WO2004080502A1

WO2004080502A1 - Antiadhesive material

Info

Publication number: WO2004080502A1
Application number: PCT/JP2004/002938
Authority: WO
Inventors: Tohru Tani; Kazuyoshi Hanazawa; Yoshihiro Tsutamoto; Mitsuhiro Fujino; Seijiro Uchiyama; Noriaki Shirahama; Tomokazu Mukai
Original assignee: Kawasumi Laboratories, Inc.
Priority date: 2003-03-10
Filing date: 2004-03-08
Publication date: 2004-09-23
Also published as: JPWO2004080502A1; JP4854299B2

Abstract

An antiadhesive material for wounded region, comprising a bioabsorbable polymer as a main component, wherein at least one type of cure accelerating drug is contained. Preferably, the bioabsorbable polymer is constituted of a composition of at least two types of polysaccharides and derivatives thereof, and the bioabsorption of antiadhesive material can be controlled by regulating the component ratio of polysaccharides and derivatives thereof in the composition. This antiadhesive material is easily applicable to wounded region of complex configuration or structure, and appropriate absorption and excretion thereof by biotissues can be realized. Thus, antiadhesive effects can be stably exerted over a desired period of time, and infections can be prevented.

Description

TECHNICAL FIELD The present invention relates to a material and a shape of an adhesion preventing material for preventing adhesion in a living body, particularly for preventing adhesion at a wound site. Adhesion is an invasion caused by surgery or other injuries such as injuries, such as injuries (tissue damage), inflammation, etc. to living tissues such as kidney, liver, heart, and stomach, blood vessels, intestine, and uterus. When it occurs, it is a fusion of living tissues that occur between the wound sites or between the wound site and surrounding healthy tissues.

The occurrence of adhesions not only causes pain to the patient over a long period of time, but also causes complications such as dysfunction of the body, and in severe cases, may even require reoperation, so that the patient is mentally and physically ill. It is a serious problem with serious pain. In order to prevent such adhesion, various anti-adhesion materials and their materials have been proposed and attempted.

As the most basic form of currently used anti-adhesion material, the wound site is physically shielded and separated from other living tissues for a period of time until the tissue at the wound site is repaired or healed. Prevention methods are widely adopted. As described above, plastics such as polypropylene, silicon resin, polyurethane, and polytetrafluoroethylene are used as materials for physically shielding and separating living bodies and tissues. However, since these plastic materials are generally non-bioabsorbable polymer materials, they remain in living tissues for a long time, not only delaying the repair of tissues but also causing infectious diseases and inflammation. Become. Also, it must ultimately be separated from the wound site and, if fused to the tissue, the separation will cause considerable pain to the patient.

For this reason, attempts have been made to use a bioabsorbable polymer that is decomposed in the body and absorbed into the living body as an adhesion preventing material.

For example, aqueous solutions of natural polysaccharides such as sodium alginate and hyaluronic acid are mainly used. An intraperitoneal adhesion preventing material is known as an agent (see, for example, JP-A-57-169919). The aqueous adhesion preventive material can be easily applied to the affected area, for example, by applying it to a wound site or injecting it into the abdominal cavity, but since it is an aqueous solution, it is quickly absorbed and excreted by the living body. It has the drawback that it cannot be used for injuries that are slow to heal because of its short duration, which can only be expected to have a short-term anti-adhesion effect (shielding effect).

The anti-adhesion material made of such a low-viscosity aqueous solution is based on the idea of maintaining a gap between organs and obtaining a shielding effect by filling a large amount of the gap between organs in the abdominal cavity. This is not desirable because it places an excessive burden on patients. Furthermore, since the low-viscosity aqueous solution filled into the abdominal cavity is filled in large amounts around the wound, it naturally enters the site where tissue should be regenerated and adhered quickly, such as the suture. However, there is a risk of adverse effects such as incomplete sutures.

In order to improve such a defect, it has been proposed to use an anti-adhesion material mainly composed of a low-viscosity aqueous solution of hyaluronic acid as a crosslinked gel (for example, see Japanese Patent Application Laid-Open No. 60-23448). See No. 6.) However, since such a crosslinked gel is crosslinked in the presence of a catalyst with a polyfunctional epoxide such as 1,4-butanediol diglycidyl ether (BDDE), for example, the crosslinked gel contains There is a possibility that the cross-linking agent and catalyst may remain, and there is a question as to whether high safety is maintained.Complete removal of the cross-linking agent etc. requires a complicated process. There's a problem.

On the other hand, as an anti-adhesion material composed of a bioabsorbable polymer used in the form of a molded body other than an aqueous solution, an anti-adhesion material mainly composed of chitin or chitosan (see, for example, Japanese Patent No. 2948852). ), Polylactic acid, polyglycolic acid, polyfunctional prolactone (or lactate / glycolic acid copolymer, lactic acid / glycolic acid / force prolactone copolymer, etc.) Copolymers) (see, for example, Japanese Patent Application Laid-Open No. 2001-192,337 and Japanese Patent Application Laid-Open No. Hei 4-2,827) have been proposed. It is said that they can be used in any form such as fiber, film, tube, etc., but most preferably, they are intended to be used in the form of a film. Examples of the use of these film-shaped adhesion preventive materials include, for example, laparoscopic surgery on digestive organs such as the stomach, small intestine, large intestine, esophagus, and rectum, and then rounding the film-shaped adhesion preventive material It is made into a tubular shape, and this is put into the abdominal cavity from the port and used. In addition, during general anesthesia, laparotomy, gastrointestinal surgery, hepatectomy, inguinal hernia, gynecological ovariectomy, uterine fibroid nucleus removal, etc. It can be applied and adhered and adhered to the wound site, and can exhibit a certain degree of adhesion prevention effect.

However, in the case where the wound site is not simple and the wound site has a complicated shape or is used under laparoscopic surgery, various problems occur with the film-shaped adhesion preventing material formed of the conventional material as described above. In other words, the film may break when contacting the body fluid inside the living body and forming a hydrated gel at the same time as a lump, or during various attempts to adhere the film in order to adapt it to a wound part with a complicated shape. In some cases, the shape could not be recovered due to folding. In addition, operability is not always good because air may remain in the gap. Furthermore, even if the patient can be safely attached to the wound site, the patient may subsequently move out of the wound site as the patient moves. Moreover, in some cases, these adhesion preventing materials have a higher decomposition rate than desired, so they disappear before the wound site is completely healed, causing a problem that the adhesion preventing ability is interrupted.

In addition, infectious diseases are a common problem for patients when applying conventional anti-adhesion materials. In other words, wounds that result from surgery, injuries, or other reasons cause the patient's physical strength to be significantly reduced, so that infections can often be easily caused by resident bacteria present in the body. . In particular, infections from the anastomotic intestinal tract in the abdominal gastroenterology are becoming a major problem. Thus, the use of an anti-adhesion material causes various dysfunctions due to infectious diseases, and in some cases, necessitates reoperation.

Thus, an object of the present invention is to solve the problems associated with conventional anti-adhesion materials, to be easily applied to wounds having complicated shapes and structures, and to be appropriately absorbed and excreted by living tissue, and Therefore, by providing a stable anti-adhesion effect for a desired period of time and providing a biologically safe anti-adhesion material for preventing infectious diseases. is there.

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According to the present invention, the following inventions are provided.

(1) An anti-adhesion material for a wound site comprising a bioabsorbable polymer as a main component, wherein the anti-adhesion material contains at least one kind of healing-promoting agent. Wood.

(2) The adhesion preventing material according to (1), wherein the bioabsorbable polymer is in the form of a gel, a solid, or a granule, and is easily deformable according to the shape of a wound site.

(3) The gel or solid bioabsorbable polymer has a viscosity of 0.1 to 500,000 Pas when dried or swelled with water, a Young's modulus at 25 ° C of 1 to 40 MPa, and an average molecular weight of 100. ~; The adhesion preventing material according to (1) or (2), which is L000000.

(4) The gel-like bioabsorbable polymer, a viscosity 0.:!~ ⁵ 00000Pa · s, 18 gate - by di smaller injection needle, to be injected into the wound site (1) to (3) The anti-adhesion agent according to any one of the above.

(5) the particulate bioabsorbable polymer has an average particle size of i to ² ooo / m, complex wound wound site can easily be covered (1) or anti-adhesion material according to (2).

(6) The anti-adhesion material according to any one of (1) to (5), wherein the gel-like or particulate bioabsorbable polymer is injectable into a wound site from a very small space.

(7) The bioabsorbable polymer comprises a composition of at least two or more types of polysaccharides and derivatives thereof, and adjusts the composition ratio of the polysaccharides and derivatives thereof in the composition to obtain a bioabsorbable polymer. The adhesion preventing material according to claim 1, wherein the adhesion preventing material can be controlled.

(8) The adhesion preventing material according to (7), wherein the adhesion preventing material is in the form of a film or a gel, and is deformable according to the shape of the wound site.

(9) The anti-adhesion material according to (7) or (8), wherein the film-like anti-adhesion material has a rigidity when dried of from 0 to 1: LOOOOmN.

(10) The adhesion preventing material according to any one of (7) to (9), wherein the film-like adhesion preventing material has an adhesion strength of 2 gf / cm ² or more.

(11) The gel-like anti-adhesion material has a viscosity at the time of drying or swelling with water. 0.1 or more: The adhesion preventing material according to (7) or (8), which is! OOOOOPa.s.

(12) The anti-adhesion material according to any one of (7) to (11), wherein at least one of the polysaccharide and its derivative forming the composition is pullulan and its derivative.

(13) The adhesion preventing material according to any one of (1) to (12), wherein the gel, solid, granular, or film-like adhesion preventing material is decomposed and absorbed in vivo within 3 months.

(14) The adhesion preventive material according to any one of (1) to (13), which contains 0.001 to 10 parts by mass of a healing-promoting agent based on 100 parts by mass of the bioabsorbable polymer.

(15) The healing promoting agent is at least one selected from the group consisting of an antibacterial agent, an antibiotic, an anti-inflammatory agent, an anti-adhesion agent, a pile cancer agent, and a disinfectant (1) to

(14) The adhesion preventing material according to any one of (1) and (2).

Invention The most self-shaped bear for skewering

Hereinafter, the best mode for carrying out the present invention will be described in detail.

The anti-adhesion material of the present invention contains a bioabsorbable polymer as a main component and contains at least one kind of a drug for promoting healing.

'(Bioabsorbable polymer)' '

The bioabsorbable polymer in the present invention is absorbed into a living body, is easily hydrolyzed or enzymatically decomposed therein, and its decomposition products are finally metabolized into carbon dioxide gas and water and excreted outside the body. It is a polymer.

The bioabsorbable polymer which is a main component of the adhesion preventive material of the present invention is not particularly limited. For example, lactic acid, glycolic acid, ε-force prolactone, or the like is a polymer having a polymerized unit. A bioabsorbable polymer composed of a union or a copolymer, or a bioabsorbable polymer containing hyalponic acid / alginic acid as a main component is preferably used.

The bioabsorbable polymer having lactic acid, glycolic acid, or one-pot prolactone as a polymer unit is a hydrolyzable bioabsorbable polymer, for example, polylactic acid, polyglycolic acid, polyprolactone, Lactic acid / glycolic acid binary copolymer, lactic acid / dalicholic acid / ε-force prolactone terpolymer and the like are mentioned as good examples.

The bioabsorbable polymer containing hyaluronic acid-alginic acid as a main component is itself an enzyme-degradable bioabsorbable polymer. For example, hyaluronic acid alone, hyaluronic acid A good example is a copolymer of lonic acid and carboxymethylcellulose. As the bioabsorbable polymer containing alginic acid as a main component, for example, alginic acid alone is preferable.

In addition, it may be an enzymatically degradable bioabsorbable polymer mainly composed of collagen, atherocollagen (collagen is made to be water-soluble by protease treatment), gelatin and the like.

(Water-swellable bioabsorbable polymer)

The bioabsorbable polymer, which is the main component of the adhesion preventing material of the present invention, can be used as a solid, for example, as a particle, depending on the shape of the wound site. The polymer can also be used in the form of a swollen gel. The gel, solid, or granular form of the bioabsorbable polymer can be selected by adjusting the molecular weight.

The water-swellable bioabsorbable polymer includes a water-soluble polymer and a water-insoluble polymer, but in the present invention, a water-insoluble polymer is preferable. The water-swellable bioabsorbable polymer is formed into a gel or a solid, and can be applied to a wound site as an adhesion preventing material in this form. '

Examples of the water-swellable bioabsorbable polymer include, but are not particularly limited to, polysaccharides such as the aforementioned hyaluronic acid, alginic acid, and chitosan; protein such as gelatin; and lactic acid / glycolic acid / £ -force prolactone terpolymer (below

It may be referred to as “LA / GA / £ -CLT copolymer”. ) Is a good example.

When the LAZG A / £-CLT copolymer is used as an anti-adhesion material by using it as a water-swellable bioabsorbable polymer, that is, in obtaining a gel-like anti-adhesion material, This is to reduce the molecular weight of the bioabsorbable polymer from that in the case of a solid. For example, a gel-like adhesion preventing material preferably has a molecular weight of 10 to 20,000. On the other hand, in the case of a solid (granular) adhesion preventing material, the molar ratio of the LA / GA / e-CLT copolymer is (3 to 75) / (5 to 90) / (5 to 40) , Molecular weight 20000-

The thing of 300000 is usually used.

The molar ratio (or compounding ratio) and molecular weight of the terpolymer in the present invention are gel viscosity, It can be set as appropriate depending on the biodegradability, etc., and is not limited to the above-described range and those described in Examples below. In addition, from the viewpoint of ease of production, it is preferable that the terpolymer has a higher molar content of glycolic acid, but it can be appropriately changed depending on the application conditions, and is limited to this molar content. It is not done.

(Physical properties of gel-like bioabsorbable polymer)

The water-swellable bioabsorbable polymer has a viscosity of 0.1 to 500,000 Pas when dried or swelled with water, a Young's modulus at 25 ° G of 1 to 40 MPa, and an average molecular weight of 100 to 1000000, preferably. It is preferable to use those having a swelling ratio of 5 to 50,000%, preferably 20 to 20,000%, from 100 to L00000. The average molecular weight in the present invention means a molar average molecular weight Mn measured by GPC.

In the gel-like anti-adhesion material, the lower the viscosity of the swollen gel, the easier it is to inject the gel, but if it is too low and less than O.lPa ■ s, the anti-adhesion material easily flows out Or it is absorbed into the body very quickly and cannot remain at the wound site for a sufficient time. On the other hand, when the viscosity of the swelling gel is too high and exceeds 500,000 Pa-s, the swelling gel is too hard, which is not preferable because the wound may be damaged. '

If the Young's modulus of the swelling gel is too small and less than lMPa, the gel is too soft, on the contrary too high, and if it exceeds 40MPa, the gel is too hard. It is not preferable because the injection operation becomes difficult.

In the case of a swollen gel, if the swelling ratio is too small and less than 5%, after the gel is brought into close contact with the wound site, the gel moves with the patient's movement and is not fixed to the wound site. There is a risk of deviation from the wound site. If the swelling ratio of the gel is too high and exceeds 50,000%, the operation of injecting the anti-adhesion material into a living body may cause the anti-adhesion material to come into contact with bodily fluids, and at the same time, the whole may rapidly become hydrogel. Therefore, a serious problem occurs in the operability, which is not preferable.

The average molecular weight of the bioabsorbable polymer in the present invention is generally 100 to 1,000,000, preferably 300 to 500,000. If the molecular weight is too small and less than 100, the macromolecule will decompose and disappear before the wound site is completely cured, so that the function as an anti-adhesion material cannot be sufficiently exhibited, while the average molecular weight is Too big, If it exceeds 1,000,000, it is not preferable because the absorption polymer is extremely decomposed and remains without being decomposed for a long time even after the wound is completely cured. The gel-like bioabsorbable polymer according to the present invention can be injected into a wound site with an injection needle smaller than 18 gauge when the viscosity is 0.1 to 500,000 Pa ·.

(Granular bioabsorbable polymer)

Examples of the granular bioabsorbable polymer in the present invention include, for example, polylactic acid, polyglycolic acid, polyp-force prolactone, and the like. The average molecular weight is 1,000 to; l ~ 2000〃m, preferably 1 ~: 1000

.Mu.m, more preferably i-700 .mu.m, and can easily cover even a complicated wound site as shown in Examples below.

The bioabsorbable polymer of the present invention, whether in the form of a solid, gel, or particle, can be injected from a microcavity. In addition, the amount can be adjusted according to the wound site and filling can be performed

(How to use anti-adhesion material)

As an example of a specific method of using the adhesion preventive material of the present invention, as shown in Examples below, for example, laparoscopic surgery on digestive organs such as stomach, small intestine, large intestine, esophagus, and rectum is performed. Thereafter, an anti-adhesion material in the form of a gel having a swelling ratio of 18000%, a viscosity of 2 Pa's at the time of swelling with water, a Young's modulus of 1.5 MPa, and an average molecular weight of 300 is administered intraperitoneally from a port.

After the same operation, an anti-adhesion material in the form of particles having a swelling ratio of 40%, a viscosity at the time of swelling with water of 420,000 Pa's, a Young's ratio of 38 MPa, an average molecular weight of 78,000, and an average particle diameter of 500 m was used. It is administered intraperitoneally from one time.

The above is the basic mode of the adhesion preventive material containing the bioabsorbable polymer of the present invention as a main component. In a more preferred embodiment, the bioabsorbable polymer is at least two or more polysaccharides and A composition of a derivative thereof (hereinafter sometimes referred to as “polysaccharide, etc.”). By adjusting the composition ratio of the polysaccharide, etc. in the composition, bioabsorbability can be improved. It can be controlled according to the mode of use. (Polysaccharides, etc.)

Thus, in a more preferred embodiment of the present invention, a composition is formed by selecting at least two or more types of polysaccharides and derivatives thereof as the bioabsorbable high molecule as a main component. This is because a composition made by mixing several types of polysaccharides has an extremely good anti-adhesion effect due to physical sequestration, a biological adhesion prevention effect, The present inventors have found that, depending on the mixing ratio of polysaccharides, some of them have excellent retention on the tissue surface, and that they can remain in the living body for an arbitrary period of time to exhibit the adhesion-preventing effect. It is based on

Examples of such polysaccharides include simple polysaccharides such as agarose, starch, and pullulan; polyperonic acids such as alginic acid; Polysaccharides (or polyglycosamines) and the like. These polysaccharides and the like may be in the form of a biocompatible salt as a derivative thereof.

As described above, the polysaccharide and the like in the present invention are not particularly limited, and include all those in which the substance itself and its metabolites are harmless to the living body and are absorbed and excreted in the living body. Derivatives of polysaccharides include, for example, salts of alkaline metals such as Na and K, alkaline earth metals such as Ca and Mg, and those in which the hydroxyl group of the polysaccharide is acetylated or esterified and chemically modified. Is mentioned.

(Preferred combinations of polysaccharides etc.)

The polysaccharide used in the present invention exerts its basic action as an adhesion preventive material, that is, a physical isolation action at an affected part (wound site) where adhesion prevention is required, and furthermore, it is effective for a living body. What can control absorptivity is preferable. However, in practice, it is difficult to satisfy all the various requirements as an anti-adhesion material with a single polysaccharide or the like. According to a composition in which two or more polysaccharides having different physical properties such as a degree of water solubility such as poor water solubility, gelling ability, and viscosity, are mixed, the physical properties of the respective polysaccharides constituting the composition, By arbitrarily changing the composition ratio, it is possible to obtain an anti-adhesion material that satisfies various requirements that have been difficult with a single polysaccharide or the like. For example, carrageenan, xanthan gum, alginic acid and its derivatives and mucopolysaccharides, which are poorly water-soluble and generally known as thickeners; have high gelling ability and are known as gelling agents (gel-forming polysaccharides). Agarose, glucomannan, xylo-glucan, 1,3-/-glucan, 1,4-glucan, etc .; water-soluble pullulan, sodium alginate, etc., and any combination of these having different physical properties It is preferable to combine them.

As one preferable example of the combination of two or more kinds of polysaccharides, it is preferable to combine polysaccharides and the like having different solubility in water. In particular, a water-soluble polysaccharide and a poorly water-soluble polysaccharide are particularly preferable. It is preferable to consist of a combination of Depending on the selection and combination of water-soluble and poorly water-soluble polysaccharides and their composition ratio, it is possible to greatly control the absorption in vivo.

In a preferred embodiment, pullulan is selected as a basic component among these polysaccharides and the like, and a composition in which pullulan is combined with other polysaccharides and the like is used. Pullulan is a neutral polysaccharide composed of natural white powder in which maltotriose (having three, four, four glucose molecules bound together) is regularly bound, and is dissolved in water. sticky 'adhesion strong low viscosity (IX 10 one ³ ~ 2 X 10 one ^3: P a' without gelation. to form a s solution also the pullulan aqueous solution, the film-shaped formed resistance, film formability Pullulan has the characteristic that it is possible to form a tough film by the casting method and the coating method. It is applied without restrictions on the use of goods and cosmetics.

Therefore, by using pullulan as a basic conjugate such as a polysaccharide, it is possible to form an anti-adhesion material that is extremely excellent in biocompatibility, coatability and adhesion to a wound site, and retention in a wound site. Can be. For example, as shown in Examples below, a composition in which poorly water-soluble agarose is appropriately blended with easily water-soluble pullulan to appropriately form a film or a film depending on the condition of the wound site, etc. A gel-like adhesion preventing material can be used, and any of them can exhibit a suitable adhesion preventing function. In the case of the composition mainly comprising pullulan, the mass ratio of pullulan to other gel-forming polysaccharides such as agarose is, for example, pullulan / other polysaccharides = (5-95) / (95- Five ) It is about.

(Molecular weight of polysaccharides etc.)

The average molecular weight Mn of the polysaccharide or the like used in the present invention is not particularly limited, and is appropriately selected in consideration of the required biodegradability and absorption depending on the target application site of the adhesion preventing material. Normally, those in the range of ιοοο to ιοοοοοο are preferred.

(Form of anti-adhesion material)

The anti-adhesion material mainly comprising a polysaccharide or the like of the present invention is preferably applied to a wound site as a film or a gel, and can be appropriately deformed according to the shape and conditions of the wound site. Here, the film-shaped or gel-shaped adhesion preventing material can be easily produced by a general or known production method. That is, the film-like adhesion preventing material can be produced as a cast film from an aqueous solution in which a polysaccharide or the like is mixed, for example, by a casting method, or can be produced by a dipping method and a coating method. The gel-like adhesion preventing material can be easily obtained by, for example, adding water or an aqueous medium to the gel-forming polysaccharide to cause gelation. It should be noted that, in addition to the composition composed of polysaccharides and the like, other bioabsorbable polymers such as polylactic acid, polyglycolic acid, and polyprolactone (or lactic acid / glycolic acid copolymer, lactic acid Z glyco A protein such as luic acid / force prolactone copolymer) and gelatin may be added within a range that does not impair the effect of the anti-adhesion material of the present invention. The amount added is 50% or less, preferably 30% or less, more preferably 15% or less, by mass, relative to the polysaccharide or the like.

(Characteristics of film-shaped adhesion preventing material)

The rigidity of the anti-adhesion material when dried in the form of a film formed from a composition such as a polysaccharide is preferably from 0.1 to 10,000 mN · thigh, and more preferably from 10 to: 100 mN · band. If the stiffness of the film is less than O.ImN · mm, the film is too flexible and the operation procedure is complicated, and if the stiffness exceeds lOOOOmN · mm, the flexibility of the film becomes less. It is not preferable because it becomes extremely severe and may damage the tissue at the adjacent site to which the adhesion preventing material is applied. In addition, since there is no flexibility, when the wound site has a complicated shape, it is difficult to adapt the film to the wound site in accordance with the shape. The adhesion of the film-shaped anti-adhesion material can be evaluated by measuring the tensile resistance in a direction parallel to the contact surface when the film comes into contact with an organ in a living body. , 2 gf / cm ² or more, preferably 5 gfZcm ² . With an adhesion strength of less than 2 gf / cm ² , the adhesion preventing material does not adhere well to a wound having a complicated shape and tends to come off.

Although the thickness of the film-shaped adhesion preventing material is not particularly limited, it is usually 1 to 1000 m, preferably io to 500 / im, and more preferably 30 to about L00 / m.

■ Θ o

(Characteristics of gel-like anti-adhesion material)

The viscosity of the gel-like anti-adhesion material formed from a composition such as a polysaccharide is preferably in the range of 0.1-lO O OOOPa-S, more preferably in the range of 1 to 1000 Pa · s. In order for the gel-like anti-adhesion material to smoothly prevent adhesion, the anti-adhesion material is generally present in the affected area (wound site) for a period of about 3 days to 3 months, preferably about 7 days to 2 months. However, if the viscosity is less than O.lPa's, the stagnation property in the affected area is too low, the adhesion preventing effect is lost in a short time, and the stable adhesion preventing effect cannot be exhibited. . If it exceeds 100000 Pa's, the composition such as the polysaccharide stays in the affected area for an unnecessarily long time, and even after healing, it may not be decomposed and absorbed in vivo and may remain as a foreign substance. There is not preferred. (Healing promoting drug)

The anti-adhesion material of the present invention is characterized by containing at least one healing-promoting agent. A healing-promoting agent is to be interpreted in the broadest sense, in the process of healing a wound site, controlling bioabsorbability, improving stability in the body, adjusting viscosity, adjusting softness or bacterial infection. Means any drug that contributes in some way to the promotion of healing, such as prevention of bleeding, for example, at least one selected from antimicrobial agents, antibiotics, anti-inflammatory agents, anti-adhesion agents, pile cancer agents, disinfectants, etc. One kind of drug.

In the present invention, as the healing-promoting agent which can be contained in the adhesion preventing material, if necessary, penicillins, ampicillins, tetracyclines, kanamycins, streptomycins, polymyxin B, new quinolones , Sulpha drugs, polylysine, chitosan, septums, carbavanems, amino Antibiotics and antibacterial agents such as glycosides, chloramphenyls, and tetracyclines;

Structural proteins such as collagen, fibronectin, and keratin; inorganic salts such as sodium chloride, calcium chloride, and magnesium chloride; polyvalent alcohols such as ethylene glycol, propylene glycol, glycerin, and polyethylene glycol; Blood circulation improving drugs such as Pros Evening Grandin El (PGEI), enzyme inhibitors such as Perinas Yunan, issue Inhibitor of Metalloproteinase (TIMP), and angiotensin converting enzyme inhibitor;

FGF ^ fibroblast growth factory BMP (, bone morphoaenetic protein) _N TGF? 1 (transforming growt factor) Growth factors such as NGF (nerve growth factor); and anti-inflammatory drugs such as steroids and indomethacin And disinfectants such as anticancer agents, pigments, isodine, etc., and calcium ion inactivators (chelators) which are considered to be deeply involved in adhesion in vivo.

(Content of healing promoting drug)

One or more of these healing-promoting agents may be contained in combination. In the present invention, it is desirable to mix 0.001 to 10 parts by mass, preferably 0.1 to 0.5 parts by mass, of a healing promoting agent with 100 parts by mass of the bioabsorbable polymer. If the mixing amount of the drug is too small and less than 0.001 part by mass, the effect of the drug is not exhibited. If the amount of the drug is too large and exceeds 10 parts by mass, excessive administration is not preferred.

The bioabsorbable polymer of the present invention can be uniformly mixed without inactivating the effects of these healing-promoting agents to be incorporated, and stay at the wound site during the healing period of the wound site. However, the sustained release of the drug mixture, without inhibiting the effect of the drug, after healing can be safely absorbed and decomposed into the body.

More specifically, in the present invention, in view of the problem of infectious diseases that may be caused by the adhesion preventing material, an antibacterial agent is preferable as the healing promoting agent to be contained. Among them, a drug having a broad antibacterial spectrum with respect to antibacterial properties is desirable, and a new quinolone-based norfloxacin is particularly desirable.

In the anti-adhesion material of the present invention, any method may be employed for mixing these healing-promoting agents into the bioabsorbable polymer, and may be any method. It may be mixed with bioabsorbable polymers (particularly polysaccharides, etc.) without losing the efficacy of the drug.

(The invention's effect)

The anti-adhesion material of the present invention can be easily applied to a wound site having a complicated shape (for example, a joint between small intestines, a resected portion of colorectal cancer), or a procedure under a laparoscopic approach with a narrow entrance. At the same time, the shape of the adhesion preventing material can be freely changed to a gel, particle, film, etc., and it can be adhered to the wound site without dislocation after mounting. In addition, in the anti-adhesion material of the present invention, in particular, by combining two or more kinds of polysaccharides and the like and using them as a composition, it is possible to obtain an appropriate rate of in vivo degradation, so that the wound site is completely cured. The anti-adhesion effect can be maintained without decomposing and disappearing, and it does not cause inflammation and other abnormalities to the living body.

Further, the anti-adhesion material of the present invention contains an antibacterial agent and the like as a healing promoting agent, so that the action of the antibacterial agent and the like can reduce the possibility of inflammation and infection.

(Evaluation method of adhesion prevention material)

The methods for measuring and evaluating the properties and the like of the adhesion preventing material of the present invention were as follows.

(Rigidity)

Tests were performed and evaluated according to the JIS L 1096 B method (slide method). However, the size of the adhesion preventive test piece was defined as 50 thighs x 6.35 thighs.

(Adhesion strength)

A 3 O mmX 3 O mm adhesion-preventing material test piece was brought into close contact with a sufficiently moist sponge. Immediately afterwards, a load test was performed horizontally at a speed of 5 Onra / min against the area where the test piece was in contact with the test piece (Shimadzu Corporation). The maximum tensile resistance (gf) generated until the test piece was completely peeled was measured. The measured tensile resistance was divided by the size (surface area) of the test piece to obtain the adhesion strength per unit area.

(Viscosity)

Using a viscoelasticity measuring device (manufactured by REOLOGICA), the viscosity was determined from the viscous friction torque by a conversion multiplier.

(Young's modulus) Using the above-mentioned road tester (manufactured by Shimadzu Corporation), the film-like adhesion preventing material cut into a test piece of 64 mm X 6.3 5 marauder is pulled at a chuck distance of 20 mm and a pulling speed of 50 thighs / min. The Young's modulus at 10% elongation was determined from the tensile resistance at 10% elongation.

Example

Hereinafter, specific embodiments of the present invention will be described with reference to Examples and Comparative Examples.

A-Low 'Cow gel or mosquito-shaped shrimp I'

As an anti-adhesion material, an anti-adhesion material comprising a low-viscosity gel-like or particulate bioabsorbable polymer containing a healing-promoting agent was tested.

The names of the bioabsorbable polymer and the healing promoting drug (antibacterial agent) used in Examples 1-3 and Comparative Examples 1-2, the composition ratio of the composition of the bioabsorbable polymer and the drug, the bioabsorbability Table 1 summarizes the morphology and the like of the polymer. Hereinafter, unless otherwise specified,% indicates% by mass. table 1

(Note) LA: Lactic acid, GA: Glycolic acid, ε-CLT: _£ -force prolactone

(Example 1)

An incision was made in the abdomen of the rat, the small intestine was rubbed with sandpaper, and a hole was made with a 23G needle with a germ attached to a part of it, and the gel-like anti-adhesion material shown in Table 1 (swelling rate) 18000%, a bioabsorbable polymer gel having a viscosity of ² Pa · s upon swelling with water, a Young's modulus of 1.5 MPa, and an average molecular weight of 300).

When administering the anti-adhesion material, the user (operating doctor) evaluated the operability. The anti-adhesion performance (whether there is displacement from the wound site, adhesion or infection, presence or absence of inflammation, and degradation status) was also evaluated. Table 2 shows the results.

(Example 2)

The dog's abdomen was incised, and the small intestine was rubbed with sandpaper to which various bacteria had adhered. The gel-like anti-adhesive material shown in Table 1 (swelling rate: 18000%, viscosity when swelled with water: 2 Pa · s, Young's modulus l, 5 MPa, and a bioabsorbable polymer gel having an average molecular weight of 300).

In the same manner as in Example 1, the operability of the adhesion preventing material and its adhesion preventing performance were evaluated. Table 2 shows the results.

(Example 3)

The dog's abdomen was incised, and the small intestine was rubbed with sandpaper to which various bacteria had adhered, and the particulate anti-adhesion material shown in Table 1 (swelling rate 40%, viscosity when swelling with water was 420000 Pa * s, Young's rate Was administered (filled) with 38 MPa, an average molecular weight of 78000, and an average particle diameter of 500 Zm.

(Comparative Example 1)

An incision was made in the abdomen of the rat, the small intestine was rubbed with sandpaper to which various bacteria had adhered, and a hole was made with a 23G needle with a portion of the bacteria adhered to it, and a film made of hyaluronic acid shown in Table 1 was placed there. Was administered.

(Comparative Example 2)

The dog's abdomen was incised, and the small intestine was rubbed with sandpaper to which various bacteria had adhered, and a film-like anti-adhesion material was administered there.

In the same manner as in Example 1, the operability of the adhesion preventing material and its adhesion preventing performance were evaluated. Table 2 shows the results. Table 2

From Table 2 which summarizes the results of the examples and comparative examples, the effectiveness of the adhesion preventing material of the present invention was confirmed. Further, since the anti-adhesion material of the present invention (Example 13) contains an antibacterial agent as a healing-promoting agent, Comparative Example 1 containing no such agent was used. By contrast with Nos. ~ 2, it was also confirmed that the expression of the anti-infection effect promoted the anti-inflammatory effect, and thus further improved the safety of the anti-adhesion material.

B-Ninuka ¾§ 务 Test of adhesion prevention material made of parent material

As an anti-adhesion material, an anti-adhesion material comprising a composition of two types of polysaccharides containing a therapeutic agent was tested. Experimental methods (animal experiments with rats) and evaluation methods are as follows.

(Animal experimentation)

An incision is made in the abdomen of the rat, and the small intestine is rubbed with sandpaper to which various bacteria have adhered. The anti-adhesion material is attached to the created pseudo-infected wound when it is in the form of a film, or in the case of gel, sol, or aqueous solution. The inside was filled with gel and the like, and the abdomen was closed. In each of the examples and comparative examples, 10 implants were implanted.

(Evaluation method)

1.

Two weeks and four weeks later, the rats implanted with the anti-adhesion material were opened again, and the degree of adhesion was visually observed.

2. Infection

Two weeks and four weeks later, the rats implanted with the anti-adhesion agent were re-opened to observe the presence of infection.

3. Biodegradability and absorption

After the implantation, the dry weight of the adhesion preventing material was measured 2 weeks and 4 weeks after the implantation, and the decomposition absorption was determined.

4. Operation

The operability during the implantation procedure was heard from the surgeon.

(Type of polysaccharide, etc.)

Table 3 summarizes the types of polysaccharides, compositions and forms of the polysaccharide compositions constituting the anti-adhesion materials used in Examples 4 to 6 and Comparative Examples 3 to 5. The anti-adhesion materials of the examples were all mixed with 0.3 mass% of norfloxacin, which is an antibacterial agent, as a cure-promoting agent. Table 3

(Example 4)

Dissolve 80 g of pullulan, two types of polysaccharides, 20 g of agarose, and 0.3 g of norfloxacin, a therapeutic agent, in 300 Oml of hot distilled water, apply the solution to a glass substrate, dry and cast A film was prepared. The thickness of the obtained cast film was 75 m. The softness was 280mN · thigh.

The animal experiment described above was performed using the above cast film (film-like adhesion preventing material) and evaluated. The results are summarized in Table 4 (anti-adhesion property), Table 5 (incidence rate of infectious disease), Table 6 (in vivo absorption of keratosis) and Table 7 (operability).

(Example 5)

60 g of pullulan, 40 g of agarose and 0.3 g of norfloxacin were dissolved in 200 Om1 of hot distilled water, and the solution was allowed to gel by cooling. The prepared jelly-like solid was strained through a wire mesh (hole diameter: 1 thigh, XI thigh) to prepare a gel-like anti-adhesive material having fluidity. The viscosity of this gel-like adhesion preventing material was 580 Pa · S. The above-described animal experiment was performed and evaluated in the same manner as in Example 4 using the above gel-like adhesion preventing material. The results are summarized in Table 4 (anti-adhesion property), Table 5 (incidence rate of infectious disease), Table 6 (biodegradability and absorption), and Table 7 (operability).

(Example 6)

40 g of pullulan, 60 g of agarose, and 0.3 g of norfloxacin were dissolved in 3000 ml of hot distilled water. Using the solution, cast as in Example 4. Was prepared. The thickness of the cast film was 96 m. The softness was 380 mN · mm.

The animal experiment described above was performed using the above film-like adhesion preventing material, and evaluated. The results are summarized in Table 4 (anti-adhesion property), Table 5 (incidence rate of infectious disease), Table 6 (biodegradability and absorption), and Table 7 (operability).

(Comparative Example 3)

An animal experiment similar to that of Example 4 was performed using a polypropylene mesh (linear shape: 340 m, opening area: 68%) as an anti-adhesion material, and evaluated. Table 4 shows the results.

(Anti-adhesion properties), Table 5 (Infectious disease incidence rate), Table 6 (Biodegradability and absorption), and Table 7 (Operability).

(Comparative Example 4)

3 g of sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in ΙΟΟΟπιΙ to obtain an aqueous solution (viscosity: 500P3 ■ s). Using the aqueous sodium alginate solution as an anti-adhesion agent, an animal experiment similar to that in Example 4 was performed and evaluated. The results are summarized in Table 4 (anti-adhesion properties), Table 5 (incidence rate of infection), Table 6 (biodegradability and absorption), and Table 7 (operability).

(Comparative Example 5)

The same animal experiment as in Example 4 was performed without using an adhesion preventing material, and evaluated. The results are summarized in Table 4 (anti-adhesion property), Table 5 (incidence rate of infectious disease), Table 6 (biodegradability and absorption), and Table 7 (operability). Table 4 No.

Example 4 Adhesion was prevented at a rate of 80%.

Example 5 Adhesion was stopped in the P direction at a rate of 70%.

Example 6 Adhesion was prevented at a rate of 90%.

Comparative Example 3 Adhesion was prevented at a rate of 50%.

Comparative Example 4 Adhesion was prevented at a rate of 30%.

Comparative Example 5 Adhesion did not occur at a rate of 20%. Table 5

Table 6

(Discussion of results)

(1) From Table 4 showing the anti-adhesion properties, it can be seen that in Examples 4 to 6 in which the anti-adhesion material of the present invention (a composition of two kinds of polysaccharides of pullulan and agarose) was used, Prevention of adhesions was observed at some degree. On the other hand, in Comparative Example 3, in which a non-bioabsorbable propylene mesh was used as an adhesion preventing material, the physical shielding effect prevented some adhesions, but the mesh did not completely adhere to the wound site. Therefore, the effect of preventing adhesion (frequency of prevention) is much lower than that of the present invention. In Comparative Example 4, in which an aqueous sodium alginate solution was used as an adhesion preventing material, the adhesion preventing effect was even lower. This may be because the aqueous solution is absorbed by the living body at an early stage, and cannot be retained in the wound for a sufficient time to prevent adhesion.o

(2) From Table 5 showing the incidence of infectious diseases, it can be seen that in Examples 4 to 6 using the adhesion preventive material of the present invention, no infectious disease was caused. It is easily understood that this is due to the antibacterial activity of the contained drug, norfloxacin. On the other hand, in Comparative Examples 3 to 5 in which norfloxacin was not added at all, infection occurred very frequently.

(3) From Table 6 showing the biodegradability and absorbency, it can be seen that in Examples 4 to 6 using the anti-adhesion material of the present invention composed of two kinds of polysaccharide compositions, the composition differs depending on the composition. It is thought that it stayed to some extent without being decomposed in the living body for 2 weeks, and exhibited an adhesion-preventing effect. That is, the anti-adhesion material of Example is composed of a composition of easily water-soluble pullulan and poorly water-soluble agarose.In Example 4, which has a high content of pullulan, it is relatively quickly absorbed into the living body. On the other hand, in Examples 5 and 6 in which the content of poorly water-soluble agarose is high, the bioabsorption rate is slow, and it can be seen that the decomposition and absorption in the living body can be controlled by the mixing ratio of the two. That is, specifically, the higher the composition ratio (mixing ratio) of the poorly water-soluble agarose, the lower the bioabsorbability.

In the case of the anti-adhesion material composed of an aqueous sodium alginate solution (Comparative Example 4), sodium alginate had completely disappeared after 2 weeks had passed, which was necessary to exhibit the anti-adhesion effect in vivo. It is clear that it has been absorbed without stagnation for an appropriate period.

(4) Table 7 shows the results of the operability. The adhesion preventing materials of the present invention (Examples 4 to 6) all had appropriate operability. (5) The above results are summarized in Table 8. From Table 8, it can be seen that the anti-adhesion material of the present invention (Examples 4 to 6) is extremely effective in all of the anti-adhesion properties, the incidence of infectious diseases, the biodegradability and absorption, and the operability. This was confirmed. In particular, since the anti-adhesion material of the present invention contains, for example, an antibacterial agent as a healing-promoting agent, it exhibits an effect of preventing infection by contrasting with Comparative Examples 3 to 5, which do not contain such an agent. It was also confirmed that the anti-inflammation effect was exerted, so that the safety of the adhesion preventing material was further improved. Table 8

Mate no Haze II Noh

ADVANTAGE OF THE INVENTION The adhesion preventing material of this invention is excellent in biocompatibility, is easy to apply to the damaged part of the living tissue which requires prevention and reduction of adhesion, is excellent in safety, and stably for a desired period. As well as exhibiting good adhesion prevention effects, it is possible to effectively prevent infectious diseases, which have been a problem in the past, and its industrial applicability is extremely large.

Claims

The scope of the claims

I. An adhesion preventing material for a wound site containing a bioabsorbable polymer as a main component, characterized in that the adhesion preventing material contains at least one kind of a healing promoting agent. Prevention material.

2. The adhesion preventing material according to claim 1, wherein the bioabsorbable polymer is in the form of a gel, a solid, or a granule, and is easily deformable according to the shape of a wound site.

3. The gel or solid bioabsorbable polymer has a viscosity of 0. 500000Pa · s at 25 ° C when dried or swelled with water: 25 to 40 MPa, and an average molecular weight. 3. The adhesion preventing material according to claim 1, wherein the amount is 100 to 1,000,000.

4.The gel-shaped bioabsorbable polymer according to any one of claims 1 to 3, which has a viscosity of 0.1500,000 Pa · s and can be injected into a wound site with an injection needle smaller than 18 gauge. The adhesion preventing agent according to the above.

5. The adhesion preventing material according to claim 1, wherein the granular bioabsorbable polymer has an average particle size of l2000 / m and can easily cover a complicated wound site.

6. The anti-adhesion material according to any one of claims 1 to 5, wherein the gel-like or particulate bioabsorbable polymer is injectable into a wound site from a very small space.

7. The bioabsorbable polymer is composed of a composition of at least two or more types of polysaccharides and derivatives thereof, and by adjusting the composition ratio of the polysaccharides and derivatives thereof in the composition, the bioabsorbability is improved. 2. The adhesion preventing material according to claim 1, wherein the material can be controlled.

8. The adhesion preventing material according to claim 7, wherein the adhesion preventing material is in the form of a film or a gel, and is deformable according to the shape of the wound site.

9. The anti-adhesion material according to claim 7, wherein the film-like anti-adhesion material has a dry softness of 0.1 LOOOOmN '.

10. The adhesion preventing material according to any one of claims 7 to 9, wherein the film-like adhesion preventing material has an adhesion strength of 2 gf / cm ² or more.

II. The gel-like anti-adhesion material has a viscosity when dried or swelled with water.

0.1-: The adhesion preventing material according to claim 7 or 8, which is LOOOOOPa ■ s.

12. The anti-adhesion material according to any one of claims 7 to 11, wherein at least one of the polysaccharide and its derivative forming the composition is pullulan and its derivative.

13. The adhesion preventing material according to any one of claims 1 to 12, wherein the gel, solid, granular, or film-like adhesion preventing material is decomposed and absorbed in vivo within 3 months.

14. The anti-adhesion material according to any one of claims 1 to 13, further comprising 0.001 to 10 parts by mass of a healing-promoting agent per 100 parts by mass of the bioabsorbable polymer.

15. The method according to claim 1, wherein the healing promoting agent is at least one selected from the group consisting of an antibacterial agent, an antibiotic agent, an anti-inflammatory agent, an anti-adhesion agent, a pile cancer agent, and a disinfectant. The adhesion preventing material according to any one of the above.