JPH0592925A - Therapeutic agent for wound - Google Patents

Abstract

PURPOSE:To obtain a curing agent for wounds, closely adhering to wound surfaces and having protective effects without irritancy to the wound surfaces, absorbing an exudate, drying the wound surfaces, preventing wound infection and further direct curing and analgesic effects on the wounds without any side effects on living bodies. CONSTITUTION:A therapeutic agent is composed of chitosan cotton which is an aggregate of filamentous chitosan, (B) chitin, chitosan and derivatives thereof, e.g. carboxymethylated chitin, hydroxyethylated chitin, acetylated chitin or sulfonated chitin or (C) chitin cotton which is an aggregate of filamentous chitin. The therapeutic agent has various advantages as follows. The agent has analgesic effects together with protection on wound surfaces, filling in tissual deficient parts and dead spaces and both properties of a sprinkling agent and a filling agent. Since the therapeutic agent is capable of regulating the number of treatment and amount according to the shape or extent of the wounds at any time, an exudate which is one of wound curing inhibitory factors can be prevented from storing and the therapeutic agent is effective in drying wound surfaces. Furthermore, since the wound surfaces can be observed by direct sight, prognosis can accurately be judged, etc.

Description

Detailed Description of the Invention

[0001]

This invention is obtained from chitin, chitosan, etc. as a raw material, and has an analgesic effect in addition to protection of the wound surface, filling of tissue defect and dead space, and both properties of spraying agent and filler. A wound healing agent comprising:

[0002]

BACKGROUND OF THE INVENTION Not only chitin and chitosan, various therapeutic agents have been developed for the purpose of accelerating wound healing, but also for burn injury, skin removal for skin grafting, skin graft damage, etc. Many materials have been proposed and commercialized as a wound covering protection agent. Wound covering protective agents are classified into those mainly composed of synthetic products and those composed of natural products. Examples of synthetic materials include velvet-like sheets made of nylon fibers and polyester fibers, woven fabrics, polyurethane porous body sheets, crosslinked polyvinyl alcohol porous body sheets, and the like. Meipack, Meiji Pharmaceutical Co., Ltd.), frozen pig skin (trade name Metaskin, Mitsui Pharmaceutical Co., Ltd.),
There is a fibrin film etc.

Recently, a biological dressing derived from a natural product has been attracting attention because of its good affinity to living bodies, and it has been used as a protective agent for skin defect damage. However, these preparations cannot completely fulfill the function as a damage coating protective agent, and their materials, shapes, etc. are still being investigated. Furthermore, the spray agents currently used as wound surface protection agents include dermatol, iodoform, and zinc-fructose starch. These are used for the purpose of covering and protecting the wound surface and promoting healing by drying a moist wound surface by utilizing its astringent action and absorbency.

However, the drug itself does not have a direct healing action or analgesic action, and the use of a large amount thereof may cause damage to the nervous system or digestive system as a side effect.

In addition to these, there are also antibacterial sprays such as francetine powder, but these are mainly for the purpose of sterilizing infectious pathogens or preventing infections, and the effect of protecting the wound surface or drying is not necessarily sufficient. In addition, there is a limitation in the period of use and amount due to hypersensitivity and local irritation.

[0006] As an anti-inflammatory analgesic, there is a pup as an anti-inflammatory analgesic fixative, but it is too irritating for open wounds to be applied.

[0007] As a botanical anti-inflammatory agent, there is melilot extract which is a therapeutic agent for soft tissue swelling, but it has been recognized that it has side effects on the circulatory system, gastrointestinal tract and the like.

Furthermore, the conventional wound healing agents are intended to remove factors that inhibit the wound healing mechanism possessed by the living body, and are expected to have an indirect effect on the healing mechanism. On the other hand, not only body surface damage but also in-vivo deep tissue soft tissue deficiency due to abscess or tumor excision requires burial of the in-vivo filler to promote wound healing. However, the in-vivo filler is used only for the purpose of shaping to maintain the shape of a specific soft tissue defect such as artificial breast, artificial nose, or artificial eye. As alternative materials for maintaining the shape, mainly silicone, vinyl chloride, styrofoam and other synthetic compounds are used, but these are simply buried in the living body to physically adjust the shape,
The material itself does not have a wound healing promoting action. At present, little filler has been developed to be embedded in the wound cavity for the purpose of promoting healing for lack of damage to deep soft tissues in vivo, and gelatin sponge (trade name: Sponzel Yamanouchi Pharmaceutical Co., Ltd., slightly as a hemostatic agent has not been developed. Zelfoam Sumitomo / Upjohn) may be used instead, but it is not suitable for large damage that requires filling and burial. In particular, the inner crotch, the lower armpit, the lower jaw, and the like have rough subcutaneous tissue and have important nerves and large blood vessels, which makes it extremely difficult to close the wound cavity by suturing. Conventionally, drainage gauze was inserted and the growth of granulation tissue had to be waited for, and the treatment period was prolonged, and patients (including animals) were extremely burdened.

[0009]

Biological dressings, such as collagen nonwoven fabric and frozen pig skin, which have hitherto been commercially available as a wound covering protective agent against skin deficiency damage,
It is not always sufficient as a wound covering protection agent. One of the drawbacks is that the adhesion to the wound surface is not sufficient. In general, a covering / protecting agent is required to have some artificial skin-like function even if its function is not perfect. That is, it is preferable that the protective agent works integrally with the wound surface during the treatment to promote healing. If the adhesion of the protective agent to the wound surface is poor, a large amount of exudate accumulates on the affected area interface, which delays drying and eventually delays epidermal formation. Secondly, there is a drawback that the protective agent is easily decomposed early by the exudate. This not only loses the function as a protective agent, but also causes external infection, resulting in insufficient epidermal formation. Thirdly, the ability to move the exudate generated on the wound surface to the outside is also small, and the exudate is likely to accumulate in the affected area, which is a cause of delaying healing of the wound surface. Fourthly, there is no suitable method for immobilizing the wound-covering protective agent on the wound, and it is easy to detach from the wound and acts as a protective agent.
The effect cannot be said to be efficient. Therefore, there has been a long-felt demand for the development of a protective agent which is a biological material and which has improved the above-mentioned drawbacks.

Chitin and chitosan fibers are biological materials,
It is expected that a nonwoven fabric, a woven fabric, a knitted fabric or the like made of the same will be preferable as a wound surface protection agent and a wound healing promoter, since it has excellent affinity with the living body. However,
The sheet composed of chitin and chitosan has not always been a superior wound-covering protective agent or wound-healing accelerator as compared with the conventional biotechnology dressing. For example, non-woven fabric composed of chitin and chitosan fiber,
When a sheet or the like is brought into contact with the wound, it has a drawback that it stimulates the contact surface of the wound and produces a large amount of exudate. As described above, there is still room for improvement in the shape of the preparation and the like for the clinical application of chitin and chitosan.

On the other hand, the application of the spray agent for skin damage or the like is simple in the treatment method and has a very wide range of application, but it is problematic in terms of immobilization on the wound surface, adhesion, prevention of infection or side effects due to large-scale use. Is also pointed out.

Wound therapeutic agents for wounds include (1)
No irritation on the wound surface, (2) having a protective effect by closely adhering to the wound surface, (3) absorbing exudate and drying the wound surface, (4) preventing wound infection, (5) Having direct wound healing and analgesic effects,
(6) It is desired to have, for example, no side effects on the living body.

[0013]

Means for Solving the Problems The inventors of the present invention can solve the conventional drawbacks by using chitin, chitosan and their derivatives to effectively utilize their characteristics, and can solve the above problems (1) to (). The present invention has been completed by finding that a wound healing agent having the action and effect of the item 6) can be obtained.
That is, the present invention provides a wound healing agent comprising chitosan cotton which is an aggregate of filamentous chitosan, a wound healing agent comprising chitin, a sponge-like processed product of chitosan and a derivative thereof, and chitin cotton which is an aggregate of filamentous chitin. The present invention provides a wound healing agent consisting of

[0014]

The wound treatment agent of the present invention will be described in detail below. The chitin used in the present invention includes N-acetyl-D-glucosamine which is widely distributed in nature and is contained in crustaceans such as shrimp and crabs, insects such as grasshoppers and beetles, and squid shells. Is a polysaccharide
It has a structure similar to that of cellulose. As can be inferred from such a structure, chitin is chemically stable and does not react with most reagents under mild conditions. Further, until now, no suitable solvent for dissolving chitin under mild conditions has been found, so that chitin is extremely difficult to handle, and therefore it is rarely used. However, in recent years, it has been proposed that an antitumor agent containing chitin as an active ingredient has excellent antitumor activity (for example, Japanese Patent Publication No. 59-27826).

Further, chitin and its derivatives have high lysozyme acceptability, excellent in vivo digestibility, biocompatibility, good compatibility at the cell level, and high permeability to medium-molecular weight substances in serum, It is expected that it has a large adsorption ability for blood components such as serum proteins, and that it becomes more immunogenic as the deacetylation of chitin progresses. Furthermore, it is also known that chitin having a deacetylation degree of 70% exhibits the highest macrophage activating ability.

In the present invention, chitin has a degree of deacetylation of 50 in addition to chitin obtained by purifying from natural products.
It also contains chitin within%. Also included are various chitin derivatives obtained by chemically modifying chitin. Examples of the chitin derivative include carboxymethylated chitin, etherified chitin such as hydroxyethylated chitin, acetylated chitin, and sulfonated chitin. Examples of the esterified product include carboxylic acids such as formic acid, acetic acid, propionic acid, oxalic acid, valeric acid, isopropionic acid, isocapric acid, isovaleric acid, benzoic acid, cinnamic acid, salicylic acid, anthranilic acid, and phthalic acid. Examples thereof include sulfonic acids such as sulfuric acid, toluenesulfonic acid, and sulfanilic acid, and carbonates, or esterified products of their anhydrides.

Chitosan obtained by deacetylating chitin is described in JP-A-56-26049, JP-A-59-88424,
It has been proposed in JP-A-62-170254, etc. that chitosan has an effect as a healing promoter for wounds. Furthermore, the chitosan thin film has the property of permeating water and low molecular weight substances,
It has a good affinity with living tissues, does not cause tissue reaction,
It has performance as a biomaterial and is being applied to microcapsule materials, dialysis membranes, artificial organs, surgical materials, vascular reinforcing materials, and the like.

The method of treatment with a wound healing agent containing chitin and chitosan as a main component of the present invention allows the treatment method (the number of treatments and the amount) to be adjusted at any time depending on the shape and degree of the wound. That is, it has many advantages such as preventing the storage of exudate, which is effective for drying the wound surface, and being capable of observing the wound surface under direct vision so that accurate prognosis can be made.

Chitin and chitosan have an extremely excellent granulation tissue-promoting action by themselves, and have a direct promoting effect on healing mechanism. This is an action not seen in conventional wound healing agents, and is the most significant feature of chitin and chitosan as wound healing agents. Also, due to its bactericidal action, local anti-inflammatory, analgesic action, necrotic tissue melting / absorption action, etc.,
The ability to remove multiple wound healing mechanism inhibitors is also a major feature. In addition, it is biocompatible and non-toxic, non-irritating, cotton-like, flaky,
Since chitin and chitosan prepared in sponge form can be used directly, their application range is extremely wide and effective compared with conventional wound healing agents.

[0020]

EXAMPLES Next, the wound healing agent of the present invention will be described in detail with reference to Examples. (1) Production of chitosan cotton: Chitosan yarn obtained by spinning chitosan is hydrothermally heated overnight (60-90 ° C.).
After washing for 2 to 7 hours with water, it is immersed in a volatile solvent having a high affinity for water such as methanol, ethanol, and acetone for one day or more. A cotton-like processed product of chitosan is obtained by treating the yarn cut to a length of about 1 to 4 cm with a mixer and then drying it. The resulting chitosan cotton fibers have a length of 2-20.
mm, width 20-50μm, thickness 3-15μm, apparent specific gravity 0.01
It was -0.2 g / cc.

Example 1: 200 g of chitosan (Flownac C, particle size 50-60 μm) manufactured by Kyowa Yushi Kogyo Co., Ltd. was dissolved with stirring in water-acetic acid mixed water (23: 1 volume ratio) and added twice. After performing pressure filtration (1-2 kg / cm2), the mixture is left overnight to defoam. This stock solution was extruded into a solution prepared by mixing 10 liters of ethylene glycol, 1.5 kg of ice and 1.8 kg of potassium hydroxide through a nozzle of 0.1 mm × 500 holes, and after spinning, it was mixed in a methanol-water (1: 1) mixed solution. After further coagulation, the yarn stretched 1.15 times in air was washed with running water overnight and treated with hot water at 70-80 ° C for 3-5 hours.
Soak in methanol for one day or more, wind on a skein machine and let it dry naturally. The obtained chitosan yarn was cut into 1-2 cm and then treated with a mixer to obtain a cotton-like processed product of chitosan. The apparent specific gravity of the obtained chitosan cotton was 0.026 g / cc, and the fiber had a length of 9 mm, a width of 26 μm, and a thickness of 9 μm.

Example 2: A chitosan yarn spun under the same conditions as in Example 1 is wound on a bobbin and washed with running water overnight.
Further, after washing with hot water at 70-80 ° C for 3-5 hours, it is immersed in methanol for one day or more. Remove the thread from the bobbin and cut it to a length of about 2 cm. The cut yarn is processed with a mixer.

Table 1 shows the results of animal experiments using the chitosan cotton produced in Example 1 above. The determination of the therapeutic effect in Table 1 is as follows. +: Very well cured. ±: Storage and outflow of viscous bloody exudate were observed after surgery, but there was no macroscopic inflammatory image and granulation tissue increased. -: Those that had no effect.

[0024]

[Table 1]

As shown in Table 1, chitosan cotton was mainly used as a wound healing agent by filling wounds and surgical wounds. The breakdown is 2 dogs, 8 cats, 8 cows, and 1 horse, for a total of 19 cases. The application effect was 17/19 in which a good reaction was observed, and no tissue reaction was observed in one case of cat contusion (No. 9). However, in this one case, the peripheral artery was torn due to the severe tissue damage due to the traffic accident and the physical rotation of the affected area due to the dislocation of the phalanx, and the blood circulation in the affected area was blocked. As a case in good contrast with this case, the No. 5 cat had severe tissue damage due to a traffic accident and fracture of the metacarpal bone, but blood circulation to the fingertip was opposite to the damaged site. , And showed a very good reaction to chitosan cotton. In addition, when the crushed site of No. 9 was dismembered and a fresh wound was filled with chitosan cotton, the wound showed good healing. From the above, the application of this drug requires the presence of blood circulation, and the regeneration of dead tissues cannot be expected.

For the dehiscence of the sutured wound due to infection of the surgical wound, this product was filled in 3 cases (No. 12 to 14), and the effect was remarkable in cats. This effect was also seen in cattle and horses, and the body surface abscess of dairy cows, which had been hardly treated until now, was completely cured by one dose of this product. Furthermore, hoof ulcers of dairy cows were completely cured by filling and compressing this product once. One of the horses is malignant chronic dermatitis, which is a disease that is not expected to be cured as it is also called hoof cancer. However, it will be extremely severe from the next day due to surgical excision of the affected area and filling pressure of this drug into the defective area. Good landing gait was seen, and no subsequent recurrence was observed, and he could be cured completely. In addition, after healing, neither hardening nor dysfunction due to scar formation in the affected area was observed in any of the cases. As described above, the wound treatment agent of the present invention causes good tissue repairing power in dogs, cats, cows, and horses by applying it to the affected area once to several times, and it is possible to treat chronic diseases that have been considered incurable until now. Since it was completely cured, it is considered to be a therapeutic agent having a surprising ability.

(2) Production of sponge-like processed product consisting of chitin, chitosan and derivatives thereof: chitin, chitosan and derivatives thereof or water-soluble polymers such as polyvinyl alcohol, polyacrylamide, starch and gelatin added thereto Then, the mixture is treated with a mixer for 0.5-2 hours to obtain a dispersion of 0.1-5% (w / v). The dispersion alone or a composite consisting of felt, sponge-like polyester, polyurethane and the prepared dispersion is frozen at -10 to -40 ° C. This was freeze-dried to obtain a sponge containing chitin, chitosan and their derivatives.

Example 1 A 1.5% (w / v) aqueous dispersion of squid chitin is prepared using a mixer. A chitin sponge was obtained by putting 5.5 ml of the prepared dispersion liquid in a polystyrene petri dish (φ40 mm, H5 mm), freezing at -20 ° C., and freeze-drying overnight.

Example 2 A 2% (w / v) aqueous dispersion of squid chitin is prepared using a mixer. Cut the felt into a circle with a diameter of 5 cm and place it on the bottom of a glass container. Add 15 ml of the dispersion to the felt and freeze at -20 ° C. Overlay the felt on top of the frozen felt,
Impregnate 15 ml of the dispersion and freeze again at -20 ° C. This was freeze-dried all day and night to obtain a chitin sponge.

Table 2 shows the results of animal experiments using the chitin sponge prepared in Example 1 above. The determination of the therapeutic effect in Table 2 is the same as that described in Table 1 above.

[0031]

[Table 2]

As shown in Table 2, chitin sponge was mainly used for 7 infected wounds. The breakdown is 3 dogs and 3 cats.
An example and a cow example. The effect of application was confirmed on 6/7, and the effect was uncertain in one case of dehiscence of the skin suture wound due to infection of the surgical wound. In this case, several subcutaneously embedded sutures remained after the re-operation, and it was considered that good granulation did not occur because this thread was a non-absorbable thread.

Topical filling of this drug was performed on 2 cases (No. 1 and No. 7) of periodontal disease in dogs, and good granulation was observed and complete healing was achieved. In addition, good tissue repair was also observed when bovine arthritis (No. 5) was filled with this drug. No.2 ~
With regard to the trauma of No. 4, extremely good therapeutic mechanism was obtained by filling the drug with this drug once to several times. As described above, it can be expected to be an ideal wound healing agent because it can be expected to be applied to trauma and oral diseases, and no side effects are observed.

Furthermore, the chitin sponge prepared in Example 1 was used in two dogs as shown in Table 3. One example is filling into a tissue defect portion by castration, and one example is filling between fractures. Both cases were completely cured without any side effects. In particular, it was thought that the promotion of the regenerative power of bone tissue could be expected even for fractures.

[0035]

[Table 3]

(3) Production of chitin cotton: A cotton-like processed product of chitin was produced by crushing chitin threads, granules, or flakes using a crusher. Milling uses hammers and liners of various shapes and the number of revolutions is 1,000-
It was performed at 9,000 rpm and a rated current of 20-30A. The obtained chitin cotton has an apparent specific gravity of 0.01-0.3g / cc, length of 0.1-10mm, width of 5-4.
It had a fibrous shape of 00 μm.

Example 1: ACM Pulverizer 10 manufactured by Hosokawa Micron Co., Ltd. was used as a crusher, and 3.6 kg of squid chitin was crushed with a rotation speed of 6,800 rpm, a rated current of 24.2 A, a bar-shaped hammer, and a groove-shaped liner for 25 minutes. I went. The obtained chitin cotton has an apparent specific gravity of 0.05-0.129 g / cc and a length of 200-800 μ.
The width was 10 to 120 μm.

Experiments of local reaction by subcutaneous implantation of the chitin cotton obtained in the above Example 1 were conducted in the following animals. Animal: Dog Breed: Hybrid Age: 2 years

After experimentally creating an abscess with staphylococcus, the affected area was filled with chitin cotton and the clinical course was observed. As a result, pain in the affected area disappeared on the first day after filling, and swelling and redness were also observed by 5 days. Disappeared. General symptoms also improved 3 days after filling.

[0040]

EFFECTS OF THE INVENTION The erosions and ulcers of the skin are exposed at the sensory parts, and the pain is remarkably high. Therefore, a therapeutic agent for wounds which is effective for analgesia and rapid granulation is expected. The wound healing agent of the present invention has no pain at the time of coating, forms a coating that protects the wound, exerts an analgesic effect, and shows vigorous granulation, and normalization of the wound by activation of macrophages peculiar to chitin It is considered that the compound has all the properties as a wound dressing from the viewpoint of cosmetic surgery with almost no unnecessary scar formation.

The cotton-like or sponge-like wound healing agent of the present invention can be applied to any shape of wound cavity,
In addition, the filling amount can be adjusted very easily. When embedded in the wound cavity, there is no macroscopic inflammatory image due to the effect of chitin,
It migrates various cells as a biological defense function, first treats contaminants and necrotic tissue in the wound, stimulates fibroblasts to increase, and at the same time develops vascular system, which is extremely good Leading to the development of various granulation tissue. This activity of fibroblasts and the development of blood vessels naturally enhances the healing of the skin, and in the case of an open wound, although conventional treatments cause rapid atrophy of the skin, most of the application of this drug Atrophy of the skin is not observed and the filling effect in the body is excellent. Furthermore, the granulation formed by this wound healing agent is rich in capillaries, and atrophy of the surrounding skin is unlikely to occur.First, the contaminated wound is cleaned and the wound cavity is narrowed by forming benign granulation by covering or filling. Therefore, it can be expected that a very good curative effect due to the secondary closure will be achieved in cases where temporary closure is difficult. When the wound treatment agent is chitosan cotton or chitin cotton, it is particularly useful for covering the wound from the outside, and when the wound treatment agent is a sponge-like processed product of chitin, chitosan or a derivative thereof, it is used to remove a tumor. It is especially useful when filling a hole.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Akira Matsuhashi 1-357 Nishi, Koyama-cho, Tottori-shi 357 Tottori University Shirahama Dormitory RA-12 (72) Inventor Minamisaburo 3-251 Kitayama, Koyama-cho, Tottori-shi Koyama Housing RCK3-401 (72) Inventor Shoumon Ota 5-133, Higashi 5-chome, Koyama-cho, Tottori City

Claims (3)

[Claims] 1. A wound healing agent comprising chitosan cotton, which is an aggregate of filamentous chitosan. 2. A wound healing agent comprising a sponge-like processed product of chitin, chitosan and derivatives thereof. 3. A wound healing agent comprising chitin cotton, which is an aggregate of filamentous chitin.