Low X-ray attenuation variable hard shell oral contrast material

Abstract

The present invention provides hollow borosilicate particulate contrast media for use in CT imaging, comprising a shell material containing less than 8% oxides of non-silicon elements with atomic numbers greater than 10. In an exemplary embodiment, the present invention provides an enteric contrast medium formulation that provides a CT value different from that of water, soft tissue, and fat. An exemplary formulation includes (a) an enteric contrast medium comprising hollow borosilicate microparticles suspended in water. In various embodiments, the hollow borosilicate microparticles are suspended in an aqueous medium with an agent compatible with enteral administration of the formulation to a subject in need of such administration. The present invention also provides a method of imaging the abdomen and pelvis by delivery of hollow borosilicate particulate contrast material to the intestinal lumen and simultaneous CT imaging.

Description

[Background technology]

[0001] 2. Background of the Invention

[0001] Medical computed tomography (CT) imaging is used to evaluate a wide range of clinical indications including abdominal pain, to assess possible malignancies, to staging and monitoring of tumors, to determine intestinal injury or inflammation, and to further evaluate intestinal and non-intestinal diseases. During CT imaging, the x-ray attenuation (CT number) of the tissue being imaged is measured in Hounsfield Units (HU), which range from -1000 HU (air or vacuum, which exhibits only negligible x-ray attenuation) to 0 HU (water, which is by definition 0 HU) to over 3000 (very dense materials, including metals, which have extremely high x-ray attenuation).

[0002]

[0002] During CT imaging, various x-ray spectra may be used to image a subject such as a patient. Current CT scanners may use x-ray spectra generated by x-ray tube voltages that can be set from 70 kVp to 150 kVp depending on clinical requirements. Lower x-ray tube voltage settings generate x-ray spectra with relatively lower energy compared to higher tube voltage settings. For any given x-ray tube voltage, the CT number of water is defined as 0 HU and the CT number of air / vacuum is defined as -1000 HU. Actual measurements in humans often vary by about 20 HU due to image noise and other artifacts. Thus, the relative x-ray attenuation of other materials compared to water is measured.

[0003]

[0003] Human non-adipose soft tissue, such as muscle, solid organ parenchyma, and blood, which is composed primarily of atoms with atomic numbers less than 20, is similar to water insofar as its CT numbers do not change significantly with low versus high x-ray tube voltage (kVp). Human non-adipose soft tissue generally exhibits CT numbers between 20 and 70 HU, regardless of tube voltage setting. Similarly, gas molecules in room air, which are generally composed of molecules with low atomic numbers, tend to exhibit CT numbers of approximately -1000 HU, regardless of CT tube voltage setting.

[0004]

[0004] In order to better visualize anatomical structures, positive contrast agents are commonly delivered intravenously or orally during CT imaging. All intravenous contrast agents and most positive oral contrast agents used in clinical practice are currently based on iodine (z=53), which attenuates x-rays much more than soft tissue or water, especially when imaged at low kVp. Some positive oral contrast agents are based on barium (z=56), which has very similar x-ray attenuation properties to iodine due to its similar atomic number, and therefore iodine and barium signals cannot be distinguished during CT imaging, including multi-energy CT, regardless of the imaging technique.

[0005]

[0005] Given that positive contrast media are generally in aqueous solutions or suspensions, such positive contrast agents generally exhibit CT values ​​greater than 0, regardless of aqueous dilution. As the positive contrast material becomes more concentrated, the CT value of the fluid or tissue in which it resides at the time of CT imaging increases. Typically, 1 mg iodine / mL is approximately the detection limit for iodine in contrast-enhanced tissues, and this threshold generally refers to an enhancement of about 20-25 HU when imaged at 120 kVp, the most common CT kVp setting. To be visually convincing, positive contrast materials generally need to increase the CT value on post-contrast CT images by 50 HU or more compared to pre-contrast CT images, which corresponds to about 2 mg iodine / mL or more. Quantitative detection of contrast enhancement below 1 mg iodine / mL is generally unreliable in clinical CT due to image noise or artifacts, although some believe that detection at even lower thresholds, such as 0.8 mg iodine / mL, may also be reliable. Similarly, visual detection of changes of less than 20 HU from pre- to post-contrast clinical CT is considered unreliable.

[0006]

[0006] Some oral contrast agents in CT are called "neutral" or "negative" and closely resemble the CT value of water or soft tissue in CT (0-50 HU). These agents include solutions of water or water with excipients that prevent the intestine from rapidly reabsorbing water. These oral contrast agents allow visualization of bowel wall capillary enhancement with positive intravenous contrast agents that is difficult to visualize when positive oral contrast agents are given. However, because these neutral contrast agents resemble the CT values ​​of water and non-enhanced soft tissue at all kVps used in medical CT imaging, these agents may make it more difficult to visualize the intestine from adjacent soft tissue CT attenuating lesions, such as abscesses, fluid retention, hematomas, and poorly vascularized or necrotic tumors, which also predominantly exhibit CT values ​​of 0-50 HU or slightly higher during CT imaging over the full range of CT kVps used in medical imaging.

[0007]

[0007] The X-ray attenuation of a CT contrast agent is traditionally determined entirely based on the concentration of the reporter atom / material in the aqueous medium. Iodine contrast agents are described in terms of mg of iodine / mL. Barium sulfate contrast agents are described as w / w% barium sulfate. Neutral contrast agents do not have any material that substantially changes the CT attenuation compared to water (hence 0±20 HU, which is the CT attenuation of water).

[0008]

[0008] Humans can only perceive about 30 different shades of light and shade. 1Because medical CT values ​​range from -1000 to over 3000 HU, medical CT images are viewed using CT value windows and levels tailored to assess different structures (bone, lung, soft tissue, etc.). To assess soft tissue, the "level" (mid-level shading) is set to the expected CT value of soft tissue (40 or 50 HU), and the "window" is set to capture the typical range of fat and medium- to high-intensity positive contrast enhancement (-100 and 200 HU, respectively). To assess critical soft tissues, the most common window / level settings for viewing abdominal CT views are 350 / 50 HU (which displays voxels below -125 HU as pure black and voxels above 225 HU as pure white, with voxels between -125 and 225 HU displayed as increasingly bright signals) or 400 / 40 HU (which displays voxels below -160 HU as pure black and voxels above 240 HU as pure white, with voxels between -160 and 240 HU displayed as increasingly bright signals).

[0009]

[0009] A major problem with the use of positive and neutral oral contrast agents is that the appearance of the intestinal lumen contents is not uniform, regardless of the observation window / level setting. The intestinal lumen often exhibits variability from section to section, with some sections containing gas, some containing fluid, some containing solids, and some containing a mixture of these materials. Intestinal gas has a dense CT value (-50 to -1000 HU, depending on the amount of mixed material). Therefore, regardless of whether the oral contrast agent used is positive (100-400 HU) or neutral (0-40 HU), there is almost always heterogeneity of the intestinal lumen due to the extent to which the significantly dense gas signal is mixed with the oral contrast agent. This heterogeneity creates complications with respect to image interpretation by humans or machines.

[0010]

[0010] Prior art descriptions of dense oral contrast agents include insufflation gases such as room air or carbon dioxide, which result in extremely dense CT numbers approaching -1000HU in the lumen, and the insufflation gas is physically uncomfortable for the patient. Such agents generally require intestinal intubation and insufflation of the intestine, which is invasive. Alternatively, orally ingested contrast materials may undergo chemical reactions in the intestine to release gases such as carbon dioxide. Such gas-releasing agents may also cause discomfort from gas bloating or chemical involvement. Other proposed dense oral contrast agents include perfluorocarbons, which may or may not expand in volume in the intestine and may cause extremely dense signals in the intestinal lumen, but 2 , was associated with anal leakage and abdominal discomfort.

[0011]

[0011] Other descriptions of dense enteral contrast agents include those for rectal administration. 3 Or for oral administration 4 (U.S. Patent Application Publication No. 20200000942) lists foam-like liquids that can be formulated to give a high CT value (-100 to -800 HU). These agents cannot be used in the small intestine because they do not have a hard shell around the bubbles and therefore may have stability issues. 3 , or may exhibit heterogeneous CT values ​​ranging up to hundreds of HU. 4 A further limitation is that special machinery may be required to prepare such formulations on-site. 4 .

[0012] Other described high-staining contrast agents include Calogen 5 or corn oil emulsion 6~8 Oil emulsions and paraffin suspensions such as 9While these contrast agents may have useful weakly enhancing CT values ​​of -20 to -60 HU, the underlying contrast material is made of lipids / hydrocarbons that exhibit similar x-ray attenuation as human fat across all kVp and keV, making the contrast agent indistinguishable from natural body fat when imaged with conventional CT or even dual-energy / multi-energy CT.

[0013]

[0013] Microbubble contrast agents have been described for CT, including polymeric shell agents (US Patent Publication No. 005726121A, US Patent Publication No. 5205290A) that provide strongly negative CT values ​​when formulated in aqueous suspension. Such agents have not been developed for commercial CT applications. Furthermore, the physical stability of the particles in such materials is expected to be insufficient for use in small intestine imaging, where they must remain stable for at least one hour.

[0014]

[0014] Dual energy CT (DECT) and multi-energy CT (MECT) scanners, including photon counting CT (PCCT), have been developed for clinical imaging. These scanners improve upon conventional monochromatic energy spectrum CT by simultaneously assessing the x-ray attenuation of the imaged object with different x-ray spectra. For DECT, the relative attenuation of the imaged object with low vs. high energy x-ray spectra is compared. The low vs. high x-ray energy spectrum is generally obtained by setting the CT tube voltage (kVp) to a low value (e.g., 80 kVp) or a high value (e.g., 140 kVp), respectively. Various other implementations are also utilized, including tin and gold filtering of the x-ray beam, or using split-layer x-ray detectors to preferentially detect x-rays of lower or higher energy, or photon counting detectors to better quantify and classify the energy of the detected x-rays.

[0015]

[0015] These DECT, MECT and PCCT scanners take advantage of the fact that atoms in the object being imaged attenuate x-rays of different energies to characteristic degrees based on their atomic number. Regardless of the x-ray energy used to image water or air, water is assigned a CT value of 0 HU, vacuum / room air is assigned a CT value of -1000 HU, and the CT values ​​of all other materials are determined relative to these two standards.

[0016]

[0016] The effective atomic number of H2O is about 7.5, which is the weighted average of the constituent atoms oxygen (z=8) and hydrogen (z=1). Because of the small size of the proton and its effect on the overall X-ray attenuation of water, the effective atomic number of water is much closer to that of oxygen. The CT number of water is, by definition, 0 HU regardless of the kVp setting, so the CT numbers of other materials at low and high kVp settings are determined relative to water. In general, molecules with effective atomic numbers smaller than water (such as fats / hydrocarbons made of carbon z=6 and hydrogen z=1) will show relatively lower CT numbers at low kVp compared to high kVp (Figure 2). And molecules with effective atomic numbers larger than water (such as iodine, z=53) will show relatively higher CT numbers at low kVp compared to high kVp (Figure 2). Soft tissue, which is composed primarily of carbon, hydrogen, oxygen, and nitrogen, has a slightly higher CT value than water, around 20-50 HU, but because its effective atomic number is similar to water, it does not exhibit much higher CT values ​​at low kVp compared to high kVp CT settings.

[0017]

[0017] The primary value of DECT, MECT and PCCT is the ability to quantify the magnitude of enhancement of intravenous contrast material in image voxels without the need to acquire a separate unenhanced CT scan. Iodine exhibits significantly higher CT numbers at low kVp compared to high kVp CT settings. In aqueous solutions, the 80:140 kVp CT number ratio of iodine is approximately 1.75, whereas water is 1.0 (by definition), soft tissue is 1.05, etc. In DECT, this difference can be used to quantify iodine and make an iodine map. A similar method is used for MECT and PCCT quantification of iodine contrast enhancement without the need for a separate unenhanced CT scan. Below approximately 1 mg iodine / mL, iodine quantification becomes unreliable due to noise in CT data in living organisms that exhibit CT image artifacts for a number of reasons. CT artifacts are common due to quantum mottle, mass attenuation in thick body parts, bone, motion, metal and non-circular shapes of the imaged object. Typically, an iodine map image is reconstructed as a pair with a water map image, also known as a virtual non-contrast (VNC) or virtual non-enhanced (VUE) image. The iodine map can be considered as the inverse of the water map. The CT number values ​​from the low and high kVp parent images are divided such that the iodine values ​​are assigned to the iodine map and the other values ​​are assigned to the water map.

[0018]

[0018] Unlike conventional CT, which uses a detector that integrates the sum of the X-ray energies that hit the detector, PCCT scanners use special X-ray detectors that determine the energy of each individual X-ray that hits the detector. Since the X-ray energy spectrum produced by the X-ray source is known, photon-counting CT can therefore determine which X-rays are preferentially attenuated by the imaged object. This allows for better discrimination of the imaged elements / materials than is possible with dual-energy CT. Dual-energy CT and photon-counting CT are collectively referred to as multi-energy CT.

[0019]

[0019] DECT, MECT and PCCT images can be reconstructed to simulate the appearance of CT scans at different mono-energy x-ray energies. Using pairs of iodine and water maps, the voxel intensities of a simulated mono-energy CT scan are determined at any given keV, usually chosen between 40 keV and 200 keV. Different materials exhibit characteristic CT number curves when plotted against keV (Figure 2). Summary of the Invention [Means for solving the problem]

[0020] BRIEF SUMMARY OF THE INVETION

[0020] The present invention substantially improves the formulation of a conventional hollow borosilicate microparticle (RHBM) oral contrast agent, so that the agent of the present invention can depict the anatomy of the small intestine in a more precise manner than previously presented when the small intestine is imaged with conventional CT and multi-energy CT. The realization of the advantageous agent involved several unexpected technological innovations and the fortunate discovery of the beneficial properties of high silicon hollow borosilicate microparticles (HSHBM) that are unexpectedly different from those of conventional hollow borosilicate microparticles (RHBM) during CT imaging. Furthermore, by targeting a specific CT value range for the intestinal contrast agent, it becomes possible to unexpectedly improve the depiction of the anatomical details of the intestine, regardless of whether conventional CT or DECT or multi-energy CT is used.

[0021]

[0021] Many hollow borosilicate microparticles, i.e., RHBM shell materials, include a blend of silicon dioxide (SiO2, typically >60%, Si z=14) and boron oxide (B2O3, >5%, B z=5) with small additions of several other oxides, including sodium oxide (Na2O, Na z=11), aluminum oxide (Al2O3, Al z=13), magnesium oxide (MgO, Mg z=12), calcium oxide (CaO, Ca z=20), and zinc oxide (ZnO, Zn z=30), as well as other trace materials with higher atomic numbers. During CT, the x-ray attenuation of conventional contrast agents is generally dependent on the most prevalent atoms and atoms with higher atomic numbers. Prior art borosilicate glass particles have shown substantially greater x-ray attenuation when imaged with low kVp CT compared to high kVp. This relative attenuation is compared to water (H2O), which by definition is assigned a CT number of 0 HU regardless of the kVp used for CT imaging. US Patent Publication No. 20180110492A1 further discloses that adding barium (z=56) or other high atomic number oxides to further increase the 80:140 kVp CT number ratio further increases the calculated but artifactual iodine concentration on the iodine map during MECT.

[0022]

[0022] A previous study on pure silicon dioxide as an oral CT contrast agent (US Patent Application Publication No. 20140276021A1) showed an 80:140 kVp CT number ratio of 1.25-1.56, meaning that there was a substantial difference, i.e., CT numbers were 25-56% higher for silicon dioxide when imaged at 80 kVp compared to 140 kVp, and that the ratio was far from 1.0.

[0023]

[0023] Thus, it was unexpected and counterintuitive to find that high silicon hollow borosilicate microparticles (HSHBM), having very high amounts of silicon dioxide and very low amounts of boron and other oxides, could be engineered into a contrast agent that exhibits an 80:140 kVp CT number ratio approaching 1.0, resulting in minimally increased x-ray attenuation compared to RHBM during CT imaging at low versus high kVp.

[0024]

[0024] Based on the effective atomic number, one would expect that the shell material of the HSHBM would have a higher effective atomic number and therefore would exhibit higher relative CT values ​​at low kVp than at high kVp compared to the shell of the RHBM, but the opposite has been found to be true. An exemplary high silicon borosilicate has more than 92% oxide of silicon (z=14) and less than 2% boron (z=4) trioxide (which has a relatively low effective atomic number). In comparison, a typical borosilicate is only about 70%-80% silicon oxide, has a high amount of boron trioxide (about 15%), and most of the remainder of the composition is attributable to oxides of Na, Mg, and Al (z=11, 12, and 13, respectively, each of which has an atom smaller than silicon z=14).

[0025]

[0025] Only upon further evaluation does it become more clear that the oxides of silicon have only one silicon atom for every two oxygen atoms of SiO2 (a molar ratio of 1:2), and thus the effective atomic number of SiO2 is in fact similar to or less than the effective atomic number of the oxides of Na, Mg, and Al, which have higher relative molar ratios compared to oxygen of 2:1, 1:1, and 2:3, respectively. Similarly, upon further analysis, the high silicon borosilicates contain relatively small amounts of calcium oxide (z=20) and zinc (z=30) oxide, as well as other low proportions of materials found in standard borosilicates, including other atoms with higher atomic numbers.

[0026]

[0026] The use of HSHBM for medical imaging purposes is novel. Generally, HSHBM is used to blend with other materials to make them physically lighter, such as for aerospace or marine applications, or HSHBM is used in electronics and devices that require low dielectric effects, or HSHBM is used in thermal ablation products (heat shielding). One description of HSHBM for medical devices uses such materials by compounding HSHBM into silicone polymer gels to physically lighten the weight of breast implants (US Patent Application Publication No. 20120277860A1). The description of this breast implant patent does not suggest the use of HSHBM as a diagnostic medical imaging contrast material. Therefore, the use of HSHBM for diagnostic medical imaging purposes is not self-evident.

[0027] A further innovation of our invention is the use of borosilicate hollow particles of lower true density than previously tested for RHBM contrast agents. US Patent Application Publication No. 20180110492A disclosed particles of a range of possible specific gravities for use in contrast materials, but noted that there is value in using particles with a specific gravity similar to that of water (close to 1 g / mL) because such particles can be easily suspended in aqueous formulations. This disclosure includes a particle with a specific gravity of 0.45 g / cm 3 There is no mention of lower borosilicate hollow particles. Aqueous formulations with concentrations of borosilicate hollow particles below 20% w / w are not explicitly disclosed. Surprisingly, the present invention achieves its effective results using aqueous formulations with concentrations of HBM of about 0.5 to about 10% w / w.

[0028]

[0028] In an exemplary embodiment, the present invention provides a sterile aqueous pharmaceutical formulation of low-density hollow borosilicate microparticles at a low concentration. An exemplary formulation of the present invention includes low-density hollow borosilicate microparticles at a concentration of about 10% or less, for example about 9% or less, 8%, 7%, 6%, 5%, 4%, 3%, 2% or about 1% or less (w / w) of the formulation. An exemplary formulation is suitable for enteral administration to a subject immediately before, simultaneously with, or a combination of, acquiring images from at least one cross-section of the subject's abdomen (e.g., intestine). The formulation is stable, and "stable" refers to a formulation of the present invention in which a substantial portion of the particles (e.g., more than about 50%, 60%, 70%, 80%, 90% or more than about 95%) remains in suspension in a pharma- ceutically acceptable aqueous solvent for the duration of the time required for preparation of the formulation and administration to a subject and acquisition of images. Typical times between ingestion of the contrast material and image acquisition (the time during which the formulation is stable) can range from a few minutes (e.g., less than 20 minutes) for imaging of the esophagus and stomach, to about 20 to about 120 minutes for imaging of the small intestine, and about 1 hour to about 2 days for imaging of the colon.

[0029] In various embodiments, the particles are maintained in suspension, at least in part, by incorporating a suspending agent into the formulation. Exemplary suspending agents are incorporated into the formulation in an amount of about 0.1% to about 20%, such as about 0.5% to about 15%, such as about 1% to about 10%, such as about 3% to about 8%. Exemplary formulations of the present invention are prepared as unit dosage formulations, the dosage being determined for an individual patient prior to administration of the drug, and the formulation being prepared immediately prior to its administration to a subject in a clinical setting.

[0030]

[0030] In various embodiments, the present invention provides formulations and methods for using low concentrations of low true density hollow borosilicate microparticles, for example about 1 to about 10% w / w, to achieve a formulation with a target CT value range of about -20 to about -70 HU or about -160 to about -300 HU. In other embodiments, the present invention provides the use of low concentrations of low true density hollow borosilicate microparticles to achieve a formulation with a minimum calculated iodine concentration of less than about 1 mg iodine / mL during dual-energy CT or multi-energy CT image reconstruction. Such low concentrations of low true density hollow borosilicate microparticles are, in various embodiments, in the range of about 0.2% to about 12% w / w of the aqueous suspension. Alternatively, such low concentrations of low true density hollow borosilicate microparticles are, in various embodiments, in the range of about 0.5% to about 9% w / w of the aqueous suspension or about 0.5% to about 4% or about 5% to about 9% of the aqueous suspension. The low true density hollow borosilicate microparticles of the present invention, in various embodiments, have a density of about 0.10 to about 0.40 g / cm 3 In another embodiment, the low true density hollow borosilicate microparticles of the present invention have a true density of about 0.2 to about 0.35 g / cm. 3 The range is.

[0031]

[0031] In various embodiments, our invention describes a formulation of highly stained HSHBM oral contrast material that stains the intestinal lumen below about -160 HU, resulting in CT values ​​that are just outside the range of soft tissue window level viewing settings typical for CT (e.g., 400 / 40 HU window / level settings, which assign a visible grayscale to voxel signals between -160 and +240 HU, pure black to voxel signals below about -160 HU, and pure white to voxel signals above about +240 HU). In various embodiments, the invention provides a method, including artificial intelligence segmentation or evaluation of CT images resulting from scans obtained with our HSHBM formulations, that incorporates an informed selection of HSHBM formulations to allow the intestinal lumen to appear much more uniform in terms of CT value (all stained) at typical soft tissue viewing window and level settings (Figures 9 and 14), thereby facilitating the perception and delineation of more hypostained disease.

[0032]

[0032] In various embodiments, the present invention provides formulations of oral contrast material that stain the intestinal lumen to values ​​that are about 50 to about 300 HU below the CT value of the intestinal wall, thereby allowing for more accurate measurement and perception of the thickness of the intestinal wall (Figures 4, 15 and 16). The informed concentrations of various embodiments of the present invention provide a CT value of the intestinal lumen contrast material that is between the CT value of the intestinal wall and the CT value of fat, or below the CT value of fat, but not more than about 100 HU below the highest HU value that is rendered as solid black in typical abdominal CT window and level settings.

[0033] In various embodiments, the present invention provides formulations of high-staining oral contrast material that provide greater spatial resolution of intestinal folds when viewed in a typical soft tissue intestine (FIG. 15).

[0034]

[0034] In various embodiments, the present invention provides formulations of HSHBM as oral contrast material having a CT number of less than about -20 HU and a 80:140 kVp CT number ratio of about 0.90 to about 1.00. In various embodiments, the present invention provides formulations of HSHBM contrast material that exhibit an apparent iodine concentration of less than about 1.0 mg iodine / mL upon iodine image reconstruction from dual-energy CT, multi-energy CT and photon-counting CT scans. In various embodiments, our invention describes formulations of HSHBM contrast material that exhibit an apparent iodine concentration of less than about 0.8 mg iodine / mL upon iodine image reconstruction from dual-energy CT, multi-energy CT and photon-counting CT scans (Figure 17).

[0035] In various embodiments, sugar alcohols, magnesium hydroxide, polyethylene glycol, cellulose or other materials known to increase the rate of intestinal transit may be added, either alone or in combination, to the aqueous pharmaceutical formulation.

[0036] In various embodiments, one or more of tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethylsiloxane silica, or other flow agents may be added during manufacture or to improve powder dispersion of the powder product (i.e., hollow particles or hollow particles and one or more suspensions or other additives useful prior to hydration in producing an aqueous pharmaceutical formulation).

[0037] In various embodiments, excipients may be added to improve the degree of intestinal fullness. To achieve this goal, excipients such as xanthan gum, gellan gum, guar gum, polyethylene glycol, magnesium hydroxide, cellulose, silica, sugar alcohols, or other fillers may be introduced to modify the thickening (e.g., viscosity or osmolality) of the formulation. In various embodiments, thicker formulations prevent collapse of the intestinal lumen, particularly the proximal small intestine and stomach, compared to less viscous formulations. In various embodiments, higher osmolality formulations prevent water absorption from the intestinal lumen, thus maintaining fullness of the intestinal lumen, compared to lower osmolality formulations. In various embodiments, the osmolality ranges from about 90 to about 450 milliosmoles per kilogram, or from about 120 to about 180 milliosmoles per kilogram, or from about 180 to about 295 milliosmoles per kilogram. In various embodiments, the viscosity of the contrast agent ranges from about 150 to about 2000 centipoise (cP), or from 300 to about 1500 cP, or from about 600 to about 1500 cP.

[0038]

[0038] The negative enteric contrast agents of the present invention may be used with or without intravenous contrast for CT imaging. The negative enteric contrast agents of the present invention may be formulated to provide CT values ​​that improve the clarity of intravenous contrast material enhancement of the intestinal wall and adjacent vascularized structures.

[0039] In various embodiments, the intestinal contrast agents of the present invention exhibit one or more leachable arsenic (As), cadmium (Cd), lead (Pb) and mercury (Hg) levels of less than 15, 5, 5 and 30 micrograms per dose, respectively, when incubated with simulated gastric fluid for 4 hours. In various embodiments, the intestinal contrast agents of the present invention exhibit one or more leachable arsenic (As), cadmium (Cd), lead (Pb) and mercury (Hg) levels of less than 1.5, 0.5, 0.5 and 3.0 micrograms per dose, respectively, when incubated with simulated gastric fluid for 4 hours.

[0040]

[0040] In various embodiments, the present invention provides CT images of the dense HSHBM intestinal contrast-enhanced CT scans of the present invention used in conjunction with software including artificial intelligence or deep learning for segmentation of the intestine during CT and image interpretation, including visualization of the intestine from non-intestinal structures, visualization of the intestinal centerline, measurement of intestinal segment lengths, and identification of abnormally thickened intestinal wall, abnormally over- or under-enhanced intestinal wall, or focal lesions in or around the intestine.

[0041]

[0041] In an exemplary embodiment, the present invention provides an enteral contrast medium formulation, HSHBM in water suspension. The material is formulated in a pharma- ceutically acceptable aqueous solvent in which the particles are suspended. In an exemplary embodiment, the shell material is covalently or weaker intermolecular forces bound to a polymer, organic material, or hydrogel to improve dispersion in the aqueous medium. In an exemplary embodiment, the solvent contains an additive to retain fluid in the intestinal lumen. In an exemplary embodiment, the aqueous solvent contains an agent to promote intestinal motility. In an exemplary embodiment, the shell material is covalently or weaker intermolecular forces bound to a polymer, organic material, or hydrogel that reduces the CT value of the entire formulation at low CT kVp compared to high CT kVp settings.

[0042] In various embodiments, the HSHBM utilized in the formulation contains less than 5% by weight of non-buoyant particles, such as broken or fractured microparticles and microparticles with small internal voids and a dense outer shell.

[0043]

[0043] Isostatic crush strength determines the volume percentage of HBM that will collapse or break when a specified pressure is applied. Breaking of HBM can result in undesirable small irregular particles in the contrast agent, which can reduce the usefulness of the resulting formulation. In various embodiments, the present invention provides for the use of HSHBM such that less than about 10% of the volume of HSHBM utilized in the formulation breaks at a pressure of 500 psi. In various embodiments, less than 3% of the volume of HSHBM utilized in the formulation breaks at a pressure of 500 psi. Breaking of HSHBM for accurate breakage measurements is performed when the HSHBM is in an isolated dry powder form, rather than when in a liquid formulation. By way of example, in exemplary embodiments, volume refers to the volume of dry powder HSHBM prior to formulation, as measured by a pycnometer.

[0044]

[0044] Non-buoyant particles of HBM in aqueous suspension are undesirable because non-buoyant particles may include broken or damaged particles and particles with small internal voids and dense outer shells. Such particles may cause undesirable stratification in the intestinal lumen. In various embodiments of our invention, less than about 5% of the volume of HSHBM used in the formulations of the invention is non-buoyant. In various embodiments of the invention, less than about 3% of the volume of HSHBM particles is non-buoyant. As a non-limiting example, this measurement of the non-buoyant volume fraction may be performed by simple suspension in water of a known volume of HSHBM as determined by dividing the mass of the sample by true gravity, and then measuring the volume of the non-buoyant fraction in mL using a separatory flask with a graduated cylinder at the dependent end. Alternatively, the measurement of the non-buoyant volume fraction may be performed by isolating and drying the floating and non-buoyant fractions and measuring the volume of each by gas pycnometer.

[0045]

[0045] In an exemplary embodiment, the present invention provides a contrast medium formulation that can be delivered to the digestive system and other body cavities, which may be natural, such as the vagina or bladder, or surgically created body cavities, such as a bladder substitute, or artificial medical devices, such as tubes, catheters, pouches, reservoirs or pumps.

[0046] Further exemplary advantages, objects and embodiments of the present invention are set forth in the following description.

[0047]

[0047] The intestinal contrast agent of the present invention is substantially different from the microbubble contrast agents used in ultrasound imaging. Microbubbles in ultrasound are typically gas microbubbles of perfluorocarbon gas or nitrogen gas, with a surface coating of flexible materials such as albumin, carbohydrates, lipids, or biocompatible polymers that allow the bubbles to expand and contract with ultrasound, thereby amplifying the signal during ultrasound imaging. The mean particle size of ultrasound contrast agent microbubbles is typically in the 2-6 micron range, with commonly used concentration levels of about 10 million microbubbles per mL. Thus, it is calculated that less than 1% of the volume of a microbubble-type ultrasound contrast agent formulation is gas-filled or hollow, and such a small volume fraction of gas or void space does not produce a sufficiently low signal to be useful as a negative contrast agent during CT imaging. Even if the bubbles were pure gas (-1000HU, which is the lowest HU CT number on the CT number scale), a 1% volume of microbubbles in suspension in water (0 HU at CT) would give a CT number of about -10HU, which is not much different from water itself. Two recent review articles on ultrasound microbubble contrast agents are listed here: 1)Ultrasound microbubble contrast agents: Fundamentals and application to gene and drug delivery By: Ferrara, Katherine; Pollard, Rachel; Borden, Mark. Book Series: ANNUAL REVIEW OF BIOMEDICAL ENGINEERING Volume: 9 Pages: 415-447 Published: 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: JUN 2004

[0048]

[0048] The intestinal CT contrast material of the present invention differs substantially from previous perfluorocarbon oral contrast materials proposed for CT and MR and X-ray imaging. These previous agents comprise a perfluorocarbon liquid, which may or may not be emulsified; the perfluorocarbon may or may not be brominated. In these previous agents, the perfluorocarbon expands to a gas at body temperature, producing a negative contrast signal and additional intestinal distension. Disadvantages of perfluorocarbon agents are that they can be difficult to administer, they can have an oily texture that can be poorly tolerated by patients, and their expansive properties pose safety concerns when administered to diseased intestinal segments. 2 (Also US Pat. Nos. 5,205,290; 4,951,673.) Brominated perfluorocarbons have been described as CT contrast agents, which can produce a positive CT value signal.

[0049]

[0049] Other embodiments, objects and advantages of the present invention will become apparent from the detailed description that follows. [Brief description of the drawings]

[0050] [Figure 1]

[0050] The range of CT values ​​for soft tissue, fat, neutral oral contrast (OC) and positive OC typically seen in unenhanced CT and CT enhanced with intravenous contrast is shown. Gaps are seen in the range between water and fat (-20 to -70 HU) and below fat (-120 HU). Also shown on the right side of this figure are brackets showing the range of CT values ​​displayed with a typical soft tissue window / level observation setting of 400 / 40 HU. Voxels between -1000 and -160 HU are displayed as black, then gradually become whiter up to 240 HU, above which voxels are displayed as pure white. An exemplary embodiment of the present invention allows differentiation between fat and water by including an HSHBM formulation that provides a CT value between fat and water (-70 HU to -20 HU). An exemplary embodiment of the present invention includes an HSHBM formulation that exhibits CT values ​​below the fat and below the lower limits of the soft tissue viewing window / level settings (-160 HU and -300 HU), thereby providing a nearly uniformly dense appearance of the intestinal lumen when viewed with typical abdominal window and level settings. [Diagram 2]

[0051] Graph of CT numbers (y-axis) and virtual monochromatic energy image keV (x-axis) for various materials. Iodine solutions show characteristically high CT numbers at low keV and decreasing CT numbers at higher keV. Conversely, water remains unchanged at 0 HU. Soft tissues such as muscle or other solid organ parenchyma show almost no change in CT numbers at all keVs, except for a slight increase in CT numbers at low keV. Aqueous suspensions of standard hollow borosilicate microparticles show negative CT numbers at high keV and increasing CT numbers at low keV. The slope of the curves for these aqueous suspensions of normal hollow borosilicate microparticles (RHBM) is similar to iodine solutions, so such suspensions appear to show substantial undesirable spurious iodine signals in iodine maps. Unlike iodine, fat shows a positive CT number slope with increasing keV. Various embodiments of the present invention utilize an aqueous suspension of high silicon hollow borosilicate microparticles (HSHBM), which exhibit only minimal CT number elevation in low keV image reconstructions. This minimal negative slope allows these various embodiments of the present invention to be easily distinguished from fat, and the small degree of slope prevents the various embodiments of the present invention from appearing as false iodine concentrations on iodine maps. keV = kiloelectron volts. [Diagram 3]

[0052] CT scans obtained with aqueous high silica hollow borosilicate microparticle (HSHBM) enteric CT contrast material formulation are shown. A) CT scan displayed at a soft tissue window / level of 400 / 40HU. B) The same CT scan displayed at a lung window / level of 1500 / -600HU. The CT value of the HSHBM CT contrast material is -200HU in the posterior bowel (thin arrow) and is seen as a medium tone that is more dense than the surrounding fat (-100HU) on the right CT image. The bowel wall of the HSHBM enteric CT contrast material is clearly visible on the right soft tissue window / level CT image as a slightly more dense CT value than the surrounding fat (thin arrow). Conversely, for the bowel containing air (thick arrow), the bowel wall is not visible. The loss of visualization of the bowel wall for air-filled bowel is due to the volume averaging of the soft tissue bowel wall (CT value 50 HU) and adjacent air (CT value -1000 HU), which causes the interface voxels to be rendered as exhibiting a CT value below -160 HU (outside the soft tissue window / level) and therefore renders the bowel wall as black on the CT scan when viewed in the standard soft tissue viewing window. [Figure 4]

[0053] CT scans of different materials against a 2 mm thick plastic sheet simulating the CT number and thickness of the intestinal wall to demonstrate the accuracy of in vitro gut wall measurements with different oral contrast agents. An open plastic cylinder was attached to an obliquely placed plastic sheet (CIRS phantom) specifically engineered to simulate the CT number of the non-enhanced gut wall. Cylinders were filled with Readi-Cat 2™ barium sulfate positive oral contrast (CT value 375 HU), room air (CT value -1000 HU), VoLumen™ neutral oral contrast (CT value 23 HU), 9% w / w test article HSHBM intestinal CT contrast (9% w / w HSHBM with true density 0.29 in aqueous suspension, CT value -185 HU) and 4% w / w test article HSHBM intestinal CT contrast (4% w / w HSHBM with true density 0.29 in aqueous suspension, CT value -85 HU) and the setup was partially immersed in canola oil to simulate the surrounding mesenteric fat CT value. Images were viewed at standard soft tissue windows / levels. Bowel wall thickness was measured using ImageJ by the number of voxels that were within zero ± 3 standard deviations from background noise in the entire 2 cm long region of interest. The measured thickness of the simulated plastic sheet intestinal wall was 1.4 mm for the barium sulfate positive oral contrast agent, 0.9 mm for air, 6 mm for the VoLumen neutral oral contrast agent, 2.0 for the 9% w / w test article HSHBM intestinal CT contrast agent, and 2.0 for the 4% w / w test article HSHBM intestinal CT contrast agent. These results demonstrate that the exemplary HSHB aqueous suspension provides highly accurate depiction of the intestinal wall in vitro compared to the positive, neutral, and gas CT contrast agents. [Diagram 5]

[0054] CT abdominal images of a volunteer who ingested HSHBM are shown, where excessive concentrations of HSHBM create undesirable false iodine signals. A) After ingesting 1200 mL of an aqueous suspension of 15% w / w test article HSHBM intestinal CT contrast agent (15% w / w HSHBM with true density of 0.35 in aqueous suspension, CT value -195 HU), vials containing water, the same HSHBM contrast material (small white arrows) and iodine contrast agent (thick white arrows) were placed on the abdomen and the patient was scanned with a dual energy CT scanner. B) On an iodine map overlay of the same scan, a characteristically distinct iodine signal (red) was seen in the iodine contrast agent vial and an undesirable false iodine signal was seen in the HSHB contrast agent vial. Similarly, an undesirable false iodine signal was seen in the intestine containing HSHB contrast material (small black arrows). [Figure 6]

[0055] CT images (top two rows) and iodine maps (bottom rows) of vials of contrast material displayed at different window and level viewing settings are shown. Vials containing small amounts of iodine (rows A and B) are shown, with row B containing 1 mg iodine / mL iodine, the threshold for iodine detectable by dual-energy CT. For comparison, a vial of water containing no iodine is shown in row C. Note: This in vitro scan has much lower noise than clinical CT scans, which often have much higher noise and artifacts. Vials of 0.27 g / cm3 HSHBM aqueous suspension are shown in rows D, E, and F. Of these, vials of 9, 5, and 3% w / w HSHBM showed apparent iodine concentrations below 1 mg iodine / mL, while the higher concentration HSHBM vials showed undesirable apparent iodine concentrations above 1 mg iodine / mL. Comparative RHBM aqueous suspensions showed high undesirable apparent iodine concentrations (rows I, J, and K). The numerical results of this CT experiment are shown in Figure 7. [Figure 7]

[0056] CT experiments showing CT numbers, 80:140 kVp CT number ratios and apparent iodine concentrations of various contrast agents. HSHBM agents are 270TA and 350TA. RHBM agents are 45P25, 60P18, iM30K and 34P. Target CT numbers for oral contrast agents of -20 to -70 HU were achieved with 350TA and 270TA at 3% w / w in aqueous suspension, respectively. Target CT numbers for oral contrast agents of -160 HU to -290 HU were achieved by using 270TA at 9% w / w in aqueous suspension. Vials A-K correspond to the CT images in Figure 6. na=not applicable. Y=yes. N=no. [Figure 8]

[0057] Demonstration of post-CT processing display of intravenous iodized and enteric HSHBM contrast material without the use of dual energy CT. Intravenous positive contrast-enhanced CT obtained on patient after ingestion of 1200 mL of 9% w / w test article HSHB enteric CT contrast agent (9% w / w HSHBM with true density 0.29 in aqueous suspension, CT value -180 HU). A) Volume-rendered image shows blood vessels and some organs. The enteric lumen does not appear opaque due to its radiolucency. B) Same image, where enteric contrast has also been volume-rendered based on seeded growth segmentation of the intestine. This kind of display of both intravenous and enteric contrast material is not possible with current neutral or positive enteric contrast agents. [Figure 9]

[0058] Demonstration of post-CT display of intravenous iodized and enteric HSHBM contrast material using dual-energy CT. A) CT of the abdomen after ingestion of 1200 mL of 9% w / w test article HSHBM enteric CT contrast material (9% w / w HSHBM with true density 0.29 in aqueous suspension, CT value -180 HU) and without intravenous contrast, displayed in soft-tissue window / level viewing settings. B) Dual-energy CT scan obtained 2 minutes later with subsequent intravenous iodized positive contrast-enhanced CT, displayed in soft-tissue window / level viewing settings. Arrows indicate excellent detail of the gastric and jejunal anatomy with clear intravenous enhancement of the bowel wall. The bowel lumen is black as expected in this soft-tissue window / level viewing setting, regardless of whether it contains dense contrast (black arrow) or gas (white arrow), thus providing a uniform appearance of the bowel lumen. C) Iodine map overlay shows no unwanted false iodine signal in the intestinal lumen. As is typical for any DECT scan, regardless of the type of oral contrast, some unwanted false iodine signal is seen in the muscle. D) Lung window / level view settings of 1500 / -600HU reveal that the intestinal lumen in the stomach and jejunum contains dense contrast material, which appears as a slightly denser intermediate tone compared to the fat CT value (arrows). E) Iodine map shows no unwanted false iodine signal in the intestinal lumen. Note: There is some stool in the colon because the HSHBM contrast has not yet reached those sections of the colon. This stool material appears as an intermediate signal in the soft tissue view settings and as a false iodine signal. [Figure 10]

[0059] Demonstration of post-CT display of intravenous iodized and intestinal HSHBM contrast material using dual energy CT. A) CT of the abdomen with intravenous iodized positive contrast after ingestion of 1200 mL of 9% w / w test article HSHBM intestinal CT contrast (9% w / w HSHBM with true density 0.29 in aqueous suspension, CT value -180 HU) and displayed with soft tissue window / level observation settings. The intestinal lumen is stained. B) Iodine map, where iodine signal is shown as orange. No unwanted false iodine signal is seen in the intestinal lumen (however, there is some unwanted false iodine signal in the muscle as is commonly seen in clinical dual energy CT). C) Dual energy CT reconstruction with intestinal lumen HSHBM contrast rendering as purple overlay on CT and intravenous iodine contrast rendering as orange overlay. Achieving this type of software visualization of oral to intravenous contrast from soft tissues is not easy with traditional oral contrast agents because the CT values ​​of positive oral contrast are similar to positive IV contrast, and the CT values ​​of neutral oral contrast are similar to soft tissues and biological fluids. [Figure 11]

[0060] Table of CT results with various hollow particulate aqueous suspensions. HSHBM agents achieve less than -160 HU at CT, enabling visualization from fat at CT. Additionally, HSHBM agents achieve 80:140 kVp CT number ratios above 0.90 and below 1.0, which are ideal for visualization from both fat and true iodine signals at dual energy CT. Note: Polymeric phenolic hollow microspheres can also achieve these ranges, but are potentially toxic, less stable, and difficult to solubilize in aqueous suspension. [Figure 12]

[0061] Table of leachable heavy metals from various hollow borosilicate microparticles (HBM). The oral permissible daily exposures (PDEs) for the class 1 elemental impurities arsenic (As), cadmium (Cd), lead (Pb) and mercury (Hg) are shown in the second row of the table and extrapolated to a 145 gram dose of HBM in the third row of the table. The toxicity of an elemental impurity is related to its degree of exposure. The levels of leachable elemental impurities in hollow borosilicate microparticles were assessed by two methods. The first method used 75% aqua regia digestion of the samples followed by ICP-MS analysis. The results are reported in parts per million (ppm) in the table. The second method used 8 hours of sample incubation at 40 degrees Celsius in a simulated gastric fluid solution that mimics an acidic environment similar to that of the stomach. After filtration, the filtrate is analyzed by ICP-MS. In the tables below, results are reported in micrograms (ug) for normal regular HBM (RHBM) and a representative high silicon HBM (HSHBM) material and for the oral aqueous formulation. [Figure 13]

[0062] 1 is a table showing a comparison of the oxide shell composition of RHBM (normal hollow borosilicate particulate) and HSHBM (high silicon hollow borosilicate particulate) as determined by XRF (X-ray fluorescence). [Figure 14]

[0063] Coronal CT scans of the abdomen obtained with positive oral contrast (left) and HSHBM oral contrast (right image) viewed using standard soft tissue window / level settings of 400 / 40HU. The bowel lumen in the positive oral contrast scan (left) has CT values ​​ranging from -1000 (gas) to +350, spanning the entire grayscale from black to pure white, so it can be confusing to distinguish the bowel from other structures due to the extreme variability in bowel tone. The bowel lumen in the deep HSHBM oral contrast scan is much easier to visualize because it is uniformly black or nearly black, as the HSHBM was formulated to be -180HU, just below the CT value that would appear as black with standard soft tissue window level viewing settings. Furthermore, for both scans, blood vessels are enhanced with positive intravascular contrast that is >200 HU and can be difficult to distinguish from bowel enhanced with positive oral contrast (left image), but are extremely easy to distinguish from bowel enhanced with HSHBM oral contrast (right image), illustrating how the precise formulation of our inventive HSHBM contrast agent simplifies image interpretation for both human readers and artificial intelligence. [Figure 15]

[0064] Spatial resolution CT phantom scanned at 120 kVp with CT. The spatial resolution CT phantom is a block of plastic with a group of four plastic bars between five hollow slits of equal thickness. The hollow slits and plastic columns are 1.7, 1.3, 1.0, 0.90, 0.73 and 0.57 mm thick (shown on the x-axis). The plastic is 150 HU. The plastic bars mimic intestinal folds during CT, which can be less than 3 mm thick and as thin as 1 mm thick or less. The slits are filled with different types of oral contrast agents: air (-1000 HU), HSHBGM 9% w / w (-180 HU), water (0 HU) and iohexol diluent 9% I / mL (220 HU). The CT images are displayed using typical abdominal window / level settings of 400 / 40 HU. The best spatial resolution was observed when the phantom slits were filled with HSHBGM. When filled with HSHBGM, all four plastic bars of a group could be seen down to 0.90 mm thickness / spacing, whereas when filled with water, all four bars could be seen down to 1.0 mm, with iohexol positive oral contrast down to 1.3 mm, and with air up to 1.7 mm. The large difference in HU between HSHBGM and plastic bars allows the best visualization of the plastic bars without straying too far from the greyscale of a typical abdominal window / level setting. [Figure 16]

[0065] Thickness measurements of "gut wall" CT phantoms indicate that intestinal luminal contents measuring between -50 and -300 HU provide the most accurate determination of intestinal wall thickness with different CT scanners and different fields of view. Phantoms similar to those in Figure 4 were partially immersed in lard and then filled with different contrast agents or materials including air (-1000 HU), various HSHBGM aqueous suspensions to achieve HU values ​​between -700 and -50 HU, canola oil (-110 HU), water (0 HU), saline (5 HU), dilutions of iohexol in water to achieve HU values ​​between 50 and 600 HU, and the commercially available oral contrast agents Breeza (0 HU), VoLumen™ (20 HU), Omnipaque 12% I / mL (300 HU) or Readi-Cat 2™ (400 HU) (see x-axis). A 2 mm thick plastic plate was manipulated to mimic an unenhanced bowel wall CT attenuation of 40 HU (Figure 16A) or a 5 mg I / mL contrast-enhanced bowel wall of 165 HU (Figure 16B). The phantoms were scanned in two different CT scanners (Philips IQon and General Electric Revolution 256) with two different fields of view (22 cm giving a voxel size of 0.43 mm2 and 50 cm giving a voxel size of 0.98 mm2). Images were analyzed for each scanner and field of view to determine the apparent thickness of the plastic plate by defining a rectangular region of interest on the plastic plate and counting all voxels that were within 3 standard deviations of the HU measurement of the plastic plate, then multiplying by the voxel area. For the unenhanced bowel wall phantom (Figure 16A), bowel wall thickness measurements best approximated the true 2 mm thickness for bowel luminal contrast of -50 to -300 HU. Intestinal luminal contents below -300 HU and above 100 HU grossly underestimated the intestinal wall thickness, whereas intestinal luminal contents between 0 and 100 HU grossly overestimated the intestinal wall thickness, the latter because the intestinal wall CT attenuation was too close to the intestinal luminal CT attenuation.For the IV contrast-enhanced intestinal wall phantom (Figure 16B), again for intestinal luminal contrast between -50 and -300 HU, the intestinal wall thickness measurements best approximated the true 2 mm thickness.Luminal contents below -300 HU and above 100 HU resulted in gross underestimation of the intestinal wall thickness, whereas luminal contents between 0 and 100 HU resulted in gross overestimation of the intestinal wall thickness, the latter because the intestinal wall CT attenuation was too close to the intestinal luminal CT attenuation. In both experiments, a wider CT field of view resulted in a larger voxel size and therefore more volume was averaged, exacerbating the disturbance of the intestinal wall thickness measurements. [Figure 17]DECT scans of patients with HSHBM of different concentrations and true densities shown with typical abdominal window / level settings of 400 / 40HU. Top row: DECT scans obtained after oral administration of 350TA HSHBM 15% w / w show a CT attenuation of -200HU in the gastric lumen (S) on 120kVp-like images (top left). The gastric wall is well visualized on the 120kVp-like images because the gastric lumen contrast material is just slightly below the HU of the typical abdominal window / level required to appear as pure black. Unfortunately, on the corresponding iodine map (top right) there is an unacceptable spurious iodine concentration of 2.1mg iodine / mL visualized as a non-black gray-scale signal (yellow arrow), which may be misinterpreted as a true iodine signal or may mask the true iodine signal of adjacent iodine-enhanced structures on the image reconstruction. Bottom row: A DECT scan obtained after oral administration of 270TA HSHBM 9% w / w shows a CT attenuation of -180 HU in the gastric lumen (S) on a 120 kVp-like image (bottom left). For this scan, intravenous iodine contrast is also provided. Again, the gastric wall is well delineated, as the gastric lumen contrast material is just slightly below the HU of a typical abdominal window / level required to appear as pure black. In addition, the corresponding iodine map (bottom right) shows no visible iodine signal in the gastric lumen (yellow arrows), and quantitative measurements in the gastric lumen show less than 1 mg iodine / mL, pointing to a substantial lack of iodine signal artifact. Enhancement of the bowel wall by the bright iodine contrast is beautifully shown. Informed formulation of oral contrast material of appropriate concentration, individually tailored to HSHBM true density, allows for proper DECT iodine map assessment of the bowel wall. [Figure 18]DECT scans of a phantom with different borosilicate hollow microsphere suspensions obtained on a General Electric 750 HD DECT scanner, including 120 kVp-like reconstructed images (left image) and iodine maps (right image). The CT phantom was constructed by surrounding seven empty cylinders with pork fat, the latter to simulate human fat. Within the central cylinder are vials of water (W) (top left center) and one of iodine (I) (bottom right center) containing 2 mg I / mL in aqueous solution. The outer cylinders are filled with 270TA HSHBM 9% w / w (top right), 270TA HSHBM 7.5%, 270TA HSHBM 3%, 45P RHBM 30% w / w, 45P RHBM 20% w / w, and 350TA 15% w / w (top left), starting from the top right and proceeding clockwise. 270TA refers to the test material siliceous hollow borosilicate microparticles with a true density of 0.27 g / cm3, 45P refers to regular hollow borosilicate microparticles with a true density of 0.45 g / cm3, and 350TA refers to the test material siliceous hollow borosilicate microparticles with a true density of 0.35 g / cm3. All of the RHBM and HSHBM suspensions appeared to stain on the 120 kVp-like CT images with HU values ​​of -178, -143, -68, -209, -158, and -213 HU, respectively, as expected for water, which is -9 HU, and 2 mg I / mL, which is 38 HU. It should be noted that the 270TA HSHBM 9 and 7.5% w / w suspensions stain more strongly than fat, and the 270TA HSHBM 3% w / w suspension measures -95 HU, making it brighter than fat and therefore distinguishable from fat on the 120 kVp images. On iodine image reconstruction, water measures -0.4 mg I / mL and iodine measures 1.7 mg I / mL, as expected. The 270TA HSHBM suspensions measure less than 0.7 mg I / mL each, which is below the threshold of 0.8 mg I / mL that confirms the presence of iodine and would not be misinterpreted as an iodine signal or prevent the detection of iodine in adjacent structures. The 270TA HSHBM measures 0.66, 0.45, and 0.15 mg I / mL for the 9, 7.5, and 3% w / w suspensions, respectively.However, the 45P RHBM 20 and 30% w / w suspensions showed very bright signals, even higher than the actual iodine solution vials, giving measured iodine concentrations of 3.1 and 3.9 mg I / mL, respectively. The 350TA HSHBM 15% w / w also showed an artifactually high iodine concentration of 1.2 mg I / mL, which may be misleading as to actual iodine content or may obscure the presence of iodine in adjacent structures. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] II. Definition

[0066] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature and laboratory procedures of organic chemistry, pharma- ceutically acceptable formulations, and medical imaging used herein are those commonly used and well known in the art.

[0052]

[0067] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical referent of the article. By way of example, "an element" means one element or more than one element.

[0053]

[0068] A "disease" is a condition in the health of an animal in which the animal is unable to maintain homeostasis and where the animal's health will continue to deteriorate if the disease is not ameliorated.

[0054]

[0069] "Concurrent" administration refers to the use of an imaging agent in conjunction with a medical imaging procedure performed on a subject. As one of ordinary skill in the art would understand, concurrent administration of an imaging agent to a subject includes administration during or prior to performing a medical imaging procedure such that the imaging agent is visible in a medical image of the subject.

[0055]

[0070] The term "half-life" or "t 1 / 2"Half-life", as used herein in connection with administering the enteric contrast medium of the present invention to a patient, is defined as the time required for the effective enteric concentration of a drug in a patient to decrease by a factor of two. The half-life associated with a contrast medium may be more than one depending on multiple clearance mechanisms, redistribution and other mechanisms known in the art. For hollow particle contrast materials, whose effectiveness depends on the integrity of the hollow void, the effective concentration is directly related to the concentration of the hollow void volume of the particle in an aqueous formulation in vivo. For further explanation of "half-life", see Pharmaceutical Biotechnology (1997, DFA Crommelin and RD Sindelar, eds., Harwood Publishers, Amsterdam, pp 101 - 120).

[0056]

[0071] "Enteric contrast medium formulation", as used herein, unless otherwise specified, means a pharma- ceutically acceptable liquid or paste formulation for administration to a subject, comprising at least one enteric contrast medium, with or without at least one pharma- ceutically acceptable excipient for suspending the medium, prepared by dissolving, emulsifying or suspending an enteric contrast medium as described herein, e.g., in the form of a powder, emulsion or mash, in a pharma- ceutically acceptable solvent prior to use for administration to a subject. Preferably, the suspending medium is water.

[0057]

[0072] The term "hollow borosilicate microparticles", or "HBM", is used herein to describe particles composed of borosilicate with an outer diameter of less than 500 microns and with an internal void that may contain gas or a partial vacuum. The term "normal HBM", or "RHBM", is used herein to refer to some HBMs in which the shell material is composed of about 60-85% SiO2 and has more than 2% oxides of atoms with atomic numbers greater than 10 (e.g., sodium oxide or aluminum oxide). The term "high silicon HBM", or "HSHBM", is used herein to refer to HBMs in which the shell material is composed of more than about 92% silicon dioxide and less than about 2% oxides of atoms with atomic numbers greater than 10.

[0058]

[0073] The term "microsphere" as used herein refers to some microparticles that are spherical in shape. The term "microparticle" as used herein includes microspheres and other particles having diameters ranging from about 1 to about 800 microns.

[0059]

[0074] The term "residence time," as used herein in connection with administering an enteric contrast medium to a patient, is defined as the average time that an enteric contrast medium remains in the patient's body after administration.

[0060]

[0075] The term "CT" refers to any type of computed tomography imaging, including low-dose, dual-energy, multi-energy and photon-counting CT.

[0061]

[0076] As used herein, a "pharmaceutical acceptable carrier" includes any material that, when combined with the microspheres (particles), is compatible with the microspheres and tolerated by the subject to whom the pharmaceutical formulation in which the microspheres and the carrier are combined is administered. Examples include any of the standard medical carriers, such as, but not limited to, phosphate buffered saline solutions, water, emulsions such as oil / water emulsions, and various wetting agents. Other carriers may also include sterile solutions. Typically, such carriers contain excipients such as starch, milk, sugar, sorbitol, methylcellulose, certain types of clay, gelatin, stearic acid or its salts, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols, or other known excipients. Such carriers may also include flavor, texture, and color additives or other ingredients. Compositions containing such carriers are formulated by well-known conventional methods.

[0062]

[0077] As used herein, "administering" means oral administration, topical contact, rectal, intravenous, intraperitoneal, intralesional, intranasal or subcutaneous administration, intrathecal administration, or infusion into a surgically created pouch or surgically placed catheter or device, or implantation of a sustained release device, such as a mini-osmotic pump, to a subject.

[0063]

[0078] The term "enteric contrast medium" as used herein is understood to mean a dry or unsuspended component or mixture of components comprising at least one X-ray absorbing substance and, optionally, at least one pharma- ceutically acceptable excipient, which itself may contain other components, such as taste masking agents, antioxidants, wetting agents, flow or anti-caking agents, emulsifiers, etc. The "dry suspension mixture" may subsequently be dissolved or suspended in a suspending medium to form the enteric contrast medium formulation of the present invention. Terms such as "suspending medium" and "pharma-ceutically acceptable excipient" as used herein refer to a medium that emulsifies or suspends one or more components of the enteric contrast medium.

[0064]

[0079] The terms "coating" and "coated" as used herein are understood to include coatings that are biocompatible when in environments having acidic, neutral, or basic pH values.

[0065]

[0080] The term "deeply stained" as used herein to describe a contrast material refers to having a CT value of less than about -20 HU.

[0066]

[0081] The terms "particle", "particles" and "particulate" as used herein refer to any shape of free-flowing material larger than about 1 nm, such as crystals, beads (smooth, round or spherical particles), pellets, spheres and granules. Particles can be hollow bubbles or can include multiple internal cavities. Exemplary specific particle sizes of particles include about 1 nm to about 500 microns, e.g., 1 micron to about 100 microns, including each single diameter value and each diameter range within the larger range across any endpoints. In various embodiments, the particles are larger than about 5 microns. Further useful particle sizes include, for example, about 5 microns to about 100 microns, e.g., about 20 microns to about 70 microns. Particles can contain gas or partial vacuum. Particles can be solid.

[0067]

[0082] The term "suspending agent" as used herein refers to any convenient agent known in the art that aids in forming and / or maintaining a suspension of a solid in a liquid (e.g., aqueous or oily). Exemplary suspending agents are selected from xanthan gum, gellan gum, guar gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, alginates, and sodium carboxymethylcellulose, with xanthan gum being preferred. The suspending agent may be used in any useful amount. Exemplary useful amounts are within the range of about 0 to about 20% by weight of the powder formulation and about 0 to about 10% by weight of the oral suspension. Exemplary suspending agents are incorporated in the formulation in an amount of about 0.1% to about 20%, e.g., about 0.5% to about 15%, e.g., about 1% to about 10%, e.g., about 3% to about 8%.

[0068]

[0083] "Stable", in the context of the present invention, refers to a suspension that does not significantly separate into its components as distinct phases or layers between the time the suspension is made and the time medical images are obtained after its administration to a subject in diagnostic imaging, or between the time the drug is suspended in a pharma- ceutically acceptable carrier and the time medical images are obtained after its administration to a subject in diagnostic imaging. As a non-limiting example, imaging is performed after a period of about 1 minute to about 180 minutes after ingestion of the contrast agent for imaging of the esophagus, stomach, or small intestine, and at least about 1 hour to about 2 days after ingestion of the contrast agent for imaging of the colon, during which time the suspension of the present invention does not significantly separate into its components as distinct layers.

[0069]

[0084] "True density", as the term is used herein, refers to the mass of a material per volume it occupies, excluding ambient gas in free communication with the atmosphere, such as may be measured using a gas pycnometer. "Average true density", as the term is used herein, refers to the mass of a given sample of a material per volume it occupies, excluding ambient gas in free communication with the atmosphere and gas between the particles of the material. Average true density may be measured using a gas pycnometer.

[0070]

[0085] The term "hollow" as used herein refers to a gas or vacuum that is confined and has highly restricted communication with the outside environment, such that the amount of gas or vacuum that escapes from the confined space is minimal and the amount of fluid that enters the confined space is minimal during the expected residence time in vivo. Any gas within the hollow borosilicate microparticles may be at a pressure lower than, the same as, or higher than the surrounding atmosphere or suspension solvent.

[0071]

[0086] The term "deep contrast agent" as used herein refers to a material that produces a lower CT value signal than water (CT value <-20 HU).

[0072]

[0087] "Unpleasant taste", as used herein, means that the enteral contrast medium contained therein is judged to taste unpleasant when ingested orally by a majority of human patients.

[0073] III. ILLUSTRATIVE EMBODIMENTS A. Composition

[0088] In various embodiments, the present invention provides an intestinal or non-vascular contrast agent that produces a CT value of less than about -20 HU upon CT imaging. In various embodiments, the present invention provides an imaging agent containing hollow borosilicate microparticles with an overall CT value of the formulation of about -20 to about -70 HU, below the CT value of water and above the CT value of fat. In various embodiments, the present invention provides an imaging agent containing hollow borosilicate microparticles with an overall CT value of the formulation of about -160 to about -300 HU, below the range of CT values ​​that would appear as black on a standard CT image viewed with standard soft tissue window and level viewing settings (400 and 40 windows and levels), but not so negative that the visibility of the intestinal wall is excessively lost. Exemplary materials include hollow borosilicate microparticles with a shell material that contains more than about 90% SiO2 and less than about 10% of other non-silicon oxides with z>10.

[0074]

[0089] In various embodiments, the shell of the particles of the contrast medium of the present invention is formed primarily of SiO2. In various embodiments, the shell of the particles of the contrast medium contains more than about 90% SiO2. In various embodiments, the shell of the particles of the contrast medium contains more than about 90% SiO2, less than about 5% B2O3, and less than about 4% oxides of atoms with atomic numbers greater than 10.

[0075]

[0090] In various embodiments, the particles have a true density of about 0.05 g / cm 3 In various embodiments, the particles of the contrast media of the present invention have a true density of at least about 0.1, at least about 0.2, or at least about 0.25 g / cm 3 In various embodiments, the true density of the particles is 0.5 g / cm 3 Less than 0.4g / cm3 Less than or equal to 0.35g / cm 3 is less than.

[0076]

[0091] In various embodiments, the interior space of the particle is at least partially filled with a gas, as discussed herein. When the interior of the particle is at least partially filled with a gas other than air, the gas is preferably not a hydrocarbon, a fluorocarbon, a sulfur compound, or a hydrofluorocarbon. In various embodiments, the gas is an elemental gas. In various embodiments, the gas contains carbon dioxide, oxygen, nitrogen, air, or a combination thereof.

[0077]

[0092] Although the exemplary particles of the present invention have a low true density, they maintain substantial isostatic crushing strength and do not break under the forces of medical ultrasound imaging, so that the hollow voids are not easily destroyed by physiological forces within the body of the imaged organism. The exemplary particles of the present invention exhibit a loss of 5% or less of hollow volume when subjected to an isostatic pressure of 500 psi. The exemplary particles of the present invention do not exhibit a loss of more than about 2% of hollow volume when subjected to pulses during ultrasound imaging and medical imaging, including pulses used in bursts of conventional ultrasound bubble contrast materials, for about 15 minutes.

[0078]

[0093] Exemplary contrast media of the present invention reduce the CT number of the lumen of the gastrointestinal tract or other body cavities to a CT number below pure black in a soft tissue window / level viewing setting. Exemplary contrast media of the present invention reduce the CT number of the lumen of the gastrointestinal tract or other body cavities to a CT number between water and fat during CT imaging.

[0079]

[0094] The contrast agents of our invention may provide improved CT imaging applications with one or more of the following benefits: 1) The intestinal lumen or non-vascular structures containing the contrast material of the present invention can be more easily distinguished from soft tissues than when saturated with currently available contrast materials. 2) The bowel or non-vascular structures can be filled with the contrast material of the present invention and differentiated during CT imaging from vascular structures or soft tissues that are enhanced by intravenous positive CT contrast agents. 3) Intestinal or non-vascular structures can be opacified with the contrast agents of the present invention for CT imaging without precluding the determination of wall enhancement (including bowel wall, bladder wall, other walls, and associated disease such as inflammation or neoplasms) associated with intravascular positive contrast material of such structures based on CT signal in mono-energy spectral CT or by the relative ratio of low-energy to high-energy x-ray attenuation in dual-energy or spectral CT.

[0080]

[0095] In various embodiments, the present invention provides enteral contrast agent hollow borosilicate microparticles. In various embodiments, the contrast agent can be selected to provide a CT value of -20 to -70 HU. In various embodiments, the contrast agent can be selected to provide a CT value of -160 to -300 HU. In various embodiments, the contrast agent formulation comprises hollow borosilicate microparticles in an aqueous medium.

[0081]

[0096] In various embodiments, the shell material of the hollow borosilicate microparticles comprises about 0.3 to about 8%, e.g., about 0.5 to about 7%, about 1% to about 6%, e.g., about 2% to about 4% boron trioxide.

[0082]

[0097] In exemplary embodiments, the hollow lumen content of the particles is carbon dioxide or mostly oxygen, nitrogen and carbon dioxide. In various embodiments, the hollow particle content does not contain sulfur or is essentially devoid of sulfur.

[0083]

[0098] In an exemplary embodiment, the hollow borosilicate particulates have a density of about 0.1 to about 0.4 g / cm 3 In an exemplary embodiment, the hollow borosilicate particulate has an average true density of about 0.2 to about 0.35 g / cm 3 The average true density is

[0084]

[0099] One or more hollow borosilicate particulate types may be used together.

[0085]

[0100] Any useful suspending agent or combination of suspending agents can be utilized in the formulations of the present invention. In various embodiments, the suspending agent exhibits thixotropic properties, forming a gel-like medium at rest, but forms a liquid upon agitation.

[0086]

[0101] In an exemplary embodiment, the enteric contrast medium is formulated with the HBM suspended in a pharma- ceutically acceptable carrier.

[0087]

[0102] In an exemplary embodiment, the hollow borosilicate microparticles are coated to provide useful properties to the contrast material, such as improved suspension in a medium, increased true density, or to modify the CT number or 80:140 kVp CT number ratio, or to modify the apparent iodine concentration during CT, or DECT, or multi-energy CT, or photon-counting CT imaging.

[0088]

[0103] In an exemplary embodiment, the coating comprises an organic molecule of molecular weight less than about 3 kd, less than about 2 kd, or less than about 1.5 kd. In an exemplary embodiment, the coating comprises an organic molecule of molecular weight less than about 3 kd, less than about 2 kd, or less than about 1.5 kd, where the organic molecule is a member selected from organic acids (or alcohols, amines) and derivatives or analogs thereof, oligosaccharides, and combinations thereof.

[0089]

[0104] In an exemplary embodiment, the coating is a protein, such as albumin.

[0090]

[0105] 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 skill of the artisan to select a suitable coating for a particular formulation and / or application (see, for example, Yeh BM, Fu Y, Desai T, WO2014145509 A1).

[0091]

[0106] The suspension phase of the formulation of the present invention may include particles of any useful particle size and size range. Exemplary specific particle sizes for particles include about 1 nm to about 500 microns, such as 1 micron to about 100 microns, including each single diameter value and each diameter range within any larger range across any endpoint; in various embodiments, the particles are greater than about 5 microns. Further useful particle sizes include, for example, about 5 microns to about 100 microns, such as about 20 microns to about 70 microns.

[0092]

[0107] The formulations of the present invention may include a single enteric contrast medium or two or more enteric contrast media. The media may be present in similar or different concentrations according to any useful concentration scale. Exemplary embodiments include one or more particles or soluble agents in different concentrations, such that each contributes substantially to the X-ray attenuation relative to water in the overall contrast medium. Thus, in various embodiments, the particles make up about 1% (w / w, expressed as a weight percent, e.g., about 1 gram of contrast agent particles in about 100 grams of total contrast medium) to about 10% (w / w) of the weight of the formulation. In exemplary embodiments, the formulations include about 3% (w / w) to about 9% (w / w) particles. In exemplary embodiments, the formulations include about 1% to about 3% (w / w) particles.

[0093]

[0108] In an exemplary embodiment, the invention provides a formulation in which the borosilicate hollow particles comprise about 1% or more, such as about 2% or more and about 10% or less.

[0094]

[0109] The formulation of the present invention comprises a population of hollow borosilicate microparticles of the present invention suspended in a pharma- ceutically acceptable solvent.The solvent may comprise any other useful ingredient.For example, in some embodiments, the solvent comprises an aqueous medium, which further comprises additives that impart a second property to the formulation, such as slowing the dehydration of the formulation in the intestine, providing flavor, stabilizing the suspension, enhancing the fluidity of the suspension, thickening the suspension, providing pH buffering, and combinations thereof.

[0095]

[0110] Within the scope of the present invention are formulations designed for single-dose administration. Such unit-dose forms contain a sufficient amount of the formulation of the present invention to provide detectable contrast in the subject to which it is administered. In an exemplary embodiment, the unit-dose formulation includes a container that holds sufficient enteric contrast medium to enhance the diagnostic image of the subject to which the unit dose is administered in a diagnostically meaningful manner. The container can be a vial, an infusion bag, a bottle, a sachet, or any other suitable vessel. The enteric contrast medium can be in the form of a preformulated liquid, a concentrated liquid, or a powder. In an exemplary embodiment, the subject weighs about 70 kg. In an exemplary embodiment, the image is measured through the subject's abdomen, the subject's pelvis, or a combination thereof.

[0096]

[0111] In various embodiments, the unit dosage formulation contains about 800 to about 1500 mL of contrast medium per adult human dose, which may be divided into smaller containers, such as about 300 to about 600 mL in size. In an exemplary embodiment, the enteral contrast medium formulation is a unit dosage formulation of about 50 to about 100 mL. In an exemplary embodiment, the enteral contrast medium formulation is a unit dosage formulation of about 100 mL to about 800 mL.

[0097]

[0112] Any of the formulations described herein can be formulated and utilized for administration via any of a variety of routes. Exemplary routes of administration include oral, rectal, intravaginal, intravascular, intrathecal, intravesicular, and the like.

[0098]

[0113] Low concentrations of HBM contrast materials for use as contrast materials in CT imaging have not been described. In exemplary embodiments, the HBM in the formulation is at a low concentration, e.g., from about 0.5% (w / w) to about 10% (w / w), e.g., from about 1% to about 4%, e.g., from about 1.5% to about 3% of the formulation.

[0099]

[0114] In various embodiments, the enteric contrast medium of the present invention and preferably its formulations exhibit chemical stability over a wide pH range (e.g., from about 1.5 to about 10). The stomach exposes the intestinal contents to a low pH of 1.5, while the bile and small intestine can expose the intestinal contents to a high pH up to 10. Physicochemical stability is a critical component of safety and helps to minimize the risk of reactions or adverse events. Adverse reactions can occur when excessive dissolution or degradation of materials occurs in the gastrointestinal tract or when the degradation products are potentially toxic.

[0100]

[0115] In various embodiments, the present invention provides a sufficiently long t to allow imaging experiments to be completed with a sufficiently high HBM concentration remaining within the anatomical structure of interest. 1 / 2 In various embodiments, the present invention provides enteral contrast media and formulations of the contrast media that have a short enough in vivo residence time to allow essentially all of the administered HBM to be excreted from the subject's body before being altered (metabolized, hydrolyzed, acidified, etc.) by the subject's body.

[0101]

[0116] In various embodiments, the formulation has a small intestinal transit time of less than 12 hours in normal subjects. In an exemplary embodiment, the formulation includes polyethylene glycol or sugar alcohols such as sorbitol, mannitol and xylitol, or both, to accelerate the intestinal transit time.

[0102]

[0117] In an exemplary embodiment, the present invention provides an enteral contrast medium that dissolves slowly such that the majority of administered HBM particles are cleared from the gastrointestinal tract before being transformed by the subject's body, and the dissolved or transformed portions are excreted via the urinary tract.

[0103]

[0118] Pharmaceutically acceptable formulations of the present invention may optionally include excipients and other ingredients as required, such as one or more sweeteners, flavorings and / or additional taste modifiers to mask bitter or unpleasant tastes, suspending agents, flow agents, antioxidants, preservatives and other conventional excipients.

[0104]

[0119] Suspensions of the present invention may optionally contain one or more antioxidants, taste modifiers, sweeteners, flow agents, suspending agents and preservatives as required.

[0105]

[0120] As will be appreciated, the above optional ingredients may be added to the powder formulations of the present invention or may be added to the oral suspensions of the present invention.

[0106]

[0121] Antioxidants suitable for use herein include any convenient agent known in the art for this purpose, with preferred ones being sodium metabisulfite, sodium bisulfite, cysteine ​​hydrochloride, citric acid, succinic acid, ascorbic acid, sodium ascorbate, fumaric acid, tartaric acid, maleic acid, malic acid, sodium metabisulfite or sodium bisulfite containing EDTA.

[0107]

[0122] Antioxidants may be utilized in amounts that will protect the formulation from oxidation, as would be apparent to one of skill in the art.

[0108]

[0123] The sweetener for use in the formulations of the present invention may be any convenient agent known for this purpose in the art and may be selected from any compatible group of sweeteners, such as natural sweeteners such as sucrose, fructose, dextrose, xylitol, sorbitol or mannitol, and artificial sweeteners such as aspartame, acesulfame K and sucralose. Sucralose and sorbitol are preferred sweeteners.

[0109]

[0124] Flavorings and flavor modifiers or taste modifiers may also be used to further improve taste and may be any convenient agent known in the art for this purpose, including, but not limited to, orange flavor, vanilla flavor, toffee flavor, licorice flavor, orange vanilla flavor, creme de menthe, cherry flavor, cherry vanilla flavor, berry mix flavor, passion fruit flavor, pear flavor, strawberry flavor, mandarin orange flavor, bubble gum flavor, tropical punch flavor, juicy compound for grapes, grape flavor, artificial grape flavor, grape bubble gum flavor, tutti frutti flavor, citrus flavor, lemon flavor, chocolate flavor, coffee flavor, matcha flavor, and combinations thereof.

[0110]

[0125] The suspending agent may be any convenient agent known in the art for this purpose and may be selected from xanthan gum, gellan gum, guar gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, alginates, sodium carboxymethylcellulose and combinations thereof, with xanthan gum being preferred in some embodiments.

[0111]

[0126] The preservative may be any convenient agent known in the art for this purpose and may be selected from the group consisting of any compound compatible with the drug active, such as methyl- and propyl-paraben, benzoic acid, sodium benzoate, potassium sorbate and combinations thereof, with methylparaben being preferred in some embodiments.

[0112]

[0127] The present invention also provides kits for use in clinical and / or research settings. An exemplary kit includes (a) a first vial containing an enteric contrast medium of the present invention; (b) a second vial containing a suspension agent; and (c) instructions for using and / or formulating the enteric contrast medium as a suspension. In various embodiments, the kit further includes another vial containing a second contrast medium; and instructions for administering and / or formulating the first and second enteric contrast media in a clinical or research setting.

[0113] B. Method

[0128] The invention also provides a method of utilizing the formulations of the invention to obtain and enhance clinically meaningful CT images from a subject to which the formulation of the invention has been administered, the method comprising administering to the subject a diagnostically effective amount of said enteric contrast medium formulation of the invention; and obtaining a CT image of the subject.

[0114]

[0129] The invention also provides a method of utilizing the formulations of the invention in conjunction with an additional CT contrast agent, such as an iodizing agent, that can be injected or orally ingested to obtain and enhance clinically meaningful CT images from a subject to whom the formulation of the invention is administered. The method includes administering to the subject a diagnostically effective amount of an enteric contrast medium formulation of the invention, then injecting another CT contrast agent, and then obtaining a CT image of the subject. The CT image can be obtained with a conventional CT scanner or with a dual-energy CT, multi-energy CT, or photon-counting CT scanner.

[0115]

[0130] In an exemplary embodiment, the present invention provides a contrast-enhanced CT image of a subject from a region of the subject where the enteric contrast medium of the present invention is distributed. The contrast-enhanced CT image of the present invention may be a conventional monochromatic energy spectrum CT image, or may be a dual-energy, multi-energy or photon-counting CT image with or without associated CT image reconstruction utilizing dual-energy, multi-energy or photon-counting CT techniques. In an exemplary embodiment, the CT image of the present invention provides an iodine image or iodine map from a region of the subject where the enteric contrast medium of the present invention is distributed together with iodized contrast material.

[0116]

[0131] The images of the present invention and those obtained by the methods of the present invention utilize the contrast media of the present invention. The images may be taken at any cross-section of the subject's body. In an exemplary method, the images are from the abdomen and / or pelvis of the subject.

[0117]

[0132] The following examples are provided to illustrate exemplary embodiments of the invention, but are not intended to define or limit its scope. EXAMPLES

[0118] Example 1

[0133] A hollow borosilicate glass particulate "test article" (TA) with a shell material composed of 95% SiO2, 2% B2O3, and less than 3% oxides with atomic numbers greater than 10 (such as sodium, aluminum, magnesium, and calcium oxide) was measured to determine a density of 0.35 g / cm3 as determined by helium gas pycnometry. 3 The shell composition was determined by X-ray fluorescence. 350TA was then suspended in aqueous solutions containing 0.2-0.4% w / w xanthan gum and 3% w / w sorbitol.

[0119]

[0134] Four 350TA suspensions were scanned in vitro in a dual energy CT scanner, which showed the results shown in Figure 7. Of these 350TA suspensions, the 3% and 10% w / w 350TA formulations provided sufficient CT value ranges (-43 to -48 HU and -125 to -143 HU, respectively) to distinguish from both water / soft tissue (-20 to 50 HU) and fat (-70 to -120 HU) on conventional CT, while also providing calculated iodine map iodine concentrations (0.38 and 0.92 mg I / mL, respectively) below detectable iodine (1 mg I / mL). All other 350TA formulations either showed calculated iodine map iodine concentrations greater than 1 mg I / mL (15%, 20% and 30% w / w 350TA formulations) or showed CT values ​​overlapping with normal fat (5% w / w 350TA formulation). It should be noted that the accuracy of calculated iodine concentrations on iodine maps in small phantom / in vitro experiments shows much less noise than might be expected in vivo due to larger patient size and organ movement, where higher noise and lower iodine concentration detection limits are expected.

[0120]

[0135] Retesting of the formulation with additional excipients including up to 4% flavor and 2% sucralose plus preservatives yielded similar CT results.

[0121]

[0136] A 15% w / w 350TA suspension containing 4% flavoring and 2% sucralose was given by the oral route to healthy volunteers. Volunteers were scanned with a DECT scanner before and after ingestion of the 350TA suspension. The volumes of the 350TA suspension ranged from 400 to 2000 mL. The intestine was found to be marked by the 350TA suspension with a mean CT value of -170 HU, which allowed easy delineation from the body fat in the vast majority of cases. However, DECT iodine map reconstructions showed undesirably low levels of calculated iodine concentration, comparable to or higher than background soft tissues such as muscle (Figure 5). No silicon uptake was seen in the blood, and no pattern of increased urinary silicon above background levels was seen from volunteers at 1 hour, 4 hours, and 1 day after ingestion of the 270TA formulation. No serious adverse events were noted.

[0122] Example 2

[0137] True gravity is 0.27g / cm 3 A hollow borosilicate microparticle "test article" (TA) having a shell material composed of 95% SiO2, 2% B2O3, and less than 2% of oxides with atomic numbers greater than 10 (e.g., sodium, aluminum, magnesium, calcium oxide). No sulfur was involved in the formation of the hollow borosilicate microparticles. True gravity was confirmed by helium gas pycnometry. This test article was designated 270TA. Shell composition was confirmed by X-ray fluorescence. 270TA was then suspended in aqueous solutions as suspensions of 20%, 15%, 9%, 5% and 3% w / w of test article, the aqueous solutions containing 0.2-0.5% w / w xanthan gum and 3% w / w sorbitol.

[0123]

[0138] Four 270TA suspensions were scanned in vitro in a dual energy CT scanner, which showed the results shown in Figures 6 and 7. Of these 270TA suspensions, the 3% and 9% w / w 270TA formulations provided sufficient CT value ranges (-62.1 to -62.7 HU and -159 to -171 HU, respectively) to distinguish from both water / soft tissue (-20 to 50 HU) and fat (-70 to -120 HU) on conventional CT, and also provided calculated iodine map iodine concentrations (0.21 and 0.75 mg I / mL, respectively) below detectable iodine (1 mg I / mL). All other 270TA formulations either showed calculated iodine map iodine concentrations higher than 1 mg I / mL (10%, 15% and 20% w / w 270TA formulations) or showed CT values ​​that could overlap with normal fat (5% w / w 270TA formulation). It should be noted that the accuracy of calculated iodine concentrations on iodine maps in small phantom / in vitro experiments shows much less noise than might be expected in vivo due to larger patient size and organ movement.

[0124]

[0139] Retesting of the 270TA formulation with additional excipients including up to 4% flavor and 2% sucralose plus preservatives yielded similar CT results.

[0125]

[0140] A 9% w / w formulation of 270TA containing 0.3% xanthan gum, 3% sorbitol, 4% flavorings, and 2% sucralose was orally administered in a 1200 mL dose to 32 patient volunteers. Volunteers were imaged with CT before and after ingestion of the 270TA formulation. CT scans after ingestion of the 270TA formulation utilized dual energy CT and intravenous contrast material was injected. Exemplary images are shown in Figures 7, 9, and 10. The intestinal lumen was marked and distended by the 270TA formulation with a mean CT value of -180 HU in the stomach and -220 HU in the distal ileum and cecum, allowing easy visualization of the 270TA contrast material formulation from the iodized contrast material, soft tissue, and fat on conventional CT images (Figures 8 and 9). Upon reconstruction of DECT iodine map images, no visible undesired calculated false iodine signal above 1 mg I / mL was found in the intestinal lumen (Figures 9, 10, and 17). DECT images can clearly visualize true iodine signal from 270TA signal, and can visualize 270TA signal from biological fluids, such as those in the gallbladder and urinary bladder, as well as from fat and muscle (Figures 9 and 10).

[0126]

[0141] No uptake of silicon was observed in the blood, and no pattern of increased urinary silicon above background levels was observed in volunteers who had taken the 270TA formulation at 1 hour, 4 hours, and 1 day after ingestion of the 270TA formulation. No serious adverse events were noted.

[0127] Example 3

[0142] The amount of sulfur in a drug or medical device should be minimized since exposure to sulfur can cause undesirable reactions in patients. Total sulfur content between RHBM (regular hollow borosilicate particulates, including iM30K, 45P25, and 60P18) and HSHBM (high silicon borosilicate glass hollow particulates, including true densities of 0.27 and 0.35) as measured by a Leco sulfur analyzer. The method involves heating the HBM sample to 1350°C in an induction furnace while blowing a flow of oxygen through the sample. The sulfur dioxide released from the sample is measured by IR detection and the total sulfur content is reported. The HSHBM tested showed below detectable sulfur content (less than 0.01%), while the RHBM iM30K, 45P25, and 60P18 showed sulfur content of 0.08%, 0.15%, and 0.16%, respectively.

[0128]

[0143] The present invention has been described with reference to various exemplary embodiments and examples. As will be apparent to those skilled in the art, other embodiments and variations of the present invention may be devised by those skilled in the art without departing from the true spirit and scope of the present invention. The appended claims are to be construed to include all such embodiments and equivalent variations.

[0129]

[0144] The disclosures of all patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety.

[0130] Example 4

[0145] CT phantoms were constructed by attaching open plastic cylinders to 2.0 mm thick plastic sheets engineered to correspond to the CT value of an unenhanced bowel wall, which was 40 HU (FIGS. 4 and 16A), or an intravenous iodine contrast-enhanced bowel wall, which was selected to be approximately 165 HU (FIG. 16B). The phantoms were partially immersed in canola oil (FIG. 4) or lard (FIGS. 16A and 16B) to simulate the human fat that typically surrounds the bowel in the abdomen, and the cylinders were then filled with various contrast media having a range of CT values. The measured thickness of the simulated bowel wall during CT approximated the true 2.0 mm thickness most closely and consistently, regardless of whether the engineered bowel wall phantoms were unenhanced or enhanced with iodine intravenous contrast material, for contrast media with CT values ​​of -50 HU to -300 HU. These exemplary contrast media that performed well had HSHBGM concentrations between 2% and 25%.

[0131]

[0146] A spatial resolution phantom constructed of plastic simulating a range of intestinal wall folds thicknesses enhanced with iodine intravenous contrast material was filled with different commercially available oral contrast media and the exemplary HSHBGM contrast medium, the latter of which had a CT number of -180 HU (Figure 15). When CT imaged at 120 kVp using standard CT scan parameters and viewed with typical abdominal window / level settings of 400 / 40 HU, the CT images obtained with the exemplary HSHBGM contrast medium showed better spatial resolution than seen with the commercially available CT oral contrast medium.

[0132] References 1. Kreit E, Maethger LM, Hanlon RT, et al. Biological versus electronic adaptive coloration: How can one inform the other? JR Soc Interface. 2013;10(78). doi:10.1098 / rsif.2012.0601 2. Spilde JM, Lee J, Chosy SG, Krupinski EA, Kuhlman JE, Yandow DR. Evaluation of an experimental low-attenuation gastrointestinal contrast agent for CT imaging of intestinal ischernia in an animal model. Acad Radiol. 1999;6(2):94-101. doi:10.1016 / s1076-6332(99)80488-7 3. Wei X, Zhu J, Gong H, Xu J, Xu Y. A novel foam fluid negative contrast medium for clear visualization of the colon wall in CT imaging. Contrast Media Mol Imaging. 2011;6(6):465-473. doi:10.1002 / cmmi.446 4. Leander P, Adnerhill I, Book O, Casal-Dujat L, Stathis G, Fork T. A novel food-based foam as oral contrast agent with negative Hounsfield units for demarcation of small bowel loops on abdominal CT: tolerability and bowel distension in 25 volunteers. Acta radiol. 2020. doi:10.1177 / 0284185120973620 5. Ramsay DW, Markham DH, Morgan B, Rodgers PM, Liddicoat AJ. The use of dilute calogen(registered trademark) as a fat density oral contrast medium in upper abdominal computed tomography, compared with the use of water and positive oral contrast media. Clin Radiol. 2001;56(8):670-673. doi:10.1053 / crad.2001.0772 6. Raptopoulos V, Davis MA, Davidoff A, et al. Fat-density oral contrast agent for abdominal CT. Radiology. 1987;164(3):653-656. doi:10.1148 / radiology.164.3.3615862 7. Raptopoulos V, Davidoff A, Karellas A, Davis MA, Coolbaugh BL, Smith EH. CT of the pancreas with a fat-density oral contrast regimen. Am J Roentgenol. 1988;150(6):1303-1306. doi:10.2214 / ajr.150.6.1303 8. Raptopoulos V, Davis MA, Smith EH. Imaging of the Bowel Wall Computed Tomography and Fat Density Oral-Contrast Agent in an Animal Model. Invest Radiol. 1986;21(11):947-850. 9. Zwaan M, Gmelin E, Borgis KJ, Rinast E. Non-absorbable fat-dense oral contrast agent for abdominal computed tomography. Eur J Radiol. 1992;14(3):189-191. doi:10.1016 / 0720-048X(92)90084-M

Claims

[Claim 1] 1. An enteral contrast medium formulation formulated for oral delivery to a subject concurrently with a medical CT imaging procedure performed on the subject's abdomen or pelvis, comprising: More than 90% SiO ２ and a suspension of hollow borosilicate microparticles having a shell containing less than 8% non-oxide silicon with z>10, and an aqueous solvent component, the aqueous solvent component being a pharma- ceutically acceptable aqueous solvent. and upon CT imaging, provides a CT value of -70 to -20 HU or -160 to -300 HU when imaged at 120 kVp.

Images