JP7211699B2 - Ultrasound contrast agent - Google Patents

Description

The present invention relates to an ultrasound diagnostic contrast agent, and more particularly to an ultrasound diagnostic contrast agent that can also be used as an X-ray contrast agent.

In recent years, a specific part of the human body is irradiated with X-rays from various directions, the transmitted X-rays are detected, and a computer uses mathematical techniques to reconstruct and image the X-ray absorption difference for the part. CT (Computed Tomography) is widely used.

One of the characteristics of CT is the use of X-rays, but tissues with similar densities are difficult to distinguish using X-ray imaging alone. Therefore, examinations such as angiography, imaging in computed tomography, urography, and hysterosalpingography are performed using a contrast agent to give an artificial contrast difference between the tissue to be examined and the surrounding tissue. ing.

Therefore, various X-ray contrast agents based on iodine having a high X-ray absorption rate have been developed (Patent Document 1, etc.).

On the other hand, ultrasound is also widely used in the field of medical diagnostic imaging. In medical image diagnosis using ultrasound, diagnosis is made based on an image reconstructed by irradiating ultrasound into the human body and receiving the ultrasound reflected from human tissues. This image allows a doctor or the like to observe the state of tissues inside the human body.

The acoustic properties of ultrasound vary greatly at interfaces between different substances (eg solid-liquid interface, liquid-gas interface). Therefore, a clear diagnostic image can be obtained by using the ultrasonic signal from the interface. For this reason, various materials have been studied as ultrasound contrast agents, but among them, ultrasound contrast agents based on microbubbles have significantly different acoustic properties from surrounding living tissue and are excellent in ultrasound scattering properties. , Cardiovascular imaging in echocardiography, Cardiovascular, head/neck, trunk/extremity imaging in Doppler, and hysterosalpingography.

Japanese Patent No. 3054660

However, no contrast agent is known that can be used as both an X-ray contrast agent and an ultrasound contrast agent. Such a contrast agent enables both X-ray diagnosis and ultrasonic diagnosis with a single administration, so that more accurate diagnosis can be performed and the burden on the patient is reduced. Furthermore, such a contrast agent enables fusion display with an X-ray diagnostic image and an ultrasonic diagnostic image, and is particularly useful for assisting treatment, determining therapeutic effects, and the like.

An object of the present invention is to provide an ultrasound contrast agent that can also be used as an X-ray contrast agent.

An object of the present invention is to
(1) nonionic dimers of triiodobenzene compounds, (2) water, and (3) ultrasound diagnostic contrast agents containing microbubbles.

（式中
Ａ、Ｂ及びＤは、同一でも異なってもよく、－ＣＯＮ（Ｒ）Ｒ^１、又は、－Ｎ（Ｒ）ＣＯＲ^２であり、
Ｒは、水素原子、又は、直鎖若しくは分岐の、置換若しくは非置換のＣ_１～６アルキル基であり、
Ｒ^１は、水素原子、直鎖若しくは分岐の、置換若しくは非置換のＣ_１～６アルキル基、又は、炭水化物残基であり、
Ｒ^２は、直鎖又は分岐の、置換若しくは非置換のＣ_１～６アルキル基であり、
Ｅは、同一でも異なってもよく、－ＣＯＮ（Ｒ）－、－Ｎ（Ｒ）ＣＯ－、及び、－Ｎ（ＣＯＲ^３）－からなる群から選択され、Ｒは上記のとおりであり、Ｒ^３は、水素原子、又は、置換若しくは非置換のＣ_１～３アルキル基であり、
Ｘは、共有結合、又は、直鎖若しくは分岐の、置換若しくは非置換のＣ_１～８アルキレン基であり、Ｏ、Ｓ及びＮからなる群から選択される少なくとも１つのヘテロ原子を鎖中に有してもよい）
で表されるものが好ましい。 The nonionic dimer of the (1) triiodobenzene compound is represented by the following general formula (I)

(wherein A, B and D, which may be the same or different, are —CON(R)R ¹ or —N(R)COR ² ;
R is a hydrogen atom or a linear or branched, substituted or unsubstituted C _1-6 alkyl group,
R ¹ is a hydrogen atom, a linear or branched, substituted or unsubstituted C _1-6 alkyl group, or a carbohydrate residue;
R ² is a linear or branched, substituted or unsubstituted C _1-6 alkyl group,
E, which may be the same or different, is selected from the group consisting of -CON(R)-, -N(R)CO-, and -N(COR ³ )-, R is as described above, R ³ is a hydrogen atom or a substituted or unsubstituted C _1-3 alkyl group,
X is a covalent bond or a linear or branched, substituted or unsubstituted C _1-8 alkylene group having at least one heteroatom selected from the group consisting of O, S and N in the chain; may)
Those represented by are preferable.

The ultrasound diagnostic contrast agent of the present invention is preferably for hysterosalpingography.

As the (1) nonionic dimer of the triiodobenzene compound, it is preferable to use at least one selected from iotrolan, iodecimol, iodixanol, ioforminol, iosimenol and iotasul.

The iodine concentration of the ultrasound diagnostic contrast medium of the present invention is preferably 150-400 mg/ml.

The viscosity of the ultrasound diagnostic contrast agent of the present invention is preferably 1 to 10 mPa·s at 1 atmosphere and 37°C.

The pH of the ultrasound diagnostic contrast agent of the present invention is preferably 6-9.

The ultrasound diagnostic contrast agent of the present invention preferably further comprises edetate.

Preferably, the edetate is calcium sodium edetate.

The ultrasound diagnostic contrast agent of the present invention preferably further contains a water-soluble inorganic salt.

The water-soluble inorganic salt is preferably sodium bicarbonate and/or sodium chloride.

The ultrasound diagnostic contrast agents of the present invention are preferably free of surfactants.

The microbubbles are preferably made of air.

The amount of microbubbles contained in the ultrasound diagnostic contrast agent of the present invention is preferably in the range of 1 to 10% by volume.

The present invention also relates to a process for the preparation of an ultrasound diagnostic contrast agent characterized by entraining a gas in the form of microbubbles into a composition comprising a nonionic dimer of a triiodobenzene compound and water.

The temperature of the composition is preferably 36° C. or higher.

The mixing is preferably performed by fluidizing the composition in contact with the gas and/or applying vibration to the composition after dissolving the gas in the composition in an amount equal to or more than the saturated solubility.

The invention also relates to a composition for use in ultrasonic diagnostic imaging comprising a nonionic dimer of a triiodobenzene compound, water, and microbubbles.

Furthermore, the present invention relates to the use of a composition comprising a nonionic dimer of a triiodobenzene compound, water and microbubbles for the manufacture of an ultrasound diagnostic contrast agent.

The ultrasound diagnostic contrast agent of the present invention can also be used as an X-ray contrast agent.

The ultrasound diagnostic contrast agent of the present invention can be used for hysterosalpingography. It is also applicable to imaging of cardiovascular blood vessels in echocardiography, imaging of cardiovascular blood vessels, head/neck, trunk/limbs in Doppler examination, and the like.

By using the contrast agent for ultrasonic diagnosis of the present invention, both X-ray diagnosis and ultrasonic diagnosis are possible with a single administration, so that more accurate diagnosis can be performed, and the patient's burden is reduced. less. Furthermore, by performing fusion display with X-ray diagnostic images and ultrasonic diagnostic images, it is possible to assist treatment and determine therapeutic effects.・It is expected to improve the efficacy of treatment for diseases and the efficiency of examinations.

Furthermore, the contrast agent for ultrasonic diagnosis of the present invention can be prepared by mixing gas in the form of microbubbles immediately before use, and the mixing operation can be performed manually, so preparation is easy.

1 shows the preparation of the ultrasound diagnostic contrast agent of Example 1. FIG. FIG. 2 is a diagram showing the imaging ability of contrast agents for ultrasonic diagnosis of Example 1, Comparative Example 1, Reference Example 1, and Reference Example 2; FIG. 10 is a diagram showing an echocardiogram of Example 2;

The contrast agent of the present invention can be used as an ultrasound contrast agent because it contains microbubbles, and can also be used as an X-ray contrast agent because it contains a predetermined compound having X-ray contrast properties. be.

Compositions containing microbubbles are known, but not all such compositions are viable as ultrasound contrast agents. For example, even if microbubbles are contained in physiological saline, the microbubbles dissipate rapidly into the atmosphere, making it difficult to actually use them as a contrast agent for ultrasonic diagnosis. In the present invention, a practical ultrasound diagnostic contrast agent is provided by incorporating microbubbles into a composition containing a predetermined compound having X-ray contrast properties and water.

The present invention will be described in detail below.

(Compound having X-ray imaging properties)

The contrast agents of the present invention comprise nonionic dimers of triiodobenzene compounds. The contrast agent of the present invention may contain one type of the dimer, or may contain two or more types of the dimer. The nonionic dimers of triiodobenzene compounds used in the present invention have X-ray imaging properties.

A triiodobenzene compound is a compound having a skeleton in which three iodine atoms are bonded to one benzene ring. preferable. Moreover, the benzene ring contained in the triiodobenzene compound can have various substituents other than the iodine atom.

A dimer of a triiodobenzene compound is a dimer having a skeleton in which two triiodobenzene compounds are linked via a linking group, and contains six iodine atoms in one molecule. Although the number of the linking groups is not particularly limited, it is preferably one. Also, the type of the linking group is not particularly limited, but a non-hydrolyzable group is preferable.

The two triiodobenzene compounds to be bonded may be of the same type or different types, but are preferably of the same type.

The dimer of the triiodobenzene compound used in the present invention is preferably water-soluble under the conditions of 1 atm and 25°C. Here, the term "water-soluble" means exhibiting a solubility of 1 mg or more in 10 g of water under conditions of 1 atm and 25°C, preferably 10 mg or more in 10 g of water, and 100 mg. A solubility of 1 g or more is more preferred, and a solubility of 1 g or more is even more preferred.

（式中
Ａ、Ｂ及びＤは、同一でも異なってもよく、－ＣＯＮ（Ｒ）Ｒ^１、又は、－Ｎ（Ｒ）ＣＯＲ^２であり、
Ｒは、水素原子、又は、直鎖若しくは分岐の、置換若しくは非置換のＣ_１～６アルキル基であり、
Ｒ^１は、水素原子、直鎖若しくは分岐の、置換若しくは非置換のＣ_１～６アルキル基、又は、炭水化物残基であり、
Ｒ^２は、直鎖又は分岐の、置換若しくは非置換のＣ_１～６アルキル基であり、
Ｅは、同一でも異なってもよく、－ＣＯＮ（Ｒ）－、－Ｎ（Ｒ）ＣＯ－、及び、－Ｎ（ＣＯＲ^３）－からなる群から選択され、Ｒは上記のとおりであり、Ｒ^３は、水素原子、又は、置換若しくは非置換のＣ_１～３アルキル基であり、
Ｘは、共有結合、又は、直鎖若しくは分岐の、置換若しくは非置換のＣ_１～８アルキレン基であり、Ｏ、Ｓ及びＮからなる群から選択される少なくとも１つのヘテロ原子を鎖中に有してもよい）
で表されるものが好ましい。本発明の造影剤は一般式（Ｉ）で表される１種類の化合物を含んでもよく、一般式（Ｉ）で表される２種類以上の化合物を含んでもよい。 The nonionic dimer of the triiodobenzene compound has the following general formula (I)

(wherein A, B and D, which may be the same or different, are —CON(R)R ¹ or —N(R)COR ² ;
R is a hydrogen atom or a linear or branched, substituted or unsubstituted C _1-6 alkyl group,
R ¹ is a hydrogen atom, a linear or branched, substituted or unsubstituted C _1-6 alkyl group, or a carbohydrate residue;
R ² is a linear or branched, substituted or unsubstituted C _1-6 alkyl group,
E, which may be the same or different, is selected from the group consisting of -CON(R)-, -N(R)CO-, and -N(COR ³ )-, R is as described above, R ³ is a hydrogen atom or a substituted or unsubstituted C _1-3 alkyl group,
X is a covalent bond or a linear or branched, substituted or unsubstituted C _1-8 alkylene group having at least one heteroatom selected from the group consisting of O, S and N in the chain; may)
Those represented by are preferable. The contrast agent of the present invention may contain one type of compound represented by general formula (I), or may contain two or more types of compounds represented by general formula (I).

The nonionic dimers of the triiodobenzene compounds used in the present invention are nonionic. That is, the dimers do not contain ionic groups such as carboxy groups. Therefore, the contrast agents of the present invention have a lower osmotic pressure than ionic contrast agents. Therefore, the contrast agent of the present invention is preferable to ionic contrast agents because it has a lower risk of hyperpermeability/destruction of the blood-brain barrier, vasodilatation, vascular pain, and the like, and has higher safety.

As the substituent, at least one substituent selected from the group consisting of a hydroxy group, an alkoxy group and a hydroxyalkoxy group is preferred. Alkoxy groups include C _1-4 alkoxy groups such as methoxy, ethoxy and propoxy groups. Hydroxyalkoxy groups include hydroxyC _1-4 alkoxy groups such as hydroxymethoxy, hydroxyethoxy and hydroxypropoxy groups.

Accordingly, substituted C _1-6 alkyl groups include, for example, —CH(CH ₂ OH) ₂ , CH(OH)—CH ₃ , —CH ₂ —CH(OH)—CH ₂ OH, —CH(CH ₂ OH)-CH(OH)CH ₂ OH, -CH ₂ -CH ₂ -OH, -CH ₂ -OH, -CH ₂ -CH(OH)-CH ₂ -O-CH ₃ , -CH ₂ -O-CH ₃ and the like.

As carbohydrate residues, sugar residues are preferred, and glucose residues are more preferred.

As the nonionic dimer of the triiodobenzene compound, for example, at least one selected from iotrolan, iodecimol, iodixanol, ioforminol, iosimenol and iotasul can be used.

Iotrane is even more preferred as the nonionic dimer of the triiodobenzene compound. An aqueous solution containing iotrolan is more viscous at low temperatures, but the contrast agent of the present invention can exhibit excellent bubble retention even at temperatures above 30° C., which are closer to body temperature.

(contrast agent)

The contrast agent of the invention comprises water along with a non-ionic dimer of a triiodobenzene compound. The contrast agent of the present invention is liquid, preferably in the form of an aqueous solution.

The iodine concentration of the ultrasound diagnostic contrast agent of the present invention is preferably 150-400 mg/ml, more preferably 250-350 mg/ml, and even more preferably 300 mg/ml.

Consistency (viscosity) of the ultrasound diagnostic contrast agent of the present invention is preferably 1 to 10 mPa·s, more preferably 4.0 to 9.5 mPa·s at 1 atmosphere and 37°C. It is even more preferable to be 7.0 to 9.0 mPa·s.

The pH of the ultrasound diagnostic contrast agent of the present invention is preferably 6 to 9, more preferably 6.5 to 8.5, even more preferably 6.5 to 8.0.

The ultrasound diagnostic contrast agent of the present invention preferably further comprises edetate. The edetate includes, for example, EDTA, calcium sodium edetate and the like, and calcium sodium edetate is more preferable.

The ultrasound diagnostic contrast agent of the present invention preferably further contains a water-soluble inorganic salt. Examples of water-soluble inorganic salts include those that can be dissociated in water at 25°C. The aqueous inorganic salt is preferably an alkali metal salt such as a sodium salt, more preferably sodium chloride, sodium carbonate, sodium hydrogen carbonate or the like, and even more preferably sodium chloride, sodium hydrogen carbonate and mixtures thereof.

The ultrasound diagnostic contrast agents of the present invention are preferably free of surfactants. In addition, "not containing" means that the amount is less than 0.1% by weight, preferably less than 0.01% by weight of the total weight of the contrast agent, and particularly preferably it is not contained at all. means.

Surfactants include anionic surfactants, cationic surfactants, amphoteric surfactants and nonionic surfactants.

The type of anionic surfactant is not limited but may include C _6-30 fatty acids such as palmitic acid or salts thereof. Also, the types of cationic surfactant, amphoteric surfactant and nonionic surfactant are not particularly limited.

The ultrasound diagnostic contrast agent of the present invention comprises microbubbles.

The microbubbles contained in the ultrasound diagnostic contrast agent of the present invention exist independently, and for example, there is no need to apply energy by ultrasonic vibration or the like for their generation or maintenance.

The microbubbles contain gas. The type of gas is not particularly limited, and air, nitrogen, oxygen, carbon dioxide, rare gases, hydrogen, hydrocarbons (methane, ethane, propane, etc.), various halogenated hydrocarbons (C ₃ F ₈ , _{fluorocarbons} such as _C5F12 ), sulfur fluoride (such as _SF6 ), or mixtures thereof, with air being preferred.

By microbubbles is meant microscopic sized bubbles. The size of the microbubbles is not particularly limited, but the diameter can be 1 nm to 1000 μm, 10 nm to 100 μm, 10 nm to 10 μm, 100 nm to 10 μm, or 1 μm to 10 μm. For example, microbubbles can have a diameter of 5 μm or more and 10 μm or less. The size may be a volume average diameter. The density of microbubbles is also not particularly limited, but may be, for example, 1×10 ² to 1×10 ⁹ or 1×10 ⁷ to 1×10 ⁸ in 1 mL of solution.

The amount of microbubbles contained in the ultrasound diagnostic contrast agent of the present invention is not particularly limited, but is preferably in the range of 1 to 10% by volume, more preferably in the range of 2 to 8% by volume. Preferably, the range of 3-6% by volume is even more preferred.

The temperature of the ultrasound contrast agent of the present invention is preferably 36° C. or higher, more preferably 36 to 50° C., even more preferably 36.5 to 45° C., even more preferably 37 to 40° C., particularly 37 to 38° C. preferable. By controlling the temperature within the above range, a higher number of microbubbles can be maintained than at lower temperatures such as room temperature.

The ultrasound diagnostic contrast agent of the present invention can be prepared, for example, by dissolving a nonionic dimer of a triiodobenzene compound in water to form an aqueous solution, and further mixing gas in the form of microbubbles into the aqueous solution. can be done. The invention therefore also relates to a process for the preparation of an ultrasound diagnostic contrast agent, characterized in that a composition comprising a non-ionic dimer of a triiodobenzene compound and water is entrained with gas in the form of microbubbles.

The method of mixing the gas is not particularly limited. For example, an aqueous solution of the nonionic dimer of the triiodobenzene compound and a high pressure gas are brought into discontinuous contact, or the nonionic dimer of the triiodobenzene compound is brought into contact. Vibration or fluidization can be performed by, for example, introducing gas while fluidizing the aqueous solution, or irradiating supersaturated water in which gas is dissolved in an amount equal to or greater than the saturated solubility with ultrasonic waves or the like. For example, the mixing of gas is fluidization of a composition such as an aqueous solution that comes into contact with the gas, and / or ultrasonic waves to the composition after dissolving the gas in the composition such as an aqueous solution in an amount exceeding the saturation solubility. It can be implemented by applying vibration by However, since it does not require a large-scale manufacturing facility and can be prepared manually, a composition containing a nonionic dimer of a triiodobenzene compound and water and a gas are pumped to fluidize both. Preferably, the gas is incorporated into the composition in the form of microbubbles.

Although the form of pumping is not particularly limited, for example, a composition containing a nonionic dimer of a triiodobenzene compound and water and a gas are introduced into the space in a syringe (with a plunger), and the syringe is pumped into another syringe (plunger ), and the space within the two syringes is reciprocated at high speed by the action of the plunger, so that the gas can be mixed into the composition in the form of microbubbles.

When a gas in the form of microbubbles is mixed into a composition containing a nonionic dimer of a triiodobenzene compound and water, the temperature of the composition is preferably 36° C. or higher, more preferably 36 to 50° C., 36.5 ~45°C is even more preferred, 37-40°C is even more preferred, and 37-38°C is particularly preferred. By controlling the temperature within the above range, the number of microbubbles can be increased more than when the operation of mixing gas is carried out at a lower temperature such as room temperature.

If desired, the microbubble-containing composition described above may be passed through a filter of a predetermined pore size in order to reduce the size of the microbubbles to a predetermined value or less.

Preparation of the ultrasound diagnostic contrast agent of the present invention by pumping can be performed immediately prior to use, so that it can be prepared immediately before use. That is, in the preparation method of the present invention, the gas can be mixed in the form of microbubbles into the ultrasonic diagnostic contrast agent containing the nonionic dimer of the triiodobenzene compound and water immediately before use, and the mixing operation is performed manually. preparation of the contrast agent is easy.

The ultrasound diagnostic contrast agent of the present invention can be used both as an ultrasound contrast agent and as an X-ray contrast agent. By using the contrast agent of the present invention, both X-ray diagnosis and ultrasound diagnosis are possible with a single administration. For example, both 3D ultrasound and 3D-CT can be performed by using the contrast agents of the present invention. Therefore, by using the contrast agent of the present invention, more accurate diagnosis can be performed and the burden on the patient can be reduced.

In particular, the ultrasound diagnostic contrast agent of the present invention is preferably for hysterosalpingography. By using the ultrasound diagnostic contrast agent of the present invention, X-ray hysterosalpingography can also be used in conjunction with ultrasound hysterosalpingo-contrast-sonography.

The present invention
(1) It also relates to a composition for use in ultrasonic diagnostic imaging comprising a nonionic dimer of a triiodobenzene compound, water and microbubbles. Specific aspects of the composition are as follows. The composition can also be used as an X-ray contrast agent.

(2) The composition according to (1) above, wherein the nonionic dimer of the triiodobenzene compound is represented by the general formula (I).

(3) The composition of (1) or (2) for hysterosalpingography examination.

(4) The composition according to any one of (1) to (3) above, wherein the nonionic dimer of the triiodobenzene compound is at least one selected from iotrolan, iodecimol, iodixanol, ioforminol, iosimenol and iotasul. .

(5) The composition according to any one of (1) to (4) above, wherein the composition has an iodine concentration of 150 to 400 mg/ml.

(6) The use of any one of (1) to (5) above, wherein the composition has a viscosity of 1 to 10 mPa·s at 1 atmosphere and 37°C.

(7) The use of any one of (1) to (6) above, wherein the composition has a pH of 6-9.

(8) The use of any one of (1) to (7) above, wherein the composition further comprises edetate.

(9) The use of (8) above, wherein the edetate is calcium sodium edetate.

(10) Use according to any one of (1) to (9) above, wherein the composition further comprises a water-soluble inorganic salt.

(11) The use of (10) above, wherein the water-soluble inorganic salt is sodium hydrogen carbonate and/or sodium chloride.

(12) The use of any one of (1) to (11) above, wherein the composition does not contain a surfactant.

(13) The use of any one of (1) to (12) above, wherein the microbubbles consist of air.

(14) The use of any one of (1) to (13) above, wherein said microbubbles are in an amount ranging from 1 to 10% by volume.

Furthermore, the present invention provides
(1) It also relates to the use of a composition comprising a nonionic dimer of a triiodobenzene compound, water and microbubbles for the manufacture of an ultrasound diagnostic contrast agent. Specific aspects of the use are as follows. The composition can also be used for the production of X-ray contrast agents.

(2) The use of (1) above, wherein the nonionic dimer of the triiodobenzene compound is represented by the general formula (I).

(3) Use of (1) or (2) above for hysterosalpingography examination.

(4) The use according to any one of (1) to (3) above, wherein the nonionic dimer of the triiodobenzene compound is at least one selected from iotrolan, iodecimol, iodixanol, ioforminol, iosimenol and iotasul.

(5) The use of any one of (1) to (4) above, wherein the composition has an iodine concentration of 150 to 400 mg/ml.

(6) The use of any one of (1) to (5) above, wherein the composition has a viscosity of 1 to 10 mPa·s at 1 atmosphere and 37°C.

(7) The use of any one of (1) to (6) above, wherein the composition has a pH of 6-9.

(8) The use of any one of (1) to (7) above, wherein the composition further comprises edetate.

(9) The use of (8) above, wherein the edetate is calcium sodium edetate.

(10) Use according to any one of (1) to (9) above, wherein the composition further comprises a water-soluble inorganic salt.

(11) The use of (10) above, wherein the water-soluble inorganic salt is sodium hydrogen carbonate and/or sodium chloride.

(12) The use of any one of (1) to (11) above, wherein the composition does not contain a surfactant.

(13) The use of any one of (1) to (12) above, wherein the microbubbles consist of air.

(14) The use of any one of (1) to (13) above, wherein said microbubbles are in an amount ranging from 1 to 10% by volume.

Said manufacture comprises:
This can be done by entraining (3) a gas in the form of microbubbles into a composition comprising (1) a nonionic dimer of a triiodobenzene compound and (2) water.

The temperature of the composition is preferably 36°C or higher, more preferably 36 to 50°C, even more preferably 36.5 to 45°C, even more preferably 37 to 40°C, and 37 to 38°C. Especially preferred.

The mixing is preferably performed by fluidizing the composition in contact with the gas and/or applying vibration to the composition after dissolving the gas in the composition in an amount equal to or more than the saturated solubility.

EXAMPLES The present invention will be illustrated in more detail by examples below, but the present invention is not limited to the examples. All numbers in the table are based on weight.

[Example 1]
Isovist® Note 300 (Bayer Yakuhin, Ltd.) was heated to 37° C. in a water bath. Isovist® Note 300 is in the form of an aqueous solution, and its composition is as follows.

Isovist® Note 300 had an iodine concentration of 300 mg/ml and a pH in the range of 6.5-8.0. Also, the viscosity was about 8.6 mPa·s at 37°C.

4.8 ml of pre-warmed Isovist® Injection 300 and 0.2 ml of air were introduced into a 5 ml volume syringe (with plunger) (FIG. 1A). This syringe was then connected via a 3-way stopper to another syringe of 5 ml capacity (with plunger) (Fig. 1B). Air in the form of microbubbles was entrained in the Isovist® Note 300 to form a white suspension by pumping the fluid in the syringe by moving the plunger in each syringe alternately back and forth 10 times at high speed. obtained (Fig. 1C).

One end of the rubber tube was immersed in a water bath, and degassed water was injected into the rubber tube to prepare a hysterosalpingography model. Then, the white suspension obtained as described above was immediately injected into the rubber tube from the other end of the rubber tube. Ultrasonic waves of 4 MHz were applied to the rubber tube using Sonos 5500 manufactured by Philips, and echoes were imaged after 1 minute, 5 minutes, 10 minutes and 20 minutes.

The operation of Example 1 was repeated four times. However, only the first and last imaging was performed after 20 minutes. The results are shown in FIG. Imaging within the rubber tube was possible at all times.

In addition, FIG. 2 shows the result of imaging inside the rubber tube before introducing the contrast medium of Example 1 as a baseline.

[Comparative Example 1]
The same procedure as in Example 1 was repeated except that saline was used instead of Isovist® Note 300. However, imaging after 20 minutes was omitted. The results are shown in FIG. Imaging inside the rubber tube was not possible.

[Reference example 1]
As a positive control, the same operation as in Example 1 was repeated except that a suspension of Levovist (registered trademark) for injection (Bayer Yakuhin, Ltd.) was used in place of Isovist (registered trademark) Note 300. The results are shown in FIG. Levovist® Injectable is an ultrasound diagnostic contrast agent containing a galactose-palmitate mixture (999:1). Note that the display of the baseline in FIG. 2 is omitted.

[Reference example 2]
As a positive control, the same procedure as in Example 1 was repeated, except that Sonovue (Bracco) suspension was used instead of Isovist® Note 300. The results are shown in FIG. Sonovue is a contrast agent for ultrasonic diagnosis using sulfur fluoride gas.

As is clear from FIG. 2, clear imaging of Isovist (registered trademark) Note 300 containing microbubbles was possible immediately after preparation. The contrast density on the images decreased slightly over time, but was still sufficient for imaging and diagnosis after 20 minutes. At all time points, Isovist® Note 300 with microbubbles showed comparable imaging performance to the commercial ultrasound contrast agents, Levovist® Injectable and Sonovie. On the other hand, the microbubble suspension in normal saline was unable to be imaged at any time point.

Isovist® Note 300 containing microbubbles is therefore well suited for use as an ultrasound diagnostic contrast agent, in particular for Hysterosalpingo-Contrast-Sonography. That is, Isovist® Note 300 can be used for both X-ray Hysterosalpingography and Ultrasound Hysterosalpingography.

[Example 2]
A white suspension prepared in the same manner as in Example 1 (air in the form of microbubbles mixed with Isovist (registered trademark) Note 300) was intravenously administered to rats and echocardiography was performed. After administration, an increase in the brightness of the right atrium and right ventricle was observed (FIG. 3B), followed by an increase in the brightness of the pulmonary trunk (FIG. 3C).

Therefore, Isovist® Note 300 containing microbubbles is well suited for use as an ultrasound diagnostic contrast agent for echocardiography. In addition, when smaller microbubbles are used, such as by irradiating supersaturated gas with ultrasonic waves, intravenously administered Isovist (registered trademark) Note 300 containing microbubbles reaches the right atrium, right ventricle, and pulmonary artery. It migrates, passes through capillaries in the lungs, is transported to the left atrium and left ventricle, and can be imaged.

Claims (15)

(1) iotrolan,
An ultrasound diagnostic contrast agent comprising (2) water and (3) microbubbles and no albumin, polymers, liposomes, surfactants or sugars . The ultrasound diagnostic contrast agent of claim 1, wherein the iodine concentration is 150-400 mg/ml. 3. The contrast agent for ultrasonic diagnosis according to claim 1 or 2, which has a viscosity of 1 to 10 mPa·s at 1 atmosphere and 37°C. The ultrasound diagnostic contrast agent according to any one of claims 1 to 3, which has a pH of 6-9. 5. The ultrasound diagnostic contrast agent of any of claims 1-4, further comprising edetate. 6. The ultrasonic diagnostic contrast agent of Claim 5, wherein said edetate is calcium sodium edetate. 7. The ultrasound diagnostic contrast agent according to any one of claims 1 to 6, further comprising a water-soluble inorganic salt. 8. The ultrasound diagnostic contrast agent of claim 7, wherein said water-soluble inorganic salt is sodium bicarbonate and/or sodium chloride. 9. The ultrasound diagnostic contrast agent of any one of claims 1 to 8, wherein said microbubbles consist of air. The ultrasound diagnostic contrast agent of any of claims 1-9, wherein said microbubbles are present in an amount ranging from 1 to 10% by volume. (3) gas in the form of microbubbles is entrained in a composition comprising (1) iotrolan, and (2) water and no albumin, polymers, liposomes, surfactants or sugars , A method for preparing an ultrasound diagnostic contrast agent. 12. The preparation method according to claim 11, wherein the temperature of said composition is 36[deg.]C or higher. 11. The mixing is performed by fluidizing the composition in contact with the gas and/or applying vibration to the composition after dissolving the gas in the composition in an amount equal to or greater than the saturated solubility. Or the preparation method according to 12. (1) iotrolan,
A composition for use in ultrasonic diagnostic imaging comprising (2) water and (3) microbubbles and is free of albumin, polymers, liposomes, surfactants and sugars . (1) iotrolan,
Use of a composition comprising (2) water, and (3) microbubbles and free of albumin, polymer, liposomes, surfactants and sugars , for the manufacture of an ultrasound diagnostic contrast agent.

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