U.S. patent application number 12/355149 was filed with the patent office on 2009-05-28 for contrast media for using in medical and diagnostic procedures and methods of using the same.
This patent application is currently assigned to BRACCO DIAGNOSTICS INC.. Invention is credited to Archie B. Williams, III.
Application Number | 20090136426 12/355149 |
Document ID | / |
Family ID | 34394083 |
Filed Date | 2009-05-28 |
United States Patent
Application |
20090136426 |
Kind Code |
A1 |
Williams, III; Archie B. |
May 28, 2009 |
CONTRAST MEDIA FOR USING IN MEDICAL AND DIAGNOSTIC PROCEDURES AND
METHODS OF USING THE SAME
Abstract
The present invention relates to contrast media having a low
concentration of contrast agent (active ingredient) and/or low
Hounsfield value for use in medical or diagnostic procedures, or
for therapeutic use. In one alternative embodiment, the contrast
media are comprised of a contrast agent, alone or in combination
with a stabilizing agent or osmotic agent. The present invention is
directed to a contrast media having a Hounsfield value less than
250. In another embodiment, the contrast media comprises a contrast
agent, such as a less than 2% w/v barium-based compound. In another
embodiment, the present invention also relates to formulations and
methods for distending and imaging an anatomic segment of an
individual.
Inventors: |
Williams, III; Archie B.;
(Smithtown, NY) |
Correspondence
Address: |
ALSTON & BIRD LLP
BANK OF AMERICA PLAZA, 101 SOUTH TRYON STREET, SUITE 4000
CHARLOTTE
NC
28280-4000
US
|
Assignee: |
BRACCO DIAGNOSTICS INC.
|
Family ID: |
34394083 |
Appl. No.: |
12/355149 |
Filed: |
January 16, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10679052 |
Oct 3, 2003 |
7498018 |
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12355149 |
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Current U.S.
Class: |
424/9.1 |
Current CPC
Class: |
A61K 49/0404
20130101 |
Class at
Publication: |
424/9.1 |
International
Class: |
A61K 49/00 20060101
A61K049/00 |
Claims
1. A contrast media for use in imaging an individual's anatomic
segment comprising: a contrast agent comprising an iodine-based
compound and an osmotic agent; said contrast media having a
Hounsfield value from about -500 to about 250.
2. The contrast media of claim 1, wherein the Hounsfield value is
about 1 to about 200.
3. The contrast media of claim 1, wherein the Hounsfield value is
about 5 to about 45.
4. The contrast media of claim 1, wherein the Hounsfield value is
about 15 to about 35.
5. The contrast media of claim 1, wherein the Hounsfield value is
about 20 to abut 30.
6. The contrast media of claim 1, wherein the concentration of the
contrast agent is less than 2% by weight.
7. The contrast media of claim 1, wherein the concentration of the
contrast agent is from about 0.01% to about 0.8% w/v.
8. The contrast media of claim 1, wherein the concentration of the
contrast agent is from about 0.01% to about 0.5% w/v.
9. The contrast media of claim 1, wherein the concentration of the
contrast agent is from about 0.1% to about 0.5% w/v.
10. The contrast media of claim 1, wherein the concentration of the
contrast agent is from about 0.01% to about 0.2% w/v.
11-14. (canceled)
15. The contrast media of claim 1, further comprising a stabilizing
agent.
16. (canceled)
17. The contrast media of claim 1, further comprising about 0.005%
to about 40% of a stabilizing agent.
18. The contrast media of claim 1, further comprising about 0.05%
to about 10% xanthan gum.
19. The contrast media of claim 1, further comprising about 0.005%
to about 60% of an osmotic agent.
20. The contrast media of claim 19, wherein the osmotic agent
comprises a sugar-based compound.
21. The contrast media of claim 20, wherein the sugar-based
compound comprises a monosaccharide, disaccharide or
polysaccharide.
22. The contrast media of claim 21, wherein the polysaccharide
comprises sorbitol.
23. A contrast media for use in imaging an individual's anatomic
segment comprising less than 2 w/v % of an iodine-based compound;
about 0.01,% to about 30% of a stabilizing agent and about 0.05% to
about 60% of an osmotic agent.
24. The contrast media of claim 23, wherein the stabilizing agent
comprises xanthan gum and the osmotic agent is selected from
sorbitol, mannitol, or xylitol.
25. The contrast media of claim 23, comprising about 0.001% to
about 0.5% of the iodine-based compound; about 0.05% to about 1%
xanthan gum and about 0.05% to about 5% of sorbitol, mannitol, or
xylitol.
26. The contrast media of claim 23, wherein the contrast media is
provided in an aqueous suspension.
27. The contrast media of claim 23, comprising about 0.05% to about
15% of a stabilizing agent.
28. (canceled)
29. The contrast media of claim 23, comprising about 1% to about
25% of an osmotic agent.
30-31. (canceled)
32. The contrast media of claim 31, wherein the contrast media
comprises about 0.05% to about 5% of sorbitol.
33. The contrast media of claim 23, comprising about 0.001% to
about 5% of the iodine-based compound; about 0.01% to about 5%
xanthan gum and about 1% to about 15% sorbitol.
34. A method of performing a diagnostic procedure comprising: (a)
administering a contrast media to an individual; said contrast
media comprising an iodine-based contrast agent, said contrast
media having a Hounsfield value from about -500 to about 250; and
(b) performing the medical or diagnostic procedure on the
individual during or after administering the contrast media to the
individual.
35. The method of claim 34, where the contrast media has a
Hounsfield value from about -500 to about 100.
36. The method of claim 34, wherein the Hounsfield value is about 1
to about 200.
37. The method of claim 34, wherein the Hounsfield value is about 5
to about 45.
38. The method of claim 34, wherein the Hounsfield value is about
15 to about 35.
39. The method of claim 34, wherein the Hounsfield value is about
20 to abut 30.
40. The method of claim 34, wherein the concentration of the
contrast agent is less than 2% by weight.
41. The method of claim 34, wherein the concentration of the
contrast agent is from about 0.01% to about 0.8% w/v.
42. The method of claim 34, wherein the concentration of the
contrast agent is from about 0.01% to about 0.5% w/v.
43. The method of claim 34, wherein the concentration of the
contrast agent is from about 0.1% to about 0.5% w/v.
44. The method of claim 34, wherein the concentration of the
contrast agent is from about 0.01% to about 0.2% w/v.
45. A method of imaging an anatomic segment of an individual
comprising the steps of: (a) administering a contrast media
comprising an iodine-based contrast agent; said contrast media
having a Hounsfield value from about -500 to about 250; (b)
conducting an imaging procedure to obtain the image of the
individual's anatomic segment during or after administering the
contrast media to the individual; and (c) generating the image of
the anatomic segment.
46. The method of claim 45, wherein at least a portion of the
gastrointestinal tract is imaged.
47. The method of claim 45, wherein the small intestine is
imaged.
48. The method of claim 45, wherein the colon is imaged.
49. The method of claim 45, wherein the pancreas is imaged.
50. The method of claim 45, wherein the duodenum is imaged.
51. The method of claim 45, wherein the cecum is imaged.
52. The method of claim 45, wherein the bowel is imaged.
53. The method of claim 45, wherein the large intestine is
imaged.
54. The method of claim 45, wherein the jejunum is imaged.
55. The method of claim 45, wherein the ileum is imaged.
56. The method of claim 45, wherein the appendix is imaged.
57. The method of claim 45, wherein the pancreas is imaged.
58. The method of claim 45, wherein the duodenum is imaged.
59. The method of claim 45, wherein the sigmoid is imaged.
60. The method of claim 45, wherein the rectum is imaged.
61. The method of claim 45, wherein the stomach is imaged.
62. A method of diagnosing a disease in an individual comprising:
(a) administering to said individual a contrast media comprising an
iodine-based contrast agent; said contrast media having a
Hounsfield value from about -500 to about 250; (2) conducting an
imaging procedure to obtain the image of an individual's anatomic
segment; (3) generating the image of the anatomic segment; and (4)
evaluating the images to diagnose the presence of the disease.
63. The method of claim 62, wherein said disease is selected from
the group consisting of ulcerations, lesions and tumors.
64. The method of claim 62, wherein said disease is cancer.
65. The method of claim 62, wherein said disease is inflammatory
bowel disease, Crohn's Disease, ulcerative colitis or irritable
bowel syndrome.
66. The method of claim 62, wherein said disease is a disease of
the pancreas, spleen, liver or gall bladder.
67. The method of claim 62, wherein said disease is a disease of
the lymph nodes.
68. The method of claim 62, wherein said disease is a disease of
the vascular system.
69. A method of delineating the lumen of an anatomic segment of an
individual for a medical or diagnostic procedure, said method
comprising the steps of: (a) providing a contrast media comprising
an iodine-based compound into the lumen of the individual's
anatomic segment to facilitate delineation of the anatomic segment;
said contrast media having a Houndsfield value from -500 to about
250.
70. A method of distending an anatomic segment of an individual for
a medical or diagnostic procedure comprising the steps of: (a)
providing a contrast media comprising an iodine-based compound into
the lumen of the individual's anatomic segment to facilitate
distention of the anatomic segment; said contrast media having a
Houndsfield value from about -500 to about 250.
71. The method of claim 69, wherein said anatomic segment is the
gastrointestinal tract.
72. The method of claim 69, wherein said anatomic segment is the
small intestine.
73. The method of claim 69, wherein said anatomic segment is the
large intestine.
74. The method of claim 69, wherein said anatomic segment is the
colon.
75. The method of claim 69, wherein said anatomic segment is the
bowel.
76. The method of claim 69, wherein, said contrast media has a
Hounsfield value from about -500 to about 100.
77. The method of claim 69, wherein the Hounsfield value is about 1
to about 200.
78. The method of claim 69, wherein the Hounsfield value is about 5
to about 45.
79. The method of claim 69, wherein the Hounsfield value is about
15 to about 35.
80. The method of claim 69, wherein the Hounsfield value is about
20 to abut 30.
81. The method of claim 69, wherein the concentration of the
contrast agent is less than 2% by weight.
82. The method of claim 69, wherein the concentration of the
contrast agent is from about 0.01% to about 0.8% w/v.
83. The method of claim 69, wherein the concentration of the
contrast agent is from about 0.01% to about 0.5% w/v.
84. The method of claim 69, wherein the concentration of the
contrast agent is from about 0.1% to about 0.5% w/v.
85. The method of claim 69, wherein the concentration of the
contrast agent is from about 0.01% to about 0.2% w/v.
86. The contrast media of claim 20, wherein the sugar-based
compound is selected from sorbitol, mannitol, or xylitol.
87. The method of claim 70, wherein said anatomic segment is the
gastrointestinal tract.
88. The method of claim 70, wherein said anatomic segment is the
small intestine.
89. The method of claim 70, wherein said anatomic segment is the
large intestine.
90. The method of claim 70, wherein said anatomic segment is the
colon.
91. The method of claim 70, wherein said anatomic segment is the
bowel.
92. The method of claim 70, wherein, said contrast media has a
Hounsfield value from about -500 to about 100.
93. The method of claim 70, wherein the Hounsfield value is about 1
to about 200.
94. The method of claim 70, wherein the Hounsfield value is about 5
to about 45.
95. The method of claim 70, wherein the Hounsfield value is about
15 to about 35.
96. The method of claim 70, wherein the Hounsfield value is about
20 to abut 30.
97. The method of claim 70, wherein the concentration of the
contrast agent is less than 2% by weight.
98. The method of claim 70, wherein the concentration of the
contrast agent is from about 0.01% to about 0.8% w/v.
99. The method of claim 70, wherein the concentration of the
contrast agent is from about 0.01% to about 0.5% w/v.
100. The method of claim 70, wherein the concentration of the
contrast agent is from about 0.1% to about 0.5% w/v.
101. The method of claim 70, wherein the concentration of the
contrast agent is from about 0.01% to about 0.2% w/v.
Description
I. FIELD OF THE INVENTION
[0001] The present invention relates to formulations having low
concentrations of contrast agent and/or low Hounsfield values for
use in a medical or diagnostic procedure such as imaging or
surgery, or for therapeutic use. The present invention also relates
to methods for distending or imaging an anatomic segment using the
formulations of the present invention. In one alternative
embodiment, the formulations of the present invention are
especially suitable for use with diagnostic imaging procedures,
including, but not limited to, magnetic resonance imaging (MR),
computed tomography (CT), ultrasound (US), position emission
tomography (PET), and combined modalities such as CT-PET, as well
as other medical and therapeutic uses.
II. BACKGROUND OF THE INVENTION
[0002] Contrast agents are useful in diagnostic imaging because
they make it possible to determine the location, size and identity
of organs or other structures of the body in the context of their
surrounding tissues. In the early days of radiographic contrast
development, researchers realized the value of an element's density
for use as a contrast agent. Barium-based compounds, particularly
BaSO4, soon became the preferred contrast agent due to its high
atomic weight and its low cost to produce. In addition, its safety
profile reinforced this direction of development.
[0003] In time, fluoroscopic imaging enabled radiologists to
monitor contrast agents as they moved through the GI tract. This
advancement required individual BaSO4 suspensions for each segment
of the GI tract. Based on the portion of the GI tract being imaged,
different contrast media comprising barium sulfate were developed.
For the esophagus, a thick paste was used to show esophageal
motility and outline the myocardium (heart) and great vessels
(aorta) of the thorax. These pastes were high in concentrations of
barium sulfate (100% w/v). To study the stomach, a media
concentration of barium sulfate (40-80% w/v) was used. In the small
bowel, concentrations usually were the same or slightly less as
those used for the stomach. Single contrast studies of the colon
were performed by rectal administration. Here, sulfate
concentrations of 15-18% w/v were used to fill and distend the
colon and distal small bowel. In the 1960's and 1970's, double
contrast or air contrast studies were performed on both the upper
and lower GI. In these studies, the barium sulfate concentrations
for the upper and lower GI were 250% w/v and 100% w/v,
respectively.
[0004] In the development of computerized axial tomography ("CAT"
or "CT"), radiologists used orally administered barium sulfate or
dilute iodine solutions to distinguish bowel from other surrounding
tissue. Due to the sensitivity of CT, lower concentrations of BaSO4
(2.1% w/v) could be used, as well as dilute iodine solutions.
[0005] The introduction of multi-detector helical scanners provided
improved quality and image definition. With helical scanner, the
current 2.1% barium sulfate concentrations can be used to
differentiate the GI tract from the surrounding tissue, but do not
allow clear differentiation between bowel wall and bowel lumen.
When conventional bowel markets are used the adjacent soft tissues
are lost in the image acquisition phase. This is due to a phenomena
known as volume averaging. When the radiopaque contrast materials
conventionally used are in the bowel lumen, the soft tissue of the
bowel wall is lost in the image reconstruction.
[0006] The lower contrast media concentrations of the present
formulations, when used with, for example, spiral, helical and
multi-detector helical scanners (MSMD) in CT and in MR, allows for
lumen distention and clear visualization of organs and other
structures, for example:
[0007] In CT, the newer imaging technology allows for improved
image quality and allows image detail of minor HV differences to be
appreciated. The conventional oral bowel markers do not allow
imagers to take advantage of the bowel marking and imaging of
adjacent soft issues. With the older/higher concentration used in
conventional CT, the bowel wall is not visualized. The soft tissue
next to the dense contrast marking the bowel lumen will cause loss
of imaging ability of the adjacent (soft tissue) bowel wall. Much
like the penumbra when light passes through space spreading out and
including adjacent space reconstruction of high densities in CT
casts a shadow on contiguous low density soft tissue structures
called "volume averaging." This concept may be analogized in terms
of the CT image being comprised of pixels. Each pixel has a value
based on the anatomy it represents if it is bright then it is dense
and has a high HV. When you have pixels lined up in a row, as we
have in every CT image, there are dense pixels and less dense
pixels. When these adjacent pixels have great differences in HV's,
like we would expect to see in the GI tract bowel wall (45 HV) and
the lumen with conventional CT contrast (250 to 450 HV), there is
an averaging effect. The pixels of lower density values of the
bowel wall are increased and the bowel lumen contrast of higher
density pixels are slightly decreased. The net effect is the loss
of bowel wall in the image.
[0008] There is, therefore, a need for a contrast media having a
lower Hounsfield value and/or lower concentration of contrast agent
to effectuate high quality imaging of organs or other structures in
a medical or diagnostic procedure, or for therapeutic use.
III. SUMMARY OF THE INVENTION
[0009] The present invention relates to contrast media formulations
having a low concentration of contrast agent and/or low Hounsfield
value for use in medical or diagnostic procedures, or for
therapeutic use. In one alternative embodiment, the contrast media
is comprised of a contrast agent, alone or in combination with a
stabilizing agent or osmotic agent. In one embodiment, the present
invention is directed to a contrast media having a Hounsfield value
less than 250 and preferably less than 100. In another embodiment,
the contrast media comprises a contrast agent, such as a
barium-based compound. In yet another embodiment, the present
invention also relates to formulations and methods for bowel
marking, bowel distention and imaging of an anatomic bowel segment
of an individual. Additionally, the formulations of the present
invention are especially suitable for use with diagnostic imaging
procedures including, but not limited to, fluoroscopy (X-Ray),
magnetic resonance imaging (MR), computed tomography (CT), CT-PET
(position emission tomography and ultrasound (US), as well as other
medical and therapeutic uses.
IV. DESCRIPTION OF THE FIGURES
[0010] FIG. 1 shows CT image of an abdomen of an individual
administered the present invention.
[0011] FIG. 2 shows a CT image of an abdomen of an individual
administered the present invent invention.
[0012] FIG. 3 shows a CT image of an abdomen of an individual
administered the present invention.
[0013] FIG. 4 shows an MR image of an abdomen of an individual
administered the present invention.
[0014] FIG. 5 shows CT images of the present media in an HDPE
container.
V. DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention is directed to contrast media suitable
for use in a medical or diagnostic procedure such as diagnostic
imaging. Diagnostic imaging techniques suitable for use herein
include, but are not limited to, X-ray imaging, MR, CT, US, optical
imaging, SPECT, PET, flat-panel imaging, and using rigid, flexible
or capsule endoscopy. A combination of CT and PET imaging, namely,
CT-PET is also suitable for use with the present invention.
Preferably, the diagnostic imaging technique used herein is MR, CT,
CT-PET or US.
[0016] The present contrast formulations may be useful in
diagnostic imaging of any anatomic structure of the body. In one
embodiment, the present invention is especially suited for use in
diagnostic imaging of anatomic segments including, but not limited
to, the esophagus, the stomach and GI tract, including the
duodenum, small bowel (jejunum, ileum, appendix and cecum) and the
large intestine, (ascending bowel, hepatic flexure, transverse
colon, splenic flexure, descending colon, sigmoid and rectum).
Additionally, the present invention is particularly suited for
imaging tissues and organs such as the pancreas, gall bladder,
spleen, liver, lymph nodes, and the vasculature, as well as
pathologic entities such as abscesses and the like.
[0017] A. Formulation
[0018] More particularly, the present invention relates to contrast
media formulation having a low Hounsfield value (HV), including a
positive or negative HV. In one embodiment, the present invention
relates to contrast media for diagnostic imaging comprising low
concentrations of contrast agent, alone or in combination with a
stabilizing agent or an osmotic agent.
[0019] 1. Contrast Agent
[0020] The contrast media of the present invention include any
composition of matter that can, upon administration to an
individual, affect a lumen or tissue (e.g. fill, distend, label
and/or mark) so that an area of interest can be differentiated from
surrounding tissue during a medical activity, for example. Such
medical activities including, but not limited to, a diagnostic,
surgical or therapeutic procedure.
[0021] Contrast media of the present invention may comprise one or
more contrast agents, including but not limited to, barium-based
compounds, such as barium sulfate, organically-bound iodine-based
compounds of both the non-ionic and ionic type or any combination
of the above mentioned compounds. Other agents may include
gadolinium-based compounds (or any other metallic elements used in
MR imaging, including, but not limited to, Fe, Dy, Mn), stabilizing
agents, bentonite-based compounds or any other suitable inert or
insoluble compounds, including but not limited to, metallic
oxides/silicates/sulfates/hydroxides such as milk of magnesia
fat-based compounds, lipids or triglycerides, or any combination
the of the above-mentioned compounds.
[0022] In the present invention, doses of contrast agent may be
administered via many different dosage forms. The contrast media
may take many forms including but not limited to, liquid,
suspension, paste, powder, concentrate, granulated powder for
mixing to proper concentration or solid form. For example, the
contrast media may be consumed as a drink, it may also be
administered orally by other means or administered rectally. In
addition the oral or rectal route, the contrast media may be
administered percutaneously or via intubation. Also, the contrast
media may be consumed as a suspension or swallowed as a tablet,
capsule or caplet.
[0023] In another alternative embodiment, the total amount of
contrast agent (active ingredient) administered to the individual
prior to or during the medical activity may be at least about 0.01
g, 0.025 g, 0.05 g, 0.075 g, 0.1 g, 0.5 g, 1 g, 5 g, 10 g, 20 g, 30
g, 50 g, 70 g, 100 g, 120 g, 150 g, 180 g, 200 g, 300 g, 350 g, 400
g, 450 g, 500 g, 550 g, 600 g or more. The preferred range is from
about 1 g to about 3 g, more preferably about 2 g to about 2.5
g.
[0024] The contrast agent may be provided in a contrast media
having a volume of about 10 ml to about 10 L, or about 100 ml to
about 5 L, or about 200 ml, 250 ml, 300 ml, 350 ml, 400 ml, 450 ml,
500 ml, 550 ml, 600 ml, 650 ml, 700 ml, 750 ml, 800 ml, 850 ml, 900
ml, 1 L, 1.5 L, 2 L, 2.5 L, 3 L, 3.5 L, 4 L or 4.5 L.
[0025] The contrast media may be administered in single dosage, or
may be divided into multiple dosages. For example, if the contrast
media is 2 L, then the patient may consume 1 L about 2 hours prior
to the procedure, and the remaining 1 L about 1 hour prior to the
procedure. Another approach is to have the patient consume 150 ml
every 5 minutes until the total volume required for specific
procedure is consumed.
[0026] 2. Concentration of Contrast Agents
[0027] In one alternative embodiment, the contrast media of the
present invention may comprise any appropriate amount of contrast
agent, provided that the value of the contrast media comprising the
contrast agent, alone or with other excipients, is less than 250
HV.
[0028] In one alternative embodiment, the contrast media of the
present invention may comprise less than 1% by weight of a
barium-based compound. In another alternative embodiment, the
present invention may comprise from about 0.001% to about 0.8%
barium-based compound, preferably from about 0.01% to about 0.5%,
more preferably about 0.1% or about 0.5%. Other concentrations of
barium-based compound that may be suitable in the present invention
include 0.02%, 0.03%, 0.04%, 0.06%, 0.07%, 0.08%, 0.09%, 0.11%,
0.15%, 0.02%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%,
0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.90%, or 0.95% by weight. The
preferred barium-based compound is barium sulfate.
[0029] In one alternative embodiment, the contrast media of the
present invention may comprise less than 1% by weight of a contrast
agent. In another alternative embodiment, the present invention may
comprise from about 0.001% to about 0.8% iodine based compound,
preferably from about 0.01% to about 0.5%, more preferably about
0.1% or about 0.05%, most preferably, about 0.1% iodine based
compound. Other concentrations of iodine based compound that may be
suitable in the present invention include 0.02%, 0.03%, 0.04%,
0.06%, 0.07%, 0.08%, 0.09%, 0.11%, 0.15%, 0.02%, 0.25%, 0.30%,
0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%,
0.80%, 0.90%, or 0.95% by weight.
[0030] In one alternative embodiment, the contrast media of the
present invention may comprise less than 1% by weight of a contrast
agent. In another alternative embodiment, the present invention may
comprise from about 0.001% to about 0.8% gadolinium based compound,
preferably from about 0.01% to about 0.5%, more preferably about
0.1% or about 0.05%, most preferably, about 0.1% gadolinium based
compound. Other concentrations of gadolinium based compound that
may be suitable in the present invention include 0.02%, 0.03%,
0.04%, 0.06%, 0.07%, 0.08%, 0.09%, 0.11%, 0.15%, 0.20%, 0.25%,
0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%,
0.75%, 0.80%, 0.90%, or 0.95% by weight.
[0031] 3. Hounsfield Value of Contrast Media
[0032] The HV of the contrast media may be determined by CT using
procedures well known in the art. As used herein, Hounsfield units
or Hounsfield values ("HV") are units of X-ray attenuation used for
CT scans. Each pixel being assigned a value on a scale where
air=-1000, water=0, and compact bone=1000. In the present
invention, the HV of the contrast media (with excipients, if any)
may be determined by placing it in an HDPE container and placing
the container in a CT scanner (e.g., Siemens 4 channel scanner) to
determine the HV of the formulation. The container may comprise any
known HDPE used in the medical industry for packaging
non-radioactive oral contrast agents for CT.
[0033] Example of apparatuses suitable for practicing the present
invention include, but are not limited to, spiral/helical CT
scanners with multi-detector/multi-slice capabilities. Other
apparatuses include, but are not limited to, GE: CT: LightSpeed
Series and HiSpeed MR: Signa Excite Series CT/PET: Discovery Series
Philips: CT: Mx8000 Series MR: Intera Series CT/PET: Gemini
Siemens: CT: Somatom MRT: Magnetom CT/PET: biograph Toshiba: CT;
Aquilion Steion Multi MR: Ultra, Excelart and flat panel (which,
will allow for large volumes of data to be acquired over large area
instantaneously).
[0034] In one alternative embodiment, the contrast media of the
present invention comprise a contrast agent having an HV value from
about -500 to about 250. In another embodiment, the HV value may
range from about -100 to about 100, preferably from about 15 to 35,
more preferably from about 20 to 30. In another embodiment, the HV
value may range from -500 to 0 HV, more preferably less than 0. The
lower range may differentiate the lumen of the GI from surrounding
organs when the GI tract is distended with the present
invention.
[0035] Other suitable HV ranges include from about: -500 to 400;
-400 to -300; -300 to 200; -200 to 100; -100 to 0; 0 to 5; 5 to 10;
10 to 15; 15 to 20; 20 to 25; 25 to 30; 30 to 35; 35 to 40; 40 to
45; 45 to 50; 55 to 60; 60 to 65; 65 to 70; 75 to 80; 80 to 85; 85
to 90; 90 to 95; 95 to 100; 100 to 110; 110 to 120; 130 to 140; 140
to 150; 150 to 160; 160 to 170; 170 to 180; 180 to 190; 190 to 200;
210 to 220; 220 to 230; 240 to 250.
[0036] 4. Stabilizing Agent
[0037] In one alternative embodiment, the contrast media of the
present invention comprises a stabilizing agent. Such agent may
include any compound (e.g. suspending agent) that modifies the
viscosity of a substance, including any fluid, semi-fluid or solid.
Stabilizing agents suitable for use herein may include, but are not
limited to, cellulose, gelatin, natural hydrocolloids, bentonite,
locust bean gum or any compound that appropriately modifies the
viscosity of a substance so as to facilitate the imaging
process.
[0038] Natural hydrocolloids suitable for use in the present
formulations include, but are not limited to, (1) natural seaweed
extracts such as carrageenan, alginates, agar, agarose, fucellan
and xanthan gum; (2) natural seed gums such as guar gum, locust
bean gum, tara gum, tamarind gum and psillium gum; (3) natural
plant exudates acacia, tragacanth, karaya and ghatti gums; (4)
natural fruit extracts such as low and high methoxyl pectins; (5)
natural and purified clays such as bentonite and veegum to alter
viscosity and lower signal/noise ratios to improve performance in
MR imaging.
[0039] In one alternative embodiment, the stabilizing agent is a
natural seed gum, and, even more preferably, locust bean gum. The
chemical structure of locust bean gum is:
##STR00001##
[0040] In one embodiment, the present invention relates to a
formulation comprising about 0.001% to about 70% by weight of a
stabilizing agent in an aqueous solution, or about 0.05% to about
25% by weight of a stabilizing agent, or about 0.1% to about 10% of
a stabilizing agent. In another embodiment, the present invention
relates to a formulation comprising about 0.01%, 0.02%, 0.03%,
0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%,
0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1% by weight of a stabilizing agent
in an aqueous solution. Preferably, the contrast agent is a
formulation comprising about 0.01% to about 1.0% by weight.
[0041] 5. Osmotic Agent
[0042] In one alternative embodiment, the contrast media of the
present invention comprises an osmotic agent, such agents suitable
for use herein including any compound that facilitates the transfer
of fluid from the body into an anatomic segment and at least
substantially inhibits the re-absorption of fluid in the anatomic
segment by the body. It has been discovered that, when used in
combination, the stabilizing agent and the osmotic agent act
synergistically to form an improved formulation for use in a
medical diagnostic procedure such as diagnostic imaging. It is
believed that the osmotic agent facilitates the transfer of
suitable amounts of fluid into an anatomic segment of interest and
that stabilizing agent and osmotic agent cause sufficient amounts
of fluid to be retained in the anatomic interest segment of
interest. Thus, the anatomic segment is sufficiently expanded or
distended for diagnostic imaging, such that when the anatomic
segment is imaged, it appears sufficiently delineated on the
diagnostic image obtained.
[0043] Osmotic agents suitable for use in the present invention
include, but are not limited to, sugar-based compounds. Sugar-based
compounds for use herein include, but are not limited to,
monosaccharide, disaccharide and polysaccharides including sucrose,
glucose, fructose, mannitol, mannose, galactose, aldohexose,
altrose, talose, sorbitol, xylitol, lactose, nonionic seed
polysaccharide, straight chain mannan grouping with branching on
every mannose by one galactose unit, Beta-D-man, alpha-D-gal,
D-glcA, D-gal A, L-gul, beta-D-man, alpha-D-gal (4:1), D-glucuronic
acid, D-galacturonic acid, and L-glucuronic acid. The chemical
structure of a suitable polysaccharide is shown below.
##STR00002##
[0044] Preferably, the osmotic agent is sorbitol. It is believed
that the underlying chemical structure of sorbitol prevents
intestinal absorption of fluid. Thus, the inherent osmotic property
of sorbitol leads to increased distention in an anatomic segment
such as the GI tract, for example.
[0045] The formulation of the present invention may comprise about
0.005% to about 70% by weight of an osmotic agent, or about 0.1% to
about 45% by weight of an osmotic agent, or about 1%, 2%, 3%, 4%,
5%, 6%, 7%, 8%, 9%, or 10% by weight of an osmotic agent. In one
embodiment, the formulation comprises about 1% to about 4% by
weight of an osmotic agent, preferably a polysaccharide, or even
more preferably about 2% of sorbitol in an aqueous solution.
[0046] B. Exemplary Applications of the Contrast Media of the
Present Invention
[0047] In one alternative embodiment, the formulations of the
present invention are suitable for preparing an individual for a
medical activity or for use simultaneously with such medical
activity. Further, the contrast media of the present invention
provide improved marking and organ differentiation during a medical
activity. For example, in one embodiment, the image definition
allows for the computer to define the differences between bowel
wall, soft tissue, and bowel lumen distended with the contrast
media of the present invention. In addition, the marking
capabilities of the present contrast media allow for imaging of the
vascular system at the same time.
[0048] In one embodiment, the contrast media of the present
invention, when administered to an individual, will allow for
differentiation between soft tissue and the bowel lumen distended
by the low concentrations of contrast agent. The present contrast
media will mark the lumen as its predecessor did in the older CT
technology, but will enable differentiation between bowel marker,
cystic lesions, lymph nodes and bowel lumen, for example, or any
other anatomic segment with a different HV value. See Table 1.
TABLE-US-00001 TABLE 1 Standard Range Standard Tissue value (HV)
(HV) Fluid value (HV) Bone (compact) >250 Blood (coagulated) 80
.+-. 10 Bone (spongy) 130 .+-. 100 Blood (venous whole blood) 55
.+-. 5 Thyroid 70 .+-. 10 Plasma 27 .+-. 2 Liver 65 .+-. 5 45-75
Exudate (>30 g protein/l) >18 .+-. 2 Muscle 45 .+-. 5 35-50
Transudate (>30 g protein/l) <18 .+-. 2 Spleen 45 .+-. 5
35-55 Ringer's solution 12 .+-. 2 Lymphoma 45 .+-. 5 40-60 Pancreas
40 .+-. 10 25-55 Kidney 30 .+-. 10 20-40 Fatty tissue -90 .+-. 10
-80-(-110)
[0049] An additional value of the present invention is also
realized when vascular studies are performed. Thus, in an
alternative embodiment, the present invention relates to a method
of performing vascular studies on an individual using the contrast
medias described herein. Such method comprising the step of
distending the individual bowel by administering the contrast media
of the present invention to the individual. Such method may also
comprise the step of administering the present invention via IV to
enhance the vascular system. By having the bowel distended and
identified relative to the other abdominal structures for example,
an abdomen may be scanned with a spiral/helical or multi-detector
CT scanner, producing data sets that will construct a full volume
rendered data set of the area scanned. In one embodiment, the
formulations of the present invention could enable viewing of all
organs and vessels independently or together as a complete data
set. These formulations enable the lumen to be differentiated from
the bowel wall while viewing the IV enhanced vascular system at the
same time.
[0050] In one alternative embodiment, the present invention is
directed to a method of performing CTA using the present
formulations. Currently during CT Angiography (CTA) conventional
oral contrast agents interfere with the image construction. CTA
procedures are performed by injecting water soluble iodinated
contrast agents into the vascular system. The contrast enhances the
vascular structures of the abdomen. This process enhances the HV's
of arterial and venous structures. The timing of the contrast
injection and the timing of the scanning of the abdomen would
enable the IV contrast in the arterial phase or the venous phase to
be captured. During these procedures conventional oral contrast
agents would interfere in the image.
[0051] The HV's of conventional oral contrast agents would compete
with the IV contrast to create an image that would obscure vascular
structures and would cause incomplete vascular structure image
construction or masking bowel wall vascular or adjacent vascular
structures. This occurs when the Maximum Intensity Pixel (MIP)
technique is employed. Currently, specialized software will remove
and reconstruct all of the MIP pixels from the abdomen data set. If
IV contrast is used, the vessels of the abdomen become enhanced and
these structures become intense pixels in the image. These pixels
may provide a complete 3D image of the vascular structures of the
abdomen. If conventional oral contrast is also used, the intensity
of the pixels in the lumen of the GI tract competes with the
vascular pixels. This causes loss of vascular structures since it
is possible that some of the pixels in the lumen could be more
intense than some smaller vessels and vessels of lower pixel
intensity. The use of the current invention could allow for MIP
studies and other display techniques to demonstrate vascular
systems and mark the bowel during the same exam. Thus, the ability
to see all abdominal and vascular structures would add to the
overall understanding of disease in the abdomen and pelvis.
[0052] In another alternative embodiment, the present invention is
directed to producing an HV value in the area below un-enhanced
bowel wall but higher than water. Previously, radiologists used
water and fat containing products to achieve a negative HV value.
In one embodiment, the formulations of the present invention
provide a different approach by staying on the positive side of the
HV's. With the present formulations, the lumen of the bowel can be
marked, as barium sulfate and iodine have always done. But, with
the present formulation, the marking stays below the HV's of the
un-enhanced bowel wall. The low Hounsfield value of the present
invention therefore becomes advantageous during any exam that
requires enhancement of an atomic segment with IV contrast, such as
the bowel wall. When using IV contrast, conventional bowel markers
such as barium or iodine cannot be used because the density of
these agents are too similar to the IV contrast and will hide
anatomy or create artifacts when used together (i.e., oral barium
or iodine with IV contrast).
[0053] In one alternative embodiment, the contrast media of the
present invention is administered to an individual. In one
embodiment, the HV values of the present formulation would fall
below the range of the bowel wall enhanced with IV contrast,
allowing it to mark the GI tract both before and after IV contrast
enhancement. In one embodiment, the bowel wall will be enhanced
with IV contrast raising the HV's to 60-90 or higher. When the
present formulation is in the lumen, the difference in density from
lumen (22 HVs) to the enhanced bowel wall (90+HVs) would be clear.
Bowel wall is in the 45 HV range (unenhanced) and the bowel wall
can exceed 100 HVs with IV contrast. Also, the bowel may be marked
for purposes of diagnosing the GI tract and other organs and
vascular system simultaneously. This has not been previously
accomplished with a positive contrast agent in the GI tract.
Therefore, in one embodiment, the present invention is directed to
a method of marking the bowel using the present contrast media,
enabling the bowel to be differentiated from surrounding structures
and allow for additional diagnostic evaluations at the same time,
with or without enhancing other atomic segments using IV contrast.
In one alternative embodiment, the above procedure may be carried
out using spiral/helical or MSMD CT scanners.
[0054] In another alternative embodiment, the present contrast
media may comprise modified charges on the contrast agent, e.g.
barium particles to attract them to the bowel wall leaving the
lumen distended with lower concentrations of the contrast agent in
the lumen. Leaving a slightly higher coating film containing higher
concentrations of the active ingredient on the mucosal surface
could improve image quality.
[0055] In one alternative embodiment, the present invention relates
to a method of reducing the signal/noise ratio in MR. The method
comprising the step of administering the present contrast media to
the individual prior to or during an MR procedure. In one
embodiment, the present contrast media would create a darker (i.e.,
void, no signal or low signal) image with or without the addition
of such additives as bentonite, for example. This additional
contrast difference between the lumen and the unenhanced bowel wall
could allow one to mark the GI tract before or after IV contrast
enhancement. The bowel wall will enhance with IV contrast raising
its signal/noise ratio. In one embodiment, this causes the wall to
become bright. When using MR and the present formulation with or
without the addition of bentonite in the lumen (for example), the
difference in contrast from lumen (darker, void, no signal or low
signal) to the enhanced bowel wall (which appears bright, white
with increase signal/noise ratio) would be clear. Also, the bowel
may be marked for purposes of diagnosing the GI tract and other
organs and vascular system simultaneously.
[0056] In one embodiment, the formulations of the present invention
may be administered to an individual prior to the individual
undergoing an image guided biopsy of the GI tract, or any adjacent
organs such as liver, spleen, pancreas, kidney, lymph nodes and the
like. The added value of a clear visualization of the bowel wall
and lumen may allow for a better understanding of bowel location
for more precise placement of the biopsy needle. This would offer
the opportunity to avoid puncture of bowel loops that would
otherwise not be easily visualized when taking a biopsy of tissue
located in the abdomen or pelvis.
[0057] In another embodiment, the formulations of the present
invention may be used to stabilize the GI tract of an individual in
order to obtain a diagnostic image of the vasculature system or the
lymph nodes or other anatomical structures. In addition, the
ability to decrease movement of the GI tract during PET or CT-PET
leads to improvement in co-registration of CT and PET data sets.
Thus, in one embodiment, the present invention relates to a method
of stabilizing the GI tract of an individual during a surgical or
diagnostic procedure, for example. Such method comprising the step
of: (1) administering the present contrast media to the individual
prior to or during the diagnostic or medical procedure for purposes
of stabilizing an individual's GI tract; and (2) conducting the
diagnostic or medical procedure.
[0058] In another embodiment, the present invention further relates
to formulations for delineating the lumen or wall of an anatomic
segment of the GI tract on a diagnostic image. The diagnostic image
being a two- or three-dimensional or volumetric or a surface
rendered image of the anatomic segment, for example. Thus, in one
embodiment, the present invention relates to a method of
delineating the lumen or wall of an anatomic segment of an
individual's GI tract. Such method comprising the step of: (1)
administering the present contrast media to the individual prior to
or during the diagnostic procedure; (2) conducting the diagnostic
procedure; and (3) generating the image of the delineated lumen or
wall of an anatomic segment.
[0059] In another alternative embodiment, the formulations of the
present invention represent an improvement over conventional
contrast agents or formulations for distending, delineating or
marking an anatomical segment of the GI tract, or any other
anatomic segment. For example, the conventional technique of
distending the small bowel is by administering a
methylcellulose-water solution via intubation, an unpleasant
invasive procedure. The present formulations, however, may be
administered orally. Therefore, the formulations of the present
invention are non-invasive, and also may maintain the integrity of
diagnostic imaging as a non-invasive technique. Also, when
administered orally, the present formulations increase patient
comfort and compliance as compared to conventional contrast
agents.
[0060] The low HV value of the present contrast media allows for
universal acceptance in CT, CT angiography, CT-PET, PET, MR,
Fluoroscopy, and US. For example, the universal use of the contrast
agent may allow a patient to be moved from one imaging modality to
another without delay between procedure. In one embodiment, the
multi-modality use of the contrast allows an individual having the
present invention in the GI tract to be imaged by one imaging
modalities and taken to another for additional imaging. Here, the
patient need only be prepped once, and can still use different
imaging modalities by administering the present media to that
individual prior to or during an imaging procedure.
[0061] In one embodiment, the present invention relates to a method
of imaging the small intestine of an individual comprising
administering the formulations disclosed herein and using MR, CT,
US, PET or CT-PET to obtain a visible image of the small intestine.
Other anatomic segments suitable for use herein include, but are
not limited to, esophagus, the stomach and GI tract, including the
duodenum, jejunum, ileum, appendix, colon, large intestine, cecum,
ascending bowel, hepatic flexure, transverse colon, splenic
flexure, descending colon, sigmoid, rectum, pancreas, gall bladder,
and appendix. Additional adjacent normal and pathologic structures
such as spleen, liver, lymph nodes, vasculature, abcesses and the
like can be imaged.
[0062] In an alternative embodiment, the present invention relates
to a method of diagnosing a disease in an individual comprising
administering to the patient the formulations of the present
invention. In one embodiment, the method further comprises
obtaining an image of the anatomic segment and using said image to
diagnose said disease. In an alternative embodiment, the present
invention relates to a method of diagnosing a disease in a patient
comprising the steps of: (1) administering to an individual a
formulation comprising the present invention; (2) obtaining an
image of the anatomic segment using MR, CT, CT-PET, PET, (3) using
said image to diagnose or assist in diagnosing a disease, and
optionally (4) obtaining an image using a positive IV agent to
enhance bowel wall, allowing the present invention to fill, mark,
and distend the bowel, creating a double contrast effect with all
previously mentioned routes of administration.
[0063] In another alternative embodiment, the present invention
relates to a method for diagnosing a disease including, but not
limited to, diseases of the GI tract, ulcerations, lesions,
strictures intermittent or fixed and tumors of the GI tract or
stomach, Inflammatory Bowel Disease, Crohn's Disease, ulcerative
colitis, Irritable Bowel Syndrome, and cancer including, but not
limited to, cancer of the small bowel, anal cancer, stomach cancer,
colon cancer, liver cancer and pancreatic cancer, abscesses, ulcers
and disorders of the spleen, liver, lymph nodes and
vasculature.
[0064] In yet another embodiment, the present invention relates to
a method of enhancing image quality during interventional
procedures requiring placement of vascular stents or interlumenal
stents of the GI tract, and other common hepatobiliary, pancreatic
and renal interventional procedures. In one embodiment, such method
comprises the steps of: (1) administering to an individual the
present contrast media; (2) conducting one or more procedures
requiring placement of vascular stents or interlumenal stents of
the GI tract; and (3) generating a diagnostic image during said
procedures. Preferably, the diagnostic image is a two- or
three-dimensional image, volumetric and surface rendered or a
combination of the two created using MR, CT or CT-PET data.
[0065] In another embodiment, the present invention relates to a
method of improving the accuracy of knowing the exact location of
distended bowel prior to intervention, surgery, radiation therapy,
vascular or gastrointestinal stent placement, enteroscopy,
laparoscopy etc.
[0066] In one embodiment, such method comprises the steps of: (1)
administering to an individual the present contrast media; (2)
generating a diagnostic image to identify the location of a
distended bowel prior to one or more procedures, including but not
limited to, intervention, surgery, radiation therapy, vascular or
gastrointestinal stent placement, enteroscopy, or laparoscopy; and
(3) conducting such procedures.
[0067] The present formulations may be administered to an
individual to mark the GI tract during therapeutic treatment or
planning for such treatment. Here, ulcerations, lesions or tumors
of the GI tract, GI tract bleeding, Inflammatory Bowel Disease,
Crohn's Disease, ulcerative colitis or Irritable Bowel Syndrome can
be imaged by utilizing one or more of the imaging modalities
discussed herein.
[0068] The present invention may be used as a small bowel contrast
marker while performing CT Colonography. The purpose is to create
mechanical resistance by filling the lumen with contrast that can
impede the likelihood of having small bowel reflux of CO2 or room
air when administered during CT Colonography. This technique may
allow one to obtain high quality small bowel examination at the
same time and with same exposure during either a CT or MR
Colonography. Additionally, the concept may be able to impede
reflux of CO2 or room air into small bowel, optimizing distention
of the colon. Thus, the present invention is directed to marking
the small bowel while performing CT colonography, including the
step of administering the present contrast media to an individual
prior to or during a CT colonography procedure, and then generating
an image of the anatomic segment of interest.
[0069] The contrast media of the present invention comprise lower
concentrations of contrast agent than those of conventional media.
Lower concentrations of the "active ingredient" in contrast agents
provides several advantages, most notably, potentially reducing
risk of allergic or other adverse reactions.
VI. EXAMPLES
[0070] The following examples are included for illustrative
purposes only and are not intended to limit the scope of the
invention to any particular step or ingredient, for example.
Example 1
TABLE-US-00002 [0071] TABLE 2 A B C D Formulation, Formulation,
Formulation, Formulation, Function of Ingredient % w/v % w/v % w/v
% w/v Ingredient Barium Sulfate 0.0000 0.1000 0.0500 0.0500
Radiographic USP, EP Contrast Agent Xanthan Gum, NF 0.5226 0.1828
0.5226 0.1830 Suspension stabilizer Sorbitol solution 3.7616 2.8571
2.0000 2.0000 Osmoregulator 70%, USP Viscosity 719 cps 128 cps 860
cps 140 cps Density 1.0100 g/ml 1.0100 g/ml 1.006 g/ml 1.005 ag/ml
pH 4.95 4.95 5 5 Potassium 0.2090 Preservative Sorbate, NF Sodium
Benzoate, 0.0433 NF Benzoic Acid, 0.0696 USP/BP Simethicone 0.5226
Defoamer Emulsion, USP Citric Acid, USP 0.0028 pH adjuster Sodium
Citrate, 0.0076 USP Flavors & 0.4309 Flavorings artificial
sweetener Purified water q.s. to 100% volume Diluent USP
[0072] Formulations A through D were prepared as follows: Xanthan
Gum in powdered form was added in water. The temperature of the
suspension was maintained at 60-65.degree. C. throughout
manufacturing. Other ingredients were added: simethicone-water
premix; preservatives: potassium sorbate, sodium benzoate and
benzoic acid; pH adjuster: sodium citrate and citric acid;
dispersion of barium sulfate USP; addition of the rest of the
ingredients in the following order: sorbitol 70% solution,
saccharin sodium, flavours; Qs to 100% volume with purified
water.
[0073] Differences between each formulation include (1) the
equipment used in the manufacturing process and (2) the
concentration of ingredients. For example, Formulations A and B
were laboratory batches of 7000 ml. These batches were manufactured
in a glass beaker. The formulation was prepared under lightning
agitation. The product's manufacturing temperature was monitored
manually and the temperature was maintained with a water bath at
60-65.degree. C.
[0074] Formulations C and D were manufactured in a Hamilton kettle,
which is made of stainless steel and has a capacity of 200 gallons.
A Quadro Ytron mixer, a side sweep and auxiliary mixers made the
Hamilton kettle's agitation. The agitation speed of each mixer was
variable and controlled with an adjustable speed drive. The control
of the temperature, between 60-65.degree. C., was done manually by
controlling the flow of water/steam flowing into the cooling
jacket. The manufacturing process of formulations C and D used the
Quadro turbine and side sweep agitation from the beginning until
the end. The auxiliary agitation started at the barium sulfate
addition and finished after the second addition of the xanthan
powder.
[0075] Other differences between formulations A to D are the
concentrations of barium sulfate, the xanthan gum and sorbitol.
Formulation A was manufactured without barium sulfate while batch
formulation B was made with 0.1 w/v % of barium sulfate.
Formulations C and D were made with 0.05 w/v % of barium
sulfate.
[0076] Formulations A and C were made with the regular
concentration of xanthan gum found into the current banana smoothie
formula (0.5226 w/v %) while formulations B and D were manufactured
with 35% of the regular concentration of xanthan gum found in the
current banana smoothie formula (0.1830 w/v %). The xanthan gum
concentration difference gives high and low viscosities solutions
of approx. 720 and 130 cps. Formulation A was manufactured with
3.7616 w/v % of sorbitol solution 70% which is identical to the
concentration found into the banana smoothie formulation.
Formulation B was made with 2.8571 w/v % of sorbitol solution 70%.
This concentration represents 2 w/v % @ 100% of sorbitol.
Formulation B was manufactured with 2 w/v % of sorbitol solution
70%.
Example 2
[0077] A contrast media having the following formulation was
prepared in accordance with the steps described in Example 1.
TABLE-US-00003 TABLE 3 Description % Quantity 1 PURIFIED WATER USP
66.6700 2 XANTHAN GUM NF/EP/BP 0.0914 3 SIMETHICONE EMULSION 30%
USP 0.0673 4 PURIFIED WATER USP 0.0716 5 POTASSIUM SORBATE NF
0.2090 6 SODIUM BENZOATE NF 0.0433 7 BENZOIC ACID USP/BP 0.0696 8
SOD CITRATE DIHYD USP/EURPH 0.0076 9 CITRIC ACID ANH (PWD) USP
0.0028 10 PURIFIED WATER USP 0.5556 11 BARIUM SULFATE HN USP 0.1000
12 XANTHAN GUM NF/EP/BP 0.0914 13 SIMETHICONE EMULSION 30% $ USP
0.4553 14 PURIFIED WATER USP 0.4840 15 SORBITOL SOL'N 70% USP
2.8571 16 SODIUM SACCHARIN USP/EP/BP 0.0109 17 SAV BLEUET W390007F
MFR 0.1500 18 PURIFIED WATER USP QS
Example 3
[0078] Using a Seimens 4 channel scanner, the HV values of the
present contrast media were determined. The formulas evaluated
were:
[0079] 1. 0.05% w/v barium sulfate, 860 CPS, 2% sorbitol
(Formulation C)
[0080] 2. 0.05% w/v barium sulfate, 140 cps, 2% sorbitol
(Formulation D)
[0081] 3. No barium sulfate, 719 cps, 2% sorbitol (Formulation
B)
[0082] 4. 0.1% w/v barium sulfate, 128 cps, 2% sorbitol
(Formulation A)
[0083] The contrast media was placed in a 500 ml HDPE container and
then placed in the CT scanner for measurement. The containers were
arranged in a manner shown in FIG. 5. Several spiral slices were
made through the HDPE containers to establish the formulations'
HV's. The results were as follows:
[0084] 1. 0.05% w/v barium sulfate, 860 CPS, 2% sorbitol
(Formulation C) [0085] 1. Mean/SD 16.9/7.8 HV's [0086] 2. Mean/SD
16.0/7.8 HV's [0087] 3. Mean/SD 17.2/6.5 HV's
[0088] 2. 0.05% w/v barium sulfate, 140 cps, 2% sorbitol
(Formulation D) [0089] 1. Mean/SD 12.5/6.8 HV's [0090] 2. Mean/SD
14.8/6.8 HV's [0091] 3. Mean/SD 14.2/7.9 HV's
[0092] 3. No barium sulfate, 719 cps, 2% sorbitol (Formulation B)
[0093] 1. Mean/SD 12.3/8.6 HV's [0094] 2. Mean/SD 6.9/6.4 HV's
[0095] 3. Mean/SD 7.2/7.5 HV's
[0096] 4. 0.1% w/v barium sulfate, 128 cps, 2% sorbitol
(Formulation A) [0097] 1. Mean/SD 23.56.2 HV's [0098] 2. Mean/SD
22.2/7.0 HV's [0099] 3. Mean/SD 26.0/7.1 HV's
[0100] 5. The ROI on an area of the colon with barium (E-Z-EM's
banana smoothie) was Mean/SD 313.2/13.8 HV's.
[0101] This test demonstrated the 0.1% w/v barium sulfate
concentration was preferred because it had a clear difference in
HV's from the base and 0.5% BaSO4 formulations. The range of values
for the 0.1% formula at a low viscosity was 23.9 HV's, which
matched the preferred target range of 20 to 30 HV's.
[0102] The 0.1% w/v BaSO4 enabled marking of the lumen/bowel wall
in Multi-detector Scanners while preserving the contrast
differentiation of un-enhanced bowel lumen. When abdominal, pelvic
studies were conducted without IV contrast. The 0.1% w/v BaSO4 will
mark the bowel while offering an improved image of the GI tract
itself. The contrast (difference) between the bowel wall enhanced
by IV contrast and this contrast media will become more pronounced.
The bowel wall with contrast on board will demonstrate an increase
in HV's (+100 HV's) due to the increased density of the IV
contrast.
Example 4
[0103] Clinical evaluations of the formulations of the present
invention are discussed below. The HV for each contrast media is
described in Example 3. Each trial showed satisfactory bowel lumen
distention, uniform distribution, and good patient acceptance.
MR
[0104] Formulation D was administered to a healthy volunteer. The
volunteer consumed 1.35 liters or three (3) bottles (450 ml/dose)
of the contrast media within 45 minutes of an abdominal
examination. The contrast media contained banana flavoring. The
abdominal examination was performed using MR as the diagnostic
imaging modality. The MR images were generated using an MR scanner
by Siemens (Sonata).
[0105] The patient expressed no complaints about the contrast
media's formula, flavor, viscosity or volume. The patient
experienced no adverse events. The patient was placed in the prone
position while the abdomen was scanned. Images obtained from the MR
scan are shown in FIGS. 3 and 4. The MR images show total abdomen
and pelvis, with stomach and small bowel distended and/or marked by
the contrast media. These images confirm that the contrast media
marked the GI track, allowing for diagnostic evaluation of the
intestine and surrounding tissue in the abdomen and pelvis. In FIG.
3, this image of the abdomen demonstrate the present media's
ability to mark and distend the bowel. Here, the marker is dark and
the soft tissue of the GI tract is bright. In FIG. 4, this image of
the abdomen demonstrates the benefits of marking and distending the
stomach and small bowel in the contrast with the signal of bowel
wall. Here, the marker is bright and the bowel wall is dark.
Additionally, bowel distention was uniform and adequate, and the
contrast was consistent though out the length of the small
bowel.
[0106] Further, it was observed that several hundred ml of the
contrast media remained in the stomach during the exam. In FIGS. 1
and 2, the signal intensity (signal/noise ratio) was satisfactory
in all sequences used, and it was consistent through out the small
bowel lumen.
Example 5
CT
[0107] Formulation C was administered to a patient previously
scheduled for an abdominal CT. The patient consumed 2 doses (450
ml/dose, total volume 900 ml) within 45 minutes. Immediately
thereafter, the patient's abdomen was scanned in the prone
position. CT images were generated using a 16 slice CT scanner by
Siemens (Sensation 16). The CT image (FIGS. 1 and 2) shows gastric
filling with clear differentiation between contrast and stomach
wall (FIG. 2, Arrow). In FIG. 1, contrast is found in the body of
the stomach and proximal small bowel. It also shows small bowel
filling and distention (FIG. 1, Arrow). Further, the images (FIG.
2) show that the contrast media satisfactory filled and distended
the stomach. The contrast filled lumen will clearly differentiate
itself from the soft tissue density of the lumen wall due to its
low HV. The patient experienced no adverse events.
[0108] Prior to the CT exam, the patient expressed no complaints
about the contrast media's formula, flavor, viscosity or
volume.
[0109] Throughout the description, where the present invention is
described as having, including, or comprising specific components,
or where processes are described as having, including, or
comprising specific process steps, it is contemplated that the
present invention also consists essentially of, or consists of, the
recited components or processing steps. Further, it should be
understood that the order of steps or order for performing certain
actions are immaterial so long as the invention remains operable.
Moreover, two or more steps or actions may be conducted
simultaneously so long as the invention remains operable. Also, one
or more steps or elements may be omitted from the claimed
invention, or the invention described herein suitably may be
practiced in the absence of any component or step which is not
specifically disclosed herein, so long as the invention remains
operable.
[0110] Further, the present invention may be embodied in other
specific forms without departing from the spirit or essential
characteristics thereof. The foregoing embodiments are therefore to
be considered illustrative rather than limiting the invention
described herein. The content of each patent and non-patent
document referred to herein is expressly incorporated herein by
reference in its entirety.
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