JPH07188062A - Digestive tract contrast medium and its production - Google Patents

Abstract

PURPOSE:To obtain a digestive tract contrast medium preservable stably in vivo, thus also stable in diagnostic ability, capable of easily taking digestive tracts clearly in the nuclear magnetic resonance CT scanning technique, and also easy to take by a testee. CONSTITUTION:This digestive tract contrast medium can be obtained by the following processes: magnetic fine particles are dispersed in a solution of e.g. oligomerized chitosan to prepare a suspension, which is then sprayed to include the magnetic fine particles in the chitosan, and the resultant magnetic fine particles-including chitosan particles are dried and then dispersed in an alkaline solution; a chitosan crosslinking agent is then added to the dispersion followed by agitation and refluxing, and a solution containing the magnetic fine particles- including chitosan particles is left to cool and then put to filtration to recover the chitosan particles, which are then dried.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a digestive tract contrast agent used for nuclear magnetic resonance CT scan.

[0002]

2. Description of the Related Art Conventionally, it has been known that magnetic fine particles influence the contrast of light and dark of an image in the diagnosis by a nuclear magnetic resonance CT scan.

Japanese Patent Laid-Open No. 3-278834 discloses chitosan-magnetic composite particles and a method for producing the same. This "chitosan-magnetic composite particle" is used as an adsorbent that is easily separated and recovered when a magnetic field is applied to the adsorbent, and is characterized by "encapsulating a plurality of magnetic fine particles in a crosslinked chitosan granule". , `` After dispersing magnetic fine particles in an acidic solution of chitosan, then changing this solution to neutral or basic to produce chitosan granules containing a plurality of magnetic fine particles, and then cross-linking chitosan. Is manufactured by performing.

[0004]

However, since the magnetic fine particles as a single substance dissolve in acid, there is a possibility that if they are orally administered as they are, they may be dissolved by gastric acid. or,
The "chitosan-magnetic composite particle" of Heisei 3-278834 cannot be used as a digestive tract contrast agent due to its large particle diameter and low fluidity because it is an adsorbent, and it is difficult to make the particle diameter small and uniform. There is a problem.

An object of the present invention is to prepare magnetic fine particles encapsulated in chitosan to have chemical stability, have a small particle size and a uniform particle shape, and prepare a gastrointestinal tract image of a nuclear magnetic resonance CT scan. It is an object of the present invention to provide a digestive tract contrast agent that can be taken easily by a subject and can display a clear image when used as an agent.

[0006]

In order to solve the above-mentioned problems, the digestive tract contrast agent according to claim 1 of the present invention comprises magnetic fine particles containing magnetic fine particles having a particle diameter of 0.01 μm to 0.5 μm. It is composed of chitosan particles and characterized by being used for nuclear magnetic resonance CT scan.

A method for producing a digestive tract contrast agent according to claim 2 of the present invention comprises a step of lowering the molecular weight of chitosan particles,
In this chitosan solution, a particle size of 0.01 μm to 0.5 μm
Magnetic fine particles are dispersed to a concentration of 0.01% to 1% by weight, and the suspension is sprayed to dry the chitosan particles containing the magnetic fine particles in the chitosan. The dried chitosan particles are mixed and dispersed in ethanol containing 1 wt% to 1 wt% of sodium hydroxide so that the concentration of chitosan particles in the magnetic fine particles is 1% to 10%. After adding and stirring the cross-linking agent of chitosan, after cooling the solution containing the magnetic fine particle-encapsulated chitosan particles and filtering to collect the magnetic fine particle-encapsulated chitosan particles, drying the chitosan particles. , Having.

Further, the digestive tract contrast agent according to claim 3 of the present invention comprises styrene particles encapsulating magnetic fine particles having a particle diameter of 0.01 μm to 0.5 μm, and is used for a nuclear magnetic resonance CT scan. To do.

In the method for producing a digestive tract contrast agent according to a fourth aspect of the present invention, a styrene monomer and magnetic fine particles having a particle size of 0.01 μm to 0.5 μm are dispersed in either distilled water or ion-exchanged water, The styrene monomer is polymerized while being heated at a temperature of 40 ° C to 90 ° C in a nitrogen atmosphere, the magnetic fine particles not encapsulated in polystyrene are eluted with an acid, washed with distilled water, and then dried to remove the magnetic fine particle inclusions. It is characterized by obtaining styrene particles.

[0010]

According to the digestive tract contrast agent of the present invention, since the atomization method is used when preparing the magnetic substance-encapsulated particles, it is possible to reduce the diameter of the particles and make the diameters even. . In addition, when the gastrointestinal tract is administered during a nuclear magnetic resonance CT scan, the image of the gastrointestinal tract can be easily distinguished from the image of the solid organ. In this way, since the digestive tract becomes clearly visible, the dose of the gastrointestinal administration agent can be reduced as compared with the conventional one, and the viscosity becomes low when mixed with the gastrointestinal administration agent, making it easier to drink.

[0011]

EXAMPLES Hereinafter, a method for producing a digestive tract contrast agent according to an example of the present invention will be described.

A method for producing a digestive tract contrast agent according to an embodiment of the present invention includes at least the following three steps.

The first step is a step of lowering the molecular weight of chitosan as a dispersion medium of magnetic fine particles. In the first step, the chitosan particles are dissolved in hydrochloric acid of 0.1 to 0.5 normal concentration. A solution of 1 to 5% by weight of depolymerized chitosan is prepared.

The second step is a step of dispersing the magnetic fine particles in the solution of chitosan obtained in the first step and spray-drying to enclose the magnetic material in the chitosan particles. In the second step, Particle size 0.01 in chitosan solution
Magnetic fine particles such as magnetic fine particles having a particle diameter of μm to 0.5 μm are dispersed so as to have a concentration of 0.01 wt% to 1 wt%, and the resulting suspension is spray-dried to obtain chitosan particles containing magnetic fine particles. obtain.

The third step is a step of cross-linking chitosan on the surface of the magnetic fine particle-encapsulated chitosan particles to provide stability, and the third step contains 0.1% by weight to 1% by weight of sodium hydroxide. The dried magnetic fine particle-encapsulated chitosan particles were mixed and dispersed in ethanol so that the concentration of the magnetic fine particle-encapsulated chitosan particles was 1% to 10%, and the chitosan crosslinking agent was added and stirred and refluxed. Then, the solution of the crosslinking agent containing the magnetic fine particle-containing chitosan particles is allowed to cool and filtered to collect the magnetic fine particle-containing chitosan particles, and the collected magnetic fine particle-containing chitosan particles are dried.

According to such a manufacturing method, the digestive tract contrast agent according to the embodiment of the present invention is formed.

The contrast agent for digestive tract has a particle size of 0.01 μm
Magnetic fine particles (for example, magnetic fine particles) of 0.5 μm were dispersed in a hydrochloric acid solution of chitosan, the suspension of the hydrochloric acid solution of chitosan was spray-dried, and further cross-linked to encapsulate the magnetic fine particles. It consists of chitosan particles.
By using the chitosan particles thus obtained as a digestive tract contrast agent for nuclear magnetic resonance CT scan, the contrast of the image can be made clear.

According to the digestive tract contrast agent according to this example,
Since the atomization method is used when preparing the magnetic substance-encapsulated chitosan particles, it is possible to reduce the diameter of the particles and to make the diameters even.

When observing the inside of a living body by a nuclear magnetic resonance CT scan, both the image of the digestive tract and the image of the parenchymal organ are bright images before administration of the contrast agent for the digestive tract, and it is determined that the contrast is insufficient. Although difficult, when this digestive tract contrast agent is administered to the digestive tract, the digestive tract filled with the contrast agent becomes a dark image and the real organs such as the liver and pancreas become bright images. The contrast of light and dark is easy to distinguish. Also,
The ridges and depressions of the digestive tract are clearly visible. Further, since the digestive tract contrast agent obtained in this example can be used for dark image formation at a low concentration, a small dose is required, and the contrast agent has low viscosity and is easy to drink.

Experimental Example Next, an experimental example of the method for producing a digestive tract contrast agent of the present invention will be described.

In the first step of reducing the molecular weight of chitosan, chitosan particles were refluxed with an acid-alcohol solution and neutralized with an alkali.

In the reflux treatment with hydrochloric acid, 50 g of chitosan classified to 250 μm or less was added to 500 ml of a dispersion medium of an ethanol solution of hydrochloric acid (concentrated hydrochloric acid: ethanol = 1: 9), and the mixture was refluxed at 80 ° C. for 2 hours while stirring. It was Next, this was allowed to cool and then filtered to obtain chitosan particles.

In the neutralization treatment with alkali, chitosan particles recovered by refluxing with hydrochloric acid were washed with 500 ml of 90% (v / v) ethanol, filtered and recovered. Next,
The recovered chitosan particles are used as a dispersion medium of an ethanol solution of sodium hydroxide (4N NaOH: ethanol = 1: 9).
It was poured into 500 ml and stirred at room temperature for 4 hours.

The chitosan particles neutralized with an alkali are washed with 500 ml of 90% (v / v) ethanol in the same manner as in the above method, filtered, and then dried under reduced pressure for 12 hours. As a result, low molecular weight chitosan could be obtained. The average molecular weight of the obtained chitosan is about 6
It went from 0000 to 10000.

In the second step, the low molecular weight chitosan particles were dissolved in dilute hydrochloric acid, magnetite was added and dispersed, and sprayed and dried to obtain magnetite-encapsulated chitosan particles.

The low molecular weight chitosan was dissolved in 0.1N hydrochloric acid to prepare 200 ml of a 2.0% chitosan solution. Magnetite was added to the chitosan solution in an amount of 0.
278 g, 0.555 g, 0.11 g (Fe ₃ O ₄
0.278 g was an amount corresponding to 0.2 g of Fe, which was 5.0% with respect to chitosan) and was ultrasonically dispersed.

This was dried with a spray dryer.

The conditions for spray drying at this time are shown below.

Spray nozzle diameter: 406 μm Spray air flow rate: 13 L / min Dry air flow rate: 0.5 m ³ / min Temperature: Inlet; 145 ° C., outlet; 90
° C Liquid sending pump flow rate: 4 ml / min The particles obtained above were substantially spherical particles, and the particle size was 1 to 10 μm.

In the third step, a cross-linking treatment is performed in order to stabilize the chitosan forming the surface layer of the magnetite-containing chitosan particles.

2.0 g of magnetite-encapsulated chitosan particles obtained by the spray-drying method was used as a dispersion medium (90 g containing 0.4 g of NaOH).
% (V / v) ethanol) and then ultrasonically dispersed. 0.67 ml of chloromethyloxirane as a cross-linking agent was added to this, and the mixture was refluxed at 80 ° C for 2 hours while stirring. This was allowed to cool, then filtered to collect particles, washed with 90% ethanol, and dried under reduced pressure to obtain crosslinked magnetite-encapsulated chitosan particles.

The crosslinked magnetite-encapsulated chitosan particles obtained by this experimental example are 0.0025% if the iron content ratio to chitosan is 5.0%.
By using the suspension prepared above, the contrast effect as a negative contrast agent can be obtained. In other words, if the iron content in the magnetite suspension is 1.25 ppm or more, it has the ability as a negative contrast agent. Further, since the above-described magnetite-encapsulated chitosan particles are stable to acid and alkali, there is no fear of being dissolved in gastric acid or the like even after oral administration.

Next, a second embodiment of the digestive tract contrast agent will be described.

The digestive tract contrast agent of the second embodiment is one in which magnetite is included by polystyrene instead of the chitosan of the first embodiment, and its use is the same as in the first embodiment for digestion of nuclear magnetic resonance CT scan. Use as a tube contrast agent.

The composition of this digestive tract contrast agent is composed of magnetite-encapsulated styrene particles obtained by encapsulating magnetite having a particle size of 0.01 μm to 0.5 μm in polystyrene.

In the method of producing a digestive tract contrast agent of the second embodiment, styrene monomer and magnetite having a particle size of 0.01 μm to 0.5 μm are dispersed in either distilled water or ion-exchanged water. Next, in a warmer etc. held in a nitrogen atmosphere,
This styrene monomer suspension of distilled water or ion-exchanged water is added and heated and stirred at a temperature of 40 ° C to 90 ° C.
When the temperature becomes stable, benzoyl peroxide is slowly added as a polymerization initiator to polymerize the styrene monomer.

As an experimental example, 25 ml of styrene monomer and 0.25 g of magnetite were added to 475 ml of distilled water and kept at 85 ° C., 0.27 g of benzoyl peroxide was added, and polymerization was carried out in a nitrogen atmosphere for 24 hours.

The polymerized polystyrene particles are put in a 1N hydrochloric acid solution, and the magnetite which is not included is eluted, filtered, and washed with distilled water.

Examples of the above-mentioned polymerization initiator include acetyl peroxide, azobisisobutyronitrile, etc. in addition to benzoyl peroxide.

The polystyrene particles thus obtained are suspended in water and adjusted to 0.01% to 5% to obtain a contrasting effect of showing an image with a large difference in brightness.

According to the digestive tract contrast agent of the second embodiment,
Since the magnetite is included in polystyrene to form fine particles, the particle diameter can be controlled and uniform particles can be obtained.

[0042]

According to the method for producing a contrast agent for digestive tract of the present invention, the chitosan solution containing the magnetic fine particles is sprayed and dried, so that the chitosan particles containing the magnetic fine particles can be formed very small. Since chitosan on the surface of chitosan particles is subjected to a crosslinking treatment, when the produced gastrointestinal contrast agent is suspended in water, it has excellent dispersion stability and is resistant to acids and alkalis. Further, when the magnetic fine particles are encapsulated by polystyrene, the particle size can be controlled and the particle size can be made uniform. Resistant to. Therefore, even if a suspension of chitosan particles or styrene particles containing magnetic fine particles is administered into the body, the suspension can be kept stable in the body.

When observing the inside of a living body by a nuclear magnetic resonance CT scan, both the image of the digestive tract and the image of the parenchymal organ are bright images before the administration of the contrast agent for the digestive tract. Although difficult, when this digestive tract contrast agent is administered to the digestive tract, the digestive tract filled with the contrast agent becomes a dark image, and the real organs such as the liver and pancreas become bright images. The contrast of light and dark is easy to distinguish. Also,
The ridges and depressions of the digestive tract are clearly visible. Further, since the digestive tract contrast agent obtained in this example can be used for dark image formation at a low concentration, a small dose is required, and the contrast agent has low viscosity and is easy to drink.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Hiroaki Miyatake 1676 Nakatsu-cho, Marugame-shi, Kagawa Fushimi Pharmaceutical Co., Ltd.

Claims (4)

[Claims] 1. A particle size of 0.01 μm to 0.5 μ in chitosan.
A gastrointestinal contrast agent, which comprises chitosan particles containing magnetic fine particles in which magnetic fine particles of m are included and is used for a nuclear magnetic resonance CT scan. 2. A step of lowering the molecular weight of chitosan particles, and a particle size of 0.01 μm to 0.5 μm in the chitosan solution.
A step of dispersing the magnetic fine particles of (1) to a concentration of 0.01% by weight to 1% by weight to form a suspension, and spraying the suspension to dry the chitosan particles containing the magnetic fine particles. Then, the dried chitosan particles are dispersed in ethanol containing 0.1% by weight to 1% by weight of sodium hydroxide so that the concentration of chitosan particles in the magnetic fine particles is 1% to 10%. Together with, after adding and stirring a cross-linking agent of chitosan, after cooling and filtering the solution containing the magnetic fine particle-encapsulated chitosan particles to collect the magnetic fine particle-encapsulated chitosan particles, the magnetic fine particle-encapsulated chitosan particles. And a step of drying the digestive tract contrast agent. 3. Styrene particles containing magnetic fine particles in which magnetic fine particles having a particle diameter of 0.01 μm to 0.5 μm are included,
A digestive tract contrast agent characterized by being used for a nuclear magnetic resonance CT scan. 4. A styrene monomer and magnetic fine particles having a particle size of 0.01 μm to 0.5 μm are dispersed in either distilled water or ion-exchanged water, and heated in a nitrogen atmosphere at a temperature of 40 ° C. to 90 ° C. While the styrene monomer is polymerized, the magnetic fine particles not encapsulated in the styrene polymer are eluted with an acid, washed with distilled water, and then dried to obtain styrene particles containing magnetic fine particles. Method.