CN1215342A

CN1215342A - Contrast medium

Info

Publication number: CN1215342A
Application number: CN97193663A
Authority: CN
Inventors: 纳塔拉詹·拉贾戈帕兰; 凯文·D·奥斯特兰德; 埃文·古斯托; 布赖恩·多蒂; 菲利普·哈尼什
Original assignee: Nycomed Imaging AS
Current assignee: GE Healthcare AS
Priority date: 1996-02-20
Filing date: 1997-02-20
Publication date: 1999-04-28
Also published as: HUP9901323A2; WO1997030736A3; GB9603547D0; CA2247041A1; JP2000504742A; BR9710946A; NO983828D0; NO983828L; KR19990087196A; EP0881916A2; AU1885297A; WO1997030736A2

Abstract

The invention provides a contrast medium having good lower GI tract coating properties following oral administration. The medium comprises a diagnostically effective amount of a contrast agent together with a viscosity modifier and an osmotic modifier, said modifiers together being present at a weight ratio relative to said agent of at least 1:20.

Description

Contrast agent

Invention field

The present invention relates to be used for the gastrointestinal contrast agent, be specifically related to contain contrast medium, preferably can be oral the contrast agent of granule contrast medium.The invention still further relates to and this contrast agent is used for diagnosing image, the particularly application of X-radiodiagnosis x, CT, magnetic resonance (MR) or colon ultrasonography.

Background of invention

In various formation methods,, successfully used contrast agent to strengthen the contrast of gastrointestinal (GI) road imaging as X-line, CT, ultrasonic and MR imaging.

In these situations, the route of administration of contrast agent is oral or rectally, and this route of administration generally depends on the gastrointestinal tract section that the doctor will check.

Therefore, for colon or rectum imaging, for example, when detecting colorectal carcinoma, polyp or false polyp, adopt the rectally contrast agent usually.But if some pathological condition taboo barium enema(BE) agent, then the another kind of method of Cai Yonging is the oral administration contrast agent.

Contrast agent generally shows as Space (wherein contrast agent is full of the digestive tract cavity) or surface effect (wherein contrast agent is just coated on mucosa, and is injected by gas or other non-poisonous gas in the digestive tract) to effective enhancing of digestive tract hypomere imaging.

If but contrast agent is the by oral route administration, then cause the surperficial contrast effect of colon imaging bad because the contrast agent coating is inhomogeneous with speckle occurring usually.

More particularly, present contrast media formulations can not provide enough coating for a long time and uniformly to mucous membrane of colon; Therefore, checking process generally is to check the barium agent after (" forward position ") on the mucosa begins to flow, and just obtains to have the slice, thin piece (in the perspective process and after emptying and the inflation) of diagnostic significance.This just causes barium agent medication relevant with the availability of image space.If the contrast agent prescription can provide long-time and lasting imaging window, then bigger motility is provided for patient's review time.

In addition, " forward position " of the contrast agent that check to flow must allow the patient body rotation with a kind of operation, and with the compressing method to strengthen flowing and the observability of edge details of contrast agent around the diagnostic region.Use this " forward position " technology also to be not easy to check out the dissection damage, because this technology can only be seen the sub-fraction of imaging region.A kind of improved contrast agent with even coating characteristic is the essential number of operations of acquisition high-quality inspection owing to reduced, thereby has also reduced review time and patient's misery.

The mode of taking of mobile barium agent also will match with the time section of X-ray examination.The not only consuming time and consumption power of X-ray examination imaging also can be brought higher radiation to patient and inspection personnel.Preparation with improved mucous membrane of colon coverage property can reduce the X-ray radiation in the checking process.

The certain operations that will do patient during uncomfortable and imaging that rectally brought, thereby make the barium coloclysis in patient and doctor mind, produce bad sensation.For patient, if selectable words, then many patients are reluctant to accept this inspection method, although bibliographical information its have the screening and/or diagnostic value.For the doctor, because the method is scandalous, and need the doctor to pay a lot of work, so the doctor tend to adopt expensive and dangerous inspection means to obtain identical information (as, colonoscopy) in order to obtain high-quality check result.

Therefore, the object of the invention provides a kind of oral contrast material, and this contrast agent can make the digestive tract hypomere have the good surface of comparative.

We have found can improve this surperficial comparative by the contrast agent that uses following composition at present, promptly contain a kind of permeation of modified agent in contrast agent composition, and it keeps its hydration balance in the time of making contrast agent pass through upper digestive tract, prevent the caking of this contrast agent; Also contain a kind of viscosity modifying agent that adheres to mucosa (as, a kind of cellulose composition), it can make contrast agent adhere on the wall of lower digestive tract, has reduced the drainage of contrast agent.

Summary of the invention

Therefore, one aspect of the present invention provides a kind of oral administration that is applicable to carry out the moisture diagnosis composition of colon imaging, said compositions contains a kind of contrast medium of diagnosing effective dose, as the X line, CT, MR, ultrasonic or contain the reagent of radionuclide, preferably a kind of X line contrast agent that contains heavy metal or iodine, especially preferably a kind of particle reagents, contain simultaneously a certain amount of permeation of modified agent (as, a kind of polyhydric alcohol, or poly alkylene glycol) be enough to prevent the caking of said composition in gastrointestinal tract, also containing the viscosity modifying agent that a certain amount of organic mucosa adheres to is enough to make said composition to cover on the mucous membrane of colon substantially equably.The present invention is to use the permeation of modified agent contrast agent transport can be delivered to colon, and viscosity modifying agent can guarantee that contrast agent is attached to colon surface, has reached suitable balance between the two.

From another aspect, a kind of diagnosis composition that the present invention also provides contains a kind of contrast medium and a kind of viscosity modifying agent and a kind of permeation of modified agent of diagnosing effective dose.Said these two kinds of modifier weight ratio of content and said contrast medium altogether are 1: 20.Said viscosity modifying agent is selected from: polyvinylpyrrolidone, natural gum, polysaccharide and polysaccharide derivates; Said permeation of modified agent is selected from: C ₃The derivant of-polyhydroxy alkanol, polyalkylene oxides and polyalkylene oxides.

As if these viscosity and permeability modification agent have a kind of synergism, and the inorganic viscosity modifying agent of colloid does not show this synergism in dog model, also do not produce the effective coating effect to colon.

The range of viscosities that preferred compositions has according to the present invention is 2-2000cPs, and the permeability scope is 50 to 500mOsm.

The present invention also provides the improved method of a kind of mankind of making or non-human animal's body (preferably mammal) imaging on the other hand, this method comprises to using a kind of contrast agent in the gastrointestinal tract that is tried body, makes said gastral at least a portion produce a kind of image.The improvement of this method is that used contrast agent is according to a kind of compositions of the present invention.

Another aspect of the present invention also provides a kind of method for preparing diagnosis composition, said method comprises mixes a kind of contrast medium with a kind of viscosity modifying agent and a kind of permeation of modified agent of above-mentioned definition, the weight ratio of these two kinds of modifier and contrast medium was at least 1: 20.

Another aspect of the present invention also provides viscosity modifying agent and the application of permeation of modified agent in production diagnosis composition of the present invention, and said composition is applicable to the diagnostic method of gastrointestinal tract imaging.

Compositions of the present invention preferably can be a kind of low-viscosity (mobile) liquid, especially a kind of liquid of promptly using form, for example a kind of stable storing form that may need before use to vibrate a little but need not dilute.This compositions advantage of (21 ℃) at ambient temperature is to have the viscosity that is lower than 500cP, especially be lower than 200cP, and the concentration of this contrast medium is 5-25% weight for the X line imaging, preferred 10-20%, being 0.05-10% concerning the CT imaging, is 0.001 to 0.5% concerning the MR imaging.

Though the mechanism of action for described contrast agent is still not fully aware of, but observed and between two kinds of modifier, had a kind of synergism, make contrast agent produce unexpected viscosity-Penetration Signature, behind this contrast agent of oral administration, can provide high-quality colon imaging.

Because the appropriate combination of viscosity modifying agent and permeation of modified agent can be effectively the diagnostic reagent of oral administration is transported to colon and a kind of uniform contrast medium coating is provided on mucous membrane of colon, therefore, this induction system also can be adapted to pass through the intestinal wall that oral route delivering therapeutic (also comprising prevention) reagent arrives the gastrointestinal tract hypomere, particularly arrives the intestinal wall of colon.Therefore, another aspect of the present invention also provides a kind of aqueous pharmaceutical composition that oral administration conducts drugs to patient's lower digestive tract that is suitable for, said compositions contains a kind of therapeutic agent (as can be by the medicament of intestinal absorption behind any oral or rectally), with a kind of content be organic viscosity modifying agent of 0.1 to 50%w/v, and a kind of content is 0.1 to 50%w/v permeability modification agent, and the concentration of said these modifier will be enough to be coated with substantially equably on patient's mucous membrane of colon when oral administration and covers said reagent.

The accompanying drawing summary

By accompanying drawing the present invention is done further explanation.

Fig. 1 and 2 represents is that Canis familiaris L. is before the preparation of oral administration embodiment 1 and gastrointestinal tract X line image afterwards.

What Fig. 3,4,5 and 6 represented is that Canis familiaris L. is after oral embodiment 1 preparation, and as a comparison, (50%Liquid Polibar (EZM) and commodity contain diodone Gastrografin and Omnipaque (90mgI/mL) gastrointestinal tract X line image afterwards to the agent of oral commodity barium.

Fig. 2 and Fig. 7 represent the gastrointestinal X line image that is Canis familiaris L. after respectively with oral and rectally embodiment 1 preparation.

Fig. 2 and Fig. 8 represent be Canis familiaris L. oral embodiment 1 preparation and oral equivalent is painted and the seasoning preparation after gastrointestinal X line image.

What Fig. 9 and 10 represented is the CT image of Canis familiaris L. after oral embodiment 11 preparations; With

What Figure 11 represented is the MR imaging of Canis familiaris L. after oral embodiment 12 preparations.

Detailed Description Of The Invention

Any material of Enhanced Imaging contrast that the contrast preparation in the diagnosis composition of the present invention can be can be in the diagnosing image method (calculating laminagraphy (SPECT), scintigraphy etc. such as X-ray, CT, ultrasonic, MR, electrical impedance x-ray laminagraphy, magnetic x-ray laminagraphy, single photon emission). But, The present invention be more particularly directed to those contain particle contrast preparation or emulsion (as inorganic, organic or organic metal particle or, be not very preferred molecular aggregates thing or liposome) composition. These particle reagents are insoluble at composition with in gastric juice usually, or are at most sl. sol..

Certainly, the accuracy of contrast medium depends on formation method, and usually can prepare according to the present invention with the contrast medium of oral or rectally in any formation method. Particularly preferably be, for the X-ray imaging, this contrast medium is a kind of inorganic heavy metal compound, such as barium sulfate or indissoluble or water-insoluble iodinated organic compounds basically, for example at US-A-5330739, US-A-5318768, US-A-5310537, US-A-5308607, US-A-5312616, US-A-5316755, US-A-5260049, US-A-5326553, US-A-5310538, US-A-5260478, the iodinated compounds of discussing among US-A-5318767 and the US-A-5264610. For MR imaging or magnetic measurement method, used contrast preparation is a kind of Ferrimagnetic, ferromagnetic, superparamagnetic or paramagnetic material preferably, selectively with a kind of coating or host material, such as polymer coating such as monosilane or the polystyrene of stomach juice-resistant. Therefore can use the particle with Nycomed ' s ABDOSCAN product or Advanced Magnetics ' Biomag M4200 product form. Perhaps also can use gadolinium oxalate particle or another kind of relatively insoluble paramagnetic compound. For ultrasonic imaging, can use the as a comparison agent of any echogenic material, and for composition of the present invention, these materials can be the particles more higher or lower than gastric juice density, as, the synthesized polymer composite capsule of inorganic particle (such as barium sulfate) or inflation. For scintigraphy or SPECT, contrast medium obviously must contain a kind of suitable radionuclide. Such as a kind of radionuclide metal ion chelating compound or a kind of organic or inorganic material that contains radionuclide.

This contrast medium is a kind of inorganic particle preferably, and especially preferably a kind of barium compound, especially barium sulfate. The barium sulfate composition of oral administration of the present invention can produce the imaging of good lower digestive tract radiograph, particularly colon.

If contrast medium is granular; such as barium sulfate; or if the immiscible liquid of a kind of water just exists (namely with the suspended droplet form; a kind of emulsion); the size of this particle or droplet is not vital; but preferred range at 1nm to 100 μ m is especially within 5nm to 10 μ m, particularly within 10nm to 5 μ m. Can prepare this particle or droplet by for example grinding or precipitation or emulsification. In order to make image even, preferably make the size distribution scope of this particle or droplet narrower, and be monodispersity basically preferably.

For specific contrast medium and formation method, can suitably select the concentration [concentrate that dilutes if not water before administration (or another kind of suitable aqueous carrier)] of contrast medium in the present composition, but preferably at 0.001 to 95%w/v range, further preferred 3 to 90% w/v, more preferably 5 to 30%w/v, and especially preferred 10 to 20%w/v. If the concentration of X-ray contrast medium is too high, meeting can not be enough to describe clear gastral image so that intestines and stomach X-ray light transmission is too poor. For the X-ray imaging, the concentration of this contrast medium is preferably 10 to 20%w/v. For the MR contrast medium, if concentration is too high, can in image, produce suspicious pseudo-shadow. For the MR imaging, contrast medium concentrations generally is to be lower than 1%w/v. For all contrast medium, concentration is too low then can not to provide enough strong images of contrast.

The used viscosity modifying agent of the present invention preferably natural gum (as, guar gum or xanthans), polyvinylpyrrolidone or a kind of polysaccharide or polysaccharide derivates. The branching polysaccharide, or all be preferred with the polysaccharide of monose or oligosaccharide side chain or the ether derivant of other polysaccharide. Suitable examples of materials comprises alginates, pectin, amylopectin, methylcellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and microcrystalline cellulose/carboxymethyl cellulose; Cellulose ether is preferred.

Viscosity modifying agent preferably a kind of natural gum or a kind of molecular weight ranges is the polysaccharide of 25kD to 2MD.

This cellulose ether viscosity modifying agent can be the cellulose ether of any solubility, for example C_1-6The C of alkyl or replacement_1-6Alkyl, such as hydroxyalkyl, alkoxyalkyl or carboxyalkyl ether, for example, ethyl cellulose, methylcellulose, propyl cellulose, hydroxyethylcellulose, methyl carboxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose (and with tolerating for example salt of alkali metal (such as sodium) of counter ion counterionsl gegenions on the physiology), etc. The suitable example of commercial available cellulose ether comprises Methocel K4M, K50, K100LVP and E5, Pharmacoat 615 and Avicel CL-611.

Although can produce the viscosity modifying agent of 2-2000cP range of viscosities in the time of can using those in water, to contain 1.5%w/v at ambient temperature, but especially preferred low viscosity modifier, for example those can to produce range of viscosities under condition as mentioned above be 2-100cP, preferred 2 to 60cP, more preferably the modifier of 2-50cP. In general, the content of viscosity and viscosity modifier is remained on above-mentioned range should be as much as possible low, so that maximum possible can be accepted patient. This viscosity modifying agent generally is the instant liquid, aqueous form of using, and the content in composition is 0.1 to 50%w/v, preferred 0.1 to 10 %w/v, and more preferably 1 to 2.5%w/v.

The permeation of modified agent that the present invention uses is a kind of C preferably₃-polyalcohol (for example, propane diols, or glycerine more preferably), or the derivative of a kind of polyalkylene oxides or polyalkylene oxides, for example, PAG.

The agent of this poly alkylene glycol permeation of modified can be homopolymer or copolymer, for example, and a kind of block copolymer.Usually, alkylidene unit contains 2 to 6, preferred 2,3 or 4 carbon atoms, and they can be identical or different.

Therefore, the example of this modifier can be Polyethylene Glycol (PEG), polypropylene glycol, a kind of poloxamer (Poloxamer) or poly-azanol body (Poloxamine).The product that wide range of molecular weights is arranged that this poly alkylene glycol is commercially available, what the present invention preferably used is to have molecular weight 150 to 200000D, preferred 200 to 10000D, particularly 200 to 4000D product.The suitable example of commercially available poly alkylene glycol comprises 200,400,600,1450,3350,4000, and the PEG of 6000 200K and 2M model.The example of suitable block copolymer comprises pluronic gram (pluronic) and tetronic (tetronic), as Pluronic F127 and F108, and tetronic 1508.Polyethylene Glycol is preferred.

Permeation of modified agent suitable consumption in the instant water formulation that uses is 0.1 to 50%w/v, preferred 0.1 to 25%w/v (for example 1 to 25%w/v), and more preferably 1 to 10%w/v, and especially preferably 2 to 8%w/v.The same with viscosity modifying agent, the amount of general permeation of modified agent will keep low as far as possible.

For total osmol concentration of water formulation of the present invention, the preferred content of permeability modification agent is 5 to 500mOsm, and especially 10 to 300mOsm, and particularly 15 to 150mOsm.

As mentioned above, two kinds of modifier is 1: 20 with the gross weight of contrast medium than at least.More preferably, particularly for oral barium sulfate compositions, this weight ratio is 1: 10 at least, is 1: 5 especially at least, particularly at least 1: 3, and preferably less than 1: 1.

The weight ratio of permeability modification agent and viscosity modifying agent preferably within 1: 2 to 10: 1 scope, especially 1: 3 to 8: 1, particularly 1: 1 to 4: 1.

Prove as following embodiment,, can obtain good coating according to compositions of the present invention, and cover colon surface effectively, and show in the suitable time of staying of colon to small intestinal no matter be oral or rectally.Different with existing barium sulfate product is that they do not cause diarrhoea or be deposited in small intestinal or the large intestine that they show transmission performance (also promptly: can see the multiple eclipsed intestinal collar) in wide zone, and tangible edge can occur.Said composition is owing to can have the high-quality mucosa spreadability of continuing, so can reduce operator's work load and interdependency (also be, can cover mucomembranous surface, have transmittance and can carry out the edge visual examination), and can reduce or eliminate to the needs of patient operation with to patient and doctor's excessive x radiation x, particularly reduced and done the necessity that x-ray fluoroscopy is checked.

X-ray image to gained after the oral compositions of the present invention of mammal (as Canis familiaris L.) shows, said composition has arrived colon and ascending colon, transverse colon and descending colon has been carried out complete surface coverage effectively, the transmittance of ray is good, there is better profile at the edge, does not have compositions residual in stomach and small intestinal.Do not need the actuating patient just can obtain high-quality image.

Compositions of the present invention can enter gastrointestinal tract by oral or rectally easily by the dosage of 0.1 to 15mL/kg body weight.Said composition is particularly useful for oral administration, and preferred dosage is 1.5 to 15mL/kg for this route of administration, particularly 4mL to 10mL/kg.

For rectally, the dosage of said composition depends on surface imaging or aerial image.In the previous case, 0.1 to 10mL/kg consumption imaging effectively, and under latter event, need 10 to 15mL/kg relatively large.For the research of gastrointestinal tract surface imaging, generally need inflate lower digestive tract.

After rectally, can take a picture immediately or in 60 minutes time, take a picture.If the oral administration said composition must stop the enough time,, arrive desirable intestinal zone so that said composition is passed through after administration.In general, for the imaging of adult's colon, scope is 1 to 12 hour during this period of time.

Employed imaging technique can be any known formation method.But, compositions of the present invention is specially adapted to ultrasonic and MR imaging, and especially be applicable to large-scale X-ray formation method (as, CT, plain film, counting, x-ray fluoroscopy, spiral CT, the jejunum colonoscopy, etc.).

Except cellulose ether viscosity modifying agent, the agent of poly alkylene glycol permeation of modified and contrast medium, compositions of the present invention can also contain a kind of liquid carrier medium (as, water, fruit juice or a kind of water/alcohol mixture) or one or more other be suitable for being administered into habitual additive in the preparation of gastrointestinal contrast agent, for example, add viscosity or permeability modification agent again, with medicine or veterinary drug preparation composition commonly used, as antiseptic, wetting agent, disintegrating agent, binding agent, filler, stabilizing agent, flavoring agent, coloring agent, buffer agent and pH regulator agent.

Contrast agent dosage form of the present invention can be mixed with in the water carrier medium that being present in of instant use can tolerate on the physiology (as suspension, emulsion, solution or dispersion liquid), perhaps is mixed with the conc forms that need dilute before use.Concentrate formulation before use can water, fruit juice etc. dilutes.Perhaps, contrast agent can be mixed with dried forms, for example powder, granule, piller or tablet disperse before use again.The but preferably instant water formulation that uses.

Compositions of the present invention further also contains (selectable) infiltration and viscosity modifying agent.Selectable viscosity modifying agent comprises Bentonite, dextrin, aluminium-magnesium silicate, polyvinyl alcohol, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose and polyacrylic acid.Selectable permeation of modified agent comprises Polyethylene Glycol, glycerol, propylene glycol, Sorbitol, mannitol, a-amino acid and ionic species, as NaCl, citric acid etc.

The invention will be further described with reference to following non-limiting examples: embodiment 1 contains barium sulfate preparation components and concentration (w/v) barium sulfate of a kind of viscosity modifying agent and a kind of permeation of modified agent, USP 15.00% Polyethylene Glycol, NF 1,450 5.00% hydroxypropyl methylcellulose 2910, USP ^*1.50% microcrystalline Cellulose and sodium carboxymethyl cellulose, NF 1.00% simethicone emulsion, USP 30% 0.33% anhydrous citric acids, USP 0.19% potassium sorbate, NF 0.15% sodium benzoate, NF 0.12% sodium lauryl sulphate, NF 0.05% anhydrous saccharin sodium, USP 0.04% pure water, USP adds to 100ml. ^*Trade name Methocel E5 (Dow Chemical Company, Midland, Michigan).Give Canis familiaris L. oral with above-mentioned preparation, the X-ray imaging shows that said preparation has arrived colon, and to ascending colon, transverse colon and descending colon have carried out complete sum surface coverage effectively, the permeability of ray is better, have good edge (all these all can strengthen the quality of diagnosis of radial imaging), and in stomach or small intestinal, do not stop.Do not need the actuating patient can obtain high quality graphic.The image of forward and backward radiography is seen Fig. 1 and Fig. 2.

The compositions of embodiment 1 preferably is mixed with and contains coloring agent and flavoring agent, as the FD ﹠amp of 0.015%w/v; The yellow No.6 powder of C and 0.5%w/v is natural and the preparation of synthetic citrus flavoring agent No.325070.Embodiment 2 contains the barium sulfate preparation of a kind of viscosity modifying agent and a kind of permeation of modified agent

Components and concentration (w/v) barium sulfate, USP 15% Polyethylene Glycol, NF-1450 2.5-10%Pharmacoat 615 (hydroxypropyl emthylcellulose) 2.0% microcrystalline Cellulose and sodium carboxymethyl cellulose, NF ^*1.0% simethicone emulsion, USP 30% 0.33% single hydration citric acids, USP 0.21% water potassium sorbate, NF 0.15% sodium benzoate, NF 0.12% saccharin sodium, USP 0.04% sodium laurylsulfate, NF 0.075% pure water, USP adds to 100ml. ^*Can obtain with Avicel CL611 trade name from FMC Corp..Embodiment 3 contains the barium sulfate preparation of a kind of viscosity modifying agent and a kind of permeability modification agent

Components and concentration (w/v) barium sulfate, USP 15% Polyethylene Glycol, NF-3350 2.5-10%Pharmacoat 615 2.0% microcrystalline Cellulose and sodium carboxymethyl cellulose, NF ^*1.0% simethicone emulsion, USP 30% 0.33% single hydration citric acids, USP 0.21% water potassium sorbate, NF 0.15% sodium benzoate, NF 0.12% saccharin sodium, USP 0.04% sodium lauryl sulphate, NF 0.075% pure water, USP adds to 100ml.Embodiment 4 magnetic granular preparation components and concentration (w/v) Polyethylene Glycol, NF 1,450 5.00% hydroxypropyl methylcellulose 2910, USP ^*1.50% microcrystalline Cellulose and carboxymethyl cellulose sodium, NF 1.00% magnetic granule (as, USPIOs) 0.5% simethicone emulsion, USP 30% 0.33% citric acids, USP 0.19% potassium sorbate, NF 0.15% sodium benzoate, NF 0.12% sodium lauryl sulphate, NF 0.05% saccharin sodium, USP 0.04% pure water, USP adds to 100ml. ^*Trade name Methocel E5 (Dow Chemical Company, and Mid (and, Michigan).The comparison of embodiment 5 prototype barium sulfate preparations and current commodity preparation

The preparation of embodiment 1 and a kind of 50% (clinical optium concentration) commodity barium sulfate suspending agent and two kinds are contained Operand to be compared behind the oral administration in dog model side by side.The representative diagram that is produced similarly is Fig. 3 (embodiment 1) of accompanying drawing, Fig. 4 (50%Liquid Polibar), Fig. 5 (diatrizoate methylglucamine sodium) and Fig. 6 (omnipaque 90mgI/mL).With the colon of X-ray imaging cover percentage rate, uniformity, radiability, the edge is apparent and ascending colon, transverse colon, descending colon mucosa coverage condition compare.The result shows that the performance of embodiment 1 preparation is far superior to the performance of prior art preparation, and embodiment 1 preparation formed and have more conforming high quality graphic, is to satisfy unique product that by oral route is carried out colon diagnosing image needs.Embodiment 6 prototype barium sulfate preparation performance repeatabilities are estimated

Automatically the repeatability of surveying with 20 doggies studies confirm that embodiment 1 preparation each oral and the thick colon image of rectally approach formation and repeatability of picture quality.This research and utilization oral and rectum intersect the administration design.The result of this research shows the preparation oral administration of embodiment and the high-quality colon image that the rectum approach has shown the height repeatability.Through three independently the evaluation personnel use the same hierarchical standard described in the embodiment 5 imaging compare to X-ray.The result shows that said preparation has excellent images and repeatability.

Colon is divided into 6 districts: near-end ascending colon, far-end ascending colon, near-end transverse colon, far-end transverse colon, near-end descending colon and far-end descending colon.What following table 1 was represented is when the colon Zone Full is coated, and promptly Zone Full is the persistent period that applied in 100% o'clock by three evaluation personnel score.

Table 1

The time span that colon * Zone Full 100% applies is summarized

(to each group Canis familiaris L. oral administration)

Persistent period	Number of times	Percentage ratio
Persistent period	Number of times	Percentage ratio	＜1 hour ^**1-＜2 hour 2-＜4 hours 4-＜5 hour 5-＜6 hours	????3 ????5 ????9 ????2 ????1	?????15.0 ?????25.0 ?????45.0 ?????10.0 ??????5.0

^*When thinking, whole evaluation personnel reach 100% time point that covers.

^*Had the colon Zone Full of two Canis familiaris L.s to reach 100% covering at 8 hours, be last imaging time point in this research this moment.Interval at 4 to 6 hours have the colon Zone Full of 1 Canis familiaris L. except that the descending colon far-end to reach 100% covering.Reach 100% at 8 hours descending colon far-ends and cover, but the average covering to the ascending colon near-end is chosen as 87% in the time of 8 hours.

What following table 2 was represented is to reach the mean percentage that mucous membrane of colon covers in time.

Table 2

The mean percentage that mucous membrane of colon covers

Oral administration

The Canis familiaris L. of combination

The colon section	15 minutes	45 minutes	75 minutes	105 minutes	4 hours	5 hours	6 hours	8 hours
The colon section	15 minutes	45 minutes	75 minutes	105 minutes	4 hours	5 hours	6 hours	8 hours	The ascending colon near-end	????0	????19	????60	????83	?100	?100	?100	??97
The ascending colon far-end	????0	????19	????64	????84	?100	?100	?100	?100	The ascending colon near-end	????0	????19	????60	????83	?100	?100	?100	??97
The ascending colon far-end	????0	????19	????64	????84	?100	?100	?100	?100	The transverse colon near-end	????0	????14	????63	????84	?100	?100	?100	?100
The transverse colon far-end	????0	????10	????56	????74	?98	?100	?100	?100	The transverse colon near-end	????0	????14	????63	????84	?100	?100	?100	?100
The transverse colon far-end	????0	????10	????56	????74	?98	?100	?100	?100	The descending colon near-end	????0	????10	????24	????43	?82	??94	??98	?100
The descending colon far-end	????0	????10	????18	????26	?73	??89	??93	?100	The descending colon near-end	????0	????10	????24	????43	?82	??94	??98	?100

Oral and the rectally of embodiment 7 prototype barium sulfate preparations

Described in the research described in the embodiment 6 and utilized oral and rectally to obtain similar high-quality colon image, wherein picture quality, uniformity, radiability, the edge mucosa coverage condition apparent and ascending colon, transverse colon and descending colon that applies the percentage rate evaluation with colon has shown similar quality.These mass propertys are consistent in whole reproduction research.When the retrograde administration of said preparation, observe interesting phenomenon, wherein after administration 5-10 minute, mucous membrane of colon has been shown good covering, and demonstrated the preferable image quality.This picture quality continues 60 minutes behind rectally.The prolongation of 8 prototype barium sulfate preparation time of staying in the colon imaging process of embodiment

Embodiment 1 preparation is compared with contrast product, and a viewed obvious advantage is on the imaging window that can see when oral and rectally.Observing its diagnosing image persistent period is 1-4 hour.When giving the dog model oral administration, as a rule, the covering of mucous membrane of colon was appeared at after the administration 4 hours to the administration at least 8 hours with embodiment 1 preparation.Compare with at least 60 minutes imaging window (search time) after the administration, rectally has shown high-quality imaging, with the image similarity of oral administration.In the image of this in the accompanying drawings Fig. 2 (behind the oral administration 5 hours) and Fig. 7 (behind the rectally 30 minutes) as can be seen.Embodiment 9 adds flavoring agent and toner in the barium sulfate prototype formulations

Prepare a kind of prototype suspension that contains flavoring agent and coloring agent,, sickly complexion is easily accepted to improve the palatability of dosage form.And, compare with picture quality behind embodiment 1 oral administration.As if these imaging research show, add the image quality that flavoring agent and coloring agent can not change said preparation, and it is not subjected to the influence of used flavoring agent and coloring agent.Provided a preparation for example below.Fig. 2 (embodiment 1 preparation) and the Fig. 8 (through seasoning and painted preparation) in the accompanying drawing seen in resulting representative imaging.The prototype formulations that has flavoring agent and coloring agent:

Components and concentration (w/v) barium sulfate, USP 15.00% Polyethylene Glycol, NF 1,450 5.00% hydroxypropyl methylcellulose 2910, USP ^*1.50% microcrystalline Cellulose and sodium carboxymethyl cellulose, NF 1.00%Citrus flavoring agent ^*0.50% simethicone emulsion, USP 0.33% anhydrous citric acid, USP 0.19% potassium sorbate, NF 0.15% sodium benzoate, NF 0.12% sodium lauryl sulphate, NF 0.05% saccharin sodium, USP 0.04%PD ﹠amp; The yellow color No.6 of C 0.01% pure water, USP adds to 100ml ^*Can trade name Methocel E5 obtain (Dow Chemical Company, Midland, Michigan) ^*For example, this preparation of Tastemaker No.325070 can be used as the X-ray contrast medium, also can be used as the ultrasonic contrast medium.Can with other can echogenicity the material of (echogenic), for example alternative barium sulfate of Chong Qi granule or microsphere.Embodiment 10 operators' independence

To the test shows of prototype barium sulfate preparation, do not needing to obtain good colon plain film image under the situation that the experimenter is operated.In general gastrointestinal examination method, need carry out many operations (that is upset health, compressing etc.) to patient and, avoid the gathering of preparation in a certain zone to obtain diagnostic image.Embodiment 1 and 9 described preparations do not need the operator can obtain high-quality mucosa covering to patient's operation.This effect has shown that contrast agent used in preparation of the present invention and the present practice compares and have great advantage.Wherein great advantage is medicine economy/safety (reducing X-ray examination time or raying and working doctor time) and result's a concordance (technology that is diagnostic result and operator is irrelevant).Embodiment 11CT-preparation

Components and concentration (w/v) barium sulfate, USP 3.5% Polyethylene Glycol, NF 1,450 5.00% hydroxypropyl methylcellulose 2910, USP ^*1.5% microcrystalline Cellulose and sodium carboxymethyl cellulose, NF 1.00%Citrus flavoring agent ^*0.50% simethicone emulsion, USP 0.33% anhydrous citric acid, USP 0.19% potassium sorbate, NF 0.15% sodium benzoate, NF 0.12% sodium lauryl sulphate, NF 0.05% saccharin sodium, USP 0.04%PD ﹠amp; The yellow color No.6 of C 0.01% pure water, USP adds to 100ml ^*Trade name Methocel E5 (Dow Chemical Company, Midland, Michigan) ^*For example, Tastemaker No.325070

Show that this contrast agent has arrived colon for the oral CT imaging that obtains of Canis familiaris L. in the preparation of embodiment 11, and completely effectively mucous membrane of colon is covered clear-cut margin.In addition, there is evenly complete contrast agent to cover clear-cut margin (seeing Fig. 9 and 10) from a plurality of intestinal lassos of small intestinal are provable.Therefore said composition obviously is applicable to CT and non-CT examination, for example cavity colonoscopy.Embodiment 12MR-preparation

Components and concentration (w/v) Ethanedioic acid, gadolinium(3+) salt (3:2) 0.005% Polyethylene Glycol, NF 1,450 5.00% hydroxypropyl methylcellulose 2910, USP ^*1.50% microcrystalline Cellulose and sodium carboxymethyl cellulose, NF 1.00%Citrus flavoring agent ^*0.50% simethicone emulsion, USP 0.33% anhydrous citric acid, USP 0.19% potassium sorbate, NF 0.15% sodium benzoate, NF 0.12% sodium lauryl sulphate, NF 0.05% saccharin sodium, USP 0.04%PD ﹠amp; C yellow uitramarine No.6 0.01% pure water, USP adds to 100ml ^*Trade name Methocel E5 (Dow Chemical Company, Midland, Michigan) ^*For example, Tastemaker No.325070

Show that this contrast agent has carried out effective covering to gastrointestinal mucosa for the magnetic resonance image (MRI) of the oral acquisition of Canis familiaris L. with the preparation of embodiment 12, and edge clear (seeing Figure 11).The performance of embodiment 13 other viscosity modifying agents

After cellulose has been done following replacement in embodiment 1 preparation; Show that from the picture quality of colon effect is satisfied. amylopectin 5.0mg/mL sodium carboxymethylcellulose NF 0.75-2.0mg/mL guar gum NF 1.0mg/mL hydroxypropyl cellulose NF 0.75-2.0mg/mL CMC K4M 0.25mg/mL CMC E5 2.5mg/mL methylcellulose NF (25cP and 1500cP) 2.0mg/mLAvicel CL-611 1.5mg/mL pectin USP 2.5mg/mL polyvinylpyrrolidone (PVP 40) USP 2.0mg/mL polyvinylpyrrolidone (PVP 360) USP 2.0mg/mL polyvinylpyrrolidone 90 2-7mg/mL xanthans, the performance of NF 0.25mg/mL mosanom NF 0.5mg/mL embodiment 14 other permeability modification agent

To the work of PEG 1450 in embodiment 1 preparation following replacement, show that by the colon image quality effect is satisfied.Glycerol USP 5-10mg/mL pluronic gram F108 5.0mg/mLPEG 400 2/5-10.0mg/mLPEG 1450 2.5-10.0mg/mLPEG 3350 10.0mg/mLPEG 20M 10.0mg/mLPEG 200K 3mg/mL tetronics 1508 5.0mg/mL

Claims

1. diagnosis composition, contain a kind of contrast medium and a kind of viscosity modifying agent and a kind of permeability modification agent of diagnosing effective dose, the weight ratio of said modifier summation and said contrast medium is at least 1: 20, said viscosity modifying agent is selected from: polyvinylpyrrolidone, natural gum, polysaccharide and polysaccharide derivates, said permeability modification agent is selected from: C ₃-polynary alkanol, polyalkylene oxides and polyalkylene oxides derivant.

2. the described compositions of claim 1, wherein said viscosity modifying agent is selected from: polysaccharide, natural resin, alginate and the polyvinylpyrrolidone of cellulose ether, branch's polysaccharide, band side chain.

3. the described compositions of claim 1, wherein said viscosity modifying agent contains a kind of cellulose ether.

4. the compositions of each claim of claim 1 to 3, wherein said permeability modification agent is selected from: alkylene oxide polymers, alkylene oxide block copolymer and glycerol.

5. the compositions of each claim of claim 1 to 4, wherein said permeability modification agent contains a kind of poly alkylene glycol.

6. the described compositions of claim 1, wherein said viscosity modifying agent is a kind of cellulose ether, and said permeability modification is a kind of poly alkylene glycol.

7. the compositions of each claim of claim 1 to 6, the molecular weight of wherein said permeability modification agent are 150 to 200000D.

8. the compositions of each claim of claim 1 to 7, said composition is aqueous solution, suspension or dispersion, and wherein said permeability modification agent makes the permeability of such compositions reach 5-500mOsm.

9. the compositions of each claim of claim 1 to 7, said composition is aqueous solution, suspension or dispersion, and wherein said permeability modification agent makes the permeability of such compositions reach 15-150mOsm.

10. the compositions of each claim of claim 1 to 7, said composition is aqueous solution, suspension or dispersion, and the content of said permeability modification agent is 1-10%w/v.

11. the described compositions of each claim of claim 1 to 10, the molecular weight of wherein said viscosity modifying agent are 25000 to 2000000D.

12. the described compositions of each claim of claim 1 to 11, said composition is aqueous solution, suspension or dispersion, and wherein said viscosity modifying agent makes the viscosity of such compositions reach 2-2000cP.

13. the described compositions of each claim of claim 1 to 11, said composition is aqueous solution, suspension or dispersion, and wherein said viscosity modifying agent makes the viscosity of such compositions reach 2-60cP.

14. the described compositions of each claim of claim 1 to 13, said composition is aqueous solution, suspension or dispersion, and the content of wherein said viscosity modifying agent is 0.1-10%w/v.

15. the described compositions of each claim of claim 1 to 14, wherein said contrast agent is granular.

16. the described compositions of each claim of claim 1 to 15, wherein said contrast medium are a kind of X-ray contrast medium that contains heavy metal or iodine.

17. the described compositions of claim 16, wherein said contrast medium is a barium sulfate.

18. the described compositions of claim 17, the weight ratio of wherein said modifier summation and barium sulfate is at least 1: 5.

19. the described compositions of each claim of claim 1 to 18, its range of viscosities are 2 to 100cP.

20. the described compositions of each claim of claim 1 to 19 is suitable for oral administration with instant type of service.

21. the described compositions of each claim of claim 1 to 20, the weight ratio of wherein said permeability modification agent and described viscosity modifying agent is 1: 2 to 10: 1.

22. one kind is suitable for the moisture diagnosis composition that oral administration carries out the colon imaging, said compositions contains a kind of contrast medium of diagnosing effective dose and content and is enough to prevent that compositions is enough to make said composition evenly to cover organic viscosity modifying agent on the mucous membrane of colon basically at the permeability modification agent of upper digestive tract caking and content.

23. one kind makes people or non-human animal be tried body and carries out imaging method, this method comprises a kind of contrast agent is administered in experimenter's the gastrointestinal tract, and making said gastrointestinal at least a portion produce image, its improvement comprises that the contrast agent of being given is the described compositions of each claim of claim 1 to 22.

24. the described a kind of method of claim 23, wherein said imaging is the X-ray imaging.

25. the described a kind of method of claim 23, wherein said imaging MR imaging.

26. the described a kind of method of claim 23, wherein said imaging is a ultrasonic imaging.

27. a method for preparing diagnosis composition, described method comprise a kind of viscosity modifying agent and a kind of permeability modification agent of a kind of contrast medium with claim 1 definition mixed, the weight ratio of these modifier and contrast medium is at least 1: 20.

28. viscosity modifying agent and permeability modification agent are used to produce the purposes as the defined diagnosis composition of each claim of claim 1 to 22, this diagnosis composition is applicable to a kind of diagnostic method that makes the gastrointestinal tract imaging.

29. one kind is applicable to that oral administration conducts drugs to the aqueous pharmaceutical composition of patient's gastrointestinal tract hypomere, it is that organic viscosity modifying agent of 0.1 to 50%w/v and a kind of content are 0.1 to 50%w/v permeability modification agent that said compositions contains a kind of therapeutic agent and a kind of content, and said these modifier are enough to said therapeutic agent is covered on patient's the mucous membrane of colon basically equably when oral administration.