CN1146159A

CN1146159A - X-ray contrast compositions containing cellulose derivatives

Info

Publication number: CN1146159A
Application number: CN95192256A
Authority: CN
Inventors: 卡尔·R·伊利格; 约翰·托纳; 爱德华·J·贝克; 罗伯特·李; 汤姆·考尔菲尔德; 布伦特·D·道蒂; 库尔特·约瑟夫; 爱德华·R·培根; 金伯利·埃斯特普; 索尔·多姆; 尤金·R·库珀
Original assignee: Nycomed Imaging AS
Current assignee: GE Healthcare AS
Priority date: 1994-02-25
Filing date: 1995-02-24
Publication date: 1997-03-26
Also published as: CA2184089A1; FI963299A; HUT76336A; HU9602321D0; NO963540D0; MX9603611A; NO963540L; JPH09509424A; AU1816395A; EP0746339A1; WO1995022995A1; FI963299A0

Abstract

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

Description

The X-ray contrast compositions that contains cellulose derivative

What the present invention relates to is the X-ray contrast compositions, and said composition contains contrast agent and cellulose derivative, and relates to them and be used in the method for carrying out radiodiagnosis in the gastrointestinal tract.

For the take a picture X-radiographic inspection of (being hereinafter referred to as CT) scanning of fracture and the used X-ray of other state of an illness relevant and computer body-layer, conventionally be under the condition of not using contrast agent, to implement with osseous system.But the organ that contains soft tissue, developing as the X-ray in the intestines and stomach (below be called GI) road then needs to use contrast agent to weaken the x-ray radiation effect.Medically using aspect the contrast agent imaging people such as D.P.Swanson at " Pharmaceuticals In Medieal Imaging ", 1990, provide good background technology among the Macmillaan Publishing Company.

The X-radiography of GI system can be pointed out the state of an illness that digestive system disorder, enteral performance variation, stomachache, GI are hemorrhage etc.Before the radioscopy, must take a kind of not contrast media of saturating X-ray corresponding body cavity or soft tissue mucomembranous surface are on every side suitably shown.Therefore, with oral contrast material to the inspection of developing of oral cavity, throat, esophagus, stomach, duodenum and PI.This selects the shadow medium from rectal administration, is used to check the small intestinal and the colon in distally.

The most widely used contrast agent of development to the GI system is a barium sulfate, a kind of oral suspension, perhaps a kind of enema to the rectum perfusion.(for example, can be referring to United States Patent (USP): US2,659,690; 2680,089; 3,216,900; 3,235,462; 4,038,379 and 4,120,946).Although it has goodish radiography characteristic, because the GI system absorbs atomic and promptly excretes after the oral or rectum perfusion, so barium sulfate has certain shortcoming.In the presence of the enteral liquid, it can not uniform distribution and to the poor adhesion of mucosa, and the imaging of X-ray is bad as a result.During coloclysis, carry out flocculation at the colonic contrast agent and form irregular block Excreta.

Iodinating organic compound has been used as the GI contrast agent, because the iodine atom is the agent of effective X-radiation absorption.They have versatility most, extensively are used in the kinds of processes method.They have very big absorbability to the X-ray, X-ray and iodine are interacted produce a kind of photoelectric effect, thereby make the radiography that rests on the photon generation that contains in the iodine medium that very big amplification be arranged.The amplification of this radiography has surpassed by the desired level of the relative variation of density.Because this amplification causes the contrast agent that can use suitable low concentration.(for iodinating contrast agent, can be referring to for example United States Patent (USP): US2,786,055; 3,795,698; 2,820,814; 3,360,436; 3,574,718; 3,733,397; 4,735,795 and 5,047,228).

The requirement of thirsting for obtaining for ideal GI contrast agent comprises: good toxicologic analysis: have ability that is full of whole intestinal/chamber and the ability that evenly applies intestinal mucosa, thereby do not expanding the situation that also can detect this intestinal under the enteric cavity situation easily; Palatability and do not stimulate intestinal mucosa; And by the GI road time, do not produce pseudomorphism or do not stimulate intestinal to wriggle intensely.

These requirements are proposed by many researcheres, and have had very big improvement through their effort for many years.Contrast agent evenly applies intestinal mucosa and the requirement that covers intestinal wall effectively, has proved that this is suitable difficulty, does not satisfy these and requires just can not obtain accurate X-actinogram.For this reason, once proposed to use some polymeric additive, as mentioned below.

U.S. Pat 4069306 discloses a kind of X-ray contrast preparation that allegedly can adhere to body lumen wall.Said preparation comprises a kind of finely divided water-insoluble inorganic x-ray contrast agent and subparticle or a kind of water-fast but can be by the swollen hydrophilic polymers of water.Supply in body cavity with the said preparation that is suspended in the water.This x-ray contrast agent is to exist with the form of mixtures with said polymer fine particles, or is coated on and/or adheres on this polymer fine particles.

US4,120,946 disclose a kind of Pharmaceutical composition that is used to make the muddy effect of gastral barium generation, and it contains colloidal barium sulfate and the polyacrylamide in aqueous carrier.This polyacrylamide forms a kind of viscous solution of low concentration, and it can be kept the suspension state of barium sulfate and said preparation can finely be adhered to needs according on the organ walls of X-ray.

US5,019,370 discloses a kind of biodegradable X-illumination phase contrast agent, and it contains biodegradable polymer beads, and this particle has a kind of to the lighttight element of X-light, for example iodine, bromine, samarium and erbium.This contrast media uses with dry state or liquid form, and can the intravenous injection mode, and oral way and intra-arterial injection mode are offerd medicine.

The disclosed X-ray contrast compositions of Japanese patent application 55-127322 contains barium sulfate and is selected from the polymeric material of carboxymethyl cellulose salt, propylene glycol alginate, polyacrylic acid sulfate cellulose ester, pectin and Tragacanth.These polymeric materials are used to increase the viscosity of said composition.

Though these polymeric materials have improved the tack of used contrast agent to organ walls greatly here, made it to develop preferably, also need to apply the soft tissue that those are checked by the X-roentgenodiagnosis equably with a kind of improved X-radial imaging medium.

The purpose of this invention is to provide the compositions that is used to apply the mammal gastrointestinal tract, it can form a kind of effective not coating of saturating X-ray, can realize the diagnostic inspection method of GI system thus.For this reason, took in a kind of fiber derivative that is mixed with x-ray contrast agent before developing with the x-ray irradiation device, it can form a shallow layer at the inner surface of GI system.Said composition must satisfy following several requirements: x-ray contrast agent and the cellulose thing both that spreads out must be nontoxic; Must not contain leachable or digestible component that will produce injurious effects to patient; Not by the absorbed coating ingredients in enteral surface.

The objective of the invention is to reach by the compositions that contains a kind of x-ray contrast agent, this contrast agent is among the pharmaceutically acceptable carrier that contains cellulose derivative.

The present invention also provides the method for the X-roentgenodiagnosis imaging of a kind of GI of being used for system, and this method comprises: use the above-mentioned X-ray contrast compositions that produces effective radiography amount to patient by oral or rectal administration mode.

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

(1) chemical compound shown in the following general formula or its medicinal acceptable salt:

Wherein,

Z is H, halogen, C ₁-C ₂₀Alkyl, cycloalkyl, lower alkoxy, cyano group, alkyl here and cycloalkyl can be replaced by halogen or halogenated low alkyl group;

R ₁And R ₂Represent H, C independently ₁-C ₂₅Alkyl, cycloalkyl, acetyl group or halogenated low alkyl group, wherein said C ₁-C ₂₅Alkyl, cycloalkyl and halogenated low alkyl group can be replaced or not replace by fluoro low alkyl group, aryl, lower alkoxy, hydroxyl, carboxyl, lower alkoxycarbonyl or lower alkoxy carbonyl oxygen base, and said acetyl group can be replaced or not replace by fluoro low alkyl group, aryl, lower alkoxy, hydroxyl, lower alkoxycarbonyl or rudimentary alkyl oxy carbonyl oxygen;

N is 1-4;

Y is 1-4; With

X is 1 or 2;

(2) chemical compound shown in the following general formula:

Wherein,

R is replacement or the unsubstituted alkyl that contains 2～8 carbon atoms, and wherein said substituent group is selected from C ₁-C ₆Alkyl, hydroxyl and alkoxyl; With

N is 1～5;

(3) chemical compound of following general formula:

In the formula,

R is C ₁-C ₂₅Alkyl, cycloalkyl or junior alkyl halides, each in them can be replaced or not replace by halogen, fluoro low alkyl group, aryl, lower alkoxy, hydroxyl, carboxyl, lower alkylcarbonyl or rudimentary alkyl oxy carbonyl oxygen; Or (CR ₁R ₂) _p-(CR ₃=CR ₄) _mQ or (CR ₁R ₂) _p-C ≡ C-Q;

R ₁, R ₂, R ₃And R ₄Represent low alkyl group independently, also can replace or not replace with halogen;

X is 1-3;

Y is 1-4;

N is 1-5;

M is 1-15;

P is 1-10; With

Q is H, low alkyl group, low-grade alkenyl, low-grade alkynyl, low-grade alkylidene, aryl or aromatic yl elementary alkyl;

(4) chemical compound shown in the following general formula or its medicinal acceptable salt:

In the formula,

R be methyl, ethyl, just-propyl group, C ₄-C ₂₅Alkyl, cycloalkyl, undersaturated pi-allyl or junior alkyl halides, each in them can replace or not replace with halogen, fluoro low alkyl group, aryl, lower alkoxy, hydroxyl, carboxyl or lower alkoxycarbonyl; Or (CR ₁R ₂) _p-(CR ₃=CR ₄) _mQ or (CR ₁R ₂) _p-C ≡ C-Q;

R ₁, R ₂, R ₃And R ₄Represent H, low alkyl group independently, also can replace or not replace with halogen;

N is 2～5;

M is 2～5;

P is 1-10; With

(5) chemical compound of following general formula or its medicinal acceptable salt:

In the formula,

Z is H, halogen, C ₁-C ₂₀Alkyl, cycloalkyl, lower alkoxy, alkoxy carbonyl group, cyano group, the alkyl here and cycloalkyl can enough halogens or halogenated low alkyl group replace;

R is C ₁-C ₂₅Alkyl, cycloalkyl, Or junior alkyl halides; In them each can replace or not replace with halogen, fluoro low alkyl group, aryl, lower alkoxy, hydroxyl, carboxyl, lower alkoxycarbonyl or rudimentary alkyl oxy carbonyl oxygen; Or (CR ₁R ₂) _p-(CR ₃=CR ₄) _mQ or (CR ₁R ₂) _p-C ≡ C-Q;

R ₁, R ₂, R ₃And R ₄Represent H or low alkyl group independently, can replace or not replace with halogen;

X is 1-4;

N is 1-4;

M is 1～15;

P is 1～20; With

(6) chemical compound of following general formula or its medicinal acceptable salt:

Wherein,

X is

Or-SO ₂-;

Z is H, halogen, C ₅-C ₂₀Alkyl, cycloalkyl, lower alkoxy, cyano group, the alkyl here and cycloalkyl can enough halogens or junior alkyl halides replace;

R is C ₁-C ₂₅Alkyl, cycloalkyl, aryl or junior alkyl halides, each in them can replace or not replace with lower alkoxy, hydroxyl, carboxyl or elementary alkoxy carbonyl, low-grade alkenyl, low-grade alkynyl, low-grade alkylidene or rudimentary alkyl oxy carbonyl oxygen;

N is 1～5;

Y is 0～4; With

W is 1～4;

(7) chemical compound shown in the following general formula or its medicinal acceptable salt:

Wherein,

Z is H, halogen, C ₁-C ₂₀Alkyl, cycloalkyl, lower alkoxy, cyano group, alkyl wherein and cycloalkyl can enough halogens or junior alkyl halides replace;

R is methyl, ethyl, propyl group, C ₉-C ₂₅Alkyl, cycloalkyl or junior alkyl halides, can replace or not replace with halogen, fluoro low alkyl group, aryl, lower alkoxy, hydroxyl, carboxyl, lower alkoxycarbonyl or low alkyl oxy carbonyl oxygen; Or (CR ₁R ₂) _p-(CR ₃=CR ₄) _mQ or (CR ₁R ₂) _p-C ≡ C-Q;

R ₁, R ₂, R ₃And R ₄Represent low alkyl group independently, also can replace with halogen;

X is 1～4;

N is 1～5;

M is 1～15;

P is 1～10; With

(8) inhale the granular X-ray crystallization contrast agent that surface modifier is arranged from the teeth outwards;

(9) iodinating water-insoluble polymer beads, its granularity is approximately 0.01～1000 μ, and wherein said iodinating polymer beads comprises a kind of polymer that contains repetitive shown in the general formula (I):

Wherein,

A is the organic repetitive that is present in the polymer backbone chains; With

X is the organic group part that contains iodinating aryl and hydrophilic group, and said this part content of iodine is a benchmark in the molecular weight of X, is about 40～about 80wt%;

(10) barium salt.

Here employed term halogen (or halogen) refers to fluorine, chlorine, bromine or iodine.

Here employed term cycloalkyl refers to the isocyclic ring with 3-8 ring carbon atom, they comprise cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and ring octyl group, and any one ring carbon atom of these cycloalkyl can be replaced by one or more low alkyl groups, lower alkoxy or halogen.

Here employed term lower alkyl and lower alkoxy refer to the monovalence aliphatic group with 1～10 carbon atom, comprise branched chain group.Therefore, the low alkyl group of these groups partly comprises, for example, methyl, ethyl, propyl group, isopropyl, just-butyl, the second month in a season-butyl, tert-butyl, just-amyl group, 2-methyl-3-butyl, 1-methyl butyl, 2-methyl butyl, neopentyl, just-hexyl, 1-methyl amyl, 3-methyl amyl, 1-ethyl-butyl, 2-ethyl-butyl, 2-hexyl, 3-hexyl, 1,1,3,3-tetramethyl amyl group, 1,1-dimethyl octyl group etc.

Here used term low-grade alkenyl and low-grade alkynyl refer to the monovalence unsaturated group (comprising branched chain group) of 3～10 carbon atoms of tool, therefore comprise 1-vinyl, 1-(2-acrylic), 1-(crotyl), 1-(1-methyl-2-acrylic), 1 (4-methyl-pentenyl), 4,4,6-trimethyl-2-heptenyl, 1-acetenyl, 1-(2-propynyl), 1-(2-butyne base), 1-(1-methyl-2-propynyl), 1-(4-methyl-valerylene base) etc.

The terminology used here alkylidene refers to the saturated base of the bivalence with 2～10 carbon atoms (comprising branched chain group), and the free valency that on different carbon atoms, contains them, therefore comprise 1,2-ethylidene, 1,3-propylidene, 1,4-butylidene, 1-methyl isophthalic acid, 2-ethylidene, octamethylene etc.

Term aryl used herein refers to the aromatic hydrocarbon with 6～10 carbon atoms.The phenyl and the naphthyl of the replacement that preferred aryl groups is phenyl, replaced by 1～3 substituent group, these substituent groups can be identical or different, and they are low alkyl group, halogen, hydroxyl low-grade alkyl, alkoxyl low alkyl group and hydroxyl.

The X-ray contrast chemical compound of above-mentioned (1)-(7) type can contain 1,2,3 or 4 iodine atoms in each molecule, preferred type is to contain at least two iodine atoms in the per molecule, and more preferably type is to contain 3 iodine atoms in the per molecule at least.

Implementing the useful granular solids x-ray contrast agent of the present invention can be by known technology preparation of the prior art.Adopt conventional Ginding process, for example aerojet or crushing grinding grind to form needed granule size with this solid contrast agent.We have found that the granule that effective particle mean size is lower than about 100 μ can produce good distribution and apply uniformly in the GI road.Wherein said granular size refers to uses conventional method, for example deposits the number average particle size that moving staging of field flow and disc type centrifugal separation are measured.Effectively particle mean size is lower than about 100 μ and refers to about at least 90% granule average particle size and be lower than about 100 μ (when using recognized techniques to measure).

The cellulose derivative that is used for the present invention comprises methylcellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose; And the cellulose of crystallite; Its particle mean size is 0.01～100 μ m, more preferably 0.05～10 μ m, most preferably 0.1～1 μ m.

Contrast agent and cellulose derivative are to use physiologically acceptable carrier or excipient by a kind of method preparation of the prior art, and this contrast agent and cellulose derivative add medicinal acceptable assistant (for example surfactant or emulsifying agent) and excipient is to suspend or partly be dissolved in to make dispersion liquid, solution, suspension or emulsion in the aqueous medium.

Comprise for the diagnostic imaging method in the GI road that uses in the therapy that according to the present invention the compositions of the present invention that can produce effective radiography amount by oral or rectally mode is offerd medicine to the mammals patient who needs the X-radiological survey X.After the dispensing, the GI road x-ray irradiation that will contain at least a portion of throwing compositions to some extent, there is position corresponding X-ray image figure in generation with this contrast agent, with the state of the art this check result is explained in the image development and the arrangement of this X-ray then.

Type defined above (1) chemical compound is described in EP-A-613689.For example wherein introduced N-acetyl group-N-2 '-octyl group-4-iodo aniline and N-(4 '-iodine substituted phenyl)-2-amino-octane.

The chemical compound of type defined above (2) is described in EP-A-568155.For example wherein have 2,4,6-phenyl triiodide oxygen base-2-octane, 2,4,6-phenyl triiodide oxygen base-2-butane, 2,4,6-phenyl triiodide oxygen base-2-hexane and 4-iodo phenoxy group-2-octane.

The contrast agent of preferred type (2) has following general formula:

R is the secondary alkyl that contains 4～8 carbon atoms in the formula.

The contrast agent of most preferred type (2) has 2,4 of following general formula, the second month in a season-Octyl Ether of 6-three riodoxol:

The contrast agent of type (2) is slightly soluble in water, has to be equal to or greater than 10 partition coefficient.When containing necessary excipient in the prescription, this dissolubility can make it to form the stabilization formulations of emulsion form and form of suspension.Term " is stablized " and is referred to after oral or rectal administration, carries out in the process of radioscopy in the GI road, and each contained composition of said composition does not separate.The micro dissolution of contrast agent in aqueous medium makes this contrast agent can be spread in the intestinal mucosa and concealment is got up forms coating at enteral thus.On the other hand, because their micro dissolution, contrast agent absorbs minimum at the enteral wall, and this just can reduce toxicity and pay effect.

The chemical compound of type defined above (3) is described in EP-A-614669.That for example, wherein introduces has 2-octyl group-2,3, a 5-phenyl triiodide formic acid esters, 3,3,4,4,5,5,6,6,7,7,8,8-12 fluoro-2-octyl groups-2,3,5-phenyl triiodide formic acid esters, two (2-hexyl)-2,3,5,6-tetraiodo generation-terephthalate, 3-(2 octyloxy)-2,4,6-phenyl triiodide Ethyl formate and two (2-octyl group)-2,4,6-three iodo isophthalates.

The chemical compound of type defined above (4) is stated at EP-A-609589.For example wherein have 1,3,5-three-N-hexyl-2,4, the 6-phenyl triiodide, 1,3,5-triethyl group-2,4, the 6-phenyl triiodide, 1,3,5-three-N-butyl-2,4, the 6-phenyl triiodide, 1,3,5-three-(4-methyl amyl)-2,4, the 6-phenyl triiodide, 1,3,5-three-N-amyl group-2,4, the 6-phenyl triiodide, 1,3,5-three-(3-methyl butyl)-2,4, the 6-phenyl triiodide, 1,3,5-three-N-propyl group-2,4, the 6-phenyl triiodide, 1,3,5-three-N-heptyl-2,4, the 6-phenyl triiodide, 2-(4-iodine substituted phenyl) nonane, 9-(right-iodine substituted phenyl)-10-hendecoic acid, ethyl ester and (E)-11-(P-iodine substituted phenyl)-9-hendecoic acid.

The chemical compound of type defined above (5) is described in EP-A-614670, two-(4-iodine substituted phenyl) ether that Polyethylene Glycol-400 is arranged of for example wherein describing, 1,8-pair-O-(2,4,6-phenyl triiodide base)-tripropylene glycol, 1,11-two-(2,4,6-phenyl triiodide oxygen base)-3,6,9-trioxa hendecane, 1,2-two-(2,4,6-phenyl triiodide oxygen base)-ethane, two-O-(2,4, the 6-phenyl triiodide base) ether of PEG400,1-(3-iodo phenoxy group)-3,6,9-trioxa decane, 1,3-two-(2,4,6-phenyl triiodide oxygen base)-butane, 1-(3-iodo phenoxy group)-6-(2,4,6-phenyl triiodide oxygen base-hexane and 1,12-two-(2,4,6-phenyl triiodide oxygen base)-12 carbon alkane.

The chemical compound of type defined above (6) is described in EP-A-617970.2-ethyl-caproic acid 2,4 is for example wherein arranged, 6-phenyl triiodide base ester, 2 methyl valeric acid 2,4,6-phenyl triiodide base ester, 3-cyclopentanepropanoiacid acid 2,4,6-phenyl triiodide base ester, (2-propyl group) valeric acid 2,4,6-phenyl triiodide base ester, perfluoro-heptanoic acid 2,4,6-phenyl triiodide base ester, 2,4,6-phenyl triiodide base-three-(2-ethyl)-alkyl caproate, dodecylic acid 2,4,6-phenyl triiodide base ester, 2 ethyl hexanoic acid 3-trifluoromethyl-2,4,6-phenyl triiodide base ester, 2,4,6-phenyl triiodide base-two-(2 methyl valeric acid ester), hexane sulfonic acid 2,4,6-phenyl triiodide base ester, heptanesulfonic acid 2,4,6-phenyl triiodide base ester and decane sulfonic acid 2,4,6-phenyl triiodide base ester.

The chemical compound of type defined above (7) is stated in EP-A-605987, wherein said for example have 2-(4-iodo phenoxy group)-decane, 2-(2,4,6-phenyl triiodide oxygen base)-pentadecane, 2-(2,4,6-phenyl triiodide oxygen base)-decane, (2,4,6-phenyl triiodide oxygen base)-1H, 1H, 2H, the 2H-PFO, 1-(2,4,6 three iodos-3-trifluoro-benzene oxygen base) octane, 2-(2,4,6-phenyl triiodide oxygen base) nonane, 2-ethyl-1-(2,4,6-phenyl triiodide oxygen base)-hexane, 3,3-diphenyl-1-(2,4,6-phenyl triiodide oxygen base) propane, 3-(2,4,6-phenyl triiodide oxygen base)-nonane, 2-(4-iodo phenoxy group)-hendecane, 2-iodobenzene oxygen basic ring pentane, 3-iodobenzene oxygen basic ring pentane, (3,5-dimethyl-2,4,6-phenyl triiodide oxygen base) Pentamethylene., 2-(4-iodo phenoxy group)-pentadecane, 4-iodobenzene oxygen basic ring pentane, 2,4,6-phenyl triiodide oxygen basic ring pentane, 2,4,6-phenyl triiodide oxygen ylmethyl Pentamethylene., 2-(2,4,6-phenyl triiodide oxygen base) ethyl cyclopentane, (E, E)-1-(2,4,6-phenyl triiodide oxygen base)-3,7,11-trimethyl-2,6,10-12 carbon triolefins, 1-(2,4,6-phenyl triiodide oxygen base)-3,7-dimethyl-6-octene, (E)-1-(3,5-dimethyl-2,4,6-phenyl triiodide oxygen base)-3,7-dimethyl-2, the 6-octadiene, (E)-1-(2,4,6-phenyl triiodide oxygen base)-3,7-dimethyl-2, the 6-octadiene, 1-(2,4,6-phenyl triiodide oxygen base)-the 3-octyne, 2-(2,4,6-phenyl triiodide oxygen base)-the 4-octyne, 1-(2,4,6-phenyl triiodide oxygen base)-the 3-octyne, 2-(2,4,6-phenyl triiodide oxygen base)-1, the 3-diethyl malonate, 2-(2,4,6-phenyl triiodide oxygen base)-1, the 3-Diisopropyl malonate, 2,2-pair-(3-iodo phenoxy group) ethyl acetate, 5-(2,4,6-phenyl triiodide oxygen base) ethyl hexanoate, 5-(2,4,6-phenyl triiodide oxygen base)-and oneself-1-alcohol, 10-(4-iodo phenoxy group)-11 carbon-1-alcohol, 5-(2,4,6-phenyl triiodide oxygen base) hexyl ethyl carbonate and 10-(3-iodo phenoxy group)-hendecoic acid ethyl ester.

The chemical compound that is used for type (8) compositions defined above is inactive and exists as the discontinuous crystallization of organic substance.This crystalline phase is different from unformed or noncrystalline phase, and it is to be obtained by for example solvent deposition technology described in the US4826689.This organic substance can exist with one or more suitable crystalline phases.Can implement the present invention with diversified crystalline inactive x-ray contrast agent.Yet this x-ray contrast agent must be bad molten with dispersive at least a liquid medium." bad molten " refers to the dissolubility of this contrast agent in liquid dispersion medium (for example water) and is less than about 10mg/ml greatly, preferably is lower than about 1mg/ml.

X-ray contrast agent can be iodinating chemical compound.This iodinating chemical compound can be aromatic or non-aromatic.But optimization aromatic.Can contain one, two, three or more carbon atom in each molecule of this iodinated compounds.Preferred type is to contain at least two in the per molecule, more preferably at least three carbon atoms.Selected iodinated compounds can contain does not make this chemical compound increase deliquescent substituent group, for example, alkyl urea groups, alkoxyl amide groups, glycoloyl amido, butyrolactam base, succinimido, trifluoroacetyl amido, carboxyl, carbonyl amide groups (carboxamido), hydroxyl, alkoxyl, acylamino-and other similar substituent group.

A preferred class contrast agent comprises, the various esters and the amide-type of iodate aromatic acid.This esters preferred alkyl or substituted alkyl esters.This amide-type can be uncle or secondary amide class, preferred alkyl or substituted alkyl amide-type.For example, this contrast agent can be the ester or the amide of the triiodide benzoic acid (as the methyl substituted phenyl triiodide formic acid of acyl group, carbamoyl and/or acyl group) of replacement.The example that can enumerate representational iodate aromatic acid includes, but is not limited to, amidotrizoic acid (diatrizoic acid), Acidum Metrizoicum (metrizoicacid), iothalamic acid (iothalamic acid), trimesic acid (trimelsic acid), vinegar iodo-benzoic acid (urokonicacid), Ioxaglic Acid [ioxaglic acid (Ioxaglic Acid sodium Portugal amine)], methanol iothalamic acid (ioxitalamic acid), the tetraiodo for p-phthalic acid, adipiodone (iodipamide), iocarmic acid (icarmic acid), or the like.

If many above-mentioned iodate molecules with monomeric form, also can be made with dimer (being called two chemical compounds sometimes), trimer (being called three chemical compounds sometimes) etc. and form existence, and these all can adopt the known technology in present technique field to be prepared.Can expect that can the be enough bad molten iodinated compounds of the present invention realizes with the form of monomeric form, dimer, trimeric form and polymer.

Preferred contrast agent type has following general structure: The amidotrizoic acid ester

The iothalamic acid ester

[adipiodone]

R can be OR in the said structure formula ¹, NR ²R ³, alkylidene ,-COOR ¹Or-O-alkylidene-COOR ¹, R wherein ¹Be alkyl, R ²And R ³Represent H or alkyl independently.

Each alkyl can contain 1～20 respectively, and preferred 1～8 and 1～4 carbon atom more preferably.

This alkylidene preferably contains 1～4 carbon atom, for example methylene, ethylidene, propylidene or the like.

Particularly preferred contrast agent comprises, the ethyl ester of amidotrizoic acid, that is, and 3; 5-diacetamide-2,4,6-phenyl triiodide Ethyl formate also is called 3; two (acetyl-amino)-2,4 of 5-, 6-phenyl triiodide Ethyl formate or amidotrizoic acid ethyl ester, its structural formula are wherein R=-OCH of above-mentioned A ₂CH ₃The ethyl glycinamide carboxylic ester of amidotrizoic acid, promptly (3,5 pairs of (acetyl-amino)-2,4,6-phenyl triiodide formyloxy) ethyl acetate, also be called general shadow acyloxy acetic acid ethyl ester; And 2-(3, two (acetyl-amino)-2,4 of 5-, 6-phenyl triiodide formyloxy) ethyl n-butyrate., also be called the general shadow acyloxy of 2-ethyl n-butyrate..

In addition, can implement the present invention with the water-insoluble carbon tetraiodide acid esters described in the PCT/EP90/00053.

Above-mentioned x-ray contrast agent is a compound known and/or can be with the chemical compound of technology known in the art preparation.For example, the water-insoluble ester and the end-blocking amide-type of acid (as above-mentioned iodate aromatic acid) can be prepared by conventional alkylation known in the art or amidation technology.Can be commercial commercially available and/or can be from the preparation of the known technology this area as the above-mentioned acid of raw material and other acid.

The microgranule that is used for type defined above (8) compositions comprises surface modifier.Here the surface modifier of usefulness is that physical adherence self is carried out chemical reaction on the surface of x-ray contrast agent rather than with this contrast agent or it.Each of this surface modifier is adsorbed molecule not to be had intermolecular crosslinked basically.The surface modifier that is fit to can be selected from some known organic and inorganic pharmaceutical excipients, for example various polymer, low-molecular-weight oligomer, natural product and surfactant.Preferred surface modifier comprises the surfactant of nonionic and anionic.The representative example of surface modifier comprises gelatin, casein, lecithin (phospholipid), arabic gum, cholesterol, the tragakanta, stearic acid, Benasept, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan fat, the polyoxyethylene alkyl ether, for example, polyglycol ether such as cetomacrogol 1000, the polyoxyethylene castor oil derivative, the polyoxyethylene sorbitan fatty acid esters, for example, the various tweens (Tweens) that can buy on the market, Polyethylene Glycol, the polyoxyethylene stearate, colloidal silica, phosphate, sodium lauryl sulphate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, the amorphous cellulose element, aluminium-magnesium silicate, triethanolamine, polyvinyl alcohol, and polyvinyl pyrrolidone (PVP).Great majority in these surface modifiers are known pharmaceutical excipients, and unite on the medical excipient handbook of delivering in the pharmaceutical society by American Medical Association and GreatBritain and to describe in detail in the medicine tabletting (1986).

Particularly preferred surface modifier comprises polyvinyl pyrrolidone, tyloxapol, poloxamer such as Pluronic F68 T F108 (Pluronic F-68 and F108).(it is the block copolymer of oxirane and expoxy propane), and poly-azanol (Poloxamines) (it is the four functional blocks copolymers that the order addition of ethylenediamine obtained by expoxy propane and oxirane as special window (Tetronic) 908 (also be called poly-azanol 908), derive from BASF), glucose, lecithin, the dialkyl of sulfo-sodium succinate (aerosol (Aerosol) OT for example, it is the dioctyl ester of sulfo-pearl Meticortene Solu-Delta-cortef, available from American Cyanamid, Duponol p, it is a sodium lauryl sulphate, available from Du Pont (Dupont)), Te Lidun X-200＜nonionic surfactant, trade name〉(Triton X-200) (it is the alkyl aryl polyether sulphonic acid ester, available from Rohm and Heas), (it is the polyoxyethylene sorbitan aliphatic ester to Tween 80, available from ICISpecialty Chemicals), and Carbowax 3350 and 934 (they are Polyethylene Glycol, available from UnionCarbide).Found that useful especially surface modifier comprises: Tetronic 908, Tween class, Pluronic F-68 and polyvinyl pyrrolidone.

Other useful surface-modifying agent comprises:

Capryl-N-methyl glucoside amide;

Just-decyl β-D-pyranglucoside;

Just-decyl β-D-pyrans maltoside;

Just-dodecyl β-D-pyranglucoside;

Just-dodecyl β-D-maltoside;

Heptanoyl group-N-methyl glucoside amide;

Just-heptyl β-D-pyranglucoside;

Just-heptyl β-D-thioglycoside;

Just-hexyl β-D-pyranglucoside;

Pelargonyl group-N-methyl glucoside amide;

Just-nonyl β-D-pyranglucoside;

Caprylyl-N-methyl glucoside amide;

Just-octyl group β-D-pyranglucoside;

Octyl group β-D-sulfo-pyranglucoside; Or the like.

That particularly preferred surface modifier type comprises water soluble or the dispersible chemical compound of water, its general formula is as follows

Wherein

L is

Or

L ' be chemical bond ,-O-,-S-,-NH-,-CONH-or-SO ₂NH-;

R is hydrophobic replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl or replacement or unsubstituted aryl;

Each R ¹And R ²Represent hydrogen independently or have the alkyl of 1～4 carbon atom;

Each a and b represent 0 or 1～3 integer independently, and its condition is that a and b sum are not more than 3; With

Each x and y are respectively 3～7 integers.

The preferred compound that meets in this type of said structure is that wherein R contains 6～36 carbon atoms, for example, R be contain 6～18 carbon atoms just-alkyl, each R ₁And R ₂Independently for methyl, ethyl, propyl group or butyl and a be 0 and b be 0 chemical compound.This class surface modifier was narrated in the U.K. patent application 9104957.7 of submitting on March 8th, 1991, and can make by corresponding dicarboxylic ester and corresponding monosaccharide amine reaction, preferably under condition of no solvent, under 140～200 ℃ temperature, react.

This surface modifier is that buy on the market and/or the known technology of available this area makes.

Two or more surface modifiers can be mixed use.

The granule that uses in the compositions of Ding Yi type (8) can be prepared according to the polishing described in the US5145684 in the above.This method comprises that the x-ray contrast agent with bad dissolubility disperses and carry out wet lapping in the presence of abrasive media in the liquid dispersed liquid medium, it is about 0.05 μ～about 100 μ that the granularity of contrast agent is reduced to effective particle mean size, 0.05 μ-about 5 μ preferably approximately, more preferably about 0.1 μ-about 1 μ.This granule can reduce its granularity in the presence of surface modifier.Perhaps, can after grinding, this granule be contacted with surface modifier.

Here used granularity refers to number average particle size, is the ordinary skill with mensuration granularity known in the art, for example precipitates that the method for the moving classification of field flow, photon correlation spectrum or disc type centrifugalize measures.Said " effectively about 0.05 μ of particle mean size～about 100 μ " refer to when with above-mentioned technical measurement, and it is about 0.05 μ～about 100 μ that at least 90% granule has average particle size.Such particle size range makes has the distribution of particles of sufficient amount in the composition film that forms when applying the GI road thus, and can guarantee again not absorb by intestinal wall.

The water-insoluble iodate polymer beads that is used in the combination of type defined above (9) was narrated in US4406878 and WO94/25075.

Iodate polymer architecture formula of the present invention is to be represented by said structure formula I.The skeletal chain of this iodate polymer can be expressed as:

(i) condensation polymer, for example polyester, polyamide, polyurethane, Merlon, polyepoxide, polyethers, condensation polymer that the P-F polymer is suitable with other;

(ii) addition polymers, but by the polymerization preparation of the monomer (for example vinyl monomer) of the addition polymerization that contains polymerisable unsaturated double-bond.This class addition polymer comprises as poly-(vinyl alcohol), poly-(alkyl methacrylate), poly-(alkyl acrylate) addition polymer suitable with other; Or

(iii) naturally occurring polymer for example, contains the polysaccharide of glucose repeat units, for example starch, glycogen, cellulose, naturally occurring polymer that cellulosic derivant is suitable with other.

Preferably, the repetitive A of general formula I represents to have the residue of the repetitive of additional hydroxyl, for example the repetitive of the repetitive of poly-(vinyl alcohol), the repetition epoxy unit of polyepoxide, the hydroxylated acrylate copolymer glucose repeat units of poly-(hydroxyethyl acrylate) or naturally occurring polysaccharide for example.This additional hydroxyl or can be used as crosslinked position or can be used as response location for the precursor compound of the organic moiety X in the general formula I.This precursor compound can by with the condensation reaction of additional hydroxyl, carry out chemical bond-linking with repetitive on the polymer backbone chains.

A kind of organic fragment that contains iodine of organic moiety X representative of general formula I, it contains aromatic radical and one or more hydrophilic groups of an iodo.In order to obtain being used for the polymer with high content of iodine characteristic of the present invention, this iodo aryl has many iodine substituent group and is linked on the aromatic ring carbon atom by key directly.Particularly preferably be in these iodo aromatic radicals and contain three, the aromatic radical of preferred four ring carbon atoms that replaced by iodine.Although naphthalene nucleus also can be used with the nitrogen heterocyclic ring that contains 5-7 annular atoms, preferred iodo aromatic radical is the iodo phenyl ring.Particularly preferably be and on 4 ring carbon atoms, have the substituent phenyl ring of iodine.

Hydrophilic group X is normally as directly, or the key by chemistry connect base indirectly key link that substituent group on one or more ring carbon atoms of iodo aromatic radical exists.Preferred key connects the aliphatic group that base comprises short chain, for example has alkylidene, acylamino-and the suitable aliphatic group of 1～4 carbon atom.Typical hydrophilic group can be selected from some different groups like this, promptly comprises carboxyl; Sulfo group; Amino; Its esters such as carboxylate, sulfonate, ammonium salt; Polyalcohols such as glucose; The hydrophilic group suitable with other.

Usually, the derive precursor of general formula I organic moiety x contains one and forms the reactive group of chemical bond-linking base with the repetitive of polymer backbone chains.In a preferred embodiment of the invention, wherein the repetitive of polymer backbone chains is the residue that representative has the repetitive of hydroxyl, and the reactive group that is contained on the precursor of x is a kind of and group hydroxyl reaction.For example this reactive group can be a carboxyl, and the additional hydroxyl condensation of it and skeletal chain forms ester group, and key connects polymer backbone iodo aromatic portion.Form other various reactive groups of such chemical bond-linking base with hydroxyl reaction, as ether, amide, monothioester, carbonic ester, carbamate, thioether and various etc. work as thing, also can use.

The a part of precursor listed for the X portion part of general formula I comprise, for example, and 3-(3-amino-2,4,6-phenyl triiodide base)-2-propionic acid ethyl; 3-(3-hydroxyl-2,4,6-phenyl triiodide base)-2-propionic acid ethyl; 3-(3-bytyry amino-2,4,6-phenyl triiodide base)-2-ethylacrylic acid sodium; 3,5-two iodos-4-pyridone-N-acetic acid; 3-acetylaminohydroxyphenylarsonic acid 2,4,6-phenyl triiodide formic acid; The tetraiodo is for phthalic anhydride; Or the like.The tetraiodo can be useful especially for phthalic anhydride, because its content of iodine height.

Based on above-mentioned explanation, the structural formula of some preferred iodate polymer can be described as follows:

Wherein:

A is as defined in the general formula I of front;

X is as defined in the general formula I of front;

On behalf of above-mentioned key, L connect base, for example ester, ether, amide, monothioester, carbonic ester, carbamate, thioether etc.; And each R ¹～R ⁶Can be identical or different, represent hydrogen, contain the substituent group of iodine or contain the substituent group of hydrophilic group, about 40～80% (in the molecular weight of X) of content of iodine that its condition is X.

Preferred iodo polymer is crosslinked.It can increase the water-insoluble and the resistance to swelling of polymer.By carrying out crosslinked effectively introducing suitable crosslinked position on the skeletal chain of polymer or on the X part or on the two.For example, in a preferred embodiment, polymer contains the repetition skeleton unit of an additional hydroxyl of band and the side chain radical A that contains carboxyl as hydrophilic group, append to a hydroxyl on the polymer backbone chains can with the carboxyl reaction on the side chain X that is connected in another polymer, come crosslinked two polymer by ester bond thus.

Polymer contrast agent of the present invention contains hydrophilic group and hydrophobic group.The repetition skeleton unit A of structural formula I is hydrophobic basically, is the mass part as the X part.Certainly X also contains one or more hydrophilic groups.This of hydrophobic group and hydrophilic group combines, and believes that its importance is to provide suitable polymers surface and electrology characteristic, and then the compatibility of suitable polymers and human body organ and tissue is provided.

This iodate polymer can make by the polymerization and the chemical reaction technology of various routines.Preferred reactions steps is the precursor compound that makes side chain radical X and the preformed polymer that contains as the additional base (as hydroxyl) of suitable reaction position carries out chemical reaction.This preformed polymer can be prepared by addition or polycondensation according to the difference of polymer; Perhaps the polymer that exists for the nature situation of polysaccharide class for example can obtain from the source that nature exists.Precursor compound for the X part can react by various known reaction methods and the reaction position on polymer backbone, and this reaction method is decided according to the character that key in the above-mentioned general formula I that forms in this reaction connects basic L.More advantageously, being reflected under the emulsification condition of these precursor compounds carried out, so that the polymer that obtains is the particle form of segmentation.Crosslinked can or carrying out afterwards in the connection procedure of polymer backbone x part.

In above-mentioned WO94/25075, narrated for the example of the polymer of phthalic acid based on poly-(vinyl alcohol) and the tetraiodo.

The iodate polymer of a kind of water-insoluble and non-water swelling that has made as mentioned above, pulverizing or milled processed are so that obtain the polymer beads of suitable particle size scope in addition.Certainly, at this polymer is under the situation of felicity condition preparation, for example prepare under pearl polymerization or the emulsion polymerisation condition, then this polymer has had suitable granularity, thereby do not need other grinding and pulverizing, its granularity scope that is suitable for is about 0.01～1000 micron, preferred 0.1～100 micron for these polymer beads.

Preferred barium salt (contrast agent of the above-mentioned type (10)) is a barium sulfate, and it is white, roentgenopaque, water-fast crystalline powder basically.Granularity is that the barium sulfate of 0.001～0.1 micron diameter can be bought on the market.Yet, other available good barium salt product, promptly particulate, inorganic, water-insoluble barium salt basically comprises Barium hexaboride, chromous acid barium, Barium fluogallate., three-just-barium phosphate, barium silicate, Barium metatitanate., barium zirconate and zirconium oxide.Compositions of the present invention contains the barium salt of about 5%w/w to about 95%w/w.Said composition can be the form of dispersion liquid, colloid or suspension, yet we preferably use colloid as embodiment preferred.

The dispensing preparation that is used for contrast agent of the present invention can use physiologically acceptable carrier or excipient preparation by the method that this area is familiar with.All cpds adds pharmaceutically acceptable auxiliary agent (for example surface activity and emulsifying agent) and excipient can suspend or be partly dissolved in the aqueous medium, forms dispersion liquid, solution or suspension.Yet, preferred oil contrast media emulsion.

Use the compositions of the present invention of the contrast agent of type defined above (1)～(8) to contain following pharmaceutically acceptable various components (based on %w/v):

The component wide region is the scope most preferred range more preferably

Contrast agent 30～200 40～160 85～120

(the mg I/ml of total suspension)

Cellulose derivative 0.05～10 0.1～4 0.2～1

(％w/v)

Oiliness carrier 0.0～55 0.1～25 7～15

(％w/v)

Surfactant 0.0～20 0.1～10 3～7

(％w/v)

Viscosity modified

Excipient (%w/v) 0.0～15 0.001～4 0.05～1

Water-capacity to 100% (by volume)

Use the present composition of type defined above (9) contrast agent to contain following pharmaceutically acceptable each component (based on %w/v):

Component wide region preferable range

Iodinating polymer beads 5～95 20～70

(％w/v)

Cellulose derivative 0.05～10 0.1～4

(％w/v)

Surfactant 0.1～20 3～7

(％w/v)

The excipient of viscosity modified (%w/v) 0.001～4 0.05～1

Water capacity to 100% (by volume)

Use the combination of the present invention of barium salt to contain pharmaceutically acceptable following each composition (based on %w/v):

Component coarse adjustment range preferable range

Barium salt (w/v) 5～95 40～70

Cellulose derivative 0.1～10 0.2～1

(％w/v)

Oiliness carrier (%w/v) 0.1～55 7～15

Surfactant (%w/v) 0.1～20 3～7

The excipient of viscosity modified (%w/v) 0.001～15 0.05～1

Water capacity to 100% (by volume)

When said composition was used to the CT imaging in GI road, the concentration range of x-ray contrast agent should be 0.01～40mg I/ml, preferred 0.25～25mg I/ml and 4～12mg I/ml most preferably.

Being used in preferred cellulose derivant of the present invention is AVICEL ^_RC-591, it is the mixture of about 89 parts of microcrystalline celluloses and about 11 parts of sodium carboxymethyl cellulose.

Should be noted that following item about the component that is used for the present composition.

X-ray contrast agent exist concentration to be lower than minima in the above-mentioned prescription time can not produce fine X-ray or CT image, and its concentration is when being higher than the Cmax of above-mentioned prescription, become radiopaque too thereby can not demonstrate the image in GI road fully of GI road.

In the embodiment of this invention, O/w emulsion is better than water-in-oil emulsion, suspension and dispersion liquid.The oiliness material, its density can make emulsion-stabilizing near water density.Therefore low-density oil as mineral oil, is that the preparation emulsion is needed.When x-ray contrast agent at room temperature is oily mater, generally not necessarily need to add the oily carrier.This emulsion no longer was an oil-in-water emulsion and be transformed into water-in-oil emulsion when oil surpassed about 55%w/v.

The compositions that does not have surfactant to exist still can provide good X-ray image, it is emulsified that yet the surfactant-free compositions is difficult to, can only produce suspension/dispersion, this is not enough to meet the demands for applying the GI road, and stability is also little and storage life short.Owing to some surfactant concentrations of toxic reason should be low as far as possible; Its toxicity risk rate will increase sharply when surpassing about 20%w/v.

The various types of chemical compounds and the pharmaceutically acceptable carrier that are used for the present invention's prescription provide fine X-ray image, and add the quality that cellulose derivative has also been improved the X-ray image greatly in prescription.Can not obtain or seldom obtain good image with the lower limit of concentration range, and surpass the upper limit of concentration range, emulsion is too sticking to be unfavorable for administration.

Whether being necessary to add viscosity modifier can decide according to used cellulosic form or consumption; Then viscosity is too high when the viscosity modifier consumption is higher than 15%w/v will be tending towards forming gel.

Following formulation examples can further specify the present invention

Embodiment 1

Amounts of components (%w/v)

N-acetyl group-N-2-octyl group-4-iodo aniline 17.50

Light mineral oil, NF 12.50

Polyoxyethylene sorbitan monoleate (tween (Tween) 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (span (span) 80) 1.64

AVICEL ^_?RC-591 0.50

With enough water to 100% (by volume)

Embodiment 2

Amounts of components (%w/v)

N-(4 '-iodine substituted phenyl)-2-amino-octane 95.00

(at room temperature being oily)

Polyoxyethylene sorbitan monoleate (Tween 80) 5.00

AVICEL ^_?RC-591 6.50

With enough water to 100% (by volume)

Embodiment 3

Amounts of components (%w/v)

2,4,6-phenyl triiodide oxygen base-2-octane 14.50

Light mineral oil, NF 12.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_?RC-591 0.50

With enough water to 100% (by volume)

Embodiment 4

Amounts of components (%w/v)

2,4,6-phenyl triiodide oxygen base-2-butane 17.00

Polyoxyethylene sorbitan monoleate (Tween 80) 5.00

AVICEL ^_?RC-591 6.50

With enough water to 100% (by volume)

Embodiment 5

Amounts of components (%w/v)

2,4,6-phenyl triiodide oxygen base-2-hexane 25.40

AVICEL ^_?RC-591 10.00

With enough water to 100% (by volume)

Embodiment 6

Amounts of components (%w/v)

4-iodo phenoxy group-2-octane 30.00

Light mineral oil, NF 20.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.00

AVICEL ^_?RC-591 0.15

With enough water to 100% (by volume)

Embodiment 7

Amounts of components (%w/v)

2-octyl group-2,3,5-phenyl triiodide formic acid esters 17.50

Light mineral oil, NF 12.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_?RC-591 0.50

With enough water to 100% (by volume)

Embodiment 8

Amounts of components (%w/v)

3,3,4,4,5,5,6,6,7,7,8,8-12

Fluoro-2-octyl group-2,3,5-phenyl triiodide formic acid esters

Polyoxyethylene sorbitan monoleate (Tween 80) 5.00

AVICEL ^_?RC-591 6.50

With enough water to 100% (by volume)

Embodiment 9

Amounts of components (%w/v)

1,3,5-three-N-hexyl-2,4,6-phenyl triiodide 17.50

Light mineral oil, NF 12.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_?RC-591 0.50

With capacity 100% (by volume)

Embodiment 10

Amounts of components (%w/v)

1,3,5-triethyl group-2,4,6-phenyl triiodide 25.00

(at room temperature being oily)

Polyoxyethylene sorbitan monoleate (Tween 80) 5.00

AVICEL ^_?RC-591 6.50

With enough water to 100% (by volume)

Embodiment 11

Amounts of components (%w/v)

1,3,5-three-N-butyl-2,4,6-phenyl triiodide 20.50

Light mineral oil, NF 5.00

Polysorbate 20 (polysorbas20) 2.50

Sorbitan monolaurate (span 20) 2.50

AVICEL ^_?RC-591 0.50

With enough water to 100% (by volume)

Embodiment 12

Amounts of components (%w/v)

2-(4-iodine substituted phenyl) nonane 25.00

Polysorbate 20 (polysorbas20) 2.50

Sorbitan monolaurate (span 20) 2.50

AVICEL ^_?RC-591 0.75

With enough water to 100% (by volume)

Embodiment 13

Amounts of components (%w/v)

Two-(4-iodobenzene) ether 17.50 of Polyethylene Glycol-400

Light mineral oil, NF 12.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_?RC-591 0.50

With enough water to 100% (by volume)

Embodiment 14

Amounts of components (%w/v)

1,8-pair-O-(2,4,6-phenyl triiodide base)-

Tripropylene glycol 25.00

(being oily under the room temperature)

Polyoxyethylene sorbitan monoleate (Tween 80) 5.00

AVICEL ^_?RC-591 6.50

With enough water to 100% (by volume)

Embodiment 15

Amounts of components (%w/v)

1,11-pair-(2,4,6-phenyl triiodide oxygen base)-

3,6,9-trioxa hendecane 17.50

Light mineral oil, NF 12.50

Polysorbate 20 (polysorbas20) 2.50

Sorbitan monolaurate (span 20) 2.50

AVICEL ^_?RC-591 0.50

With enough water to 100% (by volume)

Embodiment 16

Amounts of components (%w/v)

1-(3-iodo phenoxy group)-3,6,9-trioxa decane 25.50

Polysorbate 20 (polysorbas20) 2.50

Sorbitan monolaurate (span 20) 2.50

AVICEL ^_?RC-591 0.50

With enough water to 100% (by volume)

Embodiment 17

Amounts of components (%w/v)

2 ethyl hexanoic acid 2,4,6-phenyl triiodide base ester 17.50

Light mineral oil, NF 12.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_?RC-591 0.50

With enough water to 100% (by volume)

Embodiment 18

Amounts of components (%w/v)

2,4,6-phenyl triiodide-three-(2 ethylhexoate) 95.00

Polyoxyethylene sorbitan monoleate (Tween 80) 5.00

AVICEL ^_?RC-591 6.50

With enough water to 100% (by volume)

Embodiment 19

Amounts of components (%w/v)

2,4,6-phenyl triiodide base-3-cyclopentanepropanoiacid acid ester 20.00 light mineral oils, NF 12.50

Polysorbate 20 (polysorbas20) 2.50

Sorbitan monolaurate (span 20) 2.50

AVICEL ^_?RC-591 0.50

With enough water to 100% (by volume)

Embodiment 20

Amounts of components (%w/v)

3-trifluoromethyl-2,4,6 phenyl triiodide bases-three

-(2-ethylhexanoate) 20.00

Polysorbate 20 (polysorbas20) 5.00

AVICEL ^_?RC-591 1.00

With enough water to 100% (by volume)

Embodiment 21 amounts of components (%w/v)

2,4,6-phenyl triiodide base hexane sulphonic acid ester 20.00

Light mineral oil, NF 12.50

Polyoxyethylene sorbitan monoleate (Tween 80) 2.00

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.00

AVICEL ^_?RC-591 1.00

With enough water to 100% (by volume)

Embodiment 22

Amounts of components (%w/v)

2,4,6-phenyl triiodide oxygen ylmethyl Pentamethylene. 14.50

Light mineral oil, NF 12.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_?RC-591 0.50

With enough water to 100% (by volume)

Embodiment 23

Amounts of components (%w/v)

2-(4-iodo phenoxy group) pentadecane 17.00

Polyoxyethylene sorbitan monoleate (Tween 80) 5.00

AVICEL ^_RC-591 6.50

With enough water to 100% (by volume)

Embodiment 24

Amounts of components (%w/v)

2-iodobenzene oxygen basic ring pentane 25.20

Light mineral oil, NF 20.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.00

AVICEL ^_RC-591 0.15

With enough water to 100% (by volume)

Embodiment 25

Amounts of components (%w/v)

3, two (acetylamino)-2,4 of 5-, 6-

Phenyl triiodide Ethyl formate 17.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_RC-591 0.50

With enough water to 100% (by volume)

Embodiment 26

Component consumption (%w/v)

Ethyl (3, two (acetylamino)-2,4 of 5-, 6-

Three iodos-benzoyloxy) acetas 25.00

Light mineral oil, NF 10.00

Polyoxyethylene sorbitan monoleate (Tween 80) 5.00

AVICEL ^_RC-591 6.50

With enough water to 100% (by volume)

Embodiment 27

Amounts of components (%w/v)

2-(3, two (acetylamino)-2,4 of 5-, 6-triiodo

Generation-benzoyloxy) ethyl n-butyrate. 30.00

Pluronic (Pluronic) F-68 10.00

AVICEL ^_RC-591 2.00

With enough water to 100% (by volume)

Embodiment 28

Amounts of components (%w/v)

3, two (acetylamino)-2,4 of 5-, 6-three iodos

Benzene methyl ethyl ester 17.50

Light mineral oil, NF 12.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_RC-591 0.50

With enough water to 100% (by volume)

Embodiment 29

Amounts of components (%w/v)

Iodinating polymer beads 17.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_RC-591 0.50

With enough water to 100% (by volume)

Embodiment 30

Amounts of components (%w/v)

Iodinating polymer beads 25.00

Polyoxyethylene sorbitan monoleate (Tween 80) 5.00

AVICEL ^_RC-591 6.50

With enough water to 100% (by volume)

Embodiment 31

Amounts of components (%w/v)

Iodinating polymer beads 20.00

Polysorbate 20 (polysorbas20) 5.00

AVICEL ^_RC-591 1.00

With enough water to 100% (by volume)

Embodiment 32

Amounts of components (%w/v)

Iodinating polymer beads 30.00

Mineral oil, NF 10.00

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_RC-591 0.50

With enough water to 100% (by volume)

Embodiment 33

Amounts of components (%w/v)

Barium sulfate 17.50

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_RC-591 0.50

With enough water to 100% (by volume)

Embodiment 34

Amounts of components (%w/v)

Barium hexaboride 25.00

Light mineral oil, NF 9.50

Polyoxyethylene sorbitan monoleate (Tween 80) 5.00

AVICEL ^_RC-591 6.50

With enough water to 100% (by volume)

Embodiment 35

Amounts of components (%w/v)

Barium chromate 70.00

Light mineral oil, NF 5.00

Polysorbate 20 (polysorbas20) 2.50

Sorbitan monolaurate (span 20) 2.50

AVICEL ^_?RC-591 0.50

With enough water to 100% (by volume)

Embodiment 36

Amounts of components (%w/v)

Barium silicate 85.00

Polysorbate 20 (polysorbas20) 2.50

Sorbitan monolaurate (span 20) 2.50

AVICEL ^_RC-591 0.75

With enough water to 100% (by volume)

Embodiment 37

Amounts of components (%w/v)

Barium fluogallate. 50.00

Mineral oil, NF 10.00

Polyoxyethylene sorbitan monoleate (Tween 80) 3.37

Dehydrated sorbitol mono-fatty acid ester (sorbester p17) 1.64

AVICEL ^_RC-591 0.50

With enough water to 100% (by volume)

Embodiment 38

Component consumption (%w/v)

Three orthophosphoric acid barium 60.00

Polyoxyethylene sorbitan monoleate (Tween 80) 5.00

AVICEL ^_RC-591 2.00

With enough water to 100% (by volume)

Such as known to persons skilled in the art, surfactant or emulsifying agent can reduce the interfacial tension between two immiscible phases (i.e. oil in water-bearing media).These agent can be used separately, also can be used with other emulsifying agent and surface activity.Dow Corning Medical AntifoamAF for example, this product itself just can use, it is the compositions of 30%w/v polydimethylsiloxane dimethicone and silica aerogel, 14%w/v stearate emulsifying agent and 0.075%w/v sorbic acid, watering balance.Refined lecithin is that a kind of emulsion of fatty acid needs the suspending agent existence so that make its formation contain the acceptable emulsion of contrast agent of the present invention.Surfactant can be two or more a mixture of cationic, anionic, nonionic, amphoteric ion type or they.

Suitable cationic surface active agent comprises cetyl trimethyl ammonium bromide.Suitable anionic surface activity comprises sodium lauryl sulphate, heptadecyl sodium sulfate, alkyl benzene sulphonate and salt, sodium butylnaphthalenesulfonate and thio succinate.Amphoteric ionic surfactant is that those work as when water-soluble that they play the material of binary acid effect, and plays weak acid and weakly alkaline effect again when their ionizing.Because these two kinds of electric charges then play a part neutral molecule in the mutual balance of intramolecularly in the molecule outside.PH value when amphion concentration is maximum is called isoelectric point, IP.The chemical compounds such as some aminoacid that have isoelectric point, IP under the present invention fills a prescription desired pH value can be used to implement the present invention.

We preferably use nonionic emulsifier or surfactant in preparation preparation of the present invention, and are similar with non-ionic contrast agent, compare with anion, cation or amphoteric ion type agent to have fabulous toxicity study analysis.Hydrophilic and ratio hydrophobic group approximately is the balance of equity in nonionic emulsifier.Owing in molecule, there is not electric charge, thus be different from anionic and cationic surface active agent, therefore, its zest little than cationic or anionic surfactant usually.Nonionic surfactant comprises the alkyl phenol of carboxylate, carboxylic acid amide, ethoxylation and the aliphatic alcohol of ethoxylation.

A kind of carboxylate nonionic surfactant of particular type is a partial ester, monoesters for example, it is (this polyhydric alcohol is glycols, sorbitan and other analog of glycerol,, two, four and six ethylidene glycols etc. for example) that forms by fat and the resinic acid with 8～18 carbon atoms etc. and polyol reaction; And the oxirane by various mol ratios is to the formed similar compound of hydroxyl direct reaction of fatty acid.

Another kind of carboxylate is condensation product, the ethylene oxide ester of fat and resin meta-acid (for example single acid), for example fat of polyoxyethylene sorbitan and Sorbitol or resinate, for example polyoxyethylene sorbitan, single tall oil esters.They can contain, for example about 3～about 80 ethylene oxide units and fat or resin acidic group with 8～18 carbon atoms in the per molecule.The example of the fatty acid mixt that operable nature exists is those fatty acids of taking from Oleum Cocois and tallow, and the example of pure fatty acid is dodecylic acid and oleic acid.

The carboxylic acid amide nonionic surfactant is the amide-type of ammonia, single ethylamine and diethylamide of fatty acid that the acyl chain of about 8～about 18 carbon atoms is arranged.

The alkyl phenol nonionic surfactant of ethoxylation comprises the polyethylene oxide condensation compound of various alkyl phenols, especially (alkyl wherein contains about 6～about 12 carbon atoms for monoalkyl phenol or dialkyl phenol, and can be side chain or be linear configuration, linear configuration particularly, for example octyl group cresols, octyl phenol or nonyl phenol) with the condensation product of oxirane, the content of said oxirane is that every mole of alkyl phenol is about 5～about 25 moles oxirane.

The aliphatic alcohol nonionic surfactant of ethoxylation comprises the aliphatic alcohol of the straight or branched configuration with about 8～18 carbon atoms, for example oleyl alcohol or 16 carbon alcohol, with the condensation product of oxirane, said oxirane is about 30～about 60 moles oxirane to the amount of every mol of alcohol.

Preferred nonionic surfactants comprises: the sorbitan ester [trade name of sale is span (Span)] with following general structure:

Wherein, R ₁=R ₂=OH, R ₃=R is for sorbitan monoesters class;

R ₁=OH, R ₂=R ₃=R is for sorbitan two esters;

R ₁=R ₂=R ₃=R is for sorbitan three esters;

R=(C wherein ₁₁H ₂₃) COO, for laurate;

(C ₁₇H ₃₃) COO, for oleate;

(C ₁₅H ₃₁) COO, for cetylate;

(C ₁₇H ₃₅) COO, for stearate;

Its general structure of polyoxyethylene Arrcostab (being Brijs) is as follows:

CH ₃(CH ₂) _x(O-CH ₂-CH ₂) _yOH

Wherein (x+1) is the carbon number on the alkyl chain, usually:

12 lauryls (12 carbon alkyl)

14 myristyls (tetradecane base)

16 cetyls (hexadecane base)

18 stearyl (octadecyl)

Y is the number of oxyethylene group in hydrophilic chain, is generally 10～60.

The pears sugar alcohol fatty acid ester of poly-ethylidene dehydration, commercially available commodity are polysorbate 20,40,60,65,80 and 85, its general structure is (1) and (2)

In the formula

W+x+y+z=20 (polysorbate 20,40,60,65,80 and 85)

W+x+y+z=5 (sorbimacrogol oleate 100)

W+x+y+z=4 (Polysorbate 21 and 61)

Poly-ethylidene stearate, for example:

Poly-(oxygen-1,2-ethane two bases), α-hydrogenation-ω-hydroxyl octadecane acid esters; With

Poly-(oxygen-1,2-ethane two bases), α-(1-hydrogenation octadecyl)-ω-hydroxyl-polyethylene glycol mono stearate.

The contrast agent dose that the inventive method is used will change according to the clear and definite character of used contrast agent.But preferably should keep to reach the high low dosage of radiography image quality.By using low dose of as far as possible contrast agent, make toxic influence reduce to minimum.For most of contrast agent of the present invention, that its dosage range should be is about 0.1～approximately 16.0g iodine/kg body weight, 0.5～approximately 6.0g iodine/kg body weight preferably approximately, most preferably about 1.2～approximately 2.0g iodine/kg body weight, this scope is applicable to that the X-ray in conventional GI road develops.For CT scan, the amount ranges of contrast agent of the present invention should be about 1～approximately 600mg iodine/kg body weight, and preferably approximately 20～approximately 200mg iodine/kg body weight are heavy, especially preferably approximately 40～approximately 80mg iodine/kg body weight.

The concentration range of contrast agent should be the 75%w/v of about 0.001%w/v～approximately of preparation, the 50%w/v of 0.05%w/v～approximately preferably approximately, the most preferably about 20%w/v of 0.1%w/v～approximately.

Claims

1. one kind is used for X-ray contrast compositions oral or that the intestines and stomach degeneration is checked, and it comprises:

(a) x-ray contrast agent is selected from:

(1) every ml compositions content of iodine is the x-ray contrast agent chemical compound with following general formula or its pharmaceutically acceptable salt of about 0.01～200mg,

In the formula:

Z is H, halogen, C ₁-C ₂₀Alkyl, cycloalkyl, lower alkoxy, cyano group, the alkyl here and cycloalkyl can replace with halogen or junior alkyl halides;

R ₁And R ₂Represent H, C independently ₁-C ₂₅Alkyl, cycloalkyl, acetyl group or halogenated low alkyl group, wherein said C ₁-C ₂₅Alkyl-cycloalkyl and junior alkyl halides can replace or not replace and said acetyl group can use fluoro low alkyl group, aryl, lower alkoxy, hydroxyl, lower alkoxycarbonyl or lower alkoxy carbonyl oxygen base to replace with fluoro low alkyl group, aryl, lower alkoxy, hydroxyl, carboxyl, lower alkoxycarbonyl or lower alkoxy carbonyl oxygen base;

N is 1-4

Y is 1-4; With

X is 1 or 2

(2) every ml compositions content of iodine is the x-ray contrast agent chemical compound with following general formula of about 0.01～200mg, or its pharmaceutically acceptable salt,

Wherein:

R is that replace or the unsubstituted alkyl that contains 2～8 carbon atoms, and wherein said substituent group is selected from C ₁-C ₆Alkyl, hydroxyl and alkoxyl; And n is 1～5;

(3) every ml compositions content of iodine is the x-ray contrast agent chemical compound with following general formula or its pharmaceutically acceptable salt of about 0.01～200mg:

Wherein,

Z is H, halogen, C ₁-C ₂₀Alkyl, cycloalkyl, lower alkoxy, cyano group, alkyl here and cycloalkyl can be replaced by halogen or junior alkyl halides;

R is C ₁-C ₂₅This wherein each of alkyl, cycloalkyl or junior alkyl halides can be replaced or not replace by halogen, fluorine low alkyl group, aryl, lower alkoxy, hydroxyl, carboxyl, elementary alkoxy carbonyl or lower alkoxy carbonyl oxygen base; Or (CR ₁R ₂) _p-(CR ₃=CR ₄) _mQ or (CR ₁R ₂) _p-C ≡ C-Q;

R ₁, R ₂, R ₃And R ₄Represent low alkyl group independently, can also be replaced or not replace by halogen;

X is 1-3;

Y is 1-4;

N is 1-5;

M is 1-15;

P is 1-10; With

(4) every ml compositions content of iodine is the x-ray contrast agent chemical compound with following general formula or its pharmaceutically acceptable salt of about 0.01～200mg:

Wherein,

R be methyl, ethyl, just-propyl group, C ₄-C ₂₅Alkyl, cycloalkyl, undersaturated pi-allyl or junior alkyl halides, each in them can be replaced or not replace by halogen, fluoro low alkyl group, aryl, lower alkoxy, hydroxyl, carboxyl or elementary alkoxy carbonyl; Or (CR ₁R ₂) _p-(CR ₃=CR4) _mQ or (CR ₁R ₂) _p-C ≡ C-Q;

R ₁, R ₂, R ₃And R ₄Represent H, low alkyl group independently, also can be replaced or not replace by halogen;

N is 2-5;

M is 2-5;

P is 1-10; With

(5) every ml compositions content of iodine is the x-ray contrast agent chemical compound with following general formula or its pharmaceutically acceptable salt of about 0.01～200mg:

Wherein Z is H, halogen, C ₁-C ₂₀Alkyl, cycloalkyl, lower alkoxy, alkoxy carbonyl, cyano group, alkyl here and cycloalkyl can be replaced by halogen or junior alkyl halides;

R is C ₁-C ₂₅Alkyl, cycloalkyl, Or junior alkyl halides, each in them can be replaced or not replace by halogen, fluoro low alkyl group, aryl, lower alkoxy, hydroxyl, carboxyl, elementary alkoxy carbonyl or lower alkoxy carbonyl oxygen base; Or (CR ₁R ₂) _p-(CR ₃=R ₄) _mQ or (CR ₁R ₂) _p-C ≡ C-Q;

X is 1-4;

N is 1-4;

M is 1-15;

P is 1-20; With

(6) every ml compositions content of iodine is the x-ray contrast agent chemical compound with following general formula or its pharmaceutically acceptable salt of about 0.01～200mg:

Wherein,

X is

Or-SO ₂-;

Z is H, halogen, C ₅-C ₂₀Alkyl, cycloalkyl, lower alkoxy, cyano group, alkyl here and cycloalkyl can be replaced by halogen or junior alkyl halides;

R is C ₁-C ₂₅Alkyl, cycloalkyl, aryl or junior alkyl halides, each in them can replace or not replace with lower alkoxy, hydroxyl, carboxyl or elementary alkoxy carbonyl, low-grade alkenyl, low-grade alkynyl, low-grade alkylidene or lower alkoxy carbonyl oxygen base;

N is 1-4;

M is 0,4; With

W is 1-4;

(7) every ml compositions content of iodine is the x-ray contrast agent chemical compound with following general formula of about 0.01～200mg, or its pharmaceutically acceptable salt:

Wherein Z is H, halogen, C ₁-C ₂₀Alkyl, cycloalkyl, lower alkoxy, cyano group, the alkyl here and cycloalkyl can enough halogens or junior alkyl halides replace;

R is methyl, ethyl, propyl group, C ₉-C ₂₅Alkyl, cycloalkyl or junior alkyl halides, can replace or not replace with halogen, fluoro low alkyl group, aryl, lower alkoxy, hydroxyl, carboxyl, elementary alkoxy carbonyl or low-alkoxy carbonyl oxygen base; Or (CR ₁R ₂) _p-(CR ₃=CR ₄) _mQ or (CR ₁R ₂) _p-C ≡ C-Q;

X is 1-4;

N is 1-5;

M is 1-15;

P is 1-10; With

(b) cellulose derivative of 0.05～10%w/v is selected from methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose and microcrystalline Cellulose;

(c) oiliness carrier of 0～55%w/v;

(d) surfactant that is selected from nonionic, anionic, cationic and amphoteric ionic surfactant class of 0～20%w/v;

(e) 0～15% viscosity modification excipient; With

(f) make volume reach 100% water.

2. according to the X-ray contrast compositions of claim 1, wherein the amount of said x-ray contrast agent is to be 30～200mg in content of iodine in every ml compositions.

3. according to the X-ray contrast compositions of claim 1, wherein said oiliness carrier constituent content is 0.1～25%w/v of compositions.

4. according to the X-ray contrast compositions of claim 1, wherein the content of said surface active agent composition is 0.1～10%w/v of compositions.

5. one kind is used for X-ray contrast compositions oral or that the intestines and stomach degeneration is checked, comprising:

(a) every ml compositions content of iodine is about 40～160mg the crystallization contrast agent is selected from amidotrizoic acid, Acidum Metrizoicum, iothalamic acid (iothalamic acid), trimesic acid, the vinegar iodo-benzoic acid, the methanol iothalamic acid, the tetraiodo is for p-phthalic acid, Ioxaglic Acid, adipiodone, ethyl-3,5-diacetylamino-2,4,6-phenyl triiodide formic acid, ethyl-2-(3, two (the acetic acid amino)-2 of 5-, 4,6-three iodos-benzoyloxy) butyrate, and ethyl-(3, two (acetylamino)-2 of 5-, 4,6-phenyl triiodide formyloxy)-acetas, said crystallization contrast agent has and is adsorbed on its lip-deep surface modifier, and it is about 0.5 μ～about 100 μ that its consumption is enough to keep effective particle mean size; Be selected from the four functional blocks copolymers that the order addition of ethylenediamine obtained by expoxy propane and oxirane with said surface modifier;

(b) cellulose derivative of 0.1～4%w/v, it is selected from methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose and microcrystalline Cellulose;

(c) oiliness carrier of 0.1～25%w/v;

(d) surfactant that is selected from nonionic, anionic, cationic and amphoteric ionic surfactant class of 0.1～10%w/v;

(e) the viscosity modification excipient of 0.001～4%w/v; With

(f) make cumulative volume reach 100% water.

6. one kind is used for X-ray contrast compositions oral or that the intestines and stomach degeneration is checked, comprising:

(a) the water-insoluble iodinating polymer beads of about 5～95%w/v, its granularity are about 0.01～about 1000 μ, and wherein said iodinating polymer beads comprises the polymer that contains the repetitive shown in the following general formula (I),

Wherein: A is the multiple organic unit on the polymer backbone chains; With

X is the organic moiety that contains iodate aromatic radical and hydrophilic group, and said part has content of iodine, is benchmark in the molecular weight of X, is about 40～about 80 weight %;

(b) cellulose derivative that is selected from methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose and microcrystalline Cellulose of 0.05～10%w/v;

(c) surfactant of 0.1～20%w/v is selected from the various surfactants of nonionic, anionic, cationic and amphoteric ion type;

(d) the viscosity modification excipient of 0.001～4%w/v; And

(e) make cumulative volume reach 100% water.

7. according to the X-ray contrast compositions of claim 6, X representative wherein contains the organic moiety of iodate aryl, and said part is represented by following structural:

Wherein: L represents that key connects base, is selected from ester group, ether, amide groups, sulfo-ester group, carbonate group, carbamate groups, thioether group; With

R ¹～R ⁶In each, they can be identical or inequality, represent hydrogen, contain the substituent group of iodine or contain the substituent group of hydrophilic group, its condition is that (i) content of iodine is that the 40～80%wt of X and (ii) said hydrophilic group are selected from carboxyl, sulfo group, amino, above-mentioned carboxyl, sulfo group and amino salt, and polynary alcohol radical.

8. according to the X-ray contrast compositions of claim 7, wherein said surface active agent composition content is 3～7% of compositions.

9. one kind is used for X-ray contrast compositions oral or that the intestines and stomach degeneration is checked, comprising:

(a) barium salt of about 5～95%w/v;

(b) cellulose derivative of 0.1～10%w/v, it is selected from methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose and microcrystalline Cellulose;

(c) oiliness carrier of 0.1～55%w/v;

(d) surfactant of 0.1～20%w/v is selected from the various surfactants of nonionic, anionic, cationic and amphoteric ion type;

(e) the viscosity modification excipient of 0.001～15%w/v; With

(f) make cumulative volume reach 100% water.

10. according to the X-ray contrast compositions of claim 9, wherein said oiliness carrier constituent content is 7～15%w/v of compositions.

11. according to the X-ray contrast compositions of claim 9, wherein said surface active composition content is the 3-7% of compositions.

12. according to the X-ray contrast compositions of any one claim of front, wherein said its particle mean size of microcrystalline Cellulose is 0.01～100 μ.

13. according to the X-ray contrast compositions of claim 12, wherein said microcrystalline Cellulose is about 89 parts microcrystalline Cellulose and about 11 parts of sodium carboxymethyl cellulose.

14. according to the X-ray contrast compositions of any one claim of front, wherein said nonionic surfactant is to be selected from the induced by alkyl hydroxybenzene of carboxylic acid esters, carboxylic acyloxy amine, ethoxylation and the aliphatic alcohols of ethoxylation.

15. according to any one the X-ray contrast compositions of claim 1-13, wherein said surfactant is a sorbitan ester, its structural formula is as follows:

In the formula:

For sorbitan monoesters class R ₁=R ₂=OH, R ₃=R;

For sorbitan two esters R ₁=OH, R ₂=R ₃=R;

For sorbitan three esters R ₁=R ₂=R ₃=R;

R=(C wherein ₁₁H ₂₃) COO, for laurate;

(C ₁₇H ₃₃) COO, for oleate;

(C ₁₅H ₃₁) COO, for cetylate;

(C ₁₇H ₃₅) COO, for stearate.

16, according to any one the X-ray contrast compositions of claim 1-13, wherein said surfactant is the polyoxyethylene alkyl ether, and its structural formula is:

CH ₃(CH ₂) _x(O-CH ₂-CH ₂) _yOH

(x+1) is the carbon number on the alkyl chain in the formula, is generally:

12 lauryls (12 carbon alkyl)

14 myristyls (tetradecane base)

16 cetyls (hexadecane base)

18 stearyl (octadecyl)

With y be the number of Oxyranyle in hydrophilic chain, its value is for about 10～about 60.

17, according to any one the X-ray contrast compositions of claim 1-13, wherein said surfactant is the polyoxyethylene sorbitan fatty acid esters, and its structural formula is represented as shown in the formula (1) and (2):

Wherein:

w＋x＋y＋z＝20；

w＋x＋y＋z＝5；

w＋x＋y＋z＝4。

18. being used for the X-ray contrast compositions of the claim 1 of oral or the inspection of gastrointestinal tract degeneration comprises:

(a) contrast agent of every ml compositions content of iodine generation X-ray contrast that is about 85～120mg;

(b) cellulose derivative that is selected from methylcellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose and microcrystalline Cellulose of 0.2～1%w/v;

(c) mineral oil of 7～15%w/v;

(d) surfactant that is selected from nonionic, anionic, cationic and amphoteric ionic surfactant class of 3～7%w/v;

(e) the viscosity modification excipient of 0.05～1%w/v; With

(f) make cumulative volume reach 100% water.

19. according to the X-ray contrast compositions of claim 18, wherein the particle mean size of said microcrystalline Cellulose is 0.05～10 μ.

20. patient's intestines and stomach carries out the method for X-radiological survey X, said method comprises the X-ray contrast preparation oral administration of any one claim of front or rectally in the patient.