JPH11276572A - Material for medical care made of poly(gamma-glutamic acid) salt complex - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a suture thread for operation which is excellent in its organism adaptability, power to hold nodes, flexible and easy to ligate, a material for covering an injury part that is excellent in its softness, adhesion, water-permeability and anti-bac terial ability and facilitates the affected part's recover, and an anthemorrhagic material that has no allergic action, can prevent an affected part, e.g. hurt surgically, from being adhered and also prevent organs inside a material for preventing adhesion from bleeding. SOLUTION: This material for medical care is composed of poly(γ-glutamic acid) salt and a compound that has a part which can be hydrogen-bonded to carboxyanion of the poly(γ-glutamic acid) salt. As the salt of the poly(γ-glutamic acid), alkali metals, e.g. sodium, potassium, lithium and so on, alkaline earth metals, e.g. magnesium, calcium, barium and so on, and ammonium salts are shown as examples. Also, for the composition that has the part which can be hydrogen-bonded so as to compose a complex of poly(γ-glutamic acid) salt, if it can be bonded to at least a part of carboxyanion (COO) of poly(γ-glutamic acid) sulfate through hydrogen-bond in an aqueous solution or a water solution, any kind of compound can be used. As such a compound, chitosan and its carboxymethyl derivative, hydroxyethyl derivative, or O-acyl derivative is preferred.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a medical material comprising a poly (γ-glutamic acid) salt complex having excellent biocompatibility and bioabsorbability. More specifically, the present invention provides a surgical suture that is excellent in biocompatibility, has high knot holding power, is flexible and easy to ligate, has excellent flexibility, adhesion, moisture permeability, and antibacterial properties, and promotes wound healing. Coating material, non-allergic, non-allergic, biodegradable in vivo, suitable for biocompatibility, anti-adhesion material to prevent adhesion of affected area after injury such as surgical injury, and bleeding of internal organs caused by injury It relates to a hemostatic material to be blocked.

[0002]

2. Description of the Related Art At present, surgical sutures made of silk, polyethylene fibers, aramid fibers, or polyvinyl alcohol fibers are used in clinical practice because of their high strength. These surgical sutures are removed after adhering body surface tissues such as the abdominal wall, but are not used for sutures inside the body such as large blood vessels, hearts, organ transplants, tendons, ligaments, bone marrow, and periosteum. It is still left in the body. These fibers are inferior in biocompatibility, and their improvement has been desired. In addition, when suturing living tissues, especially living tissues in the body, they are soft and strong at the time of suturing, have sufficient knot strength, and have excellent handling properties, but ideally, they are digested and disappear after the tissue is adhered. is there.

[0003] Wound dressings are used to cover and protect important areas of human skin such as wounds after severe burns, trauma, tumors and the like. It temporarily covers the wound, reduces fluid loss and prevents infection, and promotes healing. For example, dry pork skin, catabaskin, chitin membrane, chitosan membrane and the like have been proposed. Of these, dried pork skin and catabaskin are of biological origin,
Biocompatibility issues such as supply and storage stability and antigenicity when used as artificial skin remain. In addition, chitin / chitosan has a hemostatic effect and promotes wound healing, and is therefore excellent as an artificial skin. However, since the raw material is derived from crustaceans such as crabs and shrimp, it has been desired that the membrane made of chitin / chitosan is hard and more flexible when used as artificial skin.

[0004] The form of the wound dressing is to minimize the irritation applied to the wound surface in order to alleviate the pain in the affected area and make the treatment scar less noticeable, while keeping the wound surface in an appropriate moisture state. It is often a soft material made of natural polymer materials. As these wounds heal, attempts have been made recently to ensure that there is no problem if they remain in the body by being decomposed and absorbed by living tissues,
It is difficult to control the rate of biodegradability such that the wound surface may be excessively decomposed and dissolved at the wound surface, and the wound surface may not be sufficiently retained. There is a need for a material having appropriate biocompatibility that is suitable for a wound dressing material, does not exhibit allergic effects, and does not excessively dissolve, but a wound dressing material using such a material is known. Absent.

[0005] Adhesions arise from numerous medical conditions and surgical procedures. Diseases involved in adhesion formation include pelvic inflammation or other pelvic or abdominal inflammation resulting from infection or endometritis. The surgical procedures required by these diseases and other pathological conditions, such as cysts, tumors, may also result in adhesion formation. Adhesions can lead to infertility, such as by inducing oviductal obstruction and interfering with fallopian tube function. For example, suppression of egg pick-up is mentioned.

[0006] The formation of adhesions is believed to result from trauma to the serosal surface, followed by the release of fibrinogen-rich effluents, and fibrin formation. This may result in the formation of a thick or thin adhesion zone bridging the pelvic organs or tissues, or the mutual immobilization of these structures. The presence of pelvic or abdominal adhesions is known to be a major cause of infertility in human women.

Over the years, a great number of natural or artificial implants have been used to reduce the formation of adhesions on traumatic surfaces, but with less remarkable results. Natural substances include peritoneum, retina, fat, and amniotic membrane, and amniotic membrane plus sclera. Artificial materials such as polyvinyl alcohol thin films and tantalum oil have been used in the past, but recently, gel films and gel foams (manufactured by Upjohn), surge gels (manufactured by Johnson & Johnson) ) And SIRASTEC (manufactured by Dow Corning), and Gore-Tex
(Gore-Tex Corp.) and Interseed (Johnson & Johnson Corp.) meshes and the like are used. However, damage that causes bleeding to the internal organs such as the liver, the spleen, the spleen, and the kidney has been problematic for many years, including ineffectiveness and loss of organs and death.

[0008] Regarding the use of medical materials other than those described above, there is no material having excellent biocompatibility and bioabsorbability.
The provision of such materials has been eagerly desired.

[0009]

SUMMARY OF THE INVENTION In view of the state of the prior art, it is an object of the present invention to provide a surgical suture that is excellent in biocompatibility, has high knot holding power, is flexible and easy to ligate. Providing a wound dressing material that has excellent antibacterial properties and promotes wound healing, has no allergic effects, has appropriate biocompatibility to control degradation in the living body, and can adhere to affected areas after injury such as surgical injury. Providing an anti-adhesion preventive material, providing a hemostatic material for preventing bleeding of internal organs caused by damage, furthermore, an artificial bone filler excellent in bioabsorbability and biocompatible, a splint for vascular anastomosis, and a soft tissue prosthesis It has been desired to provide medical materials such as materials, absorbable membranes, artificial blood vessels, splints for intestinal anastomosis, artificial ligaments, and artificial bladders.

[0010]

Means for Solving the Problems In order to solve the above problems,
The present inventors have conducted intensive studies and found that a poly (γ-glutamic acid) salt comprising a poly (γ-glutamic acid) salt and a compound having a site capable of hydrogen bonding to a carboxy anion of the poly (γ-glutamic acid) salt The present inventors have found that a salt complex is used as a medical material and completed the present invention.

That is, a first aspect of the present invention is a poly (γ-glutamic acid) salt and a poly (γ-glutamic acid) salt comprising a compound having a site capable of hydrogen bonding to a carboxy anion of the poly (γ-glutamic acid) salt. The present invention relates to a medical material comprising a glutamic acid) salt complex. A preferred embodiment relates to a medical material characterized in that the medical material is a surgical suture.

Another preferred embodiment relates to a medical material characterized in that the medical material is a wound dressing. Another preferred embodiment relates to a medical material, wherein the medical material is an adhesion preventing material. Yet another preferred embodiment relates to a medical material characterized by being a hemostatic material.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. Poly (γ-glutamic acid) used in the present invention is a known substance, and can be obtained by various methods such as a chemical bonding method, a fermentation method, and a semi-synthesis method. However, in order to obtain poly (γ-glutamic acid) efficiently, a fermentation method described in, for example, JP-A-7-135991 is preferable.

Examples of the salt of the poly (γ-glutamic acid) salt used in the present invention include alkali metals such as sodium, potassium and lithium, alkaline earth metals such as magnesium, calcium and barium, and ammonium salts. The poly (γ-glutamic acid) salt of the present invention
Any of these salts may be used, and two or more kinds of salts may be combined.

The poly (γ-glutamic acid) of the present invention
The salt is obtained by dispersing poly (γ-glutamic acid) in water, adding an aqueous solution or fine powder of sodium hydrogencarbonate, ammonium carbonate, sodium hydroxide or the like at room temperature, stirring for 5 to 30 minutes, and freeze-drying the poly (γ-glutamic acid). It is produced by obtaining a powder of (γ-glutamic acid) salt. The poly (γ-glutamic acid) salt in the present invention is usually 5,000,000 (g / mo).
l) Those having the following average molecular weight are preferred. This is because those having a higher molecular weight are difficult to produce and are not practical.

The compound having a site capable of hydrogen bonding to form a poly (γ-glutamic acid) salt complex used in the present invention includes a carboxy anion of a poly (γ-glutamic acid) salt in an aqueous solution or an aqueous solution. COO
^-) of long as it can bind via hydrogen bonds to at least a portion, any compound can be used. As such a compound, chitosan, its carboxymethyl derivative, hydroxyethyl derivative, and O-acyl derivative are preferable.

Since chitosan has a hemostatic action and an effect of promoting wound healing, chitosan is used as a compound having a hydrogen bondable site for forming a poly (γ-glutamic acid) salt complex of the present invention. Is particularly preferred. Chitosan is a deacetylated product of chitin, and any one produced by any production method can be used. The degree of polymerization and the degree of deacetylation of chitosan affect the solubility and stability of chitosan.The lower the degree of polymerization, the better the solubility, but the strength of the composite membrane tends to decrease, The lower the degree of deacetylation, the lower the reactivity and the lower the solubility. From their nature,
The degree of polymerization and the degree of deacetylation of chitosan are appropriately selected.

In order to prepare a complex comprising a poly (γ-glutamic acid) salt and a compound having a site capable of hydrogen bonding to a carboxy anion of the poly (γ-glutamic acid) salt used in the present invention, for example, disinfection is performed. Agents, antibacterial agents such as antibiotics, actosin, prostaglandin E1 (PGE
1) and other blood circulation improving agents, steroids, anti-inflammatory analgesics such as indomethacin, transforming factors (TCFβ), growth factors such as platelet-derived growth factor (PDCF), fibroblast growth factor (FGF), urinastatin, metalloproteinases Enzyme inhibitors such as tissue inhibitory factor (TIMP), bone cell growth factors such as osteoinductive factor (BMP) and parathyroid hormone (PTH), interleukin 1 (IL-1) inhibitor, bone resorption such as bisphosphonate and calcitonin Inhibitors, drugs such as neocarzinostatin, anti-cancer drugs such as adriamycin, and inflammatory drugs such as steroids and non-steroidal anti-inflammatory drugs may be included in the complex, for example, as reported by Tomita et al. (H. Tomita et al. Chem. Pharm. Bull., 42, 979-981.
(1994)) can be used.

The ratio of the poly (γ-glutamic acid) salt used in the present invention and the compound having a site capable of hydrogen bonding to the carboxy anion of the poly (γ-glutamic acid) salt is based on the poly (γ-glutamic acid) salt. The proportion of the compound having a site capable of hydrogen bonding to the carboxy anion of the poly (γ-glutamic acid) salt is selected in the range of 3 to 97% by weight, and is appropriately used depending on medical applications. If this ratio is out of the above range, it will be difficult to form a complex from the viewpoint of ion pair balance.

The medical material of the present invention includes a surgical suture, a wound covering material, an adhesion preventing material, a hemostatic material, an artificial bone filling material, a splint for vascular anastomosis, a soft tissue prosthetic material, an absorbable membrane, an artificial blood vessel, and a splint for intestinal anastomosis. , An artificial ligament, an artificial bladder and the like. The surgical suture of the present invention is a poly (γ-glutamic acid) salt composite comprising a poly (γ-glutamic acid) salt and a compound having a site capable of hydrogen bonding to a carboxy anion of the poly (γ-glutamic acid) salt. It can be used as a suture obtained by spinning the body. As a means for spinning, a known method, for example, any of a wet forming method, a dry-wet forming method, and a dry forming method as described in JP-A-7-138364 can be used.

[0021] The wound dressing, adhesion preventing material and hemostatic material of the present invention comprise a poly (γ-glutamic acid) salt and the poly (γ-glutamic acid) salt.
A poly (γ-glutamic acid) salt complex composed of a compound having a site capable of hydrogen bonding to the carboxy anion of the glutamic acid) salt can be used as a sheet-formed film. As a means for forming the sheet, a known method, for example, any of a wet forming method, a dry-wet forming method, and a dry forming method as described in JP-A-7-138364 can be used.

The complex may be spray-applied to the affected part in the form of powder or hydrogel. Since the complex is insoluble in water, it has the property of forming a hydrogel. The actual operation is performed by a known method, for example, the method of Sakiyama et al. (T. Sakiy
ama et al. J. Appl. Polym. Sci., 50, 2021-2025 (199
3)) and so on. In order to increase the strength of the gel, the gel may be further cross-linked by a cross-linking reagent or irradiation with radiation.

[0023]

EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples. Example 1 Preparation of Medical Material Consisting of Poly (γ-glutamic acid) Salt Complex [Preparation of Poly (γ-glutamic acid) Salt] Poly (γ-glutamic acid) (hereinafter abbreviated as “γPGA”; manufactured by Meiji Seika Co., Ltd.) 1 After dissolving 0.3 g in 50 ml of water, 0.84 g of sodium hydrogen carbonate was added at room temperature and 25 ° C. After stirring for 60 minutes, a powder of poly (γ-glutamic acid) sodium salt (γPGANa) was obtained by freeze-drying. [Preparation of chitosan quaternary amine] A quaternary amine salt was obtained by dissolving 0.16 g of chitosan (manufactured by Wako Pure Chemical Industries, Ltd.) in 10 ml of a 60% diluted formic acid solution. [Preparation of poly (γ-glutamic acid) salt complex] The aqueous solution of sodium poly (γ-glutamic acid) obtained as described above was added to the solution of the quaternary amine salt of chitosan obtained as described above at room temperature. While stirring at a molar ratio of poly (γ-glutamic acid) sodium salt to chitosanamine (0:10
(0, 25:75, 50:50, 100: 0) and mixed to adjust the solution to a total concentration of 2%. [Formation of Medical Material Consisting of Poly (γ-glutamic acid) Salt Complex] The obtained poly (γ-glutamic acid) salt complex solution was evaporated at room temperature for 48 hours by a film casting method to obtain a film (thickness: 100 μm). Could be obtained. Example 2 Bioabsorbability Test of Poly (γ-glutamic acid) Salt Complex The test animals were group A to F composed of 7-week-old Crj: CD (SD) male rats, each of which was 5 animals. Under the anesthesia of Nembutal 35 mg / kg (ip), the skin near the scapula was incised along the median line under anesthesia of 35 mg / kg (ip) of these rats whose back was shaved with a hair clipper. Film fragments (Group A is γPG
A, group B was embedded with chitosan, group C was embedded with γPGA-chitosan (25:75), and groups D, E and F were embedded with γPGA-chitosan (50:50), and the incised portions were sewn.

Each animal was reopened 14 days after the A group, 28 days after the E group, and 84 days after the F group, and the presence or absence of the fragments was examined. The residual ratio was calculated by removing the fragments and measuring the weight. Table 1 shows the results.

[0025]

[Table 1]

As is apparent from the results, the composite comprising a poly (γ-glutamic acid) salt and a compound having a site capable of hydrogen bonding to the carboxy anion of the poly (γ-glutamic acid) salt has a mixing ratio of It has been found that it is possible to control the biocompatibility and bioabsorbability by changing. By using this composite, a surgical suture that is excellent in biocompatibility, has high nodule retention, and is flexible and easy to ligate, or a wound that excels in flexibility, adhesion, moisture permeability and antibacterial properties and promotes wound healing Coating material, anti-adhesive material that has no allergic effects, has appropriate biocompatibility that can control degradation in the living body, prevents adhesion of the affected area after surgical damage, etc., and prevents bleeding of internal organs caused by damage Medical materials such as hemostatic materials to be blocked can be created. Example 3 Preparation of Surgical Suture 1.4 g of γPGANA and 5 cm ^{3 of} chitosan respectively
Of formic acid, mixed at a ratio of 1: 3, and centrifuged to remove bubbles to obtain a spinning solution. Spinning was performed by wet spinning.
That is, 0.21mmφ in a coagulation bath of 100% ethanol.
The yarn was extruded with a × 28 hole nozzle, and the obtained yarn was dried in a relaxed state. After drying, it was stored in 70% ethanol. Six fiber bundles were used as core yarns, and 12 fiber bundles were used as sheath yarns to prepare a suture having a diameter of 0.6 mm. This suture was excellent in flexibility, the knot holding force was 3.8 g / d, and the ligated part did not slide. Example 4 Bioabsorbability Test of Surgical Suture The obtained suture was cut into the back of an experimental rat and implanted subcutaneously, sutured, and observed 84 days later. Both the sutured thread and the thread implanted under the skin were absorbed and no presence was observed. Example 5 Wound dressing In the same manner as in Example 1, γPGA-chitosan (25:75)
A film (210 μm thick) was made to obtain a wound dressing.

A 75-year-old male patient who had suffered a pressure ulcer in the sacrum and became paralyzed and bedridden due to brain damage was treated using this film. The wound at the start of treatment is 5c
It had an ellipse diameter of mx 9 cm and a depth reaching the muscle. For treatment, the affected area was thoroughly washed and sterilized with a local gauze dipped in oxyur, and then the film was lightly pressed onto the wound surface. Gauze was applied from above and fixed with adhesive tape. Exchanges were performed every two days, and treatment was performed as in the first case.
As a result, the formation of good-quality granulation was observed from about one week, and it became better with the passage of days, and the area of the wound shrank. After 7 weeks, the wound was completely closed and healed completely. Example 6 Preparation of Poly (γ-glutamic acid) Salt Complex in Gel State Chitosan and 0.2 g of γPGANa were dissolved in 4.8 g of a 1% acetic acid solution and distilled water, respectively. N for each solution
aCl was added to 5%. Chitosan and γPGA
Was mixed in hot water so that the ratio became 25:75, centrifuged for 30 minutes to remove bubbles, and left at 5 ° C for 1 day. Thereafter, the gel was immersed in distilled water and desalted for 5 days. Example 7 Anti-adhesion experiment As test animals, 10 female New Zealand rabbits that gave birth to a plurality of offspring having a body weight of 3.5 kg or more were used. The rabbits were experimentally injured with a series of notch incisions made by tearing the mucous membrane into the serosal and muscular layers of the uterine horn extending into the endometrium recess. Five of the mice were covered with the layer of the gel prepared in Example 6, and the other five groups closed their abdomen. Thirty days later, laparotomy was performed again, and the state of adhesion was observed. In the group not covered with gel, all had adhesions. On the other hand, no adhesion was observed in the group covered with the gel. Example 8 Visceral Hemorrhage Prevention Experiment When the internal organs such as the gel, liver, pancreas, spleen, and kidney prepared in Example 6 were damaged and bleeding was wrapped or covered, the bleeding was effectively stopped. Worked. Therefore, it was found that the gel of the present invention was effective in preventing adhesion and also in stopping hemostasis.

[0028]

Industrial Applicability The medical material of the present invention has excellent biocompatibility, high knot holding power, and is a soft and easy to ligate surgical suture, or has excellent flexibility, adhesion, moisture permeability and antibacterial properties, and is excellent in wound healing. Wound dressing that promotes, or anti-adhesive material that has no allergic effects, has adequate biocompatibility to control degradation in vivo, and prevents adhesion of the affected area after injury such as surgical injury, and internal organs caused by injury It can be used as a hemostatic material or the like for preventing bleeding.

Claims (5)

[Claims] 1. A poly (γ-glutamic acid) salt comprising a poly (γ-glutamic acid) salt and a compound having a site capable of hydrogen bonding to a carboxy anion of the poly (γ-glutamic acid) salt.
-A medical material comprising a glutamic acid) salt complex. 2. The medical material according to claim 1, which is a surgical suture. 3. The medical material according to claim 1, which is a wound dressing. 4. The medical material according to claim 1, which is an adhesion preventing material. 5. The hemostatic material according to claim 1, wherein the material is a hemostatic material.
The medical material as described.