HUT76336A - X-ray contrast compositions containing cellulose derivatives - Google Patents

Description

BACKGROUND OF THE INVENTION The present invention relates to x-ray contrast compositions comprising contrast agents and cellulose derivatives and methods of using them in diagnostic radiology of the gastrointestinal (gastrointestinal) tract.

Fractures and other conditions related to the skeletal system are x-rayed using X-rays and computed tomography (CT) imaging is usually performed without the use of contrast agents. In order to visualize soft tissue such as the gastrointestinal (GI) tract with X-rays, contrast agents are required which weaken the X-rays. D. P. Swanson et al., Pharmaceuticals In Medical Imaging (1990, MacMillan Publishing Company), provides an excellent overview of medical imaging using contrast agents.

RI radiographic examination of the GI tract involves indigestion, altered bowel behavior, lower abdominal pain, GI bleeding, etc. recommended. Prior to radiological examination, a radiation-impermeable contrast medium is required to allow proper delineation of said cavity or mucosal surface from surrounding soft tissue. Accordingly, contrast media are orally administered to visualize the mouth, throat, esophagus, stomach, duodenum, and proximal small intestine. For the examination of the small intestine and colon, the contrast agent 3 is administered rectally.

The most commonly used contrast agent for visualizing the GI tract is barium sulfate, which is administered orally in suspension or rectally by enema. (See, for example, 2,659,690; 2,680,089; 3,216,900; 3,235,462;

U.S. Patent Nos. 038,370 and 4,120,946. Despite the relatively good contrast characteristics, negligible absorption from the GI tract following oral or rectal administration, and rapid excretion from the body, have certain disadvantages. It is not homogeneous in the presence of intestinal fluids and has poor adhesion to the mucosa, which can result in poor X-rays. When administered in the form of an enema, the colon becomes fluffy and forms irregular lumps in the stool.

Iodinated organic compounds have also been used as GI contrast media, since the iodine atom absorbs X-rays efficiently. These contrast agents are the most versatile and are used in a variety of procedures.

It absorbs very strongly the X-rays with which iodine interacts and produces a so-called photoelectric effect, resulting in high contrast intensification as a result of the introduction of photons into the iodine-containing medium. The contrast enhancement is above the level we would expect from a change in relative density. Due to this enhancement, relatively low concentrations of contrast media can be used. (For example, for iodinated substances see

-42,786,055; 3,795,698; 2,820,814; 3,360,436; 3,574,718;

733 397; U.S. Patent Nos. 4,735,795; and 5,047,228.)

What we want from an ideal GI contrast agent include: a good toxicological profile; be able to fill the entire intestine / cavity and evenly coat the intestinal mucosa to detect the presence of the intestine when the cavity is not dilated; it should have a pleasant taste and should not irritate the intestinal mucosa; and pass through the GI tract without inducing artificial change or vigorous bowel movement.

Numerous researchers have set goals to meet these requirements, and their work has resulted in great advances over the years. To meet the condition that the intestinal mucosa is evenly coated with the contrast agent to effectively cover the intestinal wall has proved to be quite difficult. Without these requirements, it is impossible to obtain high-precision X-rays. In this regard, the use of certain polymeric additives has been recommended, which are described below.

U.S. Patent 4,069,306 discloses an X-ray contrast composition that is said to adhere to the walls of body cavities. The formulation contains finely divided, water-insoluble inorganic X-ray contrast media and tiny particles of a hydrophilic polymer that are water-insoluble but swell. The cavity is filled with an aqueous suspension of such a formulation. The X-ray contrast agent forms a mixture with the tiny polymer particles mentioned above and / or is embedded in the polymer particles and / or adheres to the polymer particles.

U.S. Patent 4,120,946 describes a pharmaceutical composition for barium opacification of the gastrointestinal tract comprising colloidal barium sulfate and polyacrylamide in an aqueous vehicle. Polyacrylamide forms a low viscous solution which allows the barium sulfate to remain in suspension while allowing the formulation to adhere well to the walls of the organ to be x-rayed.

U.S. Patent No. 5,019,370 discloses a biodegradable radiographic contrast agent consisting of a biodegradable polymer sphere which contains a radiographically impermeable element such as iodine, bromine, samarium and erbium. The contrast medium is provided in a dry or liquid state, which can be administered intravenously, orally and intraarterially.

Japanese Patent Application No. 55-127322 discloses X-ray contrast compositions comprising a polymeric material selected from barium sulfate and carboxymethylcellulose salts, propylene glycol alginate, cellulose sulfate polyacrylate, pectin and tragacanth. The polymeric material is used to increase the viscosity of the composition.

-6 Although these polymeric materials greatly enhance the binding of the contrast agent used with them to the walls of the organ to make it more visible, there is still a need for an improved X-ray imaging material that uniformly covers soft tissues subjected to diagnostic X-ray examination.

It is an object of the present invention to provide a composition for coating the gastrointestinal tract of a mammal, which provides an effective, opaque coating for diagnostic testing of the GI tract. To do this, a thin coating is made on the inner surface of the GI tract, the formation of which is triggered by the consumption of a cellulose derivative prior to being visualized by an X-ray delivery device, which cellulose derivative is X-ray contrast and capable of coating the GI tract. Such a preparation has to meet several requirements: neither the X-ray contrast agent nor the cellulose derivative should be toxic; not contain leachable or digestible components that would be detrimental to the patient; and no component of the coating should be absorbed and penetrated through the intestinal surface.

The object of the present invention is achieved by a composition comprising an X-ray contrast agent in a pharmaceutically acceptable carrier comprising a cellulose derivative.

In accordance with the present invention, a GI tractor

Also provided is a method for the diagnostic imaging of a-7tus X-ray, characterized in that the patient is administered an effective contrast-producing amount of the X-ray contrast composition described above orally or rectally.

The X-ray contrast agent of the present invention is selected from:

(1) a compound of formula (E), or a pharmaceutically acceptable salt thereof, wherein:

Z is hydrogen, halogen, C 1-20 alkyl, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted by halogen or halo-lower alkyl; βΐ and independently are hydrogen, C1-C25 alkyl, cycloalkyl, acetyl or halo-lower alkyl, where C1-C25 alkyl, cycloalkyl and halo-lower alkyl are optionally fluoro; lower alkyl, aryl, lower alkoxy, hydroxy, carboxyl, lower alkoxy-carbonyl or lower alkoxy-carbonyloxy, and the acetyl optionally fluoro- substituted with lower alkyl, aryl, lower alkoxy, hydroxy, (lower alkoxy) carbonyl, or (lower alkoxy) carbonyloxy;

····················································································································································· ······· The complete list of photos is based on these criteria.

-δη is 1-4;

y is 1-4; and x is 1 or 2;

(2) Compounds of formula F or pharmaceutically acceptable salts thereof

R is substituted or unsubstituted C 2 -C 8 alkyl, wherein the substituents are selected from C 1 -C 6 alkyl, hydroxy and alkoxy; and n is 1-5;

(3) Compounds of formula (G) wherein Z is hydrogen, halogen, C1-20 alkyl, cycloalkyl, lower alkoxy, cyano, wherein alkyl and cycloalkyl are substituted with halo or halo (lower alkyl). may;

R is C 1 -C 25 alkyl, cycloalkyl or halo-lower alkyl, each of which is optionally halogen, fluoro-lower alkyl, aryl, lower alkoxy, hydroxy, carboxyl, ( it may be substituted by lower alkoxy) carbonyl or (lower alkoxy) carbonyloxy; (CR | _R2) ^_ p ^{(CR3 = CR4) va} SY (CR ^ R ₂₎ pC = CQ radical;

R |, _R2, R3 and R4 are independently lower alkyl, which is optionally substituted by halogen;

-9>

············

x is 1-3;

y is 1-4;

n is 1-5;

m is from 1 to 15;

p is 1-10; and

Q is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, aryl or aryl (lower alkyl);

4) Compounds of formula (H) or pharmaceutically acceptable salts thereof

R is methyl, ethyl, n-propyl, C 4 -C 25 alkyl, cycloalkyl, unsaturated allyl or halo-lower alkyl, each of which is optionally halogen, fluoro-lower alkyl, aryl, lower it may be substituted by C alk-Cox alkoxy, hydroxy, carboxyl or C kevés-C alk alkoxy; or (CR 1 R 2) p - (CR 3 = CR 4) _m Q or (CR 1 R 2) p C = CQ;

R1, R2, R3 and R4 are each independently hydrogen, lower alkyl optionally substituted with halo;

n is from 2 to 5;

m is 2-5;

P is 1-10; and ···· ······ · ·

Q is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, aryl or aryl (lower alkyl);

or a pharmaceutically acceptable salt thereof;

5) Compounds of formula J or pharmaceutically acceptable salts thereof

Z is hydrogen, halo, C 1-20 alkyl, cycloalkyl, lower alkoxy, alkoxycarbonyl, cyano, wherein the alkyl and cycloalkyl groups may be substituted by halogen or halo-lower alkyl;

R is C 1-25 alkyl, cycloalkyl, a) or halo-lower alkyl, each optionally halogen, fluoro-lower alkyl, aryl, lower alkoxy, it may be substituted by hydroxy, carboxyl, (lower alkoxy) carbonyl or (lower alkoxy) carbonyloxy; or (CR 1 R 2) p - (CR 3 = CR 4) _m Q or (CR 1 R 6) p C = CQ;

R1, R2, R3 and R4 are each independently hydrogen or lower alkyl optionally substituted with halo;

x is 1-4;

-11n is 1-4;

m is from 1 to 15;

p is 1-20; and

Q is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, aryl or aryl (lower alkyl);

6) Compounds of formula (K) or pharmaceutically acceptable salts thereof

X is -C (= O) - or -SC 4 ^- ;

Z is hydrogen, halogen, C 5-20 alkyl, cycloalkyl, lower alkoxy, cyano, wherein alkyl and cycloalkyl may be substituted with halo or halo (lower alkyl);

R is C 1 -C 25 alkyl, cycloalkyl, aryl or halo-lower alkyl, each of which may be optionally substituted with lower C 5 -C 6 alkoxy, hydroxy, carboxyl, or C 1 -C 6 alkoxy-carbonyl; lower alkenyl, lower alkynyl, lower alkylene or lower alkoxycarbonyloxy;

n is 1-4;

y is 0-4; and w is 1-4;

7) Compounds of formula (L) or a pharmaceutically acceptable salt thereof

-12 their acceptable salts, in the formula

Z is hydrogen, halogen, C 1-20 alkyl, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted by halogen or halo-lower alkyl;

R is methyl, ethyl, propyl, C 9 -C 25 alkyl, cycloalkyl or halo-lower alkyl optionally substituted with halogen, fluoro-lower alkyl, aryl, lower alkoxy, hydroxyl, , they may be substituted by carboxyl, (lower alkoxy) carbonyl or (lower alkoxy) carbonyloxy; or (CR ₁ R ₂ ) p - (CR ₃ = CR ₄ ) _m Q or (CR ₁ R ₂ ) p ^- C = CQ;

R 1, R ₂ , R ₃ and R 4 are each independently lower alkyl optionally substituted with halo;

x n

m

P

Q is 1-4;

1-5;

1-15;

1-10; and is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, aryl or aryl (lower alkyl);

8) a granular X-ray crystalline contrast agent,

-13 comprising a surface modifier adsorbed on its surface;

9) iodinated polymer, water insoluble beads having a particle size of approx. 0.01 to approx. Between 1000 μ, where the above iodinated polymer beads contain a repeating unit of formula (I)

A is a repeating organic unit in the backbone of the polymer chain;

and

X is an organic group containing an iodinated aromatic group and a hydrophilic group, with an approx. 40 and approx. 80% by weight of iodine;

10) a barium salt.

As used herein, the term halogen means fluorine, chlorine, bromine or iodine.

Cycloalkyl means carbocyclic rings containing from three to eight ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl, which on one or more of the ring carbon atoms have one or more lower alkyl or lower alkoxy groups. may be substituted.

The definition of lower alkyl and lower alkoxy also refers to monovalent aliphatic groups, including branched groups containing from 1 to 10 carbon atoms. Examples of lower alkyl include methyl, ethyl, propyl, isopropyl, n-butyl,

-14sec-butyl, tert-butyl, η-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, η-hexyl, 1-methyl pentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,

2-hexyl, 3-hexyl, 1, 1,3-3-tetramethylpentyl, 1,1-dimethyloctyl and the like.

Lower alkenyl and lower alkynyl mean monovalent unsaturated groups, including C3-C10 groups which may be branched and thus define 1-ethenyl, 1- (2-propenyl), 1- (2-butenyl) ) -, 1- (1-methyl-2-propenyl) -, 1- (4-methyl-2-pentenyl) -, 4,4,6-trimethyl-2-heptenyl, Ι-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" refers to divalent saturated groups, including C2-C10 branched chain groups having free valencies on various carbon atoms, such as 1,2-ethylene, 1,3-propylene, 1,4-butylene. -, 1-methyl-1,2-ethylene, 1,8-octylene and the like.

The term aryl means an aromatic hydrocarbon group having from 6 to 10 carbon atoms. Preferred aryl groups are phenyl, substituted phenyl and naphthyl, which is

1-3 substituted with the same or different groups, these groups are selected from the group consisting of lower alkyl, halogen, hydroxy (lower alkyl), alkoxy (lower alkyl) and hydroxy.

-15The above-described X-ray contrast compounds of types 1) to 7) may contain one, two, three or four iodine atoms per molecule; the preferred compounds contain at least two, and more preferably at least three iodine atoms per molecule.

Solid X-ray contrast agents useful in the practice of the present invention may be prepared in the form of particles in a manner known in the art. The solids are crushed to the desired size using conventional milling techniques such as air jet or fragmentation milling. We found that approx. An effective average particle size of less than 100 μ provides good distribution and coating in the GI tract. As used herein, particle size refers to an average particle size as determined by conventional techniques such as sedimentation fractionation and plate centrifugation. An approx. An effective mean particle size of less than 100 μ means that the particles have a mean particle size of at least about 1 μm. 90% is approx. It has a weighted average particle size of less than 100 μ as determined by methods well known in the art.

The cellulose derivatives used in the present invention include methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose; and microcrystalline cellulose; having an average particle size of from 0.01 to 100 μ, more preferably from 0.05 to 10 μ, and most preferably from 0.1 to 1 μπι.

Contrast agent and cellulose derivative for administration

-16 are conveniently formulated using physiologically acceptable carriers or excipients in a manner known in the art. The contrast agent and the cellulose derivative are suspended or partially dissolved in an aqueous medium with the addition of pharmaceutically acceptable excipients (such as surfactants, emulsifiers) and additives to form a dispersion, solution, suspension or emulsion.

The method of the present invention for use in diagnostic imaging of the GI tract is characterized by administering an effective amount of a composition of the present invention orally or rectally to a mammalian patient in need of x-ray examination. Following administration, at least a portion of the GI tract containing the administered composition is subjected to X-ray imaging to obtain an X-ray imaging pattern corresponding to the presence of the contrast agent, then visualized and interpreted by methods known in the art.

The compounds of type 1) as defined above are the compounds of formula

EP-A-613689.

For example, N-acetyl-N- (2'-octyl) -4-iodoaniline and

N- (4'-iodophenyl) -2-amino-octane.

Compounds of type 2) as defined above are

EP-A-568155.

Examples include 2,4,6-triiodo-phenoxy-2-octane, 2,4,6-triiodo-phenoxy-2-butane, 2,4,6-triiodo-phenoxy-2-hexane and ··· · · »« * ·

-174-iodo-phenoxy-2-octane.

Preferred compounds of type 2) are those compounds of formula (FI) wherein R is C4-C8 secondary alkyl.

The most preferred type 2 contrast agent is 2,4,6-triiodophenyl (sec-octyl) ether (F2).

Type 2 contrast agents are sparingly soluble in water and have a partition coefficient of 10 or greater. This degree of solubility allows the preparation of stable formulations in the form of an emulsion or suspension when the formulation contains the requisite excipients. Stable means that the components of the composition do not separate after oral or rectal administration and during radiological examination of the GI tract. Due to the poor solubility of contrast agents in aqueous media, contrast agents diffuse into the intestinal mucosa and mucus, thereby forming a coating in the intestines. On the other hand, due to their poor solubility, absorption of contrast agents into the intestinal wall is minimal, which reduces the potential for toxic side effects.

The compounds of the type 3) as defined above are the

EP-A-614669.

For example, 2-octyl-2,3,5-triiodobenzoate, a

3,3,4,4,5,5,6,6,7,7,8,8-dodecafluoro-2-octyl-2,3,5-triiodobenzoate, bis (2-hexyl) -2, 3,4,6-tetraiodo terephthalate, ethyl 3- (2-octyloxy) -2,4,6-triiodobenzoate and bis (2-octyl) -2,4,6-triiodoisophthalate .

-18A compounds of type 4) as defined above

EP-A-609589.

For example, 1,3,5-tri (n-beoxyl) -2,4,6-triiodobenzene, 1,3,5-triethyl-2,4,6-triiodobenzene, 1,3 5-tri (n-butyl) -2,4,6-triiodobenzene; 1,3,5-1ri (4-methylpentyl) -2,4,6-triiodobenzene; 5-tri (n-pentyl) -2,4,6-triiodobenzene; 1,3,5-tri (3-methylbutyl) -2,4,6-triiodobenzene; 5-tri (n-propyl) -2,4,6-triiodobenzene; 1,3,5-tri (n-heptyl) -2,4,6-triiodobenzene; 2- (4- iodophenyl) nononane, 9- (p-iodophenyl) -10-undecenoic acid ethyl ester and (E) -11- (p-iodophenyl) -9-undecenoic acid ethyl ester.

The compounds of type 5) as defined above are the compounds of

EP-A-614670.

For example, 400 bis (4-iodophenyl) ether of polyethylene glycol,

1,8-bis (0-2,4,6-triiodophenyl) tripropylene glycol;

bis (2,4,6-triiodophenoxy) -3,6,9-trioxa undecane, 1,2-

-bis (2,4,6-triiodophenoxy) ethane, 400 bis (O-2,4,6-triiodophenyl) ether of polyethylene glycol, 1- (3-iodophenoxy) -3,6,9 trioxadecane, 1,3-bis (2,4,6-triiodophenoxy) butane, 1- (3-iodophenoxy) -6- (2,4,6-triiodophenoxy) hexane, and 1,12-bis (2,4,6-triiodophenoxy) dodecane is described.

Compounds of the type 6) as defined above are

EP-A-617970.

For example, 2,4,6-triiodophenyl-2-ethylhexanotate, a

2,4,6-triiodophenyl-2-methylpentanoate; 2,4,6-triiodophenyl-3-cyclopentylpropionate; 2,4,6-triiodophenyl (2-propyl); pentanoate, 2,4,6-triiodophenyl perfluoroheptanoate,

-19a 2,4,6-triiodophenyl tris (2-ethyl) hexanoate, 2,4,6-triiodophenyl dodecanoate, 3- (trifluoromethyl) -2,4,6-tri iodophenyl 2-ethylhexanoate, 2,4,6-triiodophenylbis (2-methylpentanoate), 2,4,6-triiodophenylhexanesulfonate,

2,4,6-triiodophenyl-heptanesulfonate; and 2,4,6-triiodophenyl-decanesulfonate.

The compounds of type 7) as defined above are the compounds of formula

EP-A-609587.

For example, 2- (4-iodo-phenoxy) -containing, 2- (2,4,6-triiodophenoxy) pentadecane, 2- (2,4,6-triiodophenoxy) -containing, (2,4,6-triiodophenoxy) -ΙΗ, ΙΗ, 2H, 2H-perfluorooctane, 1- (2,4,6-triiodo-3-trifluorophenoxy) octane, 2- (2) 4,6-triiodophenoxy) nonane, 2-ethyl-1- (2,4,6-triiodophenoxy) hexane,

3,3-diphenyl-1- (2,4,6-triiodophenoxy) propane, 3- (2,4,6-triiodophenoxy) nonane, 2- (4-iodophenoxy) - undecane, 2-iodo-phenoxy-cyclopentane, 3-iodo-phenoxy-cyclopentane, (3,5-dimethyl-2,4,6-triiodo-phenoxy) -cyclopentane, 2- (4-iodo-phenoxy) ) pentadecane, 4-iodophenoxycyclopentane, 2,4,6-triiodophenoxycyclopentane, 2,4,6-triiodophenoxymethylcyclopentane, 2- (2,4,6) triiodophenoxy) ethylcyclopentane, (E, E) -1- (2,4,6-triiodophenoxy) -3,7,11-trimethyl-2,6,1O-dodecatriene, 1- (2,4,6-triiodophenoxy) -3,7-dimethyl-6-octene, (E) -1- (3,5-dimethyl-2,4,6-triiodophenoxy) -3 7-dimethyl-2,6-octadiene, (E) -1- (2,4,6-triiodophenoxy) -3,7-dimethyl-2,6-octadiene,

1- (2,4,6-triiodophenoxy) -3-octine, 2- (2,4,6-triiodophenoxy) -4-octine, 1- (2,4,6-triiodophenoxy) ) -3-octine, diethyl 2- (2,4,6-triiodophenoxy) -1,3-propanedioate, diisopropyl 2-20- (2,4,6-triiodophenoxy) -1, 3-propanedioate, ethyl 2,2-bis (3-iodophenoxy) acetate, ethyl 5- (2,4,6-triiodophenoxy) hexanoate, 5- (2,4,6) -triiodophenoxy) hexan-1-ol, a

10- (4-iodo-phenoxy) -undecan-1-ol, ethyl 5- (2,4,6-triiodophenoxy) hexyl carbonate and ethyl 10- (3-iodo-phenoxy) - undecanoate.

The compounds used in the Type 8 formulations defined above are non-radioactive and exist as a discrete crystalline phase in an organic material. The crystalline phase is different from an amorphous or non-crystalline phase which has a

It is available as a result of the solvent precipitation method described in U.S. Patent No. 826,689. The organic material may 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 very poorly soluble and dispersed in at least one liquid medium. Poor solubility means that the agent in the liquid dispersant medium, such as water, is less than about 10%. 10 mg / ml and preferably less than about 10 mg / ml. Soluble in 1 mg / ml.

The X-ray contrast agent may be an iodinated compound. The iodinated compound may be aromatic or non-aromatic. Aromatic compounds are preferred. The iodinated compound may contain one, two, three or more iodine atoms per molecule. Preferred species contain at least two, and more preferably at least three iodine atoms per molecule. The chosen one

21-iodinated compounds may carry substituents that do not increase the solubility of the compound, such as alkyl-ureido, alkoxyacylamido, hydroxyacetamido, butyrolactamido, succinimido, trifluoroacetamido, carboxy, carboxamido. , hydroxy, alkoxy, acylamino and the like.

A preferred class of contrast agents include various esters and amides of iodinated aromatic acids. The esters are preferably alkyl or substituted alkyl esters. The amides may be primary or secondary amides, preferably alkyl or substituted alkyl amides. For example, the contrast agent is an ester or amide of a substituted triiodobenzoic acid, such as a triiodobenzoic acid substituted with an acyl, carbamyl and / or acylmethyl group. Iodinated aromatic acids include, but are not limited to, diatrizoic acid, metrizoic acid, Ithalamic acid, trimesic acid, uroconic acid, joxaglinic acid (hexabrix), joxitalamic acid, tetraiodoterephthalic acid, iodipamide, icarminic acid and the like.

Many of the iodinated molecules described above, when mentioned in monomeric form, can be made into diners (referred to as bis compounds), trimers (referred to as tris compounds), and the like. in the form known in the art. It can be said that the present invention can be carried out with poorly soluble iodinated compounds in the monomeric, dimeric, trimeric and polymeric forms.

Groups of preferred contrast agents are characterized by the general structural formulas (A), (B), (C) and (D).

-22In these structures, R is OR 1, NR ² R ² , alkylene, -CO.OR ¹ , or -O-alkylene-CO.OR 4 where R ² and R ² are independently hydrogen or alkyl.

Each alkyl group may independently have from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, and more preferably from 1 to 4 carbon atoms.

The alkylene groups are preferably C 1 -C 4, such as methylene, ethylene-propylene and the like.

Particularly preferred contrast agents include ethyl ester of diatrizoic acid, i.e., ethyl 3,5-diacetamido-2,4,6-triiodobenzoate, which is ethyl-3,5-bis (acetylamino) -2,4, Also known as 6-triiodobenzoate or ethyl diatriazoate, it has the structure of Formula A, wherein R is -OCH 2 CH 3; an ethyl glycolate ester of diatrizoic acid, i.e. ethyl [3,5-bis (acetylamino) -2,4,6-triiodobenzoyloxy] acetate, also known as ethyl diatrizoxy acetate; and ethyl 2- [3,5-bis (acetylamino) -2,4,6-triiodobenzoyloxy] butyrate, also known as ethyl 2-diatrizoxybutyrate.

In addition, the invention may be carried out with water-insoluble iodinated carbonate esters as described in PCT / EP90 / 00053.

The above-mentioned X-ray contrast agents are known compounds and / or can be prepared by methods known in the art. For example, water-insoluble esters and terminal amides of the iodinated aromatic acids described above may be synthesized by conventional alkylation and amidation techniques known in the art. The aforementioned acids and other acids which are useful as starting materials are commercially available and / or can be prepared by methods known in the art.

The particles for use in the type 8 formulation as defined above contain a surface modifier. The surface modifiers used herein are physically adherent to the surface of the X-ray contrast agent, but do not react chemically with the agent or with themselves. The individually adsorbed molecules of the surface modifiers are substantially free of intermolecular crosslinking. Suitable surface modifiers may be selected from known organic and inorganic pharmaceutical excipients such as various polymers, low molecular weight oligomers, natural materials and surfactants. Preferred surfactants include nonionic and anionic surfactants. Typical examples of surface modifiers include gelatin, casein, lecithin (phosphatides), gum arabic, cholesterol, tragacanthate, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrylate, cetomacetol ethers such as macrogol ethers such as cetomacrogol 1000, polyoxyethylene glycine oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g. , sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, non-crystalline cellulose, magnesium aluminum silicate, thirethanolamine, polyvinyl alcohol and polyvinylpyrrolidone (PVP). Most of these surface modifiers are known pharmaceutical excipients and are detailed in the Handbook of Pharmaceutical Excipients

Britain, The Pharmaceutical Press, 1986).

Particularly preferred surface modifiers are polyvinylpyrrolidone, tyloxapol, poloxamers such as Pluronic F68 and F108, which are block copolymers of ethylene oxide and propylene oxide, and poloxamines such as Tetronic 908 (also known as Poloxamine 908), which is propylene. a tetrafunctional block copolymer obtained by sequential addition of oxide and ethylene oxide to ethylenediamine, available from BASF, dialkyl esters of dextran, lecithin, sodium sulfobenzoic acid such as Aerosol OT, which is a sodium sulfobenzoate available from American Cyanamid, Duponol P, which is sodium lauryl sulfate, available from DuPont, Triton X-200, which is available from an allyl-aryl-polyether sulfonate, from Rohm and Haas, Tween 80, a polyoxyethylene sorbitol fatty acid and available from ICI Specialty Chemicals, and Carbowax 3350 and 934, which

-25 polyethylene glycols, available from Union Carbide. Particularly suitable surface modifiers are Tetronic

908, Tween's, Pluronic F-68 and polyvinylpyrrolidone.

Other suitable surface modifiers include:

decanoyl-N-methylglucamide;

n-decyl .beta.-D-glucopyranoside;

n-decyl .beta.-D-maltopyranoside;

n-dodecyl-β-D-glucopyranoside;

n-dodecyl-J3-D-maltoside;

heptanoyl-N-methylglucamide;

n-heptyl] -3-D-glucopyranoside;

n heptϋ-β-D-thioglucoside;

n-hexyl .beta.-D-glucopyranoside;

nonanoyl-N-methylglucamide;

η-ηοηΐΙ-β-D-glucopyranoside;

octanoyl-N-methylglucamide;

n oktϋ-β-D-glucopyranoside;

octyl .beta.-D-thioglucopyranoside;

and the like.

A particularly preferred group of surface modifiers include water-soluble or water-dispersible compounds of formula (M) wherein L is (b), (c), (d) and (e), wherein

L 'is a bond, -O-, -S-, -NH-, -CONH- or -SC ^ NH-;

R is hydrophobic substituted or unsubstituted

-26alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;

9

R ¹ and R ^{1 '} are each independently hydrogen or C 1-4 alkyl;

each of a and b is independently 0, 1, 2 or 3, provided that the sum of a and b is not more than 3; and x and y are each independently 3, 4,

5, 6 or 7.

Within this group, compounds having the above structure in which R has from 6 to 36 carbon atoms are preferred, for example, R is a C 6 -C 18 n-alkyl group, R 1 and R 2 are independently methyl, ethyl, propyl or buthyl, and a is 0 and b is 0. This group of surface modifiers is described in British Patent Application No. 9104957.7, filed March 8, 1991, in the absence of a suitable dicarboxylic acid ester and a suitable monosaccharide amine, preferably a solvent, They can be prepared by reacting them at 140-200 ° C.

Surface modifiers are commercially available and / or can be prepared by methods known in the art. Two or more surface modifiers may be used in combination.

Particles suitable for use in the compositions of the type 8) defined above are described in U.S. Patent No. 5,145,684, which describes a grinding process.

-27 method. According to the method, the poorly soluble X-ray contrast agent is dispersed in a liquid dispersant medium and wet-comminuted in the presence of a grinding medium to reduce the particle size of the contrast agent to an approx. 0.05 μ and approx. 100 μ, preferably approx.

0.05 µ to 5 µ, and most preferably approx. Up to an effective average particle size of 0.1 μ to 1 μ. The particle size may be reduced in the presence of a surface modifier. Alternatively, the particles may be brought into contact with the surface modifier after shredding.

As used herein, particle size refers to a number average particle size determined by methods well known in the art such as sedimentation fractionation, photon correlation spectroscopy, or plate centrifugation. One

0.05 μ and approx. An effective mean particle size of 100 μ means that at least 90% of the particles have a weighted average particle size of about 100 µm. Between 0.05 and 100 μ, as measured by the above methods. The particle size range allows for the distribution of a sufficient number of particles in the film-forming composition when the GI tract is coated with it, yet provides a guarantee of absorption through the intestinal walls.

The water-insoluble iodinated polymer beads used in the Type 9 formulation as defined above are a

U.S. Patent No. 406,878 and International Patent Application Publication No. WO 94/25075.

The structure of the iodinated polymers of the present invention is represented by formula (I). The backbone of the iodinated polymer may be represented

i) a condensation polymer such as a polyester, polyamide, polyurethane, polycarbonate, polyepoxide, polyether, a phenol-formaldehyde polymer and equivalent condensation polymers;

(ii) an addition polymer made of one or more additionally polymerizable monomers containing polymerizable double bonds, such as vinyl monomers, including addition polymers such as polyvinyl alcohol, polyalkyl methacrylates, poly (alkyl acrylates) and equivalent addition polymers; or (iii) a naturally occurring polymer such as a polysaccharide containing repeating glucose units such as starch, glycogen, cellulose, cellulose derivatives, and naturally occurring equivalent polymers.

Preferably, the repeating unit (A) present in formula (I) is a residue of a repeating unit having an attached hydroxyl group, such as a poly (vinyl alcohol) repeat unit, a polyepoxide repeat epoxy unit, a hydroxylated acrylic polymer such as a poly (hydroxy) ethyl acrylate), or a glucose unit of a naturally occurring polysaccharide. As the linking hydroxyl group, either the organic moiety X in the cross-linking position or in formula I

It can serve as a reaction site for a precursor compound of -29. Such precursor compounds may be chemically coupled to the repeating units of the polymer backbone by condensation reaction with the hydroxyl group.

Organic moiety X of the above compound (I) represents an iodine-containing organic moiety comprising an iodinated aromatic group and one or more hydrophilic groups. In order to form a high iodine content characteristic of the polymers used in the present invention, the iodinated aromatic group contains a plurality of iodine substituents directly attached to the aromatic ring carbon atoms. Of these iodinated aromatic groups, aromatic groups containing three, preferably four, iodine ring carbon atoms are particularly preferred. A preferred iodinated aromatic group is the iodinated phenyl ring, although naphthyl rings and nitrogen-containing heterocycles containing 5-7 ring atoms may also be used. A particularly preferred iodinated aromatic group is the phenyl ring, which carries an iodine substituent on four of the ring carbon atoms.

The hydrophilic group X i) is typically attached directly or via a chemical linking group to one or more ring carbon atoms of the iodinated aromatic group. Preferred linking groups include lower aliphatic groups such as alkylene groups, amido groups and equivalent aliphatic groups having from 1 to 4 carbon atoms. Hydrophilic groups are typically one of several such groups, including carboxyl groups; sulfo; amino 30portok; salts thereof, such as carboxylate salts, sulfonate salts, ammonium salts; polyols such as glucose groups; and equivalent hydrophilic groups.

Typically, the precursors from which the organic portion X of the compound of formula I is derived contain a reactive group which forms a chemical bond with the repeating unit of the polymer backbone. In a preferred embodiment of the invention, wherein the repeating unit of the polymer backbone is a residue of a repeating unit containing a hydroxy group, the reactive group on the X precursor is a group capable of reacting with the hydroxyl group. For example, the reactive group may be a carboxyl group which reacts with the linked hydroxyl group to form an ester group attached to the iodinated aromatic portion of the polymer backbone.

A number of other reactive group compounds can be used which form such chemical linking groups, such as ethers, amides, thioesters, carbonates, carbamates, sulfides and equivalent groups.

Some of the precursors in Part X of Formula I include: 3- (3-amino-2,4,6-triiodophenyl) -2-ethyl-propionic acid; 3- (3-hydroxy-2,4,6-triiodo-phenyl) -2-ethyl-propionic acid; Sodium 3- (3-butyrylamino-2,4,6-triiodo-phenyl) -2-ethyl acrylate; 3,5-diiodo-4-pyridone-N-acetic acid; 3-acetamido-2,4,6-triiodo-benzoic acid; tetraiodo phthalic anhydride and the like. Tetraiodo phthalic anhydride is particularly useful due to its high iodine content.

According to the above description, certain preferred iodinated polymers have the structure (N):

A is as defined above for formula (I);

X is as defined above for formula (I);

L is one of the above linking groups such as ester, ether, amide, thioester, carbonate, carbamate, sulfide and the like; and fi

R ^x -R ^o , which may be the same and different, are hydrogen, a substituent containing iodine or a substituent containing a hydrophilic group, with the proviso that X has about i. 40 and 80% (based on the molecular weight of X).

Preferred iodinated polymers are cross-linked. This can increase the water insolubility of the polymer and the swelling! resistance. The crosslinking can be accomplished by constructing appropriate crosslinking sites on the polymer backbone or on the X group or both. For example, in a preferred embodiment, wherein the polymer comprises a repeating unit bearing a linked hydroxyl group and a side chain group A containing a carboxyl group as a hydrophilic group, the hydroxyl group attached to one polymer backbone is another polymer.

It reacts with a carboxyl group attached to its X-side chain so that the two polymers can be linked via an ester group.

The polymeric contrast agents of the present invention contain both hydrophilic and hirophobic groups. The (I)

-32 repeating units of general formula A are essentially hydrophobic, as are many subgroups of X. Naturally

X also contains one or more hydrophilic groups. This combination of hydrophilic and hydrophobic groups is considered important for the perfect polymer surface and electrical properties which, in turn, make the polymer compatible with body organs and tissues.

The iodinated polymers can be prepared by any of a variety of conventional polymerization and chemical reaction methods.

In a preferred sequence of reactions, the precursor compound of the X-side chain is chemically reacted with a previously prepared polymer containing related groups, such as hydroxyl groups, as appropriate reaction sites.

The prepared polymer may be prepared by addition or condensation polymerization, depending on the polymer; or available from naturally occurring sources for naturally occurring polymers such as polysaccharides. The

The precursor compounds of group X can be reacted with the reaction site on the polymer backbone by a variety of well-known reaction procedures, depending on the nature of the linking group L in formula (I) that occurs in this reaction.

Preferably, the reaction of these precursor compounds is carried out under emulsifying conditions so that the resulting polymers are obtained in the form of finely divided particles. The crosslinking may be carried out during or after the coupling of the X group to the polymer backbone.

An example of a polyvinyl alcohol based polymer and tetraiodo-phthalic acid is described in the aforementioned WO 94/25075.

Once a water-insoluble and water-swellable iodinated polymer has been prepared as described above, the polymer may be crushed or milled to obtain polymer particles of appropriate size. Of course, in cases where the polymers are prepared under suitable conditions, such as bead polymerization or emulsifying conditions, the polymers may already have a suitable particle size so that further grinding or shredding may be unnecessary. These polymer particles have a suitable particle size of about. 0.01 to 1000 microns, preferably 0.1 to 100 microns.

The preferred barium salt (contrast agent of the type 10 mentioned above) is barium sulfate, which is a white, non-radiation, crystalline powder and is essentially insoluble in water. It is commercially available with a particle size in the range of 0.001 to 0.1 microns. However, good results are obtained with other finely divided, inorganic, substantially water-insoluble barium salts, including barium hexaboride, barium chromite, barium fluorogallate, barium tri (orthophosphate), barium metasilate, , barium zirconate and zirconium oxide. The formulations of the present invention have a concentration of about. 5% w / w and ca. They contain 95% by weight of barium salt. The compositions may be dispersions, colloids or suspensions, however, in preferred embodiments, the colloids may be

-34 is preferred.

The contrast agents used in the present invention may be formulated with physiologically acceptable carriers or excipients in a manner known in the art. The compounds may be suspended or partially solubilized in aqueous media by addition of pharmaceutically acceptable acids (such as surfactants or emulsifiers) and excipients to give a dispersion, solution, or suspension.

However, the oily contrast agents are preferably converted into emulsions.

The compositions of the present invention employing the above-described contrast agents type I-8) contain the following pharmaceutically acceptable components by weight / volume:

provinces

components Wide advantageous optimum Contrast times 30-200 40-160 85-120 (mg I / ml suspension) cellulose derivatives 0.05-10 0.1 to 4 0.2-1 (% W / v) Oily vehicle 0.0-55 0.1-25 7-15 (% W / v) Surfactant 0.0 to 20 0.1 to 10 3-7 (% W / v) Viscosity modifier 0.0 - 15 0.001 - 4 0.05 - 1

excipients (weight / volume)

Water - q.s. Up to 100% by volume

The formulations of the present invention that utilize a contrast agent of the type 9 defined above may contain the following pharmaceutically acceptable components by weight / volume;

components Wide range Preferred range Iodinated polymer beads 5-95 20-70 (% W / v) cellulose derivatives 0.05-10 0.1 to 4 (% W / v) Surfactant 0.0 to 20 3-7 (% W / v) Viscosity modifier 0.001 - 4 0.05 - 1

excipients (% w / v)

Water - q.s. Up to 100% by volume

Formulations of the present invention employing barium salts contain the following pharmaceutically acceptable components by weight / volume:

components Wide range Preferred range barium 5-95 40-70 (% W / v) Cellulose derivatives 0.1 to 10 0.2-1 (% W / v) Oily vehicle 0.1-55 7-15 Surfactant 0.1-20 3-7 (% W / v) Viscosity modifier 0.001 - 15 0.05 - 1

excipients (% w / v)

Water - q.s. Up to 100% by volume

When used for CT imaging of the GI tract, the concentration of the X-ray contrast agent should be between 0.01 and 40 mg / ml, more preferably between 0.25 and 25 mg / ml, and most preferably between 4 and 12 mg / ml.

The preferred cellulose derivative used in the present invention is AVICEL ^ RC-591, which is ca. 89 parts microcrystalline cellulose and ca. 11 parts mixture of sodium carboxymethyl cellulose.

In the following, the following should be noted with regard to the components used in the composition of the present invention.

If X-ray contrast agents are present in the formulations at concentrations below the minimum levels stated above, they will not provide good quality X-ray or CT images, while at maximum concentrations the GI tract will become impermeable to radiation and will not allow proper GI tract separation. .

In the practice of the present invention, an oil-in-water emulsion is preferred over a water-in-oil emulsion, suspension or dispersion. Oily substances having a density close to that of the aqueous phase render the emulsion stable. For this reason, low-density oils, such as mineral oils, are desirable for the preparation of emulsions. When X-ray contrast agents are oily substances at room temperature, the presence of an additional oily vehicle is not always necessary. Above 55% w / v the emulsion is no longer oil-in-water

-37 emulsion but also passes into a water-in-oil emulsion.

The formulations still provide excellent X-rays in the absence of surfactants, but without the surfactants the formulations are very difficult to emulsify and only suspensions / dispersions can be prepared which are less desirable for coating the GI tract and less stable during storage. Due to toxicity, it is desirable to keep the concentration of certain surfactants as low as possible; approx. Above 20% w / v the risk of toxicity is rapidly increasing.

Although the various compounds claimed in the present invention provide a good X-ray image with a pharmaceutically acceptable carrier, the addition of a cellulose derivative to the composition greatly improves the quality of the X-ray image. At the lower end of the range there is no or little benefit, while above the upper end of the concentration the emulsion is too viscous for administration.

Depending on the form and amount of the cellulose derivative used, viscosity modifiers may not be required; At levels greater than 15% w / v, the viscosity is too high and gels are expected to form.

The following examples further illustrate the invention.

-381.

components

N-Acetyl-N- (2-octyl) -4-iodoaniline

Light petroleum, NF

Polysorbate 80 (Tween 80)

Sorbitan Monooleate (Span 80) AVICEL ^R RC-591 qs Water Example 100%

Quantities by weight / volume

17:50

12:50

3.37

1.64

0.50 supplemented

components

N- (4'-Iodo-phenyl) -2-amino-octane (oil at room temperature)

Polysorbate 80 (Tween 80)

AVICEL ^R RC-591

qs water to 100% volume

Quantities by weight / volume

25.00

5.00

6.50 supplemented

Third

components

2,4,6-Triiodophenoxy-2-octane

Light petroleum, NF

Polysorbate 80 (Tween 80) Example AVICEL ^R RC-591

Quantities by weight / volume

14:50

12:50

3.37

0.50

qs water to 100% volume

-394. example

components Quantities w / v% of 2,4,6-Triiodophenoxy-2-Butane 17,00 Polysorbate 80 (Tween 80) 5.00 AVICEL ^R RC-591 6.50 qs water to 100% volume supplemented 5. example components Quantities w / v% of 2,4,6-Triiodophenoxy-2-Hexane 25.40 AVICEL ^R RC-591 10.00 qs water to 100% volume supplemented 6th example components Quantities w / v% of 4-Iodophenoxy-2-octane 30.00 Light petroleum, NF 20.50 Polysorbate 80 (Tween 80) 3.00 AVICEL ^R RC-591 0.15 qs water to 100% volume supplemented 7th example components Quantities w / v% of

2-Octyl-2,3,5-triiodobenzoate 17.50

Light mineral oil, NF 12.50

Polysorbate 80 (Tween 80) 3.37

Sorbitan Monooleate (Span 80) 1.64

AVICEL ^R RC-591 0.50

qs water to 100% volume

8th example components Quantities w / v% of 3,3,4,4,5,5,6,6,7,7,8,8- Dodecafluoropentane 2-octyl-2,3,5- -trijód benzoate 25.00 Polysorbate 80 (Tween 80) 5.00 AVICEL ^R RC-591 6.50 qs water to 100% volume supplemented 9th example components Quantities by weight / volume 1,3,5-Tri (n-hexyl) - -2,4,6-triiodo-benzene 17.50 Light petroleum, NF 12.50 Polysorbate 80 (Tween 80) 3.37 Sorbitan monooleate (Span 80) 1.64

AVICEL ^R RC-591 0.50

qs water to 100% volume

Example 10 Components Quantities w / v% of l, 3,5-Triethyl-2,4,6 -trijód benzene 25.00 (oil at room temperature) Polysorbate 80 (Tween 80) 5.00 AVICEL ^R RC-591 6.50

qs water to 100% volume

-4 111. example

Components Quantities by weight / volume

1,3,5-Tri (n-butyl) -2,4,6-triiodobenzene 20.00

Light mineral oil, NF 5.00

Polysorbate 20 (Tween 20) 2.50

Sorbitan Monolaurate (Span 20) 2.50

AVICEL ^R RC-591 0.50

qs water to 100% volume

Example 12 components Quantities w / v% of 2- (4-iodophenyl) nonane 25.00 Polysorbate 20 (Tween 20) 2.50 Sorbitan Monolaurate (Span 20) 2.50 AVICEL ^R RC-591 0.75 qs water to 100% volume supplemented 13 . example components Quantities w / v% of

Polyethylene glycol 1-400-bis (4-iodophenyl) ether 17.50

Light mineral oil, NF 12.50

Polysorbate 80 (Tween 80) 3.37

Sorbitan Monooleate (Span 80) 1.64

AVICEL ^R RC-591 0.50

qs water to 100% volume

-42Komponensek

1,8-Bis-O- (2,4,6-triiodophenyl) tripropylene glycol (oil at room temperature)

Polysorbate 80 (Tween 80)

AVICEL ^R RC-591

qs water to 100% volume

Quantities by weight / volume

25.00

5.00

6.50 supplemented

Example 15

Components Quantities

1,11-Bis- (2,4,6-triiodophenoxy) -3,6,9-trioxaundekán

Light petroleum, NF

Polysorbate 20 (Tween 20)

Sorbitan Monolaurate (Span 20)

AVICEL ^R RC-591

qs water to 100% v / v

17:50

12:50

2.50

2.50

0.50

Example 16

Components Quantities by weight / volume

1- (3-Iodophenoxy) -3,6,9-trioxadecane 25.00

Polysorbate 20 (Tween 20) 2.50

Sorbitan Monolaurate (Span 20) 2.50

AVICEL ^R RC-591 0.50

qs water to 100% volume

-4 317. example

Components Quantities

2,4,6-triiodo-phenyl (2-ethylhexanoate)

Light petroleum, NF

Polysorbate 80 (Tween 80)

Sorbitan Monooleate (Span 80)

AVICEL ^R RC-591

qs water to 100% volume / volume / volume

17:50

12:50

3.37

1.64

0.50

Example 18

Components Quantities by weight / volume

2,4,6-Triiodophenyl tris (2-ethylhexanoate) 25.00

Polysorbate 80 (Tween 80) 5.00

AVICEL ^R RC-591 6.50

qs water to 100% volume

Example 19

components Quantities w / v% of 2,4,6-triiodo-phenyl-3- cyclopentyl propionate 20.00 Light petroleum, NF 12.50 Polysorbate 20 (Tween 20) 2.50 Sorbitan monolaurate (Span 20) 2.50 AVICEL ^R RC-591 0.50

qs water to 100% volume

-44 ······· • • · · · · · · · · · · · · · • ·· • · · · · · · β ·· • · · · · · · ·

Example 20

components Quantities w / v% of 3- (Trifluoromethyl) -2,4,6- -trijód-phenyl-tris (2-ethyl- hexanoate) 20.00 Polysorbate 20 (Tween 20) 5.00 AVICEL ^R RC-591 1.00 qs water to 100% volume supplemented 21 . example components Quantities w / v% of 2,4,6-triiodo-phenyl -hexánszulfonát 20.00 Light petroleum, NF 12.50 Polysorbate 80 (Tween 80) 2.00 Sorbitan Monooleate (Span 80) 1.00 AVICEL ^R RC-591 1.00 qs water to 100% volume supplemented 22 . example components Quantities w / v% of 2,4,6-phenoxymethyl cyclopentane 14.50 Light petroleum, NF 12.50 Polysorbate 80 (Tween 80) 3.37 Sorbitan Monooleate (Span 80) 1.64 AVICEL ^R RC-591 0.50

qs with water to 100% by volume «· • · · ·

-45 "·

components 23 . example Quantities w / v% of 2- (4-Iodo-phenoxy) -pentadek on 17,00 Polysorbate 80 (Tween 80) 5.00 AVICEL ^R RC-591 6.50 qs with water 100% by volume to supplemented 24 . example components Quantities w / v% of 2-Iodo-phenoxy-cyclopentane 25,20 Light petroleum, NF 20.50 Polysorbate 80 (Tween 80) 3.00 AVICEL ^R RC-591 0.15 qs with water 100% by volume to supplemented 25 . Nelda components Quantities w / v% of

Ethyl 3,5-bis (acetylamino) -2,4,6-triiodobenzoate 17.50

Polysorbate 80 (Tween 80) 3.37

Sorbitan Monooleate (Span 80) 1.64

AVICEL ^R RC-591 0.50

qs with water to 100% volume • · ·

Example 26

Components Quantities by weight / volume

Ethyl [3,5-bis (acetylamino) -2,4,6-triiodobenzoyloxy) acetate 25.00

Light petroleum, NF 10.00 Polysorbate 80 (Tween 80) 5.00 AVICEL ^R RC-591 6.50

qs water to 100% volume

Example 27

Components Quantities by weight / volume

Ethyl 2- [3,5-bis (acetylamino) -2,4,6-triiodobenzoyloxy] furniture 30.00

Pluronic F-68 10.00

AVICEL ^R RC-591 2.00

qs water to 100% volume

Example 28

Components Quantities

Ethyl 1- 3,5-bis (acetylamino) -2,4,6-triiodobenzoate

Light petroleum, NF

Polysorbate 80 (Tween 80)

Sorbitan Monooleate (Span 80)

AVICEL ^R RC-591

qs water to 100% v / v

17:50

12:50

3.37

1.64

0.50

-4 729. example

components Quantities w / v% of Iodized polymer beads 17.50 Polysorbate 80 (Tween 80) 3.37 Sorbitan Monooleate (Span 80) 1.64 AVICEL ^R RC-591 0.50 qs with water 100% to volume Example 30 components Quantities w / v% of Iodized polymer beads 25.00 Polysorbate 80 (Tween 80) 5.00 AVICEL ^R RC-591 6.50 qs with water 100% to volume Example 31 components Quantities w / v% of Iodized polymer beads 20.00 Polysorbate 20 (Tween 20) 5.00 t AVICEL ^R RC-591 1.00 qs with water 100% to volume Example 32 components Quantities w / v% of Iodized polymer beads 30.00 Petroleum, NF 10.00

Polysorbate 80 (Tween 80)

Sorbitan Monooleate (Span 80)

AVICEL ^R RC-591

qs water to 100% volume

3.37

1.64

0.50

Example 33 components Quantities w / v% of Barium-born tree 17.50 Polysorbate 80 (Tween 80) 3.37 Sorbitan monooleate (Span 80) 1.64

AVICEL ^R RC-591 0.50

qs water to 100% volume

Example 34 components Quantities w / v% of Barium hexaboride 25.00 Light petroleum, NF 9.50 Polysorbate 80 (Tween 80) 5.00 AVICEL ^R RC-591 6.50 qs water to 100% volume Example 35 components Quantities w / v% of Barium chromite 70.00 Light petroleum, NF 5.00 Polysorbate 20 (Tween 20) 2.50 Sorbitan Monolaurate (Span 20) 2.50 AVICEL ^R RC-591 0.50 qs with water 100% by volume complete with Example 36 components Quantities w / v% of

Barium metasilicate

85.00

-49Polysorbate 20 (Tween 20) 2.50 Sorbitan Monolaurate (Span 20) 2.50 AVICEL ^R RC-591 0.75 qs with water to 100% volume

Example 37

Components Quantities

Barium fluogallát

Petroleum, NF

Polysorbate 80 (Tween 80)

Sorbitan Monooleate (Span 80)

AVICEL ^R RC-591

qs water to 100% v / v

50.00

10.00

3.37

1.64

0.50

Example 38

Components Quantities by weight / volume

Barium triorthophosphate 60.00

Polysorbate 80 (Tween 80) 5.00

AVICEL ^R RC-591 2.00

qs water to 100% volume

As is known to those skilled in the art, surfactants or emulsifiers may reduce the interfacial tension in two immiscible phases, such as in an oil-in-water medium. These agents may be used alone or in combination with other emulsifiers or surfactants. For example, Dow Corning Medical Antifoam AF, which contains 30% w / v polydimethylsiloxane simethicone and silica aerogel, 14% w / v stearate emulsifiers and 0.075% w / v sorbic acid, the remainder being water alone to use. Intralipid, an emulsion of fatty acids, requires the presence of suspending agents in order to form an acceptable emulsion with the contrast agents of the invention. Surfactants may be cationic, anionic, nonionic, zwitterionic, or may be a mixture of two or three such agents.

Suitable cationic surfactants include cetyltrimethylammonium bromide. Suitable anionic agents include, for example, sodium lauryl sulfate, sodium heptadecyl sulfate, alkylbenzenesulfonic acids and their salts, sodium butylnaphthalenesulfonate and sulfosuccinates. Zwitterionic surfactants are substances which, when dissolved in water, act as diprotic acids and, when ionized, act as a weak base and a weak acid. Because the two charges on the molecule balance each other, the molecule acts as a neutral molecule. The pH at which the zwitterion concentration is maximum is known as the isoelectric point. Compounds such as certain amino acids having an isoelectric point at the desired pH of the composition of the present invention may be used in the practice of the present invention.

In the preparation of the compositions of the present invention, it is preferable to use nonionic emulsifiers or surfactants which are non-ionic contrast agents.

As with 51 agents, they have a better toxicological profile than anionic, cationic or zwitterionic agents. In nonionic emulsifiers, the ratio of hydrophilic to hirophobic groups is approx. leveling off. They differ from anionic and cationic surfactants in that they lack charge in the molecule and are therefore generally less irritating than cationic or anionic surfactants. Nonionic surfactants include carboxylic acid esters, carboxylic acid amides, ethoxylated alkyl phenols, and ethoxylated aliphatic alcohols.

A particular type of carboxylic acid ester nonionic surfactant is the partial, e.g. monoesters, which are fatty acids and resin acids, e.g. C8-C18 and are formed by the reaction of polyhydric alcohols such as glycerol, glycols such as mono-, di-, tetra- and hexaethylene glycol, sorbitan and the like; and the like are formed by the addition of ethylene oxide to the hydroxyl group of fatty acids in various molar ratios.

Another type of carboxylic acid ester is the condensation products of partial acids of fatty acids and resin, such as monoesters with ethylene oxide, such as fatty or resinic acid esters of polyoxyethylene sorbitan, such as polyoxyethylene sorbitan, monoalloic esters. These are, for example, approx. 3 and approx. They may contain between 80 and 80 oxyethylene units per molecule, and fatty or resinic acid moieties of about 80 to about 50 ppm. They have 8-18 carbon atoms. Examples of naturally occurring fatty acid mixtures that may be used include coconut oil

-52 and tall oil, and simple fatty acids are dodecanoic and oleic.

Carboxylic acid amide is a nonionic surfactant at ca. Acid amides of fatty acids having 8 to 18 carbon acyl chains with ammonia, monoethylamine and diethylamine.

The ethoxylated alkylphenol nonionic surfactants are various condensates of alkylphenols and polyethylene oxide, in particular monoalkylphenols or dialkylphenols, wherein the alkyl group is ca. C 6 -C 12, branched or particularly straight-chain condensates with ethylene oxide of octylcresol, octylphenol or nonylphenol, in which the ethylene oxide is ca. 5 and approx. It is present in an amount of 25 mol of ethylene oxide / molecule alkylphenol.

Ethoxylated aliphatic alcohol nonionic surfactants are, for example, C8-C18 aliphatic alcohols which are straight or branched chain, e.g. 30 and approx. It is present in an amount of about 60 moles per molecule of alcohol.

Preferred anionic surfactants include:

- the sorbitan esters (marketed under the trade name Span) having the structure (0), wherein ^R 1 = ^R 2 = ° H, ^r 3 ^{-R for the} sorbitan monoesters,

R 1 = OH, R 2 = R 3 = R for sorbitan diesters,

R _t = R ₂ = R 3 = R for sorbitan triesters, where R = (01-23) 000 for laurate,

-53 (? Ci H33) COO for oleate, (C | ^ gH ₃₎ COO of palmitate (Ci7H3s) COO for sztearátészter;

polyoxyethylene alkyl ethers (i.e. Brijs) having the structure a

CH ₃ (CH ₂ ) _X (O-CH ₂ -CH ₂ ) _y 0 H, where (x + 1)

The number, typically 12 lauryl (Dodecyl) 14 myristyl (Tetradecyl) 16 cetyl (Hexadecyl) 18 stearyl (Octadecyl) and y is ethylene oxide groups of thread their profiles 10-60;

- the polyethylene sorbitan fatty acid esters marketed as Polysorbate 20, 40, 60, 65, 80 and 85 are characterized by formulas (1) and (2), where w + x + y + z = 20 ( polysorbate 20, 40, 60, 65, 80 and 85) w + x + y + z = 5 (polysorbate 81) and w + x + y + z = 4 (polysorbate 21 and 61);

polyethylene stearates, such as polyoxyoxy-1,2-ethanediyl) hydro-omega-hydroxyoctadecanoate; polyethylene glycol monostearate; and polyoxyoxy-1,2-ethanediyl) -α- (1-oxooctacecyl) omega-hydroxy polyethylene glycol monostearate.

The amount of contrast agent used according to the method of the present invention is the amount of contrast agent used

varies depending on the exact nature of the raster. Preferably

-54 However, the dose should be kept low enough to achieve enhanced contrast imaging. To minimize toxicity, use the lowest possible amount of contrast agent. For most of the contrast agents of the present invention, the dose is about 1 to about 10 mg. 0.1 to approx. 16.0 g iodine / kg body weight, preferably approx. 0.5 to approx. 6.0 g iodine / kg body weight, and most preferably ca. 1.2 and approx. It varies in the range of 2.0 g iodine / body weight for regular X-ray imaging of the GI tract. For CT scanning, the contrast agents of the present invention are approx. 1 and approx. 600 mg iodine / kg body weight, preferably approx. 20 and approx. 200 mg iodine / kg body weight, and most preferably ca. 40 and approx. 80 mg iodine / kg body weight.

The concentration of the contrast agent in the composition is about 10%. 0.001% w / v and ca. 75% w / v, preferably about 0.05% w / v to about 5% w / v. 50% w / v, and most preferably ca. 0.1% w / v and ca. 20% w / v.

Claims (7)

Patent claims: 1. X-ray contrast preparation for oral or retrograde examination of the gastrointestinal tract, a) in an amount of from 0.1 mg to 200 mg iodine per ml of an (1) X-ray contrast agent or a pharmaceutically acceptable salt thereof, wherein: Z is hydrogen, halo, C 1-20 alkyl, cycloalkyl, lower alkoxy, cyano, wherein alkyl and cycloalkyl may be substituted with halo or halo (lower alkyl); R ¹ and ir independently are hydrogen, C 1 -C 25 alkyl, cycloalkyl, acetyl or halo-lower alkyl, where C 1 -C 25 alkyl, cycloalkyl and halo-lower alkyl are optionally fluoro (lower alkyl), aryl, lower alkoxy, hydroxy, carboxyl, (lower alkoxy) carbonyl or (lower alkoxy) carbonyloxy, and the acetyl group is optionally substituted by fluoro (lower alkyl), aryl, lower alkoxy, hydroxy, (lower alkoxy) carbonyl or (lower alkoxy) carbonyloxy; n is 1-4; -56y is 1-4; and x is 1 or 2; (2) an X-ray contrast agent or a pharmaceutically acceptable salt thereof having the formula: wherein: R is substituted or unsubstituted C 2 -C 8 alkyl, wherein the substituents are selected from C 1 -C 6 alkyl, hydroxy and alkoxy; and n is 1, 2, 3, 4 or 5; (3) an X-ray contrast agent or a pharmaceutically acceptable salt thereof of formula (G) wherein: Z is hydrogen, halogen, C1-20 alkyl, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted by halogen or halo-lower alkyl; R is C 1 -C 25 alkyl, cycloalkyl or halo-lower alkyl, each of which is optionally halogen, fluoro-lower alkyl, aryl, lower alkoxy, hydroxy, carboxyl, ( lower alkoxy) carbonyl or (lower alkoxy) carbonyloxy; or (CR 1 R 8) _p - (CR 8 = CR 4) _m Q or (CR 1 R 8) _p C = CQ; R 1, R ₂ , R 8 and R 4 are each independently lower alkyl optionally substituted with halo; x is 1-3; y is 1-4; n is 1-5; m is from 1 to 15; p is 1-10; and Q is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, aryl or aryl (lower alkyl); (4) an X-ray contrast agent or a pharmaceutically acceptable salt thereof having the formula: wherein: R is methyl, ethyl, n-propyl, C4-C25 alkyl, cycloalkyl, unsaturated allyl or halo (lower alkyl) each optionally substituted with halogen, fluoro (lower alkyl), aryl. may be substituted by lower alkoxy, hydroxy, carboxyl or lower alkoxy) carbonyl, or by the formula (CR 1 R 2) p - (CR ₉ = CR ₄ ) _m Q or (CR 1 R 2) p C = CQ group; R 1, R 2, R 3 and R ₄ are each independently hydrogen, lower alkyl optionally substituted with halo; n is from 2 to 5; m is 2-5; p is 1-10; and -58Q is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, aryl or aryl (lower alkyl); (5) an X-ray contrast agent or a pharmaceutically acceptable salt thereof of formula (J): Z is hydrogen, halo, C 1-20 alkyl, cycloalkyl, lower alkoxy, alkoxycarbonyl, cyano, wherein the alkyl and cycloalkyl groups may be substituted by halogen or halo-lower alkyl; R is C 1-25 alkyl, cycloalkyl, a) or halo-lower alkyl, each optionally halogen, fluoro-lower alkyl, aryl, lower alkoxy, it may be substituted by hydroxy, carboxyl, (lower alkoxy) carbonyl or (lower alkoxy) carbonyloxy; or (CR 1 R ₂ ) p - (CR 8 = CR 4) _m Q or (CR 4 R ₂ ) p C = CQ; R ₂ , R ₂ , R 8 and R 4 are each independently hydrogen or lower alkyl optionally substituted with halo; x is 1-4; n is 1-4; -59m is from 1 to 15; p is 1-20; and Q is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, aryl or aryl (lower alkyl); (6) an X-ray contrast agent or a pharmaceutically acceptable salt thereof, wherein X is -C (= O) - or -SO 4 -; Z is hydrogen, halogen, C 5-20 alkyl, cycloalkyl, lower alkoxy, cyano, wherein alkyl and cycloalkyl may be substituted with halo or halo (lower alkyl); R is C 1 -C 25 alkyl, cycloalkyl, aryl or halo-lower alkyl, each of which may be optionally substituted with lower alkoxy, hydroxy, carboxyl or (lower alkoxy) carbonyl, lower carbon 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 agent or a pharmaceutically acceptable salt thereof having the formula: wherein: -60Z is hydrogen, halogen, C1-20 alkyl, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted by halogen or halo-lower alkyl; R is methyl, ethyl, propyl, C 9 -C 25 alkyl, cycloalkyl or halo-lower alkyl optionally substituted with halogen, fluoro-lower alkyl, aryl, lower alkoxy, hydroxyl, , they may be substituted by carboxyl, (lower alkoxy) carbonyl or (lower alkoxy) carbonyloxy; or (CR 4 R 2) _{p -} (CR 3 = CR 4) _m Q or (CR 1 R 2) _{p -} C = C Q; R 1 - R 2> R 3 and R 4 are independently lower alkyl optionally substituted with halo; x is 1-4; n is 1-5; m is from 1 to 15; p is 1-10; and Q is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, aryl or aryl (lower alkyl); a compound selected from; (b) 0.05 to 10% w / v of microcrystalline cellulose; -61 (c) 0-55% w / v oily vehicle; (d) 0-20% w / v surfactant selected from nonionic, anionic, cationic and zwitterionic surfactants; (e) 0-15% w / v viscosity modifier; and (f) contain water to make up the volume to 100%. The x-ray composition of claim 1, wherein said x-ray contrast agent is present in an amount of 30-200 mg iodine per ml of composition. The X-ray contrast composition of claim 1, wherein the oily vehicle comprises 0.1 to 25% w / v of the composition. The X-ray contrast composition of claim 1, wherein the surfactant comprises 0.1 to 10% of the composition. An X-ray contrast preparation for oral or retrograde examination of the gastrointestinal tract, which (a) 40-160 mg iodine / ml of the composition obtains a crystalline contrast obtained by diatrizoic acid, metrizoic acid, iotaalamic acid, trimesic acid, uroconic acid, ixatalraic acid, tetraodate-62-terephthalate. Ixaglinic acid, iodipamide, ethyl 3,5-diacetamido-2,4,6-triiodobenzoate, ethyl 2- [3,5-bis (acetylamino) -2,4,6-triiodobenzoyloxy] butyrate and ethyl [3,5-bis (acetylamino) -2,4,6-triiodobenzoyloxy] acetate, and the above crystalline contrast agent, adsorbed on its surface, contains an amount of a surface modifier an effective average particle size of 0.5 μ and approx. 100 μ; and said surface modifier is selected from tetrafunctional block copolymers obtained by sequential addition of propylene oxide and ethylene oxide to ethylenediamine; (b) 0.1-4% w / v microcrystalline cellulose; (c) 0.1-25% w / v oily vehicle; (d) 0.1 to 10% w / v of a surfactant selected from nonionic, anionic, cationic and zwitterionic surfactants; (e) a 0.001 to 4% w / v viscosity modifier; and (f) contain water to make up the volume to 100%. 6. An X-ray contrast composition for oral or retrograde examination of the gastrointestinal tract comprising (a) 5 to 95% (w / v) iodinated polymeric water-insoluble beads having a particle size of approx. 0.01 to approx. 1000 μ, wherein the iodinated polymer beads are comprised of a polymer having a repeating unit of formula (I). ··· · «· contains, in this A is an organic unit repeating in the chain forming the polymer backbone; and X is an organic group containing an iodinated aromatic group and a hydrophilic group, this moiety having an iodine content of ca. 40 and approx. 80% by weight, based on the molecular weight of X; (b) 0.05 to 10% w / v of microcrystalline cellulose; (c) 0.1-20% w / v of a surfactant selected from nonionic, anionic, cationic and zwitterionic surfactants; (d) 0.001 to 4% w / v viscosity modifier; and (e) contains water to make up the volume to 100%. The X-ray contrast composition of claim 6, wherein X is an organic moiety having the iodinated aromatic group represented by formula (P), wherein: L is a linking group selected from ester groups, ether groups, amide groups, thioester groups, carbonate groups, carbamate groups and sulfide groups; and each of r 1 -r 6 may be the same or different and represents a hydrogen atom, a iodine-containing substituent or a hydrophilic group substituent, with the proviso that ♦ -64 (i) X has an iodine content of from 40 to 80% w / v; and (ii) said hydrophilic group is selected from carboxyl groups, sulfo groups, amino groups and salts and polyol groups of said carboxyl groups, parent groups and amino groups. The x-ray contrast composition of claim 7, wherein the surfactant comprises 3-7% of the composition. An X-ray contrast composition for oral or retrograde examination of the gastrointestinal tract, comprising (a) 5-95% w / v of the barium salt; (b) 0.1 to 10% w / v of microcrystalline cellulose; (c) 0.1-55% w / v oily vehicle; (d) 0.1 to 20% w / v of a surfactant selected from nonionic, anionic, cationic and zwitterionic surfactants; (e) 0.001 to 15% w / v viscosity modifier; and (f) contain water to make up the volume to 100%. The X-ray contrast composition of claim 9, wherein the oily vehicle comprises 7-15% w / v of the composition. • · · -65 ·· ♦ »» The x-ray contrast composition of claim 9, wherein the surfactant comprises 3-7% of the composition. An X-ray contrast composition according to any one of the preceding claims, wherein the microcrystalline cellulose has an average particle size of 0.01 to 100 µ. 13. An X-ray contrast composition according to claim 12, wherein the microcrystalline cellulose is ca. 89 parts microcrystalline cellulose and ca. 11 parts consist of sodium carboxymethyl cellulose. An X-ray contrast composition according to any one of the preceding claims, wherein the nonionic surfactant is selected from carboxylic acid esters, carboxylic acid amides, ethoxylated alkylphenols and ethoxylated aliphatic alcohols. 15. An X-ray contrast composition according to any one of claims 1 to 6, wherein the surfactant is a sorbitan ester of the formula (0), wherein R 1 = R ₂ = OH, R 3 = R for sorbitan monoesters, R 1 = OH, R ₂ = R 3 = R for sorbitan diesters, R 1 = R ₂ = R 3 = R for sorbitan triesters, where R = (C ₁ H ₂ 3) COO for laurate, (C 1 H 33) COO for oleate, (Cis H 5 J COO for palmitate, • ·· -66 (CjjHggjCOO for stearate ester. 16. An X-ray contrast composition according to any one of claims 1 to 6, wherein the surfactant is a polyoxyethylene alkyl ether having the structure CH ₃ (CH ₂ ) _x (O-CH ₂ -CH ₂ ) _y 0 H, wherein (x + 1) 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 ethylene oxide the number of groups in the hydrophilic chain, their profiles approx. 10 and approx . 60. 17 . 1-13. An x-ray according to any one of claims 1 to 4 a contrast composition wherein the surfactant is a polyethylene sorbitan fatty acid ester of formulas (1) and (2), wherein w + x + y + z = 20 w + x + y + z = 5 w + x + y + z = 4. The X-ray contrast composition of claim 1 for oral or retrograde examination of the gastrointestinal tract, which comprises (a) an amount of 85 to 120 mg iodine per ml. C «Ρ -67x-contrast contrast agent; (b) 0.2 to 1% w / v of microcrystalline cellulose; (c) 7-15% w / v mineral oil; (d) 3-7% w / v surfactant selected from nonionic, anionic, cationic and zwitterionic surfactants; (e) 0.05 to 1% w / v viscosity modifier; and (f) contain water to make up the volume to 100%. The X-ray contrast composition of claim 18, wherein the microcrystalline cellulose has an average particle size of 0.05 to 10 µ. 20. A method of x-raying a patient's gastrointestinal tract, comprising administering to a patient the composition of any one of the preceding claims orally or rectally.