KR100778241B1 - Contrast media composition for computerized tomography and the method of preparing thereof - Google Patents

Abstract

A contrast media composition for computerized tomography is provided to obtain an excellent contrast image during computer tomography and be stored for a long period of time by optimizing ingredients and contents of barium sulfate, a tackifying agent, a surfactant and an osmotic pressure controlling agent. A contrast media composition for computerized tomography comprises 0.001-1.0 wt./vol.% of barium sulfate, 0.05-1.0 wt./vol.% of carboxymethylcellulose sodium(Na-CMA) as a tackifying agent, 0.2-1.5 wt./vol.% of a mixture of microcrystalline cellulose and carboxymethylcellulose sodium, 0.005-0.01 wt./vol.% of ammonium glycyrrhizinate as a surfactant, 0.0001-0.01 wt./vol.% of polysorbate, 1.0-10.0 wt./vol.% of D-sorbitol as an osmotic pressure controlling agent and purified water. A method for preparing the contrast media composition for computerized tomography comprises the steps of: (a) after putting purified water in a preparation tank and adding a mixture of microcrystalline cellulose and carboxymethylcellulose sodium thereto to disperse it, swelling it; (b) after putting purified water in a separate container and adding di-sorbitol solution, ammonium glycyrrhizinate and polysorbate thereto, putting barium sulfate therein and then dispersing it; and (c) after mixing the mixture obtained from the step(b) with the mixture obtained from the step(a) and putting purified water therein, milling a prepared solution.

Description

 Contrast media composition for computerized tomography and the method of preparing Technical

1 is a diagram showing the results of computed tomography after administration of the contrast composition prepared in Example 3.

Figure 2 is a diagram showing the results of computed tomography after administration of the contrast agent composition prepared in Example 3.

Figure 3 is a diagram showing the results of computed tomography after administration of the contrast agent composition prepared in Comparative Example 1.

Figure 4 is a diagram showing the results of computed tomography after administering the contrast agent composition prepared in Comparative Example 4.

FIG. 5 is a diagram showing the results of observing the contrast agent of the contrast agent composition prepared in Example 3 at a magnification of 400 times using a Meiji CK-3900N electron microscope. FIG.

6 is a diagram showing the results of observing the contrast agent of the contrast agent composition prepared in Comparative Example 2 with a Meiji CK-3900N electron microscope at a magnification of 400 times.

7 is a diagram showing the results of observing the contrast agent at a magnification of 400 times with Meiji CK-3900N electron microscope after 6 months of accelerated storage experiment of the contrast agent composition prepared in Example 3.

8 is a view showing the results of observing the contrast agent at a magnification of 400 times with Meiji CK-3900N electron microscope after 4 months of accelerated storage experiment of the contrast agent composition prepared in Comparative Example 3.

9 is a diagram showing the results of observing the contrast agent at a magnification of 400 times with Meiji CK-3900N electron microscope after 6 months of accelerated storage experiment of the contrast agent composition prepared in Comparative Example 3.

10 is a diagram showing the results of observing the contrast agent at a magnification of 400 times with Meiji CK-3900N electron microscope after 4 months of accelerated storage experiment of the contrast agent composition prepared in Comparative Example 4.

FIG. 11 is a diagram showing the results of observing the contrast agent at a magnification of 400 times using Meiji CK-3900N electron microscope after 6 months of accelerated storage experiment of the contrast agent composition prepared in Comparative Example 4. FIG.

The present invention relates to a contrast agent composition for computed tomography and a method of preparing the same.

Contrast agent refers to a substance that can be used to make artificially contrasted images and display them for diagnostic purposes. The following conditions must be met:

 1) Provide proper contrast with surrounding tissue.

 2) It should be harmless and non-irritating to human body and have no unpleasant taste, smell and color. Substances that are not toxic to the living body and have small side effects

 3) Biochemically stable substance

 4) The concentration required for contrast should be obtained in as small amount as possible, and have adequate persistence.

 5) Purpose To be introduced quickly and easily in the organ.

 6) Purpose To have consistency that is suitable for organ imaging.

 7) Substances that are easily excreted in vitro after the test and easily removed

 8) The price is low.

 Among these contrast agents, barium sulfate suspension is used for most of the gastrointestinal tract examination because it contrasts the inside of the gastrointestinal tract well, provides information on the state of the mucosa with excellent contrast and is harmless to the human body.

A high concentration and low viscosity barium sulfate suspension is used to fill the gastrointestinal tract or to observe microscopic lesions of the mucosal structures. This is to observe the micro lesion of the mucosal structure by increasing the concentration of air and barium sulfate by coating barium sulfate thinly to the mucosa wall to 0.5 mm or less. However, when the concentration is high, the viscosity increases as well, so if you emphasize too much concentration of the barium on the mucous membrane thick coating can be missed. Therefore, it is necessary to select a contrast agent having a high concentration and a low viscosity. Currently used products are concentration 70 ~ 240% w / v, viscosity 450 ~ 750 cps and the appropriate one is selected according to the patient's test site and application. Usually, 120-140% w / v is used for simple imaging of the stomach.

As such, barium sulfate has been widely used as an x-ray contrast agent for a long time, but has not been used in computerized tomography (CT). Introduced in the 1970s, computed tomography is programmed to detect the absorption ability of various human tissues by sending ion X-rays at various angles around a particular cross section of the human body and detecting the absorption of X-rays at various angles as they pass through the human body. Is delivered to the computer. Computers combine information from different x-ray directions and project a composite image onto the screen for specific areas such as the abdomen, chest, and head. Therefore, it is superior to typical radiography because it is possible to obtain an image of a thin section of an object at a specific point, line or plane.

 As a related contrast agent, stabilizing barium sulfate aqueous suspension with a mixture of microcrystalline cellulose and carboxymethylcellulose sodium has been disclosed in DE 19535428 A1 and Korean Patent No. 339485.

However, new imaging techniques, such as the following, require contrast agents with lower concentrations to achieve high quality imaging.

 MDCT (multidetector CT) reduces the time required for inspection because multiple CT images can be obtained simultaneously, compared to conventional CT images obtained through one 360-degree rotation. It is now possible to perform ultra-thin image cross-sectional examinations to enable early detection. PET / CT is a dual-image diagnosis method in which conventional CT (positive emission tomography) equipment is equipped with CT (computerized tomography) equipment. This method adds the CT image that provides anatomical detailed information to the PET image for diagnosing functional abnormalities of the human body as a sketch. It provides additional information on the function and metabolic changes of the tissues for more accurate diagnosis. .

Conventional oral barium sulfate CT contrast agents cannot be used in this imaging technique. As a suitable contrast agent, Korean Laid-Open Patent Publication No. 10-2006-0052675 suggested a barium sulfate suspension containing 70% sorbitol solution and xanthan gum, but there is an obstacle in anatomical imaging and the barium sulfate suspension cannot maintain a homogeneous suspension within the expiration date. There are disadvantages.

Taken together, the contrast agents suitable for the new imaging technique must meet all of the following conditions.

(1) Proper radio opacity: It must have adequate opacity to see the lesion state of the barrier, and the opacity of the barrier is too difficult to read.

(2) Proper homogeneity: Even after oral contrast agents have been injected into the gastrointestinal tract, there should be no minor or minimal chemical reaction with the secretions or contents in the gastrointestinal tract.

(3) Stability: Oral contrast agents are administered about 60 to 90 minutes prior to computed tomography, depending on the application. Should be.

(4) Reduced intratracheal transit time: As soon as possible, the time required for the examination of the patient and the hospital is shortened as soon as possible, while achieving the desired objectives of the stomach, small intestine, and large intestine until the examination. It helps a lot.

In addition, since the barium sulfate suspension is used as a contrast agent, the following suspension conditions must also be provided.

(1) When the sedimentation is slow and the container is lightly shaken, the redispersing force is to be fast.

(2) Suspensions should be free of agglomeration between particles and should remain nearly constant for a long time during stationary preservation.

(3) When dispensing suspension from the container, it should be easy and equal.

Accordingly, the present invention is to provide a contrast agent composition and a method for preparing the same, which can obtain excellent contrast images during computed tomography by optimizing components and contents of barium sulfate, a viscous agent, a surfactant, and an osmotic pressure control agent.

In order to achieve the above object, the present invention is a barium sulfate 0.001 ~ 1.0% (w / v), sodium carboxymethyl cellulose (Na-CMC) 0.05 ~ 1.0% (w / v) as a viscous agent and microcrystalline cellulose and carboxymethyl 0.2 to 1.5% (w / v) of microcrystalline cellulose and carboxymethylcellulose sodium, ammonium glycyrrhizinate 0.005 to 0.1% (w / v) and polysorbate 0.0001 to 0.01 A contrast agent composition for computerized tomography imaging containing% (w / v), D-sorbitol 1.0 to 10.0% (w / v) and purified water as an osmotic pressure regulator.

Barium sulfate in the contrast composition of the present invention is of the quality and purity used in the general contrast medium, the preferred content is 1.0% (w / v) or less, more preferably 0.01 to 0.5% (w / v). If the content of barium sulfate is too small, the contrast is reduced, and if used in excess, there is a problem that the lumen and the barrier cannot be distinguished.

Viscosity agents included in the contrast agent composition of the present invention serves to control the viscosity of the contrast agent, to ensure that a sufficient amount of contrast agent is retained in the stomach, intestinal tract and to swell properly. It also plays a role in securing product stability by slowing down the settling rate of barium sulfate. The carboxymethylcellulose sodium (Na-CMC) and the microcrystalline cellulose and carboxymethylcellulose sodium mixture (microcrystalline cellulose and carboxymethylcellulose sodium) included in the contrast agent composition of the present invention are used in a specific amount together. The preferred content thereof is 0.05 to 1.0% (w / v) of sodium carboxymethylcellulose, 0.2 to 1.5% (w / v) of a mixture of microcrystalline cellulose and sodium carboxymethylcellulose. If less than the above range, there is a problem that the sedimentation of the barium sulfate is faster, the homogeneity and the redispersibility of the suspension are poor, and it is difficult to store for a long time. As for the viscosity of such a contrast agent, 10-100 cps is preferable.

The surfactant included in the contrast agent composition of the present invention assists in the wetting of suspended particles and enables the dispersion to be maintained continuously or stabilized when the suspension is settled by the effects of particle interaction, respectively. In the contrast composition of the present invention, it is preferable to use a specific amount of ammonium glycyrrhizinate 0.005 to 0.1% (w / v) and polysorbate 0.0001 to 0.01% (w / v) together. If its content is smaller than the above range, wetting is insufficient. If it exceeds the above range there is a problem causing reaggregation of particles.

The contrast agent composition of the present invention comprises an osmotic pressure regulator which facilitates the transfer of a suitable amount of contrast agent into the stomach, intestinal tract and promotes the inhibition of gastric and intestinal fluid resorption by the body. The osmotic pressure control agent suitable for use in the contrast agent composition of the present invention is preferably D-sorbitol 1.0 to 10.0% (w / v), more preferably 2.0 to 5.0% (w / v).

In addition, the particle size of barium sulfate is an indicator for determining the degree of application to the gastric and mucosal surfaces. As the particle size is large, the particle size of the barium sulfate is 0.5 in the contrast composition of the present invention because the smallest particles are effective. -1.5 micrometers is preferable.

The contrast agent composition of the present invention is a substance used as a pH adjusting agent in addition to the above components (barium sulfate, viscosifiers, surfactants, osmotic pressure regulators) and other commonly citric acid, sodium citrate and / or aspartame, acesulfame potassium, short syrup Substances commonly used as sweeteners, such as sodium saccharin, saccharin calcium, sugar, and / or other commonly used as antifoaming agents such as silicon resins and / or alcohols, phenols, organic acids and salts thereof, organic Other commonly used as preservatives such as mercury compounds, parabens and / or other commonly used as flavoring agents such as pineapple, strawberry, orange, lemon, chocolate, cola, grape, pine, etc. It may further contain one or more additives selected from the materials. In addition, it is preferable to use 0.001-1.0% (w / v) as an additive.

The contrast agent composition of the present invention is preferably suitable for computed tomography, wherein the computed tomography is multi-detector computed tomography (MDCT) or quantum emission tomography (PET / CT).

The present invention also provides a method for preparing a composition according to the present invention, the method comprising the following steps:

(1) adding purified water to the preparation tank, adding a dispersion of microcrystalline cellulose and carboxymethyl cellulose sodium as a viscosity agent, and carboxymethyl cellulose sodium to disperse and swell;

(2) adding purified water to a separate container, adding di-sorbitol liquid as an osmotic pressure regulator, adding ammonium glycyrizinate and polysorbate as surfactants, and then adding and dispersing barium sulfate; And

(3) mixing the mixture prepared in step (2) into the container of step (1), and then adding a residual amount of purified water to prepare a preparation, followed by milling the preparation;

The final concentration of the components used above is 0.2 to 1.5% (w / v) of microcrystalline cellulose and carboxymethylcellulose sodium mixture as a viscosity agent, 0.05 to 1.0% (w / v) sodium carboxymethylcellulose, di-sorbitol as an osmotic pressure regulator. Liquid 1.0-10.0% (w / v), surfactant ammonium glycyrizinate 0.005-0.1% (w / v), polysorbate 0.0001-0.01% (w / v), barium sulfate 0.001-1.0% (w / v) v).

In step (1) of the above production method of the present invention, it is preferable to swell while maintaining the viscosity agent at 50 to 60 ° C. In addition, it is preferable to disperse the mixture of microcrystalline cellulose and sodium carboxymethyl cellulose as the viscosity agent, and then to completely disperse and leave swelling by adding sodium carboxymethyl cellulose. More preferably, the preservative is dissolved in an appropriate amount of sterile purified water, the microcrystalline cellulose and carboxymethyl cellulose sodium mixture is dispersed by stirring at a maximum rpm while maintaining the solution at 50 to 60 ° C, and then dispersed by adding carboxymethyl cellulose sodium and left to stand. Swelling. When the microcrystalline cellulose and carboxymethyl cellulose sodium mixture and the carboxymethyl cellulose sodium are dispersed, the microcrystalline cellulose and carboxymethyl cellulose sodium mixture is not sufficiently swollen and the viscosity is lowered even if the same amount is added. This is because the settling speed is increased.

In another aspect, the present invention further comprises the addition of 0.001 to 1.0% (w / v) of one or more additives selected from pH adjusters, sweeteners, antifoaming agents and flavoring agents in step (2) of the preparation method to prepare a contrast agent composition for computed tomography. Provide a method.

The contrast agent compositions of the present invention are useful for diagnostic imaging of any anatomical structure of the body. For example, the esophagus, stomach and gastrointestinal tract, duodenum, small intestine (plant, ileum, appendix and cecum) and large intestine (ascending bowel, hepatic flexion, transverse colon, spleen flexion, descending colon, sigmoid colon and rectum) It is suitable for use in diagnostic imaging of anatomical parts. It is also suitable for the imaging of tissues such as pancreas, gallbladder, spleen, liver, lymph nodes, and vasculature and pathological essences such as organs and pus.

 The contrast agent compositions of the present invention can be administered in a number of ways. The contrast agent can be administered, for example, in liquid, suspension, paste, powder, concentrate, granulated powder or solid form for mixing in appropriate concentrations. For example, the compositions of the present invention may be administered orally or rectally. In addition to oral or rectal methods, it may be administered transdermally or via intubation. It may also be consumed as a suspension or administered as a tablet, capsule or caplet.

The total amount of contrast agent (active ingredient) administered is about 0.01 g, 0.025 g, 0.05 g, 0.075 g, 0.1 g, 0.5 g, 1 g, 5 g, 10 g, 20 g, 30 g, 50 g, 70 g, 100 g, 120 g, 150 g, 180 g , 200g, 300g, 350g, 400g, 450g, 500g, 550g, 600g, or more. The preferred range is about 0.1 g to about 5 g, more preferably 1 to 1.5 g. The contrast medium is about 10ml to about 10L, about 100ml to about 5L, or about 200ml, 250ml, 300ml, 350ml, 400ml, 450ml, 500ml, 550ml, 600ml, 650ml, 700ml, 750ml, 800ml, 850ml, 900ml, 1L, 1.5L Or 2L, 2.5L, 3L, 3.5L, 4L or 4.5L. The contrast agent may be administered in a single dose or divided into multiple doses. For example, if the contrast agent is 2 L, the patient may be administered 1 L about 2 hours before entering the diagnostic procedure and the remaining 1 L about 1 hour prior to entering the procedure. Alternatively, 150 ml is administered to the patient every 5 minutes until the total amount required for the particular procedure is consumed. In addition, 1L is orally administered at regular intervals 45 minutes before the test, and an additional 225 mL is administered immediately before the test. However, the method of administration and dosage of the contrast agent composition may be changed according to the instructions of a specialist during the examination process.

Hereinafter, examples will be described to help understand the advantages and features of the present invention and how to achieve the same. However, the present invention is not limited to the embodiments disclosed below, but may be implemented in various forms, only the embodiments of the present invention make the disclosure of the present invention complete, and those of ordinary skill in the art to which the present invention belongs. It is provided to fully inform the scope of the invention, and the invention is defined only by the scope of the claims.

Examples 1 to 4

Methyl paraoxybenzoate and propyl paraoxybenzoate were dissolved in purified water (6 L) sterilized at 90 to 100 ° C. in the preparation tank. After complete dissolution, the mixture is cooled and maintained at 50 to 60 ° C., followed by the viscosity of microcrystalline cellulose and sodium carboxymethyl cellulose (FMC Biopolymer, carboxymethyl cellulose content: 8.3 to 18.8%), followed by stirring (T 50 basic Ultra-Turrax, IkaGmbH & Co). KG, Staufen, Germany), and the mixture was stirred and dispersed at 6400 rpm for 2 hours, followed by complete dispersion by addition of sodium carboxymethylcellulose, followed by standing and swollen. In a separate container, di-sorbitol solution, ammonium glycyrizinate, polysorbate, aspartame, and potassium acetate were dissolved in purified water (1.5 L) sterilized at 90 to 100 ° C., followed by completely dispersing barium sulfate to prepare a suspension. The suspension was added to a vessel containing a viscous agent, mixed together, and dissolved by adding citric acid, sodium citrate, silicon resin, and flavoring agent to 10 L with sterile purified water. The preparation was then milled for 70 seconds using a colloid mill (T.K. Mycolloider, Model SL, Tokushu Kika Kogyo Co., Ltd., Osaka, Japan).

PH, viscosity, and specific gravity were measured with the contrast agent composition obtained by the above method by the method according to the 8th Amendment.

(1) pH: It measured by the pH meter (691 pH meter, Metrohm, Herisau, Switzerland) at 25 degreeC.

(2) Viscosity: It measured with the No. 1 spindle by the viscometer (DV-II + Viscometer, Brookfield, Massachusetts, USA) at 20 degreeC.

(3) Specific gravity: Specific gravity was measured at 20 ℃ with a specific gravity bottle (25mL, Korean Science, Seoul, Korea).

The measurement results of the pH, viscosity and specific gravity of the components and contents used to prepare the titled contrasting agent composition and the titled contrasting agent are shown in Table 1 below.

Ingredient (g) Example 1 Example 2 Example 3 Example 4 chief ingredient Barium sulfate (g) ¹⁾ One 5 10 50 Antifoam Silicon resin (g) 1.5 1.5 1.5 1.5 Viscous agent Na-CMC (g) ²⁾ 30 30 30 30 Avicel RC 581 (g) ³⁾ 80 80 80 80 Osmotic pressure regulator Di-sorbitol solution 335 335 335 335 pH regulator Citric acid (g) 8.5 8.5 8.5 8.5 Sodium citrate (g) 0.8 0.8 0.8 0.8 Preservative MP (g) ⁴⁾ 9 9 9 9 PP (g) ⁵⁾ One One One One Sweetener Aspartame (g) 0.2 0.2 0.2 0.2 Acesulfame Potassium (g) 0.1 0.1 0.1 0.1 Surfactants Polysorbate 20 (g) 0.1 0.1 0.1 0.1 Glycamyl (g) ⁶⁾ 5 5 5 5 Flavor Pineapple Essence (g) 0.9 0.9 0.9 0.9 Lemon ZKF-97370 (g) 0.5 0.5 0.5 0.5 Orange ZKW-95001 (g) 0.4 0.4 0.4 0.4 Purified water Apply to 10L total. pH 4.25 4.27 4.27 4.29 Viscosity (cps) 27.3 28.5 28.8 28.6 Specific gravity (g / ml) 1.0124 1.0141 1.0151 1.0149  1) Barium sulfate with particles of 0.5 to 1.5 μm 2) Sodium carboxymethylcellulose 3) Microcrystalline cellulose and carboxymethylcellulose mixture 4) Methyl paraoxybenzoate 5) Propoxy paraoxybenzoic acid 6) Ammonium glycyrinate

Comparative example  One - Barium sulfate  Preparation of Contrast Composition with Concentration 1.5% (W / V)

Next, a contrast agent composition was prepared in the same manner as in Examples 1 to 4 using the composition and content of Table 2, and pH, viscosity, and specific gravity were measured.

Ingredient (g) Comparative Example 1 chief ingredient Barium sulfate ¹⁾ 150 Antifoam Silicon resin 1.5 Viscous agent Na-CMC ²⁾ 30 Avicel RC 581 ³⁾ 80 Osmotic pressure regulator Di-sorbitol solution 335 pH regulator Citric acid 8.5 Sodium citrate 0.8 Preservative MP ⁴⁾ 9 PP ⁵⁾ One Sweetener Aspartame 0.2 Acesulfame Potassium 0.1 Surfactants Polysorbate 20 0.1 Glycamyl ⁶⁾ 5 Flavor Pineapple Essence 0.9 Lemon ZKF-97370 0.5 Orange ZKW-95001 0.4 Purified water Apply to 10L total. pH 4.21 Viscosity (cps) 26.0 Specific gravity (g / ml) 1.0141  1) Barium sulfate with particles of 0.5 to 1.5 μm 2) Sodium carboxymethylcellulose 3) Microcrystalline cellulose and carboxymethylcellulose mixture 4) Methyl paraoxybenzoate 5) Propoxy paraoxybenzoic acid 6) Ammonium glycyrinate

Comparative example  2 - Not milling  Contrast agent compositions

A contrast agent composition was prepared in the same composition, concentration, and method as in Example 3, except that the preparation was not milled.

Comparative example  3- Preparation of Contrast Agent Composition Without Surfactant

Next, a contrast agent composition was prepared in the same manner as in Examples 1 to 4 using the composition and content of Table 3, and pH, viscosity, and specific gravity were measured.

Ingredient (g) Comparative Example 3 chief ingredient Barium sulfate ¹⁾ (g) 10 Antifoam Silicon resin 1.5 Viscous agent Na-CMC ²⁾ 30 Avicel RC 581 ³⁾ 80 Osmotic pressure regulator Di-sorbitol solution 335 pH regulator Citric acid 8.5 Sodium citrate 0.8 Preservative MP ⁴⁾ 9 PP ⁵⁾ One Sweetener Aspartame 0.2 Acesulfame Potassium 0.1 Surfactants Polysorbate 20 0 Glycamyl ⁶⁾ 0 Flavor Pineapple Essence 0.9 Lemon ZKF-97370 0.5 Orange ZKW-95001 0.4 Purified water Apply to 10L total. pH 4.25 Viscosity (cps) 28.0 Specific gravity (g / ml) 1.0156  1) Barium sulfate with particles of 0.5 to 1.5 μm 2) Sodium carboxymethylcellulose 3) Microcrystalline cellulose and carboxymethylcellulose mixture 4) Methyl paraoxybenzoate 5) Propoxy paraoxybenzoic acid 6) Ammonium glycyrinate

Comparative example  4-Viscosifier With xanthan gum  Preparation of Used Contrast Composition

Methyl paraoxybenzoate and propyl paraoxybenzoate were dissolved in purified water (6 L) sterilized at 90 to 100 ° C. in the preparation tank. After dissolving completely, xanthan gum, a viscosity agent, was added to disperse completely, and left to swell. After dissolving di-sorbitol solution, ammonium glycyrizinate, polysorbate, aspartame, and acesulfame potassium in purified water (1.5L) sterilized at 90 to 100 ° C. in a separate container, barium sulfate was added to disperse completely, and then the suspension was dissolved. While adding to the container with the viscous agent, while continuing to mix, add citric acid, sodium citrate, silicon resin and flavoring agent to dissolve and make 10L with sterile purified water and then colloid mill (TKMycolloider, Model SL, Tokushu Kika Kogyo Co., Ltd.). Ltd., Osaka, Japan) for 70 seconds.

PH, viscosity, and specific gravity were measured for the contrast agent composition prepared by the said method by the method similar to Examples 1-4.

The measurement results of the pH, viscosity and specific gravity of the components and contents used in the preparation of the title contrast agent and the title contrast agent are shown in Table 4 below.

Ingredient (g) Comparative Example 4 chief ingredient Barium sulfate ¹⁾ (g) 10 Antifoam Silicon resin 1.5 Viscous agent Xanthan gum 17 Osmotic pressure regulator Di-sorbitol solution 335 pH regulator Citric acid 8.5 Sodium citrate 0.8 Preservative MP ²⁾ 9 PP ³⁾ One Sweetener Aspartame 0.2 Acesulfame Potassium 0.1 Surfactants Polysorbate 20 0.1 Glycamyl ⁴⁾ 5 Flavor Pineapple Essence 0.9 Lemon ZKF-97370 0.5 Orange ZKW-95001 0.4 Purified water Apply to 10L total. pH 4.32 Viscosity (cps) 61.7 Specific gravity (g / ml) 1.0010  1) Barium sulfate with particle size of 0.5 ~ 1.5 µm 2) Methyl paraoxybenzoate 3) Propyl paraoxybenzoic acid 4) Ammonium glycyrinate

Test Example  1: Check the contrast effect

The contrast agent composition prepared in Example 3, Comparative Example 1 and Comparative Example 4 was orally administered to the Crohn's disease patient (age: 19 years, gender: female) at least 1 minute at 1 hour 45 minutes before the test and immediately before the test. Immediately after administration of an additional 225 mL, the abdomen was scanned using a multiplex tomography (Somatom Sensation 16, Siemens, Munich, Germany).

Computed tomography results after administration of the contrast agent composition prepared in Example 3 are shown in FIGS. 1 and 2, and the stomach and small intestine of the patient are properly inflated and the lumen is distinguished from the lumen wall. (FIG. 1). Small intestine mass (malignant neuroendocrine tumor) was well observed (Fig. 2).

Computed tomography after administration of the contrast agent composition prepared in Comparative Example 1 is shown in Figure 3, the small intestine mass and the small intestine filled with contrast medium was not distinguished.

Computed tomography of the contrast agent composition prepared in Comparative Example 4 is shown in Figure 4, the ileum of the patient was well expanded (jejunum) area is not well expanded.

Therefore, it can be seen that the contrast agent composition according to the present invention is an excellent contrast agent for computed tomography compared to Comparative Example 1 or Comparative Example 4.

Test Example  2: check the particle size of the suspension

The contrast agent composition prepared in Example 3 and Comparative Example 2 was observed at a magnification of 400 times by Meiji CK-3900N electron microscope to confirm the particle size of the contrast agent.

As shown in FIG. 5, the contrast agent composition prepared in Example 3 is homogeneously suspended in barium sulfate having particles of 0.5 to 1.5 μm.

On the other hand, the contrast agent composition prepared in Comparative Example 2 was prepared with barium sulfate having the same particle size as in Example 3, but the particles were agglomerated and not homogeneously suspended.

Test Example  3: Check storage stability

1) Check the storage stability of the contrast agent composition prepared in Example 3

The contrast agent composition prepared in Example 3 of the present invention was observed for physical properties change during the course of 6 months under accelerated conditions of temperature 40 ℃, moisture 75% RH (relative humidity). The stability test results are shown in Table 5 below. As shown in FIG. 7, the contrast agent composition prepared in Example 3 had good redispersibility after 6 months of acceleration, so that the barium sulfate particles were uniformly suspended without aggregation.

Test Items    standard At the time of manufacture 2 months 4 months 6 months 1. Appearance 2. Content ^{1 )} 3. pH ^{2 )} 4. Viscosity ^{3 )} 6. Redispersibility ^{4 )}  90.0 to 110.0% of the white aqueous suspension indicated. 3.5 to 6.5 15 to 50 cps Redispersibility should be good. Aqueous suspension of white 99.2% 4.27 28.5 fits White aqueous suspension 98.8% 4.21 28.7 Fit Aqueous suspension of white 98.9% 4.23 27.9 fits Aqueous suspension of white 99.0% 4.26 28.0 fits

¹⁾ Content: Should follow the procedure in the “assay” test in section 30 of the USP 28 "barium sulfate suspension".

²⁾ pH: measured with a pH meter (691 pH meter, Metrohm, Herisau, Switzerland) at 25 ℃.

³⁾ Viscosity: Viscosity was measured at 20 ° C. with a spindle 1 (DV-II + Viscometer, Brookfield, Massachusetts, USA).

^{4) The} redispersibility was measured by using Burrell Wrist action shaker (model 75) for 3 minutes at a frequency of 300 ± 10 stokes per minute and the suspension was observed by Meiji CK-3900N electron microscope to observe the dispersion of barium sulfate particles. .

2) Confirmation of the storage stability of the contrast agent composition prepared in Comparative Example 3

The contrast agent composition prepared in Comparative Example 3 was tested under the same conditions as the stability test of the contrast agent composition prepared in Example 3, and the test items described in Table 6 were measured in the same manner. As shown in Figures 8 and 9, it was observed that the barium sulfate particles agglomerated after 4 months of accelerated storage test (Fig. 8 shows the dispersion of barium sulfate particles after redispersion after 4 months of accelerated storage, Figure 9 is Dispersion of barium sulfate particles after redispersion after 6 months). The stability test results of the contrast agent composition prepared in Comparative Example 3 are shown in Table 6 below.

Test Items    standard At the time of manufacture 2 months 4 months 6 months 1. Appearance 2. Content 3. pH 4. Viscosity 6. Redispersibility 90.0 to 110.0% of the white aqueous suspension indicated. 3.5 to 6.5 15 to 50 cps Redispersibility should be good. Aqueous suspension of white 98.8% 4.25 28.0 fits White aqueous suspension 99.0% 4.27 28.2 Fit White aqueous suspension 98.5% 4.20 27.5 nonconformity White aqueous suspension 99.1% 4.18 27.6 nonconformity

3) Confirmation of the storage stability of the contrast agent composition prepared in Comparative Example 4

The contrast agent composition prepared in Comparative Example 4 was tested under the same conditions as the stability test of the contrast agent composition prepared in Example 3, and the test items described in Table 7 were measured by the same experiment. As a result, the contrast agent composition prepared in Comparative Example 4 appeared to have a problem of low redispersibility even though xanthan gum was added as a surfactant. That is, as shown in Fig. 10 or 11, it was observed that after 4 months of accelerated storage test, barium sulfate particles aggregated and can no longer be used as a uniform suspension (Fig. 10 shows barium sulfate after redispersion after 4 months. The degree of dispersion of the particles is shown, and FIG. 11 shows the degree of dispersion of the barium sulfate particles after redispersion after 6 months).

The stability test results of the contrast agent composition prepared in Comparative Example 4 are shown in Table 7.

Test Items    standard At the time of manufacture 2 months 4 months 6 months 1. Appearance 2. Content 3. pH 4. Viscosity 6. Redispersibility 90.0 to 110.0% of the white aqueous suspension indicated. 3.5 to 6.5 15 to 50 cps Redispersibility should be good. Aqueous suspension of white 99.5% 4.32 61.7 fits White Aqueous Suspension 99.9% 4.28 60.3 Fit White aqueous suspension 98.8% 4.29 59.8 nonconformity White aqueous suspension 99.3% 4.25 58.1 nonconformity

The contrast agent composition of the present invention has no clumping and reacts quickly with gastric acid and has a lower density (HU) than the unenhanced soft tissue as well as the intestinal swelling of the stomach, small intestine and large intestine. (soft tissue) can be seen clearly, and in particular, it provides a very clear image of the area angiographically enlarged by the gastrointestinal tract expanded by the product facilitates early diagnosis of the invention. In addition, the contrast agent composition of the present invention has almost no rejection reaction upon oral administration and has excellent homogeneity and redispersibility, and thus has a function effect that can be maintained as a uniform suspension even after long-term storage.

Claims (10)

Barium sulfate 0.001 to 1.0% (w / v), sodium carboxymethylcellulose (Na-CMC) as a viscous agent 0.05 to 1.0% (w / v) and microcrystalline cellulose and carboxymethylcellulose sodium 0.2 ~ 1.5% (w / v), ammonium glycyrrhizinate as surfactant 0.005 ~ 0.1% (w / v) and polysorbate 0.0001 ~ 0.01% (w / v), osmotic pressure regulator D -Contrast composition for computerized tomography containing D-sorbitol 1.0-10.0% (w / v) and purified water. The contrast agent composition for computed tomography according to claim 1, wherein the particle size of barium sulfate is 0.5 to 1.5 µm. The contrast agent composition for computed tomography according to claim 1 or 2, wherein the content of barium sulfate is 0.01 to 0.5% (w / v). 4. The tomography composition for computed tomography according to claim 3, further comprising 0.001-1.0% (w / v) of an additive selected from a preservative, a pH adjuster, a sweetener, an antifoaming agent, and a flavoring agent. The composition of claim 4, wherein the computed tomography is multi-detector computed tomography (MDCT) or quantum emission tomography (PET / CT). (1) adding purified water to the preparation tank, adding a dispersion of microcrystalline cellulose and carboxymethyl cellulose sodium as a viscosity agent, and carboxymethyl cellulose sodium to disperse and swell; (2) adding purified water to a separate container, adding di-sorbitol liquid as an osmotic pressure regulator, adding ammonium glycyrizinate and polysorbate as surfactants, and then adding and dispersing barium sulfate; And (3) After the mixture prepared in step (2) is mixed into the container of step (1), the remaining amount of purified water is added to prepare a preparation, followed by milling the preparation. Manufacturing method; The final concentration of the components used above is 0.2 ~ 1.5% (w / v) of the mixture of microcrystalline cellulose and carboxymethylcellulose sodium as the viscosity agent, 0.05-1.0% (w / v) as the sodium carboxymethylcellulose, di-sorbitol as the osmotic pressure regulator. Liquid 1.0-10.0% (w / v), surfactant ammonium glycyrizinate 0.005-0.1% (w / v), polysorbate 0.0001-0.01% (w / v), barium sulfate 0.001-1.0% (w / v) v). The method according to claim 6, wherein in step (2), 0.001 to 1.0% (w / v) of an additive selected from a pH adjusting agent, a sweetening agent, an antifoaming agent and a flavoring agent is further added and mixed. The method for producing a contrast agent composition for computed tomography according to claim 6 or 7, wherein the swelling agent is swelled while maintaining the viscosity at 50 to 60 ° C in step (1). The method of claim 8, wherein the microcrystalline cellulose and carboxymethyl cellulose sodium mixture is dispersed, and then carboxymethyl cellulose sodium is added to completely disperse and leave it to swell. 10. The method of claim 9, wherein the computed tomography is multi-detector computed tomography (MDCT) or quantum emission tomography (PET / CT).

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