JP2002136588A - Medical occlusion material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medical occlusion material excellent in tissue bondability and operability, and especially, the occlusion material which is useful as an occlusion material for blocking a wound due to surgical operation in the opthalmologic field and functions without stitching up a cut and is excellent in the tissue bondability and operability. SOLUTION: The material comprises powder of a polycationic material and powder of a polyanionic material. To be more precise, chitosan is included as the polycationic material, and alginic acid is included as the polyanionic material.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a medical plug material. INDUSTRIAL APPLICABILITY The medical plug material of the present invention is useful as a plug material for closing a wound caused by a surgical operation or the like because of its excellent adhesion to tissue and easy operability. It is useful as a plug material for plugging.

[0002]

2. Description of the Related Art In ophthalmology, in the operation of an intermediate translucent body (anterior chamber / lens / vitreous body), an incision is made in the anterior eye (cornea / conjunctiva), and various operations are performed using the incision. There are many. In the past, the incision was closed with a suture or the like after the operation, but in recent years, a method of closing the incision without suturing has been used. However, when the incision is naturally closed without suturing, an inflammation-inducing substance such as bacteria may enter the ocular tissue from the incision and cause endophthalmitis. Under such circumstances, development of a plug material that can close the incision is desired, and further development of a plug material that is biodegraded and disappears after the incision is closed is particularly desired.

Hitherto, as an ophthalmic plug, application of fibrin glue, cyanoacrylate adhesive and the like, which are used as an adhesive in ophthalmology, has been attempted. However, fibrin glue contains fibrinogen,
It is composed of factor XIII and thrombin, and is currently marketed by several companies.However, all of them use human plasma-derived fibrinogen, so there is a problem that the possibility of infection with a pathogen such as a virus cannot be ruled out. above,
Adhesion to ocular tissues was low, and its use in ophthalmology was extremely limited. In addition, the cyanoacrylate-based adhesive may not be well compatible with eye tissues, and it is difficult to apply a small amount to a site to be bonded or a site to be closed, and there is a problem in operability.

By the way, it is well known that when a polycationic substance and a polyanionic substance are mixed in the coexistence of water, a polyion complex is quickly formed, and the polyion complex is widely used in a wide range of fields including pharmaceuticals and medical devices. It's being used. For example, a hemostatic agent made into a powder, granule or tablet of a polymer complex obtained by reacting an anionic partially substituted dextran with a cationic partially substituted polysaccharide (JP-A-53-110693). ,
Multilayer body for wound treatment having a structure in which chitosan, alginic acid, chitin and a support are sequentially laminated (Japanese Patent Laid-Open No. 8-2)
No. 24293) and an agent for promoting periodontal tissue regeneration comprising a polyelectrolyte complex injected into a periodontal pocket as an active ingredient (JP-A-3-278538). However, no attempt has been made to use the polyion complex as a medical plug material, particularly an ophthalmic plug material.

[0005]

SUMMARY OF THE INVENTION It is, therefore, an object of the present invention to provide a medical plug having excellent tissue adhesion and operability. In particular, it is an object of the present invention to provide a medical plug having excellent tissue adhesiveness and operability in eye tissue.

[0006]

Means for Solving the Problems The present inventors have found that a film of a polyion complex formed from a polycationic substance and a polyanionic substance absorbs blood or tissue exudate from the affected area after being applied to the affected area and forms a gel. At the same time, it was found to have sufficient gel strength for tissue adhesion, and was filed earlier (Japanese Patent Application Laid-Open No. 2000-5296).
And JP-A-2000-116765). Further, the present inventors have found that a hemostatic material composed of a powder of a polycationic substance and a powder of a polyanionic substance exerts a hemostatic effect by adhering to an affected tissue and gelling, and has filed an earlier application (Japanese Patent Application Laid-Open No. 2000-186048). issue).

As a result of further studies based on the above-mentioned research, the present inventors have surprisingly found that a material comprising a powder of a polycationic substance and a powder of a polyanionic substance has a medical plug material. In particular, they have found that they are useful as ophthalmic plugs, and have completed the present invention.

That is, the present invention is a medical plug comprising a powder of a polycationic substance and a powder of a polyanionic substance. Further, the present invention is a medical plug material in which a powder of a polycationic substance and a powder of a polyanionic substance are suspended in a water-soluble liquid dispersion medium.

[0009]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The medical plug material of the present invention comprises a powder of a polycationic substance and a powder of a polyanionic substance. The polycationic substance in the present invention has a plurality of cationic groups in its molecule, and can form a gel-like polyion complex with the polyanionic substance described below in the presence of water. There is no particular limitation as long as it has little adverse reaction to the living body, because it can adhere to the tissue and close the opening of the tissue such as the incision.
It is preferable that the material is bioabsorbable so that it is decomposed and absorbed into the living body after the opening of the tissue is closed. The polycationic substance preferably has such a hydrophilicity that it can be dissolved or swelled in water, and has a property that the cationic group has a positive charge in water.

The cationic group includes, for example, an amino group;
Monoalkylamino groups such as methylamino group and ethylamino group; dialkylamino groups such as dimethylamino group and diethylamino group; imino groups; guanidino groups; and the like. Substances having an amino group of are preferred.

As the polycationic substance, chitosan,
Basic polysaccharides such as partially deacetylated chitin and aminated cellulose; homopolymers or copolymers of basic amino acids such as polylysine, polyarginine, and copolymers of lysine and arginine; bases such as polyvinylamine and polyallylamine Vinyl polymers and their salts (hydrochloride,
And the like. One or more of these can be used. Among these, a basic polysaccharide or a salt thereof is preferable from the viewpoint of safety for a living body, and chitosan or a salt thereof is more preferable. Further, a crosslinked polymer obtained by crosslinking these polycationic polymers can also be used. As a method for crosslinking the polycationic polymer, any of known methods can be used. When the polycationic polymer has an amino group, a method of cross-linking by conducting a condensation reaction of the amino group of the polycationic polymer with dicarboxylic acid or dicarboxylic anhydride is preferable.

Although the molecular weight of the polycationic substance is not particularly limited, the viscosity of the aqueous solution tends to increase as the molecular weight increases, and the production of powder tends to be difficult. 20 ° C aqueous solution
Is preferably 10,000 cp or less,
More preferably, it is 5,000 cp or less.

The polyanionic substance in the present invention has a plurality of anionic groups in its molecule, and can form a gel-like polyion complex with the polycationic substance in the presence of water. The polyion complex adheres to the living tissue and can close the opening of the tissue such as the incision.There is no particular limitation as long as there is little adverse reaction to the living body, and it decomposes after the opening of the tissue is closed. It is preferably a substance having bioabsorbability so that it can be absorbed into the living body. The polyanionic substance has such a degree of hydrophilicity that it can be dissolved or swelled in water, and a substance having a property of being negatively charged by dissociation of an anionic group in water is preferably used. .

Examples of the anionic group include a carboxyl group, a sulfate group, a sulfonic acid group, and a phosphoric acid group. As the polyanionic substance, a substance having two or more carboxyl groups in one molecule is preferable. Acidic polysaccharides are more preferred.

Examples of the acidic polysaccharide include natural acid polysaccharides having a carboxyl group such as alginic acid, hyaluronic acid, chondroitin sulfate, dextran sulfate and pectin and anionic groups such as sulfate group; and natural carboxyl groups such as cellulose, dextran and starch Groups, acidic polysaccharides artificially synthesized by introducing an anionic group into a polysaccharide having no anionic group such as a sulfate group, for example, carboxymethylcellulose, carboxymethyldextran, carboxymethylstarch, carboxymethylchitosan, Sulfated cellulose, sulfated dextran and the like can be mentioned, and from the viewpoint of safety for living organisms, alginic acid or a derivative thereof is preferable.

The acidic polysaccharide is obtained by reacting a part or all of the hydroxyl groups of the acidic polysaccharide with acetic acid, nitric acid, sulfuric acid, phosphoric acid, etc .; Compounds esterified with low molecular alcohols such as ethylene glycol and propylene glycol can also be used. Specific examples include carboxymethyl cellulose acetate, carboxymethyl dextran acetate, ethylene glycol alginate, propylene glycol alginate, ethylene glycol hyaluronate, propylene glycol hyaluronate, and the like. The above can be used.
The degree of esterification in these acidic polysaccharides is not particularly limited, but if the degree of esterification is too high, the proportion of carboxyl groups, that is, the anionicity decreases, and a polyion complex formed between the polycationic substance and the polyionic complex is formed. , The degree of esterification is preferably 80% or less, more preferably 30% or less.

As the polyanionic substance, a homopolymer or a copolymer of an acidic amino acid such as polyglutamic acid, polyaspartic acid, a copolymer of glutamic acid and aspartic acid, and an acidic vinyl polymer such as polyacrylic acid are used. You can also. Further, a crosslinked polymer obtained by crosslinking these polyanionic substances can also be used. As a method for crosslinking the polyanionic substance, any known method can be used. When the polyanionic substance has a carboxyl group, a method of crosslinking by performing a condensation reaction of the carboxyl group of the polyanionic substance with a diamine is preferable.

These polyanionic substances can be used in the form of a salt with a monovalent ion, for example, an alkali metal salt such as a sodium salt or a potassium salt; an ammonium salt.

The molecular weight of the polyanionic substance is not particularly limited, but as the molecular weight increases, the viscosity of the aqueous solution increases and the production of powder becomes difficult. Measured with)
Is preferably 10,000 cp or less,
It is more preferably 0 cp or less.

The combination of the polycationic substance and the polyanionic substance used in the present invention may be any combination as long as it forms a polyion complex and gels when mixed in the presence of water. From the viewpoint of sex, at least one of the polycationic substance and the polyanionic substance is preferably a bioabsorbable substance.

The mixing ratio of the polycationic substance and the polyanionic substance is determined by mixing the powder of the polycationic substance and the powder of the polyanionic substance or the powder of the polycationic substance and the powder of the polyanionic substance in water. When water is added to a suspension suspended in an aqueous liquid dispersion medium, any mixing ratio may be used so long as a polyion complex is formed and gelled.

The powder of the polycationic substance and the powder of the polyanionic substance may contain water to such an extent that they do not substantially form a gel-like polyion complex when they are mixed. From the perspective of raising
The water content is preferably at most 40%, more preferably at most 20%.

The medical plug material of the present invention is prepared by separately preparing a powder of a polycationic substance and a powder of a polyanionic substance,
It can be manufactured by mixing. The powder of the polycationic or polyanionic substance can be prepared by crushing the dried polycationic or polyanionic substance, or by micronizing and drying the solution of the polycationic or polyanionic substance. . As a method for drying the polycationic substance and the polyanionic substance, any method can be adopted as long as the method does not cause deterioration of the polycationic substance and the polyanionic substance.For example, a freeze-drying method, a vacuum drying method, Heat drying method, hot air drying method, spray drying (spray drying)
And a solvent displacement drying method. Among them, a method of atomizing and drying a solution of a polycationic substance or a polyanionic substance by a spray drying method, an aqueous solution of a polycationic substance or a polyanionic substance in a water-insoluble organic solvent using a surfactant. After emulsification, if necessary, an insolubilizing agent is added to insolubilize the fine particles of the emulsion, water, an organic solvent, and a surfactant are removed by a solvent displacement drying method, and further drying is performed as necessary to obtain a polycation. It is preferable to use a method of obtaining fine particles of an anionic substance or a polyanionic substance. The solvent for dissolving the polycationic substance or the polyanionic substance is not particularly limited as long as the solvent dissolves the polycationic substance or the polyanionic substance. Water or an aqueous solution of an inorganic salt such as sodium chloride or sodium acetate is used. preferable. As the above-mentioned insolubilizing agent having an effect of stabilizing the fine particles of the emulsion, when obtaining fine particles of a polycationic substance, basic substances such as sodium hydroxide and potassium hydroxide, and when obtaining fine particles of a polyanionic substance, , Hydrochloric acid, sulfuric acid, acetic acid and the like are preferred. These insolubilizing agents are preferably used as an aqueous solution. The concentration in the solution when drying the polycationic substance and the polyanionic substance is not particularly limited,
What is necessary is just to set suitably according to the use purpose.

The size of the powder of the polycationic substance and the polyanionic substance is not particularly limited, but as the particle size increases, the density of the polyion complex at the time of gelation decreases and the mechanical strength of the gel decreases. The particle size of the powder is 100 μm
Or less, more preferably 20 μm or less.

As a method of mixing the powder of the polycationic substance and the powder of the polyanionic substance, a method of mixing the powder with the tissue without absorbing the moisture without forming a polyion complex until the powder is applied to the tissue is used. Any method can be adopted as long as the method enables formation of a polyion complex and gelation. For example, a method in which a powder of a polycationic substance and a powder of a polyanionic substance are stirred and physically mixed,
A method of suspending and mixing the powder of the polycationic substance and the powder of the polyanionic substance in an appropriate solvent and then removing the solvent can be used. As a solvent for mixing by suspending in a solvent, any solvent can be used as long as the powder of the polycationic substance and the powder of the polyanionic substance do not dissolve or gel, but it is necessary to remove the solvent after mixing. Therefore, volatile solvents such as ethyl ether, ethanol, methanol, and acetone are preferred.

Although the medical plug material of the present invention absorbs moisture and gels, an appropriate water-soluble powder can be added to adjust the water absorption rate. The powder in this case is not particularly limited as long as it absorbs water at an appropriate rate and does not adversely affect the living body without inhibiting the formation of the polyion complex. Substances having bioabsorbability, such as glucose, lactose, sucrose, etc., are preferred so that they can be absorbed into the body.

The medical plug material of the present invention can be used in the form of a powder. By suspending the medical plug material in a water-soluble liquid dispersion medium, the medical plug material applied to the tissue can be completely and rapidly gelled. In addition, the scattering of the powder is suppressed and the operability is improved. Medical stoppers made by suspending a powder of a polycationic substance and a powder of a polyanionic substance in a water-soluble liquid dispersion medium can be stored in the form of a suspension. Can be used without doing.

The water-soluble liquid dispersion medium used for preparing the above-mentioned suspension may be one which does not dissolve or gel the powder of the polycationic substance and the powder of the polyanionic substance and absorbs water at an appropriate rate. There is no particular limitation, and examples thereof include ethanol, methanol, isopropanol, glycerin, and water-soluble alcohols such as propylene glycol.From the viewpoint of safety for living organisms, ethanol,
Glycerin and propylene glycol are preferred. If the water content of the water-soluble liquid dispersion medium is large, the powder of the polycationic substance or the powder of the polyanionic substance dissolves or gels, so that the water content of the water-soluble liquid dispersion medium should be 40% or less. It is more preferably at most 20%.

A medical plug material obtained by suspending a powder of a polycationic substance and a powder of a polyanionic substance in a water-soluble liquid dispersion medium is obtained by mixing a powder of a powder of a polycationic substance and a powder of a polyanionic substance, It can be produced by suspending in a water-soluble liquid dispersion medium. Further, it can also be produced by a method of directly mixing a polycationic substance powder and a polyanionic substance powder in a water-soluble liquid dispersion medium.

The medical plug material of the present invention can be suitably used as a plug material in the field of ophthalmology. For example, a capsular ostium opened for removing a clouded lens substance by suction, an incision around the cornea, and the like can be used. The plug material can be effectively used as a plug material for closing a conjunctival incision in a vitrifying operation, a glaucoma operation, or the like. Further, examples of applications of the medical plug material of the present invention in fields other than the ophthalmology field include a plug material for closing an incision in a postoperative skin, a plug material for closing a suture hole at the time of suturing, and prevention of air leakage from a lung. Plug material for use.

[0031]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited thereto. In the following examples, the effects and biodegradability of the medical plugs were evaluated as follows.

Evaluation of the effect of the medical plug material: After incising the periphery of the cornea of a healthy rabbit (Japanese white male rabbit, weighing 2.5 to 3.0 kg), a small hole was made in the lens capsule and the lens parenchyma was removed. It was removed by suction using ultrasonic emulsification suction. Thereafter, 0.3 ml of a hyaluronic acid aqueous solution (Healon) was administered into the lens capsule with a 24G injection needle, and 200 mg of the sample obtained in the example or comparative example was applied to the small hole. One day after the operation, the thickness of the lens was observed with a slit lamp microscope, and if there was no change in the thickness compared to immediately after the operation, there was no leakage of the hyaluronic acid aqueous solution filled in the lens capsule. When a change in the thickness was observed, it was judged as x because the filled aqueous solution of hyaluronic acid had leaked into the lens capsule.

Evaluation of biodegradability: A normal rabbit (Japanese white male rabbit, body weight 2.5 to 3.0 kg) was incised around the cornea, a small hole was made in the lens capsule, and the lens substance was ultrasonically emulsified. It was removed by suction by suction. Then, an aqueous solution of hyaluronic acid (Healon) was injected into the capsular bag with a 24G injection needle by 0.3 g.
ml, and 200 mg of the sample obtained in the example or the comparative example was applied to the small hole. The remaining amount of the sample applied 30 days after the operation was observed with a slit lamp microscope, and if the sample was observed, the biodegradability of the medical stopper was poor, and the sample was not observed. In this case, it was judged as ○ because the medical plug material was excellent in biodegradability.

Example 1 1 g of chitosan (Chitosan 500, manufactured by Wako Pure Chemical Industries, Ltd., degree of deacetylation: 85%) was dissolved in 100 ml of 0.1 N acetic acid to obtain a dry powder by a spray drying method.
Those that passed through a 0 mesh sieve were collected. Sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., viscosity 100 to 15
0 cp) 1 g was dissolved in 100 ml of distilled water to obtain a dry powder by a spray-drying method, and then collected through a 440 mesh sieve. 1.0 g of the dry powder of chitosan acetate and 0.5 g of the dry powder of sodium alginate were mixed, and 2.5 ml of propylene glycol was mixed.
Was added and suspended uniformly. This suspension was evaluated as described above. Table 1 shows the results.

Example 2 1 g of chitosan (Chitosan 500, manufactured by Wako Pure Chemical Industries, Ltd., degree of deacetylation: 85%) was dissolved in 100 ml of 0.1 N acetic acid to obtain a dry powder by a spray drying method.
Those that passed through a 0 mesh sieve were collected. Sodium alginate (Wako Pure Chemical Industries, Ltd., viscosity 500 to 60
0 cp) 1 g was dissolved in 100 ml of distilled water to obtain a dry powder by a spray-drying method, and then collected through a 440 mesh sieve. 1.0 g of the dry powder of chitosan acetate and 0.5 g of the dry powder of sodium alginate were mixed, and 2.5 ml of propylene glycol was mixed.
Was added and suspended uniformly. This suspension was evaluated as described above. Table 1 shows the results.

Example 3 Poly-L-lysine (manufactured by Sigma, molecular weight 70,000 to 15)
1 g was dissolved in 100 ml of 0.1N hydrochloric acid, freeze-dried, crushed, and collected through a 440 mesh sieve. 3 g of sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd., viscosity: 100 to 150 cp) was dissolved in 100 ml of distilled water, lyophilized, and collected through a 440 mesh sieve. 0.5 g of the dry powder of poly-L-lysine hydrochloride and 0.5 g of the dry powder of sodium alginate were mixed, and 2 ml of propylene glycol was added to suspend the mixture uniformly. This suspension was evaluated as described above. Table 1 shows the results.

Comparative Example 1 A fibrinogen solution of Tisseal (a biological tissue adhesive manufactured by Nippon Organ Pharmaceutical Co., Ltd.) and thrombin S were mixed in a ratio of 1: 1 in advance, and the above evaluation was performed. Table 2 shows the results.

Comparative Example 2 The above evaluation was performed using Aron Alpha A "Sankyo" (manufactured by Toagosei Co., Ltd.). Table 2 shows the results.

[0039]

[Table 1]

[0040]

[Table 2]

As is clear from Tables 1 and 2, when the samples of Examples 1 to 3 were used, all of them exhibited a sufficient effect as a medical stopper material and were excellent in biodegradability. I have. In contrast, when the samples of Comparative Examples 1 and 2 were used, the sample did not sufficiently adhere to the tissue, the contents of the capsular bag leaked out of the capsule, and the sample of Comparative Example 2 was Degradability is also poor.

[0042]

According to the present invention, there is provided a medical plug material excellent in tissue adhesiveness and operability, particularly an ophthalmic plug material excellent in tissue adhesiveness and operability in eye tissue.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Tatsuhiko Higaki 1-12-39 Umeda, Kita-ku, Osaka, Osaka F-term in Kuraray Co., Ltd. EA16

Claims (10)

[Claims] 1. A medical plug comprising a powder of a polycationic substance and a powder of a polyanionic substance. 2. The medical plug material according to claim 1, wherein the polycationic substance powder and the polyanionic substance powder are suspended in a water-soluble liquid dispersion medium. 3. The medical plug according to claim 1, wherein the polycationic substance is a substance having two or more amino groups in one molecule. 4. The medical plug material according to claim 3, wherein the substance having two or more amino groups in one molecule is a basic polysaccharide or a salt thereof. 5. The basic polysaccharide is chitosan.
A medical stopper according to claim 1. 6. The medical plug material according to claim 1, wherein the polyanionic substance is a substance having two or more carboxyl groups in one molecule. 7. The medical plug material according to claim 6, wherein the substance having two or more carboxyl groups in one molecule is an acidic polysaccharide or a salt thereof. 8. The method according to claim 7, wherein the acidic polysaccharide is alginic acid.
A medical stopper according to claim 1. 9. The water-soluble liquid dispersion medium is ethanol, glycerin or propylene glycol.
The medical stopper according to any one of claims 1 to 7. 10. The medical plug according to claim 1, which is an ophthalmic plug.