U.S. patent application number 12/014154 was filed with the patent office on 2008-05-22 for composition comprising low density microspheres.
This patent application is currently assigned to Bristol-Myers Squibb Medical Imaging, Inc.. Invention is credited to EVAN C. UNGER.
Application Number | 20080118435 12/014154 |
Document ID | / |
Family ID | 24733297 |
Filed Date | 2008-05-22 |
United States Patent
Application |
20080118435 |
Kind Code |
A1 |
UNGER; EVAN C. |
May 22, 2008 |
COMPOSITION COMPRISING LOW DENSITY MICROSPHERES
Abstract
Low density microspheres, methods for preparing same, and use of
same as contrast agents are described. The microspheres have a void
which contains a gas or the vapor of a volatile liquid selected
from the group consisting of aliphatic hydrocarbons,
chlorofluorocarbons, tetraalkyl silanes and perfluorocarbons.
Inventors: |
UNGER; EVAN C.; (Tucson,
AZ) |
Correspondence
Address: |
LOUIS J. WILLE;BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Assignee: |
Bristol-Myers Squibb Medical
Imaging, Inc.
|
Family ID: |
24733297 |
Appl. No.: |
12/014154 |
Filed: |
January 15, 2008 |
Related U.S. Patent Documents
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Application
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Patent Number |
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11252659 |
Oct 18, 2005 |
7344705 |
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12014154 |
Jan 15, 2008 |
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10864965 |
Jun 10, 2004 |
6998107 |
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11252659 |
Oct 18, 2005 |
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10280844 |
Oct 25, 2002 |
6773696 |
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10864965 |
Jun 10, 2004 |
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08878233 |
Jun 18, 1997 |
6528039 |
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10280844 |
Oct 25, 2002 |
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08594269 |
Jan 30, 1996 |
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08878233 |
Jun 18, 1997 |
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08456738 |
Jun 1, 1995 |
5527521 |
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08594269 |
Jan 30, 1996 |
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08449090 |
May 24, 1995 |
5547656 |
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08456738 |
Jun 1, 1995 |
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08116982 |
Sep 7, 1993 |
5456900 |
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08449090 |
May 24, 1995 |
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07980594 |
Jan 19, 1993 |
5281408 |
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08116982 |
Sep 7, 1993 |
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07680984 |
Apr 5, 1991 |
5205290 |
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07980594 |
Jan 19, 1993 |
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Current U.S.
Class: |
424/9.1 |
Current CPC
Class: |
A61K 49/0419 20130101;
Y10T 428/31862 20150401; A61P 9/00 20180101; Y10T 428/2982
20150115 |
Class at
Publication: |
424/009.1 |
International
Class: |
A61K 49/00 20060101
A61K049/00 |
Claims
1. A composition comprising low density microspheres having an
outside diameter of about 50 microns, said microspheres comprising
a polymer and having a void containing the vapor of a volatile
liquid perfluorocarbon, wherein said microspheres, when combined
with an aqueous solution to form a contrast agent, are suitable for
administration to a patient either orally, rectally or by
injection.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/252,659, filed Oct. 18, 2005, now allowed, which is a
continuation of U.S. application Ser. No. 10/864,965, filed Jun.
10, 2004, now U.S. Pat. No. 6,998,107, which is a continuation of
U.S. application Ser. No. 10/280,844, filed Oct. 25, 2002, now U.S.
Pat. No. 6,773,696, which is a continuation of U.S. Ser. No.
08/878,233, filed Jun. 18, 1997, now U.S. Pat. No. 6,528,039, which
in turn is a continuation of U.S. application Ser. No. 08/594,269,
filed Jan. 30, 1996, now abandoned, which is a divisional of U.S.
application Ser. No. 08/456,738, filed Jun. 1, 1995, now U.S. Pat.
No. 5,527,521, which is a divisional of U.S. application Ser. No.
08/449,090, filed May 24, 1995, now U.S. Pat. No. 5,547,656, which
is a divisional of U.S. application Ser. No. 08/116,982, filed Sep.
7, 1993, now U.S. Pat. No. 5,456,900, which is a divisional of U.S.
application Ser. No. 07/980,594, filed Jan. 19, 1993, now U.S. Pat.
No. 5,281,408, which in turn is a divisional of U.S. application
Ser. No. 07/680,984, filed Apr. 5, 1991, now U.S. Pat. No.
5,205,290.
BACKGROUND OF THE INVENTION
[0002] Computed tomography (CT) is a widespread diagnostic imaging
method which measures, in its imaging process, the radiodensity
(electron density) of matter. This radiodensity is depicted using
CT in terms of Hounsefield Units (HU). Hounsefield Units, named
after the inventor of the first CT scanner, reflect the relative
absorption of CT X-rays by matter, the absorption being directly
proportional to the electron density of that matter. Water, for
example, has a value of 0 HU, air a value of -1000 HU, and dense
cortical bone a value of +1000 HU. Because of the similarity in
density of various tissues in the body, however, contrast agents
have been sought to change the relative density of different
tissues, and improve the overall diagnostic efficacy of this
imaging method.
[0003] In the search for contrast agents for CT, researchers have
generally sought to develop agents that will increase electron
density in certain areas of a region of the body (positive contrast
agents). Barium and iodine compounds, for example, have been
developed for this purpose. For the gastrointestinal tract, barium
sulfate is used extensively to increase the radiodensity of the
bowel lumen on CT scans. Iodinated water soluble contrast media are
also used to increase density within the gastro-intestinal tract,
but are not used as commonly as the barium compounds, primarily
because the iodine preparations are more expensive than barium and
prove less effective in increasing radiodensity within this region
of the body.
[0004] Despite their widespread use, however, barium and iodine
compounds are suboptimally effective as gastro-intestinal contrast
agents for CT. For example, if the concentration is too low, there
is little contrast. Conversely, if the concentration is too high,
then these radiodense contrast agents cause beam hardening
artifacts which are seen as streaks on the CT images. It is also
difficult to visualize the bowel mucosa with either the barium or
iodine contrast agents.
[0005] In an attempt to improve upon the efficacy of contrast
agents for the gastrointestinal tract, lipid emulsions that are
capable of decreasing electron density (negative contrast agents)
have been developed. Because lipids have a lower electron density
than water, lipids provide a negative density on CT (a negative HU
value). While these lipid emulsions appear to be more effective
than the barium and iodine agents at improving visualization of the
mucosa of the bowel, these contrast agents have limitations. First,
there is a limitation to the concentration of lipid which a patient
can tolerably drink, which puts a limit on the change in density
(or HU) which the lipid based CT contrast agent can provide. Lipid
emulsions are also frequently expensive. Furthermore, these lipid
formulations are generally perishable, which provides for packaging
and storage problems.
[0006] New and/or better contrast agents for computed tomography
imaging are needed. The present invention is directed toward this
important end.
SUMMARY OF THE INVENTION
[0007] The present invention is directed to computed tomography
imaging, and more particularly to the use of a contrast medium
comprising a substantially homogeneous aqueous suspension of low
density microspheres to image the gastrointestinal region and other
body cavities of a patient. In one embodiment, the low density
microspheres are gas-filled.
[0008] Specifically, the present invention pertains to methods of
providing an image of the gastrointestinal region or other body
cavities of a patient comprising (i) administering to the patient
the aforementioned contrast medium, and (ii) scanning the patient
using computed tomography imaging to obtain visible images of the
gastrointestinal region or other body cavities.
[0009] The present invention is further directed to methods for
diagnosing the presence of diseased tissue in the gastrointestinal
region or other body cavities of a patient comprising (i)
administering to the patient the aforementioned contrast medium,
and (ii) scanning the patient using computed tomography imaging to
obtain visible images of any diseased tissue in the patient.
[0010] The present invention also provides diagnostic kits for
computed tomography imaging of the gastro-intestinal region or
other body cavities which include the subject contrast medium.
DETAILED DESCRIPTION OF THE INVENTION
[0011] A wide variety of different low density micro-spheres may be
utilized in the present invention. Preferably, the microspheres
(which are small spheres having a central void or cavity), are
composed of biocompatible synthetic polymers or copolymers prepared
from monomers such as acrylic acid, methacrylic acid,
ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl
methacrylate, 2-hydroxyethyl methacrylate (HEMA), lactic acid,
glycolic acid, .epsilon.-caprolactone, acrolein, cyanoacrylate,
bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane,
dimethylsiloxane, ethylene oxide, ethylene glycol,
hydroxyalkyl-methacrylates, N-substituted acrylamides,
N-substituted methacrylamides, N-vinyl-2-pyrrolidone,
2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene,
p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate,
sodium 2-sulfoxyethylmethacrylate, vinyl pyridine, aminoethyl
methacrylates, 2-methacryloyloxy-trimethylammonium chloride, and
polyvinylidene, as well polyfunctional crosslinking monomers such
as N,N'-methylenebisacrylamide, ethylene glycol dimethacrylates,
2,2'-(p-phenylenedioxy)-diethyl dimethacrylate, divinylbenzene,
triallylamine and methylenebis-(4-phenyl-isocyanate), including
combinations thereof. Preferable polymers include polyacrylic acid,
polyethyleneimine, polymethacrylic acid, polymethylmethacrylate,
polysiloxane, polydimethylsiloxane, polylactic acid,
poly(.epsilon.-caprolactone), epoxy resin, poly(ethylene oxide),
poly(ethylene glycol), and polyamide(nylon). Preferable copolymers
include the following: polyvinylidene-polyacrylonitrile,
polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and
polystyrene-polyacrylonitrile. A most preferred copolymer is
polyvinylidene-polyacrylonitrile. The term biocompatible, as used
herein in conjunction with the terms monomer or polymer, is
employed in its conventional sense, that is, to denote polymers
that do not substantially interact with the tissues, fluids and
other components of the body in a adverse fashion in the particular
application of interest, such as the aforementioned monomers and
polymers. Other suitable biocompatible monomers and polymers will
be readily apparent to those skilled in the art, once armed with
the present disclosure.
[0012] The microspheres of the present invention are low density.
By low density, it is meant that the microspheres of the invention
have an internal void (cavity) volume which is at least about 75%
of the total volume of the microsphere. Preferably, the
microspheres have a void volume of at least about 80%, more
preferably at least about 85%, even more preferably at least about
90%, of the total volume of the microspheres.
[0013] The microspheres may be of varying size, provided they are
low density. Suitable size microspheres include those ranging from
between about 1 and about 1000 microns in outside diameter,
preferably between about 5 and about 70 microns in outside
diameter. Most preferably, the microspheres are about 50 microns in
outside diameter.
[0014] The microspheres of the invention may be prepared by various
processes, as will be readily apparent to those skilled in the art,
once armed with the present disclosure, such as by interfacial
polymerization, phase separation and coacervation, multiorifice
centrifugal preparation, and solvent evaporation. Suitable
procedures which may be employed or modified in accordance with the
present disclosure to prepare microspheres within the scope of the
invention include those procedures disclosed in Garner et al., U.S.
Pat. No. 4,179,546, Garner, U.S. Pat. No. 3,945,956, Cohrs et al.,
U.S. Pat. No. 4,108,806, Japan Kokai Tokkyo Koho 62 286534, British
Patent No. 1,044,680, Kenaga et al., U.S. Pat. No. 3,293,114,
Morehouse et al., U.S. Pat. No. 3,401,475, Walters, U.S. Pat. No.
3,479,811, Walters et al., U.S. Pat. No. 3,488,714, Morehouse et
al., U.S. Pat. No. 3,615,972, Baker et al., U.S. Pat. No.
4,549,892, Sands et al., U.S. Pat. No. 4,540,629, Sands et al.,
U.S. Pat. No. 4,421,562, Sands, U.S. Pat. No. 4,420,442, Mathiowitz
et al., U.S. Pat. No. 4,898,734, Lencki et al., U.S. Pat. No.
4,822,534, Herbig et al., U.S. Pat. No. 3,732,172, Himmel et al.,
U.S. Pat. No. 3,594,326, Sommerville et al., U.S. Pat. No.
3,015,128, Deasy, Microencapsulation and Related Drug Processes,
Vol. 20, Chs. 9 and 10, pp. 195-240 (Marcel Dekker, Inc., N.Y.,
1984), Chang et al., Canadian J. of Physiology and Pharmacology,
Vol 44, pp. 115-129 (1966), and Chang, Science, Vol. 146, pp.
524-525 (1964), the disclosures of each of which are incorporated
herein by reference in their entirety.
[0015] In accordance with the preferable synthesis protocol, the
microspheres are prepared using a heat expansion process such as is
described in Garner et al., U.S. Pat. No. 4,179,546, Garner, U.S.
Pat. No. 3,945,956, Cohrs et al., U.S. Pat. No. 4,108,806, British
Patent No. 1,044,680, and Japan Kokai Tokkyo Koho 62 286534. In
general terms, the heat expansion process is carried out by
preparing microspheres of an expandable polymer or copolymer which
contain in their void (cavity) a volatile liquid. The microsphere
is then heated, plasticising the microsphere and volatilizing the
gas, causing the microsphere to expand to up to about several times
its original size. When the heat is removed, the thermoplastic
polymer retains at least some of its expanded shape. Microspheres
produced by this process tend to be of particularly low density,
and are thus preferred. The foregoing described process is well
known in the art, and is referred to herein as the heat expansion
process for preparing low density microspheres.
[0016] Polymers useful in the heat expansion process will be
readily apparent to those skilled in the art and include
thermoplastic polymers or copolymers, including polymers or
copolymers of many of the monomers described above. Preferable of
the polymers and copolymers described above include the following
copolymers: polyvinylidene-polyacrylonitrile,
polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and
polystyrene-polyacrylonitrile. A most preferred copolymer is
polyvinylidene-polyacrylonitrile.
[0017] Volatile liquids useful in the heat expansion process will
also be well known to those skilled in the art and include:
aliphatic hydrocarbons such as ethane, ethylene, propane, propene,
butane, isobutane, neopentane, acetylene, hexane, heptane;
chlorofluorocarbons such as ##STR1## tetraalkyl silanes such as
tetramethyl silane, trimethylethyl silane, trimethylisopropyl
silane, and trimethyl n-propyl silane; as well as perfluorocarbons
such as those having between 1 and about 9 carbon atoms and between
about 4 and about 20 fluorine atoms, especially C.sub.4F.sub.10. In
general, it is important that the volatile liquid not be a solvent
for the microsphere polymer or copolymer. The volatile liquid
should also have a boiling point that is below the softening point
of the microsphere polymer or co-polymer. Boiling points of various
volatile liquids and softening points of various polymers and
copolymers will be readily ascertainable to one skilled in the art,
and suitable combinations of polymers or copolymers and volatile
liquids will be easily apparent to the skilled artisan. By way of
guidance, and as one skilled in the art would recognize, generally
as the length of the carbon chain of the volatile liquid increases,
the boiling point of that liquid increases. Also, by mildly
preheating the microspheres in water in the presence of hydrogen
peroxide prior to definitive heating and expansion may pre-soften
the microsphere to allow expansion to occur more readily.
[0018] For example, to produce microspheres of the present
invention, vinylidene and acrylonitrile may be copolymerized in a
medium of isobutane liquid using one or more of the foregoing
modified or unmodified literature procedures, such that isobutane
becomes entrapped within the microspheres. When such microspheres
are then heated to between about 80 EC and about 120 EC, the
isobutane gas expands, which in turn expands the microspheres.
After heat is removed, the expanded polyvinylidene and
acrylo-nitrile copolymer microspheres remain substantially fixed in
their expanded position. The resulting low density microspheres are
extremely stable both dry and suspended in an aqueous media.
Isobutane is utilized merely as an illustrative liquid, with the
understanding that other liquids which undergo liquid/gas
transitions at temperatures useful for the synthesis of these
microspheres and formation of the very low density microspheres
upon heating can be substituted for isobutane. Similarly, monomers
other than vinylidene and acrylonitrile may be employed in
preparing the microsphere.
[0019] Most preferably, the low density microspheres employed are
those commercially available from Expancel, Nobel Industries,
Sundsvall, Sweden, such as the EXPANCEL 551 DE.TM. microspheres.
The EXPANCEL 551 DE.TM. microspheres are composed of a copolymer of
vinylidene and acrylo-nitrile which have encapsulated therein
isobutane liquid. Such microspheres are sold as a dry composition
and are approximately 50 microns in size. The EXPANCEL 551 DE.TM.
microspheres have a specific gravity of only 0.02 to 0.05, which is
between one-fiftieth and one-twentieth the density of water.
[0020] In one embodiment, the microspheres of the present invention
are gas-filled. By gas-filled, it is meant that at least part of
the void volume inside the microspheres is occupied by the gas.
Preferably, substantially all of the void volume inside the
microspheres is occupied by the gas. The gas may be any type of
gas, such as, for example, carbon dioxide, oxygen, nitrogen, xenon,
argon, neon, helium and air. Preferably, the gas is carbon dioxide,
oxygen, nitrogen, xenon, argon, neon and helium. Most preferably,
the gas is inert, that is, a gas that is substantially resistant to
chemical or physical action. The gas-filled low density
microspheres may be synthesized under pressure such that gases are
solubilized in the liquid employed in microsphere synthesis. When
the pressure is removed, the gas comes out of solution to fill the
microsphere void. Such microspheres can further be subjected to a
heat expansion process, as described above.
[0021] For example, to produce the gas-filled microspheres of the
invention, one may copolymerize vinylidene and acrylonitrile using
one or more of the foregoing procedures, such as phase
separation/coacervation techniques in a pressurized and/or low
temperature environment (e.g., at about 300 psi, and/or at about 0
EC) with a high concentration of dissolved gas (e.g., dissolved
nitrogen) in solution, to form a large microsphere containing the
dissolved gas. When the pressure is removed and/or the temperature
raised, the gas bubbles come out of solution, forming gas filled
microspheres. Such microspheres can further be subjected to a heat
expansion process, as described above.
[0022] It is preferable that the microspheres be relatively stable
in the gastrointestinal tract or other body cavities during the
length of time necessary for completing an imaging examination. Low
density microspheres prepared from the aforementioned monomer and
polymer compositions will provide such stable microspheres.
[0023] In order for these microspheres to serve as effective CT
contrast agents, it is necessary for the microspheres to be mixed
in solution in a substantially homogeneous suspension. This can be
accomplished by using thickening and suspending agents. A wide
variety of thickening and suspending agents may be used to a
prepare the substantially homogeneous suspensions of the
microspheres. Suitable thickening and suspending agents, for
example, include any and all biocompatible agents known in the art
to act as thickening and suspending agents. Particularly useful are
the natural thickening and suspending agents alginates, xanthan
gum, guar, pectin, tragacanth, bassorin, karaya, gum arabic,
casein, gelatin, cellulose, sodium carboxymethylcellulose,
methylcellulose, methylhydroxycellulose, bentonite, colloidal
silicic acid, and carrageenin, and the synthetic thickening and
suspending agents polyethylene glycol, polypropylene glycol, and
polyvinylpyrrolidone. As those skilled in the art would recognize,
once armed with the present disclosure, the suspending agents may
be formulated, if desired, to be either less dense than water or of
neutral density, so as to not subtract from the density lowering
capabilities of the microspheres. For example, a cellulose
suspension may have a somewhat lower density than water, e.g., a 2
weight % cellulose solution with 0.25 weight % xanthan gum has a
density of 0.95. The thickening and suspending agents may be
employed in varying amounts, as those skilled in the art would
recognize, but preferably are employed in amounts of about 0.25 to
about 10 weight % preferably about 0.5 to about 5 weight % of the
contrast medium.
[0024] The substantially homogeneous, aqueous suspension of low
density microspheres of the invention are useful as CT contrast
agents. These agents are capable of producing negative contrast in
the gastrointestinal tract or in other body cavities, providing
effective contrast enhancement and improved visualization in these
areas of the body. Specifically, the present invention is directed
to a method of providing an image of or detecting diseased tissue
in the gastrointestinal region and other body cavities of a
patient, the method comprising administering to the patient a
contrast medium comprising a substantially homogeneous aqueous
solution of low density microspheres, and scanning the patient
using computed tomography imaging to obtain visible images of the
gastrointestinal region or other body cavities or of diseased
tissue in these areas of the body. The phrase gastrointestinal
region or gastrointestinal tract, as used herein, includes the
region of a patient defined by the esophagus, stomach, small and
large intestines, and rectum. The phrase other body cavities, as
used herein, includes any region of the patient, other than the
gastrointestinal region, having an open passage, either directly or
indirectly, to the external environment, such regions including the
sinus tracts, the fallopian tubes, the bladder, etc. The patient
can be any type of mammal, but most preferably is a human. As one
skilled in the art would recognize, administration of the contrast
medium to the patient may be carried out in various fashions, such
as orally, rectally, or by injection. When the region to be scanned
is the gastrointestinal region, administration of the contrast
medium of the invention is preferably carried out orally or
rectally. When other body cavities such as the fallopian tubes or
sinus tracts are to be scanned, administration is preferably by
injection. As would also be recognized by one skilled in the art,
wide variations in the amounts of the gas filled microspheres can
be employed in the methods and kits of the invention, with the
precise amounts varying depending upon such factors as the mode of
administration (e.g., oral, rectal, by injection), and the specific
body cavity and portion thereof for which an image is sought (e.g.,
the stomach of the gastrointestinal tract). Typically, dosage is
initiated at lower levels and increased until the desired contrast
enhancement is achieved.
[0025] For CT imaging, it is generally desirable to decrease the
density of the lumen of the gastrointestinal tract or other body
cavities to at least about -30 HU, the maximum decrease being
limited by the practical amount of the microspheres which may be
suspended in the aqueous media and ingested by the patient. In
general, a decrease in HU to between about -30 HU and about -150 HU
is sufficient to mark the inside of the bowel or other body cavity.
By way of general guidance, and as a rough rule of thumb, to
decrease the density of the microsphere aqueous suspension to about
-150 HU, the microspheres must occupy about 15% of the total volume
of the aqueous suspension. To achieve a density of about -50 HU,
the microspheres must occupy about 5% of the total volume of the
solution. The volume of contrast agent administered to the patient
is typically between about 50 to about 1000 cc. Using the EXPANCEL
551 DE.TM. microspheres as a model, it has been found that about
0.6 grams of the dry 50 micron spheres in 100 cc of aqueous
suspension is sufficient to decrease the density of the suspension
to nearly -150 HU.
[0026] It should be noted that smaller microspheres are generally
more stable in suspension, but usually have higher specific gravity
than larger microspheres. Therefore, for CT, the size and
particular microspheres, as well as the suspending media
(thickening and suspending agents) should selected to minimize
specific gravity, while maximizing the stability of the
suspension.
[0027] The contrast medium utilized of the present invention may
also be employed with other conventional additives suitable for use
in the applications contemplated for the subject invention.
[0028] Where gastrointestinal applications are concerned, such
additives include conventional biocompatible anti-gas agents,
osmolality raising agents, gastrointestinal transit agents (the
later agents serving to decrease the gastrointestinal transit time
and increase the rate of gastrointestinal emptying) and, in some
instances, gas-forming agents.
[0029] As used herein the term anti-gas agent is a compound that
serves to minimize or decrease gas formation, dispersion and/or
adsorption. A number of such agents are available, including
antacids, antiflatulents, antifoaming agents, and surfactants. Such
antacids and antiflatulents include, for example, activated
charcoal, aluminum carbonate, aluminum hydroxide, aluminum
phosphate, calcium carbonate, dihydroxyaluminum sodium carbonate,
magaldrate magnesium oxide, magnesium trisilicate, simethicone,
sodium carbonate, loperamide hydrochloride, diphenoxylate,
hydrochloride with atropine sulfate, KaopectateJ (kaolin) and
bismuth salts. Suitable antifoaming agents useful as anti-gas
agents include simethicone, protected simethicone, siloxyalkylene
polymers, siloxane glycol polymers,
polyoxypropylene-polyoxyethylene copolymers, polyoxyalkylene amines
and imines, branched polyamines, mixed oxyalkylated alcohols,
finely divided silica either alone or mixed with dimethyl
polysiloxane, sucroglycamides (celynols), polyoxylalkylated natural
oils, halogenated silicon-containing cyclic acetals, lauryl
sulfates, 2-lactylic acid esters of unicarboxylic acids,
triglyceride oils. Particles of polyvinyl chloride or silica may
also function as anti-foaming agents in the subject invention.
Suitable surfactants include perfluorocarbon surfactants, such as,
for example, DuPont Zonyl.TM. perfluoroalkyl surfactants known as
Zonyl.TM. RP or Zonyl.TM. NF, available from DuPont, Chemicals and
Pigments Division, Jackson Laboratory, Deepwater, N.J. 08023. Of
course, as those skilled in the art will recognize, any anti-gas
agents employed must be suitable for use within the particular
biological system of the patient in which it is to be used. The
concentration of such anti-gas agents may vary widely, as desired,
as will be readily apparent to those skilled in the art. Typically,
however, such agents are employed in concentrations of between
about 20 and about 2000 ppm, most preferably in concentrations
between about 50 and about 1000 ppm.
[0030] Suitable osmolality raising agents include polyols and
sugars, for example, mannitol, sorbitol, arabitol, xylitol,
glucose, sucrose, fructose, dextrose, and saccharine, with mannitol
and sorbitol being most preferred. The concentration of such
osmolality raising agents may vary, as desired, however, generally
a range of about 5 to about 70 g/l, preferably about 30 to about 50
g/l of the contrast medium. Such compounds may also serve as
sweeteners for the ultimate formulation, if desired.
[0031] Gastrointestinal transit agents include algin, as well as
many of the compounds listed above as thickening and suspending
agents, with algin being most preferred. The amount of such agents
will, of course, vary as those skilled in the art will recognize,
but generally will be employed in an amount of between about 5 and
about 40 mmol/l.
[0032] In some applications, it may be helpful to incorporate
gas-forming agents into the contrast medium. Gas-forming agents
include sodium bicarbonate, calcium carbonate, aminomalonate, and
the like, which will form gas, for example, upon introduction into
the gastro-intestinal tract. Such gas-forming agents will serve to
distend the gastrointestinal tract and create a form of "double
contrast" between the gas and the low density microspheres.
[0033] Kits useful for computed tomography imaging of the
gastrointestinal region or other body cavities in accordance with
the present invention comprise low density microspheres, and a
thickening or suspending agent, in addition to conventional
computed tomography imaging kit components. Such conventional
computed tomography kit components will be readily apparent to
those skilled in the art, once armed with the present
disclosure.
[0034] Where imaging of the gastrointestinal region is
contemplated, such computed tomography kit components may include,
for example, anti-gas agents, osmolality raising agents,
gastrointestinal transit agents and, in some instances, gas-forming
agents.
[0035] The computed tomography imaging principles and techniques
which are employed are conventional and are described, for example,
in Computed Body Tomography, Lee, J. K. T., Sagel, S. S., and
Stanley, R. J., eds., Ch. 1, pp. 1-7 (Raven Press, NY 1933). Any of
the various types of computed tomography imaging devices can be
used in the practice of the invention, the particular type or model
of the device not being critical to the method of the
invention.
[0036] The present invention is further described in the following
Examples. Examples 1-7 are prophetic examples based at least in
part on the teachings of Garner, U.S. Pat. No. 3,945,956, and
describe the preparation of microspheres by a heat expansion
process. Examples 8-9 are actual examples that describe the
preparation of contrast media of the invention. The following
Examples are not to be construed as limiting the scope of the
appended Claims.
EXAMPLES
Example 1
[0037] A vessel is filled with 50 parts by weight of deionized
water and 6 parts by weight of a 25 percent by weight aqueous
colloidal silica dispersion. A mixture of 0.3 parts by weight of a
10 weight percent solution of diethylamine-adipic acid copolymer is
added to the above. A condensation reaction occurs creating a
mixture having a viscosity of about 95 centipoise at a temperature
of about 27 E C. Potassium dichromate (0.05 parts by weight) is
added to the aqueous phase as a water phase polymerization
inhibitor. Sodium chloride (1 part by weight) is also present in
the water phase; hydrochloric acid is used to adjust the pH of the
aqueous phase to 4.0. Styrene (15 parts by weight), acrylonitrile
(10 parts by weight), a mixture of diethylbenzene and
divinylbenzene (0.21 parts by weight comprising a 55:45 percent
mixture of each respectively), 6.25 parts by weight of isobutane
and 0.07 parts by weight of secondary butyl peroxydicarbonate. The
oil phase is added to the water phase with violent agitation
created by a shearing blade rotating at 10,000 RPM employing a
mixing blender. After the material has reacted for about 30
minutes, the mixture is poured into a citrate bottle and capped.
The material is maintained at about 50 EC in the citrate bath for
about 24 hours and agitated throughout this time. At the end of 24
hours, the reaction bottle is cooled and the material is removed,
washed and dried. A portion of the microspheres are set aside and
the remainder are heated in an air oven for a period of about 30
minutes at about 150 EC. A sample of the dry unexpanded and dry
expanded microspheres are then studied by a Coulter Counter. The
dry unexpanded microspheres have a size of about 2 to 12 microns.
About half of the microspheres exposed to the heating process show
expansion.
Example 2
[0038] The procedures of Example 1 are substantially repeated with
the exception that 1 part by weight of methanol is added to the
reaction mixture. The dry unexpanded and dry heat expanded
microspheres are then studied by Coulter Counter. The dry
unexpanded microspheres measure about 8 to 10 microns in size.
Essentially all the microspheres exposed to heat expand.
Example 3
[0039] The procedures of Example 2 are substantially repeated
except that after synthesis of the microspheres, a slurry of the
microspheres is added to an aqueous solution containing 35 weight
percent hydrogen peroxide. This slurry is heated to a temperature
of about 50 EC for about 3.5 hours and subsequently cooled and
air-dried. A portion of the microspheres is then added to water and
heated to a temperature of about 75 EC with vigorous stirring for
about 30 seconds. Study with Coulter Counter shows that
pretreatment with hydrogen peroxide enables a lower temperature and
briefer period of heating to be used for definitive heating and
expansion.
Example 4
[0040] The procedures of Example 1 are substantially repeated with
the exception that 5 parts by weight of ethanol are included in the
reaction mixture forming the microspheres. Coulter Counter shows
that the dry unexpanded particles have diameters of about 24 to 28
microns. When heated, essentially all of the microspheres
expand.
Example 5
[0041] The procedures of Example 1 are substantially repeated with
the exception that in place of methanol, 1 part by weight of normal
butanol is used. The diameter of the dry unexpanded microspheres is
about 10 to 12 microns and on heating, essentially all of the
microspheres expand.
Example 6
[0042] The procedures of Example 1 are substantially repeated with
the exception that the volatile liquid isobutane is replaced with
perfluorocarbon liquid (C.sub.4F.sub.10). The remainder of the
process is similar. The resulting microspheres are filled with
perfluorocarbon liquid rather than isobutane.
Example 7
[0043] The procedures of Example 1 are substantially repeated with
the exception that the reaction is conducted in a pressurized
vessel enabling pressurization with gas and simultaneous agitation
(agitation accomplished with either sonication or shearing blades
within the device). As the microspheres are formed within the
device, the vessel is pressurized to about 300 psi with nitrogen
gas. The vessel is then depressurized, allowing the gas to come out
of solution. The microspheres are then subjected to heat as
substantially described in Example 1.
Example 8
[0044] A suspension of 2% of 22 micron fiber length cellulose in
0.25% xanthan gum in water was prepared. Scans by CT showed a CT
density of about -45 HU for the cellulose suspension. EXPANCEL 551
DEJ polyvinylidene-polyacrylonitrile microspheres, 50 microns in
size, were then suspended in the aqueous cellulose suspension at a
concentration of 0.4 grams of microspheres per 100 ml of cellulose
suspension using vigorous shaking. The resulting suspension
remained substantially homogeneous for about 10 minutes. The
suspension was again shaken vigorously to render it substantially
homogeneous and scanned immediately by CT. The resulting CT density
as measured by the scanner was about -96 HU.
Example 9
[0045] A suspension of 1% algin was prepared. EXPANCEL 551 DEJ
microspheres were added to the algin suspension in an amount of
about 0.2 grams of microspheres per deciliter of algin suspension,
using vigorous shaking, to form a substantially homogeneous
suspension. The resulting suspension was found to have much greater
stability than the cellulose/microsphere suspension of Example 1.
The algin/microsphere suspension was then scanned by CT, with the
density as measured by the scanner being about -40 HU.
[0046] Various modifications of the invention in addition to those
shown and described herein will be apparent to those skilled in the
art from the foregoing description. Such modifications are also
intended to fall within the scope of the appended claims.
* * * * *