JP2000239303A - Product formed in sheet shape - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject sheet-shape formed product that is homogeneous without unevenness, wrinkle, ant the like and can prevent the contamination with foreign substance and environmental pathogen and is useful as a medical material, for example, an adhesion preventive, a vulnerary covering material, an artificial skin or the like by making the sheet-like formed product from granular hyaluronic acid gel. SOLUTION: This sheet-shaped product is formed preferably from granular hyaluronic acid gel with an average particle size of 10-10,000 μm. In the production of this formed product, for example, a powder of hyaluronic acid (preferably with a molecular weight of about 1×105-1×107 dalton) is mixed with water, preferably the pH is ad-justed to 0.5-2.0, to prepare an acidic aqueous solution of hyaluronic acid. The aqueous solution is cast in an arbitrary vessel, frozen, preferably at -30 to -10 deg.C for >=4 hours, then thawed to give hyaluronic acid gel and the resultant gel is crushed to granular hyaluronic acid gel. This gel is neutralized with a phosphate-buffered physiological saline solution with a pH of 7, rinsed with the water for injection and the suspension of the granular hyaluronic acid is spread in an arbitrary vessel and dried to give the objective formed product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sheet-like molded product formed from granular hyaluronic acid gel and a medical material containing the same.

[0002]

2. Description of the Related Art Hyaluronic acid is a linear high molecular polysaccharide in which β-DN-acetylglucosamine and β-D-glucuronic acid are alternately bonded. Hyaluronic acid is known to be distributed in connective tissues of mammals and also present in chicken crusts, capsular streptococci, and the like. In addition to using chicken crest, umbilical cord and the like as an extraction material, purified products are also prepared from streptococcal cultures. It is known that hyaluronic acid has no species and organ specificity and exhibits excellent biocompatibility even when transplanted or injected into a living body.

[0003] Further, a variety of chemical modifications of hyaluronic acid have been proposed because of its drawbacks derived from the water solubility of hyaluronic acid itself when applied to living organisms, for example, the relatively short residence time in living organisms. (U.S. Pat. No. 4,582)
2,865, JP-B-6-37575, JP-A-7-97401, JP-A-60-130601
JP, JP-A-3-105003, European Patent 0341
745A1, see JP-A-6-73103).

[0004] Hyaluronic acid has extremely high viscosity and moisturizing properties, is essentially non-antigenic, and has high biocompatibility. Therefore, it is used as a remedy for osteoarthritis of the knee and an auxiliary agent for ophthalmic surgery. ing. In addition, the use of a hyaluronic acid solution itself as an anti-adhesion material after surgery has been studied,
The effect is weak because of its relatively short retention in the living body, and it diffuses and flows from the wound surface in a short time due to its water solubility (Journa
l of Gynecologic Surgery vol.7 No.2 97-101 (1991).

A hyaluronic acid having a long residence time in a living body that can be used as a biocompatible medical material without using any chemical crosslinking agent or chemical modifying agent and without forming a complex with a cationic polymer. The acid gel was found to be obtained by adjusting the aqueous solution of hyaluronic acid to a specific pH, freezing and then thawing the aqueous solution at least once, and furthermore, in the water of the hyaluronic acid gel thus obtained. Was found to have a very slow dissolution rate.

[0006] Hyaluronic acid gel has been found to have ideal biocompatibility and storage properties as a medical material, and particularly has ideal biocompatibility and storage properties as an anti-adhesion material, and has a remarkable effect on postoperative adhesion. Suppress.

However, when these sheet-like molded articles are manufactured, if the highly viscous hyaluronic acid acidic solution is directly spread in a container, there is a problem that the viscosity of the liquid prevents uniform spread of the solution, causing unevenness and wrinkles on the sheet. Was.

[0008]

SUMMARY OF THE INVENTION The present inventors prepared particles obtained by crushing gelled hyaluronic acid or gel particles obtained by freezing a low-concentration aqueous solution of hyaluronic acid. By suspending in a neutral solution, the viscosity of the process liquid is reduced, and a sheet molded product that is uniform without unevenness, wrinkles, etc., and is prevented from being contaminated with foreign substances and environmental bacteria can be obtained. The object was found to be suitable as a medical material, and the present invention was completed.

[0009]

That is, the present invention provides (1)
(2) a sheet-shaped molded article characterized by being formed from granular hyaluronic acid gel; (2) an average particle diameter of the hyaluronic acid gel is 10 to 10,000 µm;
(3) The sheet-like molded product according to (1) or (2), wherein the gel particles molded with hyaluronic acid alone or the crushed product of gel are formed into a sheet. 4) A medical material containing the sheet-shaped molded product according to any one of (1) to (3).

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The hyaluronic acid gel referred to in the present invention is a polymer having a three-dimensional network structure and a swollen body thereof. The three-dimensional network structure is formed by a cross-linked structure of hyaluronic acid.

[0011] The hyaluronic acid gel referred to in the present invention also includes a gel formed of hyaluronic acid alone. Of these, hyaluronic acid alone here means that no chemical crosslinking agent or chemical modifier is used other than hyaluronic acid, and that it is not complexed with a cationic polymer, meaning self-crosslinking. Is what you do. The use of a chemical cross-linking agent or a chemical modifying agent may adversely affect the biocompatibility due to the use of the chemical cross-linking agent or the chemical modifying agent.

[0012] Among the hyaluronic acid gels of the present invention, those formed solely of hyaluronic acid are characterized in that they are poorly soluble in neutral aqueous solutions. It shows significant poor solubility compared to unconverted hyaluronic acid. Poorly soluble, neutral 37
It is defined by the retention of the gel form in an aqueous solution at a temperature of ° C. and the dissolution rate of the gel. The gel formed of hyaluronic acid alone also has a feature that it is rapidly dissolved when poured into an alkaline aqueous solution, for example, an alkaline buffered aqueous solution having a pH of 11.

Among the hyaluronic acid gels referred to in the present invention, the gel formed by hyaluronic acid alone can be decomposed and solubilized by treating the hyaluronic acid gel under the conditions of the accelerated acid hydrolysis reaction of hyaluronic acid. . When the solubilized hyaluronic acid has a crosslinked structure, it can be distinguished from a linear hyaluronic acid in terms of polymer solution as a hyaluronic acid having a branch point.

Suitable conditions for the accelerated acid hydrolysis reaction of hyaluronic acid are pH 1.5 of the aqueous solution and a temperature of 60 ° C. The main chain scission reaction by hydrolysis of the glycosidic bond of hyaluronic acid is remarkably promoted in an acidic or alkaline aqueous solution as compared with a neutral aqueous solution. Further, the acid hydrolysis reaction is promoted at a higher reaction temperature.

In the present invention, the GPC-MALLS method is used,
The molecular weight and the degree of branching of the molecular weight fraction separated by GPC were continuously measured online. In the present invention, the degree of branching is measured by using the elution volume method of calculating the degree of branching by comparing the molecular weight of the solubilized hyaluronic acid of the fraction having the same elution volume with the molecular weight of the linear hyaluronic acid as a control. Was. The degree of branching is the number of branch points present per one polymer chain of solubilized hyaluronic acid, and is plotted against the molecular weight of solubilized hyaluronic acid.

The solubilized hyaluronic acid was diluted with a GPC solvent to adjust the concentration, filtered through a 0.2 μm membrane filter, and used for measurement. Among the hyaluronic acid gels referred to in the present invention, when a gel formed of hyaluronic acid alone has a cross-linking structure that is stably present even under conditions of accelerated acid hydrolysis of hyaluronic acid, the solubilized hyaluronic acid has a branched structure. Is confirmed by polymer solution theory. Among the hyaluronic acid gels referred to in the present invention, the degree of branching of the gel formed by hyaluronic acid alone is 0.5 or more.

The hyaluronic acid used in the present invention can be used regardless of its origin, whether it is extracted from animal tissues or produced by fermentation. The strain used in the fermentation method is a microorganism having hyaluronic acid-producing ability, such as Streptococcus sp.
No. 3-123392, Streptococcus equi FM-100 (Microtechnical Laboratories No. 9027), and Streptococcus equi FM-300 described in Japanese Patent Application Laid-Open No. Hei 2-234689 (Microtechnical Labs No. 2319) )), A mutant which stably produces hyaluronic acid in high yield is desirable. Those cultured and purified using the above mutant strains are used.

The molecular weight of the hyaluronic acid used in the present invention is preferably in the range of about 1 × 10 ⁵ to about 1 × 10 ⁷ daltons. In addition, as long as it has a molecular weight within the above range, those obtained by subjecting them to hydrolysis treatment or the like from those having a higher molecular weight can also be preferably used. It should be noted that the hyaluronic acid according to the present invention is used in a concept that also includes alkali metal salts thereof, for example, sodium, potassium and lithium salts.

The aqueous solution of hyaluronic acid is obtained by mixing hyaluronic acid powder and water and stirring. Further, it can also be obtained by a method in which hyaluronic acid is charged into water prepared with an acid. The concentration of hyaluronic acid of 5.0% by weight or less is convenient for treating the aqueous solution. The acid used to adjust the pH of the aqueous solution of hyaluronic acid is pH 2.
Any acid can be used as long as it can be adjusted to 0 or less. In order to reduce the amount of acid used, it is desirable to use a strong acid, for example, nitric acid, hydrochloric acid, sulfuric acid and the like.

The sheet-like molded product formed from the granular hyaluronic acid gel of the present invention is provided as a medical material in a dry state after being subjected to a treatment such as air drying, reduced pressure drying or freeze drying, depending on the purpose of use. Gamma rays, electron beams,
Even after sterilization treatment with plasma, light pulse, ethylene oxide gas, hydrogen peroxide gas, or the like, a suitable medical material having no change in form or the like can be obtained.

Examples of the granular hyaluronic acid gel include a granular hyaluronic acid gel obtained by crushing a hyaluronic acid gel and a granular hyaluronic acid gel obtained by freezing a low-concentration aqueous solution of hyaluronic acid. It is not limited.

A method for producing a granular hyaluronic acid gel obtained by crushing the hyaluronic acid gel used in the present invention will be described. The aqueous solution of hyaluronic acid is obtained by mixing and stirring the powder of hyaluronic acid and water. Further, it can also be obtained by a method in which hyaluronic acid is charged into water prepared with an acid. The pH of the aqueous solution of hyaluronic acid is adjusted to 0.5 to 2.0.

The acidic aqueous solution of hyaluronic acid is frozen at a temperature of -30 ° C to -10 ° C after being poured into an arbitrary container. Freezing may be performed by a method of freezing from the bottom surface or a method of freezing by air cooling. Hyaluronic acid gel can be obtained by freezing for more than 4 hours and then thawing. Hyaluronic acid gel with low gelling rate is obtained in the case of freezing for a short time, and hyaluronic acid gel with high gelling rate is obtained in the case of freezing for a long time. A gel is obtained. In any case, a suitable sheet-like molded product can be produced by crushing and forming a sheet into granular hyaluronic acid.

For the crushing of the hyaluronic acid gel, the following crusher is selected depending on the desired crushing particle size. Compression crushing type crushing type (brake, dodge, single, toggle jaw crusher), swiveling type (gyretri, cone, hydro cone crusher), rotary type (roll crusher, single roll crusher, disk crusher). Milling mill (stamp mill), hammer mill (hammer mill, impact crusher, impeller breaker, raymond vertical mill,
Titanium mill, Novo rotor, Micron mill, Disintegrator, Dismembrator), Fluid energy type (Jet mill, Jet pulperizer, Micronizer, Reducerizer crusher, Air mill),
Rotating cylindrical type (ball, tube, compartment, rod, conical, tricon, Hildebrand mill). Rotary type of shear pulverization (cutting mill, shear roll mill, U-Hee mill). Rotary type of friction grinding method (mill, pan mill, attrition mill, age runner),
Rotating type (screw crusher, tower mill, side glider), centrifugal force type (centrifugal roller mill, centrifugal ball mill), rotating cylindrical type (ring roller mill, high speed ball mill, low speed ball mill, high swing ball mill, vibrating ball mill), Wet colloid mill type (Premier mill,
Charlotte mill) and ultrasonic crushing method
It is not limited to these as long as it can be crushed.

The average crushed particle size of the hyaluronic acid gel is 10 to
10,000 μm, preferably 50 to 5000 μm
m. If the thickness is less than 10 μm, it is difficult to obtain sufficient strength for the dried sheet molded product, and
If it exceeds, the sheet becomes uneven and it is difficult to form a uniform sheet, which is not preferable. Then, a uniform sheet-like molded product is obtained by the following operation.

The granular hyaluronic acid gel obtained by crushing the hyaluronic acid gel was neutralized with a phosphate buffered saline of pH 7 prepared by adding a phosphate buffer component to physiological saline at a concentration of 50 mM. Thereafter, the plate is washed with water for injection. The obtained suspension of granular hyaluronic acid is developed in an arbitrary container and dried to obtain a sheet-like molded product.

Next, a method for producing a granular hyaluronic acid gel obtained by freezing a low-concentration aqueous solution of hyaluronic acid used in the present invention will be described. The preparation of the aqueous solution of hyaluronic acid is the same as in the method of granulation by crushing.

The concentration of hyaluronic acid is 0.005 to 0.5% by weight, preferably 0.01 to 0.2% by weight. 0.
If less than 005% by weight, the gel is not formed, and
If the ratio exceeds the above range, no granular hyaluronic acid gel can be obtained, and a group of hyaluronic acid gels depending on the container shape can be obtained.

Next, the pH of the aqueous solution of hyaluronic acid is adjusted to 0.5
Adjust to ~ 2.0. The pH of the aqueous solution of hyaluronic acid is adjusted to 0.5 to 2.0. Any acid can be used as long as the pH can be adjusted to 2.0 or less. In order to reduce the amount of acid used, it is preferable to use a strong acid, for example, nitric acid, hydrochloric acid, sulfuric acid and the like.

Freezing of the low-concentration aqueous solution of hyaluronic acid is carried out at a temperature of -30 ° C to -10 ° C after being poured into an arbitrary container. At a freezing temperature lower than −30 ° C., the progress of gelation is slow and takes a long time, which is not preferable. If the temperature is higher than −5 ° C., the solution may not freeze, which is not preferable.

The freezing may be performed by a method of freezing from the bottom surface or an air-cooling type freezing method. After freezing for 2 days or more, thawing gives a granular hyaluronic acid gel.

The acidic aqueous solution containing the granular hyaluronic acid gel obtained by freezing the low-concentration hyaluronic acid acidic solution was collected with a membrane filter to recover the granular hyaluronic acid gel, and then phosphate buffered at 50 mM in physiological saline. The mixture is neutralized with a phosphate buffered saline at pH 7 prepared by adding the components, and then washed with water for injection. The obtained suspension of granular hyaluronic acid is developed in an arbitrary container and dried to obtain a sheet-like molded product.

The sheet-shaped molded product of the hyaluronic acid gel formed from the granular hyaluronic acid gel obtained in the present invention can be used without particular limitation as long as it is a field in which general biodegradable medical materials and hyaluronic acid are used. Can be. For example, an anti-adhesion material, a carrier of a pharmacologically active substance, a wound dressing material, artificial skin, a tissue-replacement-type living tissue repair material, a joint injection, a surgical suture, a hemostatic agent, an artificial organ, an artificial extracellular matrix or an artificial base Use in biomedical products or pharmaceutical compositions such as membranes, medical devices and medical devices used for diagnosis and treatment, and the like.

The sheet-shaped molded article composed of granular hyaluronic acid gel may be used in a single form, or may be mixed or used in combination with different hyaluronic acid gel forms, or further mixed or used in combination with ungelled hyaluronic acid. The combination can be expected to enhance the effect. For example, when a hyaluronic acid solution and a sheet-like molded article made of granular hyaluronic acid gel are used in combination with a hyaluronic acid solution as an anti-adhesion preventive material, a local effect and a whole intra-abdominal effect can be expected.

Next, the anti-adhesion material among the medical materials of the present invention will be described. The adhesion preventing material for a sheet-like molded article made of the granular hyaluronic acid gel obtained in the present invention is used for a surgical operation, and is preferably applied directly to a surgical operation site.
The adhesion preventing material comprising a sheet-shaped molded product of the granular hyaluronic acid gel can be applied to any animal in which adhesion occurs, and can suitably prevent adhesion after surgery in mammals, particularly humans.

The place of administration in a living body is abdominal surgery, gynecological surgery, thoracic surgery, orthopedic surgery involving tendons and ligaments, hard tissues related to various organs in the abdominal cavity, thoracic cavity, tendon sheath, skull, nerve, eyeball, etc. It is useful everywhere, such as in neurosurgery involving membranes.

The adhesion preventing material for the sheet-shaped molded article made of the granular hyaluronic acid gel obtained in the present invention may be administered at any time that can prevent post-operative adhesion, and may be administered during or at the end of surgery. In particular, it is preferable to administer immediately before the end of the operation.

[0038]

The present invention will be described in more detail with reference to the following examples. Note that the present invention is not limited to this.

Example 1 Sodium hyaluronate having a molecular weight of 2 × 10 ⁶ daltons was dissolved in water for injection to prepare a 1% by weight aqueous solution of hyaluronic acid. The pH of this aqueous solution was adjusted to pH 1.5 with 1N hydrochloric acid to obtain an acidic aqueous solution of hyaluronic acid. 80 ml of this aqueous solution of hyaluronic acid was placed in a 100 ml sample bottle and placed in a freezer set at -20 ° C. Hyaluronic acid gel was obtained after freezing for 120 hours. Next, this was washed three times with 10 ml of water for injection, left standing for 10 minutes, and then decanted. After that, phosphate buffered saline of pH 7 adjusted by adding a phosphate buffer component to physiological saline at a concentration of 50 mM. After repeating neutralization twice by adding 100 ml and decanting, it was sufficiently washed with water for injection to obtain a hyaluronic acid gel. Further, a hyaluronic acid gel was added to water for injection according to the following experiment, and a microhomogenizer (NI
When crushing treatment is performed using SSEI EXCEL AUTO HOMOGENIZER), a suspension of granular hyaluronic acid gel having a particle size of 300 to 1,000 μm is obtained. The suspension is spread on a 90 mm × 90 mm plastic petri dish and dried. as a result,
A sheet-shaped molded material made of 20 granular hyaluronic acid gels was obtained. This suspension and a 0.5% by weight aqueous solution of hyaluronic acid are mixed, spread on a 90 mm × 90 mm plastic petri dish, and dried. As a result, 2
A medical material of a sheet-like molded product comprising zero granular hyaluronic acid gel and hyaluronic acid was obtained. Details of the preparation are shown in Table 1. In addition, these series of operations were performed in an aseptic and dust-free environment, and a chemical solution and the like to be used had been previously sterilized.

Example 2 Sodium hyaluronate having a molecular weight of 2 × 10 ⁶ daltons was dissolved in water for injection to prepare a 0.01% by weight aqueous solution of hyaluronic acid. The pH of this aqueous solution is adjusted to pH with 1N hydrochloric acid.
It was adjusted to 1.5 to obtain a low-concentration aqueous solution of hyaluronic acid. 8 liters of this low-concentration aqueous solution of hyaluronic acid is
Placed in a 10 liter container and placed in a freezer set at -20 ° C. Particle size 100-500 μm after 120 hours of freezing
A granular hyaluronic acid gel was obtained. The acidic aqueous solution containing the granular hyaluronic acid gel was collected with a membrane filter to collect the granular hyaluronic acid gel, and then 10 ml of water for injection was used.
, And the mixture was left for 10 minutes and then decanted. After washing was repeated three times, 100 ml of a phosphate buffered saline of pH 7 adjusted by adding a phosphate buffer component to a physiological saline at a concentration of 50 mM was added, followed by decantation. The sum was repeated twice and washed thoroughly with water for injection. Further, the hyaluronic acid gel was added to water for injection according to the following experiment to obtain a suspension of the hyaluronic acid gel. This suspension is 90mm x 90m
m and spread it on a plastic petri dish. As a result, a sheet-shaped molded material made of 20 granular hyaluronic acid gels was obtained. This suspension and a 0.5% aqueous solution of hyaluronic acid were mixed, spread on a 90 mm × 90 mm plastic petri dish, and dried. As a result, 20
A sheet-like molded material made of granular hyaluronic acid gel and hyaluronic acid was obtained. Details of the preparation are shown in Table 1. In addition, these series of operations were performed in an aseptic and dust-free environment, and a chemical solution and the like to be used had been previously sterilized.

Comparative Example 1 The pH of 160 ml of a 0.5% by weight aqueous solution of hyaluronic acid obtained by diluting the aqueous solution of hyaluronic acid prepared in Example 1 was
The pH was adjusted to 1.5 with 1N hydrochloric acid, and the mixture was spread on a 90 mm × 90 mm plastic Petri dish in 8 ml increments at -20 ° C.
Put in the freezer set. Hyaluronic acid gel was obtained after freezing for 120 hours. Next, this was washed three times with 10 ml of water for injection, left standing for 10 minutes, and then decanted. After that, phosphate buffered saline of pH 7 adjusted by adding a phosphate buffer component to physiological saline at a concentration of 50 mM. After neutralization by adding 10 ml and decanting twice was repeated, the resultant was sufficiently washed with water for injection to obtain a sheet-shaped hyaluronic acid gel.

[0042]

[Table 1]

Example 3 An evaluation test of the sheet forming condition was performed under various conditions shown in Table 1. Whether the sheet-like molded product obtained in each experiment can be formed,
Table 2 shows the results of evaluation in terms of appearance, operability, and strength.

[0044]

[Table 2]

<Evaluation method> Sheet molding: good molding / ◎, molding / ○, poor molding / △,
Not molded / × Appearance; uniform and good /／, good / ○, poor / × (20
Evaluation during production of sheets) Yield: Uniform, good and good ratio in appearance Appearance Strength: High / A, Medium / O, Low / A, Very low / X

Sheet No. Comparative Test A sheet-shaped hyaluronic acid gel obtained by developing and freezing the aqueous solution of hyaluronic acid obtained in Example 11 as it is, A sheet-shaped molded product of hyaluronic acid gel consisting of granular hyaluronic acid gel obtained by crushing hyaluronic acid gel of Experimental Nos. 1 to 5; A visual inspection of the surface shape of a sheet-like molded product made of granular hyaluronic acid gel obtained from a low-concentration hyaluronic acid acidic solution of 6 to 10 was performed. The evaluation was uniform and good / ◎, good / ○, poor /
×, and the appearance at the time of production of 20 sheets, as a uniform, good and good ratio, are shown by yield [%].

As shown in Table 2, a sheet-shaped molded product comprising a granular hyaluronic acid gel obtained by crushing and a hyaluronic acid gel and a hyaluronic acid obtained by crushing, A sheet-shaped molded product comprising a granular hyaluronic acid gel obtained from a low-concentration hyaluronic acid acidic solution, a sheet-shaped molded product comprising a granular hyaluronic acid gel obtained from a low-concentration hyaluronic acid acidic solution and hyaluronic acid are good. The improvement of the yield of the sheet and the operability and strength were recognized.

Example 4 Measurement of Degree of Branching of Granular Hyaluronic Acid Gel The granular hyaluronic acid gel obtained in Examples 1 and 2 was subjected to pH measurement.
The gel was immersed in 15 ml of 1.5 hydrochloric acid aqueous solution and hydrolyzed at 60 ° C. for 6 hours to completely solubilize the gel. This is GPC
Diluted 2 times with solvent to adjust the concentration to 0.05% by weight,
After filtration through a 0.2 μm membrane filter, the solution was filtered.
As a result of injecting 1 ml and measuring by GPC-MALLS, the degree of branching was 0.5 or more in each case.

Example 5 Adhesion Prevention Effect Test of Anti-Adhesion Material of Hyaluronic Acid Gel Using Mouse Uterus Model The sheet-shaped hyaluronic acid obtained in each of Examples 12 to 13 was cut into a rectangular shape of 1 cm × 2 cm as a control. An anti-adhesion material for a sheet-like molded product comprising the granular hyaluronic acid gel obtained in 1 to 10,
One cut into a rectangle of 1 cm × 2 cm was subjected to the following test.

Seven-week-old female ICR mice (body weight 25-30)
g) was anesthetized with an intraperitoneal pentobarbital injection, followed by median incision. The uterine horn was injured by applying iodine tincture to a length of about 10 mm. No treatment was applied to 10 mice in each group as a control, A sheet-shaped molded article comprising the granular hyaluronic acid gel obtained by the crushing obtained in Example 1; No. 3, a sheet-like molded product comprising the granular hyaluronic acid gel obtained by the crushing and hyaluronic acid; No. 4, a film-shaped sheet-shaped molded product composed of the granular hyaluronic acid gel obtained by the crushing and hyaluronic acid, 5, a film-shaped sheet-shaped molded product composed of the granular hyaluronic acid gel obtained by the crushing obtained in Example 5 and hyaluronic acid. No. 6, a sheet-shaped molded article made of granular hyaluronic acid gel obtained from the low-concentration hyaluronic acid acidic solution; 8
, A sheet-shaped molded product comprising hyaluronic acid and a granular hyaluronic acid gel obtained from the low-concentration acidic solution of hyaluronic acid obtained in Experiment No. 9, a film-shaped sheet-shaped molded product comprising granular hyaluronic acid gel obtained from the low-concentration hyaluronic acid acidic solution obtained in Experiment No. 9. A film-shaped sheet-shaped molded product composed of granular hyaluronic acid gel obtained from the low-concentration hyaluronic acid acidic solution obtained in 10 and hyaluronic acid was used. As a comparison, the aqueous solution of hyaluronic acid obtained in Example 1 was used. Sheet-shaped molded products of 12 to 13 hyaluronic acid were used.

Each of the sheet-like molded articles made of the above-mentioned sheet-like hyaluronic acid and granular hyaluronic acid gel was used.
Wrap a rectangular sheet of cm x 2 cm around the damaged area,
In the case of a hyaluronic acid aqueous solution, 1 ml of the hyaluronic acid solution prepared in Preparation Example 1 was added to the damaged site. In each case, the abdomen was closed at 5-0 dexone.

Ten days after the operation, 10 untreated, sheet-shaped molded articles made of granular hyaluronic acid gel, and 10 mice to which sheet-shaped hyaluronic acid and an aqueous solution of hyaluronic acid were administered were killed by cervical dislocation, and the abdomen was restarted. Then, the presence or absence of adhesion formation was determined. Adhesion formation was judged as adhesion when a very slight adhesion in the form of a film was not adhered, but when a strong adhesion which was fibrous and thick and was not easily peeled off even when pulled with forceps was produced.
Table 3 shows the results.

[0053]

[Table 3]

From Table 3, it can be seen that the rate of formation of adhesions without treatment was 10%.
When 9 out of 9 animals, the hyaluronic acid aqueous solution obtained in Example 1 was used in 6 out of 10 animals. The number of the hyaluronic acid sheets of Experiment No. 12 was 5 out of 10 animals. The film-shaped hyaluronic acid sheet obtained in Experiment No. 13 was used for 5 out of 10 animals, and the experiment No. 1 out of 10 sheet-shaped molded articles made of the granular hyaluronic acid gel obtained by the crushing obtained in Example 1, No. 10 out of 10 sheet-shaped molded articles composed of the granular hyaluronic acid gel obtained by the crushing obtained in Example 3 and hyaluronic acid were obtained. 4 out of 10 film-shaped sheet-shaped molded articles composed of the granular hyaluronic acid gel obtained by the crushing obtained in Example 4 and hyaluronic acid. The film-shaped sheet-like molded product composed of the granular hyaluronic acid gel obtained by the crushing obtained in 5 and hyaluronic acid is 10
0 of the animals, Experiment No. 6 out of 10 sheet-shaped molded articles made of granular hyaluronic acid gel obtained from the low-concentration hyaluronic acid acidic solution obtained in Experiment No. 6. The sheet-like molded product comprising the granular hyaluronic acid gel and hyaluronic acid obtained from the low-concentration hyaluronic acid acidic solution obtained in 8 is 10
One of the animals, Experiment No. 9 out of 10 film-shaped sheet-like molded articles made of granular hyaluronic acid gel obtained from the low-concentration hyaluronic acid acidic solution obtained in 9
o. In 1 out of 10 film-shaped sheet-like molded articles composed of granular hyaluronic acid gel and hyaluronic acid obtained from the low-concentration hyaluronic acid acidic solution obtained in 10, it was confirmed that they had an excellent anti-adhesion action. .

[0055]

As described above, according to the present invention, a uniform sheet molded product can be obtained by molding a sheet from granular hyaluronic acid gel. In addition, complicated steps can be avoided at the time of scale-up, and the danger of contamination of foreign substances and environmental bacteria and the corrosion of piping and the like to acidic solutions can be avoided. Further, this sheet-like molded product is suitably used for medical materials.

 ────────────────────────────────────────────────── ─── Continuing from the front page (72) Inventor Shinichi Yanagi 3-5-1 Asahicho, Machida-shi, Tokyo Denka Kagaku Kogyo Co., Ltd. F-term (reference) 4C090 AA02 AA09 BA67 BB03 BB18 BB22 BB35 BB53 BB65 BB94 BC19 BC27 BD05 BD11 BD19 BD24 BD37 CA01 CA31 CA32 DA10 DA22

Claims (4)

[Claims] 1. A sheet-shaped molded article formed from a granular hyaluronic acid gel. 2. The hyaluronic acid gel has an average particle size of 10-1.
The sheet-like molded product according to claim 1, wherein the thickness of the sheet-shaped molded product is 000 µm. 3. The sheet-like molded product according to claim 1, wherein particles of the gel molded with hyaluronic acid alone or a crushed product of the gel are formed into a sheet. 4. A medical material comprising the sheet-shaped molded product according to claim 1.