KR101853949B1 - Composition containing x-ray contrast and bubble accelerator and method for producing the same - Google Patents

Abstract

The present invention relates to a contrasting composition containing a non-ionic surfactant as an X-ray contrast agent and a foam promoter, and to a method for producing the composition. The contrasting composition of the present invention has a high tackiness, which is advantageous over a conventional contrast agent for long-term contrast. Therefore, it is possible to maintain the contrast effect similar to the conventional contrast agent for a long time and to reduce the amount of the contrast agent used in the gastrointestinal fluoroscopic examination, the biliary system contrast test, the vascular system disorder test and the like which require adhesiveness.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a contrast composition containing an X-ray contrast agent and a foam promoter,

The present invention relates to a contrasting composition containing an X-ray contrast agent and a foam promoter and containing fine bubbles and a method for producing the same.

Contrast agent is the X-ray absorption difference of each tissue to be able to see the tissue or blood vessels in radiography such as magnetic resonance imaging (MRI) imaging or computed tomography (CT) imaging in the stomach, intestines, vessels, cerebrospinal fluid, It is a medication that increases the degree of contrast of images by artificially enlarging it. Therefore, by using contrast agent, biocompatibility and lesion can be distinguished from the surroundings to improve diagnostic value.

Contrast agents are usually divided into a contrast agent and a contrast agent. The contrast agent transmits the X-rays more than the surrounding tissues. Examples of the positive contrast agent include an iodine-containing contrast agent, barium sulfate, and the like. Examples of the negative contrast agent include air, gas, and carbon dioxide.

The condition of the contrast agent should form an appropriate contrast with the surrounding tissues and be a biochemically stable substance which is harmless to the human body and has no irritation and unpleasant taste, smell, and color. In addition, it should be possible to obtain the necessary concentration for imaging, to have adequate continuity, to be able to be injected quickly and easily into the target organ, to have radiopacity suitable for the purpose of the target organ, It should be easy to get material.

Conventionally used contrast agents use a stable substance that is harmless to the human body while forming an appropriate contrast. However, the conventional contrast agent has a low viscosity so that the contrast agent is easily flowed in the direction of gravity and the contrast effect is rapidly decreased, so contrast agent should be frequently injected during the procedure and the use of the contrast agent should be increased.
EP-A-10-0332166 further comprises both affinity materials which are composed of a liquid / liquid emulsion having a liquid dispersed phase and a liquid aqueous continuous phase and selected from proteins, poloxamers and fluorine-containing surfactants, The present invention relates to a contrast agent composed of a colloidal dispersion suitable for a living body undergoing a phase change to become a dispersed gas or a kugelshark at the time when the dispersed phase is a liquid under the production conditions and is administered to an organism to be tested. Lt; RTI ID = 0.0 > a < / RTI >

Therefore, there is a need for a contrast agent that can maintain the long-term contrast effect while maintaining the conventional contrast effect.

The present invention provides a contrasting composition containing fine bubbles and containing an X-ray contrast agent and a foam promoter in order to maintain a contrast effect for a longer time than a conventional contrast agent and to reduce the amount of contrast agent at the time of diagnosis, .

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

One embodiment of the present invention provides a composition comprising an X-ray contrast agent and a foam promoter, wherein the composition comprises microbubbles.

Another embodiment of the present invention provides a method of making the composition comprising mixing an X-ray contrast agent, a foam promoter solution and a gas.

Hereinafter, the present invention will be described in detail.

The present invention relates to a contrasting composition comprising fine bubbles having high tackiness (viscosity) by mixing an X-ray contrast agent, a foam promoter and a gas. It is possible to maintain the long-time contrast effect because of the excellent tackiness, thereby reducing the amount of the contrast agent.

One embodiment of the present invention provides a contrasting composition containing an X-ray contrast agent and a foam promoter and incorporating a gas therein.

The imaging composition is 1 × 10 ⁵ to 1 × ¹⁰ 10 of micro air bubbles can and comprise, 2.16 × 10 per the imaging composition cubic centimeters (cm ³⁾ to maximize the long-term contrast effects per cubic centimeter (cm ^{3) 6} to 5.82 x 10 < ⁹ > microbubbles.

The X-ray contrast agent is conventionally used in a contrast test, and an iodine-containing contrast agent can be used. For example, it may be at least one selected from the group consisting of iopamide, iohexol, iomeprol, iopamidol, ioxitaramic acid, iovitriptol, iodixhynol, and dioxagluconic acid.

The bubble promoter refers to promoting the formation of fine bubbles in the contrasting composition. In order to promote the formation of the fine bubbles, one or more surfactants may be selected from the group consisting of various kinds of surfactants, specifically, an anionic surfactant, a cationic surfactant, a nonionic surfactant and a positive surfactant.

The surfactant includes any surfactant known in the art and may be an ionic surfactant or a nonionic surfactant. The ionic surfactant may be an anionic, cationic, or amphiphatic surfactant. The anionic surfactant is a surfactant that is ionized by anionic part of the hydrophilic group when it is dissolved in water, for example, a sulfate anionic surfactant, a sulfonate anionic surfactant, a phosphate anionic surfactant or a carboxylate anionic surfactant . The cationic surfactant may be a surfactant, which is a part of the hydrophilic group ionized in the cation when dissolved in water, for example, an amine salt, a quaternary ammonium salt, a phosphonium salt, or a sulfonium salt. The amphoteric surfactant refers to a surfactant which, when dissolved in water, exhibits properties of an anionic surfactant in the alkaline region and a cationic surfactant in the acid region. The nonionic surfactant is a surfactant having a hydrophilic group which is not ionized when dissolved in water, and examples thereof include an ester type, an ether type, an ester type, and an ether type. The surfactant is preferably a nonionic surfactant, and more preferably a polyoxamer belonging to polyoxyethylene alkyl ether.

The micro-bubble gas contained in the contrasting composition may be suitably selected in accordance with the object of the present invention. For example, the gas may be at least one selected from the group consisting of carbon dioxide, nitrogen, and oxygen.

The diameter of the fine bubbles contained in the contrasting composition may be from 1 to 100 μm, preferably from 6.9 to 20.69 μm. In order to maintain a long-term imaging effect, 70% or more of the fine bubbles contained in the contrasting composition may be 1 to 50 μm in diameter, or 85% or more of the minute bubbles may be fine bubbles of 5 to 20 μm in diameter.

The diameter of the microbubbles varies depending on the mixing ratio of the X-ray contrast agent and the bubble promoter, and the stability of the microbubbles varies with time. Therefore, in order to maintain a long-term contrast effect, the contrast composition should be mixed at an appropriate mixing ratio. The proportion of solids content of the X-ray contrast agent and the foam promoter contained in the contrasting composition may be suitably adjusted, for example, in the range of 1: 1 to 1: 6 or 1: 1 to 1: 1: 3. ≪ / RTI >

The contrasting composition has excellent tackiness. For example, the composition may have a viscosity of from 180 to 220, 190 to 210, or 195 to 205 cp at 23 占 폚.

The contrasting composition can be usefully used in related medical fields due to a long-term imaging effect upon X-ray examination. Specifically, the composition may be administered to a human or animal body, the body may be examined with a diagnostic device, and the data obtained from such a test may be synthesized to provide an accurate diagnosis. The composition can be used for diagnosis of various organs such as benign and malignant tumors, infectious diseases and the like, and can also be used for gastrointestinal transit examination, vasculopathological examination, vascular disease test, urinary mechanical examination, and biliary examination.

Methods for determining the amount administered for the composition at the time of diagnosis are known in the art. For example, for an average adult, it may be used in a daily dose in the range of about 0.1 mg to 1200 mg, several times per day, for example, one to two times a day. However, it may vary depending on the mode of administration, and the degree of progression of the disease state. In addition, dosage adjustments may also be required depending on factors related to the subject, such as age, weight, diet and time of administration of the patient.

The composition may be administered to a subject by any conventional route of administration including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral. For example, the composition can be administered to a blood vessel, gastrointestinal tract, bile duct, or urinary tract. The composition may be in any form, for example, suitable forms for oral administration include liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions. Other forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

And another embodiment of the present invention comprises the step of mixing a X- ray contrast agent, the bubble and the gas accelerator solution, 1 × 10 ⁵ to 1 × ¹⁰ 10 per the gas is mixed therein, cubic centimeters (cm ³⁾ of A method of producing a contrasting composition comprising microcellular bubbles is provided.

The X-ray contrast agent, the foam promoter, the gas and the microbubbles are as described above.

The method comprises dissolving the X-ray contrast agent powder in a solution of a foam promoter to prepare a mixed solution; And mixing the mixed solution with a gas to form fine bubbles. Since the microbubbles are stably maintained in a suitable proportion to maintain the long-term imaging effect, the gas is preferably mixed at a volume ratio of 1:10 to 10: 1 by volume of the mixed solution And a method of preparing a contrasting composition.

The method may be a method of producing a contrasting composition which forms fine bubbles by simultaneously mixing an X-ray contrast agent solution, a foam promoter solution and a gas. Since the microbubbles are stably maintained in a suitable proportion, the long-term imaging effect is maintained. Therefore, for example, the gas may be added to the X-ray contrast agent solution and the bubble promoter solution in an amount of 1 : 10 to 10: 1 by volume.

The contrasting composition must be prepared at an appropriate pH and temperature to stably maintain minute bubbles, and thus, it has high tackiness to maintain a long-term contrast effect.

In the method of preparing the contrasting composition, when the temperature is higher than 35 ° C, the diameter of the microbubbles is large and the microbubbles have instability. Thus, for example, the composition can be manufactured at a temperature ranging from 0 to 35 ° C. In order to reduce the diameter of the fine bubbles to improve the stability, preferably, the contrasting composition may be prepared at a temperature range of 0 to 25 캜.

When the pH of the contrast composition is 9 or more and 5 or less in the method of preparing the contrast composition, the diameter of the microbubbles is large and the microbubbles are unstable. For example, the pH of the contrast composition may be 5 to 9, More preferably at a pH of from 6 to 8 in order to improve the stability by reducing the diameter of the particles.

The contrasting composition of the present invention has a high tackiness, which is advantageous over a conventional contrast agent for long-term contrast. Therefore, it is possible to maintain the contrast effect similar to the conventional contrast agent for a long time and to reduce the amount of the contrast agent used in the gastrointestinal fluoroscopic examination, the biliary system contrast test, the vascular system disorder test and the like which require adhesiveness.

1 shows photographs of two 10 ml syringes and 3 ways tubes used in the preparation of the composition of Example 1. Fig.
2 is an optical microscope photograph of the contrast agent composition according to the present invention.
FIG. 3 is a photograph showing the results of measurement of the volume of the composition at 0, 1, 2, 3, 5, 10, and 20 minutes after the contrast agent composition according to the present invention.
4 shows the analytical instrument used in the viscosity analysis according to Example 3. Fig.
5 is a photograph showing a measurement result of the horns field unit of the contrast agent according to the fourth embodiment of the present invention. From the top up in the image is water, conventional contrast agents and foam contrast agents according to the invention.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

[Example]

Example  1. Composition prepared with contrast agent powder

For preparation of the composition, Poloxamer 188 powder was dissolved in distilled water to prepare a 20% solution.

Two 10 mg syringes and 3 way tubes as shown in Fig. 1 were prepared. The 20% poloxamer solution was added to the ultra-bist 300 prescription A mixed solution was prepared by dissolving 612 mg of the contrast agent powder, 1 mg of tromethamine (buffer), and 0.39 mg of edentate calcium disodium (stabilizer) per 1 mL of the poloxamer solution, 4 mL of the mixed solution and 4 mL of air were filled in two syringes, and the two syringes were connected to a 3 way tube. Then, the pumping method (Tessari's method or technique: Or a gas is connected by 3 ways connecting pipes, and the respective syringes are alternately pumped and mixed) 20 to 30 times to prepare a foam contrast agent composition containing a total of 8 mL of iopamidol powder at pH 7 and 25 ° C .

Example  2. Stability test ( Foam decay )

The volume of the composition was measured at each time point with the elapsed time after the preparation of the composition being 0, 1, 2, 3, 5, 10 and 20 minutes in order to measure the degree of decrease in the volume of the composition according to Example 1 with time And the results are shown in FIG. 3 and Table 2.

The volume of the composition to be reduced is expressed as decay (%) according to the volume of liquid calculated as shown in Equation 1 below.

[Equation 1]

Decay (%) = (liquid volume + air volume) / total volume * 100

Fig. 3 shows the volume of the composition after 0, 1, 2, 3, 5, 10, and 20 minutes of the composition according to Example 1. Fig. Table 1 shows the results of Decay (%) calculated according to the volume of the composition over time of the composition.

start After 1 minute After 2 minutes After 3 minutes 5 minutes later After 10 minutes After 20 minutes Iopamidol powder in poloxamer 188: air
= 1: 1 0 0.6 1.9 3.1 5.0 8.1 17.5

Example  3. Viscosity Experiment

In order to compare the viscosity of the composition prepared in Example 1 with the viscosity of Ultravist 300, which is a conventional contrast agent, an experiment was commissioned to Korea Polymer Research Institute Co., Ltd., a research institute for component analysis / special property / custom analysis. Specifically, the viscosity was measured at 23 ° C using Brookfield's HBDV-II + Pro (Enhanced UL Adapter) as an analyzer shown in FIG. 4, and the results are shown in Table 2.

Table 2 shows the viscosity analysis results of the composition prepared in Example 2 at 23 캜, SD means standard deviation, CV means Coefficient of variation = (SD / average) * 100, and cP means centipoise.

Number of trials (Run) Viscosity (cP) Average viscosity (cP) SD CV One 270.8 269.7 1.15 0.427 2 269.7 3 268.5

As shown in Table 2, the average viscosity of the composition prepared in Example 1 was 269.7 cP, and the viscosity of Ultrabist 300, which is a conventional contrast agent, was 4.6 cP, which is similar to the viscosity of blood (4.0 cP) The viscosity of the composition prepared by the method of the present invention is remarkably higher than that of the conventional contrast agent.

Example  4. Hounsfield unit measurement

In the hounsfield unit, when an X-ray passes through a specific substance, the amount of X-ray attenuates due to the physical characteristics of the specific substance. The attenuation of X-ray of the specific substance Is a numerical representation of the Hounsfield unit. The higher the Hounsfield unit, the greater the degree of attenuation of the X-ray, that is, the degree of blocking the X-ray.

For the house field unit measurement, the hunting field unit of the contrast agent solution for vascular injection was measured using the Inveon CT apparatus of Siemens Co. for the composition prepared in Example 1.

Along with the composition according to the present invention, as a comparative group, existing contrast agents Ultrabist 300 and Hounsfield units were measured using distilled water as a control, and the results are shown in Table 3 and FIG.

Contrast agent Hounsfield Unit The present invention (Poloxamer 188) 3002.6 The comparative group (Ultrabist 300) 4343.3 Distilled water 0

As shown in Table 3 and FIG. 5, although the hornsfield unit of the ultraviolet 300 as the comparative group was high, the composition according to the present invention occupies only 50% of the total volume of the contrast agent, Showed excellent horns unit units even with a small amount of contrast agent.

Example  5. Specific gravity experiment

In order to analyze the specific gravity of the composition prepared in Example 1, an experiment was commissioned to Korea Polymer Research Institute Co., Ltd., a research institute for component analysis / special property / custom analysis. Specifically, the specific gravity was measured using an Electronic densimeter MD-300S (manufactured by Alfa Mirage) at 23 占 폚 according to ASTM D792. The weight of the used hydrometer is already known and there is a part of the glass bulb with a long neck that is sealed. The specific gravity of the liquid can be measured from the degree of immersion in the liquid to be measured. The results are shown in Table 4.

The standard deviations are shown in the following table, and CV means Coefficient of variation = (SD / average) * 100.

Number of trials (Run) importance Average specific gravity SD CV One 0.633 0.634 0.002 0.241 2 0.634 3 0.636

As can be seen in Table 4, the composition according to the present invention has a relatively small specific gravity and it is confirmed that the viscosity increases. Therefore, when the composition is used in a body fluid, it can be positioned in the upper layer, You can have an advantage.

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (16)

1: 1 to 1: 6, based on the solids content ratio, of poloxamer 188 as an iopamidol and a foam promoter as an X-ray contrast agent,
As the X-ray contrast agent, fine bubbles formed by mixing gas with a mixed solution having a pH of 6 to 8 obtained by dissolving iopamidol powder as a foam promoter in Poloxamer 188 solution are added to a mixed solution having a concentration of 1 × 10 ⁵ to 1 × It contains 10 ^{to 10,} and at 23 ℃ has a viscosity of 180 to 220cp,
Wherein the gas is incorporated therein. delete delete delete The composition according to claim 1, wherein the gas is at least one selected from the group consisting of carbon dioxide, nitrogen and oxygen. The contrast composition according to claim 1, wherein 70% or more of the minute bubbles have a diameter of 1 to 50 μm. delete delete Preparing a mixed solution by dissolving the Iopamin stone powder as an X-ray contrast agent in a solution of Poloxamer 188 as a foam promoter at a weight ratio of 1: 1 to 1: 6 on a solid content basis; And
Adjusting the pH of the mixed solution to 6 to 8 and mixing the gas to form fine bubbles,
Wherein the microbubbles are contained at 1 x 10 ⁵ to 1 x 10 ¹⁰ per cubic centimeter (cm 3) and have a viscosity of 180 to 220 cp at 23 ° C. delete delete 10. The method of claim 9, wherein the gas is selected from the group consisting of carbon dioxide, nitrogen, and oxygen. 10. The method of claim 9,
Wherein the gas is mixed in a volume ratio of 1:10 to 10: 1 by volume of the mixed solution. 10. The method of claim 9, wherein the fine bubbles have a diameter of 1 to 50 .mu.m. 10. The method of claim 9,
Wherein the method is performed at a temperature ranging from 0 to 35 占 폚.
delete

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