently available.

[0012]

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

[0013]

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

[0014]

[0014] Modern dual-energy CT images and spectral CT images can be reconstructed as virtual monochromatic energy images (images that simulate what a CT scan image would look like if it were obtained with monochromatic energy X-rays of any given X-ray energy (such as an energy selected from 40 to 140 keV)). In these virtual monochromatic energy images, iodized contrast materials and barium contrast materials appear highly positive at low keV settings (40 to 70 keV) and gradually decrease in signal at high keV settings (140 keV), so that the signals of iodized contrast materials and barium contrast materials decrease to the signals of water or soft tissue (approximately -20 to 50 HU). In other words, barium and iodine can act as positive contrast agents at low keV and neutral contrast agents at high keV. However, signals from iodized and barium-based contrast agents remain indistinguishable from each other, even with dual-energy CT or virtual monochromatic energy imaging. This greatly undermines the advantage of being able to convert positive CT signals from contrast materials into neutral CT signals. Similarly, the signals from available neutral agents resemble those of water, and the signals from available negative contrast agents resemble those of fat or gas in dual-energy CT, making meaningful conversion to other color signals impossible with dual-energy CT or spectral CT.

[0015]

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

[0016]

[0016] There are several clinical scenarios in general in which CT diagnosis would be improved through the use of a single type (positive, neutral, or negative) of intestinal contrast medium, which can also be transformed 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 intestinal ischemia, neutral or negative intestinal contrast agents would be useful in finding either hyper-enhancing or hypo-enhancing of the intestinal wall to detect inflammation or ischemia, respectively. In this same scenario, a positive contrast agent would allow for the identification of intestinal perforation, abscesses, and fistulas. Since commercial intestinal agents can never be both positive and negative, imaging physicians must choose one or the other agent, and are aware that with any available CT protocol, some findings may be revealed while other important findings may be obscured, and therefore the CT scan is a suboptimal option.

[0017]

[0017] The development of safe, clinically usable, and identifiable contrast materials for iodized and barium-based contrast agents or other contrast agents under development (such as those based on heavy metals like tungsten, ytterbium, or tantalum) will transform CT imaging for millions of patients with a wide range of diseases. Different "color" contrast agents can be injected into multiple body compartments and queryed simultaneously, enabling single-CT, DECT, or multi-energy CT scans to provide timely, high-resolution, and perfectly aligned anatomical images for rapid and confident diagnosis. This capability will change our ability to urgently and accurately assess multi-organ failure from trauma, invasive tumors, surgical complications, and inflammatory diseases. The applicant's prior patents demonstrate that low atomic number (Z<30) contrast agents or silicon-based polymer agents can provide a positive CT signal that can be identified with iodine-based and barium-based contrast agents in DECT.

[0018]

[0018] The development of safe clinical bowel CT contrast materials that can be digitally manipulated to appear as negative, neutral, or positive contrast materials under the control of the interpreting physician will provide powerful diagnostic capabilities and eliminate not only diagnostic errors but also guesswork and protocol errors. The reduction in errors will lead to faster diagnoses and a reduced need for additional follow-up examinations. Physicians will no longer need to weigh the merits and demerits of administering neutral or negative vs. positive bowel contrast materials for a given clinical scenario.

[0019]

[0019] Non-iodized positive contrast materials tested for use with CT imaging include a wide range of high atomic number (Z) elements: in particular tungsten, tantalum, ytterbium, bismuth, lanthanide elements (such as gadolinium), and gold [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, and practical DECT scanners have only been available for eight years.

[0021]

[0021] In clinical CT imaging, the CT count for water is defined as 0 HU, while the CT count for room air / vacuum is defined as -1000 HU, regardless of the kVp setting. The CT count for non-fatty soft tissue is generally in the range of 10 to 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-phase or liquid-phase materials with an effective Z greater than 8. These materials include the positive contrast materials described above.

[0024]

[0024] Dual-energy CT can provide an image similar to a CT scan obtained with only intravascular contrast material by digitally subtracting a positive intestinal contrast material having a substantially different CT number ratio of 80:140kVp from the CT image. However, this signal separation can introduce some image artifacts and noise that may cause diagnostic ambiguity or confusion. It is currently very difficult to highlight neutral or negative intestinal contrast materials in conventional CT because the signals of such agents are not reliably distinguishable from the signals of water, liquid, fat, or gas that may be present in normal or diseased tissue, respectively. [Overview of the Initiative]

[0025]

[0025] The present invention solves these and other problems by providing safe and effective encapsulated gas or partial vacuum particles as a contrast material suitable for human use when imaging CT, including dual-energy CT and spectral CT. In exemplary embodiments, the contrast material contains particles that are encapsulated gas or vacuum, the shell consists mainly of silicon dioxide, silicon-containing rubber, ceramic, or other inert insoluble material, and the formulation consists of encapsulated gas or vacuum particles suspended in a water or oil medium. In various embodiments, additives are added to the shell, coat the shell, are contained in the lumen of the shell, or are 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 advantages of negative, neutral, and positive bowel contrast agents in CT without any shortcomings in judgment regarding these types of bowel contrast media. In various embodiments, the present invention may appear as a negative contrast material in conventional CT, but the signal of the contrast material can be converted to an even stronger negative, neutral, or positive signal in dual-energy CT or spectral CT imaging. Alternatively, in various embodiments, the present invention may appear as a positive contrast material in conventional CT, but the signal of the contrast material 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 signal of the contrast material can be converted to a negative or positive signal in DECT or spectral CT imaging. Advantages of a positive intestinal contrast signal include excellent identification of intestinal leakage, detection of extraluminal accumulation (e.g., abscesses), detection of intra-abdominal and intrapelvic tumors and masses, evaluation of intestinal transit time, evaluation of intestinal obstruction metastasis sites, and excellent evaluation of intestinal wall thickening. Failures of positive intestinal contrast agents include obscuration of crucial findings regarding intestinal wall ischemia or intestinal inflammation when intravascular contrast material is simultaneously administered, obscuration of abdominal and pelvic vessels, obstruction of 3D reconstruction of CT angiography, ambiguity of the origin of spilled contrast material, and obscuration of active intraluminal gastrointestinal bleeding.Advantages of negative or neutral intestinal contrast agents include excellent evaluation of over-enhancement or under-enhancement of the intestinal wall; excellent evaluation for enhancing intraluminal masses; no interference with three-dimensional reconstruction of CT angiography; and lower radiation dose when CT scans are obtained by automatic exposure control due to lower X-ray attenuation of the negative agent on CT scout images. Deficiencies of neutral or negative intestinal contrast agents include reduced ability to detect intestinal leakage or extra-luminal fluid accumulation, abscesses, injury to fat, or hematomas.

[0026]

[0026] In CT imaging, the materials of the present invention may provide CT numbers lower or higher than the range produced by water and non-adipose soft tissue (range, -20 to 60 Hounsfield Units or HU). The combination of low X-ray attenuation material and high X-ray attenuation material in substantial proportions makes it possible to modify the X-ray attenuation of the new material such that 1) the new X-ray attenuation is significantly different from the attenuation of other bodily or medically relevant materials in CT images, and 2) the new X-ray attenuation at 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 -1000 HU, while silicon dioxide produces a high CT signal of approximately 550 HU at a 50% w / w suspension in water. The gas and vacuum within the gas and vacuum particles encapsulated with silicon dioxide allow the extremely negative CT numbers of gas and vacuum to drastically reduce the overall CT number produced by the entire particle across all CT kVp settings. This reduction in CT number can be used to substantially modify the ratio of the low kVp CT number to the high kVp CT number of a material to a level that is significantly different from the ratio of the CT numbers of iodine contrast materials, barium contrast materials, or other materials naturally present in the human body. For example, the 80:140 kVp CT number ratio of silicon dioxide, gas and vacuum (which are 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 example, the 80:140 kVp ratio of the iodine contrast material or the barium contrast material can be varied to be higher than 2.4 when the encapsulated gas and vacuum particles are mixed with the iodine material or the barium material in a suspension medium. In another example, the 80:140 kVp number ratio of the iodine contrast material or the barium contrast material can be reduced to less than 0.6 when the 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 glass) include inertness, low solubility, stability, high strength, and a 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 temperatures.

[0029]

[0029] Enteral agents for CT are generally safer than injectable ones for several reasons: 1) Enteral agents require substantially lower doses and concentrations of material than intravascular agents. A typical intravenous administration of iodized agents requires up to 150 mL of 350 mg iodine / mL contrast agent (a dose of 52 grams) for an abdominal CT scan. A typical oral dose is only 800 mL of 10 mg iodine / mL contrast agent (a total iodine dose of 8 grams); 2) The contrast material is hardly absorbed into the bloodstream through the intestinal wall; 3) Viscosity and osmotic pressure are of minimal concern for enteral contrast materials; 4) Nephrotoxicity seen with all intravascular agents is unlikely with enteral agents; 5) Anaphylactic-like reactions and immune responses are probably far less likely to occur with enteral administration than with intravascular administration.

[0030]

[0030] Notably, in addition to the safety and effectiveness of the intestinal preparation for CT imaging, other aspects, including physical uniformity, storage stability, flowability (and therefore potentially high but acceptable viscosity), and even oral taste, are considered in order to optimize the final intestinal contrast preparation to meet practical clinical applications.

[0031]

[0031] Furthermore, the encapsulated gaseous or partially vacuum particle intestinal contrast agents of the present invention offer the advantage of enabling the simultaneous administration of intestinal agents and separated intravascular agents or other body compartment agents, which can be easily identified by DECT or multi-energy CT. Since the agents are imaged when they are simultaneously present in the body, in one embodiment, an essentially perfect alignment of the image of the contrast-enhanced region is provided when a signal is extracted from each agent. The well-aligned resulting image provides better information for diagnostic evaluation than if the contrast material were each delivered, imaged, and separated CT scans were performed independently. Furthermore, in exemplary embodiments, the radiation dose is less than half of that irradiated by two separate scans (each with a different contrast agent). In various embodiments, the media and formulations of the present invention facilitate repeated CT scanning and reduce the ambiguity caused by oral contrast agents based on different materials previously delivered. In various embodiments, multiple intestinal agents (including encapsulated gaseous or partially vacuum particle and other intestinal agents) are simultaneously present at the time of CT imaging.

[0032]

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

[0033]

[0033] In exemplary embodiments, when the intestinal contents are not very radiopaque (e.g., neutral or negative CT number), less CT tube current is required to generate an X-ray beam sufficient to achieve diagnostic level image noise, thus reducing the CT radiation dose compared to the use of currently available positive intestinal contrast materials. For example, automated 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 exemplary embodiments, the present invention provides a drug that can be sufficiently separated from iodized contrast agents or barium contrast agents and from both soft tissue or water in dual-energy CT than other previously described contrast materials, due to a very high 80:140kVp CT number ratio exceeding 2.4 of various embodiments of the present invention, or a very low 80:140kVp CT number ratio (e.g., less than 0.5).

[0035]

[0035] In exemplary embodiments, the present invention provides encapsulated gas or partial vacuum particles in an aqueous suspension, which are intestinal contrast medium formulations. The exemplary formulations comprise an intestinal contrast medium containing gas or vacuum encapsulated within a shell material to form small particles. The material is formulated in a pharmaceutically acceptable aqueous or oil-based vehicle in which the particles are suspended. In exemplary embodiments, the shell material of the particles of the present invention contains silicon, and this material is a silicon-based polymer. In exemplary embodiments, the shell material contains silicon, and this material is in the form of glass (e.g., borosilicate). In exemplary embodiments, the shell material is a polymer plastic, rubber, wax, ceramic, or resin. In exemplary embodiments, the shell material contains or is coated with additional high atomic number materials with z between 40 and 84. In exemplary embodiments, the vehicle contains a material that exhibits high X-ray attenuation (e.g., a material containing barium or iodine), thereby modifying the resulting contrast agent's CT count and low-CT count to high-CT count ratio.

[0036]

[0036] In exemplary embodiments, the present invention provides contrast media formulations that can be delivered to the digestive system and to other bodily cavities, which may be natural (e.g., vagina or bladder) or surgically generated (e.g., neobladder), or to artificial medical devices (e.g., tubes, catheters, pouches, reservoirs, or pumps).

[0037]

[0037] Additional exemplary advantages, purposes, and embodiments of the present invention are shown below.

[0038]

[0038] The intestinal contrast agent of the present invention is substantially different from microbubble contrast agents used in ultrasound imaging. Microbubbles in ultrasound are typically gaseous microbubbles of perfluorocarbon gas or nitrogen gas, and are surface-coated with materials such as albumin, carbohydrates, lipids, or biocompatible polymers, which 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 typically in the range of 2 to 6 microns, and a common concentration level is about 10 million microbubbles per mL. Thus, it can be calculated that less than 1% of the volume of a microbubble type ultrasound contrast agent is filled with gas or is hollow, and such a small volume fraction of gas or void space does not produce a sufficiently large signal useful when imaging with CT or X-ray. Two recent reviews are presented here. 1) Ultrasound microbubble contrast agents: Fundamentals and application to gene and drug delivery. By Ferrara, Katherine; Pollard, Rachel; and 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 the prior perfluorocarbon oral contrast materials proposed for CT, MR, and X-ray imaging. These prior agents contain liquid perfluorocarbons, which may or may not be emulsified; the perfluorocarbons may or may not be bromised. In these prior agents, the perfluorocarbons expand into a gas at body temperature, which can produce a negative contrast signal and further intestinal distension. Disadvantages of perfluorocarbon agents include the possibility of difficulty in administration, and their swellability raises safety concerns when administered to diseased intestinal segments (U.S. Patent No. 5,205,290; No. 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). Perfluorocarbon bromides are described as CT contrast agents and can produce a positive CT signal.

[0040]

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

[0041] [Figure 1]

[0041] This is a computer simulation of the 80:140kVp CT number ratio for individual atoms with atomic numbers (Z, bottom) in the range of 1 to 100 (grayscale from black to white, top, in boxes outlined in black). This simulation is 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. This simulation accurately predicts that conventional iodine-based and barium-based CT contrast agents (I and Ba, respectively) have a high 80:140kVp CT number ratio of approximately 1.7, calcium-based materials (such as bone) have an intermediate 80:140kVp CT number ratio slightly above 1.4, and silica (SiO2) has an intermediate 80:140kVp CT number ratio of approximately 1.27. However, it is clear that this atom-based model did not predict that the material would have a very high CT number ratio of 80:140kVp above 1.8 or less than 0.9 or a negative number (top, grayscale gradient, outside the box outlined in black). The applicant's prior knowledge (WO2015 / 024025A1) that silicon-based polymers (especially polydimethylsiloxane (PDMS)) have such a high CT number ratio of 80:140kVp (2.6–2.8) was also not initially anticipated by itself. Similarly, the applicant's knowledge that encapsulated gas or partially vacuum particles could provide a wide range of CT number ratios of 80:140kVp below 0.8 (including negative or well above 2.0, which is beyond the range predicted by the initial computer simulations) was also not anticipated. [Figure 2]

[0042] Transverse (left image) and coronal (right image) CT images show motion artifacts around gas-filled intestines (black intra-abdominal structures), rather than around fluid-filled intestines (small arrows). Intra-intestinal gas is highly negative in CT numbers (-950 to -1005 HU) and can cause artifacts that may be bright signals (large arrows) and dark signals (arrowheads) around the intestines. [Figure 3]

[0043] Modification of CT numbers of borosilicate-encapsulated gaseous and partially vacuum microsphere suspensions by addition of heavy metals. A) Addition of heavy metals to aqueous suspensions: The CT numbers of aqueous suspensions of borosilicate-encapsulated gaseous and partially vacuum microsphere particles (specific gravity 0.6 g / mL) are shown with or without the addition of a high-X-ray attenuation material (0.1% iodine in an aqueous medium). The combination of the two materials results in a novel contrast agent with a much higher CT number at lower virtual monochromatic energy keV and a steeper gradient of signal loss from low to high keV. This novel contrast agent provides a strongly negative CT signal when the virtual monochromatic energy keV is above 75 and a strongly positive CT signal when the virtual monochromatic energy keV is below 55. Borosilicate microsphere suspensions alone do not provide as high a signal as the formulation of iodine and borosilicate microspheres combined. The addition of large amounts of iodine or barium to the formulation allows for an upward adjustment of the CT number signal at lower monochromatic energy keV levels (not shown). B) Addition of heavy metals into particles. The CT numbers of two 20% wt / wt aqueous suspensions (specific gravity 0.50 g / mL) of gaseous and partially vacuum microsphere particles encapsulated with different borosilicates are shown (one with 0.5% barium incorporated into the shell material, the other without). Again, the addition of barium preferentially causes an increase in the measurement of the CT number in the CT imaging 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 keVs 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 80kVp (left image) and 140kVp (right image). 1 = 18 micron hollow silica microspheres of iM30K, 30% w / w with 15 mg I / mL iohexol in water; 2 = Pepto-bismol® bismuth salicylate; 3 = iodine in water (15 mg I / mL iohexol); 4 = 18 micron hollow silica microspheres of iM30K in 40% w / w water; 5 = 30% w / w iM30K with 1% w / w barium and water with sorbitol; 6 = 2% BaSO4 (Readi-Cat2®) (containing sorbitol in water); 7 = 30 micron silica microspheres of S60HD in 40% w / w water; 8 = 2% barium sulfate in water. Partially suspended hollow silica microspheres (#4 and 7) are not as radiopaque as water at 80 and 140 kVp, and even show a lower signal at 140 kVp than at 80 kVp. Layering of water (which has a physically higher specific gravity than hollow silica microspheres) is observed at the bottom of both of these vials. A small amount of high-X-ray attenuation material (presenting non-hollow borosilica) is present at the bottom of the S60HD vial. In vial #1, iohexol is uniformly dissolved in water and layers at the bottom of the vial. Iodine-enhanced and barium-enhanced materials (#3, 6, and 8) show a signal that decreases from 80 to 140 kVp, respectively. Tubes with hollow silica microspheres mixed with iodine (1) and barium (5) show a very substantial relative decrease in CT signal from 80 to 140 kVp. The ratio of CT numbers at 80:140 kVp for iodine silica microsphere mixtures was 2.8, while for barium silica microspheres it was 4.1. Bismuth materials (Pepto-bismol®) show relatively little change in CT numbers between 80 and 140 kVp. [Figure 5]

[0045] Dual-energy CT scans of different materials, reconstructed at virtual monochromatic energies of 40 keV (left image) and 140 keV (right image). 1 = 18 micron hollow silica microspheres of iM30K, 30% w / w with 15 mg I / mL iohexol in water; 2 = Pepto-bismol® bismuth salicylate; 3 = iodine in water (15 mg I / mL iohexol); 4 = 18 micron hollow silica microspheres of iM30K in water at 40% w / w; 5 = 30% w / w iM30K with 1% w / w barium and water with sorbitol; 6 = 2% BaSO4 (Readi-Cat2®) (containing sorbitol in water); 7 = 30 micron silica microspheres of S60HD in water at 40% w / w; 8 = 2% barium sulfate in water. Partially suspended hollow silica microspheres (#4 and 7) show signal loss from 40 keV and become very low signal at 140 keV. Layering of water (heavier than silica microspheres) is observed at the bottom of these tubes. In vial #1, iohexol is uniformly dissolved in water and layers at the bottom of the vial. Iodine-enhanced and barium-enhanced materials (#3, 6, and 8) show signals that decrease from 40 keV to 140 keV, respectively, so 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 decrease in CT signal on 140 keV images, so that the CT number is less than -100 HU on 140 keV image reconstruction. Bismuth material (Pepto-bismol®) shows relatively little 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 = 30% w / w borosilicate hollow microspheres 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 shows little change in CT number 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 signals at low keV and negative signals at high keV reconstructions. When 1% iodine or 1% barium is added to a mixture of borosilicate hollow microspheres, the CT number substantially increases at low keV. [Figure 7]

[0047] The CT count values ​​correspond to the contrast material images in Figure 6. [Figure 8]

[0048] A 3.8 kg rabbit was imaged by dual-energy CT with 30% wt / wt borosilicate hollow microspheres in 300 mL of intestinal tract and intravenous iodized contrast agent. Intestinal wall-enhanced images (e.g., rabbit cecum (arrowhead)) are well observed at 140 kVp (left image) and show intravenous iodized contrast agent, but small hematomas (thin arrows) and free fluid (large arrows) are not well observed. Two-substance discrimination with a threshold of -50 HU was performed to extract the signal from the intestinal contrast agent, and then the signal was inverted and doubled to produce the positive signal seen in the oral contrast agent image (center image). Note that this image does not show signals from soft tissue, fat, and iodized contrast agent. The signal from the oral contrast agent was then added to the 140 kVp image to generate a composite image. Here, hematomas (thin arrows, right image) and free fluid (large arrows) are more clearly presented. As in any image with a positive intestinal contrast agent, enhancement of the intestinal wall by intravenous contrast material becomes obscured in intestinal segments containing the signal from the positive contrast material. If only conventional iodized agents and barium agents are used, separation of signals from the intestinal contrast agent and intravenous contrast agent cannot be achieved in this example. [Figure 9]

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

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

[0051] Examples of mixing high X-ray attenuation materials with a gas or partial vacuum to produce materials with a CT number ratio of 80:140 kVp far exceeding the range of 1.0 to 1.8. When a substantial amount of gas is combined with the high X-ray attenuation material, the CT number of the material and the CT number ratio of 80:140 kVp can be substantially varied. [Figure 12]

[0052] A table of CT counts (e.g., low X-ray attenuation materials (gas / vacuum), high X-ray attenuation materials, and gaseous or partially vacuum particles encapsulated by high X-ray attenuation material shells) in the reconstruction of dual-energy CT or spectral CT images of virtual monochromatic energy. By definition, the CT count for pure water is set to 0HU in the reconstruction of all virtual monochromatic energy images. [Figure 13]

[0053] Table of the number of CTs for high X-ray attenuation materials in examples, encapsulated gas or partial vacuum particle formulations, and further additional CTs for other high X-ray attenuation materials in formulations, under different kVp tube potential settings and dual-energy CT virtual monochromatic energy CT settings. Note: The number of CTs for gas / vacuum in these examples is approximately -1000 HU. [Figure 14]

[0054] Table of potential benefits of encapsulated gaseous or partially vacuum particle contrast materials compared to commercially available, previously described intestinal CT contrast agents. [Figure 15]

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

[0056] An exemplary hollow borosilicate glass microsphere (e.g., iM30K from 3M Inc.) is shown in this schematic diagram. This exemplary microsphere has a density of 0.60 g / cm³ and an average diameter of 18 microns. For 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 partially vacuumed, shown in gray). The shell material (black) has an average thickness of approximately 10% of the microsphere's radius, approximately 0.9 microns. Small defects of trapped gas and partial vacuum may be present in the shell material. In exemplary embodiments of the present invention, a suspension agent is used to maintain hollow microspheres in an aqueous formulation to produce a useful intestinal contrast material having 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 CT or spectral CT, with or without the presence of an additional high-Z contrast agent (iodine or barium material). The shell may or may not have small defects within it. The overall particle may have a major hollow space or may be subdivided by a diaphragm of shell material. [Figure 17]

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

[0058] Coronal dual-energy CT images of rats with intravenous iodized contrast material (black arrowhead) and an exemplary intestinal preparation of the present invention (white arrow). The intestinal preparation is 30% w / w encapsulated gaseous and partially 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-substance discrimination was performed using 40 keV and 140 keV virtual monochromatic images as source data to produce iodine contrast image, oral contrast image, and water image. The iodine image shows a positive signal from the iodine contrast with no signal from the intestinal drug. The oral contrast image shows a positive signal from the intestinal drug with no signal from the intravenous drug. The water image simulates an unenhanced CT scan without either drug. [Figure 19]

[0059] Dual-energy CT images of transverse bowel necrosis in a rabbit abdomen, imaged with intravenous iodized contrast material and an exemplary bowel preparation of the present invention. The anterior bowel was necrotized by percutaneous microwave ablation (ablation at 65 watts for 12 minutes using a 17g P15 antenna, Certus 140 generator, NeuWave, Madison, WI). The bowel contrast preparation is 30% w / w encapsulated gas and partially vacuum borosilicate microspheres (iM30K, 3M) suspended in 0.3% xanthan gum in water. The 140kVp image (left image) shows normal bowel wall enhancement with intravenous contrast material for the left and right abdominal bowels. The bowel lumen (star) is filled with negative contrast material measuring -60 HU, which is analogous to the signal of postperitoneal fat measuring -80 HU in this example. A decrease in bowel wall enhancement is observed in the anterior central abdomen (arrow), suggesting necrosis. The 40 keV virtual monochromatic energy image (right image) more clearly shows that the anterior central intestinal wall is not enhanced by the intravenous contrast agent. The absence of intestinal wall enhancement confirms intestinal wall necrosis in these intestinal segments. In contrast, the left and right abdominal intestines show normal bright enhancement of the intravenous contrast agent at 40 keV. The signal of the intestinal contrast material is 45 HU at 40 keV. In contrast, the postperitoneal fat is approximately -150 HU on this 40 keV image. In other words, even though the intestinal contrast material and postperitoneal fat have similar HU values ​​at 140 kVp, the two materials are shown to differ in the 40 keV image of dual-energy CT. Notably, even though the intestinal contrast material is negative, no substantial artifacts are seen around the intestine filled with this negative contrast material. However, bright artifacts are seen adjacent to the gas-filled segments of the intestine (thin arrows). The relative absence of gaseous imaging artifacts in the intestines is a benefit of the negative intestinal contrast agent of the present invention that outweighs the benefits of non-encapsulated gaseous negative intestinal contrast agents (see Figure 2). [Figure 20]

[0060] Improved sensitivity for abdominal diseases on CT and dual-energy CT with encapsulated gas and partially vacuum borosilicate microspheres as enteroscopic contrast materials compared with commercially available enteroscopic contrast agents. Three enteroscopic contrast agents were compared in a rabbit model of abdominal diseases imaged on intravenously iodine-enhanced CT, which are: 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 vacuum borosilicate microspheres ("Hollow", iM30K, 3M). The encapsulated gas and partially vacuum agents of the negative contrast agent were also post-processed on dual-energy CT ("Hollow DECT") to produce additional images with positive and neutral appearances of the enteroscopic contrast agent signal. Areas of intestinal ischemia or congestion were generated in rabbits by transplanting approximately 2 cm hematomas into the abdomen or by performing focused microwave ablation. Lesions were pathologically confirmed macroscopically and microscopically. Six radiologists examined each set of images on a DICOM viewer to detect abdominal lesions. Sensitivity for hematomas was nearly perfect when positive barium or negative hollow intestinal contrast agents were used (with or without DECT post-processing), but only 57% with neutral agents. Conversely, leader sensitivity for intestinal ischemia or congestion was only 26% and 17% for positive barium contrast agents, respectively, but 82% and 73% for neutral sorbitol contrast agents, and even higher for negative hollow intestinal contrast agents. The addition of DECT post-processing further improved sensitivity for detecting intestinal ischemia and congestion. The specificity of different intestinal contrast agents for each type of abdominal lesion was all above 94%. [Modes for carrying out the invention]

[0042] I. Introduction

[0061] A key issue with current bowel contrast agents for CT is that each type (positive, negative, and neutral) reliably identifies only the essential anatomical subsets required for various CT diagnoses. Positive bowel contrast materials can mark the bowel lumen with a bright signal, allowing for the differentiation of the intestine from fluid accumulation and diseased non-intestinal tissue, although this positive signal cannot be distinguished from the positive signal from intravenous contrast materials. Neutral bowel contrast materials, on CT, allow for visualization of the intestinal wall enhanced by positive intravenous contrast agents, but are similar to soft tissue and fluid. Negative bowel contrast agents, as described to date, are not approved by the FDA. While these negative bowel contrast agents adequately demonstrate all the anatomical and positive signals of intravenous contrast agents, they may cause undesirable side effects, be inconvenient to administer, and may cause artifacts on 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 achieved by using CT count thresholds. For example, CT counts >80 HU are unlikely to be produced by normal soft tissue, and CT counts <-20 HU are unlikely to be produced by normal soft tissue other than fat. Positive contrast material giving a CT count higher than 80 HU is readily identified as non-soft tissue material. Similarly, negative contrast material with a CT count less than -20 HU can be reliably identified as non-soft tissue material, with the exception that fat may give a similar CT count. Notably, fat is a pathological process in the intestinal lumen that is hardly considered.

[0044]

[0063] Alternatively, in dual-energy CT or spectral CT, materials can be identified based on their relative attenuation of low-energy X-rays versus high-energy X-rays. Dual-energy CT and spectral CT are increasingly common features in modern scanners. Current dual-energy techniques enable simultaneous imaging of a patient with X-rays of two or more different energy spectra, such as those provided by two or more different tube potentials (80 and 140 kVp, or 100 and 140 kVp, etc.). Dual-energy CT and spectral CT imaging can also be achieved using other methods (including sandwich detectors, split-beam X-rays filtered by different materials, or photon counts that quantify or classify the energy of X-rays observed by the detector). Materials in the body are identified based on the ratio of their CT numbers at lower tube potentials versus their CT numbers at higher tube potentials (e.g., the ratio of CT numbers at 80:140 kVp), which is related to the atomic number of atoms in the material and their physical density. Simulations of CT number ratios for clinical CT scanners show that iodine and barium represent a high 80:140kVp CT number ratio of approximately 1.7, measured by the Hunsfield unit (HU), which is close to the maximum value predicted for a given element on the periodic table for current clinical scanners. Materials with a wider range of different ratios are more clearly distinguishable by DECT, and thus iodine and barium can be fairly well distinguished from water or most soft tissues (which have an 80:140kVp CT number ratio of approximately 1.0). Signals from materials with intermediate 80:140kVp CT number ratios (1.25-1.45) can be somewhat distinguished from signals from iodized contrast materials or barium contrast materials, in addition to both water and most soft tissues, by using two-substance, three-substance, or multi-substance discrimination algorithms. Signals from materials with very high or very low CT number ratios of 80:140kVp (>2.1 or <0.6, respectively) are better separated from signals from soft tissue and iodized contrast materials.The intestinal contrast agent of the present invention may be adjusted to have a CT number ratio of 80:140 kVp, which is very high, very low, or in some cases negative.

[0045]

[0064] In single-energy spectral CT, the signal from certain positive intestinal contrast materials of the present invention may be difficult to distinguish from the signal from positive intravenous iodized contrast agents or other heavy atom contrast agents. However, in dual-energy CT or spectral CT, the CT number ratio of the positive intestinal contrast agent of the present invention at 80:140 kVp can be selected to be substantially different (e.g., >2.1 or less than 0.9) from the ratio of iodized contrast agents (1.7–1.8) or other heavy atom contrast agents (0.9–1.3), so that the signal from positive intestinal contrast materials of the present invention is easily distinguishable from iodized intravenous contrast materials.

[0046]

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

[0047]

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

[0048]

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

[0049]

[0068] Historically, positive contrast agents for CT have preferred the use of a single high-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 signal. The addition of gas or partial vacuum to the high-X-ray attenuating material to modify the signal of the 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 contrast agent formulation to improve its value as a contrast agent for CT and dual-energy CT or spectral CT.

[0050]

[0069] Historically, gaseous CT contrast agents did not utilize other elements to modify the gaseous signal in CT. Gas-filled microsphere contrast agents (including fluorocarbon contrast agents) did not utilize shell materials to substantially alter the CT number of the encapsulated gas, nor did they utilize shell materials to substantially alter the 80:140 kVp CT number ratio of the encapsulated gas. In various embodiments, the present invention utilizes other non-gas atoms and molecules to modify the signals produced by gas and vacuum in CT, thereby improving the value of contrast agents for CT and dual-energy CT or spectral CT.

[0051]

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

[0052] II. Definition

[0071] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. Generally, the nomenclature and laboratory procedures used herein in organic chemistry, pharmaceutical formulations, and medical imaging are well known and commonly used in the art.

[0053]

[0072] The articles “a” and “an” are used herein to refer to one or more (i.e., at least one) grammatical objects of the articles. For example, “an element” means one or more elements. Iodine, barium, or contrast agents with other atoms higher than 40 Z are exemplary “high-Z” materials.

[0054]

[0073] A "disease" is a state of animal health in which the animal is unable to maintain homeostasis, and subsequently, if the disease is not brought into remission, the animal's health continues to deteriorate.

[0055]

[0074] "Concurrent" administration refers to the use of a contrast agent in conjunction with a medical imaging procedure performed on a subject. As will be understood by those skilled in the art, concurrent administration of a contrast agent to a subject includes administration during or prior to the medical imaging procedure being performed so that the contrast agent is visible in the medical image of the subject.

[0056]

[0075] "Half-life" or "t 1 / 2The term "half-life," when used herein in the context of administering the intestinal contrast medium of the present invention to a patient, is defined as the time required for the intestinal concentration of the drug in the patient to be reduced by half. Depending on multiple clearance mechanisms, redistribution, and other mechanisms well known in the art, there may be two or more half-lives associated with the contrast medium. A further explanation of "half-life" can be found in Pharmaceutical Biotechnology (1997, DFA Crommelin and RD Sindelar, eds., Harwood Publishers, Amsterdam, pp. 101-120).

[0057]

[0076] When used herein, “intestinal contrast medium preparation” means, unless otherwise specified, a pharmaceutically acceptable liquid or paste preparation for administration to a subject, comprising at least one intestinal contrast medium with or without a pharmaceutically acceptable excipient suspending at least one medium, and is prepared by dissolving, emulsifying, or suspending an intestinal contrast medium, as described herein, in a pharmaceutically acceptable vehicle, for example, in the form of a powder, emulsion, or mash, prior to use for administration to a subject. Preferably, the suspension medium is water.

[0058]

[0077] When the term "residence time" is used herein in the context of administering a colonoscopy medium to a patient, it is defined as the average time that the colonoscopy 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 the detector records an X-ray beam 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 and can be produced by different X-ray sources set at different tube potentials, different X-ray sources filtered by different materials, or a given X-ray source that is switched between different tube potentials. Alternatively, the X-ray spectra can be separated after the X-rays have passed through the object being imaged and can be obtained using a multilayer detector array or a photon count detector, etc.

[0060]

[0079] As used herein, “pharmaceutically acceptable carrier” includes any material that, when combined with a conjugate, retains the activity of the conjugate 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, water, emulsions (oil / water emulsions, etc.), 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 stearate or calcium stearate, talc, vegetable fat or vegetable oil, gum, glycol, or other known excipients. Such carriers may also contain fragrances, textures, colorants, or other components. Compositions containing such carriers are formulated by well-known conventional methods.

[0061]

[0080] As used herein, “administer” means oral administration, administration as a suppository, topical contact, rectal administration, intravenous administration, intraperitoneal administration, intramuscular administration, intrafocal administration, intranasal or subcutaneous administration, intrathecal administration, or infusion into a surgically generated pouch or surgically implanted catheter or device, or implantation of a delayed-release device (e.g., a mini osmotic pump) into the subject.

[0062]

[0081] When used herein, the term “intestinal contrast medium” is understood to mean a dry component, a non-suspended component, or a mixture of components comprising at least one X-ray absorbing substance and optionally at least one pharmaceutically acceptable excipient (which itself may include other components such as flavoring agents, antioxidants, wetting agents, emulsifiers, etc.). A “dry suspension mixture” can then be dissolved or suspended in a suspension medium to form the intestinal contrast medium formulation of the present invention. When used herein, the terms “suspension medium” and “pharmaceutically acceptable excipient,” etc., refer to a medium in which the component(s) of the intestinal contrast medium are emulsified or suspended.

[0063]

[0082] When used herein, the terms “coating” and “coated” are understood to include biocompatible coatings in environments with acidic, neutral, or basic pH values.

[0064]

[0083] The terms “particle (singular)” and “particle (plural)” as used herein refer to any form of free-flowing material larger than about 1 nm (crystals, beads (smooth, round, or spherical particles), pellets, spheres, and granules, etc.). Particles may 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 a larger range across all endpoints; in various embodiments, 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 may contain gas or partial vacuum. Particles may 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 a suspension of a solid in a liquid (e.g., aqueous or oil). Exemplary suspending agents are selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and alginates, with sodium carboxymethylcellulose containing xanthan gum being preferred. The suspending agent can be used in any useful amount. Exemplary useful amounts range from about 0 to about 20% by weight of a powder formulation and from about 0 to about 10% by weight of an oral suspension.

[0066]

[0085] In the context of the present invention, “stable” means a suspension that does not significantly separate into its constituent parts as different phases or layers between the preparation of the suspension and its administration to a subject in imaging studies.

[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 external environment so that a minimum amount of gas or vacuum is released from the confined space during the expected residence time of its biological use. The encapsulated gas may be at a pressure lower than, equal to, or higher than the ambient atmospheric pressure or suspension vehicle pressure.

[0068]

[0087] As used herein, the term "high X-ray attenuation" refers to a material that produces a higher number of CTs in single-energy spectral CT imaging than water and non-fatty soft tissue.

[0069]

[0088] When used herein, the term "low X-ray attenuation" refers to a material that produces a lower number of CTs in single-energy spectral CT imaging than water and non-fatty soft tissue.

[0070]

[0089] When used herein, “unpleasant taste and / or bitter taste” means that the majority of human patients would determine that the intestinal contrast medium contained therein has an unpleasant taste and / or bitter taste and / or extremely bitter taste after ingestion.

[0071]

[0090] With reference to the ability of the shell material of particles in the contrast medium of the present invention to affect the CT number, the term “substantially” means the following: The exemplary shell material substantially contributes to the CT number of the contrast medium and / or cavities in the body where the contrast medium is present when the CT image is acquired. “Substantially” contributes to the CT number of the contrast medium and / or cavities in the body where the contrast medium is present when the CT image is acquired. In various embodiments, the shell material contributes to the CT number by at least about 50 HU, at least about 100 HU, at least about 150 HU, or at least about 200 HU. In exemplary embodiments, the shell material contributes to the CT number more than an equal amount of organic polymer at the same density would contribute under the same imaging conditions. In various embodiments, the shell material contributes to the CT number by at least about 10%, at least about 25%, at least about 50%, at least about 75%, or at least about 100% more HU units than an equal 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 machine's scanner tube potential (kVp) setting (typically in the range of 80–140 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 CT scanners that produce X-rays with energy spectra where the maximum energy X-rays are 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, which is proportional to a) the density of atoms, b) the distance the X-rays travel 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 for any given kVp setting for a given scanner, the ratio of X-ray attenuation at 80 kVp vs 140 kVp can be determined for any given material when measured by a Hunsfield unit (HU). Generally, iodine and barium have an 80:140 kVp CT number ratio of approximately 1.7–1.8. Since water is defined as having 0 HU for any given X-ray spectrum in CT, water has an 80:140 kVp CT number ratio of 1.0 by definition. Elements of the periodic table have 80:140 kVp CT number ratios ranging from approximately 0.9–1.8. Materials with a more widely dispersed 80:140 kVp CT number ratio are more easily distinguished in dual-energy CT or spectral CT. Other methods for obtaining dual-energy CT include selecting different tube potential settings (e.g., 70, 100, and 120 kVp), which yield results similar to dual-energy CT at 80 kVp and 140 kVp.Alternative methods for obtaining dual-energy CT or multi-energy CT include modifying the X-ray spectrum to obtain higher separation of energy spectra (e.g., by applying a tin or gold filter to one of the kVp setting tubes), or using other methods to quantify the absorption of X-rays at different energies (e.g., sandwich detectors, where the upper layer(s) of the X-ray detector and filter detect and block low-energy X-rays, thereby modifying the X-ray spectrum to which the lower layer(s) are exposed; photon count detectors, where detected X-rays are classified according to their energy). The use of these other methods is still limited in distinguishing iodized materials from barium-based materials, while materials with atoms of significantly different atomic numbers can be distinguished more effectively.

[0073]

[0092] A virtual monochromatic energy CT image is an image reconstruction obtained from dual-energy CT or spectral CT data, and the resulting X-ray absorption of individual voxels in 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 composed entirely of two materials (e.g., iodine and water), and to perform two-substance discrimination based on dual-energy CT or spectral CT data to determine the relative X-ray attenuation due to iodine and water for each voxel in the image. Then, the virtual monochromatic energy CT image can be inversely extrapolated to any monochromatic energy X-ray energy using reference X-ray attenuation coefficients corresponding to iodine and water (e.g., found at the National Institutes of Standards and Technology) to determine the CT number at the X-ray energy corresponding to each voxel in the image. In this manner, virtual monochromatic energy images can be obtained over a wide range of keV (e.g., 40 keV or 140 keV, or any energy between, above, or below these thresholds). Virtual monochromatic energy images can be filtered to reduce noise and improve image quality. Virtual monochromatic energy images can also be obtained by multi-material discrimination or photon counting.

[0074] III. Exemplary Embodiments A. Composition

[0093] In various embodiments, the present invention provides intestinal or non-angiogenic contrast agents that can be readily distinguished in CT imaging from body tissues and from available CT contrast materials that are on the market or have been described in the past. By using encapsulated gas or partially vacuum particles, contrast agents can be produced that have a relative CT number signal significantly different from body tissues or conventional iodized and barium CT contrast materials, with or without high X-ray attenuation materials (such as iodine or barium). 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 X-ray attenuation of the particles, thereby producing novel contrast material formulations with useful X-ray attenuation properties. As an example, such encapsulated gaseous or partially vacuum particle contrast materials can be easily distinguished in conventional CT from conventional iodized CT contrast materials and barium CT contrast materials, as well as from soft tissue and water. The use of dual-energy CT or spectral CT allows for further differentiation of these contrasts from commercial iodized and barium contrasts, as well as from fat, soft tissue, and water. For example, in high-energy virtual monochromatic CT images (e.g., 120 keV), the material may show a negative contrast signal, and in low-energy virtual monochromatic CT images (e.g., 40 keV), the material may show a neutral or positive contrast signal. The agents of the present invention enable the development of a new class of contrast materials with adjustable CT numbers and a low-kVp to high-kVp CT number ratio that can be separated from each other, as well as from existing contrasts and naturally occurring body tissues.

[0075]

[0094] In various embodiments, the particle shells of the contrast medium 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, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate (HEMA), lactic acid, glycolic acid, ε-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkyl acrylate, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl methacrylate, N-substituted acrylamide, N-substituted methacrylamide, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-aminostyrene, p-aminobenzylstyrene, sodium styrene sulfonate, sodium 2-sulfoxyethyl methacrylate, vinylpyridine, aminoethyl methacrylate, 2-methacryloyloxy-trimethylammonium chloride, and polyvinylidene. In various embodiments, the particle shells of the present invention are formed from materials other than polyfunctional crosslinked monomers (such as N,N'-methylenebisacrylamide, ethylene glycol dimethacrylate, 2,2'-(p-phenylenedioxy)diethyl dimethacrylate, divinylbenzene, triallylamine, and methylenebis-(4-phenyl-isocyanate) or combinations thereof). Exemplary particle shells of the present invention include materials other than polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethyl methacrylate, polysiloxane, polydimethylsiloxane, polylactic acid, polyε-caprolactone), epoxy resin, 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, such as: polyvinylidene-polyacrylonitrile, polyvinylidene-polyacrylonitrile-polymethyl methacrylate, and polystyrene-polyacrylonitrile. In exemplary embodiments, the particle shells of the contrast medium of the present invention are formed from materials other than the copolymer polyvinylidene-polyacrylonitrile.

[0076]

[0095] In various embodiments, the specific gravity of the particles is approximately 0.05 g / cm³. 3 Higher. In various embodiments, the specific density of particles in the contrast medium 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 / cm³. 3 In various embodiments, the specific gravity of the particles of the contrast medium of the present invention is at least the specific gravity of water.

[0077]

[0096] The exemplary particles of the present invention are at least partially vacuumed. In various embodiments, the internal space of the particles 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, as discussed herein, the internal space of the particle is at least partially filled with gas. If the interior of the particle is at least partially filled with a gas other than air, the gas is preferably not a hydrocarbon, fluorocarbon, or 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 “low-density” particles. Low density means that the particles in the medium of the present invention have an internal void volume of at least about 75% of the total volume of the particle. Low density also refers to particles having 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 medium of the present invention contain a void volume of 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 medium of the present invention have outstanding properties compared to other particulate contrast media. For example, since the particles generally have a higher specific gravity than the contents of the lumen of the gastrointestinal tract or other body cavities, the various particles of this contrast medium do not decrease the density of the contents of the lumen of the gastrointestinal tract or other body cavities. In various embodiments, the particles of the medium increase the density of the contents of the lumen of the intestinal tract or other body cavities.

[0081]

[0100] The exemplary contrast medium of the present invention does not reduce the CT count of the lumen of the gastrointestinal tract or other body cavities, or does not significantly reduce the CT count in CT images. The exemplary particles of the contrast medium do not reduce the CT count of the lumen to at least about -30 HU. The exemplary particles do not provide a reduction in HU between about -30 HU and about -150 HU and are sufficient to mark the interior of the intestine or other body cavities.

[0082]

[0101] An exemplary intestinal contrast medium of the present invention substantially reduces the CT count to less than 100 HU per 10% volume of the intestinal contrast medium formulation by the volume of the aqueous suspension, and as a result, to achieve a CT count of -100 HU, at least 12.5% ​​or more of the total volume of the formulation must be the intestinal contrast medium, and to achieve a CT count of -200 HU, at least 25% or more of the total volume of the formulation must be the intestinal contrast medium. In other embodiments of the present invention, the intestinal contrast medium of the present invention can also increase the CT count of the intestinal contrast medium formulation.

[0083]

[0102] The contrast agent of the present invention can provide an improved CT application with one or more of the following benefits: 1) Intestinal lumen or non-vascular structures stained by the contrast material of the present invention can be more easily distinguished from soft tissue than those stained by currently available CT contrast materials. 2) The intestine or non-vascular structures are stained by the contrast material of the present invention and can be distinguished from vascular structures or soft tissues stained by CT contrast materials currently available in CT imaging; 3) Intestinal or non-vascular structures can be enhanced with the contrast agent of the present invention for CT imaging based on the CT signal in single-energy spectral CT, or by the relative low-energy X-ray attenuation to high-energy X-ray attenuation ratio in dual-energy CT or spectral CT, without interfering with the assessment of contrast-material-relevant wall enhancement of structures (including intestinal walls, bladder walls, and other walls, including associated diseases such as inflammation or neoplasms).

[0084]

[0103] In various embodiments, the present invention provides intestinal contrast agents based on encapsulated gas or partially vacuum particles. In various embodiments, the contrast agent can be selected to give a negative, neutral, or positive signal on 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 (e.g., a CT number ratio of 80:140 kVp greater than about 2.1, and may be even 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 other different atoms incorporated into the particles or suspension medium. In various embodiments, the contrast agent formulation comprises an iodized material or a barium material to modify the CT number for use with single-energy spectral CT and to modify the CT number ratio of 80:140 kVp for use with dual-energy or spectral CT.

[0085]

[0104] The benefit of the present invention lies in the novel X-ray imaging properties of the agent. In CT scans, all conventional positive CT contrast materials produce similar signals, and they all cause increased X-ray attenuation (positive enhancement) in their presence, making them indistinguishable except by context. The material of the present invention has a significantly different relative low-energy X-ray attenuation to high-energy X-ray attenuation ratio in dual-energy CT or spectral CT, and is therefore easily distinguishable from other positive contrast agents when used in dual-energy CT or spectral CT. For example, iodized CT contrast agents or barium-based CT contrast agents have an 80:140kVp CT number ratio of about 1.7 to about 1.8. Computer simulations have shown that elements of the periodic table have an 80:140kVp CT number ratio of about 0.9 to about 1.8. Notably, the 80:140kVp CT number ratio of water is 1.0 by definition. In the simulations, iodine-based and barium-based materials had the highest theoretical 80:140 kVp CT ratio of all elements in the periodic table. It was not predicted that materials could have substantially higher 80:140 kVp CT ratios than iodine and barium, nor that drugs could have substantially lower 80:140 kVp CT ratios than water. Figure 1.

[0086]

[0105] Therefore, it is indeed surprising that in vitro experiments have shown that materials with a CT number ratio of 80:140 kVp substantially lower than approximately 0.9 or higher than approximately 1.8 can exist or be produced. The concentrations of two contrast materials with significantly different CT number ratios from low X-ray energy spectra to high X-ray energy spectra can be quantified far more accurately in dual-energy CT compared to contrast materials with CT number ratios from low X-ray energy spectra 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 quantified very accurately. The present invention of composite low-X-ray attenuation material and high-X-ray attenuation material particles offers a significantly larger difference in the CT number ratio of 80:140 kVp compared to soft tissue, water, and iodized / barium contrast materials of any compound previously described in the literature (including those in our prior patent application). 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 microparticles or microspheres (with or without biocompatible shells or coatings) are known to have minimal and acceptable toxicity for use as intestinal contrast materials.

[0087]

[0106] Accordingly, in exemplary embodiments, the present invention provides a enteric contrast medium formulation formulated for intraintestinal administration to a subject concurrent with a medical imaging procedure performed on the abdomen of the subject. An exemplary formulation comprises an enteric contrast medium comprising a suspension of at least one encapsulated gas or partially vacuum particle, an aqueous or oil-based component, and a suspending agent. The suspending agent maintains at least one encapsulated gas or partially vacuum particle in the aqueous or oil suspension as a pharmaceutically acceptable enteric contrast material. Another exemplary formulation comprises an enteric contrast medium comprising at least one encapsulated gas or partially vacuum particle that incorporates a radiopaque material (such as iodine, barium, tungsten, tantalum, bismuth, or ytterbium in the particle or in the aqueous or oil suspension).

[0088]

[0107] In exemplary embodiments, the present invention provides a bowel contrast medium and a formulation thereof that is readily distinguishable from other currently available contrast materials in single-energy spectral CT images and dual-energy CT images or spectral CT images. The present invention is illustrated by reference to a bowel contrast medium formulation. An exemplary formulation comprises a bowel contrast medium comprising a suspension of at least one encapsulated gas or partially vacuum particle, an aqueous or oil component, and a suspending agent. The suspending agent maintains at least one encapsulated gas or partially vacuum particle in an aqueous or oil suspension comprising an aqueous or oil component which is a pharmaceutically acceptable aqueous or oil vehicle. In various embodiments, the particle is coated with a material suitable for bowel administration of the formulation to a subject requiring such administration.

[0089]

[0108] Exemplary encapsulation materials for encapsulated gases or partially vacuum particles according to the present invention may be glass, gel, resin, ceramic, metal, or rubber, or a combination of these materials.

[0090]

[0109] In exemplary embodiments, the encapsulation material for a gas or partial vacuum of particles is glass. The exemplary glass used in the present invention contains silicon dioxide (e.g., silicon dioxide blended with additives such as potash (potassium oxide), soda (sodium carbonate or sodium oxide), sodium oxide, lime (calcium oxide), boron trioxide, boric acid, magnesia, alumina, iron oxide, or other oxides). In exemplary embodiments, the glass shell of the hollow microsphere contains silicon dioxide as a base or core component, and other chemical components (primarily oxides) in the glass are present in minor amounts for the purpose of melting improvement, processing, and property modification, as found in the current art of the glass industry. In exemplary embodiments, the borosilicate glass shell consists of about 80% silica, about 13% boron oxide, about 4% sodium oxide, and about 2-3% aluminum oxide.

[0091]

[0110] In various embodiments, particles are formed from a shell material that defines the internal space. An exemplary shell material contributes at least about 30 HU to the CT number of the body cavity where the contrast medium is present when the contrast medium is acquired and / or CT image is taken. 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 an exemplary embodiment, the shell material contributes more to the CT number than an equal 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%, at least about 25%, at least about 50%, at least about 75%, or at least about 100% more HU units to the CT number than an equal 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. Since the specific gravity of glass is approximately 2.3 g / mL, 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% wt / wt, the encapsulated gaseous or partially vacuum microparticles constitute approximately 35% of the volume of the formulation, where the gaseous and partially vacuum portion constitutes 28% of the volume of the formulation and the glass constitutes 7% of the volume of the formulation. In CT images, the gaseous and partially vacuum are -1000 HU at all kVp, the 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. Therefore, in this exemplary formulation, the gaseous and partially vacuum portions contribute 28% × (-1000 HU at all kVp) = -280 HU, water contributes 0 HU (by definition), and glass contributes 7% × (1332 HU at 80 kVp) = 93 HU and 7% × (1031 HU at 140 kVp) = 72 HU, resulting in formulations with an overall CT number of -187 HU at 80 kVp and -208 HU at 140 kVp. In an example of the practice of physical reduction, a 20% wt / kg 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 ​​is 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 exemplary embodiments, the gas encapsulating the particles is a sulfur-containing gas, oxygen, or carbon dioxide. In various embodiments, the gas is sulfur dioxide or sulfite.

[0094]

[0113] In an exemplary embodiment, the partial vacuum in which the particles are encapsulated is at a pressure of 0.01 to 1.0.

[0095]

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

[0096]

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

[0097]

[0116] Exemplary encapsulated gaseous or partially vacuum particles used in the formulations of the present invention contain borosilicate microspheres having a specific gravity similar to that of water (e.g., about 0.3 to about 1.5 g / cc). A preferred specific gravity is about 0.4 to about 1.4 g / cc.

[0098]

[0117] One or more encapsulated gas or partially vacuum particles can be used together.

[0099]

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

[0100]

[0119] In exemplary embodiments, the intestinal contrast medium is formulated into a pharmaceutically acceptable carrier in which encapsulated gas or partially vacuum particles are suspended.

[0101]

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

[0102]

[0121] In various embodiments, radiopaque materials (such as iodine, barium, tungsten, tantalum, ytterbium, gold, or bismuth) are present in the contrast agent as separated suspended particles or as materials dissolved in an aqueous or oil-based vehicle.

[0103]

[0122] In exemplary embodiments, encapsulated gas or partially vacuum particles are coated to provide properties useful for contrast materials, 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 exemplary embodiments, the coating comprises organic molecules having a molecular weight of less than about 3 kD, less than about 2 kD, or less than about 1.5 kD, which are members selected from organic acids (or alcohols, amines) and their derivatives or analogues, oligosaccharides, and combinations thereof.

[0105]

[0124] In exemplary embodiments, the coating is a protein (e.g., 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 capabilities of those skilled in the art 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 may contain particles of any useful size. Specific sizes of particles are exemplified from 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 a larger range across all endpoints; in various embodiments, 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 intestinal contrast medium or two or more intestinal contrast media. The media may be present in similar or different concentrations according to any useful concentration measurements. An exemplary embodiment includes one or more particles or soluble agents at different concentrations in the overall contrast formulation, each contributing substantially to X-ray attenuation compared to the X-ray attenuation of water. Thus, in various embodiments, the weight of the formulation is approximately 5% (w / w, expressed as weight percent, for example, approximately 5 grams of contrast agent particles are contained in approximately 100 grams of the total contrast formulation) to 90% (w / w). In an exemplary embodiment, the formulation contains approximately 10% (w / w) to approximately 50% (w / w) of particles.

[0109]

[0128] In exemplary embodiments, the present invention provides a formulation comprising at least about 5% (e.g., at least about 20%) of the encapsulated gas or partially vacuum particles.

[0110]

[0129] The formulations of the present invention comprise a collection of encapsulated gas or partially vacuum particles of the present invention suspended in a pharmaceutically acceptable vehicle. The vehicle comprises other useful components. For example, in some embodiments, the vehicle comprises an aqueous medium, which further comprises additives to impart second properties to the formulation (e.g., slowing dehydration of the formulation in the intestines, providing flavor, stabilizing the suspension, promoting the fluidity of the suspension, thickening the suspension, providing pH buffering, and a combination thereof).

[0111]

[0130] The formulations of the present invention are molecularly and functionally distinct and can be recognized by both characteristics. For example, in one embodiment, the intestinal contrast medium has a CT number of -200 HU in a CT image at 120 kVp. In another exemplary embodiment, the intestinal contrast medium has an 80:140 kVp CT number ratio of about 0.8 or less. Formulations with exemplary useful values ​​for this ratio include formulations with an 80:140 kVp CT number ratio 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 an 80:140 kVp CT number ratio 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 by those skilled in the art for any contrast medium of the present invention.

[0112]

[0131] In exemplary embodiments, the present invention provides a bowel contrast medium formulation, the bowel contrast medium having a CT ratio of 80:140kVp higher than approximately 2.1. In exemplary embodiments, the present invention provides a bowel contrast medium formulation, the bowel contrast medium having a CT ratio of 80:140kVp between approximately 1.5 and 2.1. In exemplary embodiments, the present invention provides a bowel contrast medium formulation, the bowel contrast medium having a CT ratio of 80:140kVp less than approximately 1.5.

[0113]

[0132] In exemplary embodiments, the formulation of the present invention comprises a second contrast medium distinct from a first contrast medium. The second contrast medium may be soluble or insoluble in a pharmaceutically acceptable vehicle. If the second contrast medium is a particulate drug, it may have a different diameter, contain different atoms in the particulate core, have different coatings, etc., compared to the first contrast medium. The second contrast medium may also be one or more of iodized contrast media, Ba-based contrast media, Gd-based contrast media, Bi-based contrast media, W-based contrast media, Mg-based contrast media, Ta-based contrast media, Yb-based contrast media, or other Si-based contrast media.

[0114]

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

[0115]

[0134] In exemplary embodiments, the second contrast medium is a barium-based contrast material (e.g., barium sulfate).

[0116]

[0135] Within the scope of the present invention, formulations are designed for single-dose administration. These unit dose forms contain a sufficient amount of the formulation of the present invention to provide detectable contrast in the subject to which they are administered. In exemplary embodiments, a unit dose formulation includes a container holding a sufficient amount of intestinal contrast medium to enhance the diagnostic image of the subject to which the unit dose is administered in a diagnostically meaningful manner. The container may be a vial, an infusion bag, or other suitable container. The intestinal contrast medium may be in the form of a pre-formulated liquid, concentrate, or powder. In exemplary embodiments, the subject weighs approximately 70 kg. In exemplary embodiments, the image is measured through the abdomen of the subject, the pelvis of the subject, or a combination thereof.

[0117]

[0136] In various embodiments, the unit dose formulation contains approximately 800 to 1500 mL of contrast agent per adult human dose, which can be divided into smaller containers of approximately 300 to 600 mL, etc. In exemplary embodiments, the intestinal contrast medium formulation is a unit dose formulation of approximately 50 to 100 mL. In exemplary embodiments, the intestinal contrast medium formulation is a unit dose formulation of approximately 100 mL to 800 mL.

[0118]

[0137] Any formulation described herein can be formulated and used for administration via any variety of routes. Exemplary routes of administration include oral, rectal, vaginal, intravascular, intraspinal, intravesical, and similar routes.

[0119]

[0138] High-concentration encapsulated gaseous or partially vacuum particle contrast materials have not been described as contrast materials for use with CT. In exemplary embodiments, the gaseous or partially vacuum particles encapsulated 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 constitute about 5% (w / w)–90% (w / w) of the formulation (e.g., about 5% (w / w)–60% (w / w)).

[0120]

[0139] In various embodiments, the intestinal contrast medium and, preferably, the formulation thereof of the present invention exhibit chemical stability over a wide pH range (e.g., about 1.5 to about 10). The intestinal contents may be exposed to a low pH of 1.5 by the stomach, and may be exposed to a high pH of up to 10 by bile and the small intestine. Physicochemical stability is an important component of safety and helps minimize the risk of reaction or adverse events. Adverse reactions may occur if excessive dissolution or degradation of the material occurs in the gastrointestinal tract, or if the degradation products are potentially toxic.

[0121]

[0140] In various embodiments, the present invention enables the completion of imaging experiments with encapsulated gas or partially vacuum particles remaining at a sufficiently high concentration within the target area for a sufficiently long duration. 1 / 2 The present invention provides intestinal contrast media and formulations thereof. In various embodiments, the present invention provides intestinal contrast media and formulations having an in vivo residence time short enough to essentially allow all administered encapsulated gases or partially vacuum particles to be expelled from the subject's body before they are modified (metabolized, hydrolyzed, oxidized, etc.) by the subject's body.

[0122]

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

[0123]

[0142] In exemplary embodiments, the present invention provides a gradually dissolving intestinal contrast medium such that the majority of administered encapsulated gases or partially vacuum particles are expelled through the gastrointestinal tract before being modified by the subject's body, and the dissolved or modified portions are excreted through the urinary tract.

[0124]

[0143] The pharmaceutical formulation of the present invention may optionally contain excipients and other components (one or more sweeteners, flavorings and / or additional taste modifiers to mask bitter or unpleasant tastes, suspending agents, flow enhancers, antioxidants, preservatives, and other conventional excipients as needed).

[0125]

[0144] The suspension of the present invention may optionally contain one or more antioxidants, and if necessary, a taste modifier, a sweetener, a flow enhancer, a suspending agent, and a preservative.

[0126]

[0145] As recognized, the optional components described above may be added to the powder formulation or oral suspension of the present invention.

[0127]

[0146] Suitable antioxidants for use in this specification include any convenient agent known in the art for this purpose (such as sodium metabisulfite, sodium bisulfite, cysteine ​​hydrochloride, citric acid, succinic acid, ascorbic acid, sodium ascorbate, fumaric acid, tartaric acid, maleic acid, malic acid, EDTA, etc.), with sodium metabisulfite or sodium bisulfite being preferred.

[0128]

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

[0129]

[0148] The sweetener used in the formulation of the present invention may be any suitable agent known in the art for this purpose and can be selected from any suitable 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] Flavorings and flavor modifiers or taste modifiers may also be used to further improve the taste, and for this purpose may be any suitable agent known in the art, including, but not limited to, orange flavoring, vanilla flavoring, licorice flavoring, orange vanilla flavoring, crème de mint, cherry flavoring, cherry vanilla flavoring, berry mix flavoring, passion fruit flavoring, pear flavoring, strawberry flavoring, mandarin orange flavoring, bubblegum flavoring, tropical punch flavoring, grape juice formulations, grape flavoring, artificial grape flavoring, grape bubblegum flavoring, tutti frutti flavoring, citrus flavoring, lemon flavoring, chocolate flavoring, coffee flavoring, and combinations thereof.

[0131]

[0150] The suspending agent can be any convenient agent known in the art for this purpose, and can be selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, alginate, and sodium carboxymethylcellulose, with xanthan gum being preferred. The suspending agent can be used in an amount ranging from about 0 to about 20% by weight of the powder formulation and from about 0 to about 10% by weight of the oral suspension.

[0132]

[0151] The preservative can be any suitable agent known in the art for this purpose, and can be selected from the group consisting of any compound compatible with the drug activity (methylparaben 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 the intestinal contrast medium of the present invention; (b) a second vial containing a suspension; and (c) instructions for using and / or formulating the intestinal contrast medium as a suspension. In various embodiments, the kit further includes: another vial containing the second contrast medium; and instructions for administering and / or formulating the first and second intestinal contrast mediums in a clinical or research setting.

[0134]

[0153] The contrast medium contained in the second vial may be soluble or insoluble in a pharmaceutically acceptable vehicle. If the second contrast medium is a particulate drug, it may have different atoms in the particulate core, different coatings, different encapsulation materials, different gases, different diameters, etc., compared to the first contrast medium. The second contrast medium may also be one or more of the following: 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 for acquiring and enhancing clinically meaningful CT images from a subject administered with the formulation of the present invention. Accordingly, in exemplary embodiments, the present invention provides a method for acquiring contrast-enhanced CT projection data from a subject and then reconstructing it into a CT image. The method comprises: administering a diagnostically effective amount of the intestinal contrast medium formulation of the present invention to a subject; acquiring CT projection data from the subject and then reconstructing it into a CT image. In various embodiments, the intestinal contrast medium has an 80:140kVp CT-to-image ratio of less than approximately 0.8 in the images in a DECT imaging study. In various embodiments, the intestinal contrast medium has an 80:140kVp CT-to-image ratio greater than approximately 2.0 in the images 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 to which the intestinal contrast medium of the present invention is distributed.

[0137]

[0156] Images and methods obtained by the present invention utilize the contrast medium of the present invention. Images are obtained through any part of the subject's body. In an exemplary method, the image is obtained through the subject's abdomen and / or pelvis.

[0138]

[0157] The present invention also provides a method for digitally separating CT signals produced by the intestinal contrast medium of the present invention from CT signals produced by soft tissue, body fluids, or other contrast media by post-processing CT projection data, CT images, or both. In various embodiments, dual-energy CT or spectral CT signals produced by the intestinal contrast material of the present invention are separated from CT signals produced by other contrast media or body tissues based on relative differences in X-ray attenuation in low X-ray energy spectra vs. high X-ray energy spectra, using two-substance discrimination, three-substance discrimination, multi-substance discrimination, or virtual monochromatic energy imaging, or a combination thereof. In various embodiments, signal intensity (e.g., threshold signal) is also considered in the material discrimination method to assist in separating CT signals produced by the contrast medium of the present invention from CT signals produced by other imaging materials. In exemplary embodiments of the present invention, if the CT signal from the contrast material of the present invention is highlighted or subtracted from CT signals produced by other contrast materials or body tissues, post-processing of the material discrimination image produces a new CT image. In exemplary embodiments of the present invention, if a CT signal from a contrast material other than the contrast agent of the present invention is highlighted or subtracted from a CT signal produced by the contrast material of the present invention or body tissue, post-processing of the material discrimination image produces a new CT image.

[0139]

[0158] One of the advantages of the contrast medium and the formulations of the present invention is their compatibility with the administration of one or more additional contrast agents via any desired route. In various embodiments, the method further comprises administering a second contrast medium, different from the intestinal contrast medium of the present invention, to a subject. In various embodiments, the second contrast medium is administered via a route selected from intravascular, intestinal, rectal, and administration into a cavity of a different body, which is natural (e.g., vagina, bladder), caused by injury (e.g., fistula, abscess, sinus duct), surgically generated (e.g., neobladder, ileal pouch), or artificial (e.g., medical devices such as catheters, reservoirs, tubes, or pumps). Multiple contrast materials can be administered into different body compartments. In exemplary embodiments, 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 exemplary embodiments, the second or third contrast medium is an embodiment of the contrast medium of the present invention.

[0140]

[0159] In exemplary embodiments, the contrast agent of the present invention is used simultaneously with and distinguished from iodized agents and barium agents or other contrast agents under development (such as those based on heavy metals such as tungsten, ytterbium, bismuth, or tantalum). It is injected into one or more body compartments, and in cases of two or more body compartments, it is simultaneously queried for single DECT or multi-energy CT examinations to provide timely, high-resolution, and perfectly aligned anatomical images of each system for rapid and confident diagnosis. The method of the present invention provides a means for accurately assessing multi-organ failure from trauma, tumors, surgical complications, and inflammatory diseases.

[0141]

[0160] In exemplary embodiments, the first and second contrast agents are distinguishable from each other in an image set encompassing the regions in which the first and second contrast media are distributed. The exemplary second contrast medium is an iodized contrast medium.

[0142]

[0161] The second contrast medium may be soluble or insoluble in a pharmaceutically acceptable vehicle. If the second contrast medium is a particulate agent, it may have different diameters, contain different atoms in the particulate core, have different coatings, etc., compared to the first contrast agent. The second contrast medium may also be one or more of the following: iodized contrast medium, Ba-based contrast medium, Gd-based contrast medium, W-based contrast medium, Si-based contrast medium, Mg-based contrast medium, Yb-based contrast medium, Bi-based contrast medium, or Ta-based contrast medium.

[0143]

[0162] In exemplary embodiments, 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 a single type (positive, neutral, or negative) of intestinal contrast medium, which can also be transformed by post-processing of the image to show one or more of the other types of signals (positive, neutral, or negative) in CT. For example, in suspected intestinal ischemia, neutral or negative intestinal contrast agents are useful for finding either hyper-weighted or hypo-weighted intestinal wall, respectively, to detect inflammation or ischemia. In another exemplary method, a positive contrast agent enables the identification of intestinal perforation, abscess, and fistula.

[0146]

[0165] The development of safe clinical bowel CT contrast materials that can be digitally manipulated to appear as negative, neutral, or positive contrast materials under the control of the interpreting physician will provide powerful diagnostic capabilities and eliminate not only diagnostic errors but also guesswork and protocol errors. The reduction in errors will lead to faster diagnoses and a decrease in the need for additional follow-up examinations. Physicians will no longer need to weigh the merits and demerits of administering neutral or negative vs. positive bowel contrast materials for a given clinical scenario.

[0147]

[0166] The following examples are provided to illustrate exemplary embodiments of the present invention and do not define or limit their scope.

[0148] Examples

[0167] Example 1 Encapsulated gaseous or partially vacuum microparticles are common, commercially available, and can be produced by many methods well known to those skilled in the art. A common range of methods utilizes a “foaming agent,” which is a substance capable of releasing gas when heated to a high temperature. An example of producing encapsulated gaseous or partially vacuum microparticles involves heating a shell material (in the form of glass or ceramic frit, powder, or solution) and a foaming agent to a temperature sufficient to melt the shell material, then causing gas release from the foaming agent to produce hollow microparticles, and then cooling them. To produce different types of encapsulated gaseous or partially vacuum microparticles, the heating temperature can range, for example, from 800 to 1500 degrees Celsius, depending on the need for variations in the shell material. Another process involves heating a porous glass or ceramic material to slightly melt it and sealing the surface so that the gas or partial vacuum is retained inside the particles. Partial vacuum in a heating chamber can be utilized by the above methods to adjust the resulting fraction and physical properties of the encapsulated gaseous or partially vacuum microparticles in the product. By utilizing gravity with or without updrafts or downdrafts, the residence time of particles in the heating zone can be modified, thereby influencing the diameter and specific gravity of the resulting encapsulated gas or partial vacuum microparticles. Further selection of microparticle subgroups can be achieved by various mechanical means based on their physical properties (diameter, specific gravity, etc.).

[0149]

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

[0150]

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

[0151]

[0170] Stable suspensions of encapsulated gases or partially vacuumed microparticles in aqueous solutions of dissolved iodized iohexol or suspended barium sulfate were prepared 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 in CT imaging for more than 8 months after formulation. A slight increase in CT count was observed in the suspensions after the first 2 months at all kVp settings. These slight increases in CT count did not substantially alter the ability of the formulations to separate from water, soft tissue, or conventional iodized or barium contrast materials in dual-energy CT imaging. The viscosity of the suspensions ranged from 50–1000 g / cm-sec.

[0152]

[0171] In vivo imaging experiments in rabbits, rats, and mice demonstrated that the encapsulated gaseous or partially vacuum particle contrast agents of the present invention simultaneously provide positive, neutral, and negative intestinal 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 can be devised by those skilled in the art without departing from the true spirit and scope of the invention. The appended claims should be construed to include all such embodiments and equivalent variations.

[0154]

[0173] Each and every patent, patent application, and disclosure of publications cited herein is incorporated herein by reference to them in their entirety.

Claims

1. A pharmaceutical preparation comprising a stable suspension of a first intestinal CT imaging contrast agent, The first intestinal CT imaging contrast agent comprises a stable aqueous suspension, the first CT imaging contrast agent consisting of a plurality of hollow particles made of silicon dioxide glass shells that encapsulate a partial vacuum or gas within their internal space. The first intestinal CT imaging contrast agent is stably suspended in a sterile, pharmaceutically acceptable aqueous suspension medium that is suitable for simultaneous CT imaging of the region of the subject containing the first intestinal CT imaging contrast agent and intestinal administration of the pharmaceutical preparation to the subject. The pharmaceutical preparation comprises 5% (w / w) of the first intestinal CT imaging contrast agent, The sterile, pharmaceutically acceptable aqueous suspension medium is a pharmaceutical preparation comprising 10% or less of a suspending agent for stabilizing the suspension of the first intestinal CT imaging contrast agent.

2. The unit dose administered per intestinal administration is sufficient to provide detectable contrast enhancement in CT imaging of the subject to which the unit dose is administered. The pharmaceutical preparation according to claim 1, wherein the unit dose is contained in a container suitable for intestinal administration of the contrast agent to the subject simultaneously with the acquisition of a CT image of the subject.

3. The pharmaceutical preparation according to claim 2, wherein the unit dose of the preparation is 800 mL to 1500 mL of the preparation.

4. The pharmaceutical formulation according to claim 1, wherein the suspension is selected from xanthan gum, guar gum, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, alginate, and sodium carboxymethylcellulose.

5. The pharmaceutical preparation according to claim 1, wherein the suspension is xanthan gum and is present in the preparation in an amount of up to 10% (w / w) of the preparation.

6. The pharmaceutical formulation according to claim 1, wherein the hollow particle has an internal void that accounts for at least 75% of the total volume of the particle.

7. The pharmaceutical formulation according to claim 1, further comprising a second CT imaging contrast agent different from the first intestinal CT imaging contrast agent.

8. The pharmaceutical formulation according to claim 7, wherein the second CT imaging contrast agent is selected from barium, tungsten, tantalum, ytterbium, gold, bismuth, iodized contrast agents, and combinations thereof.

9. The pharmaceutical preparation according to claim 1, further comprising one or more additives that slow dehydration in the intestines, provide flavor, and bring about a combination thereof.

10. The pharmaceutical preparation according to claim 1, which is distributed in the intestines of the subject after intestinal administration to the subject.

11. The pharmaceutical preparation according to claim 3, wherein the unit dose is distributed in the intestines of the subject after intestinal administration to the subject.

12. The pharmaceutical preparation according to claim 10, wherein the subject is located inside a CT scanner.

13. The pharmaceutical formulation according to claim 1, wherein the stable pharmaceutical formulation is packaged in a kit having instructions for using the stable pharmaceutical formulation of the first intestinal CT imaging contrast agent.

14. The pharmaceutical formulation according to claim 1, wherein the first intestinal CT imaging contrast agent is the only contrast agent in the stable pharmaceutical formulation.

15. A stable aqueous pharmaceutical suspension of a single-dose administration form of a single intestinal CT imaging contrast agent for administration to a subject simultaneously with a CT imaging procedure performed on a region of the subject, In the region of the subject, at least a portion of the single dose of the CT imaging contrast agent is distributed, The single-dose administration method comprises a container containing a single intestinal CT imaging agent in an amount sufficient to provide detectable contrast enhancement to CT images of the subject acquired during the CT imaging procedure for the region of the subject to which at least a portion of the single dose of the CT imaging agent is distributed. The aforementioned pharmaceutical suspension A single intestinal CT imaging contrast agent comprising at least 20% (w / w) of the single CT imaging contrast agent, the single CT imaging contrast agent comprising a plurality of hollow microparticles made of silicon dioxide glass shells that encapsulate a partial vacuum or gas within an internal void, A sterile, pharmaceutically acceptable suspension medium comprising a suspension agent for stabilizing the suspension of the single intestinal CT imaging contrast agent, the suspension medium being compatible with intestinal administration in the form of a single dose to the subject concurrently with the CT imaging procedure, A stable aqueous pharmaceutical suspension containing [the specified ingredient].

Images