JPH0788111A - Contact medium for probe of ultrasonic diagnostic device - Google Patents

Abstract

PURPOSE:To provide the safe contact medium for a probe which is usable for pricking and during operation as well by using a gel consisting essentially of beta-1, 3 glucan which is a natural polysaccharide and contg. a compd. capable of forming a complex with this beta-1, 3 glucan as the contact medium for the probe. CONSTITUTION:The gel consisting essentially of the beta-1, 3 glucan which is the natural polysaccharide and contg. the compd. capable of forming the complex with the beta-1, 3 glucan is used as the contact medium for the probe. The beta-1, 3 glucan has extremely high safety and has the nature to be gradually dissolved in a living body even if the beta-1, 3 glucan remains in the body. The gel prepd. by adding a complex formable compd. to the beta-1, 3 glucan can be sterilized by the most commonly used sterilizing device and radiations. As a result, the ultrasonic characteristics, mechanical strength and safety are improved, the use of ordinary heating and sterilizing devices is made possible and asepsis is facilitated.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a contact medium for a probe of an ultrasonic diagnostic apparatus.

[0002]

2. Description of the Related Art In recent years, in order to reduce the physical load on the patient and to improve the prognosis, many treatment methods have been attempted without performing a major surgical operation. Even if a laparotomy is performed, it is extremely meaningful to know the state of the lesion before the operation and to know the internal state of the organ without cutting the surface of the organ during the operation. It will bring information. In order to meet such needs, in recent years, ultrasonic diagnosis has been remarkably developed and spread,
The accuracy of preoperative diagnosis using this has greatly contributed to the improvement of recent surgical results. Especially in thyroid disease,
The combination of ultrasonic diagnostic method and fine-needle aspiration cytology has dramatically improved diagnostic ability.

However, when the probe of the ultrasonic diagnostic apparatus is directly applied to the surface of the body or the organ to observe the internal state, due to the characteristics of the ultrasonic diagnostic apparatus, it is clear within a region of several cm below the surface. It is very difficult to obtain a good image. In addition, the actual surface of the body or organ is not flat, but each has characteristic curvatures and irregularities, so it is not possible to attach it to the target site with an immutable probe that maintains a certain shape. It is impossible. That is, if air is present between the living body and the probe, the ultrasonic wave transmissivity is significantly reduced, and an accurate image cannot be formed on the screen of the diagnostic device.

In order to solve the above problems, it is effective to interpose an appropriate spacer (contact medium) between the probe and the living body. The contact medium is preferably in the form of a sheet, which is sandwiched between the probe and the body surface or the like at the time of diagnosis, or formed into an appropriate shape and can be used by being attached to the probe directly or by a jig. Such a contact medium is required to have appropriate flexibility, mechanical strength, and good acoustic characteristics (low ultrasonic attenuation rate, etc.). For example, JP-A-55-63636 discloses Certain hydrous polymer gels have been disclosed. However, the gels disclosed herein have problems such as insufficient mechanical strength and large attenuation of sound waves, and various efforts have been made to improve such problems thereafter. There is. For example, polyvinyl alcohol-based polymer gel (Japanese Patent Laid-Open No. 62-298342, Japanese Patent Publication No. 2-462).
11), superabsorbent resin (JP-A-4-53544), and various organic / inorganic polymers (JP-B-2-212).
No. 52) is known.

[0005]

However, the various proposed polymer gels described above still have various problems. That is, the one using the synthetic polymer, there is a possibility that a part of the gel or the gel itself may be mixed and left in the living body during the puncture or during the operation, and there is a concern that the gel itself, or the toxicity derived from the residual monomer, There was a safety issue. In addition, natural polymers and polyvinyl alcohol gels, which are considered to have high safety, do not always have sufficient acoustic characteristics (for example, high attenuation rate), and it is necessary to increase the water content in order to improve such acoustic characteristics. However, there is a drawback that the mechanical strength is lowered when the water content is increased. In addition, polyvinyl alcohol gel easily releases water when pressure is applied, and is not suitable as a gel for a probe that is pressed against the surface of the body or an organ, and is inferior in sterilization (that is, heating at 121 ° C by an autoclave, which is a simple sterilization method). Therefore, it has not been put to practical use because it completely dissolves and cannot keep its original shape. Under such circumstances, it has been desired to develop a safe contact medium for a probe that can be used during puncture and surgery.

[0006]

The inventors of the present invention have conducted extensive studies to solve the above problems, and as a result, have β-1,3 glucan, which is a natural polysaccharide, as a main component and β-1,3 glucan. 3
By using a gel containing a compound capable of forming a complex with glucan as a contact medium for a probe, it has been found that all of the above problems can be solved, and the present invention has been completed. That is, β-1,3 glucan, which is a raw material, has extremely high safety and has a property of gradually degrading in vivo even if it remains in the body (Pharmaceutical Journal 110 (10) 869-875, 1990).
reference). In addition, gels prepared by adding complex-forming compounds to β-1,3 glucan can be sterilized by the most popular sterilizers (autoclaves) and radiation, and are used as ultrasonic probe probes. The contact medium is particularly excellent as a contact medium for a probe used during puncture or surgery. The structure of the present invention will be described in detail below.

That is, according to the present invention, ultrasonic diagnosis comprising a gel containing β-1,3 glucan as a main component and containing a complex-forming compound capable of forming a complex with β-1,3 glucan. A contact medium for a probe of the device is provided.

The concentration of β-1,3 glucan constituting the contact medium for a probe according to the present invention is preferably 1 to 10% by weight, and the concentration of the complex-forming compound is preferably 5 to 900 mM. Specific examples of the complex-forming compound constituting the probe contact medium according to the present invention include boric acid, borax, phenylboric acid, sulfonated phenylboric acid, germanic acid, molybdic acid, etc. Alternatively, it can be used as a mixture of two or more kinds.

The contact medium for a probe according to the present invention is β-
It is a cross-linked highly hydrous gel containing 1,3 glucan as the main component.
β-1, 3 glucan is a general term for polysaccharides in which glucose is a structural unit and the main chain is bound to β-1, 3; to date, curdlan, scleroglucan, sclerotan, sizofiran, lentinan, Many are known such as paramylon, callose, and laminaran. Among these,
Curdlan is relatively inexpensive and stably supplied to the market, and is considered to be most suitable as a material for a contact medium for a probe.

Curdlan is a microorganism (Alcaligenes faecal
is a var. myxogenes or a kind of polysaccharide produced by many strains of Agrobacterium and Rizobium), whose constituent sugar is only D-glucose, and 9 of its glucoside bonds.
9% or more are β-1,3 bonds. Curdlan is insoluble in water but soluble in alkaline aqueous solutions such as sodium hydroxide. The curdlan dispersion is, for example, water added to curdlan powder and vigorously stirred with a high-speed homogenizer or a cutter mixer, or curdlan is added to warm water of about 55 ° C. while stirring manually or with a propeller stirrer, and then cooled. By doing so, a uniform dispersion can be obtained.

This aqueous dispersion forms a gel when heated. Gels obtained by heating are roughly classified into two types depending on the treatment temperature. That is, a thermo-irreversible gel obtained by heating at 80 ° C. or higher and a thermo-reversible gel obtained by heating at about 60 ° C. and then cooling, which are called high-set gel and low-set gel, respectively.
Also, even if the curdlan is not heated, it is dissolved in an alkaline aqueous solution and neutralized with carbon dioxide gas or the like while standing still,
The gel can also be prepared by removing sodium hydroxide using a dialysis membrane. Alternatively, a gel can be formed by adding a cation such as calcium or magnesium ion to an alkaline aqueous solution to form a crosslinked structure with the dissociated hydroxyl group and the cation. A gel can be formed from β-1,3 glucan other than curdlan according to the method described above.

Contact media used for puncture and intraoperative use must be sterile at the time of use. Therefore, for sterilization of the contact medium, it is desirable that the sterilization operation can be easily performed in a hospital and that the most popular heat sterilizer (autoclave) can be used. However, when the gel of Curdlan is sterilized by heating, the gel becomes cloudy as the temperature rises (mostly 100 ° C. or higher), and when this is used as a contact medium for a probe of an ultrasonic diagnostic apparatus, the obtained ultrasonic image is a haze. It will be blurred and blurred.

The present inventors have found that there is a high correlation between the transparency of the gel and the ultrasonic diagnostic image, that is, the clearer the gel, the clearer the image can be obtained. . As a cause of the above-mentioned white turbidity, crystallization of curdlan molecules due to heating is expected, but in order to suppress such crystallization, a method of adding another substance is generally used. However, in the case of curdlan, since it is insoluble in water, it is difficult to prepare a completely homogeneous mixture at the molecular level. Therefore, it is very difficult to avoid the cloudiness of curdlan gel with conventional additives. It was very difficult. However, according to the present invention, by adding the complex-forming compound, it became possible to solve the problem of white turbidity of the gel due to heating.

Β-1, 3 such as curdlan according to the invention
The concentration of glucan is not particularly limited as long as a uniform dispersion can be obtained, but is preferably 1 to 10% by weight, more preferably 2 to 5% by weight. If the concentration of β-1,3 glucan is less than 1% by weight, the strength of the prepared gel may be insufficient, and if it exceeds 10% by weight, the viscosity of the dispersion becomes high, and a uniform gel containing no bubbles is obtained. Tends to be difficult to obtain. Further, when using a gel containing β-1,3 glucan as a main component according to the present invention as a contact medium, it is necessary to have a high water content in order to give excellent acoustic characteristics. Is more preferably 5% by weight or less. The strength of the gel is sufficient even if the concentration of β-1,3 glucan is 2 to 5% by weight, and the gel is not destroyed by the operation of pressing it against the body surface and causing deformation.

The complex-forming compound typified by boric acid or borate used in the present invention reacts easily and quickly with a sugar or a polyoxy compound related thereto to form a complex compound having a negative charge. It is known that (Natur
e, 161, 96, 1948). As other complex-forming compounds, phenylboric acid, sulfonated phenylboric acid, germanic acid, molybdic acid and the like are known. The addition amount of these is, for example, preferably 5 to 900 mM (the number of millimoles of the complex-forming compound in 1 liter of gel), and more preferably 30 to 400 mM. 5mM addition amount
If it is less than 100 mM, the effect of improving the physical properties and transparency tends to be small. Conversely, if it exceeds 400 mM, further improvement effect cannot be expected, and if it exceeds 900 mM, it becomes difficult to dissolve it. Further, considering that the gel is used during puncture and during surgery, it is desirable that the amount of the complex-forming compound added is around the isotonic concentration. Further, the transparency of the prepared gel depends on the pH of the added boric acid solution, the reaction proceeds under weak alkaline conditions, the rate of formation of the complex compound is high, and the transparency of the gel is improved. However, considering that the contact medium of the present invention can be used during puncture and during surgery, it is desirable that the pH is around 7.4, which is close to that of blood.

In the contact medium for a probe according to the present invention, in addition to β-1,3 glucan as a main component, other polymer substances (eg, alginic acid, carrageenan, agar, glucomannan, starch, hyaluronic acid, cellulose). , Methylcellulose, ethylcellulose, nitrocellulose, polyvinyl alcohol) and various salts (eg, sodium or potassium salts of phosphoric acid, acetic acid, lactic acid, citric acid, sodium chloride), various sugars (eg, glucose, sucrose) , Maltose, galactose, mannose, lactose, etc.), urea, glycerin, silicone and the like, if necessary, may be added alone or as a mixture of two or more kinds to obtain a gel exhibiting excellent properties.

The gel thus prepared has an appropriate flexibility and is extremely easy to mold, which is extremely advantageous when considering the connection between the probe having a certain shape and the gel. The gels thus prepared all exhibit good acoustic properties. That is, the speed of sound is 1499 to 1540 m / s, which is close to that of water, and the attenuation rate is 0.06 to
It is 0.20 dB / MHz · cm. Moreover, the mechanical strength of this gel was measured, and the breaking strength was 5.43 x 10 ^{2 to} 1.32 x 1
0 ⁴ g / cm ² , Young's modulus 1.49 x 10 ^{6 to} 1.57 x 10 ⁷ dyn / cm ²
And has sufficient strength to be used as a contact medium for a probe.

[0018]

The present invention will be described in more detail with reference to the following examples. Example 1 1 to 3.5 parts by weight of curdlan (manufactured by Takeda Pharmaceutical Co., Ltd.)
70-510 mM boric acid solution (96.5 parts by weight (pH 7.4)) was added, and the mixture was stirred at 13000 rpm for 10 minutes using a high-speed homogenizer (manufactured by Nippon Seiki; Power Homogenizer PM-1) to obtain a uniform dispersion liquid. . After deaeration under vacuum, the mixture was poured into a mold and deaerated again under vacuum, followed by heating at 80 ° C. for 20 minutes for gelation. The gel thus obtained was sealed in an appropriate heat-sealed pack, and heated with a heat sterilizer (manufactured by Tommy Seiko Co., Ltd .; Autoclave SS-245) for 12 hours.
Sterilization was performed by heating at 1 ° C. for 20 minutes. For the gel prepared as described above, a rheometer (Fudo Kogyo Co., Ltd.)
Manufactured by NRM-2010J-CW), and the breaking strength and Young's modulus were measured. The results are shown in FIGS. 1 and 2, respectively.

The physical properties of the boric acid-added curdlan gel prepared as described above tended to increase in both breaking strength and Young's modulus as the amount of boric acid added increased, but the breaking strength reached its maximum near 400 mM, On the contrary, the strength was decreased by adding more than that. Also, in order to evaluate transparency,
The curdlan gel prepared above was cut into 20 × 20 × 1 mm and 660 with a spectrophotometer (V-550 manufactured by JASCO Corporation).
Table 1 shows the results obtained by measuring the absorbance value at nm and the transmittance.

[0020]

[Table 1]

From the results shown in Table 1, it is clear that transparency is improved by adding boric acid to curdlan. In addition, the absorption value became minimum in the range of 272 to 408 mM boric acid added, and the transparency was lowered with the addition of more than that. In the ultrasonic image diagnosis using the above-mentioned boric acid-added curdlan gel, a clear image was clearly obtained as compared with the case where no gel was used. That is, a high correlation was observed between the transparency of the gel and the ultrasonic image, and it was confirmed that a clear image can be obtained by ultrasonic diagnosis using the transparent gel according to the present invention.

Comparative Example 1 96.5 parts by weight of water was added to 3.5 parts by weight of curdlan powder, and the mixture was stirred with a high speed homogenizer for 10 minutes. The resulting aqueous dispersion of curdlan was thoroughly deaerated under vacuum, poured into a mold, and heated at 80 ° C. for 20 minutes to gel. Then cool, remove from the mold, and heat in a heat sterilizer at 121 ° C for 20
Complete gelation and sterilization was performed by heating for 1 minute. Physical properties and transparency of the gel prepared as described above were measured as in Example 1, and the results are shown in FIGS. 1 and 2 and Table 1. Ultrasound image diagnosis using this results in blurred images with blurry images.

Example 2 2 to 10 parts by weight of curdlan was added to a 340 mM boric acid solution (adjusted to pH 7.4 with NaOH) and stirred in a high speed homogenizer in the same manner as in Example 1 to obtain a uniform dispersion liquid. . After deaeration under vacuum, the mixture was poured into a mold and deaerated under vacuum again, followed by heating at 80 ° C. for 10 minutes to cause gelation. After cooling, it was removed from the mold and heated at 121 ° C. for 20 minutes to perform complete gelation and sterilization at the same time. Allow the gel to cool at room temperature and
Finely slice into 0x20x1mm and spectrophotometer (JASCO: V
-550), the absorption value at 660 nm and the transmittance were measured.

[0024]

[Table 2]

It was revealed that the gel became stronger and harder as the amount of curdlan added increased. The transparency was most improved when the curdlan concentration was 5%. In ultrasonic diagnosis using the gel, a clear image was obtained as compared with the case where the gel was not used.

Example 3 3.5 parts by weight of curdlan was adjusted to each pH (6.2, 6.
6, 7.0, 7.4, 7.6, 7.8, 8.0) boric acid solution was added, and a boric acid-added curdlan gel at each pH was obtained in the same manner as in Example 1. After heat sterilizing this at 121 ° C. for 20 minutes, the physical properties were measured, and the results are shown in FIG. In addition, the transparency of the gel was determined by allowing the gel after heat sterilization to cool at room temperature and then cutting it into 20 × 20 × 1 mm pieces, and measuring the absorbance at 660 nm with a spectrophotometer (J-V spectroscopy: V-550). And the transmittance were measured, and the results are shown in Table 3. As is clear from these results, the breaking strength reached its maximum at pH 7.6 and the Young's modulus at pH 7.8. The transparency was most improved at pH 7.4.

[0027]

[Table 3]

Example 4 750 mM phenyl boric acid solution 92 was added to 8 parts by weight of curdlan.
Add parts by weight, stir for 10 minutes with a high speed homogenizer,
After deaeration under vacuum, the mixture was poured into a mold and heated at 70 ° C. for 30 minutes to gel. After cooling and removing from the mold, it was heated in a heat sterilizer at 121 ° C. for 20 minutes, and this operation enabled complete gelation and sterilization. Ultrasonic diagnosis using the obtained gel gave a clearer image than in the case where no gel was used.

EXAMPLE 5 To 2.7 parts by weight of curdlan and 0.3 parts by weight of alginic acid, 97 parts by weight of 300 mM boric acid solution (adjusted to pH 7.6 with NaOH) was added, and a high-speed homogenizer was operated at 13,000 rpm for 5 minutes. After stirring and degassing under vacuum, the mixture was poured into a mold and heated at 80 ° C. for 10 minutes to cause gelation. Cool down
After removing from the mold, add 2 to 10% calcium chloride solution.
It was soaked for 4 hours to gel the alginic acid. Then, it heat-sterilized for 20 minutes at 121 degreeC using the heat sterilizer. When ultrasonic diagnosis was performed using the obtained contact medium for a probe, a clear image was clearly obtained as compared with the case where the contact medium was not used.

Example 6 2 parts by weight of curdlan and lentinan (manufactured by Ajinomoto Co., Inc.)
97.5 parts by weight of a 500 mM boric acid solution (adjusted to pH 7.2 with NaOH) was added to 0.5 parts by weight, and the mixture was stirred with a high speed homogenizer at 13000 rpm for 5 minutes. This was degassed under vacuum, poured into a mold, and heated at 100 ° C. for 10 minutes to gel. Then, it sterilized at 121 degreeC for 20 minutes using the heat sterilizer. When ultrasonic diagnosis was performed using the obtained contact medium for a probe, a clear image was clearly obtained as compared with the case where the contact medium was not used.

Example 7 10 g of scleroglucan (manufactured by Sanei Gen FFI Co., Ltd.)
Was dissolved in 10 liters of 0.03 M NaIO _{4 and} left at 5 ° C. for 5 days. Next, after adding 500 ml of ethylene glycol and stirring,
It was dialyzed at 5 ° C. for 2 days. Aqueous ammonia was added to the dialyzed solution to make it weakly alkaline, and then 5 g of NaBH ₄ was added and allowed to stand. Next, the mixture was neutralized with 1N acetic acid, dialyzed with running water again at 5 ° C., and concentrated to dryness with an evaporator. The powder thus prepared was decomposed with β-1,3 glucanase, and the decomposed solution was spotted on No.50 paper (Toyo Paper) and n-butanol: iso-
When developed with propanol: water = 3: 12: 4 (weight ratio),
In this product, it was revealed that the β-1,6-linked side chain of scleroglucan is a curdlan-like β-1,3 glucan thinned by about 95% of the whole. Then, 92 parts by weight of a 340 mM boric acid solution (pH 7.4) was added to 8 parts by weight of this product, and the mixture was stirred for 10 minutes by a high-speed homogenizer. After thoroughly degassing under vacuum, the mixture was poured into a mold and heated at 80 ° C. for 20 minutes for gelation. After cooling and removing from the mold, 121 with a heat sterilizer
Complete gelation and sterilization was performed by heating at 0 ° C for 20 minutes. When ultrasonic diagnosis was performed using the obtained contact medium for a probe, a clear image was clearly obtained as compared with the case where the contact medium was not used.

[0032]

The contact medium for the probe of the ultrasonic diagnostic apparatus of the present invention is made of a gel having a high water content and has extremely excellent ultrasonic characteristics and mechanical strength. Moreover, since the natural polysaccharide is used as a raw material, it is highly safe, and in addition, it can be inexpensively supplied in large quantities. In addition, an ordinary heat sterilizer can be used and sterilization is easy. Further, the contact medium for a probe of the present invention can be directly fixed to the probe of the ultrasonic diagnostic apparatus by using an appropriate connecting part, and its usability is considered to be much improved as compared with the conventional one. .

[Brief description of drawings]

FIG. 1 is a graph showing the change in breaking strength of gels due to the addition of boric acid in Example 1 and Comparative Example 1, which is a curdlan gel prepared according to Example 1 (80 ° C. heated gel, 121
The sterilized gel (heated at 0 ° C.) was cut into pieces of 20 × 20 × 10 mm, and the breaking strength was measured using a rheometer (each point represents the average value of the values obtained by measuring the same sample three times).

FIG. 2 is a graph showing changes in Young's modulus due to addition of boric acid in Example 1 and Comparative Example 1, in which the curdlan gel (80 ° C. heated gel, 121 ° C. heated sterilized gel) prepared according to Example 1 was treated with 20 ×. The pieces were cut into pieces of 20 × 10 mm and Young's modulus was measured using a rheometer (each sample was 3
The average value of the values measured twice is shown).

FIG. 3 is a graph showing the relationship between the curdlan concentration and the breaking strength of gel in Example 2, in which 20 × 20 curdlan gel (80 ° C. heat gel, 121 ° C. heat sterilized gel) prepared according to Example 2 was used. The pieces were cut into pieces of 10 mm and the breaking strength was measured using a rheometer (each point represents an average value of values obtained by measuring the same sample three times).

FIG. 4 is a graph showing the relationship between the curdlan concentration and the Young's modulus of the gel in Example 2, showing 20 × 20 curdlan gel (80 ° C. heated gel, 121 ° C. heat sterilized gel) prepared according to Example 2. The pieces were cut into pieces of 10 mm, and Young's modulus was measured using a rheometer (each point represents an average value of values obtained by measuring the same sample three times).

5 is a graph showing the effect of pH on the physical properties (breaking strength, Young's modulus) of curdlan gel in Example 3, showing the curdlan gel (121 ° C.) prepared according to Example 3;
Heat-sterilized gel) was sliced into pieces of 20 × 20 × 10 mm, and the breaking strength and Young's modulus were measured using a rheometer (each point represents the average value of three measurements of the same sample).

Claims (4)

[Claims] 1. A β-1,3 glucan as a main component, and β
A contact medium for a probe of an ultrasonic diagnostic apparatus, comprising a gel containing a complex-forming compound capable of forming a complex with 1,3 glucan. 2. The β-1,3 glucan concentration is 1 to 10% by weight.
The contact medium for a probe of the ultrasonic diagnostic apparatus according to claim 1. 3. The contact medium for a probe of an ultrasonic diagnostic apparatus according to claim 1, wherein the concentration of the complex-forming compound is 5 to 900 mM. 4. The contact medium for a probe of an ultrasonic diagnostic apparatus according to claim 1, wherein the complex-forming compound is boric acid.