CA2187019A1 - X-ray contrast compositions containing pharmaceutically acceptable clays - 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 combination with a pharmaceutically acceptable clay in a pharmaceutically acceptable carrier; and methods for their use in diagnostic radiology of the gastrointestinal tract.

Description

WO95/28969 r. ~ 't~
....

X-RZ~Y rnNTRZ~.~T CnliqposITION~c~ Ct)NTh~NTN(~:
PFr~RMAr~zuTIrz~T~Tly Ar~F~PT~RT,~ ('T,Z~YS
This invention relates to an x-ray contrast composition for oral or retrograde administration to a mammal comprising an x-ray contrast producing agent and a rhA~re~lt; cally acceptable clay.
Roentgenographic ~ nA t i on 1l t; l; 7 i nrJ x- rays and c ~ Prl t~ _ ~hy (hereina~t,er CT) scans of ~ractures and other conditions Aqæor;Ate~ with t~e skeletal system is routinely practiced without the use of contrast agents. X-ray v;~-lAl;7At;nn o~ organs rontA;n;nr~ so~t t,issue, such as the gastrointestinal (hereinafter GI) tract, requires the use o~ contrast agents whic_ attenuate x-ray rArl; At; nn . D. P . Swanson et al in "Phar~-ce~t;ra1q In Medical Imaging", 1990, MacMillan pllhl;qh;nrJ Company, provide an P~rl~llPnt ba~:h~L.,u.ld in medical imaging ~1t;1;7;nr, contrast agents.
Roentgenographic, nAt; nn of the GI tract is indicated ~or conditions of digestive disorders, changes in bowel habit, Ahrln-;nAl pain, GI bleeding and the like. Prior to rA~l;olorJical ~ nAt;nn, administration o~ a radiopaque contrast medium is necessary to permit adequate cl~l; n~At; nn of the respective lumen or mucosal sur~ace ~rom ~uLLuu--ding so~t tissues. Accordingly, a contrast medium is administered orally to visualize the mouth, pharynx, ~ænrhA~lQ, stomach, r~llntll and proximal small intestine. The contrast medium is administered rectally ~or ~.Am; n~ti nn of the distal small intestine and the colon.
T_e most widely used contrast agent ~or the v; qllAl; 7At; nn of the GI tract is barium sulfate administered orally as a suspension or rectally as an enema. (See, for example, U.S. Patent Nos.: 2,659,690;
. ... _ _ , .. . .. .

218701~ _ 2 -62043/001 . 588 2,680,089; 3,216,900; 3,235,462; 4,038,379 and 4,120,946) Notwithstanding its relatively good contrast characteristics, negligible absorption f rom the GI tract following oral or rectal administration and speedy excretion from the body, barium sulfate has certain disadvantages . In the presence of intestinal f luids 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 produces a so-called photoelectric effect which is a large magnification in contrast caused by the photons stopped in the iodine-rr~nt~;n;ng 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 l~t;l;7Pd. (~or iodinated agents see, for example, U.S. Patent Nos.: 2,786,055;

3,795,698; 3,360,436; 3,574,718, 3,733,397; 4,735,795 and 5,047,228, also ~nited Kingdom Patent No. 767,788 and Swiss Patent No . 338, 274 which both disclose contrast ~nh;~nr; nrJ compositions comprising iodinated contrast agents and suspending and/or antacid agents such as kaolin. ) The desiderata for an ideal GI contrast agent include: good toxicological profile; the ability to fill the entire bowel/lumen and evenly coat the gut mucosa 80 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 ~ENO~ SHEE~

- 2a -vigorous intestinal peristalsis.
These requirements were addressed by many investigators and their efforts resulted in great improvements over the years. The requirement of evenly 5 coating the gut mucosa with, and sufficiently adhering ~WO 95/28969 ~ . 75 1 ~~ ~
2187~19: 3_ thereto, a contrast agent to effectively cover the walls of the intestines proved to ~e rather dif f icult .
Without meeting these reguirements 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. Patent 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-;n~olllhlP inorganic x-ray contrast agent and minute particles of a hydrophilic polymer which is ;n~olllhlP in water but is water-swellable. The body cavity is s~lrrl; ed with such preparation 5l~rPn~lPfl in water. The x-ray co~trast agent is present in Al~ tllre with and/or Pnrl nsefl in and/or adhered to said minute polymer particles.
U.S. Patent No. 4,120,946 discloses a phar-~ce~lt;r~l composition for barium opacification of the digestive tract, comprising rol 1 oi~;~l barium sulfate and a polyacrylamide in an aqueous vehicle. The polyacrylamide forms a viscous solution at low .-nn- Pntration which makes it pogsible to ~;nt~l;n the barium sulfate in suspension and at the same time permit good adherence of the prPr~rPt; nn to the walls of the organ which it is desired to x-ray.
U . S . Patent No . 5, 019, 370 discloses a biodegradable radiographic contrast medium comprising b; nflP~r~hl~
polymeric spheres which carry a radiogr~rh;r~1ly 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.
While these polymeric materials greatly enhance att~` of the contrast agent used therewith to the walls of organs for better v; ~ ; 7~tinn thereof, there is still a need for an improved x-ray imaging medium that uniformly coats the soft tissues subjected to wo95/28969 ~ 7~19 ,~. .. ..
diagnostic x-~ay examination.
We have now discovered that the use of certain natural clays in c ' ;n~t;nn with an x-ray producing agent Pnh~nrPR the lln; fnrm; ty of coating on the gastrointestinal tract and the quality of x-ray images.
In addition, these clays mask the llnrlP~R~nt odor and taste of the x-ray contrast or~ tinnR as well as enhance the physical stability thereof.
It is the object of the prese~t invention to provide compositions for coati~g the gastrointestinal tract of mammals to form an effective r~rl;op~riue coating thereon by which diag~ostic n~t; nn of the GI tract may be ~rcn~ ~1; qhPfl . To that end, a thi~ coating is formed on the inner surface of the GI tract ef~ected by ingesting, prior to v; RllZIl; 7:1t; nn by an x-ray emitting device, a composition cnnt~;n;ng a rh~rr~rPllt; cally acceptable clay and an x-ray contrast agent. Such compositions must meet several requirements: both the x-ray contrast agent and the clay must be nontoxic; must not contain l P~rh~hl P or digestible ~ _ R that would IlPlPtpr;nllRly affect the patient; and no components of the coating should be ~hsorhed by, and pa6s through, the inner surface of the intestine.
The object of the present invention is achieved by a composition comprising: an x-ray contrast agent and a phar--rPut;r~lly acceptable clay in an aqueous rh~rr'rPUt; cally acceptable vehicle.
In accordance with the inve~tion 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 ef f ective co~trast producing amount of the above-described x-ray contrast compostion.
The contrast agent and the rh~rr-rPlltically acceptable clay are incorporated in liquid media f or administration to a mammal for x-ray v;Rll~1;7~t;nn of the GI tract.

W095l28969 r~-,. '( '' 218701~ 5_ The contrast agents utili2 ed in the present invention are selected from (1) compounds of the ~ormula (I) OR
lu ( I ) wherein R is a substituted or unsubstituted alkyl group rr~n1-~;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;
(2) a c~ ~ 1 of the formula ~, o--[tCH2)p 1 ~ O}R
In 21~
or a rhAr~--CP~t1r~l ly acceptable salt thereof wherein Z is H, halo, Cl-C20 alkyl, cycloalkyl, lower alkoxy, alkoxycarbonyl, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo - l ower - alkyl group s;
5~Zx R is Cl-Czs alkyl, cycloalkyl, In or halo-lower-alkyl, each of which may be optionally substituted with halo, ~luoro-lower-alkyl, aryl, lower-alkoxy, 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 ;nrlPrPnrlPntly H or lower-alkyl, optionally substituted with halo;
x is 1-4i n is 1-4;
~n is 1-15;

Wo 95l28969 P~~ C
~!187019 t-Q is H, lower-aIkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower alkyl;
(3) a compound of the formula ~ Rl ~
In/~ R2 ) X
or a rh~ Pll~; cally 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;
R1 and R2 are inde~e.~de..~ly H, Cl-C2s alkyl, cycloalkyl, acetyl or halo-lower-alkyl, wherein said Cl-C2s alkyl, cycloalkyl and halo lower-alkyl are optionally substituted with ~luoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy, lower-alkoxy carbonyl or lower-alkoxy-carbonyloxy and said acetyl is optionally substituted with ~luoro-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;
( 4 ) a ,- _ ' o~ the ~ormula ~ R)x In z~
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 15 CL_C25 alkyl, cycloalkyl, or halo-lower-alkyl, . , .

WO95/28969 P~ l,. ' ~'' 21.8~1n ... . ..

each of which may be optionally substituted with halo, f luoro - l ower- alkyl, aryl, l ower- alkoxy, hydroxy, carboxy, lower-alkoxy carbonyl or lower-alkoxy-carbonyloxy; or (CR1R2) p- (CR3=CR4) mQ, or (CRlR2) p-C~C-Q;
Rl, R2~ R3 and R4 are ;ntlPr~n~l~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 H, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower alkyl;
(5) a t t ~ ' of the formula ~OR
Z~
or a rhR~~ lt;c~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;
R is methyl, ethyl, propyl, C9-C2s 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 (CRlR2)p- (CR3=CR4)mQ, or (CRlR2)p-C~C-Q;
Rl, R2, R3 and R4 are ;n~lPrt~nt~Pntly 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 EI, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower alkyl;
,, ,, _ _ _ Wo 95l28969 : _ P~I/~rD7S.C
21~37n19_8- ' t6) a compound o_ the formula .
,~(XR)w wherein X is O
- C- or - S2 - i Z is X, halo, methyl, ethyl, n-propyl, C4-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-C2s alkyl, cycloalkyl or aryl each o_ which may be optionally substituted with halo, _luoro-lower-alkyl, 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;
(7) a particulate crystalline x-ray contrast agent having a sur_ace mrfi;f;~r A~nrh~ on the sur_ace thereof. ~
As used herein, the term halogen (or halo) means f1~1nr;n~, chlorine, bromine or iodine As used herein, the term cycloalkyl means carbocyclic rings having _rom three to eight ring carbon atoms ;nrl~l~l;nr cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl which may be substituted on any ring carbon atom thereo_ by one or more lower-alkyl groups, lower-alkoxy groups or halogens.
As used herein the terms lower-alkyl and lower-alkoxy mean monovalent Al;rhAtic rAol;rAl~, including ~W095128969 _ 9 _ r~l,~,,,,.,. -,, ~r~nrh~ 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, aec-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-tetramethylpentyl, 1,1-dimethyloctyl and the like.
As used herein, the terms lower-alkenyl and lower-alkynyl means monovalent, ungaturated r;lrl;r~ ;nrlll~;n~
hr;lnrh~l chain rAtl; c~ of fr three to ten carbon atoms and thus include 1-ethenyl, 1- (2-propenyl), 1- (2-butenyl~, 1- I1-methyl-2-propenyl), 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;n~ branched chain radicals of f rom two to ten carbon atoms having their f ree valences on differen~ carbon atoms and thus inr~ 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 CILI ; C
hydrocarbon radical having six to ten carbon atoms. The preferred aryl groups are phenyl, substituted phenyl and naphthyl substituted by f rom one to three, the same or different members of the group consisting of lower-alkyl, halogen, hydroxy-lower-alkyl, alkoxy-lower-alkyl and hydroxy.
The x-ray contrast ~ can comprise one, two, three or more iodine atoms per molecule; preferred species contain at least two, and more preferably, at least three iodine ats per 1 ec~
Solid x-ray contrast agents in particulate forms useful in the practice of the present invention can be prepared by techniques known in the art. The solid agents are comminuted to the desired size using wo ssnss6s ~ ~ r~ ,s.. ~~
218701~
- 10 - . .
co~vPntinnAl milling methods, such as airjet or fra~ tAt;nn milling. We have found that an ef~ective average particle size of less than about 100~1 provides ~or good distribution and coating in the- ~:I tract. As used herei~, Farticle size refers to a~ number average particle size as measured by conventional techniques, such as EPrli tFlt j~m field flow frartinn~tinn and disk centrifugation. An effective average particle size of less than about 100~ means that at least about 90g6 of the particles have a weight average particle size of less than about 100~ as measured by art reco~n; ~n~3 techniques .
The compositions may be in the form of dispersions, sllcpPnc; nnc when the x-ray contrast agent is a solid, or l Rinnc when the x-ray contragt agent is an oil; we prefer to use lc;nnc as the preferred: 'i t, The natural clays incorporated in the compositions of the present invention are sPl ectP~ from the group consisting of, illonite, beidelite, nontronite, hPrtl7r; tP and S~rnn; tP
A method for diagnostic imaging of the GI tract for use in medical ~ eduL~s i~ accordance with this invention comprises orally or rectally administering to the I l; An patient in need of an x-ray examination, an effective co~trast producing amount of a composition of the present invention. After administration at least a portio~ of the GI tract cnnt~;n;n~ the administered composition is exposed to x-rays to produce an x-ray image pattern corrpcpnn~;n~ to the presence of the contrast agent, then the x-ray image is visualized and interpreted using techniques known in the art.
rn~r~OIln.lc of type (1) defined above are described in EP-A-568155 . For example, 2, 4, 6-tr;; n~lnrhPnn--y-2-octane, 2, 4, 6-tr;; o~lnrhPnn~y-2-butane~ 2, 4, 6-triiodophenoxy-2-hexane and 4-inrinrhpnnl~y-2-octane are described therein.

O 95/28969 r~

Preferred contrast agents of type (1) have the f ormula: OR
1~1 wherein R i8 a sernn-lAry alkyl group cnnt:~;n;nr, f rom 4 to 8 carbon atoms .
The most preferied contrast agent of type (1~ is the sec-octyl ether of 2~4~6-tr;;n~lnrhpnnl having the f ormula:

I~I
C ,uu.-ds of type (2) defined above are described in EP-A-614670 . For example, the bis- (4-; r,-lnFhPnyl) ether of polyethylene-glycol-400, 1,8-bis-0-(2,4,6-tr;; orlnrh~nyl) -tripropylene glycol, 1,11-bis- (2, 4, 6-tr;; o~lnrhPnnl~y) -3,6, 9-I r;n~ n~lPrzln~, 1, 2-bis- (2,4,6-tr;; orlnrhPnnl~y) -ethane, the bis-O- (2, 4, 6-tr;; orlnrhPnyl) ether of polyethylene glycol 400, 1- (3-io~nrhF-nn~y) -3,6,9-tr;m~ lPr;ln~, 1,3-bis-(2,4,6-tr;;orlnrhDnn~y)-butane, 1- (3-;orlnFhPnm~y) -6- (2,4, 6-tr; ;n~lnrh-~nn~y) -hexane and 1,12-bis-(2,4,6-tr;;oflnrhF~nn-ry)-tln-9Pr~nP are described therein.
of type ( 3 ) as def ined above are described in EP-~-613689. For example, N-acetyl-N-2-octyl - 4 - ; o-l nzln ; 1; n P and N- ( 4 ~ - ; n~l nrh~nyl ) - 2 - aminooctane are d--s~ribed therein.

Wo 95/28969 P~ .'C~ '' 2187019 ~ ~ --_ uu~ds of type (4) as defined above are described in EP-A-614669. Eor example, 2-octyl 2,3,5-triiodobenzoate, 3,3,4,4,5,5r6,6,7,7,8,8-dodeca~luoro-2-octyl 2, 3, 5-tr;; orlnhpn7Q~te~ bis (2-hexyl) 2, 3, 5, 6-tetr~;rJtlntPrprhth~l~te~ ethyl 3-(2-octyloxy)-2,4,6-tri;o-lnhPn7n~t~ and bis(2-octyl) 5-(2-octyloxy)-2,4,6-tri; o~ln; ~orhth~l ~te are described therein.
'` ~ of type ( 5 ) as def ined above are described in EP-A-603587 . For example, 2- (4-~ ntlnrhPnnTy) -decane, 2- (2, 4, 6-tr;; otlnrhpnnTy) -pPnt;lriPr:3np~ 2- (2, 4, 6-tr; i orlnrhPnnTy) decane, (2, 4, 6-tr;;n~nrhpnnTy)-lH~ 2H~2H-per-fluorooctane~ 1-(2,4,6-triiodo-3-tr;flllnrophenoxy)octane, 2-(2,4,6-tr;; nrlnphPnnTy) -nonane, 2-ethyl-1- (2, 4, 6-tr;;o~lnrhPnnTy)-hexane, 3,3-diphenyl-1-(2,4,6-tr;;n~nrhPnnTy)propane~ 3-(2~4~6-tri;o~nFhpnnTy)-nonane~
2- (4-; o~lnphPnnTy) -lln~Pr~nP, 2-in~lnFhPnnTycyrl orPnt~nP, 3-;orlnrh~".".y~;y. lopPntAnP~ (3,5-dimethyl-2,4,6-tr; nrlnFhPnn~ry) cyrl nrPnt~nP, 2- (4-; orlnrhPnnTy) _ pPntA~Pr;~nP, 4- j ~tlnphPnnTycyrl npPnt~nP, 2, 4, 6-tri; o~nFhPnnTycyrlnpPnt~np~
2,4, 6-tri;or~nrhpnnTymethylcyrlQppnt~nG~ 2- (2,4, 6-tr;;o~1nrhPnnTy)ethylcyrlnr~ntAnP, (E,E)-1-(2,4,6-tr;; n-lnrhPnnTy) -3, 7 ,11-trimethyl-2, 6 ,10--ln~lPr~tr; Pn~
(2, 4, 6-tr;; o(inrhpnnTy) -3, 7-dimethyl-6-octene, (E) -1-(3, 5-dimethyl-2, 4, 6-tr;; o~nrhPnnTy) -3, 7-dimethyl-2, 6-ort~l;pnp~ (E)-l-(2~4~6-tr;;rJ~lnrhpnnTy)-3~7-dimethyl-2,6-octadiene, 1-(2,4,6-tr;;n~lnrhPnnTy)-3-octyne, 2-(2,4,6-tr;;n~lnFhPnnTy) -4-octyne, 1- (2,4,6-tr;; nt9nrhPnnTy) -3-octyne~ diethyl 2- (2, 4, 6-tr;; n~lnrhPnnTy) -1, 3-prop~nP-l; n~te, diisopropyl 2- (2, 4, 6-triiodophenoxy)-1,3-prop~nP~l;n~te, ethyl 2,2-bis-(3-iodophenoxy) acetate, ethyl 5 - ( 2, 4, 6 -tr;; ntlnrhPnnTy) hPT~nnAtP, 5 - (2, 4, 6 -tr;; n-lnrh~nn~y) -hexan-l-ol, 10- (4-i nrlnrhPnnTy) -undecan-l-ol, ethyl 5-(2,4,6-triio~nrhPnnTy) hexyl carbonate and ethyl 10-(3-.

~o 95/28969 21 8 70~9 13 -iodophenoxy)-undecanoate are described therein.
Compounds of type (6) as de~ined above are described in EP-617970. For example, 2,4,6-tr;; o~lnrhPnyl 2 -ethyl hP~Ann~tel 2, 4, 6-tr;; ~n-lrphPnyl 2-methylrPntAnn~tP, 2,4,6-tri;o~lnFhpnyl 3-cyclopentyl propionate, 2,4,6-tr;;nAnFhPnyl (2-propyl)pPnt~nn~te, 2,4,6-tr;;n-lnrhPnyl perfluoroheptanoate, 2,4,6-tr;; nf9nrhPnyl-tris- (2-ethyl) -hPY~nn~te, 2, 4, 6-tr;;nrlnrhPnyl rln~lPr~rn~tP, 3-trifluoromethyl-2,4,6-tr;;o~nrhPnyl 2-ethyl hP~nn~tP, 2,4,6-tr;;~lnrhPnyl-bis-(2-methylrPnt~nn~tP), 2,4,6-tr;;o~lnrh~nyl hP~nPClll fonate, 2,4, 6-tr; ;n~ ..yl heptAnPRlll fonate and 2,4,6-tr;;o~nrhPnyl ~lpr~npclllfonate are described therein .
Compounds used in the . - t;r,nc of type (7) defined above are non-r~l;n~rt;ve and exist as a discrete, crystalline phase of an organic substance.
The crystalline phase dif_ers from an amorphous or non-crystalline phase which results from solvent precipitation techniques such as described in U. S .
Patent 4, 826, 689 noted above. 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-radioactive x-ray contrast agents.
However, the x-ray contrast agent must be poorly soluble and dispersible in at least one liquid medium. By "poorly soluble", it is meant that the agent has a solubility in the liquid dispersion medium, e.g., water, o~ less than about 10 mg/ml, and preferably of less than about 1 mg/ml . The pref erred liquid dispersion medium is water. Additionally, the invention can be practiced with other liquid media in which the selected x-ray contrast agent is poorly soluble and dispersible, ;nrlll~l;n~, for example, aqueous saline solutions, such 2187019 1 ~

aqueous and nonaqueous ~Ql~tinnc~ for example, water and alcohol, and suitable nonaqueous solvents such as alcohol, glycerol and the like.
me x-ray contrast agent can be an ;n~l;nAtP~l compound. The iodinated compound can be àromatic or nonaromatic. ~ t; C I - tlc are preferred. The io~;n~ted ~ ,_ ' can comprise, one, two, three or more iodine atoms per ~r ~1PC~ Preferred species co~ltain at least two, and more preferably, at least three iodine atoms per, 1 Prlll P . The; n~l; n~te~l c _ _ ~c selected can contain substituents that do ~ot impart 5r-l llh; l; ty to the c~ d, such as, for example, alkylureido, alkoxyacylamido, hydlu~ydcetamido, butyrolactamido, s~c~;n;m;r~n, trifluoro~PtAm;rln, carboxy, c~rhn-r~m;cln, hydroxy, alkûxy, acylamino, and the like sUbst; tl~Pntc A preferred class ûf contrast agents ;nrlllrlPc various esters and amideG of ; nA; nAtPtl 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 tr;;ntlnhpn7o;r acid such as an acyl, carbamyl, and/or acylmethyl substituted tr;; n~lnh~n70ic acid. Illustrative representative examples of ;otl1 aromatic acids i~clude, but are not limited to, diatrizoic acid, metrizoic acid, iothalamic acid, trimesic acid, urokonic acid, ioxaglic acid (hexabrix), ;n~;tAl; c acid, totrA;rJ~loterprhthAl;r acid, in~;rAm;~P, icarmic acid, and the like.
Many of the iQ'l;nAtpfl mnlprl~le~ described above, if in -- ic form, can also be prepared as dimers (~ ~; , referred to as bis compounds), trimers (sûmetimes referred to as tris ~ ds), etc., by techniques known in the art. It is contemplated that this invention can be practiced with poorly soluble-;o~l;nAtP~1 rnmrQlln~lc in --m ic, dimeric, trimeric and polymerlc f orms .

~Wo 95/28969 r~ s~
2]870f9 - 15 ~
Classes o~ pre~erred contrast agents have the ~ollowing structural ~ormulae:
O
C-R
101 ~ 11 tdi_trizo-tc B. 0 C-R
CH3--C--HN~¢( C--NH-CH3 [io-hq~ "~
C O
C-R
C~U~

W095/28969 P~~
2187~I9 ~

D O

\E~NH--C--(CE~4 _LN~
[~ 3 r e]
In the above structures R can be OR1, NR2R3, alkylene, -CO.ORl or -O-alkylene-CO.ORl wherein Rl is alkyl, and R2 and R3 are ; nf~ f~ l l y H or alkyl .
Each alkyl group can ;nflfrf~nflf~ntly contain ~rom 1-20, pre~erably 1-8, and more pre~erably, 1-4 carbon atoms .
The alkylene group preferably rnntA;nc ~rom 1 to 4 carbon atoms such as methylene, ethylene, propylene and the like.
Particularly preferred contrast agents include the ethyl ester o~ diatrizoic acid, i . e ., ethyl 3, 5 -fl;A re t.~;f7n- 2,4, 6- tr;;of lnhfn 70At e, also known as ethyl 3,5-bis(acetylamino)-2,4,6-trioflf.h-~n70Ate or ethyl diatrizoate, having the structural ~ormula A above wherein R= -OCH2CH3; the ethyl glycolate ester o~ ~
diatrizoic acid, i.e., ethyl ~3,5-bis(acetylamino)-2, 4, 6-tr;; nflnhf-n70yloxy) acetate, also known as ethyl diatrizox~facetate; and ethyl 2-(3,5-bis(acetylamino)-2,4,6-tri-;o~lnhf~n70yloxy)butyrate, also known as ethyl 2 -diatrizoxybutyrate .
In addition, the invention can be practiced in conjunction with the water insoluble ;ofl;n~ted r~rhnnAtf.
esters described in PC~/EP90/00053.
The above described x-ray contrast agents are known r, ~,ul.ds and/or can be prepared by techni~Iues known in the art For example, water-insoluble esters and gs/28969 r~
~wo 2~87UI~ ' terminal amides of acids such as the above-described iorl;nAtP-l aromatic acids can be prepared by ConvPntinnAl alkylation or ~iAtinn tprhn;r~ pc known in the art.
The above-noted acids and other acids which can be used as starting materials are c( .:ially available and/or can be yLt:l,al~d by tprhn; rlllPR known in the art.
me particles useful in the contrast agents of type ( 7 ) include a surf ace mnr1; f; Pr ~ Surf ace - ~ f; Prs useful herein physically adhere to the surface of the x-ray contrast agent but do not rhPm; rA l l y react with the agent or itself . Individually A~l~nrhPCl lerlll P~ of the surface, f;Pr are Ps~SPnt;Ally free of ;nt~ -lPrlllAr crn~l ;nkA~R . Suitable surface modifiers can be selected from known organic and inorganic rhAr~-rP~lt; cal PTr;r;Pnts such as various polymers, low-l lerlllAr weight oligomers, natural products and SurfActAntF:.
Preferred surface ';fiPrs include nnn;nn;r and anionic surf~rtAntc. R~:~Lbs~L~atiVe P~ P~ of surface '; f; PrS include gelatin, cagein, lecithin (rhn~PhAt;'lP~), gum acacia, cholesterol, trA~arAnth, stearic acid, bPn7~lknn; rhlori~P, calcium stearate, glyceryl monostearate, cetostearyl 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 uially available Tweens, polyethylene glycols, polyoxyethylene stPAratP~, colloidol silicon dioxide, rhnsrhA~ps~ sodium dodecyl ~1l1 f:qtP, caLbu~yl ~hylcellulose calcium, caLl,u~ ~hylrPllllln~e sodium, methylrPll-llose, l~ydLu~Ly~thylr~ Pl 1 1l 1 Qse, h~dLU~y~ U~ylrPl 1 1l 1 o~e, llydLu~yyLuyylmethycellulose rhthAl AtP, noncrystalline rPlllllOSe, ~'~nP~:; Al 'nllm silicate, triethAnnlAm;nP, polyvinyl alcohol, and polyvinylpyrrolidone (PVP) . Most of these surface mn~;f;Prs are known rhArr-r~put;rAl P~r;r;Pnt~ and are described in detail in the HAn~hQnk of ph;~rr r~utica~ cipients, pllhl; ~::hPd jointly by the WO 95/28969 P~
~87~

American Pharmaceutical Association and The phArr-rf~utical Society of Great Britain, the Pharmaceutical Press, 1986, the disclosure` of which is hereby incorporated by reference in its entirety.
Particularly preferred surface, '; ~i~rs include polyvinylpyrrolidone, tyloxapol, pnl ~ ~, such as Pluronic P68 and F108, which are block copolymers of ethylene oxide and propylene oxide, and pol~ n~ such as Tetronic 908 (also known as Pol~ n~ 908), which is a tetrafunctional block copolymer derived from sequential A~l~;t;nn of propylene oxide and ethylene oxide to ethyl~nP~l;i 'n~, available from BASF, dextran, lecithin, dialkylesters of sodium sulfosur~; n; C 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 ~ aas, Tween 80, which is a polyoxyethylene sorbitan fatty acid ester, available from ICI Specialty Chemicals, and Carbowax 3350 and 934, which are polyethylene glycols available from ~nion Carbide. Surface modifiers which have been found to be particularly useful include Tetronic 908, the Tweens, Pluronic F-68 and polyvinylpyrrolidone .
Other useful surface modifiers include:
decanoyl -N-methylgl ~ Am; ~lp i n-decyl ~-D-glucopyranoside;
n-decyl~ -D-maltopyranoside;
n-dodecyl ,~-D-glucopyranoside;
n-dodecyl ~-D-maltoside;
heptanoyl-N-methylgl llCAm; ,1P
n-heptyl ~-D-glucu~yLc-~oside;
n-heptyl ¦3-D-th;~ lrnF~;~9~;
n-hexyl ,~-D-glucu~y~ oside;
nonanoyl -N-methylglucamide;

0 95/28969 - - - r~l,~b7~:c ~'' ~W ;~87~tg _ 19 -n-nonyl ~-D-glucopyr~nn~
octanoyl-N-methylgl llC~m; ~1P;
n-octyl ,~-D-glucopyranoside;
octyl ~-D-thioglucopyranoside;
and the like.
A particularly preferred class of surface modifiers ;nr~ c water-soluble or water-dispersible ~ u~ c having the f ormula Rl ~CONCH2(~HI )H) CH ,~')H
CONCH2(CHoH)~y~ )H

~herein L i~ R-CH ; , R-L'~
R-L'~ or R-L ~
L' is a chemical bond, -O-, -S-, -NH-, -CONH- or --So2N-H- - ;
R is a hydrophobic substituted or unsubstituted alkyl / substituted or unsubEtituted cycloalkyl / or a substituted or unsubstituted aryl group;
each of Rl and R2 ;n~l~r~nr9F~n~ly is hydrogen or an alkyl group having f rom 1 to 4 carbon atoms;
each of a and b ;nrl~p~nfq~nt-~y is O or an integer ~rom 1 to 3 / provided that the sum o~ a and b is not greater than 3; and/

WO 95/28s6s 2 ~. 8 7 0 t ~

each of x and y ;n~Pr~n~ntly is an integer from 3 to 7 Preferred cnmrol~ntl~ within this c~àss conform to the above structure wherei~ R cnnt~;nq from 6 to 36 carbon atoms, for example, R is an n-alkyl yroup rnntsl;nin3 from 6 to 18 carbon atoms, each of Rl and R2 independently is a methyl, ethyl, propyl or butyl group and a is 0 and b is 0. This class of surface mn-l;f;Prs is described in U.K. Patent ~rr~ t;nn No. 9104957.7 filed March 8, 1991 and can be prepared by reacting an ~-~uLu~Liate rl; cArhn~ylic acid ester with an d~yLu~Liate n8pr~hzlriflP amine, preferably in the absence of a solvent, at a reaction temperature from 140 to 200~C.
The surface ' fi~rs are commercially available and/or can be prepared by techniques known in the art.
Two or more surface, ';fiPrs can be used in cnmhin;lt inn .
The particles can be prepared in accordance with the wet grindiilg process described in U_S. E~atent No.
5 ,145, 684 . The process comprises dispersing a poorly soluble x-ray contrast agent in a liquid dispersion medium and wet-grinding the agent in the prese~ce of grinding media to reduce the particle size of the contrast agent to an effective average particle size of from about 0.05 11 to about 100 ~, preferably of from dbout O . 05 11 to about 5 IL and most preferably from about 0.1 11 to about 1 ~L. The particles can be reduced in size in the presence of a surface ~;f;Pr.
Alternatively, the particles can be contacted with a surface mn~l; f; Pr after attrition.
As used hereiI:L, particle size refers to a ~umber average particle size as measured by Conv~nt;nn;31 particle size measuring te~hn; ~ P~ well known to those skilled in the art, such as E~ tion field flow fractionation, photon correlatio~ spectroscopy, or disk centrifugation. By "an effective average particle size .
, Wo 95/28969 r L ~
218701~

of from about 0 05 ,u to aoout 100 ~LII is meant that at least 90~ of the particles have a weight average particle size of from about 0 05 ~L to about 100 ~L when measured by the above-noted techniques. The particle size range allows sufficient number of particles ' distribution in the film forming composition when the GI
tract is coated therewith, yet insures against absorption through the intestinal walls.
The natural, pharma~P~lt;r~lly acceptable clays incorporated in the present invention comprise ; ~ m;
s;l'r~t~. They are used in purified form, suitable for administration to r~t;F-r~t~. The natural, rh~ t; r~ l l y acceptable clays of the present invention, generally referred to as smectities, consist of dioctohedral smectites and trioctahedral smectites Dioctahedral smectites include:
illonite, having the f ormula M+ Al3y ~FeMg)y Si4010(0~)2 nH20;
beidelite, having the f ormula M+ Al~ (Si4 XAlx)lO(OH)2 nH20;
nontronite, having the formula M+ Fe2 (Si4 XAlx)0lo(o~)2 nH20 wherein M+ is Na, Ca or Mg.
Trioctahedral smectites include:
saponite, having the f ormula M+ (Mg3 y (AlFe)y) (si4-xAlx)olo(oH)2 nH20;
hectorite, having the f ormula M+ (Mg3 y Liy) Si4010(~) 2 nH2i W0 95/289C9 r~
2187019 . `

wherein M~ is Na, Ca or Mg.
The clays are available from chemical slirpl;Pr~:, such as, for example, American Colloid Company, Arlington E~eights, IL, under the trArlPn MAGNABRITE IHS;
TTR('T~Rl;~ TTE r DF, T~RI''TI~Rl~ rTR I LT, CARN~RCO I White, POLARGRL~NF, POLARGEL~HV, and VOLCLAY~NF -B~ .
Other sllrrl;Pr~ i~clude: RngPlhArd Corp., Iselin, NJ; Ashland ~'hpm;cAl Inc., ~nl~ ~, 0~; RT VAn-lPrh;lt Co., Inc., Norwalk, CT and Whittaker Clark & Daniels, Inc., S. plA;nf;Plrl, NJ.
The contrast agent and the rhArr-rputically acceptable clay are fl lAtP~l for administration using physiologically acceptable cArr;Pr~ or P~r;rjPnt~ in a manner within the skill of the art. The contrast agent with the Arl~; t; nn o~ rhArr-rplltically acceptable aids (such as surfPctAnt~ a~d l~;fiers) and Pl~r;riPntC may be suspended or: 1~; f j Pr9 in an a~ueous medium resulting in a suspension or 1~; nn Compositions of the present invention comprise the following pharmaceutically acceptable ~- , nnPnt~ based on 96 w/v:

~W0 95/28969 218 7 019 ~ r~

Mos t Tn~r~ n~ Broad P-nr~ Pr~f.~--. ed p~nrQ Pr~ ~ed r Contr~st agent 5 - 45 10 - 35 15 - 25 Clay 0.1 - 10 0.5 - 5 1 - 2 Sur~actant 1 - 20 2 - 10 3 - 5 ~Yr;ri~nt~ 0 - 15 0.5 - 5 1 - 2 Water - q.s. to L00~ by,volume Rl-~;ri-~nts cnnt~ ~1AtP~l by the present invention include antifoaming agents, such as simethicone, siloxyalkylene polymers and polyoxyalkylated natural oils; preservatives, such as methyl paraben, propyl paraben, benzoic acid and sorbic acid;
flavoring/sweetening agents, such as sodium saccharine;
and coloring agents, such as lakes and dyes.
nhile the i o~lnrh~nnYyalkanes of the present invention in forr~ t;nn~ with a rhA~ t;cally acceptable vehicle provide good quality x-ray images, the addition of a rhAnr~ t;rAlly acceptable clay to the f ormulations greatly increases the o~uality of the x-ray images . At the low extreme of the rnn~ Pnt~ation range there is little or no benef it gained, while above the higher extreme of the ~ tion range the f ~-l l ~ t i nn i s too viscous f or administration .
The following f~ lAt;nn examples will further illustrate the invention.
r le 1 2, 4, 6-tr;; ~-1nrh~nnYy-2-butane 20 . O g T~.('~hRR TTE DP 1 . 45 g Sorbitan monostearate 0 . 5 g Polysorbate 60 1. 0 g C

Wo 9~l28969 ~ r~
21870~9 Sodium Saccharine . 0 . 25 g Benzoic acid 0.50 g Sorbic Acid 0 . 050 g Water q. s . to make 100 ml r l_ 2 .

4-TorlnrhPnn~y-2-octane 22.5 g POLARGEL NF 2 . 2 5 g Sorbitan mono-oleate 0.40 g Polysorbate 20 1.25 g P^lyvinyl alcohol - 4 . 50 g Sodium .qAc.^h~r; n.^ O . 25 g Simethicone emulsion (food-grade) 0.10 g Water q. s . to make 100 ml C ^-~t~
2,4,6-tr;;~^,tlnE:h-n~ y-2-hexane 18.5 g M~GNABRITE ~S 1. 25 g Sorbitan, ~^,p~lm; tate 0 . 6 g Polyoxyethylene myristyl ether 0 . 6 g Polyvinylpyrrolidone 3 . 5 g Vanilla f lavoring ( artif icial ) 0 . 2 5 g Strawberry flavoring (artificial) 0.25 g Sorbitol 1. O g Water q . s . to make 100 ml r 1- 4 c ^-~q ~ ts in % w/v Bis- (4-iodophenyl) ether of polyethylene glycol-400 17 . 50 'TAR~TTE DP 1 35 Polysorbate 80 (Tween 80) 1.50 .~ .

~W09~l28969 ~ 19 - 25 - r~
Sorbitan Mono-oleate (Span 80) 1.65 q . s . with water to lOOP~ by volume '^t'q 7 tR in % W/V
1, 8-Bis-0- (2, 4, 6-tr;; otlnrhPnyl) -tripropylene glycol 25 . 00 PO~RGEL NF 2 . 3 0 Polysorbate 60 (Tween 60) 1. 00 Poloxamer 3 3 8 6 . 5 0 Benzoic Acid 0.50 Sorbic Acid 0 . 05 q. s . with water to 10096 by volume r 1- 6 q 7 t'^ in % W/~
1,11-Bis- (2,4,6-tr;;nrlnrhPnn~y) -3 ~ 6 ~ 9 - tr; m~ nriP.^:InP 17 . 5 0 MAGNA-3RITE2HS 1. 25 Polysorbate 20 (Tween 20) 1.50 Sorbitan Mono-laurate (Span 20) 2 . 00 Polyvinyl Alcohol 4 . 00 Sodium Saccharin 0 . 30 q. s . with water to 1009~ by volume r le 7 t R
N-acetyl-N-2-octyl-4-; n~ln~n; 1 ;nP 18 . 00 g HECTABRITE DP 1. 5 g Sorbitan Monostearate 0 . 5 g Polysorbate 60 (Tween 60) 1. 2 g Poloxamer 338 4.0 g Sodium Saccharine 0 . 3 g Benzoic Acid 0.1 g _ _ . ... . ... .. . _ W095l289~9 ;~ ~ 87~ ~ g Sorbic Acid i ~ 0 05 g Water q. s . to make 100 ml ~, -r le 8 q N- (4 ' -; o~lnFhpnyl) -2-amino octane 25 . 00 POL~GEL NF 2 . O g Sorbitan Mono-oleate 0.4 g Polysorbate 20 (Iween 20) 1.2 g Polvinylalcohol 4 . 5 g Sodium Saccharine 0 . 2 g Simethicone (food-grade) 0.1 g Water q. s . to make 100 ml r l_ 9 c ^-~q 2-Octyl-2, 3, 5-tr; 1 nf9nhPn7Oi~t~ 22 . OO g ~l;~t'TZ~Rl~ TTE DP 1. 5 0 g Sorbitan Monostearate 0 . 70 g Polysorbate 60 (Tween 60) 1.20 g pnl~ 338 4.00 g Sodium Saccharine 0.30 g Benzoic Acid 0 . 50 g Sorbic Acid o . 05 g Water q. s . to make 100 ml t q 3,3,4,4,5,5,6,6,7,7,8,8-Do~ flllnro-2-octyl-2, 3, 5 -tr;; nr9nhpn7o~t.^ 22 . 50 g POL~RGEL NF 2 . 30 g Sorbitan Mono-oleate o . 45 g Polysorbate 20 (Twee~ 820) 1.30 g Polyvinyl Alcohol 4.50 g Sodium Saccharine ~ 0 . 25 g WO 95/28969 Z~ 8 ~ 1 9 = I ~"~ c ~
.

Simethicone ~m~ ;nn (food-grade) 0.10 g Water q . 8 . to make 100 ml r le -r Ethyl-3- (2-acetyloxy~ -2, 4, 6-tr;;n~lnhpn~ te 18.50g MAGNABRITE~ HS 1. 25 g Sorbitan r np~lm;tate 0.60 g Polyoxyethylene myristyl ether 0 . 60 g Polyvinylpyrrolidone 3 . 50 g Vanilla flavoring (art;f;~ ) 0.25 g StLdwb~LLy flavoring (artificial) 0.25 g Sorbitol 1. 00 g Water q. 8 . to make 100 ml r le 17 r -~tq 2, 4, 6-Tr;; n~lnrhpnn~rymethylcy~ ,pPnt~n_ 22 . 00 g r~RrT_R~ rTE DP 1. 5 0 g Sorbitan Monostearate 0 . 70 g Polysorbate 60 (Tween 60) 1. 20 g pnll r 338 4.00 g Sodium Saccharine 0 . 3 0 g Benzoic Acid 0 . 50 g Sorbic Acid 0 . 05 g Water q . 8 . to make 100 ml r lP 13 .~ -~t~
2- (4-Io~lnFhpnn7~y)pAnt~ pr~n~ 22.50 g POLARGEL~NF 2 . 3 0 g Sorbitan Mono-oleate 0.45 g Polysorbate 20 (Tween 820) 1.30 g WO 95/28969 ~ ~ r~
~,187019 ., --Polyvinyl Alcohol 4 . 50 g Sodium '~;~rt~h~rinp - =~ 0 2~ g Simethicone t~ lqinn (food-grade) ~ 0.10 g Water ~ . s . to make 100 ml r lt~ 14 r ~q 2-Tn~lnrh~" ~y~;y.:lopentane 18.50 g MAGNARRITE- HS 1. 25 g Sorbitan-- np~ 1 rni tate 0 . 6 0 g Polyoxyethylene myristyl ether 0 . 60 g Polyvinylpyrrol idone 3 . 5 0 g Vanilla flavoring (artificial) 0.25 g StLt~ttbeLLy flavoring (artificial) 1.25 g Sorbitol 1. 00 g Water q.s. to make 100 ml r l,~ 1 r ~tq 2, 4, 6-Tr; i orlnrht~nyl-2-ethyl hp~n~te 22 . 00 g T~RCT~RRTTE~DP 1.50 g Sorbitan Monostearate 0 . 70 g Polysorbate 60 (Tween 60) 1. 20 g Pol~ 338 4.00 g Sodium Saccharine 0.30 g Benzoic Acid 0.50 g Sorbic Acid 0 . 05 g Water '~a . s . to make 100 ml E le 16 r ^~q 2, 4, 6-Tr; i orlnrht~nyl-tris-(2-ethylh~ nn~te) 22.50 g POLARGE~ NF 2 3 0 g W0 9SJ28969 r ~ .. ,s. ~
~ 7ni~

Sorbitan Mono-oleate 0,45 g Polysorbate 20 (Tween 820) 1.30 g Polyvinyl Alcohol 4.50 g Sodium Saccharine 0 . 25 g Simethicone: l q;nn (food-grade) o .10 g Water q. s . to make 100 ml tq 2,4,6-Tri;Q~ hPnyl hp1~npqlllfonate 18.50 g MA~NABRITE~ HS 1. 25 g Sorbitan m-)n~p~lm; t~te o . 60 g Polyoxyethylene myristyl ether 0 . 60 g Polyvinylpyrrolidone 3.50 g Vanilla flavoring (artificial) 0.25 g Strawberry flavoring (ar~;f;~ l) 0.25 g Sorbitol 1. 00 g Water q. s . to make 100 ml ~ q Ethyl 3, 5-bis (acetylamino) -2, 4, 6-tr;; t~ hpn7Q~te 22 . 00 g HECTABRITE DP 1. 5 0 g Sorbitan Monostearate 0 . 70 g Polysorbate 60 (Tween 60) 1. 20 g p~l I 338 4 . 00 g Sodium Saccharine 0.30 g Benzoic Acid 0 . 50 g Sorbic Acid o . 05 g Water q. s . to make 100 ml Wo 95l28969 P~ll~,.,,5 ~ ' 21~701~ ~

r l~ lq ~q Ethyl (3, 5-bis (acetylamino) -2, 4, 6-triiodobenzoyloxy) acetate 22 . 50 g POLARGEL N~ 2 . 30 g Sorbitan Mono-oleate 0 . 45 g Polysorbate 20 (Tween 820) 1.30 g Polyvinyl Alcohol 4 . 50 g Sodium .SArrhAr;nP 0.25 g Simethicone emulsion (food-grade) 0.10 g Water q . s . to make 100 ml r l-~ 20 r ~q Ethyl 2- (3, 5-bis (acetylamino) -2, 4, 6-tr;; r,~1nhPn7~yloxy) butyrate 18 . 50 g MAGNA~3RITEs HS 1. 25 g Sorbitan n~A l m; tate 0 . 60 g Polyoxyethylene myristyl ether 0 . 60 g Polyvinylpyrrolidone 3.50 g Vanilla flavoring (art; f; r; Al ) 0 . 25 g Strawberry flavoring (artificial) 0.25 g Sorbitol 1. 00 g Water ri. s . to make 100 ml The surface active agents used in the present invention may be cationic, anionic, nonionic or zwitterionic .
Suitable rAt;nn;c surfactants include cetyl trimethyl ; bromide, cetyl pyridinium chloride, myristyl gamma pirnl ;n; chloride and hPn7~lknn;--m rhl nri r1P Suitable anionic agents include sodium lauryl sulphate, sodium heptadecyl sl-lrhAte, alkyl benzPnP~l~lphnn;c acids and salts thereof, sodium W0 95/28969 218 7 ~ 9 31 -- ~ r~ "
butylnapthalene sulfonate, and sulphosllrr;nAtPR.
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 l~clllP
balance each other out they act as neutral 1 ecll 1 ~'R .
The pH at which the zwitterion rnnr~ntr;lt; nn is maximum is known as the iso~ ctr;r point. r~ ~QIlnrqR~ such as certain amino a,cids having an isoelectric point at the desired pH of the f, 1 At; nnR of the present invention are useful in practicing the present invention.
In preparing the f~ lAt;nnç: of the present invention we prefer to use nonionic rm~ ;f;rr5 or surface active agents which, similarly to the nnn; nn; r contrast agents, possess a 8~rrr; or tnr; c~lo~; cal prof ile to that of anionic, cationic or ~witterionic agents. ~n the nonionic emulsifying agents the proportions of hydrophilic and hydrophobic groups are about evenly hAlAnred. They differ frQm anionic and cationic surfArtAntR by the absence of charge on the l ~rlll e and, for that reason, are generally less irritating than the cationic or anionic surfactants.
Nonionic surfactants include carboxylic esters, carboxylic amides, ethoxylated alkylphenols, ethoxylated Al;rhAt;c AlrnhnlR, ethylene oxide polymer or ethylene oxide/propylene oxide co-polymers polyvinylpyrrolidone and polyvinylalcohol.
One particular type of carboxylic ester nonionic surf ace active agents are the partial, f or 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 f atty acids .
~ .

W0 95/28969 p~
' -218701~ - 32 - ~
Another type OL carboxylic esters are the rnnflPnR~t;nn products of fatty and resin partial acids, for example mono-, ester6 ethylene oxide, such as fatty or resin acid esters of polyoxyethylene sorbitan and ~orbitol, for example polyoxyethylene sorbitan, mono-tall oil esters. These may contain, for example, from rlbout 3 to about 80 oxyethylene units per r leclll P and fatty or resin acid groups of from about 8 to about 18 carbon atoms. r lPR Of naturally occurring fatty acid mixtures which may be used are those f rom coconut oil and tallow while _ 1~R of single fatty acids are tlnflPr;~nnj C acid and oleic acid.
Carboxylic amide nnn; nn; c surface active agents are the ammonia, monoethylamine and diethylamine amides of f atty acids having an acyl chain of f rom about 8 to about 18 carbon atoms.
The ethoxylated alkylphenol nonionic surface active agents include various polyethylene oxide rnnflPnRAtPR of alkyl~hPnnlR, ~R~er~lly the rr,nflPnc~t;on products of mono-alkylrhPnnlR or dialkylrhPnnlR wherein the alkyl group rnnt~;nR about 6 to ab4ut 12 carbon atomR in either br~nrhPfl chain or particularly straight chain configuration, for example, octyl cresol, octyl phenol or nonyl pheno1, with ethylene oxide, said ethylene oxide being present in amounts equal to f rom about 5 to about 25 moles of ethylene oxide per mole of alkylphenol .
Ethoxylated aliphatic alcohol nonionic surface active agents include the rnnflPnR~t;nn products of ~l ;rh~t; r 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 er~ual amounts from about 30 to about 60 moles of ethylene oxide per mole of alcohol.
Preferred nnn; nn; r surface active agents include:
.

W095/28969 r~
2187Ql!~ `

(a) Sorbitan esters (sold under the trade name Span) having the formula:
HO R, \o~C~R2 or CE~R3 wherein Rl = R2 = OH, R3 = R for sorbitan monoesters, Rl = OH, Rz = R3 = R for sorbitan diesters, Rl = R2 = R3 = R for sorbitan triesters, where R = (CllH23~ COO for laurate, (Cl7H33) COO for oleate, (ClsH31) COO for palmitate, (C17H3s) COO for stearate;
(b) Polyoxyethylene alkyl ethers (i.e. Brijs) having the f ormula:
CH3 ( CH2 ) x ( O - CH2 - CH2 ) yOH
where (x + l ) is the number of carbon atoms in the alkyl chain, typically:
12 lauryl (dodecyl) 14 myristyl (t~tr~-lPCyl) 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 Tween or Polysorbates 20, 40, 60, 65, 80 ~ 85 having the formulae (1) and (2) WO 95/28969 P~1.~

C~2 IIco(c2~o)WH
HtOC~ OCH 1) (1) HCO(C2EI~O~YH
CEI20(C2n~0)zOCR
C~I2 ICO(C2EI~O)W~I
(2) RCOtOC,H,)~OCH O
~C
lICO(C2~1~0)yOCR
CEI20(C~H~O)zoCR
wherein w+x+y+z = 20 (Polysorbate 20, 40, 60, 65, 80 and 85) w+x+y+z = 5 (Polysorbate 81) w+x+y+z = 4 (Polysorbate 21 and 61).
(d) Polyoxyethylene stearates, such as:
poly (oxy-1, 2-ethanediyl), a-hydro-~-hydroxy-ort ~ n~ e;polyethylene glycol monostearate; and poly (oxy-l ! 2 -ethanediyl ) -a- (l-oxooctadecyl ) -~hydroxy-polyethylene glyco~ monostearate.
(e) Polyethylene oxide/polypropylene oxide block co-polymers, sold.under the name PLU~ONICm, which include Poloxamer 407 (PLI~RONIC~ F127), PQ11 188 (PLURONIC~
F68), Poloxamer 237 (PLURONIC'U F87) and Poloxamer 338 ( PLURON C~ F10 8 ) .

wo s~/28969 2 ~ 8 ~ r~ s/~ s~

( f ~ Polyvinylpyrrolidone .
(g) Polyvinylalcohol.
The dosages of the contrast agent used ~r--nr-l;ng 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 Pnh~nrP~l imaging.
By employing as small amount of contrast agent as possible, toxicity potential ig m;n;m;7P,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, pref erably in the range of f rom 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 v;~ i7~t;on of the GI tract. For CT scanning the contrast agents of the pre~ent invention will be in the range of from about l 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.
When administered to mammals, the compositions of the present invention produce p~nPl 1 Pnt x-ray and CT
images .

Claims (10)

CLAIMS:

1. An x-ray contrast composition for oral or retrograde examination of the gastrointestinal tract comprising on a % weight per volume basis:
(a) a contrast agent selected from (1) from about 5 to 45% of an x-ray contrast producing agent having the formula (I) 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; or (2) from about 5 to 45% of 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 H, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower alkyl;
(3) from about 5 to 45% of 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;
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-carbonyloxy 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;
(4) from about 5 to 45% of 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 X, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower alkyl;
(5) from about 5 to 45% of 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;
(6) from about 5 to 45% of an x-ray contrast producing agent having the formula, or a pharmaceutically acceptable salt thereof wherein X is ;
Z is H, halo, methyl, ethyl, n-propyl, C4-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 aryl each of which may be optionally substituted with halo, fluoro-lower-alkyl, 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;

(7) from about 5 to 45% of a crystalline contrast producing 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 absorbed 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 about 0.1 to 10% of a pharmaceutically acceptable clay selected from the group consisting of: montmorillonite, beidelite, nontronite, hectorite and saponite;
(c) from about 1.0 to 20% of a surfactant selected from the group consisting of nonionic, anionic, cationic and zwitterionic surfactants;
(d) from about 0 to 15% of an excipient; and (e) water to make 100% by volume.

2. The x-ray contrast composition of claim 1 wherein said x-ray contrast producing agent is present in an amount of from about 10 to 35%.

3. The x-ray contrast composition of claim 1 wherein said pharmaceutically acceptable clay constitutes from 0.5 to 5% of the composition.

4. The x-ray contrast composition of claim 1 wherein said surfactant constitutes from 2 to 10% of the composition.

5. The x-ray contrast composition of claim 1 wherein said excipient constitutes from 0.5 to 5% of the composition.

6. The x-ray contrast composition of claim 1 wherein said nonionic surface active agent is selected from the group consisting of carboxylic esters, carboxylic amides, ethoxylated alklyphenols, ethoxylated aliphatic alcohols, ethylene oxide polymer, ethylene oxide/propylene oxide co-polymer, polyvinylpyrrolidone and polyvinylalcohol.

7. The x-ray contrast composition of claim 1 wherein said surfactant is sorbitan ester having the formula:
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 or (C17H35) COO for stearate

8. The x-ray contrast composition of claim 1 wherein said surface active agent is polyoxyethylene stearate.

9. The x-ray contrast composition of claim 1 wherein said surfactant is polyoxyethylene sorbitan fatty acid ester of the formulae (1) and (2) (1) Polyoxyethylene sorbitan monoester (2) wherein w+x+y+z = 20 w+x+y+z = 5 w+x+y+z = 4.

10. 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 an x-ray contrast formulation of any preceding claim.