Patent Application
20220401587
Medical computed tomography (CT) imaging is used for the evaluation of a wide range of clinical indications, including abdominal pain, evaluation for possible malignancy, staging and monitoring of tumors, assessment of bowel injury or inflammation, and to further evaluate bowel and non-bowel disease. At CT imaging, the X-ray attenuation (CT number) of the imaged tissues is measured in Hounsfield Units (HU), which range from −1000 HU (air or vacuum, which show negligible X-ray attenuation) to 0 HU (water, which is by definition 0 HU), to over 3000 (very dense material including metal with very high X-ray attenuation).
At CT imaging, different X-ray spectra may be used to image an object such as a patient. Current CT scanners may use X-ray spectra generated from X-ray tube potentials that can be set between 70 kVp to 150 kVp, depending on the clinical requirements. Lower X-ray tube potential settings generate X-ray spectra with relatively lower energy than higher tube potential settings. For any given X-ray tube potential, the CT number of water is defined to be 0 HU, and that of air/vacuum is defined to be −1000 HU. Real life measurements in humans commonly vary by about 20 HU or so due to image noise and other artifacts. The X-ray attenuation of other materials are therefore measured relative to that of water.
Human non-fatty soft tissues such as muscle, solid organ parenchyma, and blood, which are composed mostly of atoms with atomic numbers less than 20, resemble water in so far as their CT number does not change much at low versus high X-ray tube potentials (kVp). Human non-fatty soft tissues generally show CT numbers between 20 and 70 HU regardless of tube potential setting. Similarly, room air gas molecules, which are generally composed of small atomic number molecules, tend to show CT numbers of about −1000 HU regardless of CT tube potential settings.
To better delineate anatomy, positive contrast agents are commonly delivered intravenously or orally at CT imaging. All clinical intravenous contrast agents and most positive oral contrast agents are currently based on iodine (z=53) which attenuates X-rays much more strongly than does soft tissue or water, particularly when imaged at lower kVp. Some positive oral contrast agents are based on barium (z=56) which has very similar X-ray attenuation characteristics as iodine due to their similar atomic numbers, such that iodine and barium signal are not distinguishable at CT imaging regardless of imaging technique, including at multi-energy CT.
Given that positive contrast media is generally in aqueous solution or suspension, these positive contrast agents generally show CT numbers >0 regardless of aqueous dilution. The concentration of the positive contrast material increases the CT number of the fluid or tissues in which they reside at the time of CT imaging. Typically, 1 mg iodine/mL is approximately the limit of detection of iodine in contrast-enhanced tissue and this threshold generally refers to about 20 to 25 HU of enhancement when imaged at 120 kVp, which is the most common CT kVp setting. To be visually compelling, positive contrast material generally needs to increase CT numbers on a post-contrast CT image by 50 HU or more compared to the pre-contrast CT image, corresponding to about 2 mg iodine/mL or more. Quantitative detection of contrast enhancement less than 1 mg iodine/mL is generally unreliable at clinical CT due to image noise or artifacts, though some sources believe detection of lower thresholds such as 0.8 mg iodine/mL might be reliable. Similarly, visual detection of changes of 20 HU or less from pre- to post-contrast clinical CT is considered to be unreliable.
Some oral contrast agents at CT are termed “neutral” or “negative” and closely resemble the CT number of water or soft tissue at CT (0 to 50 HU). These agents include water or solutions of water with excipients to prevent rapid resorption of water by the bowel. These oral contrast agents allow for visualization of bowel wall capillary enhancement by positive intravenous contrast agents, which is difficult to delineate when positive oral contrast agent is given. However, since these neutral contrast agents resemble the CT number of water and unenhanced soft tissue at all kVps used for medical CT imaging, these agents may make it more difficult to delineate bowel from adjacent soft tissue CT attenuation lesions such as abscesses, fluid collections, hematomas, and hypovascular or necrotic tumors which predominantly also show CT numbers of 0 to 50 HU, or marginally higher, at CT imaging across the range of CT kVps used for medical imaging.
The X-ray attenuation of CT contrast agents is traditionally determined entirely based on the concentration of the reporter atom/material in aqueous vehicle. Iodine contrast agents are described based on mg of iodine/mL. Barium sulfate contrast agents are described as w/w % barium sulfate. Neutral contrast agents have no materials that substantially change the CT attenuation from that of water (hence, 0±20 HU, which is the CT attenuation of water)
Since humans can only perceive about 30 distinct shades of gray1 but medical CT numbers range from −1000 to over 3000 HU, medical CT images are viewed using a narrowed CT number window and level to assess different structures (bone, lung, soft tissues, etc). For soft tissue evaluation, the “level” (mid-level gray) is set at the expected CT number of soft tissue (40 or 50 HU) and the “window” is set to capture the typical range of fat and modest-to-bright positive contrast enhancement (−100 and 200 HU, respectively). To evaluate critical soft tissues, the most common window/level settings for displaying abdominal CT viewing are 350/50 HU (which displays voxels below −125 HU as pure black, and above 225 HU as pure white, and voxels between −125 and 225 HU as increasingly bright signal) or 400/40 HU (which displays voxels below −160 HU as pure black and above 240 HU as pure white, and voxels between −160 and 240 HU as increasingly bright signal).
A major problem with the use of positive and neutral oral contrast agents is non-uniform appearance of the bowel lumen contents, regardless of the viewing window/level settings. Bowel lumen commonly varies from segment to segment, with some segments containing gas, some containing fluid, some containing solids, and some containing admixtures of these materials. The enteric gas has dark CT number (−50 to −1000 HU, depending on the amount of admixed material). As such, regardless of whether positive (100 to 400 HU) or neutral oral contrast (0 to 40 HU) is used, there is almost always heterogeneity of the bowel lumen due to areas of markedly dark gas signal mixed with the oral contrast. This heterogeneity causes complexity with human or machine image interpretation.
Prior description of dark oral contrast has included insufflated gas such as room air or carbon dioxide, which creates extremely dark CT numbers close to −1000 HU in the lumen, and the insufflated gas is physically uncomfortable for the patient. These agents generally require enteric intubation and insufflation of the bowel, which is invasive. Alternatively, orally consumed contrast materials in the bowel may emit gas such as carbon dioxide via a chemical reaction. These gas-emitting agents may also cause discomfort from the gas distension or the chemicals involved. Other proposed dark oral contrast agents include perfluorocarbons that may or may not expand in volume within the bowel, and which may cause very dark signal in the bowel lumen2, but which were associated with anal leakage and abdominal discomfort.
Other descriptions of dark enteric contrast include foam liquids, such as for rectal administration3 or for oral administration4 (US 20200000942) which can be formulated to give a dark CT number (−100 to −800 HU). These agents do not have hard shells around the gas bubbles and hence may have stability issues that preclude their use for small bowel3, or may have inhomogeneous CT numbers that range across hundreds of HU4. A further limitation is that these formulations may require special machines for on-site preparation4.
Other described dark contrast agents include oil emulsions such as Calogen5 or corn oil emulsions6-8 and paraffin suspensions9. These dark contrast agents may have useful mildy dark CT values of −20 to −60 HU, but result in inability to differentiate the contrast agent from natural bodily fat when imaged with conventional CT or even with dual-energy/multi-energy CT because the underlying contrasting material is made of lipids/hydrocarbons that show similar X-ray attenuation as human fat across all kVps and keVs.
Microbubble contrast agents have been described for CT, including polymer shell agents (US 005726121A, U.S. Pat. No. 5,205,290 A) which give strongly negative CT number when formulated in aqueous suspension. These contrast agents were not developed for commercial CT use. Further, the physical stability of the particles in such material is unlikely to be sufficient for use in small bowel imaging which requires at least 1 hour of stability.
Dual energy CT (DECT) and multi-energy CT (MECT) including photon-counting CT (PCCT) scanners have been developed for clinical imaging. These scanners improve on conventional single energy spectrum CT by contemporaneously evaluating the X-ray attenuation of imaged objects at different X-ray spectra. For DECT, the relative attenuation of the imaged object by of X-ray spectra of low versus high energy are compared. The low versus high X-ray energy spectra are generally obtained by setting the CT tube potential (kVp) as low (e.g. 80 kVp) or high (e.g. 140 kVp), respectively. Various other implementations are also utilized, including tin and gold filtration of the X-ray beam or use of split layer X-ray detectors to preferentially detect X-rays of lower or higher energies, or photon counting detectors to better quantify and classify the energies of the detected X-rays.
These DECT, MECT, and PCCT scanners exploit the fact that atoms in the imaged object will attenuate X-rays of different energies to characteristic degrees, based on atomic number. Since water is assigned a CT number of 0 HU and vacuum/room air is assigned a CT number of −1000 HU regardless of the X-ray energy used to image the water or air, the CT number of all other materials is determined relative to these two standards.
The z-effective of H2O is about 7.5 which is the weighted average of the component atoms oxygen (z=8) and hydrogen (z=1). Owing to the small size and effect of protons on the overall X-ray attenuation of water, the z-effective of water is much closer to that of oxygen. Since the CT number of water is by definition 0 HU regardless of kVp settings, the CT number of other materials at low and high kVp settings are determined relative to that of water. Generally, molecules with z-effective smaller than water (such as fat/hydrocarbons which are made of carbon z=6 and hydrogen z=1) will show relatively lower CT numbers at low kVp than at high kVp (
A primary value of DECT, MECT, and PCCT, is the ability to quantify the amount of intravenous contrast material enhancement in image voxels without the need for acquiring a separate unenhanced CT scan. Iodine shows markedly higher CT number at low kVp than at high kVp CT settings. In aqueous solution, the 80:140 kVp CT number ratio of iodine is about 1.75, while that of water is 1.0 (by definition) and that of soft tissue is 1.05 or so. This difference can be used to quantify iodine at DECT into iodine maps. Similar methods are used for MECT and PCCT quantification of iodine contrast enhancement without the need for a separate noncontrast CT scan. Due to noise in CT data in living organisms, which show CT image artifacts due to many reasons, iodine is not reliably quantified below about 1 mg Iodine/mL. CT artifacts commonly arise due to quantum mottle, mass attenuation in thick body parts, bones, motion, metal, and non-circular shape of the imaged object. Typically, iodine map images are reconstructed as a pair with a water map image, also known as virtual noncontrast (VNC) or virtual unenhanced (VUE) image. The iodine map can be considered to be the opposite of the water map. The CT number values from the parent low and high kVp images are divided such that iodine values are assigned to the iodine map and the other values assigned to the water map.
Unlike conventional CT which use detectors that integrate the sum of 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 spectra produced by the X-ray source is known, the photon counting CT can therefore determine which X-rays were preferentially attenuated by the imaged object. This allows even better differentiation of imaged elements/materials than possible with dual energy CT. Collectively, dual energy CT and photon counting CT are termed multi-energy CT.
DECT, MECT, and PCCT images can be reconstructed to simulate the appearance of the CT scans at different monoenergetic X-ray energies. The iodine map and water map pairs are used to determine the voxel intensity of a simulated monoenergetic CT scan at any given keV, usually chosen between 40 keV and 200 keV. Different materials show characteristic CT number curves when plotted against keVs (
The present invention substantially refines the formulation of regular hollow borosilicate microparticle (RHBM) oral contrast agents to allow the agents of the present invention to delineate the anatomy of small bowel in a more precise manner than previously described when small bowel was imaged at conventional CT and multi-energy CT. Achievement of a favored agent involved several unexpected innovations and fortuitous discovery of beneficial properties of high silicon hollow borosilicate microparticles (HSHBM), which differ from regular hollow borosilicate microparticles (RHBM) in surprising ways at CT imaging. Furthermore, targeting of specific CT number ranges for enteric contrast agents allows for surprising improvement in bowel anatomic detail delineation, regardless of whether or not conventional CT or DECT or multi-energy CT is used.
The shell material of most hollow borosilicate microparticles, or RHBM, includes a blend of silicon dioxide (SiO2, generally >60%, Si z=14) and boron oxide (B2O3, >5%, B z=5) with minor amounts of multiple other oxides, including sodium (Na2O, Na z=11), aluminum (Al2O3, Al z=13), magnesium (MgO, Mg z=12), calcium (CaO, Ca z=20), and zinc (ZnO, Zn z=30) oxides as well as other trace materials of even higher atomic number. At CT, the X-ray attenuation of conventional contrast agents is generally dominated by the most common atoms and the high atomic number atoms. Prior borosilicate glass particles showed substantially greater attenuation of X-rays when imaged at CT with lower kVp than with higher kVp. This relative attenuation is in relation to that of water (H2O), which by definition is assigned a CT number of 0 HU regardless of the kVp used to image at CT.
US20180110492A1 further discloses adding barium (z=56) or other oxides of high atomic number to further increase the 80:140 kVp CT number ratio which further increases the calculated but artifactual iodine concentration on iodine maps at MECT.
Prior work on pure silicon dioxide as an oral CT contrast agent (US20140276021A1) showed that the 80:140 kVp CT number ratio was between 1.25 and 1.56, meaning that there was a substantial difference of 25 to 56% higher CT number for silicon dioxide when imaged at 80 kVp than at 140 kVp, and this ratio is far from 1.0.
As such, it was an unexpected and counterintuitive surprise to find that a high silicon hollow borosilicate microparticle (HSHBM) with very high amounts of silicon dioxide and very low amounts of boron and other oxides could be engineered into a contrast agent to show an 80:140 kVp CT number ratio close to 1.0, with only minimally higher X-ray attenuation at low versus high kVp CT imaging compared with RHBMs.
Based on z-effective, one would predict that the shell material of HSHBM would have a higher z-effective and hence show a greater relative CT number at low than at high kVp's compared with the shell of RHBM, but the opposite was found to be true. An exemplary high silicon borosilicate has 92% or more oxide of silicon (z=14) with <2% boron (z=4) trioxide (which has a relatively small z-effective). By comparison, regular borosilicate has only about 70% to 80% oxide of silicon, a large amount of boron trioxide (about 15%), with most of the rest of the composition due to oxides of Na, Mg, and Al (z=11, 12, and 13, respectively, atoms of which are each smaller than silicon z=14).
Only on further evaluation is it clearer that the oxide of silicon has only one silicon atom per two oxygen atoms of SiO2 (molar ratio 1:2), hence the z-effective of SiO2 is actually similar or smaller than that of the z-effective of the oxides of Na, Mg, and Al which each have a higher molar ratio relative to oxygen of 2:1, 1:1, and 2:3. Also on further analysis, high silicon borosilicate has relatively lower amounts of other small proportion materials that are seen in standard borosilicate, including oxides of calcium (z=20) and zinc (z=30) oxides as well as other atoms with higher atomic numbers.
The use of HSHBM for medical imaging purposes is novel. Generally, HSHBM is used to blend with other materials to physically lighten those materials, such as for aerospace or marine applications, or HSHBM is used for electronics and devices where low dielectric effects are needed, or HSHBM is used for thermoablative products (heat shields). One description of HSHBM for a medical device uses these materials to physically lighten the weight of breast implants by incorporating the HSHBM into silicone polymer gels (US20120277860A1). That breast implant patent description does not suggest use of the HSHBM as diagnostic medical imaging contrast material. As such, the use of HSHBM for a diagnostic medical imaging purpose is non-obvious.
A further innovation of our invention is the use of lower true density hollow borosilicate particles than previously tested for RHBM contrast agents. Although US20180110492A disclosed a range of possible specific gravity particles for use in contrast materials, it described the value of using particles with specific gravity similar to that of water (closer to 1 g/mL) because such particles may be easier to suspend in aqueous formulation. The disclosure is silent with respect to hollow borosilicate particles with specific gravity lower than 0.45 g/cm3. Aqueous formulations with concentrations of hollow borosilicate particles below 20% w/w are not expressly disclosed. Surprisingly, the present invention achieves its efficacious results using aqueous formulations with concentrations of HBMs of from about 0.5 to about 10% w/w.
In an exemplary embodiment, the invention provides a sterile aqueous pharmaceutical formulation of low-density hollow borosilicate microparticles at low concentrations. Exemplary formulations of the invention include low density hollow borosilicate microparticles at a concentration of not more than about 10%, e.g., not more than about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or not more than about 1% (w/w) of the formulation. An exemplary formulation is appropriate for enteric administration to a subject immediately prior to, contemporaneous with (or a combination thereof), acquiring an image through at least a section of the subject's abdomen (e.g., bowel). The formulation is stable, wherein “stable” refers to a formulation of the invention in which a substantial portion (e.g., > about 50%, 60%, 70%, 80%, 90% or > about 95%) of the particles remain in suspension in a pharmaceutically acceptable aqueous vehicle during the period necessary to prepare and administer the formulation to the subject, and to acquire the image. Typical durations of time between oral ingestion of contrast material and image acquisition (period in which the formulation is stable) may range from a few minutes (e.g., under 20 min) for imaging of the esophagus and stomach, to from about 20 to about 120 minutes for imaging of the small bowel, to from about an hour to about 2 days for imaging of the colon.
In various embodiments, the particles are at least partially maintained in suspension by incorporation into the formulation of a suspending agent. Exemplary suspending agents are incorporated into the formulation in an amount of from about 0.1% to about 20%, e.g., from about 0.5% to about 15%, e.g., from about 1% to about 10%, e.g., from about 3% to about 8%. An exemplary formulation of the invention is prepared as a unit dosage formulation, with the dosage determined for an individual patient prior to administering the agent, and the formulation prepared in the clinical setting immediately prior to its administration to the subject.
In various embodiments, the invention provides formulations and methods using low true density hollow borosilicate microparticles at low concentrations, e.g., from about 1 to about 10% w/w, to achieve formulations with target CT number ranges of from about −20 to about −70 HU or from about −160 to about −300 HU. In other embodiments, the invention provides the use of low concentrations of low true density hollow borosilicate microparticles to achieve formulations with minimal calculated iodine concentrations of less than about 1 mg iodine/mL at dual energy CT or multi-energy CT image reconstructions. These low concentrations of low true density hollow borosilicate microparticles, in various embodiments, range from about 0.2% to about 12% w/w of the aqueous suspension. Alternatively, these low concentrations of low true density hollow borosilicate microparticles, in various embodiments, range from about 0.5% to about 9% w/w of the aqueous suspension, or from about 0.5% to about 4%, or from about 5% to about 9% of the aqueous suspension. The low true density hollow borosilicate microparticles of the invention, in various embodiments, range from a true density of about 0.10 to about 0.40 g/cm3. In other embodiments, the low true density hollow borosilicate microparticles of the invention range in true density from about 0.2 to about 0.35 g/cm3.
In various embodiments, our invention describes formulations of dark HSHBM oral contrast material such that it darkens the bowel lumen to less than about −160 HU so that the CT number is just outside the typical soft tissue window level viewing settings for CT (e.g. window/level settings of 400/40 HU, which assigns visible gray scale to voxel signal between −160 and +240 HU, and pure black to voxel signal below about −160 HU, and pure white to voxel signal above about +240 HU). In various embodiments, the invention provides a method incorporating informed selection of the HSHBM formulation to allow the bowel lumen to appear much more uniform in CT number (all dark) at typical soft tissue viewing window and level settings (
In various embodiments, the invention provides formulations of dark oral contrast material such that it darkens the bowel lumen to a value from about 50 to about 300 HU below that of the CT number of bowel wall so that the thickness of the bowel wall can be more accurately measured and perceived (
In various embodiments, the invention provides formulations of dark oral contrast material such that it provides greater spatial resolution of bowel folds when viewed at typical soft tissue bowel (
In various embodiments, the invention provides formulations of HSHBM as oral contrast material with CT numbers less than about −20 HU and with 80:140 kVp CT number ratio from about 0.90 to about 1.00. In various embodiments, the invention provides formulations of HSHBM contrast material showing apparent iodine concentrations of less than about 1.0 mg iodine/mL at iodine image reconstructions from dual energy CT, multienergy CT, and photon counting CT scans. In various embodiments, our invention describes formulations of HSHBM contrast material that shows apparent iodine concentrations of less than about 0.8 mg iodine/mL at iodine image reconstructions (
In various embodiments, sugar alcohols, magnesium hydroxide, polyethylene glycol, cellulose, or other materials, alone or in combination, known to increase bowel transit speed, may be added to the aqueous pharmaceutical formulation.
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 aluminium silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethylsiloxane silica, or other flow agents may be added to improve the powder dispersion in the manufacturing or powder product (i.e., the hollow particles, or the hollow particles and one or more suspending agent or other additive of use in producing the aqueous pharmaceutical formulation prior to hydration.
In various embodiments, excipients may be added to improve the extent of bowel distension. 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 alter the thickness (e.g., viscosity or osmolarity) of the formulation. In various embodiments, thicker formulations prevent collapse of the bowel lumen, particularly of the proximal small bowel and stomach, compared with less viscous formulations. In various embodiments, higher osmolality formulations prevent the absorption of water from the bowel lumen, and hence maintain distension of the bowel lumen compared with lower osmolarity 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.
The negative enteric contrast agent of the invention may be used either without or with an intravenous contrast agent for CT imaging. The negative enteric contrast agent of the invention may be formulated to produce CT numbers that improve the conspicuity of intravenous contrast material enhancement of the bowel wall and adjacent vascularized structures.
In various embodiments, the enteric contrast agent of the invention shows one or more levels of leachable Arsenic (As), Cadmium (Cd), Lead (Pb), and Mercury (Hg) that are less than 15, 5, 5, and 30 micrograms per dose, respectively, when incubated with simulated gastric juice for 4 hours. In various embodiments, the enteric contrast agent of the invention shows levels of leachable Arsenic (As), Cadmium (Cd), Lead (Pb), and Mercury (Hg) that are less than 1.5, 0.5, 0.5, and 3.0 micrograms per dose, respectively, when incubated with simulated gastric juice for 4 hours.
In various embodiments, the invention provides CT images of dark HSHBM enteric contrast agent-enhanced CT scans of the invention to be used in conjunction with software including artificial intelligence or deep learning for segmentation of the bowel at CT and image interpretation, including the delineation of bowel from non-bowel structures, delineation of the center line of the bowel, measuring bowel segment lengths, and identifying abnormally thickened bowel wall, abnormally hyper- or hypo-enhancing bowel wall, or focal lesions of or around the bowel.
In an exemplary embodiment, the invention provides HSHBM in water suspension which is an enteric contrast medium formulation. The material is formulated in a pharmaceutically acceptable aqueous vehicle in which the particles are suspended. In an exemplary embodiment, the shell material is bound covalently or by weaker intermolecular forces to polymers, organic material, or hydrogel to improve dispersion in the aqueous media. In an exemplary embodiment, the vehicle contains additives to retain fluid in the bowel lumen. In an exemplary embodiment, the aqueous vehicle contains agents to promote intestinal motility. In an exemplary embodiment, the shell material is bound covalently or by weaker intermolecular forces to polymers, organic material, or hydrogel that decreases the CT number of the overall formulation at low CT kVp compared to high CT kVp settings.
In various embodiments, the HSHBM utilized in the formulation contain less than 5% by weight non-floating particles, e.g., broken or damaged microparticles, as well as microparticles with a small internal void and dense outer shell.
Isostatic crush strength determines the percentage volume of HBM that collapses or breaks at a specified applied pressure. Breakage of HBM may result in unwanted small irregular particles in the contrast agent and may decrease the utility of the resulting formulation. In various embodiments, the invention provides use of HSHBM where less than about 10% of the volume of HSHBM utilized in formulation breaks at 500 psi of pressure. In various embodiments, less than 3% of the volume of HSHBM utilized in formulation breaks at 500 psi of pressure. The breakage of the HSHBM, for the purpose of accurate measurement of breakage, is made when the HSHBM is in isolated dry powder form, rather than in liquid formulation. By way of illustration, in an exemplary embodiment, the volume refers to the volume of the dry powder HSHBM, prior to formulation, is measured in a pycnometer.
Nonfloating particles of HBM in aqueous suspension may be undesired because nonfloating particles may include broken or damaged microparticles, as well as microparticles with a small internal void and dense outer shell. Such particles may result in undesired layering in the bowel lumen. In various embodiments of our invention, less than about 5% of the volume of HSHBM used in formulation of the invention are nonfloating. In various embodiments of the present invention, less than about 3% of the volume of HSHBM particles are nonfloating. By way of non-limiting illustration, this measurement of nonfloating volume fraction may be made by simple floatation of a known volume of HSHBM, as determined by mass of the sample divided true gravity, in water then measuring the volume of the nonfloating fraction in mL using a separation flask having a graduated cylinder at the dependent end. Alternatively, measurement of the nonfloating volume fraction may be made by isolating and drying the floating and nonfloating fractions and measuring the volumes of each by gas pycnometer.
In an exemplary embodiment, the invention provides a contrast medium formulation that may also be delivered into the digestive system and other bodily cavities that may be natural such as the vagina or bladder, or surgically created such as neobladders, or artificial medical devices such as tubes, catheters, pouches, reservoirs, or pumps.
Additional illustrative advantages, objects and embodiments of the invention are set forth in the description that follows.
The enteric contrast agents of the invention are substantially different from microbubble contrast agents used in ultrasound imaging. Microbubbles in ultrasound are usually gas microbubbles of perfluorocarbon gas or nitrogen gas surfaced-coated by flexible material such as albumin, carbohydrates, lipids, or biocompatible polymers that allow ultrasound to cause expansion and contraction of the bubbles to thereby amplify signal at ultrasound imaging. The mean size of ultrasound contrast microbubbles is usually in the 2-6 micron range, and the common concentration level is about 10 million microbubbles per mL. It is thus calculated that less than 1% of the volume of microbubble-type ultrasound contrast formulations is gas-filled or hollow, and such a small volume fraction of gas or void space does not produce sufficiently low signal to be useful at CT imaging as a negative contrast agent. Even if the bubbles were pure gas (−1000 HU, which is the lowest HU CT number on the CT number scale), a 1% volume of microbubble in water (0 HU at CT) suspension would give a CT number of about −10 HU, which is not much different than that of water itself. Two recent review articles on ultrasound microbubble contrast agents are given here:
The enteric CT contrast materials of the present invention are substantially different than previous perfluorocarbon oral contrast materials proposed for CT and MR and X-ray imaging. These previous agents include liquid perfluorocarbon, which may or may not be emulsified; the perfluorocarbon may or may not be brominated. In these previous agents, the perfluorocarbon may expand into a gas at body temperature and create negative contrast signal and further bowel distension. Drawbacks of perfluorocarbon agents are that they may be difficult to administer, have an oily texture that may be unacceptable to patients, and their expansile characteristic carries safety concerns when administered into diseased bowel segments2 (also U.S. Pat. Nos. 5,205,290; 4,951,673). Brominated perfluorocarbons have been described as CT contrast agents and may produce positive CT number signal.
Other embodiments, objects and advantages of the invention will be apparent from the detailed description that follows.
Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, pharmaceutically acceptable formulation, and medical imaging are those well-known and commonly employed in the art.
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 object of the article. By way of example, “an element” means one element or more than one element.
A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.
“Contemporaneous” administration refers to use of a contrast agent in conjunction with a medical imaging procedure performed on a subject. As understood by one of skill in the art, contemporaneous administration of the contrast agent to the subject includes administration during or prior to the performance of the medical imaging procedure such that the contrast agent is visible in the medical image of the subject.
The term “half-life” or “t ½”, as used herein in the context of administering an enteric contrast medium of the invention to a patient, is defined as the time required for an effective enteric concentration of a drug in a patient to be reduced by one half. There may be more than one half-life associated with the contrast medium depending on multiple clearance mechanisms, redistribution, and other mechanisms well known in the art. For a hollow particle contrast material where the effectiveness of the contrast material 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 the aqueous formulation in vivo. Further explanation of “half-life” is found in Pharmaceutical Biotechnology (1997, D F A Crommelin and R D Sindelar, eds., Harwood Publishers, Amsterdam, pp 101-120).
“Enteric contrast medium formulation” as herein used means, unless otherwise stated, a pharmaceutically acceptable liquid or paste formulation for administration to a subject, which comprises at least one enteric contrast medium, and with or without at least one pharmaceutically acceptable excipient suspending the medium, and which is prepared by dissolving, emulsifying, or suspending an enteric contrast medium as herein described, e.g. in the form of a powder, emulsion or mash, in a pharmaceutically acceptable vehicle, before use for administration to the subject. Preferably the suspending medium is water.
The term “hollow borosilicate microparticle,” abbreviated “HBM”, is used herein to describe a particle composed of borosilicate with outer diameter <500 microns and an internal void that may contain gas or partial vacuum. The term “regular HBM,” abbreviated “RHBM” is used herein to refer to a subset of HBM where the shell material is composed of about 60 to 85% SiO2 and which has >2% oxides of atoms with atomic number greater than 10 (e.g., sodium oxide or aluminum oxide, etc). The term “high silicon HBM,” abbreviated “HSHBM” is used herein to refer to HBM where the shell material is composed of more than about 92% silicon dioxide and less than about 2% oxides of atoms with atomic number greater than 10.
The term “microsphere”, as used herein, refers to a subset of microparticles where the outer shape is spherical. The term “microparticle”, as used herein, includes microspheres and other particles with diameter in the range of from about 1 to about 800 microns.
The term “residence time”, as used herein in the context of administering an enteric contrast medium to a patient, is defined as the average time that the enteric contrast medium stays in the body of the patient after dosing.
The term “CT” refers to computed tomography imaging of any sort, including low dose, dual energy, multi-energy, and photon counting CT.
As used herein, “pharmaceutically acceptable carrier” includes any material, which when combined with the microspheres (particles) is compatible with the microspheres and tolerated by a subject to whom a pharmaceutical formulation incorporating the microspheres and the carrier is administered. Examples include, but are not limited to, any of the standard medical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents. Other carriers may also include sterile solutions. Typically, such carriers contain excipients such as starch, milk, sugar, sorbitol, methylcellulose, certain types of clay, gelatin, stearic acid or salts thereof, 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 comprising such carriers are formulated by well-known conventional methods.
As used herein, “administering” means oral administration, topical contact, intrarectal, intravenous, intraperitoneal, intralesional, intranasal or subcutaneous administration, intrathecal administration, or instillation into a surgically created pouch or surgically placed catheter or device, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject.
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 pharmaceutically acceptable excipient, which may itself include other components, e.g., taste-masking agents, antioxidants, wetting agents, flow or anti-caking agents, emulsifying agents, etc. The “dry suspension mixture” may subsequently be dissolved or suspended in a suspending medium to form the enteric contrast medium formulation of the invention. Terms such as “suspending medium” and “pharmaceutically acceptable excipient”, as used herein, refers to the medium in which the component(s) of the enteric contrast medium are emulsified or suspended.
The terms “coating” and “coated” as herein used are understood to include coatings which are biocompatible within an environment having an acidic, or a neutral, or a basic pH value.
The term “dark” as herein used to describe contrast material refers to having CT number less than about −20 HU.
The terms “particle”, “particles” and “microparticle(s) as used herein refers to free flowing substances of any shape which are larger than about 1 nm, such as crystals, beads (smooth, round or spherical particles), pellets, spheres, and granules. A particle may be a hollow bubble or contain multiple internal cavities. Exemplary specific sizes for the particles include from about 1 nm to about 500 microns, e.g., 1 micron to about 100 microns encompassing each single diameter value and each diameter range within the larger range across all endpoints; in various embodiments, the particles are larger than about 5 microns. Further useful particle sizes include, for example, from about 5 microns to about 100 microns, e.g., from about 20 microns to about 70 microns. A particle may contain gas or partial vacuum. A particle may be solid.
The term “suspending agent” as used herein refers to any convenient agent known in the art to be of use in forming and/or maintaining a suspension of a solid in a liquid (e.g., aqueous or oil). Exemplary suspending agents are selected from xanthan gum, gellan gum, guar gum, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, alginates, and sodium carboxylmethylcellulose with xantham gum being preferred. Suspending agents may be employed in any useful amount. Exemplary useful amounts are within the range from about 0 to about 20% by weight of the powder formulation, and from about 0 to about 10% by weight of the oral suspension. Exemplary suspending agents are incorporated into the formulation in an amount of from about 0.1% to about 20%, e.g., from about 0.5% to about 15%, e.g., from about 1% to about 10%, e.g., from about 3% to about 8%.
“Stable” in the context of the invention refers to suspensions that do not significantly separate into their components as different phases or layers between manufacture of the suspension and the time of medical image acquisition after its administration to a subject in an imaging study or from the time of suspension of the agent in the pharmaceutically acceptable carrier and the time of medical image acquisition after its administration to a subject in an imaging study. By way of non-limiting illustration, imaging occurs after a period of from about 1 minute to about 180 minutes after ingestion of the contrast agent for imaging of the esophagus, stomach, or small bowel, and from at least about 1 hour to about 2 days after ingestion of the contrast agent for imaging of the colon, during which time the suspensions of the invention do not significantly separate into their components as different layers.
“True Density”, as this term is used herein, refers to the mass of the material per volume that it occupies, excluding surrounding gas that is in free communication with the atmosphere, such as may be measured using a gas pycnometer. “Mean true density”, as this term is used herein, refers to the mass of a given sample of material per the volume that it occupies, excluding surrounding gas and gas between particles of the material that is in free communication with the atmosphere. Mean true density may be measured using a gas pycnometer.
The term “hollow” as used herein refers to gas or vacuum that is confined and highly restricted from communication with the external environment such that a minimal amount of the gas or vacuum is released from the confined space, and a minimal amount of fluid enters the confined space, during the expected residence time of biological use. Any gas within the hollow borosilicate microparticle may be at a lower, same, or higher pressure than the surrounding atmosphere or suspending liquid vehicle.
The term “dark contrast” as used herein refers to material producing lower CT number signal than water (CT number <−20 HU).
“An unpleasant taste” as used herein means that a majority of human patients judge said enteric contrast medium comprised as having an unpleasant taste when ingested.
In various embodiments, the present invention provides enteric or non-vascular contrast agents that produce dark CT numbers lower than about −20 HU at CT imaging. In various embodiments, the present invention provides contrast agents containing hollow borosilicate microparticles with overall CT numbers of the formulation from about −20 to about −70 HU which is below the CT number of water and higher than the CT number of fat. In various embodiments, the present invention provides contrast agents containing hollow borosilicate microparticles with overall CT numbers of the formulation from about −160 to about −300 HU which is below the range of CT numbers that would be displayed as black on standard CT images viewed with standard soft tissue window and level viewing settings (window and level of 400 and 40), yet not so negative in CT number as to cause excessive loss of visibility of the bowel wall. Exemplary materials include hollow borosilicate microparticles with shell material containing greater than about 90% SiO2 and < about 10% oxides of other non-silicon atoms with z>10.
In various embodiments, the shell of the particles of the contrast media of the invention is a formed from predominantly SiO2. In various embodiments, the shell of the particles of the contrast media contains over about 90% SiO2. In various embodiments, the shell of the particles of the contrast media contains over about 90% SiO2 and less than about 5% B2O3 and less than about 4% oxides of atoms with atomic number greater than 10.
In various embodiments, the true density of the particles is greater than about 0.05 g/cm3. In various embodiments, the true density of the particles of the contrast medium of the invention is at least about 0.1, at least about 0.2, or at least about 0.25 g/cm3. In various embodiments, the true density of the particles is less than 0.5 g/cm3, less than 0.4 g/cm3, or less than 0.35 g/cm3
In various embodiments, the interior space of the particle is at least partially gas filled 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, fluorocarbon, 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.
Exemplary particles of the invention are low in true density yet maintain substantial isostatic crush strength and do not break with medical ultrasound imaging forces so that the hollow void is not readily destroyed by physiologic forces within the imaged organism. Exemplary particles of the invention show no more than 5% loss of the hollow volume when subjected to isostatic pressures of 500 psi. Exemplary particles of the invention do not show more than about 2% loss of the hollow volume when subjected to ultrasound imaging and pulses at medical imaging for about 15 minutes, including pulses used to burst conventional ultrasound bubble contrast materials.
Exemplary contrast media of the invention decrease the CT number of the lumen of the gastrointestinal tract or other body cavity to below that of pure black on soft tissue window/level viewing settings. Exemplary contrast media of the invention decrease the CT number of the lumen of the gastrointestinal tract or other body cavity to between that of water and fat at CT imaging.
The contrast agents of our invention can provide improved CT imaging applications with one or more of the following benefits:
In various embodiments, the invention provides enteric contrast agents hollow borosilicate microparticles. In various embodiments, the contrast agent can be selected to provide a CT number between −20 and −70 HU. In various embodiments, the contrast agent can be selected to provide a CT number between −160 and −300 HU. In various embodiments, the contrast agent formulation includes hollow borosilicate microparticles in an aqueous media.
In various embodiments, the shell material of the hollow borosilicate microparticles includes from about 0.3 to about 8%, e.g., from about 0.5 to about 7%, from about 1% to about 6%, e.g., from about 2% to about 4% boron trioxide
In an exemplary embodiment, the hollow lumen contents of the particle is carbon dioxide, or is largely oxygen, nitrogen and carbon dioxide. In various embodiments, the contents of the hollow particle does not contain sulfur, or is essentially devoid of sulfur.
In an exemplary embodiment, the hollow borosilicate microparticle has a mean true density of from about 0.1 to about 0.4 g/cm3. In an exemplary embodiment, the hollow borosilicate microparticle has a mean true density of from about 0.2 to about 0.35 g/cm3.
One or two or more hollow borosilicate microparticle types may be used together.
Any useful suspending agent or combination of suspending agents can be utilized in the formulations of the invention. In various embodiments, the suspending agent is thixotropic and forms a gel-like medium at rest but a liquid with agitation.
In an exemplary embodiment, the enteric contrast medium is formulated into a pharmaceutically acceptable carrier in which the HBM is suspended.
In an exemplary embodiment, the hollow borosilicate microparticle is coated to provide useful properties for the contrast material, such as improved suspension in media, increased true density, or alter the CT number or 80:140 kVp CT number ratio, or alter the apparent iodine concentration at CT or DECT or multienergy CT or photon counting CT imaging.
In an exemplary embodiment, the coating comprises an organic molecule with a molecular weight of less than about 3 kd, less than about 2 kd or less than about 1.5 kd. In an exemplary embodiment, the coating comprises an organic molecule with a molecular weight of less than about 3 kd, less than about 2 kd or less than about 1.5 kd, which is a member selected from an organic acid (or alcohol, amine) and its derivatives or analogs, an oligosaccharide and a combination thereof.
In an exemplary embodiment, the coating is a protein, e.g., albumin.
In various embodiments, the particles of the invention are coated with a biocompatible coating. Appropriate coatings are known in the art and it is within the abilities of one of skill in the art to select an appropriate coating for a particular formulation and/or application. (See, for example, Yeh B M, Fu Y, Desai T, WO 2014145509 A1).
The suspended phase of formulations of the invention can include particles of any useful size and size range. Exemplary specific sizes for the particles include from about 1 nm to about 500 microns, e.g., 1 micron to about 100 microns encompassing each single diameter value and each diameter range within the larger range across all endpoints; in various embodiments, the particles are larger than about 5 microns. Further useful particle sizes include, for example, from about 5 microns to about 100 microns, e.g., from about 20 microns to about 70 microns.
The formulations of the invention can include a single enteric contrast medium or two or more enteric contrast media. The media can be present in similar or different concentrations according to any useful measure of concentration. An exemplary embodiment includes different concentrations of one or more particles or soluble agents such that each contributes substantially to the x-ray attenuation, relative to that of water, in the overall contrast formulation. Thus, in various embodiments, from about 1% (w/w, expressed as a weight percent, e.g., about 1 gram of contrast agent particle contained in about 100 grams of total contrast formulation) to about 10% (w/w) of the weight of said formulation is said particles. In an exemplary embodiment, the formulation includes about 3% (w/w) to about 9% (w/w) of the particles. In an exemplary embodiment, the formulation includes about 1% to about 3% (w/w) of the particles.
In an exemplary embodiment, the invention provides a formulation comprising at least about 1%, e.g., at least about 2% but not more than about 10% of said hollow borosilicate particle.
The formulations of the invention include a population of hollow borosilicate microparticle of the invention suspended in a pharmaceutically acceptable vehicle. The vehicle includes any other useful component. For example, in some embodiments, the vehicle comprises an aqueous medium, and it further comprises an additive to impart a second property to the formulation, for example, retard dehydration of said formulation in the bowel, provide flavoring, stabilize the suspension, enhance flowability of the suspension, thicken the suspension, provide pH buffering and a combination thereof.
Within the scope of the invention are formulations designed for single dosage administration. These unit dosage formats contain a sufficient amount of the formulation of the invention to provide detectable contrast in a subject to whom they are administered. In an exemplary embodiment, the unit dosage formulation includes a container holding sufficient enteric contrast medium to enhance, in a diagnostically meaningful manner, a diagnostic image of a subject to whom the unit dosage has been administered. The container can be a vial, an infusion bag, bottle, sachet, or any other appropriate vessel. The enteric contrast medium may be in the form of a preformulated liquid, a concentrate, or powder. In an exemplary embodiment, the subject weighs about 70 kg. In an exemplary embodiment the image is measured through the abdomen of the subject, the pelvis of the subject, or a combination thereof.
In various embodiments, the unit dosage formulation includes from about 800 to about 1500 mL of the contrast agent per adult human dose, which may be divided into smaller containers such as from about 300 to about 600 mL in size. In an exemplary embodiment, the enteric contrast medium formulation is a unit dosage formulation of from about 50 to about 100 mL. In an exemplary embodiment, the enteric contrast medium formulation is a unit dosage formulation of from about 100 mL to about 800 mL.
Any of the formulations described herein can be formulated and utilized for administration through any of a variety of routes. Exemplary routes of administration include oral, rectal, intravaginal, intravascular, intrathecal, intravesicular, and the like.
Low concentrations of HBM contrast materials have not been described for use with CT imaging as a contrast material. In an exemplary embodiment, the HBM in the formulation are of low concentration, e.g., 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.
In various embodiments, the enteric contrast medium of the invention and preferably its formulation exhibits chemical stability across a wide pH range (e.g., from about 1.5 to about 10). The stomach exposes enteric contents to low pH of 1.5 and bile and small bowel may expose enteric contents to high pH of up to 10. Physicochemical stability is a critical component of safety and helps minimize the risk of reactions or adverse events. Adverse reactions may occur if excessive dissolution or degradation of the materials were to occur in the gastrointestinal tract, or if the breakdown products are potentially toxic.
In various embodiments, the invention provides an enteric contrast medium and a formulation of a contrast medium with a t1/2 that is sufficiently long to allow the completion of an imaging experiment with the concentration of HBM remaining sufficiently high within the anatomy of interest. In various embodiments, the invention provides an enteric contrast medium and a formulation having an in vivo residence time that is sufficiently short to allow essentially all of the administered HBM to be eliminated from the body of the subject before being altered (metabolized, hydrolyzed, oxidized, etc.) by the subject's body.
In various embodiments, the small bowel enteric transit time of the formulation is 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 enteric transit times.
In an exemplary embodiment, the invention provides an enteric contrast medium that dissolves slowly such that the majority of the administered HBM particles are eliminated via the gastrointestinal tract prior to being altered by the subject's body, and a dissolved or altered portion is excreted by the urinary tract.
The pharmaceutically acceptable formulation of the present invention may optionally include excipients and other ingredients such as one or more sweeteners, flavors and/or additional taste modifiers to mask a bitter or unpleasant taste, suspending agents, glidants, antioxidants, preservatives and other conventional excipients as needed.
The suspension of the invention may optionally include one or more antioxidants, if necessary, taste modifiers, sweeteners, glidants, suspending agents, and preservatives.
As will be appreciated, the above optional ingredients may be added to the powder formulation of the invention, or to the oral suspension of the invention.
Antioxidants suitable for use herein include any convenient agents known in the art for this purpose such as sodium metabisulfite, sodium bisulfite, cysteine hydrochloride, citric acid, succinic acid, ascorbic acid, sodium ascorbate, fumaric acid, tartaric acid, maleic acid, malic acid, EDTA with sodium metabisulfite or sodium bisulfite being preferred.
Antioxidants may be employed in an amount which will protect the formulation from oxidation as will be apparent to one skilled in the art.
Sweeteners for use in the formulations of the invention may be any convenient agents known in the art for this purpose and may be selected from any compatible sweetener groups such as natural sweeteners like sucrose, fructose, dextrose, xylitol, sorbitol, or manitol, as well as artificial sweeteners such as aspartame, acesulfame K and sucralose. Sucralose and sorbitol are preferred sweeteners.
Flavors and flavor modifiers or taste modifiers can also be used to further improve the taste and can be any convenient agents known in the art for this purpose and include, but are not limited to, orange flavor, vanilla flavor, toffee flavor, licorice flavor, orange vanilla flavor, creme de mint, cherry flavor, cherry vanilla flavor, berry mix flavor, passion fruit flavor, pear flavor, strawberry flavor, mandarin orange flavor, bubble gum flavor, tropical punch flavor, juicy compound for grape, 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.
Suspending agents can be any convenient agents known in the art for this purpose and can be selected from xanthan gum, gellan gum, guar gum, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, alginates, sodium carboxylmethylcellulose and combinations thereof, with xanthan gum being preferred in some embodiments.
Preservatives can be any convenient agents known in the art for this purpose and can be selected from the group consisting of any compound compatible with drug actives such as methylparaben and propylparaben, benzoic acid, sodium benzoate, potassium sorbate, and combinations thereof, with methylparaben being preferred in some embodiments.
The invention also provides kits for use in a clinical and/or research setting. An exemplary kit includes: (a) a first vial containing the enteric contrast medium of the invention; (b) a second vial containing a suspension agent; and (c) directions for using and/or formulating the enteric contrast medium as a suspension. In various embodiments, the kit further comprises another vial containing a second contrast medium; and directions for administering and/or formulating the first and second enteric contrast medium in a clinical or research setting.
The invention also provides methods of utilizing the formulations of the invention to acquire 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 said enteric contrast medium formulation of the invention; and acquiring the CT images of the subject.
The invention also provides methods of utilizing the formulations of the invention concurrent with additional CT contrast agents such as iodinated agents which may be injected or ingested to acquire 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 the enteric contrast medium formulation of the invention then injecting another CT contrast agent then acquiring the CT images of the subject. CT images may be acquired on conventional CT scanners or with dual energy CT, multi-energy CT, or photon counting CT scanners.
In an exemplary embodiment, the invention provides a contrast enhanced CT image of a subject through a region of the subject in which the enteric contrast medium of the invention is distributed. The said contrast enhanced CT image of the invention may be a conventional single energy spectrum CT image, or may be dual energy, multienergy, or photon counting CT images with or without associated CT image reformations that exploit the dual energy, multienergy, or photon counting CT technology. In an exemplary embodiment, the CT image of the invention provides a iodine image or iodine map through a region of the subject in which the enteric contrast medium of the invention is distributed concurrent with iodinated contrast material.
The image of the invention, and those acquired by the method of the invention utilize a contrast medium of the invention. The image is taken through any section of the body of the subject. In an exemplary method, the image is through the abdomen and/or pelvis of the subject.
The following Examples are offered to illustrate exemplary embodiments of the invention and do not define or limit its scope.
Hollow borosilicate glass microparticle “Test Article” (TA) with shell material composed of 95% SiO2, 2% B2O3 and less than 3% oxides with atomic number larger than 10 (such as sodium, aluminum, magnesium, and calcium oxides) were formed with true gravity of 0.35 g/cm3 as determined by helium gas pycnometry. The formation of the hollow borosilicate microparticles did not involve sulfur. This Test Article was named 350TA. The shell composition was confirmed by X-ray fluorescence. The 350TA was then suspended in an aqueous solution as 30%, 20%, 15%, 10%, 5%, and 3% w/w suspensions of Test Article, with the water solution containing 0.2 to 0.4% w/w xanthan gum and 3% w/w sorbitol.
The four 350TA suspensions were scanned in vitro on a dual energy CT scanner which showed the results shown on
The formulations were re-tested with additional excipients including up to 4% flavoring and 2% sucralose and preservatives with similar CT results.
The 15% w/w 350TA suspension with 4% flavoring and 2% sucralose was given by the oral route to healthy volunteers. Prior to and after consumption of the 350TA suspension, the volunteers were scanned on a DECT scanner. The volumes of the 350TA suspension ranged from 400 to 2000 mL. The bowel was found to be marked by the 350TA suspension with CT number average of −170 HU, which allowed ready delineation from bodily fat in the vast majority of cases. However, DECT iodine map reconstructions showed undesired low level calculated iodine concentrations similar to or greater than background soft tissues such as muscle (
Hollow borosilicate microparticle “Test Article” (TA) with true gravity of 0.27 g/cm3 and shell material composed of 95% SiO2, 2% B2O3 and less than 2% oxides with atomic number larger than 10 (e.g. sodium, aluminum, magnesium, calcium oxide). The formation of the hollow borosilicate microparticles did not involve sulfur. The true gravity was confirmed by helium gas pycnometry. This Test Article was named 270TA. The shell composition was confirmed by X-ray fluorescence. The 270TA was then suspended in an aqueous solution as 20%, 15%, 9%, 5%, and 3% w/w suspensions of Test Article, with the water solution containing 0.2 to 0.5% w/w xanthan gum and 3% w/w sorbitol.
The four 270TA suspensions were scanned in vitro on a dual energy CT scanner which showed the results shown on
The 270TA formulations were re-tested with additional excipients including up to 4% flavoring and 2% sucralose and preservatives with similar CT results.
Formulations of 9% w/w 270TA with 0.3% xanthan gum, 3% sorbitol, 4% flavoring and 2% sucralose were administered orally as 1200 mL doses to 32 patient volunteers. The volunteers were imaged at CT prior to and after consumption of the 270TA formulation. The CT scan after consumption of the 270TA formulation utilized dual energy CT and injected intravenous contrast material. Example images are shown in
No uptake of silicon was seen in the blood and no pattern of increased urine silicon above background levels was seen of the volunteers who consumed the 270TA formulation at 1 hour, 4 hours, and 1 day after consumption of the 270TA formulation. No serious adverse events were noted.
Exposure of patients to sulfur may result in unwanted reactions, and so the amount of sulfur in a drug or medical device should be minimized. The total sulfur content between RHBM (regular hollow borosilicate microparticle, including iM30K, 45P25, and 60P18) and HSHBM (high-silicon hollow borosilicate glass microparticles, including with true density of 0.27 and 0.35) as measured via a Leco sulfur analyzer. Method involves heating HBM sample to 1350° C. in an induction furnace while passing a stream of oxygen through the sample. Sulfur dioxide released from sample is measured by IR detection, and total sulfur content is reported. The tested HSHBM each showed sulfur content below detectable (<0.01%) while the RHBMs iM30I, 45P25, and 60P18 showed sulfur contents of 0.08%, 0.15%, and 0.16%, respectively.
The present invention has been illustrated by reference to various exemplary embodiments and examples. As will be apparent to those of skill in the art other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are to be construed to include all such embodiments and equivalent variations.
The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.
CT phantoms were constructed with open-ended plastic cylinders attached to 2.0 mm thick plastic sheets that were engineered to match the CT number of unenhanced bowel wall which is 40 HU (
Spatial resolution phantoms constructed of plastic that simulated a range of thicknesses of bowel wall folds enhanced with iodine intravenous contrast material were filled with different commercial oral contrast media and exemplary HSHBGM contrast medium, the latter of which had CT number of −180 HU (
The present disclosure claims priority to U.S. Provisional Patent Application No. 63/184,708 filed May 5, 2021, which is hereby incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 63184708 | May 2021 | US |
