CA2184089A1 - X-ray contrast compositions containing cellulose derivatives - Google Patents

Abstract

Disclosed are x-ray contrast compositions for oral or retrograde examination of the gastrointestinal tract comprising an x-ray contrast producing agent in a pharmaceutically acceptable carrier comprising a cellulose derivative.

Description

W095122995 ~ ` 2 1 84~8 9 r~ r~

X-RAY CONTRAST COMPOSITIONS CONTAINING
CELLULOSE DERI~TATIVES
This invention relates to x-r~ cont~-ast compositions rnnt~;n;n~ contrast agents and cellulose derivatives, and methods for their use in diagnostic radiology of the gastrointestinal tr~
~ nPnt~nngraphic PY~~;n~tin~ ut ilizing X-rayb and computed tomography (hereinafter ~ T) scans of fractures and other conditions ~sn-;AtPd ~Fith the Ck~lPt~l system is routinely Fr~rti r~(9 without the use of contrast agents. X-ray v;C11~7i7~rinn of organs rnnt;linin~ soft tisaue, such as the gastrointestinal (hereinafter GI) tract, requires the use of contra5t agents which AttPmlAte X-ray r~fliAtinn D. P. Swanson et al in ~ph~ euticals In Medical Imaging", 1990, MacMillan pllhl;qh;n~ Company, provide an ,~YnPll~nt ba~:hyLuul-d in medical imaging llti1i7ing contrast agents.
Roentgenographic ~Y~m;n~tinn of the GI tract is ;nrlirat~ for conditions of digestive disorders, changes in bowel habit, Ah~ n~l pain, GI bleeding and the like. Prior to radiological ,~Y~minAtinn, administration of a radiopaque contrast medium is npclocs~ry to permit ade3,uate (ipl;nf~;lt;nn of the respective lumen or mucosal surface from ~tuLLvullaing E3ft tis6ues. Accordingly, a contra8t medium is administered orally to visualize the mouth, pharynY, e50phagus, stomach, ~lllntll~nllm and proximal small intestine. The contrast medium is administered rectally for ~m;n::ltinn of the distal small intestine and the co~on.
The most widely used contrast agent ~or the V; Cll~l i 7~1tinn of the GI tract is barium sulfate administered orally as a sllcr.onc;nn or rectally as an enema. (See, for e_ample, U.S. Patent Nos.: 2,659,690;
SUBSTITUTE SHEET (RULE 26) Wo gs/22995 ~Q ~ r~ , 2 1 8 4 0 8 9 ~ ib7~ ' ~

2,680,089; 3,216,900; 3,235,462; 4,038,379 and 4,120,946). Notwithstanding its relatively good contrast charactPrlctir.c, 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 hr~ PnP; ty and adheres poorly to mucus membranes which can result in poor X-ray images. In the colon, ~hen administered as an enema, it flocrlllAtp~c and forms irregular clumps with fecal matter.
Iorl;nAtQ~l organic compounds have also been used as GI contrast agents since the iodine atom is an effective X-ray absorber. They have the most VPrCAt; l; ty and are ~ltl 1; 7PI'l in the widest variety of procedures . I'hey are very absorptive of X-rays with which the iodine interacts and produce a so-called photoelectric effect which is a large ~n;f;rAt;r,n in contrast caused by the photons stopped in the iodine-rrntA;nin~ medium. The magnification of contra8t exceeds the level that would be expected f rom relative changes in density . Because of this magnification, relatively low concentrations of the contrast agent can be llt;l;~Qcl. (For in~l;nAt agents see, for example, U.S. Patent Nos.: 2,786,055i

3,795,698; 2,820,814; 3,360,436; 3,574,718, 3,733,397;

4, 735, 795 and 5, 047, 228 . ) The desiderata for an ideal GI contrast agent include: good t~lr;cnl~;cal profile; the a~ility to fill the entire bowel/lumen and evenly coat the gut mucosa so that the presence of the bowel is ~ptprtAhl P when the lumen is not distended; pAl AtAh; l; ty and nonirritation to the intestinal mucosa; and passage through the GI
tract without producing artifacts or St;r~llAt;nrJ
vigorous intestinal peristalsis.
These requirements were addressed by many investigators and their efforts resulted in great ;, ~ v~ ~ over the years . The requirement of evenly coating the gut mucosa with a contrast agent to SUBSTITUTE SHEET(RULE26) wo gsl22ggs ~ r ~ S

e~fectively cover the walls of the intestines proved to be rather dif ficult . Without meeting these requirements it is impossible t:o obtain X-~ay pictures of high precision. To that end, the use of certain polymer additives were proposed a6 illustrated hereunder.
U.S. Patent No. 4,069,306 discloses an x-ray contrast preparation which is said to adhere to the walls of body cavities. The prPr~r~t;nn comprises a finely divided water-;n~oll~h1 P inorganic x-ray CODt.l~
agent and minute particles of a hydrophilic polymer which is inco71lhlP in water but is water-swellable The body cavity is supplied with such preparation sl~ n~ d in water. The x-ray contrast agent is prese~ ~ n r ' ' Ytllre with and/or ~nrl r5Ptl in and/or adhered to said minute polymer particles.
U.S. Patent No. 4,120, 946 discloses a rh~rr--ellt;rAl composition for barium or~c;f;ration of the digestive tract, comprising rnllnirlAl barium sulfate and a polyacrylamide in an aqueous vehicle. The polyacrylamide forms a viscous solution at low rnnrPntration which makes it rnfi~;hlP to ---;ntA;n the barium sulfate in ~ pPn~;nn 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. Patent No. 5,019,370 discloses a b;~r~ rJrA~Ahle radiographic contrast medium comprising biodegradable polymeric spheres which carry a rA~l; o~phi cally 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 Patent Appl;rAt;nn No. 55-127322 discloses x-ray contrast compositions rnnt~;n;ng barium sulfate and a polymeric substance selected from carboxymethyl cellulose salts, propylene glycol alginate, cellulose sul~ate polyacrylate, pectin and tragacanth gum. The polymeric substance is used to increase the viscosity of SUBSTITUTE SHEET (RULE 26) _ _ Wo 95/22995 2 ~ 8 4 ~ 8 9 r~

the compositions. ~
While these polymeric materials greatly enhance attachment o~ the contrast agent used therewith to the walls of organs for better Vi1l~1 i 7ati nn thereof, there is still a need for an improved X-ray imaging medium that uniformly coats the soft tissues subjected to diagnostic X-ray P~;lm; n~ti r n It is the obj ect of t~he present invention to provide compositiors for ~coating the gastrointestinal tract of mammals to form an effective r~fl;op~que coating thereon by which diagnostic ~ nqt;~n of the GI tract may be ~' rnmrli qhPr~. To that end, a thin coating is formed on the inrer surface of the GI tract effected by ingesting, prior to v;q~ i7~t;nn by an x-ray emitting device, a cellulose derivative, which has incorporated therein an x-ray contrast agent, capable of coating the GI tract. Such compositions must meet several requirements: both the x-ray contrast agent and the rPllllln,qe deriva~ive must be nnntn~;C; must not contain 1 P~rh~h~ e or digestible r~ ~ nn~ntq that would deleteriously af~ect the patient; and no ~ ~ntS of the coating should be absorbed by, and pass through, the inner surface of the intestine.
The objec~ of the present invention is achieved by a composition comprising: an ~-ray contrast agent in a rh~rr^nP~ti cally acceptable vehicle comprising a rPl 1 1l l oqe derivative .
In accordance with the invention there is further provided a method f or x-ray diagnostic imaging of the GI
tract which comprises orally or rectally administering to the patient an effective contrast producing amount of the above-described x-ray contrast compostion.
The x-ray contrast agent of the present invention is selected from:
(1) compounds of the formula:
SU~STITUTE SHEET (RULE 26) Wo 9sl2~99s ~ ~ i t. ( ~ ~ 2 1 8 4 0 8 9 P.~

~ b ~x or a rl~ r~ t;r~lly acceptable salt thereof wherein Z is H, halo, Cl-C20 alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups;
Rl and R2 are ;nrll~rPn~l~nt]y H, Cl-C2s alkyl, cycloalkyl, acetyl or halo-lower-alkyl, wherein said C1-C25 alkyl, cycloalkyl and halo-lower-alkyl are optionally substituted with fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy, lower-alkoxy carbonyl or lower-alkoxy-carbonyloxy and said acetyl is optionally ~ubstituted with fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, lower-alkoxy carbonyl or lower-alkoxy-carbonyloxy;
n is 1-4;
y is 1-4; and x is 1 or 2;
(2) u~-ds of the formula OR
~ 1, wherein R is a substituted or unsubstituted alkyl group cnnt~;n;n, from 2 to 8 carbon atoms, wherein said substituents are selected from the group consisting of Cl - C6 alkyl, hydroxy and alkoxy; and n is 1 to 5;
SUBSTITUTE SHEET(RULE 26) Wo g5/2299~ t 8 4 0 8 9 (3) compounds of the formula o

5~ R)x 1~ Z"
wherein Z is H, halo, C1-C2c alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be su~stituted with halogen or ~lo-lower-alkyl groups;
R is Cl-C2s alkyl, cycloaIlcy1, or halo-lower-alkyl, each of which may be optionall~ substituted with halo, fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy, lower- alkoxy carbonyl or lower- alkoxy-carbonyloxy; or (CRlR2)p- (CRI=CR,,),,,Q, or (CRlR2)p-C}C-Q;
Rl, R2, R3 and R~ are ;n~1Prl~n~ntly lower-alkyl, optionally substituted with halo;
x is 1-3 y is 1-4;
n is 1-5;
m is 1-15;
p is 1-10; and Q is E~, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower-alkyl;
(4) compounds of the formula In Rm wherein R is methyl, ethyl, n-propyl, C4-C2s alkyl, cycloalkyl, unsaturated allyl or halo-lower-alkyl, each of which may be optionally substituted with halo, fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy SUBSTITUTE SHEET(RULE 26) ~ Wo95/22995 .~,n ~ t ~ 218~ 389 P~
or lower-alkoxy carbonyl; or (CRlR2)p- (CR3=CR4)mQ, or (CRlR2)p-C=C-Q;
Rlr R2, R3 and Rg are in~PrPn~ntly H, lower-alkyl, optionally substituted with halo;
n is 2-5;
m is 2-5;
p is 1-10; and Q is H, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower-alkyl;
or a rhAt~--rpllt; cally acceptable salt thereof;
(5) ~ of the formula o--[(CH2)pCI E~ O}R
Rl n Zx wherein Z is H, halo, Cl-C2~ alkyl, cycloalkyl, lower alkoxy, alku~y.~ bu.l~l, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or '~:alo-lower-alkyl groups;
~Z,~
R is C1-C2s alkyl, cycloalkyl, l /J or halo-lower-alkyl; each of which may be optionally substituted with halo, fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy, lower-alkoxy-carbonyl or lower-alkoxy-carbonyloxy; or ~CRlR2)p- (CR3=CR")",Q, or ~CRlR2)p-C~C-Q;
Rl, R2, R3 and R4 are ~nflPrPnrl~ntly H or lower-alkyl, optionally substituted with halo;
x is 1-4;
n is 1-4;
m is 1-15;
p is 1-20; and - Q is H, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower-alkyl;
or a rhArr-rF~llt; cally acceptable salt thereof;
SUBSTITUTE SHEET (RULE 26) wo gsl2299~ 8 4 0 8 9 ~I ~ r C - - ~
( 6 ) compounds o~ the ~ormula ,~ (oXR~w In ZY
wherein o X is -C- or -52-;
Z is H, halo, Cs-C20 alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl g~oups can be substituted with halogen or halo-lower-alkyl groups;
R is C1-C2s alkyl, cycloalkyl, aryl or halo-lower=
alkyl, each of which may be optionally substituted with lower-alkoxy, hydroxy, carboxy or lower-alkoxy-carbonyl, lower-alkenyl, lower-alkynyl, lower-alkylene or lower=
alkoxy - carbonyloxy;
n is 1-5;
y is 0-4; and w is 1-4;
or a pharmaceutically acceptable salt thereof;
7) r~ , o~ q of the formula OR
I / Z~
or a pharmaceutically acceptable salt thereof wherein Z is H, halo, Cl-C20 alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups;
R is methyl, ethyl, propyl, Cg-C2s alkyl, cycloalkyl, or halo-lower-alkyl, optionally substituted with halo, fluoro-lower-alkyl, aryl, lower-alkoxy, SUBSTITUTE SHEET (RULE 26) -WO 95/2299s ~ 2 1 ~ 4 0 ~ 9 r~
hydroxy, carboxy, lower-alkoxy-carbonyl or lower-alkoxy-carbonyloxy; or ~CRlR2) p- (CR3=CR4? mQ, or (CRlR2) p-C-C-Q;
Rl, R2, R3 and R4 are independently lower-alkyl, optionally substituted with halo x is 1-4;
n is 1-5;
m is 1-15;
p is 1-10; and Q is H, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower-alkyl;
(8) `a particulate x-ray crystalline contrast agent having a surface mnrl;f;Pr A~lcnrhP~l on the surface thereof;
(9) in~inAtPd polymeric, water-insoluble beads having a particle size of from about 0 . 01 to about 1000~ wherein said ;r"l;nArprl polymeric beads comprise a polymer r nn t A; n; n j rPrPA t; n~ unit s of the f ormula ( I ) ~A~
X
whereir A is a rPrPAt;n~ organic unit in the bArkhnnp chain of the polymer; and X is an organic moiety rnn~A;n;nrj an in~l;n~te~l aromatic ,roup and a hydrophilic group, said moiety having an iodine content within the range of from about 40 to about 80 weight percent based on the 1 er~ r weight of X;
(10) a barium salt.
As used herein, the term halogen (or halo) means f luorine, chlorine, bromine or iodine .
SUBSTITUTE SHEET (RULE 26) Wo 9s/22995 ~ ~ r ~ 2 1 8 4 0 8 9 ~ 7~
A8 used herein, the term cycloalkyl means carbocyclic rings having f rom three to eight ring carbon atoms including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl which may be substituted on any ring carbon atom thereof by one or more lower-alkyl groups, lower-alkoxy groups or halogens.
As used herein the terms lower-alkyl and lower-alkoxy mean monovalent ~l;rh;l~iC radicals, inrlll~inr branched chain radicals, of from one to ten carbon atoms. Thus, the lower-alkyl moiety of such groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 2-hexyl, 3-hexyl, 1,1,3,3-t~ ~hylpentyl, 1,1-dimethyloctyl and the like.
As used herein, the term lower-alkenyl and lower-alkynyl means monovalent, ungaturated radicals inrlllr~;n5 branched chain rArl; r;ll q of from three to ten carbon atoms and thus include 1-ethenyl, 1- (2-propenyl~, 1- (2-butenyl), 1- (1-methyl-2-prope~yl), 1- (4-methyl-2-pentenyl), 4, 4, 6-trimethyl-2-heptenyl, 1-ethynyl, 1- ~2-propynyl), 1- (2-butynyl), 1- (1-methyl-2-propynyl), 1- (4-methyl-2-pentynyl) and the like.
As used herein, the term alkylene means divalent saturated radicals, ;nrlllfl;ng hr:lnrh~1 chain radicals of from two to ten carbon atoms having their free valences on different carbon atoms and thus includes 1, 2-ethylene, 1, 3-propylene, 1, 4-butylene, 1-methyl-1, 2-ethylene, 1, 8-octylene and the like.
As used herein, the term aryl means an aromatic hydrocarbon radical having six to ten carbon atoms. The preferred aryl groups are phenyl, substituted phenyl and naphthyl substituted by from one to three, the same or different members of the group consisting of lower-alkyl, ha1ogen, hydroxy-1ower-alky1, aL'coxy-lower-alkyl and hydroxy.
SU8STITUTE SHEET (RULE 26) - G ~
WO 95/22995 I ~ ~ 2 ~ 8 9 The x-ray contrast r( ~ ol~n~q of types (1) - (7) above can comprise one, two, three or four iodine atoms per molecule; preferred species contain at least two, and more preferably, at least three iodine atoms per molecule .
~ ol id x-ray contrast agents in particulate form useful in th~ practice of the present invention can be prepared by t erhnir~ Pq known in the art. The solid agents are c nlltl~rl to the desired size using convei~tiona] milling methods, such as airjet or frar~-nt~t; nn milling. We have found that an effective average particle size of less than about 100~ provides for good distrihtlt;nn and coating in the GI tract. As used herein, particle size refers to a num~er average particle size as measured by convpnrinnAl techniques, such as ~qP~;tnPnt~t;nn field flow fr~rtinn~t;nn and disk centrifugation. An effective average particle size of less than about 100~L means that at least about 90~ of the particles have a weight average particle size of less than about 100~L as measured by art recognized tPrhni q~pq The rP~ se derivatives llti l i ~Pti in the present invention include methylcellulose, carboxymethylcellulose, sodium caLl,u-Ly..l.Lhylcellulose, llydLu~yt:thyl methylcPlllllnqe~ hydroxypropyl methylcellulose; and microcrystalline cp~ ln,qe; having an average particle size of from O . 01 to 100~L, more preferably of from 0.05 to 10~, and most preferably of 0.1 to 1 ~Lm.
The contrast agent and the rPlltllnqP derivative are f~rr~ tP-l for administration using physiolo~icAlly acceptable r~rri Prq or excipients in a manner within the skill of the art. The contrast agent and the cellulose derivative with the addition o~ pharmaCP~lrir~l ly acceptable aids (such as surfactants and ~ lq;~ierq) and excipients are suspended or partially dissolved in an ar~ueous medium resulting in a dispersion, solution, SUBSTITUTE SHEET (RULE 26) Wogs/2299s . ~. " ~
suspension or em~llsion A method for diagnostic imaging o~ the GI tract for use in medical procedures in accordance with this invention comprises orally or rectally administering to the ~ n patient in need of x-ray F~ min~tinn, an effective contrast producing amount of a composition of the present invention. After administration, at least a portion of the GI tract rnntilin;n~ the administered composition is exposed to x-rays to produce an x-ray image pattern corrp~rnnrl;n~ to- the presence of the contrast agent, then the x-ray image is V; ~ l; 7P~ and interpreted using tPrhn; quo~ known in the art .
(' _ flc of type (l) defined above are described in EP-A-613689 . For example, N-acetyl-N-2 ' -octyl-4-; orln~ n; l; n~ and N- ( 4 ~ -; o-l nrh~nyl ) - 2 - aminooctane are described therein.
r ~ dl. of type (2) defined above are described in EP-A-568155 . For example 2, 4, 6-t r;; o~lnrhpnnyy-2-octane, 2, 4, 6-trin~lnph~nm~y-2-butane, 2, 4, 6-tr;n~lnphPnn~y-2-hexane and 4-;n~lnrh-~nn7~y-2-octane are described thereir~.
Preferred contrast agents of type (2) have the f ormula: OR
wherein R is a secondary alkyl group onnt;l;n1ng from 4 to 8 carbon atoms.
The most pre~erred contrast agent of type (2) is the sec-octyl ether of 2,4,6-tr;;orlnrhonnl having the f ormula:
5U8STITUTE SHEFr (RULE 26) WO95/22995 ~ Si r~ . J ~-2 1 8~089 0~
, ~1 The contrast agent~ of type (2) are 81ightly soluble in water, hav?llg a partition 50~ff;n;F~nt ecIual or greater thar 10 . T 1is degree of solubility allows the ~nr~t;nn o~ stable f~ lAtinnc in the form of -~ lR;nnc and Rllcp~,nc;onc when the f~ lAt;nn~ contain the recluisite P~iri,~nt~. The term "stable" means that there is no s~p~r~tinn of the ingredients nnntA;n~-l in the compositions af ter oral or rectal administration thereof and during r~rlinlo~ir~ min~t;on of the GI
tract. The slight 801ubility of the contrast agents in acIueous 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 colllh; l;ty, the absorption of the contrast agent into the intestinal walls is minimal which reduces the posc;h;lity of toxic side effects.
~ 'nmrm~nA~ of type (3) defined above are described in EP-A-614669. For example, 2-octyl-2,3,5-tr;nrinh,on70ate, 3,3,4,4,5,5,6,6,7,7,8,8-decafluoro-2-octyl-2,3,5-trincl-h-~n7o~te, bis (2-hexyl)-2,3,5,6-tetraiodo-ter--rhth~ tP, ethyl 3-(2-octyloxy)-2,4,6-triotlnh~on7o~te and bis (2-octyl) -2,4, 6-triodo-isnrhth;~l~te are described therein.
rc u--ds of :type (4) defined above are described in EP-A-609589. For example, 1,3,5-tri-N-hexyl-2,4,6-triiodoben7er,e, 1,3,5-triethyl-2,4,6-trii"rlnh~n7~n~, 1,3,5-tri-N-butyl-2,4,6-triiodGbt~ e, 1,3,5-tri-(4-methylpentyl)-2,4,6-tri;nrlnh,=n7ene, 1,3,5-tri-N-pentyl-SUBSTITUTE SH EET ~RULE 26) Wo 95/2299s 2 1 8 4 Q 8 9 p~ "~ c . ' i~ r! ~ ' 2,4,6-triiodobenzene, 1,3,5-tri-(3-methylbutyl)-2,4,6-triiodobenzene, 1,3,5-tri-N-propyl-2,4,6-triinflnhPn7Pnf., 1,3,5-tri-N-heptyl-2,4,6-triiodobenzene, 2-(4-iodophenyl) nonane, 9- (p-iodophenyl) -10-~nrlPcpnni c acid, ethyl ester and (E) -11- (p-iodophenyl) -9-~nflf~cf~nnic acid, ethyl ester are described therein Compounds ~ of type ( 5 ) def ined above are described in EP-A-614670 . i Fpr example, the bis- (4-iodophenyl) ether o~ polyethylene-glycol-400, 1, 8-bis-O- (2, 4, 6-tr; i nr~nrhPnyl) -tripropylene glycol, 1,11-bis- (2, 4, 6-t~;;nflnrhPnn~y)-3,6~9-t~;n~AllnflPrAnp~ 1,2-bis-(2,4,6-triiodophenoxy)-ethane, the bis-o-(2,4,6-tr;;nflnrhPnyl) ether of polyethylene glycol 400, 1- (3-;nrlnrhPnn7~y) _ 3,6,9-tr;n~AflPrAnP, 1,3-bis-(2,4,6-tr;;nrlnrhf-nn~y)-butane, 1-(3-inflnrhPnn~y)-6-(2~4l6-tri;nflnrhpnn~y)-hexane and 1ll2-bis-(2~4~6-triiodophenoxy)-flnrlprAnp are described therein.
flC of type (6) defined above are described in EP-A-617970. For example, 2~4~6-tr;inr~nphpnyl 2-ethyl hP~Annate, 2, 4, 6-triiodophenyl 2-methyl rpntAnnAtp, 2, 4, 6 - tr;; nflnrhPnyl 3 - cyclopentyl propionate, 2, 4, 6 -triiodophenyl (2-propyl)pPnt~nnate, 2,4,6-tr;;nflnrhPnyl perfluoroheptanoate, 2,4,6-tr;;mlnphPnyl-tris- (2-ethyl) -hPl~AnnAtP, 2~4~6-tri;oflnrhpnyl dodecanoate, 3-trifluoro-methyl-2, 4, 6-tr;; n~lnrhPnyl 2 -ethyl hP~AnnAte, 2, 4, 6-triiodophenyl-bis- (2-methylpentanoate), 2, 4, 6-triiodophenyl hexanesulfonate, 2,4, 6-triiodophenyl heptanesulfonate and 2,4,6-tr;;nflnrhPnyl decanesulfonate are described therein.
Compounds of type (7) de~ined above are described in EP-A-609587 . For example, 2- (4-inflnphPnn~y) -decane, 2-(2,4,6-triioflnrhPnn~y) -rfntilflPrAnP, 2- (2,4,6-tr; i nrlnrhf-nn~y) decane, (2, 4, 6, -triiodophenoxy) -lH, lX, 2H, 2H-perflurooctane, 1- (2, 4, 6-triiodo-3 -SUBSTITUTE SHEET (RULE ~6) W0 95l2~995 , ~ 4 0 8 q F~ ~

trif luorophenoxy~ octane, 2 - ~ 2, 4, 6 - tri i ntlnphPnn~ y) -nonane, 2-ethyl-1- (2, 4, 6-triiodophenoxy) -hexane, 3, 3-diphenyl-l- (2,4, 6-triiodophenoxy)propane, 3- (2,4, 6-triiodophenoxy) -nonane, 2- (4-intlnrhpnn~ry) -undecane, 2-in~1nrhPnn~tycyclnppntAnpl 3-intlnrhPnn~ycyclopentane, (3,5-dimethyl-2,4,6-tr;ot1nrhPnt~`~vrlnr~-ntAnt~, 2-(4-iOdophenoxy)-ppnt~tlprAnpl 4-int~nrhPnr~-cyrlt-pPntAnt,, 2,4,6-triiodophenoxycyrlnpPntAnP, 2,4 t.-triint~nrhPnn~y_ methylcyrlnpPntAnPl 2-(2,4,6-triio~t.~pl~,Pnoxy)ethyl-cyclopent_ne, (ElE)-l-(2l4l6-t~;;ntlnr~pnn~ty)-3l7lll-trimethyl-2,6,10-t9ntlP~Atriene, 1- (2l4l6-tr;;o~lnrhpnn~y) -3,7-dimethyl-6-octene, (B)-1-(3,5-dimethyl-2,4,6-tr; i nt9nFhPnn~ty) - 3, 7 -dimethyl -2, 6-ortAtli PnP, (B) -1-(2,4,6-trintlnrhPnn~y)-3,7-dimethyl-2,6-octadiene, 1-(2, 4, 6-tri; ntlnrhPnn-~y) -3-octyne, 2- (2, 4, 6-triiotlnphPnn~ty) -4-octyne, 1- (2, 4, 6-triiotlnrht~nn~-y) -3-octyne, diethyl 2-(2,4,6-tr;;o~lnrhPnn~ty)-1,3-prorAnPtl;nAte, diisopropyl 2-(2l4~6-~r;;t~tlnrhpnn~ty)-l~3 proFA n Ptl; t~:q t e, ethyl 2, 2 - bi s - ( 3 - i odophenoxy ) ace tat e, ethyl 5-(2,4,6-tr;;nt1nrht~nn~y)hp~nnatpl 5-(2,4,6-tr;; ntlnrhPnn~ty) -hexan-l-ol, 10- (4-; ntqnrhPnn ty) -undecan-l-ol, ethyl 5-(2,4,6-tr;;t~tlnrhPnn~y)hexyl carbonate and ethyl 10- (3-intlnrhPnn~y) -llnt~PrAnn~tP are described therein .
Compounds used in the compositions of type (8) defined above are non-rAtl;oa~t;ve and exist as a discrete, crystalline phase of an organic substance.
The crystalline phase differs from an amorphous or Don-crystalline phase which results from solvent precipitation techniques such as described in U. S .
Patent 4, 826, 689. The organic substance can be present in one or more suitable crystalline phases. The invention can be practiced with a wide variety of crystalline, non-rAtl;oArt;ve x-ray contrast agents.
However, the x-ray contrast agent must be poorly soluble and dispersible in at least one liquid medium. By SUBSTITUTE SHEET (RULE 26) wo gs/22995 ~ ~ ~ 2 1 8 4 0 8 9 : ~

"poorly soluble", it is meant that the agent has a solubility in the liriuid dispersion medium, e.g., water, of les6 than about 10 my/ml, and preferably of less than about 1 mg/ml.
The x-ray contrast agent can be an ;nr9;n~tP~l comround. Tlle; n~; nAterl compound can be aromatic or nonaromatic. Aromatic rnmrolln~lc are preferred. The ;nr~;n~tell compound can comprise, one, two, three or more iodine atoms per molecule . Pref erred species contain at least two, and more preferably, at least three iodi~e atoms per lPrllle The ;r~fl;n~ted compounds ~PlPctP~l can contain 8ubstituents that do not impart solubility to the cn~?l~nfl, such as, f or example, alkylureido, alkoxyacylamido, hydroxy~rPt~~; ~ n ~ butyrolactamido, ~rrin;m;~ln, trifluorn;lrptAm; ~ln~ carboxy, r;~rhnY lm;~n, hydroxy, alkoxy, acylamino, and the like substituents.
A preferred class of contrast agents ;nrlllt9P~:
various esters and amides of ;nfl;n~tP~ aromatic acids.
The esters preferably are alkyl or substituted alkyl esters. The amides can be primary or secondary amides, pref erably alkyl or substituted alkyl amides . For example, the contrast agent can be an ester or amide of a substituted ~r;;nflnhpn7o;c acid such as an acyl, carbamyl, and/or acylmethyl substituted triiodobenzoic acid. Illustrative representative examples of in~;n~tPr9 aromatic acids include, but are not limited to, tr; 7nj r acid, metrizoic acid, iothalamic acid, trimesic acid, urokonic acid, ioxaglic acid (hexabrix), ioxitalamic acid, tetraiodotPrPrhth~l; c acid, ; nA;r~m;liP, icarmic acid, and the like.
Many of the ;n~;n~tPrl -lPrlllP~ described above, if in monomeric form, can also be prepared as dimers ( sometimes ref erred to as bis compounds ), trimers (80metimes referred to as tris compounds), etc., by techni~ues known in the art. It is contemplated that this invention can be practiced with poorly soluble-iodinated compounds in monomeric, dimeric, trimeric and SUBSTITUTE SHEET (RULE 26) .

~ Wo gs/22s95 ~ 0 8 q I . ~.s ~ - -polymeric f orms .
Classes of preferred contrast agents have the following structural formulae:
A. O
C-R
CH3--C--H~ C--G~3 [diatrizoate]
B. I
CH3--C--HNXX ~ NH CH3 [1~ 1 . ]

SUBSTITUTE SHEET (RULE 26) WO 95/22995 _ r~ 8 ~ ~ ~ 9 P~

C. 1l C-R
l )~( NH--C--CH3 n o NH--C--(CH2),, --C--N
r,~]

SUBSTITUTE SHEET (RULE 26) Wo95l2299s ! ' ~ r~ J ` r~ D7- ~, - 2t~4~

n the above structures R can be ORl, NR2R3, alkylene,-CO.ORi or -O-alkylene-CO.ORl wherein Rl is alkyl, and R2 and R3 are innPrPn(iPntly E~ or alkyl.
Bach alkyl group can independently contain from 1-20, preferably 1-8, and more preferably, 1-4 carbon atoms .
The alkylene group preferably r-nnt~;nc from 1 to 4 carbon atoms such as methylene, ethylene, propylene and the like.
Particularly pre~erred contrast agents include the ethyl ester o~ diatrizoic acid, i . e ., ethyl 3, 5-diacetamido-2,4,6-tri;n~lnhPn7oate, al60 known as ethyl 3, 5-bis (acetylamino) -2, 4, 6-tr; n~inhPn7n~tP or ethyl diatrizoate, having the structural formula A above wherein R=-OCE~2C~3; the ethyl glycolate ester of diatrizoic acid, i . e ., ethyl (3, 5-bis (acetylamino) -2,4,6-tri;r~lnhpn~7oyloxy)acetatel also known as ethyl diatrizoxyacetate; and ethyl 2-(3,5-bis(acetylamino)-2,4,6- tr;; n~nhPn ~oyloxy)butyrate, also known as ethyl 2-diatriz~,~yl,uLyLclte .
In ~ ;t;nT-, the invention can be practiced in conjunction with the water insoluble iodinated r;~rhnn::ltP
esters described in PCT/EP90/00053.
The above described x-ray contrast agents are known , ~,ulld~ and/or can be ~L~ aL~d by techniques known in the art. For example, water-insoluble esters and terminal amides o~ acids such as the above-described ;n-9;n~t~1 aL~ tir acids can be prepared by ConvPntinn?l alkylation or ~ t;nn tPrhnirlllPc known i~ the art.
The above-noted acids and other acids which can be used as starting materials are commercially available and/or can be prepared by techniS~ues known in the art.
The particles useful in the compositions o~ type (8) defined above include a surface ~; f;Pr. Surface modifiers useful herein physically adhere to the sur~ace of the x-ray contrast agent but do not chemically react with the agent or itself. Individually adsorbed SUBSTITUTE SHEET (RULE 26) Wo 9s/2299s ~ 2 1 8 4 ~ 8 9 . ~ II~Jb:~S, molecules of the sur~ace modifier are essentially _ree Of ;ntPrmnlPcular crosslinkages. Suitable surface modifiers can be selected from known organic and inorganic pharmaceutical excipients such as various polymers, low-molecular weight oligomers, natural product s and surf actant s . Pref erred surf ace - - i f i Prc include nonionic and anionic surfactalts.
Representative examples of surface mn~l;fiPrs include gelatin, casein, lecithin (phosphT;tides), gum acacia, cholesterol, tragacanth, stearic acid, bPn7~lknnillm chloride, calcium stearate, glyceryl monostearate, cetoste~ryl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan f atty acid esters , e . g ., the commercially available Tweens, polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcPll-llnse calcium, ~:~L~ul~yl thylcpllllloce sodium, methylcPlllllr,cP, l~y~lLuJLyr~thylcellulosel hy~lLulLy~!Lu~ylcellulose, I~yuLu~y~uLu~ylmethycellulose phthi~l ~tP, noncrystalline rf~lllllnce, ~--gnPcillm Alllmimlm c;l;c~tP~ triPth~nnl~m;np~
polyvinyl alcohol, and polyvinylpyrrolidone (PVP) Most of these surface modifiers are known ph~rr-- pllti cal Prrir; Pnt~ and are described in detail in the F~An~honk o~ phArmAreTTtical T~rr~ pnts~ pl-hl; chP.l jointly by the American ph~rT- cPIltical Association and The Pharmaceutical Society of Great Britain, the ph~rm~rPllti cal Press, 1986 .
Particularly preferred surface modifiers include polyvinylpyrrolidone, tyloxapol, p91, rs such as Pluronic F68 and F108, which are block copolymers of ethylene oxide and propylene oxide, and pnlnY~m;nP~ such as Tetronic 908 (also known as PolnY-~;np 908), which is a tetraf~lnrt~nn~l block copolymer derived ~rom sequential addition o~ propyleTle oxide and ethylene SUBSTITUTE SHEET (RULE 26) WO 95/22995 ~ 2 1 8 Q 8 9 oxide to ethylF~nPt~ npl available from BASF, dextran, lecithin, dialkylesters of sodium sulfosuccinic acid, such as Aerosol OT, which is a dioctyl ester of sodium sulfosuccinic acid, available from American Cyanamid, Duponol P, which is a sodium lauryl sulfate, available from DuPont, Triton X-200, which is an alkyl aryl polyether sulfonate, available from Rohm and llaas, Tween 80, which is a polyoxyethylene sorbitan fatty acid ester, available from ICI Specialty rhPm;~,t1~, and Carbowax 3350 and 934, which are polyethylene glycols available from Union Carbide Surface modifiers which have been found to be particularly useful include Tetronic 908, the Tweens, Pluronic F-68 and polyvinylpyrrolidone Other useful surface ~ ;f;Pr~ include:
decanoyl-N-methylgl llr,tm; ,1P;
n-decyl ~-D-glucopyranoside;
n-decyl~l~ -D-maltop~:~anoside;
n-dodecyl ~-D-glucopyr,tnr,s;rlP;
n-dodecyl ~-D-maltoside;
heptanoyl-N-methylgl llt ' t1P
n-heptyl ~-D-glucopyranoside;
n-heptyl ~-D-thiog~-oside;
n-hexyl ~-D-glucop~ noside;
nonanoyl -N-methylglacamide;
n-nonyl ~-D-glucopyranoside;
octanoyl-N-methylgl~tr~m; .1P;
n-octyl ~-D-glucuuyL~.oside;
octyl ~B-D-thioglucopyrlnnsltlt,;
and the like A particularly preferred class of surface m~rlif;er~
;nrlutlP~: water-soluble or water-dispersible compounds having the f ormula ~CONCH2(~
CONCH2( ,'T~ T, 1.2 SUBSTITUTE SHEET (RULE 26) WO 95/22995 ! ~ S~ 2 1 8 4 0 8 9 F~ o wherein (CH2),- /=<
(cH2)b R-L'~ or R L'~
L' is a rhPmir~l bond, -O-, -5~ H-, -CONH- or -SO2~-;
R is a hydrophobic substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted aryl group;
each of R1 and R2 ;n~PrPn-7Pntly is 11YdL~ 11 or an alkyl group having from 1 to 4 carbon atoms;
each of a and b i n~PrPn~7Pn~ 7 y is 0 or an integer from 1 to 3, provided that the sum of a and b is not greater than 3; and, each of x and y ;nAPrPnflPnt1y is an integer from 3 to 7.
Preferred ~ _ ~c within this class conform to the above structure wherein R contains from 6 to 36 carbon atoms, for example, R is an n-alkyl group rnntA;n;ng from 6 to 18 carbon atoms, each of R1 and R2 independently is a methyl, ethyl, propyl or butyl group and a is 0 and b is 0. This class of surface mn~7;f;PrS
is ~7P~rr;hP~7 in U.K. Patent App1;~t;nn No. 9104957.7 filed March 8, 1991 and can be ~JLL~JdL~d by reacting an appropriate ~7; r~rhnl~ylic acid e8ter ~ith an appropriate n5~-rrh~ride amine, preferably in the absence of a solvent, at a reaction temperature from 140 to 200'C.
The surface mn~7;f;PrS are commercially available and/or can be prepared by terhn;rl~lPc known in the art.
Two or more surface modifiers can be used in SUBSTITUTE SHEET (RULE 26) Wo 95l22995 ~ Q~ ~ C~ 2 1 8 4 ~ 8 9 r ~ 111 jD7511 combination The particles useful in the compositions of type ( 8 ) def ined above can be prepared in accordance with the wet grinding process described in U. S . Patent No .
5 ,145, 684 . The process comprises dispersing a poorly soluble x-ray contrast agent in a liquid dispersion medium and wet-~rin~lin~ the agent in the presence of grinding media to reduce the particle size of the contrast agent to an effective average particle size of ~rom about 0.05 11 to about 100 /1, preferably of from about 0.05 /1 to about 5 ~1 and most preferably from about O.1 ,u to about 1 1l. The particles can be reduced in size in the presence of a surface ' f;l~r.
Alternatively, the particles can be rnnt~rtPci with a surface ~n~if;~ after attrition.
As used herein, particle size refers to a nu~Dber average particle size as measured by conv~nti nn;~l particle size measuring techniques well known to those skilled in the art, such as s~ tion field flow fr::lrtinn~tinn, photon correlation spectroscopy, or disk centrifugation. By "an effective average particle size of from about 0.05 ~L to about 100 ~1ll is meant that at least 90~ of the particle6 have a weight average particle size of from about o . 05 11 to about 100 11 when measured by the above-noted techniques. The particle size range allows sufficient number of particles ' distribu~ion in the filn forming composition when the GI
tract is coated therewith, yet insures against absorption through the intestinal walls.
The water-insoluble in~lin~t~fl polymeric beads utilized in the compositions o~ type (9) defined above are disclosed in U. S. Patent No. 4,406,878 and also in W094/25075 .
The general structural f ormula of iodinated polymers of the invention is represented by structural formula I above. The h~rkhnn~ chain of the iodinated SUBSTITUTE SHEET (RULE 26) W09sl2299s ~ Q t~ ~; 2 1 84~89 P~ 7 ~ - 0 - 2~ -polymer can reprebent:
(i) a condensation polymer such as a polyester, polyamide, polyurethane, polycarbonate, polyepoxide, polyether, a phenol-fnrr~ Phyde polymer and equivalent rnn~lPn~:At; nn polymers;
(ii) an addition polymer produced by the polymerization of one or more addition polymerizable mnn( b rnnt;~;n;n~ a polymerizable unsaturated double bond, e.g., vinyl monomers, inrlllrl;ng such additi~on~
polymers as poly (vinyl alcohol), poly(alkylmethacrylates), poly(alkylacrylates), and equivalent addition polymers; or (iii) a naturally occurring polymer, for example~ a polysaccharide rnntAininr~ repeating glucose units such as starch, glycogen, cellulose, rplllllo~ic derivatives, and e~uivalent n~tllrAlly occuring polymers.
Preferably, rPrPAt;n~ units A of formula I
represent the residue of a rl~rPAtin~ unit having an ArrPn~Pr~ hydroxyl group, such as the repeating unit of poly (vinyl alcohol), the rPrP~tin~ epoxy unit of a polyepoxide, the repeating unit of a hydroxylated acrylic polymer such as poly (hydroxyet~ylacylate), or the repeating glucose unit of a naturally occurring polysaccharide. The appended hydroxyl group can serve either as a cros~l inkin~ site or as a reaction site for precursor compounds of the organic moiety X in f ormula I. Such precursor compounds can be chemically linked to the repeating units o~ the polymer backbone chain through a rnnrlpnl~At; nn reaction with the appended hydroxy group.
The organic moiety X of formula I above represents an iodine-cnntA;nin~ organic fragment comprising an inrl;nAte-l aromatic group and one or more hydrophilic groups. To obtain the high iodine content characteristic of the polymers used in the invention, the i nrlinAtPd aromatic group have multiple iodine substituents bonded directly to the aromatic carbon ring SUBSTITUTE SH EET (RU LE 26) Wo9~22995 . ,.~f ~ 2 ~ ~4089 ~ 5~; -atoms. Especially preferred among these iodinated aromatic groups are aromatic groups rnntA;ning three, preferably four, carbon ring atoms substituted by iodine. A preferred ;nrl;nAtPr~ aromatic group is an inrl; ~Ate~l phenyl ring, although napthyl rings and itrogerl-rnntA;n;ng heterocyclic rings rnn~A;ninrj 5 to 7 ring a'_oms can also be used. An especially preferred iod~ lated aromatic group is a phenyl ring bearing iodine Rubstituents on a 4 of the carbon ring atoms.
The hydrophilic group(s) of X are typically present c15 a substituent(s~ bonded directly, or indirectly through a chemical linking group, to one or more of the carbon ring atoms of the ~ inAtPd aromatic group.
Preferred linking groups include short chain Al irhAti c groups , e . g ., alkylene groups , amido groups and equivalent Al;rhAtiC groups, having 1 to 4 carbon atoms.
Typically hydrophilic groups can be selected from a variety of 8uch groups inrl~ inj carboxyl groups; sulfo groups; amino groups; salts thereof such as carboxylate salts, s~ on~tP salts, ;llm salts; polyols such as glucose groups; and er~uivalent hydrophilic groups.
Typically, the ~ from which the organic moiety X of formula I is derived rnntAinR a reactive group which forms a chemical linking group with the repeating unit of the polymer hArkh~nP chain. In the preferred embodiment of the invention wherein the repeating unit of the polymer hArkhr,nP chain represents the residue of a repeating unit bearing a hydroxyl group, the reactive group rnntAinP~l on the precursor of X is a group reactive with the hydroxy group. For example, the reactive group can be a carboxyl group which rnn~lPnRPR with the ArpPn~lPrl hydroxy group of the h~rkhnnP chain to form an ester group linking an iodinated aromatic moiety of the polymer h~rkhnnP A
variety of other reactive groups which react with a hydroxy group to form such chemical linking groups as ethers, amides, thioesters, rArh~nAtPR, I ~ teR, SUBSTITUTE SHEET (RULE 26) W095/22995 ~ r I S 2 ~ 8 4 ~J8 9 r~ iD7 ~ -sulfides, and equivalents, can also be used.
A partial listing of precursors for the moiety X of formula I includes, for example, 3-(3-amino-2,4,6-tr; 1 nflnrh~nyl) -2-ethylpropionic acid; 3- (3-hydroxy-2,4,6-tri;nAnrhl~nyl)-2-ethylpropionic acid; sodium 3-(3-butyrylamino-2,4,6-triiodophenyl)-2-ethylacrylate; 3,5-diiodo-4-pyridone-N-acetic acid; 3-acetamido-2, 4, 6-tri;n~lnh~n70ic acid; tetrA;nr~nphthAlic anhydride; and the like. Tetraiodophthalic arhydride can be particularly useful because of its high iodine content Based on the foregoing description,` a structural formula of certain preferred iorl;nAtecl polymers can be illustrated as ~A~
_--Rl R6~l~R3 ~ X.
R4 ~
wherein: ~
A is as def ined in f ormula I above;
X is as defined in formula I above;
L represents one of the above-described linking groups, e.g. ester, ether, amide, thioester, carbonate, r~rh~~~te, sulfide and the like; and each of Rl to R6 which may be the same or differént, represents hydLu~, an iodine-rnntA;n;n~ substituent, or a hydrophilic group-~nntA;nin~ substituent, with the proviso that the iodine content of X is from about 40 to 80 percent (based on the 1 ,~rlll Ar weight of X) .
Preferred iodinated polymers are crosslinked. This can enhance the water-; nq~l llh; 11 ty and resistance to swell properties of the polymer. Croqcl ;nk;n~ can be e~fected by incorporation of suitable crosslinking sites either on the polymer backbone chain or on the moiety X
SUBSTITUTE SHEET (RULE 26) ~ W0 9512299~ 2 r ~

or both. For example, in a preferred embodiment wherein the polymer contains a repeating backbone unit bearing an appended hydroxyl group and a fi;~lPrhAin group A
cC~ntA;ninr~ a carboxyl group as a hydrophilic yroup, a hydroxyl group appended to the hArkhnnP chain of one polymer can rt~' with the carboxyl group Att-Arhp~i to the siriPrhAin X of anot~er polymer, thereby crnS~:linking the two polymers thro ~gh an ester linkage.
me polymer-i- cLntrast agents of the invention contain both .Iydrophllic and hydrophobic groups.
, bac~-~bone units A of ormula I are substAntiAlly .~ydrophobic as are many portions of the moiety X. Of -ourse X also cnntri;nc one or more hydrophilic groups. This co~m~bination of hydrophobic and hydrophilic groups is believed important to provide the proper polymer sur~ace and electrical characteristics which, in turn, provide proper polymer L, ~;hil1ty with body organs and tissues.
me iodinated polyiners can be ~Le~w~e;l by any of a variety of convPnt;nni~l polymerization and chemical reaction tp~hn; ~lPC . A preferred reaction sequence is to rhPm;rAlly react precursor ~ '- for the side-chain group X with a preformed polymer rnntA;n;n~
ArpPn~lPrl groups serving as suitable reaction sites, e . g ., hydroxyl groups . The pref ormed polymer can be prepared by addition or snn~lpni At;nn poly - ~at; nn, ;PrPnri;n~ on the polyiner; or it can be obtained from naturally n~rllrr; ng sources in the case of naturally occurring polymers; e . g ., polysaccharides . The precursor rn~ro1~nrl~ for the moiety X can be reacted with the reaction site on the polymer hArkhnnr~ by a variety of well-known reaction procedures, ~iPrPn~l;n~ on the nature of the linking group 1:. in formula II above which is formed in this reaction. Advantageously, the reaction of these precursor compounds is carried out under emulsifying conditions so that the resultant polymers are obtained in finely-divided particulate SUBST~TUTE Sl IEET (RULE 26) 21 84û89 WO 95122995 ~ , h ~! ~ S 3~._1Aib~

form. crosslinking can be carried out during or following attachment of the moiety X of the polymer bA rkhnn~ .
An example o~ a polymer based on poly(vinyl alcohol) and tetrAi prlnrhthA1; c acid ls deæcribed in W094/25075 mentioned above. ~
Having obtained a water-;nqnll-hl~ and non-water-swellable iodinated polymer as described above, the polymer can be subjecte~ tp grinding or milling treatment to obtain polymer Farticles of the appropriate 3ize range. Of course, in cases where the polymers are prepared under suitable rnY~l; ti nn~, such as bead polymerization or emulsifying conditions, the polymers may already have an appropriate particle size so that additional milling or grinding may be unnecessary. A
useful particle size for these polymer particles is within the range of from about 0 . 01 to 1000 microns, preferably 0.1 to 100 microns.
The preferred barium salt (the co~trast agent o~
type (10) tlnnPfl above) i8 barium sulfate which is a white, ratli nrA'rlP, crystalline powder that is essentially insoluble in water. It is commercially available i~ the particle size range of 0 . 001 to 0 .1 micron diameter. EIowever, good results are obtainable with other finely-divided, inorganic, essentially water-insoluble salts of barium inrl~ ;n~ barium hexaboride, barium chromite, barium fll-o~ Ate, barium tri-ortho rhn~rhAte, barium metasilicate, barium titanate, barium zirconate and zirconium oxide. The compositions of the present iLvention contain from about 5~6 w/w to about 9 w/w of the barium salt. The compositions may be in the form of dispersions, colloids or suspensoids, however, we prefer to use colloids as the preferred embodiment.
The contrast ager,ts used in the invention may be formulated for administration~using physiologically SUBSTITUTE SHEET (RULE 26~

W0 95/22995 ~ h ~ ~ C~ ~ f 8 4 ~ ~ 9 Pl l,~,.,,'.`l acceptable carriers~ or excipients in a manner within the skill of the art. ~he rAmro~ with the addition of pharmaceutically acceptable aids (such as surfactants and emulsifiers) and excipients may be suspended or partially dissolved in an a~ueous medium resulting in a dispersion, solution o~ s,.3pension. Xowever, the oily contrast agents are pre~erably m~lde into emulsions.
Compositions of the p--o~ .nt invention llt; I i ~;ng contrast agents of typf~s (1) .o (~) defined above comprise the following rh~rr~~r~lt1rAlly acceptable A~te based on ~ w~v:
~ore Most In. r~ q r - p,.. ~ Pr~rred P~ e Pref~r.-ed p~nr~
ContraGt agent 30 - Z00 40 - 160 as - 120 (mg I/ml of total q-lq}lf~nqinn) Cellulose derivative 0.0s - 10 0.1 - 4 0.2 - 1 ( ~ w/v) OLly Vehicle 0 . 0 - sS 0_1 - 25 7 - lS
( ~w/v) .s--rfArtAnt 0.0 - 20 0.1 - 10 3 - 7 ( ~ w/v) Visoosity modifying 0.0 - lS. 0.001 - 4 0.05 - 1 ~rrir~rntA (~6 W/V) Water - q.s. to 100~ by volume Compositions of the present invention lltili~;ny contrast agents of type (9) defined above comprise the following rh~ rel~tl r~l ly acceptable components based on ~6 w/v:
SUBSmUTE SHEET(RULE 26) WO 95122995 . ~ 2 ~ 8 ~ ~ 8 9 1 ~ J5 C - ~

Tn~rerl~n~q ~rr-~ P~re PrDfPrrP~I p~.. nD
Iodinated Polyeric Beads 5 - 95 20 - 70 (~ w/v) Cellulose derivative 0.05 - 10 0.1 - 4 ( ~ w~v~
Cllrf~r~:~n~ 0.1 - 20 3 - 7 ~ w~v) Viscosity modifying 0.001 - 4 0.0s - 1 ~Yr~riPnl~q (% W/V) Water - q.s. to 1009~ by volume Compositions of the present invention llti1ici barium salts comprise the following IlhAr~r~llt;~lly acceptable c., ^nt~ based on 96 w/v:
Inr r~ rr~l T' PrefDrr~.~l p:~nr~.
Barium S~lt (w/v) 5 _ 95 40 _ 70 Cellulose derivative 0.1 - 10 0.2 - 1 ( ~ w/v~
Oily Vehicle 0.1 - 55 7 - 15 ( ~ w/v ) Surf~ct~nt 0.1 - 20 3 - 7 ( ~ w/v~
Viscosity modifying 0 . 001 - 15 0 0s - 1 P~rrl r~ Pnr q ( ~ w/v) W~ter - q.s. to 100% by volume When the composition is used for CT imaging o~ the GI tract, the ~nnr;~ntr~tinn o~ the x-ray contrast agent should be in the range of from 0.01 to 40 mg I/ml, more preferably of from 0.25 to 25 mg I/ml and most preferably of from 4-12 mg I/ml.
The preferred cellulose derivative llt; 1 i 7~1 in the present invention is AVICEL0 RC-591, which is a mixture of about 89 parts microcrystalline cellulose and about 11 parts of sodium carboxymethylnP~111l1O~e.
In further reference to the r, ^ntc used in the SUBSTITUTE SHEET (RULE 26) Wo 95l22995 ! ~ f~ 2 1 8 4 0 ~ 9 compositions of the present invention the following should be noted.
The x-ray contrast agent present in rnnrPntr~ti ons lower than the above-stated minimum in formulations does not provide good quality x-ray or CT imagP, ~ile rnnrPntratiOnS above the maximum rnnrPntr~r-on re~lder the GI tract too radiopaque and do not allow sltf ficient ~lPl;nP~tinn of t P GI tract.
In practicing the present inventio- ah oil-in-water Pm~ inn is pre~erred over a wa_er-i..-oil emulsion, suspension and dispersion. C~ tPriAlc, the density of which approximate the df~nsity of the ariueous phase impart stability to en~~ cions. For that reason low density oils, such as mineral oils, are desirable in preparing the: l¢jnnc. When the x-ray contrast agents are oily 6ubstances at room temperature, the presence of an additional oily vehicle is not always nPrPcq;-ry Above about 55~S W/V of oil the emulsion is no longer an oil-in-water: l ci nn but shifts to a water-in-oil: l Ainn .
Compositions without the presence of surfArt~ntc still provide PYrPl l Pnt x-ray images, however, without surfactants the rn-~ros;tinnc are very difficult to emulsify and only susppn~innc/dispersions are produced which are less tlPq; r~hl e for coating the GI tract and are also less stable on shelf-life. For reason of toxicity it is ~gPc; r~h~ e to keep the concentration of certain surf~rt~ntc as low as pnqcihle; above about 2096 w/v the risk of toxicity rapidly increases.
While the various types of , 'c used in the present invention in f. l:~t;onS with a r)h~rr~rPut; cally acceptable vehicle provide good o~uality x-ray images, the addition of a cellulose derivative to the formulations greatly increases the riuality of the x-ray images. At the low extreme of the concentration range there is little or no benefit gained, while above the higher e~treme of the rnnrpntration range the SUBSTITUTE SHEET(RULE 26) -W095/2299~ r~ 21 84089 ~ 5~- 0 emulsion is too viscous for administration.
Depending on the ~orm and amount of ~Plillloqe derivative used, additions of viscosity modifying, agents may not be necessary; at higher levels than about 15 w/v the viscosity is too high and gels will ter,d to f orm .
The following f~ tinn examples will further illustrate the ipvention E le 1 C ts ,~ nlnt~: in ~ w/v N-acetyl-N-2-octyl-4-;otlrl~n;l;nP 17.50 Light Mineral Oil, NF 12.50 Polysorbate 80 (Tween 80) 3.37 Sorbitan Mono-oleate (Span 80) 1.64 AVICEL<D RC-591 0 . 50 q. S . with water to 1009~ by volume r l~ 2 C ~nPnt~: ~m~nlntS in ~ w/v N- (4 ' -iodophenyl) -2-amino octane 25 . 00 (oil at room t~ ~ tllre) Polysorbate 80 (Tween 80) 5.00 AVICEL RC-591 6.50 q. s . with water to 10096 by volume le 3 C ^nts ,~mount~ in ~ w/v 2, 4, 6 -Tr;; nflr~hPn~fy- 2 -octane 14 . 50 I,ight Mineral Oil, NF 12.50 Polysorbate 80 (Tween 80) 3.37 Sorbitan Mono-oleate (Span 80) 1.64 AVICE~ RC-591 o . 50 q. s . with water to 1009~ by volume SUBSTITUTE SHEET (RULE 26) WO 95/22995 ~ J ~ ~ t g 4 0 8 9 . ~

r le 4 C nnPnts A~ ts in ~ W/V
2,4,6-Tr1;otlnphPno~y-2-butane 17.00 Polysorbate 80 (Tween 80~ 5 . 00 AVICE~ RC-591 6.50 .s. with water to 100~ by volume F le 5 Cn~onPnt~: A~nm~nt~ in 2, 4, 6 - Tr;, n~ nFh Pn n~y - 2 -hexane 2 5 . 4 0 AVICELI RC-591 10 . 00 q. 5 . with water to 100~ by volume r 1~ 6 t' ~nt~ ~ ts in 9~ w/v 4-TorlnrhPnn-~y-2-oCtane 30 . 00 Light Mineral Oil, NF 2 0 . 5 0 Polysorbate 80 (Tween 80) 3.00 AVICEL~> RC-591 0.15 q . s . with water to lO09~ by volume r le 7 C onPntq Amnunts in 96 w/v 2 -Octyl-2, 3, 5-t~;; nflnhPn7nAtP 17 . 50 Light Mineral Oil, NF 12.50 Polysorbate 80 (Tween 80) 3.37 Sorbitan Mono-oleate (Span 80) 1. 64 AVICEL~ RC-591 0 . 50 q. s . with water to 100~ by volume SUBSTITUTE SH EET (RULE 26) WO 9sl22995 ; ~ ~ 0 r le 8 C -ntS ~ nts in ~ W/V
3,3,4,4,5,5,6,6,7,7,8,8-Dodecafluoro- 25 00 2 - octyl - 2, 3, 5 - triiodnhpn 7n;3 te Polysorbate 80 (Tween 80) 5 00 AVICEL~' RC-591 6 50 q . 8 . with water to 100~ by volume ~le 9 ~A Ant8 t ' S in ~ w/v 1,3,5-Tri-N-hexyl-2,4,6-tr;inclnhPn7pnp 17.50 Light Mineral Oil, NF ~ 12.50 Polysorbate 80 (Tween 80) 3.37 Sorbitan Mono-oleat~e (Span 80) 1. 64 AVICELa' RC-591 0 . 50 q. 8 . with water to 100~6 by volume E le 10 8 P t~ in ~ w/v 1~3~5-Triethyl-2~4~6-tr;in~lnhpn7onp 25.00 (oil at room temperature) Polysorbate 80 (Tween 80) 5.00 AVICBL~ RC-591 - 6 . 50 g. s with water to 10096 by volume E le 11 ~mT~nnPnt~ P 8 in ~ w~v 1,3,5-Tri-N-butyl-2,4,6-tr;in,lnhPn7onP 20.00 Light Mineral Oil, NF 5 . 0 0 Polysorbate 20 (Tween 20) 2.50 Sorbitan Mono-laurate (Span 20) 2.50 AVICBL~ RC-591 - 0 50 g 8. with water to 1009~ by volume SUBSTITUTE SHEET (RULE 26) Wo95l22995 ~: It!~ 8~89 r~ bis~c ~

F ~~ le 17 rnTr~;;7nnc~ntS Ar~nunts in % w/v 2, (4-Iodophe~yl) nonane 25.00 Polysorbate 20 (Tween 20) 2.5(~
Sorbitan Mono-laurate (Span 20) 2.50 AVICEL~ RC-591 0 . 75 . L . with water to 1009~ by volume r le 1~
C rmPnts ,p ts in ~ w/v Bis- (g-; o~lnFhPnyl) ether of polyethylene glycol-400 17.50 Light Mineral Oil, NF 12 . 5 0 Polysorbate 80 (Tween 80) 3.37 Sorbitan Mono-oleate ~Span &0) 1.64 AVIOEL'5 RC-591 0.50 q. s . with water to 100~ by volume r le 14 ~'nm,cnnPnts ~ ' S in ~ W/V
1, 8-Bis-O- (2, 4, 6-tr;; n~FhPnyl~ -tripropylene glycol 25 . 00 (oil at room temperature) Polysorbate 80 (Tween &0) 5.00 AVIC13L'ID RC-591 6 . 50 q. s . with water to 100~ by volume r le 1~
AnmnnnPntS }~ ~S in 96 W/V
1, ll-Bis- (2, 4, 6-tr; ;o~nrhF-nn~y) 3, 6, 9-trin~ ll-n~lPr;lnP 17 .50 Light Mineral Oil, NF 12 . 5 0 Polysorbate 20 (Tween 20) 2.50 Sorbitan Mono-laurate (Span 20) 2.50 SUBSTITUTE SHEET(RULE 26) WO95/22995 ~ Q I '1;; 2 1 8 4 089 P~ 75~ ~

AVICEL~ RC-591 o . 50 q. 8 . with water to 100~ by volume E le 1~
r~ r on ~n t c .1~ n t ~ n ~ w /v 1- (3-Iorlnphl~n~ry) 3, 6, 9-Tri~AA-~An~ 25 .~0 Polysorbate 20 (Tween 20) 2.50 S orb i t an Mono - laurat e ( Span 2 0 ) 2 . 5 0 AVICEL'D RC-591 0.50 . s . with water to 10096 by volume r le 17 C ^-lt~ ~ ' 8 in ~ w/v 2, 4, 6-Tr;; ~dt~phF~nyl 2 - ethyl h l'~A n rl;l t " 17 . 5 0 Light Mineral Oil, NF 12.50 Polysorbate 80 (Tween 80) 3.37 Sorbitan Mono-oleate (Span 80) 1.64 AVICEL~ RC-591 0.50 q. s . with water to 1009~ by volume r le 18 C -~ltl:: .? tE3 ;n 36 W/V
2, 4, 6-Triiodophenyl-tris- (2-ethyl h l'~nf)A t e ) 2 5 . O O
Polysorbate 80 (Tween 80) 5.00 AVICEL(D RC-591 6.50 . s . with water to 100~ by volume r le l9 C ^'ltS ~ ts in ~ w/v 2, 4, 6-Triiodophenyl-3-cyclopentyl propionate 20 . 00 SUBSTITUTE SHEET(RULE 26) WO95122995 : f~ f~'~ Z~8 ~f Q89 r.~ r'~
l:ight Mineral Oil, NF 12.50 Polysorbate 20 (Tween 20) 2.50 Sorbitan Mono-laurate (Span 20) 2.50 AVICEL~ RC-591 0.50 q. s . with water to 100~ by volume r le 20 ~mT~7on~nt~ 1` 9 ;n 96 w/v 3 -Tri~luoromethyl - 2, 4, 6 -t~;; ~Anrh~nyl-tris- ~2 -ethyl hf~AnnAte) 20 . 00 Polysorbate 20 (Tween 20~ 5.00 AVICEL'I) RC-591 1. 00 q . s . with water to 100~ by volume E lc~ 21 ^nt~ I ~ in ~ w/v 2, 4, 6-Tr;; OAophP~yl hexanesul~onate 20 . 00 Light Mineral Oil, NF 12 . 5 0 Polysorbate 80 (Tween 80) 2 . O0 Sorbitan Mono-oleate (Span 80) 1.00 AVICEL(9 RC-591 1. 00 q. S . with water to 10096 by volume r le 22 ~nnl~nt~ ~ s in 9~ w/v 2, 4, 6-Tr; i oAnE~h~n~rymethylcyclopentane 14 . 50 Light Mineral Oil, NF 12 . 50 Poly80rbate 80 (Tween 80) 3.37 Sorbitan Mono-oleate (Span 80) 1.64 AVICEL RC-5gl 0 . 50 q. s . with water to 10096 volume SUBSTITUTE SHEET(RULE 26) WO 95122995 ~ 2 1 8 4 0 8 9 ~ ib7',~ i ~

r le 23 r~ on~ntS Am~-llnts in ~ w/v 2 - (4- Io~ rh~nm y) rPnt;~ nF~ - 17 . 00 Polysorbate 80 (Tween 80) 5.00 AVICEL RC-591 - 6.50 q . s . with water to 100~6 volume E le 24 ^~tS Am~ ntc in 56 w/v 2~ rh ,~ y~:y~ rl~nt~n.~ 25 . 20 Light Mineral Oil, NF 20.50 Polysorbate 80 (Tween 80) 3.00 AVICEL ~C-591 - 0.15 q . s . with water to 100~ volume r le 25 C ^~ts 7` ' s in ~ W/V
Ethyl 3, 5-bi6 ~acetylamino~ -2, 4, 6-tr; i o~l~lh~n~o;~te 17 . 50 Poly80rbate 80 ~Tween 80) 3.37 Sorbitan Mono-oleate (Span B0) 1.64 AVICEL'ID RC - 5 91 0 . 5 0 q.s. with water to 100~ by volume E le 26 C ^nt~ ~ml-unts in 9,; w/v Ethyl (3, 5-bis (acetylamino) -2, 4, 6-triiodo-benzoylox,v) acetate 25 . 00 Light Mineral Oil, NF 10.00 Polysorbate 80 (Tween 80) 5.00 AVICEL~ RC - 5 91 - 6 . 5 0 q. s . with water to 100~ by volume SUBSTITUTE SHEET (RULE 26) , ~w09s/2299s ~ .` 2`1 ~û8q P~

r le 27 nmn~A,n,nt~ A s in 96 W/V
~thyl 2- (3, 5-bis ~acetylamino) -2, 4, 6-triiodo-benzoyloxy) butyrate 3 0 . 00 Pluronic F-68 10 . 00 AV~C~:~e) RC-591 2 . 00 q s. with water to 100~ by volume E le 28 C~ nAntc P ' S in ~6 W/V
Ethyl 3, 5-bis (acetylamino) -2, 4, 6-tr;; tl~nhPn7oate 17 . 50 Light Mineral Oil NF 12 . 50 Polysorbate 80 (Tween 80) 3.37 Sorbitan Mono-oleate (Span 80) 1.64 AVICEL0 RC-591 0.50 q. s . with water to 100~6 by volume r l_ 29 C A_ltA ~mmlnts in %' W/V
T~ ;nAtA~ Polymeric reads 17.50 Polysorbate 80 (Tween 80) 3.37 Sorbitan Mono-oleate (Span 80) 1.64 AVICELI RC-591 0.50 q. s . with water to 10096 by volume r le 30 C nn,Ant~; Amm-nt~ in ~6 W/V
T~ ;nAtA~l Polymeric Beads 25.00 Polysorbate 80 (Tween 80) 5.00 AVICEL~ RC-591 6.50 q. s . with water to 1009~ by volume SUBSTITUTE SH EET (RULE 26) WO95/2t995 ~ t ~ 21 8 ~ 08 9 r~ O

r le 31 C nnPntS Am^llnts in ~ W/V
Iodinated Polymeric Beads 20.00 Polysorbate 20 ~Tweerl 20) 5 . 0 AVICEL~ RC-591 l . 00 q. s . with water to 10096 by volume E le 32 C~ " t s }~m^,l 7 n t s i n ~ w /v T.. ~;n~tP~ Polymeric Beads 30.00 Mineral Oil, NF 10.0a' Polysorbate 80 (Tweerl 80) 3.37 Sorbitan Mono-oleate (Span 80) 1.64 AVICEL~7 RC-591 0 . 50 q. s . with water to 100~ by volume E le 33 ^ntS ~ ' S in %~ W/V
Barium Sul~ate 17 . 50 Polysorbate 80 (Tween 80) 3.37 Sorbitan Mono-oleate ~Span 80) 1. 64 AVICEL~ C-591 0 . 50 q. s . with water to 100~ by volume r le 34 ^^m,~,.^,n~ntS ~` ts in 96 W/V
Barium Hexaboride 25 . 00 Light Mineral Oil, NF 9 . 50 Polysorbate 80 (Tween 80) 5.00 AVICEL~ RC-591 6 . 50 q.s. with water to 100~6 by volume SUBSTITUTE SHEET (RULE 26) WO 95/Z299~ 2 1 8 4 ~ 8 ~ F~ J, ~
.

E 1/~ 35 ~nmr~OnPnt~ ~nl1ntS in ~ W/V
Barium Chromite 70 . 00 I,ight Mi~eral Oil, NF 5.00 Polys~rbate 20 (Tween 20) 2.50 Sorbitan Mon~-laurate (Span 20) 2.50 AVICELI RC-591 0.50 q.s . with w-ter to~ 100~ by volume r le 36 ~O3~O~ ~-- tS in ~ W/V
Barium MP~S11; r~te 85 . 00 Polysorbate 20 (Tween 20) 2.50 Sorbitan Mono-laurate (Span 20) 2.50 AVICELI RC-591 0.75 q. s . with water to 100~ by volume E le 37 ~nm,~7onf~nrs ~ q in ~6 W/V
Barium Fluogallate 50 . 00 Mineral Oil, NF 10 . 00 Polysorbate 8 0 ( TWeen 8 0 ) 3 . 3 7 Sorbitan Mono-oleate (Span 80) 1. 64 AVIOEL~D RC-591 0 . 50 q. 8 . with water to 100~ by volume E 1~ 38 ^ntS 1~ t~ in ~ W/V
Barium Tri-orthophosphate 60 . 00 Polysorbate 80 (Tween 80) 5.00 AVICEL'9 RC-591 - 2 . 00 q. s . with water to 1009~ by volume SUBSTITUTE SHEET (RULE Z6) wo 95n299s 1 l q 1': ~ ~ t ~ 2 1 8 4 0 3 9 P~ b ' . o As known by those skilled in the art, surfactants or emulsifiers can reduce the interfacial tension between two immiscible phases, i.e., oil-in-ao,ueous medium. These agents can be used alone or in combination with other emulsifying agents and surfactants. For example, Dow Corning Medical Antifoam AF, which i5 a composition of 3096 w/v polydimethylsiloxane simethicone and silica aerogel, 145~
w/v stearate emulsifiers and 0 . 0759.i w/v sorbic acid, the balance being water, may be used by itself. TntrAl;ri~
which is an ~ml71 qi nn of fatty acids needs the presence of a SllqrPn~;n~ agent for it to form an ArrPrt~h~o 1 c; nn with contrast agents of the present invention.
The surf ace active agents may be cationic, anionic, nonionic, zwitterionic or a mixture of two or more of these agent6 .
Suitable cationic surfactants include cetyl trimethyl ammonium bromide. Suitable anionic agents include sodium lauryl .sl11rh~t~, sodium heptadecyl SlllrhAt-~, alkyl hPn7-~n~cll1rhnn;c acids and salts thereof, sodium butylnapthalene sulfonate, and sulphosllrr;n~t~q. Zwitterionic suriace active agents are substances that when dissolved in water they behave as diprotic acids and, as they ionize ~ they behave both a8 a weak base and a weak acid. Since the two chargeS
on the molecule balance each other out the 1er~ q act as neutral lF~rl71 ,~q . The pH at which the zwitterion cr/nr~ntrAt;on is maximum is known as the isoelectric point. Compounds, such as certain amino acids having an isoelectric point at the desired pH o~ the ~ 1At;nnq of the present invention are useful in practicing the present invention.
In preparing the fnl~ll At; nnc of the present invention we prefer to use nonionic emulsifiers or sur~ace active agents which, similarly to the nonionic contrast agents, possess a superior toxicological profile to that of anionic, cationic or zwitterionic SUBSTITUTE SHEET (RULE 26) WO 9s/22995 ~ - f~ t~ ~ ~ (; 2 t ~4 0 ~ 9 r.~

agents. In the nonio~nic emulsifying agents the proportions of hydrophilic and hydrophobic groups are about evenly hAlAnr~Pfl~ They differ from anionic and cationic surf actants by the absence o f charge on the molecule and, for that reason, are generally less of an irritant than the catio~ or anionic surf~rtAnts.
Nonionic surfArtAnt~ include ~arboxylic esters, carboxylic amides, ethoxylat~ ~ alky1rhPnn1 c and ethoxylated Al ;rhAt~ C a~ ~D~c s .
One particular t ~pe of carboxylic ester llr~ni nn; C
surface active agents arE the partial, for example monoesters formed by tl~e reaction of fatty and resin acids, for example of ~bout 8 to about 18 carbon atoms, with polyhydric alcohols, for example glycerol, glycols such as mono- di-, tetra- and hexaethylene glycol, sorbitan, and the like; and similar rnmrQ~n~l~ formed by the direct A~l;tinn of varying molar ratios of ethylene oxide to the hydroxy group of fatty acids.
Another type of carboxylic esters is the cnn~Pn~t;nn 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, monotall 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. ~xamples of naturally occurring fatty acid mixtures which may be used are those f rom coconut oil and tallow while ~ of sing~e fatty acids are dodecanoic acid and oleic acid.
Carboxylic amide nonionic surface active agents are the ammonia, monoethylamine and diethylamine amides of fatty acids having an acyl chain of from about 8 to about 18 carbon atoms.
The ethoxylated alkylphenol nonionic surf ace active agents include various polyethylene oxide rnntlPn~AtP~: of alkylphenols, especially the cnndpncAt;nn products of SUBSTITUTE SHEET (RULE 26) wo s~l2299~ i~ f ~ ~ ~ f; ~ 2 1 8 4 0 8 9 r~ .,~b ~
monoalkylphenols 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 cre601, octyl phenol or r,onyl phenol, with ethylene oxide, said ethylene oxide being present in amount6 er~ual to f rom about 5 to about 25 moles of ethylene oxide per mole of alkylphenol .
E3thoxylated ~1'rh~t;c alcohol nonionic surface active agent6 include the rnnrl~nqAt;on products of A1;rh~t;C 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 amount6 from about 30 to about 60 moles of ethylene oxide per mole of alcohol.
Preferred nnn;nnic surface active agents include:
Sorbitan esters (sold under the trade name Span) having the f ormula:
HO R
~CH-E~

whereir, Rl = R2 = OH, R3 = R for sor~itan monoesters, Rl ~ OH, R2 = R3 = R for sorbitan diesters, R1 = R2 = R3 = R for sorbitan triesters, where R = (CllH2l) COO for laurate, (C17X33) COO for oleate, (ClsX3l) COO for palmitate, (Cl,X3s) COO for stearate.
Polyoxyethylene alkyl ethers (i.e. Brijs) having the f ormula:
SUBSTITUTE SH EET (RULE 26) ~ WO 95122995 ~ 8 4 3 8 9 PL I, 1~

CH3 ( CH2 ) x ( O - CH2 - CH2 ) yO~
. where (x + 1 ) is the number of carbon atoms in the alkyl chain, typically:
12 lauryl (dodecyl J
14 myristyl (t~trilflPryl 16 cetyl (hexadecyl) 18 stearyl (octadecy;) and y is the number o~ eth~ e oxide groups in the hydrophilic chain, typically 10-S0.
Polyethylene sorbitan fatty acid esters, sold under the trade names o~ PO1YRnrh~t~R 20, 40, 60, 65, 80 & 85, having the fr~rr~ (l) and (2) CH~
HCO(C2H.O)~,H
H(OC2EI~OJH O (1) HC
HCO(C2H~O)yH
CH2O(C2H~O),OCB
HCO(C~H,O).,H
RCO(OCyH,~O IH O
Hf HCO(C2H~O)yOCR
CH~O(C2H~O),OCR
wherein w+x+y+z = 20 (Polysorbate 20, 40, 60, 65, 80 and 85) SUBSTITUTE SHEET (RULE 26) wo g5n299~ 2 1 8 4 0 8 9 p, ll". t - ~

w~x~y~z = 5 (Polysorbate 81) w+x+y+z = 4 (Polysorbate 21 and 61).
Polyethylene stearates r such as:
poly (oxy-1, 2-ethanediyl), -hydro-~-hydroxyoctadecanoate;
polyethylene glycol monostearate; and poly~oxy-1,2-eth~nP~1;yl) -t - (1-oxooctadecyl) -~-hydroxy-polyethylene glycol monostearate.
The dosages of the contrast agent used according to the method of the present invention will vary :~rcnrrli to the precise nature of the contrast agent used.
Preferably, however, the dosage æhould be kept as low as is consistent with achieving contrast Pnh~nrP~l im.aging.
By employing as small amount of contrast agent as possible, toxicity potential is minimi~l. 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 o~ 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 vi~ Al;7~t;nn of the GI tract. For CT scanning, the contrast agents of the present invention will be in the range of f rom 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 759~ w/v of the formulation, preferably from about 0.0596 w/v to about 5096 w/v and most preferably of from about 0.1 w/v to about 203i w/v.
SUBSTITUTE SHEET (RULE 26)

Claims (20)

CLAIMS:

1. An x-ray contrast composition for oral or retrograde examination of the gastrointestinal tract comprising:
(a) from 0.01 to 200 mg of iodine per ml of the composition of an x-ray contrast agent selected from (1) x-ray contrast producing agent having the formula or a pharmaceutically acceptable salt thereof, wherein Z is H, halo, C1-C20 alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups;
R1 and R2 are independently H, C1-C25 alkyl, cycloalkyl, acetyl or halo-lower-alkyl, wherein said C1-C25 alkyl, cycloalkyl and halo-lower-alkyl are optionally substituted with fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy, lower-alkoxy carbonyl or lower-alkoxy-carboxyloxy and said acetyl is optionally substituted with fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, lower-alkoxy carbonyl or lower-alkoxy-carbonyloxy;
n is 1-4;
y is 1-4; and x is 1 or 2;
(2) an x-ray contrast producing agent having the formula 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 C1-C6 alkyl, hydroxy and alkoxy; and n is 1 to 5;
(3) an x-ray contrast producing agent having the formula or a pharmaceutically acceptable salt thereof, wherein Z is H, halo, C1-C20 alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups;
R is C1-C25 alkyl, cycloalkyl, or halo-lower-alkyl, each of which may be optionally substituted with halo, fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy, lower-alkoxy-carbonyl or lower-alkoxy-carbonyloxy; or (CR1R2)p- (CR3=CR4)mQ, or (CR1R2)p-CC-Q;
R1, R2, R3 and R4 are independently lower-alkyl, optionally substituted with halo x is 1-3 y is 1-4;
n is 1-5;
m is 1-15;
p is 1-10; and Q is H, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower-alkyl;

(4) an x-ray contrast producing agent having the formula or a pharmaceutically acceptable salt thereof, wherein R is methyl, ethyl, n-propyl, C4-C25 alkyl, cycloalkyl, unsaturated allyl or halo-lower-alkyl, each of which may be optionally substituted with halo, fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy or lower-alkoxy-carbonyl; or (CR1R2)p- (CR3=CR4)mQ, or (CR1R2)p-CC-Q;
R1, R2, R3 and R4 are independently H, lower-alkyl, optionally substituted with halo;
n is 2-5;
m is 2-5;
p is 1-10; and Q is H, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower-alkyl;
(5) an x-ray contrast producing agent having the formula or a pharmaceutically acceptable salt thereof, wherein Z is H, halo, C1-C20 alkyl, cycloalkyl, lower alkoxy, alkoxycarbonyl, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups;

R is C1-C25 alkyl, cycloalkyl, or halo-lower-alkyl; each of which may be optionally substituted with halo, fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy, lower-alkoxy-carbonyl or lower-alkoxy-carbonyloxy; or (CR1R2)p-(CR3=CR4)mQ, or (CR1R2)p-CC-Q;
R1, R2, R3 and R4 are independently H or lower-alkyl, optionally substituted with halo;
x is 1-4;
n is 1-4;
m is 1-15;
p is 1-20; and Q is X, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower-alkyl;
(6) an x-ray contrast producing agent having the formula or a pharmaceutically acceptable salt thereof, wherein X is -CO- or -SO2-Z i H, halo, C5-C20 alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups R is C1-C25 alkyl, cycloalkyl, aryl or halo-lower-alkyl, each of which may be optionally substituted with lower-alkoxy, hydroxy, carboxy or lower-alkoxy carbonyl, lower-alkenyl, lower-alkynyl, lower-alkylene or lower-alkoxy-carbonyloxy;
n is 1-4;
y is 0-4; and w is 1-4;

(7) an x-ray contrast producing agent having the formula or a pharmaceutically acceptable salt thereof, wherein Z is H, halo, C1-C20 alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups;
R is methyl, ethyl, propyl, C9-C25 alkyl, cycloalkyl, or halo-lower-alkyl, optionally substituted with halo, fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy, lower-alkoxy-carbonyl or lower-alkoxy-carbonyloxy; or (CR1R2)p- (CR3=CR4)mQ, or (CR1R2)p-CC-Q;
R1, R2, R3 and R4 are independently lower-alkyl, optionally substituted with halo;
x is 1-4;
n is 1-5;
m is 1-15;
p is 1-10; and Q is H, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower-alkyl;
(b) from 0.05 to 10% w/v of microcrystalline cellulose;
(c) from 0 to 55% w/v of an oily vehicle;
(d) from 0 to 20% w/v of a surfactant selected from the group consisting of nonionic, anionic, cationic and zwitterionic surfactants;
(e) from 0 to 15% w/v of a viscosity modifying excipient; and (f) water to make 100% by volume.

2. The x-ray composition of claim 1 wherein said x-ray contrast producing agent is present in an amount of 30 to 200 mg of iodine per ml of the composition.

3. The x-ray contrast composition of claim 1 wherein said oily vehicle constitutes from 0.1 to 25% w/v of the composition.

4. The x-ray contrast composition of claim 1 wherein said surfactant constitutes from 0.1 to 10% of the composition.

5. An x-ray contrast composition for oral or retrograde examination of the gastrointestinal tract comprising:
(a) from 40 to 160 mg of iodine per ml of the composition of crystalline contrast agent selected from the group consisting of diatrizoic acid, metrizoic acid, iothalamic acid, trimesic acid, urokonic acid, ioxathalamic acid, tetraiodoterephthalic acid, ioxaglic acid, iodipamide, ethyl-3,5-diacetamido-2,4,6-triiodobenzoate, ethyl-2-(3,5-bis(acetylamino)-2,4,6-triiodo-benzoyloxy)butyrate, and ethyl(3,5-bis (acetylamino)-2,4,6-triiodobenzoyloxy)-acetate, said crystalline contrast agent having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of from about 0.5 µ to about 100 µ; and said surface modifier is selected from the group consisting of tetrafunctional block copolymers derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine;
(b) from 0.1 to 4% w/v of microcrystalline cellulose;

(c) from 0.1 to 25% w/v of an oily vehicle;
(d) from 0.1 to 10% w/v of a surfactant selected from the group consisting of nonionic, anionic, cationic and zwitterionic surfactants;
(e) from 0.001 to 4% w/v of a viscosity modifying excipient; and (f) water to make 100% by volume.

6. An x-ray contrast composition for oral or retrograde examination of the gastrointestinal tract comprising:
(a) from 5 to 95% w/v of iodinated, polymeric, water-insoluble beads having a particle size of from about 0.01 to about 1000µ wherein said iodinated polymeric beads comprise a polymer containing repeating units of the formula (I) I
wherein A is a repeating organic unit in the backbone chain of the polymer; and X is an organic moiety containing an iodinated aromatic group and a hydrophilic group, said moiety having an iodine content within the range of from about 40 to about 80 weight percent based on the molecular weight of X;
(b) from 0.05 to 10% w/v of microcrystalline cellulose;
(c) from 0.1 to 20% w/v of a surfactant selected from the group consisting of nonionic, anionic, cationic and zwitterionic surfactants;

(d) from 0.001 to 4% w/v of a viscosity modifying excipient; and (e) water to make 1005 by volume.

7. The x-ray contrast composition of claim 6 wherein X represents an organic moiety containing an iodinated aromatic group, said moiety being of the formula wherein L represents a linking group selected from the class consisting of ester groups, ether groups, amide groups, thioester groups, carbonate groups, carbamate groups, and sulfide groups; and each of R1 to R6, which may be the same or different, represents hydrogen, an iodine-containing substituent, or a hydrophilic group-containing substituent, with the provisos that (i) the iodine content of X is within the range of from 40 to 80 wt%;
and (ii) said hydrophilic group is a member selected from the class consisting of carboxyl groups, sulfo groups, amino groups, salts of the aforementioned carboxyl, sulfo and amino groups, and polyol groups.

8. The x-ray contrast composition of claim 7 wherein said surfactant constitutes from 3 to 7% of the composition.

9. An x-ray contrast composition for oral or retrograde examination of the gastrointestinal tract comprising:

(a) from 5 to 95% w/v of a barium salt;
(b) from 0.1 to 10% w/v of microcrystalline cellulose;
(c) from 0.1 to 55% w/v of an oily vehicle;
(d) from 0.1 to 20% w/v of a surfactant selected from the group consisting of nonionic, anionic, cationic and zwitterionic surfactants;
(e) from 0.001 to 15% w/v of a viscosity modifying excipient; and (f) water to make 100% by volume.

10. The x-ray contrast composition of claim 9 wherein said oily vehicle constitutes from 7 to 15% w/v of the composition.

11. The x-ray contrast composition of claim 9 wherein said surfactant constitutes from 3 to 7% of the composition.

12. The x-ray contrast composition of any preceding claim wherein said microcrystalline cellulose has an average particle size of from 0.01 to 100 µ.

13.. The x-ray contrast composition of claim 12 wherein said microcrystalline cellulose is about 89 parts microcrystalline cellulose and about 11 parts of sodium carboxymethylcellulose.

14. The x-ray contrast composition of any preceding claim wherein said nonionic surface active agent is selected from the group consisting of carboxylic esters, carboxylic amides, ethoxylated alklyphenols and ethoxylated aliphatic alcohols.

15. The x-ray contrast composition of any of claims 1 to 13 wherein said surfactant is sorbitan ester having the formula:
or wherein R1 = R2 = OH, R3 = R for sorbitan monoesters, R1 = OH, R2 = R3 = R for sorbitan diesters, R1 = R2 = R3 = R for sorbitan triesters, where R = (C11H23) COO for laurate, (C17H33) COO for oleate, (C15H31) COO for palmitate, (C17H35) COO for stearate.

16. The x-ray contrast composition of any of claims 1 to 13 wherein said surface active agent is polyoxyethylene alkyl ether having the formula:

CH3(CH2)x(O-CH2-CH2)yOH
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 from about 10 to about 60.

17. The x-ray contrast composition of any of claims 1 to 13 wherein said surfactant is polyoxyethylene sorbitan fatty acid ester of the formulae (1) and (2) wherein w+x+y+z = 20 w+x+y+z = 5 w+x+y+z = 4.

18. The x-ray contrast composition of claim 1 for oral or retrograde examination of the gastrointestinal tract comprising:
(a) from 85 to 120 mg of iodine per ml of the x-ray contrast producing agent;
(b) from 0.2 to 1% w/v of microcrystalline cellulose;
(c) from 7 to 15% w/v of a mineral oil;
(d) from 3 to 7% w/v of a surfactant selected from the group consisting of nonionic, anionic, cationic and zwitterionic surfactants;
(e) from 0.05 to 1% w/v of a viscosity modifying excipient; and (f) water to make 100% by volume.

19. The x-ray contrast composition of claim 18 wherein the average particle size of said microcrystalline cellulose is from 0.05 to 10µ.

20. A method of carrying out x-ray examination of the gastrointestinal tract of a patient, said method comprises the oral or rectal administration to the patient of an x-ray contrast formulation of any preceding claim.