X-ray contrast compositions containing film-forming materials

Disclosed are x-ray contrast compositions for oral or retrograde examination of the gastrointestinal tract comprising a polymeric material capable of forming a coating on the gastrointestinal tract and a nonionic x-ray producing agent in a pharmaceutically acceptable carrier; and methods for their use in diagnostic radiology of the gastrointestinal tract.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to an x-ray contrast composition for oral or 
retrograde administration to a mammal comprising a nonionic X-ray contrast 
producing agent and a polymeric film-forming material. 
2. Reported Developments 
Roentgenographic examination utilizing x-rays and computed tomography 
(hereinafter CT) scans of fractures and other conditions associated with 
the skeletal system is routinely practiced without the use of contrast 
agents. X-ray visualization of organs containing soft tissue, such as the 
gastrointestinal (hereinafter GI) tract, requires the use of contrast 
agents which attenuate x-ray radiation. D. P. Swanson et al in 
"Pharmaceuticals In Medical Imaging", 1990, MacMillan Publishing Company, 
provides an excellent background in medical imaging utilizing contrast 
agents and compositions therewith. 
The most widely used contrast agents for the visualization of the GI tract 
is barium sulfate administered as a suspension orally or rectally as an 
enema. (See, for example, U.S. Pat. Nos. 2,659,690; 2,680,089; 3,216,900; 
3,235,462; 4,038,379 and 4,120,946) Notwithstanding its relatively good 
contrast characteristics, negligible absorption from the GI tract 
following oral or rectal administration and speedy excretion from the 
body, barium sulfate has certain disadvantages. In the presence of 
intestinal fluids it lacks homogeneity and poorly adheres to mucus 
membranes which can result in poor x-ray images. In the colon, when 
administered as an enema, it flocculates and forms irregular clumps with 
fecal matter. 
Iodinated organic compounds have also been used as contrast agents since 
the iodine atom is an effective x-ray absorber. They have the most 
versatility and are utilized in the widest variety of procedures. They are 
very absorptive of x-rays with which the iodine interacts and produce a 
so-called photoelectric effect which is a large magnification in contrast 
caused by the photons stopped in the iodine-containing medium. The 
magnification of contrast exceeds the level that would be expected from 
relative changes in density. Because of this magnification, relatively low 
concentrations of the contrast agent can be utilized. (For iodinated 
agents see, for example, U.S. Pat. Nos. 2,786,055; 3,795,698; 3,360,436; 
3,574,718, 3,733,397; 4,735,795 and 5,047,228.) 
The desiderata for an ideal GI contrast agent includes: good toxicological 
profile; the ability to fill the entire bowel/lumen and evenly coat the 
gut mucosa so that the presence of the bowel is detectable when the lumen 
is not distended; palatability and nonirritation to the intestinal mucosa; 
and passing through the GI tract without producing artifacts or 
stimulating vigorous intestinal peristalsis. 
These requirements were addressed by many investigators and their efforts 
resulted in great improvements over the years. The requirement of evenly 
coating the gut mucosa with and sufficiently adhering thereto, a contrast 
agent to effectively cover the walls of the intestines proved to be rather 
difficult. Without meeting these requirements it is impossible to obtain 
x-ray pictures of high precision. To that end, the use of certain polymer 
additives were proposed as illustrated hereunder. 
U.S. Pat. No. 4,069,306 discloses an x-ray contrast preparation which is 
said to adhere to the walls of body cavities. The preparation comprises a 
finely divided water-insoluble inorganic x-ray contrast agent and minute 
particles of a hydrophilic polymer which is insoluble in water but is 
water-swellable. The body cavity is supplied with such preparation 
suspended in water. The x-ray contrast agent is present in admixture with 
and/or enclosed in and/or adhered to said minute polymer particles. 
U.S. Pat. No. 4,120,946 discloses a pharmaceutical composition for barium 
opacification of the digestive tract, comprising colloidal barium sulfate 
and a polyacrylamide in an aqueous vehicle. The polyacrylamide forms a 
viscous solution at low concentration which makes it possible to maintain 
the barium sulfate in suspension and at the same time permit good 
adherence of the preparation to the walls of the organ which it is desired 
to x-ray. 
U.S. Pat. No. 5,019,370 discloses a biodegradable radiographic contrast 
medium comprising biodegradable polymeric spheres which carry a 
radiographically opaque element, such as iodine, bromine, samarium and 
erbium. The contrast medium is provided either in a dry or liquid state 
and may be administered intravenously, orally and intra-arterially. 
Japanese Pat. Application No. 55-127322 discloses x-ray contrast 
compositions containing barium sulfate and a polymeric substance selected 
from carboxymethyl cellulose salts, propylene glycol alginate, cellulose 
sulfate polyacrylate, pectin and tragacanth gum. The polymeric substance 
is used to increase the viscosity of the compositions. 
While these polymeric materials enhance attachment of the contrast agent 
used therewith to the walls of organs for better visualization thereof, 
they do not provide a polymeric coating thereon or prevent flocculation. 
As such, there is still a need for an improved x-ray imaging medium that 
uniformly coats the soft tissues subjected to diagnostic x-ray 
examination. 
While these polymeric materials greatly enhance attachment of the contrast 
agent used therewith to the walls of organs for better visualization 
thereof, they do not provide a uniform coating thereon. As such, there is 
still a need for an improved x-ray imaging medium that uniformly coats the 
soft tissues subjected to diagnostic x-ray examination. 
SUMMARY OF THE INVENTION 
It is the object of the present invention to provide compositions for 
coating the gastrointestinal tract of mammals to form an effective 
radiopaque coating thereon by which diagnostic examination of the GI tract 
may be accomplished. To that end, a thin coating is formed on the inner 
surface of the GI tract effected by ingesting, prior to visualization by 
an x-ray emitting device, a polymeric film former, which has incorporated 
therein an x-ray contrast agent, capable of coating the GI tract. The 
removal of the coating occurs as a result of the normal turnover of cells, 
that is, within about 24 to 48 hours. Such compositions must meet several 
requirements: both the x-ray contrast agent and the film former must be 
nontoxic; must not contain leachable or digestible components that would 
deleteriously affect the patient; no components of the coating should be 
absorbed by, and pass through, the inner surface of the intestine; and the 
composition must be capable of forming a film in the pH range of from 
about 5 to about 8. 
The object of the present invention is achieved by a composition 
comprising: an x-ray contrast agent; a polymeric material which is at 
least partially water soluble and contains polarizable or ionizable 
groups; and a divalent metal ion selected from the group consisting of 
Mg.sup.++, Ca.sup.++, Zn.sup.++ and Ba.sup.++ which potentiates the 
effect of the polymeric material as a film former on the mucosa of the GI 
tract. 
The contrast agent, polymeric film former and the divalent metal ion are 
incorporated in a solid or liquid media for administration to a mammal for 
x-ray visualization of the GI tract. 
The contrast agent utilized in the present invention is represented by the 
formula (I) 
##STR1## 
wherein R is a substituted or unsubstituted alkyl group containing from 2 
to 8 carbon atoms, wherein said substituents are selected from the group 
consisting of C.sub.1 -C.sub.6 alkyl, hydroxy and alkoxy; and n is 1 to 5. 
Preferred contrast agents of the present invention have the formula: 
##STR2## 
wherein R is a secondary alkyl group containing from 4 to 8 carbon atoms. 
The most preferred contrast agent utilized by the present invention is the 
sec-octyl ether of 2,4,6-triiodophenol having the formula: 
##STR3## 
The compounds are readily synthesizable by methods known in the prior art. 
The compounds' desirable properties include: sufficient iodine content for 
producing adequate imaging; ability to coat the mucosal lining of the GI 
tract giving good imaging quality; and superior toxicological profile. 
The compositions may be in the form of solids, dispersions, colloids or 
suspensoids, however, we prefer to use emulsions as the preferred 
embodiment. 
The gist of the present invention resides in an x-ray contrast composition 
designed for depositing a thin, flexible film membrane onto the mucosal 
lining of the nutrient absorbing inner surface of the intestine of a 
patient to form a barrier between the nutrient absorbing inner surface and 
the content of the intestine, the flexible film membrane to remain bound 
to the mucosal lining until eliminated by normal cell turnover comprising 
based on w/v: of from about 0.001 to about 15% of a polymeric material 
capable of forming a film membrane on the gastrointestinal tract in the pH 
range of from about 5 to about 8, the polymeric material is selected from 
the group consisting of anionic polymers carrying negative charges in the 
ionized form, cationic polymers carrying positive charges in the ionized 
form and neutral polymers having polarizable electrons selected from the 
group consisting of oxygen, nitrogen, sulfur, fluoride, chloride, bromide 
and iodide in combination with of from about 0.001 to about 15% of a 
divalent cation to potentiate the binding of the flexible film membrane to 
the mucosal lining selected from the group consisting of Ca.sup.++, 
Mg.sup.++, Zn.sup.++ and Ba.sup.++ ; and of from about 0.001 to about 75% 
of a nonionic x-ray contrast producing agent having the formula 
##STR4## 
or a pharmaceutically acceptable salt thereof wherein R is a substituted 
or unsubstituted alkyl group containing from 2 to 8 carbon atoms, wherein 
said substituents are selected from the group consisting of C.sub.1 
-C.sub.6 alkyl, hydroxy and alkoxy; and n is 1 to 5; in a pharmaceutically 
acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION 
The contrast agents utilized in the compositions of the present invention 
are slightly soluble in water, having a partition coefficient equal or 
greater than 10. This degree of solubility allows the formation of stable 
formulations in the form of dispersions, emulsions, suspensions when the 
formulations contain the requisite excipients. The term "stable" means 
that there is no separation of the ingredients contained in the 
compositions after oral or rectal administration thereof and during 
radiological examination of the GI tract. The slight solubility of the 
contrast agents in aqueous media permits diffusion of the contrast agents 
into the intestinal mucosa and secretions thereby forming a coating on the 
intestines. On the other hand, due to their slight solubility, the 
absorption of the contrast agent into the intestinal walls is minimal 
which reduces the possibility of toxic side effects. 
Some of the contrast agents of the present invention can be prepared as 
described in U.S. Pat. No. 2,622,100, the disclosure of which is 
incorporated herein by reference. We, however, prefer utilizing the 
preparative methods described in the examples that follow. 
Example 1 
A. 2-Mesyloxyoctane 
##STR5## 
To 130 g (0.995 mol) of 2-octanol and 207 ml (1.19 mol, 1.2 equiv) of 
diisopropylethylamine in 1.5 L dichloromethane at 0.degree. C. under a 
CaSO.sub.4 drying tube was added dropwise 84.4 ml (1.09 mol, 1.1 equiv.) 
of methanesulfonyl chloride over 1 hour while keeping the internal 
temperature at less than 5.degree. C. The faintly yellow solution was 
stirred at 0.degree. C. for an additional 1.5 h. The cold reaction 
solution was then washed with 2.times.1 L ice-cold 1M HCl and 1 L of 
ice-cold H.sub.2 O and brine and dried over MgSO.sub.4. The residue was 
filtered through Celite and concentrated in vacuo below 35.degree. C. to 
afford 208 g of a yellow oil. The yellow oil was placed under high-vacuum 
for 2 h at 25.degree. C. to give 205 g of yellow oil. NMR spectra 
confirmed the desired title-product having only trace amounts of solvents 
present. 
2,4,6-Triiodophenoxy-2-Octane 
##STR6## 
To a 5 L round bottom flask equipped with a mechanical stirrer was added, 
under nitrogen, 71.3 g (0.342 mol) of 2-mesyloxyoctane (obtained in A), 
193 g (0.410 mol, 1.2 equiv) of 2,4,6-triiodophenol, 56.7 g (0.410 mol, 
1.2 equiv.) of anhydrous potassium carbonate and 2.00 L of 
dimethylformamide (hereinafter DMF). The mixture was warmed slowly over 
one hour to reach a temperature of 55.degree. C. to 60.degree. C. and then 
stirred at 55.degree. C. for 16 hours. 
The temperature was raised to 65.degree. C. and the mixture stirred for an 
additional 4 hours, then slowly cooled to room temperature and filtered 
through Celite to remove solids. The amber-colored DMF filtrate was 
extracted with 3.times.500 ml hexane to remove some of the product (first 
extract). TLC (25% EtOAc-hexane) indicated that the extract was the 
extremely pure title-product. 
The DMF solution remaining after extraction with hexane was diluted with 9 
L H.sub.2 O and 1 L of 1M NaOH. This mixture was extracted with 
3.times.750 ml hexane (second extract). TLC showed that the extract was 
somewhat less pure than the first extract, but still only contained minor 
impurities. 
The first extract and second extract were then separately washed with 
2.times.500 ml of 1M NaOH, 500 ml of H.sub.2 O, 500 ml of saturated 
Na.sub.2 SO.sub.3, 4.times.1 L H.sub.2 O, 1 L of brine and dried over 
Na.sub.2 SO.sub.4. 
Concentration in vacuo followed by high vacuum afforded from the first 
extract 65.5 g of a faintly yellow oil (33% yield). NMR spectra confirmed 
the extremely pure title-product containing no measurable amount of other 
materials, such as unreacted mesylate. 
The second extract afforded 92.2 g (46% yield) of a light amber-colored 
oil. NMR spectra confirmed a reasonably pure product having only trace 
amounts of impurities, such as mesylate. 
The 65.5 g of product obtained from the first extract was filtered through 
500 g of silica eluting with 6 L of hexane to remove the trace of yellow 
color. Concentration in vacuo and under high vacuum and warming for 15 
minutes afforded 64.7 g of the pure, colorless oil (99% recovery). NMR 
spectra confirmed the same very pure product as before. 
The 92.2 g of product obtained from the second extract was subjected to the 
same procedure as the first extract. The product was found to be pure (98% 
recovery) without having a yellow color and without trace amounts of 
impurities, such as mesylate. 
Example 2 
2,4,6-Triiodophenoxy-2-Butane 
##STR7## 
To a solution of 45.0 mmol of 2-butanol (4.1 ml) in dichloromethane at 
0.degree. C. was added 1.2 equiv. (9.4 ml) of diisopropylethylamine. After 
about 10 minutes, 1.1 equiv. (4.8 ml) of methanesulfonyl chloride was 
added slowly by syringe over about 10 min. The solution was stirred in an 
ice/water bath for 2.5 h, then poured over cold 5% HCl. The layers were 
separated and the organic layer was washed with cold 5% aqueous HCl and 
brine and dried over Na.sub.2 SO.sub.4. The dried residue was dissolved in 
DMF (100 ml) and 50.0 mmol (23.6 g) of 2,4,6-triiodophenol was added which 
was followed by the addition of 50.0 mmol (6.9 g) of potassium carbonate. 
(The solution at this point turned dark and was difficult to stir). 
Stirring continued for 17 h. The solution was then cooled, filtered 
through Celite using DMF. The so-obtained DMF-containing solution was 
twice extracted with hexane, diluted with 200 ml of 0.1M aqueous NaOH and 
again extracted twice with hexane. The hexane extracts were combined and 
washed with 2.times.50 ml 1M NaOH, 2.times.50 ml H.sub.2 O and brine. The 
organic layer was dried over Na.sub.2 SO.sub.4, filtered and the solvent 
removed in vacuo. Purification of the residue by flash column 
chromatography (silica, hexanes) gave 9.9 g of the title product as an 
oil. 
An alternate method of making the compound of Example 2 is described in 
Example 3. 
Example 3 
2,4,6-Triiodophenoxy-2-Butane 
##STR8## 
To a solution of 21.19 mmol (10.0 g) of 2,4,6-triiodophenol in 40 ml (0.5M) 
DMF at room temperature was added 2.0 equiv (4.6 ml) of 2-bromobutane and 
2.0 equiv. (5.86 g) of potassium carbonate. The mixture was heated to 
57.degree. C. in an oil bath and stirred for 65 h. The mixture was then 
cooled, filtered through Celite by washing with DMF. The DMF-containing 
solution was extracted with hexane, diluted with 10% NaOH (100 ml) in 
H.sub.2 O, and extracted 3 times with hexane. The extracts were combined 
and washed twice with 1M NaOH, twice with H.sub.2 O and twice with brine. 
The organic layer was dried over Na.sub.2 SO.sub.4, filtered and the 
solvent was removed in vacuo. Purification by flash column chromatography 
(hexanes, silica) yielded 10.83 g of the title product in the form of an 
oil. 
Example 4 
2,4,6-Triiodophenoxy-2-Hexane 
##STR9## 
To a solution of 63.6 mmol (30 g) of 2,4,6-triiodophenol in 125 ml of DMF 
(0.5M) at room temperature was added 1.2 equiv. (10.8 ml) of 2-bromohexane 
and 1.5 equiv. (13.2 g) of potassium carbonate. The mixture was heated to 
58.degree. C. over 1.5 h, then stirred 40 h. The reaction mixture was 
filtered through Celite using DMF. The volume of DMF was reduced to 200 ml 
by evaporation in vacuo. The mixture was extracted twice with hexane, 
diluted with 500 ml of 10% NaOH in H.sub.2 O and extracted again with 
hexane 3 times. The hexane extracts were then combined and washed twice 
with 1M NaOH, twice with H.sub.2 O and once with brine. The organic layer 
was then dried over Na.sub.2 SO.sub.4, filtered and the solvent was 
removed in vacuo. Flash column chromatography (hexanes, silica) yielded 
31.5 g of the title compound in the form of an oil. 
Example 5 
4-Iodophenoxy-2-Octane 
##STR10## 
A mixture of 50.0 g (0.227 mol) of 4-iodophenol, 45.4 g (0.189 mol) of 
2-iodooctane and 94.1 g (0.681 mol) potassium carbonate in 500 ml dry 
acetonitrile was heated to reflux under nitrogen and stirred for 20 h. The 
mixture was cooled and filtered through Celite and concentrated in vacuo. 
The brown residue was partitioned between 1 L hexanes and 500 ml 1M NaOH. 
The hexane layer was then washed with 1M NaOH (3.times.250 ml) saturated 
sodium sulfite (250 ml), water (250 ml) and brine (250 ml). The faintly 
yellow solution was dried over Na.sub.2 SO.sub.4 and concentrated in vacuo 
to 34.3 g of a light yellow oil. The material in 60 ml of hexane was 
passed through a 600 g pad of silica gel eluting with 3% ethyl 
acetate-hexanes until just prior to elution of the yellow color. 
Concentration and warming under high vacuum afforded 26.9 g (43%) of 
product as a mobile colorless oil. 
Other compounds of formula I may be prepared using the reaction techniques 
described in Examples 1 through 5 using appropriate starting materials and 
reagents. It is to be understood that all reaction conditions, including 
choice of solvents, reaction atmosphere, reaction temperature, duration of 
the experiment and workup procedures, are chosen to be conditions standard 
for that reaction, which should be readily recognized by one skilled in 
the art. It is understood by one skilled in the art of organic synthesis 
that the functionality present on portions of the educt molecule must be 
compatible with the reagents and reactions. 
Starting materials, reagents and solvents can be obtained from chemical 
suppliers, such as Aldrich, Baker and Eastman Chemical Companies, or they 
may be prepared by techniques known in the prior art. 
The polymers that were found to be suitable for forming a thin coating on 
the GI tract can be classified as anionic, cationic and neutral polymers, 
a description of which follows. U.S. Pat. No. 4,623,539, the disclosure of 
which is incorporated by reference, pertains to such polymers. 
The contrast agent is incorporated in the polymeric material along with the 
divalent cation by any suitable techniques, such as by mixing, blending, 
precipitating or by enclosing the contrast agent into minute polymeric 
particles. 
The contrast agent, polymeric material and divalent cation blend is then 
formulated for administration using physiologically acceptable carriers or 
excipients in a manner within the skill of the art. The contrast agent 
with the addition of pharmaceutically acceptable aids (such as surfactants 
and emulsifiers) and excipients may be suspended or partially dissolved in 
an aqueous medium resulting in a dispersion, solution, suspension or 
emulsion. Alternatively, the contrast agent, polymeric material and 
divalent cation may be formulated into a solid form, such as tablets or 
capsules. 
Compositions 
Compositions of the present invention comprise the following 
pharmaceutically acceptable components based on % w/v: 
______________________________________ 
Non-aqueous phase 1-45 
Polymeric Material 0.001-15 
Divalent Cation 0.001-15 
Contrast Agent 0.001-75 
Excipient 0-20 
Aids (Surfactants/Emulsifiers) 
0.01-10 
Water q.s. to 100 
______________________________________ 
The nonaqueous phase comprises vegetable oils such as safflower oil; 
non-metabolizing fat substituents, such as Simpless; fluorinated 
hydrocarbons, such as perfluorodecaline; mineral oil and simethicone. 
The contrast agent is selected from the group of compounds of formula I, 
preferably compounds where R is an alkyl group containing from 4 to 8 
carbon atoms. 
Excipients advantageously used in the formulations include viscosity 
mediating and stabilizing agents, such as microcrystalline cellulose, 
ethylcellulose, hydroxypropyl methylcellulose and gum arabic. 
Physiologically acceptable substances may also be included, such as sodium 
citrate, sodium chloride, therapeutic substances, antacid substances and 
flavoring agents. The inclusion of antimicrobial/antiseptic agents such as 
methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl 
parahydroxybenzoate, benzoic acid or sorbic acid may also be desirable in 
some formulations. 
As known by those skilled in the art, surfactants or emulsifiers can reduce 
the interfacial tension between two immiscible phases, i.e., 
oil-in-aqueous medium. These agents can be used alone or in combination 
with other emulsifying agents and surfactants. For example, Dow Corning 
Medical Antifoam AF, which is a composition of 30% w/v 
polydimethylsiloxane and silica aerogel, 14% w/v stearate emulsifiers and 
0.075% w/v sorbic acid, the balance being water, may be used by itself. 
Intralipid, which is an emulsion of fatty acids needs the presence of a 
suspending agent for it to form an acceptable emulsion with contrast 
agents of the present invention. The amount of such surfactants may be in 
the range of from 0.01 to 5% w/v of the aqueous formulations, although the 
amount, in general, is kept as low as possible, preferably in the range of 
0.05 to 2% w/v. The surface active agents may be cationic, anionic, 
nonionic, zwitterionic or a mixture of two or more of these agents. 
Suitable cationic surfactants include cetyl trimethyl ammonium bromide. 
Suitable anionic agents include sodium lauryl sulphate, sodium heptadecyl 
sulphate, alkyl benzenesulphonic acids and salts thereof, sodium 
butylnapthalene sulfonate, and sulphosuccinates. Zwitterionic surface 
active agents are substances that when dissolved in water they behave as 
diprotic acids and, as they ionize, they behave both as a weak base and a 
weak acid. Since the two charges on the molecule balance each other out 
they act as neutral molecules. The pH at which the zwitterion 
concentration is maximum is known as the isoelectric point. Compounds, 
such as certain amino acids having an isoelectric point at the desired pH 
of the formulations of the present invention are useful in practicing the 
present invention. 
In preparing the formulations of the present invention we prefer to use 
nonionic emulsifiers or surface active agents which, similarly to the 
nonionic contrast agents, possess a superior toxicological profile to that 
of anionic, cationic or zwitterionic agents. In the nonionic emulsifying 
agents the proportions of hydrophilic and hydrophobic groups are about 
evenly balanced. They differ from anionic and cationic surfactants by the 
absence of charge on the molecule and, for that reason, are generally less 
irritant than the cationic or anionic surfactants. Nonionic surfactants 
include carboxylic esters, carboxylic amides, ethoxylated alkylphenols and 
ethoxylated aliphatic alcohols. 
One particular type of carboxylic ester nonionic surface active agents are 
the partial, for example mono-, esters formed by the reaction of fatty and 
resin acids, for example of about 8 to about 18 carbon atoms, with 
polyalcohols, for example glycerol, glycols such as mono-, di-, tetra- and 
hexaethylene glycol, sorbitan, and the like; and similar compounds formed 
by the direct addition of varying molar ratios of ethylene oxide to the 
hydroxy group of fatty acids. 
Another type of carboxylic esters is the condensation products of fatty and 
resin partial acids, for example mono-, esters ethylene oxide, such as 
fatty or resin acid esters of polyoxyethylene sorbitan and sorbitol, for 
example polyoxyethylene sorbitan, mono-tall oil esters. These may contain, 
for example, from about 3 to about 80 oxyethylene units per molecule and 
fatty or resin acid groups of from about 8 to about 18 carbon atoms. 
Examples of naturally occurring fatty acid mixtures which may be used are 
those from coconut oil and tallow while examples of single fatty acids are 
dodecanoic acid and oleic acid. 
Carboxylic amide nonionic surface active agents are the ammonia, 
monoethylamine and diethylamides of fatty acids having an acyl chain of 
from about 8 to about 18 carbon atoms. 
The ethoxylated alkylphenol nonionic surface active agents include various 
polyethylene oxide condensates of alkylphenols, especially the 
condensation products of mono-alkylphenols or dialkylphenols wherein the 
alkyl group contains about 6 to about 12 carbon atoms in either branched 
chain or particularly straight chain configuration, for example, octyl 
cresol, octyl phenol or nonyl phenol, with ethylene oxide, said ethylene 
oxide being present in amounts equal to from about 5 to about 25 moles of 
ethylene oxide per mole of alkylphenol. 
Ethoxylated aliphatic alcohol nonionic surface active agents include the 
condensation products of aliphatic alcohols having from about 8 to 18 
carbon atoms in either straight chain or branched chain configuration, for 
example oleyl or cetyl alcohol, with ethylene oxide, said ethylene oxide 
being present in equal amounts from about 30 to about 60 moles of ethylene 
oxide per mole of alcohol. 
Preferred nonionic surface active agents include: 
(a) Sorbitan esters (sold under the trade name Span) having the formula: 
##STR11## 
wherein R.sub.1 =R.sub.2 =OH,R.sub.3 =R for sorbitan monoesters, 
R.sub.1 =OH,R.sub.2 =R.sub.3 =R for sorbitan diesters, 
R.sub.1 =R.sub.2 =R.sub.3 =R for sorbitan triesters, 
where R=(C.sub.11 H.sub.23)COO for laurate, (C.sub.17 H.sub.33)COO for 
oleate, (C.sub.15 H.sub.31)COO for palmitate, (C.sub.17 H.sub.35)COO for 
stearate; 
(b) Polyoxyethylene alkyl ethers (i.e. Brijs) having the formula: 
EQU CH.sub.3 (CH.sub.2).sub.x (O--CH.sub.2 --CH.sub.2).sub.y OH 
where (x+1) is the number of carbon atoms in the alkyl chain, typically: 
______________________________________ 
12 lauryl (dodecyl) 
14 myristyl (tetradecyl) 
16 cetyl (hexadecyl) 
18 stearyl (octadecyl) 
______________________________________ 
and y is the number of ethylene oxide groups in the hydrophilic chain, 
typically 10-60; 
(c) Polyoxyethylene sorbitan fatty acid esters, sold under the trade names 
of Polysorbates 20, 40, 60, 65, 80 & 85; and 
(d) Polyoxyethylene stearates, such as: 
poly(oxy-1.2-ethanediyl),.alpha.-hydro-.omega.-hydroxy-octadecanoate; 
polyethylene glycol monostearate; and 
poly(oxy-1,2-ethanediyl)-.alpha.-(1-oxooctadecyl)-.omega.-hydroxy-polyethyl 
ene glycol monostearate. 
The film former polymeric materials used in accordance with the present 
invention include anionic polymers, cationic polymers and neutral 
polymers. 
I. Anionic Polymers 
The anionic polymers carry negative charges in the ionized form and are 
capable of binding to cell surfaces mainly by electrostatic forces. 
Suitable anionic polymers include the following: 
##STR12## 
wherein R is the polymeric chain; 
##STR13## 
are anionic ligands; and M.sup.++ is a divalent cation. 
Specific anionic polymers useful in the practice of the present invention 
include: 
(1) Sulfated polysaccharides of the formula: 
##STR14## 
wherein R is 3,6-anhydro-D-galactose linked through C-4 to D-galactose; 
(kappa carrageenan) .alpha.-D-galactose units (1-3) linked; (lambda 
carrageenan) D-galactose 3,6-anhydro-D-galactose; (iota carrageenan) 
D-galactose 3,6-anhydro-L-galactose: (Agar--Agar) D-galactose 
3,6-anhydro-D-galactose; (Furcellaren) D-glucopyranose; (Laminarin 
sulfate) Galactan; and (Galactan sulfate) Galactosamino-glucuronans 
(Chondroitin sulfates); and 
M.sup.++ is Mg.sup.++, Ca.sup.++, Zn.sup.++, Ba.sup.++ or mixtures 
thereof. 
(2) Carboxylated polysaccharides of the formula: 
##STR15## 
wherein R is D-galacturonoglycan; and (Pectin) anhydro-D-mannuronic acid 
and anhydro-L-guluronic acid (Algin) residues; and 
M.sup.++ is Mg.sup.++, Ca.sup.++, Zn.sup.++, Ba.sup.++ or mixtures 
thereof. 
(3) Cellulose derivatives of the formulae: 
##STR16## 
wherein R is an anhydroglucose residue; 
R' is CH.sub.3, C.sub.2 H.sub.5 or C.sub.3 H.sub.7 ; 
R" is CH.sub.3 or C.sub.2 H.sub.5 ; and 
M.sup.++ is Mg.sup.++, Ca.sup.++, Zn.sup.++, Ba.sup.++ or mixtures 
thereof. 
Examples of cellulose derivatives include: sodium ethylcellulose sulfate, 
sodium cellulose acetate sulfate and sodium carboxymethyl cellulose. 
(4) Sulfated, sulfonated or carboxylated synthetic polymers of the formula: 
##STR17## 
wherein R is an aliphatic or aromatic hydrocarbon, such as polystyrene, 
poly(sulfon) resin or carboxylated (poly) vinyl; and 
M.sup.++ is Mg.sup.++, Ca.sup.++, Zn.sup.++, Ba.sup.++ or mixtures 
thereof. 
II Cationic Polymers 
The cationic polymers carry positive charges in the ionized form. Suitable 
polymers for practicing the present invention include: dermatan sulfate, 
keratosulfate, hyaluronic acid, heparin and chitin. 
III Neutral Polymers 
Neutral polymers having polarizable electrons such as oxygen, nitrogen, 
sulfur, fluoride, chloride, bromide and iodide are also suitable for 
practicing the present invention. In the presence of a cation, such as 
Mg.sup.++, Ca.sup.++, Zn.sup.++ or Ba.sup.++, the polymers are partially 
polarized thereby providing intermolecular interactions between the 
polymer and the intestinal wall. Examples of these polymers include: 
(a) Polysaccharides, such as starch, glycogen, glucan, fructans, mannans, 
galactomannas, glucomannas, galactans, xylans, glycuranans, dextran and 
starch amylose; 
(b) Cellulose derivatives, such as methylcellulose, hydroxyethylcellulose, 
ethylhydroxyethyl cellulose, hydroxypropyl methylcellulose and 
hydroxypropyl cellulose; and 
(c) Synthetic polymers, such as polyvinylpyrrolidone, polyvinyl alcohol and 
ethylene oxide polymers. 
Exemplary formulations of the present invention are as shown: 
______________________________________ 
Example 6 
Compound of Example 1 (114 mg I/ml) 
2.50 g (17.5% w/v) 
Dow Corning Med. Antifoam 
3.50 g (35% w/v) 
AF emulsion 
Galactan sulfate 0.5 g (5% w/v) 
Calcium lactate 0.5 g (5% w/v) 
Purified Water q.s. to 10 ml 
Example 7 
Compound of Example 1 (114 mg I/ml) 
2.50 g (17.5% w/v) 
Safflower Oil 2.00 g (20% w/v) 
Tween-21 0.25 g (2.5% w/v) 
Hydroxypropyl methylcellulose 
2.50 g of 2% solution 
(4,000 cPs) 
Calcium lactate 0.2 g (2% w/v) 
Purified Water q.s. to 10 ml 
Example 8 
Compound of Example 1 (114 mg I/ml) 
2.50 g (17.5% w/v) 
Mineral Oil 0.50 g (5% w/v) 
Heparin 0.25 g (2.5% w/v) 
Tween-21 0.25 g (2.5% w/v) 
Calcium lactate 0.25 g (2.5% w/v) 
Purified Water q.s. to 10 ml 
Example 9 
Compound of Example 1 (114 mg I/ml) 
2.50 g (17.5% w/v) 
Simplesse 100 (Nutrasweet Co.) 
3.00 g (30% w/v) 
Calcium lactate .about.0.5 (5% w/v) 
Hydroxypropyl methylcellulose 
2.50 g of 2% solution 
(4000 cPs) 
Purified Water q.s. to 10 ml 
______________________________________ 
The dosages of the contrast agent used according to the method of the 
present invention will vary according to the precise nature of the 
contrast agent used. Preferably, however, the dosage should be kept as low 
as is consistent with achieving contrast enhanced imaging. By employing as 
small amount of contrast agent as possible, toxicity potential is 
minimized. For most contrast agents of the present invention dosages will 
be in the range of from about 0.1 to about 16.0 g iodine/kg body weight, 
preferably in the range of from about 0.5 to about 6.0 g iodine/kg of body 
weight, and most preferably, in the range of from about 1.2 to about 2.0 g 
iodine/kg body weight for regular x-ray visualization of the GI tract. For 
CT scanning the contrast agents of the present invention will be in the 
range of from about 1 to about 600 mg iodine/kg body weight, preferably in 
the range of from about 20 to about 200 mg iodine/kg body weight, and most 
preferably in the range of from about 40 to about 80 mg iodine/kg body 
weight. 
The concentration of the contrast agent should be in the range of from 
about 0.001% w/v to about 75% w/v of the formulation, preferably from 
about 0.05% w/v to about 50% v/v and most preferably of from about 0.1% 
w/v to about 20% w/v. 
The concentration of the film forming polymeric material depends on the 
particular polymer used, however, it should be in the range of 0.001 to 
about 15% w/v or higher in combination with a divalent substance, such as 
calcium lactate, having a concentration range of 0.001 to 15% w/v. The use 
of less than about 0.001% of a divalent cation was found to be less than 
satisfactory in forming a film on the mucosa of the intestines. Dosage 
level of the polymeric material may be in the range of from about 2 to 
about 15 g/kg body weight or higher. 
The compositions of the present invention possess very good adherence to 
the walls of the gastrointestinal tract by forming an essentially uniform 
coating thereon. 
The invention, having been fully described, it will be apparent to one 
skilled in the art that changes and modifications can be made thereto 
without departing from the spirit and scope thereof.