JPH11269090A - Medical material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medical material, such as gauze, having a granulating action, an antibacterial action and a strong wound cure-stimulating action by including a specific peptide. SOLUTION: This medical material contains or is treated with (A) a peptide of formula I [R<1> is H, a (substituted) acyl, a (substituted) alkyl or the like; R<2> is (substituted) OH; R<3> is (protected) carboxyl; R<4> -R<13> are each H, an (substituted) alkyl or the like] except a peptide of formula II (R<14> is a group of formula III), such as a peptide of formula IV (R<15> is a group of formula V), etc., and preferably (B) a peripheral circulation-improving agent. For example, vitamin E, d or dl-camphor, etc., is preferably used as the component B, and the medical material is preferably obtained by dissolving the peptide in a solvent and impregnating a medical material such as gauze with the obtained solution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a medical material having an antibacterial action and a wound healing promoting action.

[0002]

BACKGROUND OF THE INVENTION Wounds are damages to surface tissues such as surgical incisions, gastrointestinal ulcers, burns, lacerations, or skin ulcers (such as pressure sores), and the risk of infection is very high. Therefore, topical treatment for the wound is very important, and a wound dressing has been developed for the purpose of preventing infection of the wound and promoting healing of the wound.

[0003] Conventionally, medical materials such as gauze and sutures used surgically have been processed with disinfectants, thrombin, calcium compounds, various proteins and the like.
Further, Japanese Patent Application Laid-Open No. 62-275468 proposes a medical material which is surface-treated with a fibroblast-proliferating substance or mixed therewith.

[0004]

However, these medical materials have little effect such as granulation and improvement of peripheral circulation, which are important points for promoting wound healing, and have very weak healing promoting effects. In view of the above, the object of the present invention,
It is to provide a more effective medical material in terms of a wound healing promoting action and the like.

[0005]

Means for Solving the Problems The present inventors have prepared a compound represented by the general formula [I]:

Embedded image(Where R¹Is hydrogen, an acyl group or a substituted acyl
Group, alkyl group or substituted alkyl group, hydroxyl group, etc.
Or substituted hydroxyl, amino or substituted amino groups
A group represented by R^TwoRepresents a hydroxyl group or a substituted hydroxyl group;^Three
Has a carboxyl group or a protected carboxyl group.
Show each or R^ThreeAnd R^TwoAre connected to each other by -C
An OO— group;^FourIs hydrogen, alkyl or substituted
The substituted alkyl group is represented by R^FiveIs hydrogen, alkyl or substituted
Substituted alkyl group, hydroxyl group or substituted hydroxyl group,
R⁶Is hydrogen, an alkyl group or a substituted alkyl group
And R ⁷Is hydrogen, an alkyl group or a substituted alkyl
Group, amino group or substituted amino group, hydroxyl group or
Each represents a substituted hydroxyl group, or R⁶And R⁷
Are linked to each other at some of them,⁸Is hydrogen,
A alkyl group or a substituted alkyl group is represented by R⁹Is hydrogen,
An alkyl group or a substituted alkyl group, a hydroxyl group or
The substituted hydroxyl group is represented by R^TenIs hydrogen, an alkyl group or
The substituted alkyl group is represented by R¹¹Is hydrogen, an alkyl group or
Substituted alkyl group, hydroxyl group or substituted hydroxyl group
And R¹²Is hydrogen, an alkyl group or a substituted alkyl
A group represented by R¹³Is hydrogen, alkyl or substituted alkyl
Group, amino group or substituted amino group, hydroxyl group or
Represents a substituted hydroxyl group, respectively, or R¹²And R
¹³Are connected to each other in some of them).
Among the peptides, the following formula (II)

Embedded image (Hereinafter referred to as the peptide of the present invention) has an action of promoting granulation, which is an important point in promoting wound healing, and also has an antibacterial action. Further, the present inventors thought that the combination of the peptide of the present invention and a peripheral circulation improving agent would exhibit a stronger wound healing promoting action, and as a result of earnest studies, completed the present invention.

That is, the medical material according to claim 1 of the present invention is a medical material containing the peptide of the present invention or having been subjected to surface treatment with the peptide.

[0007] A medical material according to claim 14 of the present invention contains the peptide according to any one of claims 1 to 13 and a peripheral circulation improving agent, or is surface-treated with the peptide, or either of them. This is a medical material characterized by containing one or the other and surface-treated by the other.

As a typical example of the peptide of the present invention, R⁸But
The peptide according to claim 1, which represents hydrogen (the peptide according to claim 2).
Peptide); R^Ten3. The pepti of claim 2, wherein represents hydrogen.
R (peptide according to claim 3); R^TenRepresents a methyl group
The peptide according to claim 2 (the peptid according to claim 4).
Do); R^TenIs an alkyl group other than a methyl group or
3. The peptide according to claim 2, which represents a substituted alkyl group.
Item 5) R; ⁸Represents a methyl group.
The peptide of claim 1 (the peptide of claim 6); R ^TenBut
The peptide according to claim 6, which represents a methyl group (claim 7).
Peptide); R ^TenIs hydrogen or an alkyl other than a methyl group
7. A group or a substituted alkyl group.
R (a peptide according to claim 8); R⁸Is methyl
Represents an alkyl group other than a group or a substituted alkyl group.
The peptide according to claim 1 (the peptid according to claim 9).
Do); R^TenRepresents a methyl group.
(Peptide according to claim 10); R^TenIs hydrogen, methyl group
Represents an alkyl group other than or a substituted alkyl group
The peptide according to claim 9 (the peptid according to claim 11).
Do); R^FourIs a hydroxymethyl group or its hydroxyl group is
11. A protected hydroxymethyl group.
R (a peptide according to claim 12); R^FourBut water
Substitution other than alkyl, alkyl group or hydroxymethyl group
The peptide according to claim 10, which shows a modified alkyl group.
(A peptide according to claim 13).

The substituents of the peptide of the present invention will be described in more detail.

Suitable examples of the "acyl group" include a carbamoyl group, an aliphatic acyl group, an acyl group having an aromatic ring (hereinafter, referred to as "aromatic acyl group") and an acyl group having a heterocyclic ring (hereinafter, referred to as "acyl group"). "Heterocyclic acyl group"). Suitable specific examples of the acyl group include an alkanoyl group (for example, formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, Undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, eicosanoyl, etc.), alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, t-pentyl) Oxycarbonyl, heptyloxycarbonyl, etc.), alkanesulfonyl group (eg, methanesulfonyl, ethanesulfonyl, etc.), alkoxysulfonyl (eg, Methoxysulfonyl, aliphatic acyl group such as ethoxysulfonyl, etc.), etc., an aroyl group (e.g., benzoyl, toluoyl,
Naphthoyl and the like; arylalkanoyl groups (for example, phenylalkanoyl such as phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutyryl, phenylpentanoyl, and phenylhexanoyl);
Naphthylacetyl, naphthylpropanoyl, naphthylalkanoyl such as naphthylbutanoyl, etc.), arylalkenoyl group (for example, phenylalkenoyl such as phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, Naphthylpropenoyl, naphthylbutenoyl, naphthylalkenoyl such as naphthylpentenoyl, etc., arylalkoxycarbonyl group (eg, phenylalkoxycarbonyl such as benzyloxycarbonyl), aryloxycarbonyl group (eg, phenoxycarbonyl, naphthyloxy) Carbonyl), an aryloxyalkanoyl group (eg, phenoxyacetyl, phenoxypropionyl, etc.), an arylglyoxyloyl group (eg, phenyl Aromatic acyl groups such as oxyloyl, naphthylglyoxyloyl, and arylsulfonyl groups (eg, benzenesulfonyl, p-toluenesulfonyl, etc.); heterocyclic carbonyl groups (eg, tenoyl, furoyl, nicotinoyl, etc.), heterocyclic alkanoyl Groups (eg, thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl, tetrazolylacetyl, etc.), heterocyclic glyoxyloyl groups (eg, thia Zolylglyoxyloyl,
And heterocyclic acyl groups such as thienylglyoxyloyl). Specific examples of the heterocyclic moiety in the above “heterocyclic carbonyl group”, “heterocyclic alkanoyl group” and “heterocyclic glyoxyloyl group” Examples include a saturated or unsaturated, monocyclic or polycyclic heterocyclic group having at least one heteroatom such as oxygen, sulfur, nitrogen and the like.

Suitable examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, Tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl,
Eikosil and the like.

The above-mentioned “acyl group”, “alkyl group” and “amino group” may have one or more suitable substituents. Examples of such substituents include the above-mentioned acyl group, The above alkyl group and alkenyl group (for example, vinyl, allyl, 1-propenyl, 1-, 2- or 3-butenyl, 1-, 2-, 3- or 4-pentenyl, 1-, 2-, 3-, 4- or 5-hexenyl, etc.), an aryl group (phenyl, tolyl, xylyl, naphthyl, etc.), an alkoxy group (eg, methoxy, ethoxy, propoxy, etc.), an alkylthio group (eg, methylthio, ethylthio, etc.), an alkylamino group ( For example, methylamino, ethylamino, etc.), a cycloalkyl group (eg, cyclopentyl, cyclohexyl, etc.), a cycloalkenyl group (cyclohexene, etc.) Le etc.), a halogen, an amino group, substituted amino group, a hydroxyl group, a substituted hydroxy group,
Cyano group, nitro group, carboxyl group, substituted carboxyl group, sulfo group, sulfamoyl group, imino group,
Oxo group, aminoalkyl group (for example, aminomethyl,
Aminoethyl, etc.), carbamoyloxy group, hydroxyalkyl group (eg, hydroxymethyl, 1- or 2
-Hydroxyethyl, 1-, 2- or 3-hydroxypropyl), a cyanoalkenylthio group (for example, cyanovinylthio and the like) and the like.

Suitable examples of the "hydroxyl substituent" in the "substituted hydroxyl group" include a phenylalkyl group (for example, benzyl and the like) and the above-mentioned acyl group.

Suitable "substituted carboxyl groups" include esterified carboxyl groups. Suitable examples of the ester moiety of the esterified carboxyl group include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl which may have at least one suitable substituent. Alkyl esters such as esters, pentyl esters, and hexyl esters, for example, alkanoyloxyalkyl esters (eg, acetoxymethyl ester, propionyloxymethyl ester,
Butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1- or 2-acetoxyethyl ester, 1-, 2- or 3-acetoxypropyl ester, 1-, 2 -, 3- or 4-acetoxybutyl ester, 1- or 2-propionyloxyethyl ester, 1-, 2- or 3-propionyloxypropyl ester, 1- or 2-butyryloxyethyl ester, 1- or 2- Isobutyloxyethyl ester, 1- or 2-pivaloyloxyethyl ester, 1- or 2-hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyi Riloxymethyl e Ether, 1- or 2-pentanoyloxy ethyl ester, etc.), alkanesulfonyl alkyl ester (e.g., 2-Meshiruechiru etc.), mono -,
Di- or trihaloalkyl esters (eg, 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.), alkoxycarbonyloxyalkyl esters (eg, methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxy) Carbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.), phthalidylidenealkyl ester or (5-alkyl-2-oxo-).
1,3-dioxol-4-yl) alkyl ester [for example, (5-methyl-2-oxo-1,3-dioxolol-4-yl) methyl ester, (5-ethyl-2-yl)
Oxo-1,3-dioxole) methyl ester, (5
-Propyl-2-oxo-1,3-dioxol-4-
Yl) ethyl ester, etc.], alkenyl esters (eg, vinyl esters, allyl esters, etc.), alkynyl esters (eg, ethynyl esters, propynyl esters, etc.), and arylalkyl esters optionally having at least one suitable substituent For example, unsubstituted or substituted mono-, di- or triphenylalkyl esters (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester bis (methoxyphenyl) methyl ester, 3 , 4-Dimethoxybenzyl ester, 4-hydroxy-3,5-di-
aryl esters optionally having at least one suitable substituent (e.g., phenyl ester, 4-chlorophenyl ester,
Tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester) and phthalidyl ester.

As a specific example of the peptide of the present invention, a known compound, A83586C (Smitk) represented by the formula (III)
a et al., J. Antibiotics 41: 726-733, 1988), Variapptin represented by the formula (IV) (Nakagawa et al., J. Antibi
otics 43: 477-484, 1990), Veru represented by the formula (V)
coppertin (Nishiyama et al., J. Antibiotics 46: 921
-927,1993), Azinothric represented by the formula (VI)
in (Maehr et al., J. Antibiotics 39: 17-25, 1986), formula (VI
Ciropeptin represented by I) (Nakagawa et al.,
J. Antibiotics 43: 477-484, 1990), Aurantimycin A represented by the formula (VIII), Au represented by the formula (IX)
tranmycin B, Aur represented by formula (X)
antimycin C (Grafe et al., J. Antibiotics 48: 1
19-125, 1995), L-156602 (Hen
Sen et al., J. Antibiotics 44: 249-254, 1991), IC-101 represented by the formula (XII) (Ueno et al., J. Antibiotics 46: 165).
8-1665, 1993), and GE3 represented by the formula (XIII) (Japanese Unexamined Patent Publication No.
278188) and the like.

[0016]

Embedded image

[0017]

Embedded image

[0018]

Embedded image

[0019]

Embedded image

[0020]

Embedded image

[0021]

Embedded image

[0022]

Embedded image

[0023]

Embedded image

[0024]

Embedded image

[0025]

Embedded image

[0026]

Embedded image

Examples of the above-mentioned peripheral circulation improving agent include vitamin E; d- or dl-camphor; a heparin-like substance; prostaglandin (PG); itactamol; cantharis; capsicum tincture; nicotinic acid; And nicotinic acid esters, amides or salts thereof, which can be used as pharmaceuticals.

The above-mentioned vitamin E refers to tocopherol (vitamin E) and its derivatives, and those listed in the Japanese Pharmacopoeia include, for example, tocopherol acetate,
And tocopherol succinate. Other than the above, for example, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocopherol nicotinate, tocopherol phosphate, natural vitamin E, and the like, but are not limited thereto. In addition, a conjugate of tocopherol with a monosaccharide, oligosaccharide or polysaccharide and water-soluble vitamin E are also included.

Examples of the above-mentioned heparin-like substance include heparin, pentosan polysulfate, dextran sodium sulfate and the like, but are not limited thereto.

Examples of the prostaglandins include, but are not limited to, PGE ₁ , PGI ₂ , TXA _{2 and the} like.

Examples of the nicotinic acid ester include, but are not limited to, nicotinic acid methyl ester and nicotinic acid ethyl ester.

Examples of the amide of nicotinic acid include, but are not limited to, nicotinamide.

Examples of the nicotinic acid salts include salts with various bases. Specific examples include alkali metal salts (eg, lithium salt, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), but are not limited thereto. Absent.

[0034] Examples of the medical material in the present invention include gauze, woven fabric, non-woven fabric, absorbent cotton, suture, and covering material.

As the material of the nonwoven fabric, for example, cotton,
Nylon fiber, polyester fiber, acrylonitrile fiber, vinyl chloride fiber, polyolefin fiber, collagen, chitin and the like.

Examples of the suture include bioabsorbable and non-bioabsorbable sutures. Examples of bioabsorbable sutures include collagen, polyglycolic acid, and polydioxanone. Examples of the material of the sex suture include steel, polyester, and nylon.

Examples of the material of the coating material include polyurethane, polyamino acid, regenerated collagen, chitin and the like.

In the medical materials according to claims 1 to 13, the expression "comprising the peptide of the present invention" means that the peptide of the present invention is present in the structure or on the surface of the medical material. It means that the peptide of the present invention is chemically bonded or physically adsorbed on the surface of the component in the component of the medical material.

Further, in the medical material according to claim 14, the phrase "contains the peptide according to any one of claims 1 to 13 and a peripheral circulation improving agent" means that the medical material has a structure or a surface thereof in the constitution of the medical material. Means that the peptide of the present invention and the peripheral circulation improving agent are present, and that the surface treatment with the peptide of any one of claims 1 to 13 and the peripheral circulation improving agent means that the medical material is It means that the peptide of the present invention according to any one of claims 1 to 13 and a peripheral circulation improving agent are chemically bonded or physically adsorbed on the surface of a component in the component, and either one of them is used. One is contained and the other is surface-treated by the other, one of which is present in or on the composition of the medical material and the other is chemically treated on the surface of the component in the composition of the medical material. Binding or physically adsorbing It refers to the fact that there.

The method for producing a medical material containing the peptide of the present invention according to claims 1 to 13 includes, for example, a method of dissolving the peptide of the present invention in a solvent and impregnating the medical material.
Examples of the method include coating the peptide of the present invention on the surface of a medical material using a coating agent.

A method for producing a medical material comprising the peptide of the present invention according to any one of claims 1 to 13 and a peripheral circulation improving agent is described in, for example, claim 1
A method of impregnating a medical material by dissolving the peptide of the present invention and a peripheral circulation improving agent according to any one of to 13 in a solvent,
Examples include a method of coating the peptide of the present invention according to any one of claims 1 to 13 and a peripheral circulation improving agent on the surface of a medical material using a coating agent.

As the solvent used in the above-mentioned impregnation,
Although not particularly limited, esters such as ethyl acetate, methanol, ethanol, alcohols such as propanol, ethers such as ethyl ether, acetone, ketones such as methyl ethyl ketone, dichloromethane,
Chloroform and the like can be mentioned. When the coating agent is used for coating, for example, sucrose, gelatin,
Examples include calcium carbonate, methyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, carbowax and the like.

The method for producing a medical material surface-treated with the peptide of the present invention according to claims 1 to 13 includes, for example, introducing the peptide of the present invention directly into the surface of the component of the medical material or by introducing a functional group. Immobilization using a covalent bond or the like. Examples of the functional group include an amino group, a carboxyl group, an α-chloromethyl group, an α-chloroacetamidomethyl group, and the like.

As a method for producing a medical material surface-treated with the peptide of the present invention according to any one of claims 1 to 13 and a peripheral circulation improving agent, for example, A method of immobilizing the peptide of the present invention and the peripheral circulation improving agent described in any of them directly on the surface of a component of a medical material or by introducing a functional group and using a covalent bond or the like is used. Examples of the functional group include an amino group, a carboxyl group, an α-chloromethyl group, an α-chloroacetamidomethyl group, and the like.

The peptide of the present invention according to any one of claims 1 to 13 and a peripheral circulation improving agent,
Either one is contained, as a method of manufacturing a medical material surface-treated with the other one, to produce one of the above-mentioned manufacturing method for containing, and the other for the above-described surface treatment The method of manufacturing by a manufacturing method is mentioned.

The amount of the peptide of the present invention to be contained in the medical material according to any one of claims 1 to 13 is not particularly limited and may be appropriately selected from a wide range, but is preferably 10 ^-7 to 1 in the medical material.
The range is 0% by weight.

The amount of the peptide of the present invention according to any one of claims 1 to 13 and the peripheral circulation improving agent to be contained in the medical material according to claim 14 is not particularly limited and may be appropriately selected from a wide range. Preferably, the peptide of the present invention according to any one of claims 1 to 13 is contained in a medical material at 10 ^-7 to 10 ^-7.
% By weight, and the amount of the peripheral circulation improving agent is in the range of 10 ^-4 to 10% by weight.

[0048]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Next, embodiments of the present invention will be described.
The effect described above is demonstrated.

Among the peptides represented by the general formula (I) in the present invention, A83586 represented by the above formula (III)
C, Varianpeptin represented by the formula (IV),
Verucoceptin represented by the above formula (V), Azinothricin represented by the above formula (VI), Citropeptin represented by the above formula (VII), and the above formula (V
Aurantimycin A represented by III), the above formula
(IX) Aurantimycin B represented by the formula (X), Aurantimycin C represented by the formula (X), L-156602 represented by the formula (XI), IC-101 represented by the formula (XII) or the formula (XIII) GE shown
Using No. 3, the medical materials of Examples 1 to 4 were manufactured as follows, and the pharmacological tests were performed. In addition, these peptides were produced by the method described in the aforementioned literature.

Example 1 For each peptide, 0.04 mg / ml
Using a sprayer, 10 ml of the methanol solution was uniformly sprayed on gauze (20 cm × 20 cm), and then dried to obtain a medical material comprising peptide-containing gauze.

Example 2 Polypropylene (manufactured by Mitsui Toatsu Co., Noblen, J3H-
G) 50 parts by weight of polystyrene and 50 parts by weight of polystyrene (Stylon 679, manufactured by Asahi Kasei Kogyo Co., Ltd.) were melt-spun at 280 ° C. and stretched to obtain a conjugate fiber. 700 g of a knitted fabric of this composite fiber was wound around an open bobbin and packed in a column having a diameter of 20 cm and a height of 30 cm.

In a stainless steel container, 15 kg of nitrobenzene, 15 kg of 98% concentrated sulfuric acid, N-methylol-α
A reaction liquid was prepared by mixing 2.25 kg of chloroacetamide and 32.3 g of paraformaldehyde. The reaction solution was supplied by a pump to the center of the core of the open bobbin filled in the column, and the reaction solution was allowed to flow through the knitted fabric. The reaction solution that passed through the knitted fabric and flowed out of the column was repeatedly circulated.

After reacting at 10 to 20 ° C. for 2 hours, the reaction solution was extracted from the column and the stainless steel container. The knitted fabric in the column was washed at room temperature using 20 kg of nitrobenzene and 20 kg of purified water in the same manner as in the reaction. The remaining sulfuric acid was neutralized with a 24% aqueous sodium hydroxide solution.
The remaining nitrobenzene was extracted and removed with methanol, and further washed with hot water at 70 ° C. to obtain 950 g of purified α-chloroacetamidomethylated composite fiber.

For each peptide, 1 g of the peptide was dissolved in 20 liters of anhydrous methanol to prepare an immobilization reaction solution, and the purified α-chloroform obtained at 65 ° C. by the same route as the amide methylation reaction. The knitted fabric of the acetamidomethylated conjugate fiber was supplied and circulated for 2 hours. Thereafter, the reaction solution was extracted from the column and the stainless steel container, and cooled. After washing with 20 liters of methanol and further washing with hot water at 70 ° C., a medical material comprising the peptide-immobilized conjugate fiber was obtained.

Example 3 0.04 mg of each peptide in Example 1
Instead of 10 ml of a 10 / ml methanol solution, each peptide is at a concentration of 0.04 mg / ml and nicotinic acid is 1%.
10 ml methanol solution dissolved at 0 mg / ml concentration
A medical material comprising a peptide and a nicotinic acid-containing gauze was obtained in the same manner as in Example 1 except that was used.

Example 4 A medical material composed of the peptide-immobilized conjugate fiber obtained in Example 2 having a size of 20 cm × 20 cm was added to a 10 mg / ml methanol solution of nicotinamide in 10 ml.
Was uniformly sprayed using a sprayer, and then dried to obtain a medical material composed of peptide-immobilized nicotinamide-containing composite fibers.

Pharmacological Test Test Example 1 Effect on Diabetic Mouse Skin Defect Model The wound healing promoting effect of the medical materials obtained in Examples 1 to 4 was tested as follows. The weight of the test animal is 30
４５45 g female diabetic mice (db / db) were used.

A mouse shaved 3 days before the defect was placed under the anesthesia with ether and having a diameter of 1
A 6 mm defect was made using ophthalmic scissors. The wound surface (2 cm ² ) was covered with 2 cm ² of the medical material of the present invention, and then covered with a polyurethane film material (manufactured by Johnson Corporation, trade name: Bioclusive). Administration was performed on the day of defect creation, and after 3 days the medical material was removed and the wound was washed.
After covering again with a polyurethane film material, the wound healing effect was confirmed 10 days later. The wound healing effect is determined by measuring the minor axis and major axis of the defect using calipers, determining the area of the defect (minor axis × major axis × 3.14 ÷ 4) by regarding the defect as an ellipse, The evaluation was performed by obtaining the ratio of the area of the defective part on the measurement day to the area of the defective part (this is called an area ratio).

As a control, a medical material prepared in the same manner as in Example 1 (control of Example 1) except that the above peptide was not contained, and a control material similar to that of Example 2 except that the above peptide was not contained. Medical material (control of Example 2), a medical material manufactured in the same manner as in Example 3 except that the above peptide was not contained (control of Example 3), Was performed using a medical material produced in the same manner as in Example 4 (the control of Example 4), and the other points were the same as those described above.

This test was carried out using 5 mice each, and the area of the defect was taken as the average value of the area of the defect obtained for these mice. The area ratio of the test on the 10th day of defect creation is shown in Table 1 for Example 1, Table 2 for Example 2, Table 3 for Example 3, and Table 4 for Example 4. Show.

[0061]

[Table 1]

[0062]

[Table 2]

[0063]

[Table 3]

[0064]

[Table 4]

As can be seen from Tables 1 and 2,
In the groups to which the medical materials described in 4, 5, 7, 8, 11, 12, and 13 were administered (Examples 1 and 2), the area of the defective part on the 10th day after the generation of the defect was significantly reduced as compared with the control group.
As described above, claims 3, 4, 5, 7, 8, 11, 12,
It was confirmed that the medical material described in 13 showed a remarkable wound healing promoting effect. In the group to which the medical material according to claim 14 was administered (Examples 3 and 4), claims 3, 4, 5,
The defect area was further reduced as compared with the groups to which the medical materials described in 7, 8, 11, 12, and 13 were administered. Thus, the medical material according to claim 14 is the medical material according to claims 3, 4, 5, 7,
It was recognized that the medical material described in 8, 11, 12, and 13 exhibited a more remarkable wound healing promoting effect.

Test Example 2 Antimicrobial activity The antimicrobial activity of the medical materials obtained in Examples 1 to 4 was tested as follows.

Mueller Hinton Brot
h A 2 cm × 2 cm medical material of the present invention was placed on an agar medium. Staphylococcus aureus (IFO 12732) from above
Of suspension (approximately 10 ⁶ cells / ml) was added, and 35
C. for about 20 hours. After the culture, remove the medical material,
The growth state of the bacteria just below the medical material was observed. As a control, a medical material produced in the same manner as in Example 1, Example 2, Example 3, or Example 4 was used except that the above peptide was not contained, and the other points were the same as in the above operation. .

As a result of observation, no growth of bacteria was observed in any of the medical materials obtained in Examples 1 to 4, but formation of a large number of colonies was observed in any of the above-mentioned controls. . Thus, it was confirmed that the medical material of the present invention has an antibacterial action.

[0069]

The constitution of the medical material according to the first to thirteenth aspects is as described above. According to the medical material according to the first to thirteenth aspects, the medical material has an antibacterial effect and exhibits a remarkable wound healing promoting effect. Medical materials are provided. The structure of the medical material according to the fourteenth aspect is as described above. According to the medical material according to the fourteenth aspect, the medical material has an antibacterial action, and the wound healing promotion effect is more remarkable than the medical material according to the first to thirteenth aspects. Is provided.

Claims (14)

[Claims] 1. A compound of the general formula (I)(Where R¹Is hydrogen, an acyl group or a substituted acyl
Group, alkyl group or substituted alkyl group, hydroxyl group, etc.
Or substituted hydroxyl, amino or substituted amino groups
A group represented by R^TwoRepresents a hydroxyl group or a substituted hydroxyl group;^Three
Has a carboxyl group or a protected carboxyl group.
Show each or R^ThreeAnd R^TwoAre connected to each other by -C
An OO— group;^FourIs hydrogen, alkyl or substituted
The substituted alkyl group is represented by R^FiveIs hydrogen, alkyl or substituted
Substituted alkyl group, hydroxyl group or substituted hydroxyl group,
R⁶Is hydrogen, an alkyl group or a substituted alkyl group
And R ⁷Is hydrogen, an alkyl group or a substituted alkyl
Group, amino group or substituted amino group, hydroxyl group or
Each represents a substituted hydroxyl group, or R⁶And R⁷
Are linked to each other at some of them,⁸Is hydrogen,
A alkyl group or a substituted alkyl group is represented by R⁹Is hydrogen,
An alkyl group or a substituted alkyl group, a hydroxyl group or
The substituted hydroxyl group is represented by R^TenIs hydrogen, an alkyl group or
The substituted alkyl group is represented by R¹¹Is hydrogen, an alkyl group or
Substituted alkyl group, hydroxyl group or substituted hydroxyl group
And R¹²Is hydrogen, an alkyl group or a substituted alkyl
A group represented by R¹³Is hydrogen, alkyl or substituted alkyl
Group, amino group or substituted amino group, hydroxyl group or
Represents a substituted hydroxyl group, respectively, or R¹²And R
¹³Are connected to each other in some of them).
Among the peptides, the following formula (II):Containing a peptide other than the peptide represented by, or
A medical material characterized by being surface-treated by this. 2. The medical material according to claim 1, wherein R ⁸ represents hydrogen. 3. The medical material according to claim 2, wherein R ¹⁰ represents hydrogen. 4. The medical material according to claim 2, wherein R ¹⁰ represents a methyl group. 5. The medical material according to claim 2, wherein R ¹⁰ represents an alkyl group other than a methyl group or a substituted alkyl group. 6. The medical material according to claim 1, wherein R ⁸ represents a methyl group. 7. The medical material according to claim 6, wherein R ¹⁰ represents a methyl group. 8. The medical material according to claim 6, wherein R ¹⁰ represents hydrogen, an alkyl group other than a methyl group, or a substituted alkyl group. 9. The medical material according to claim 1, wherein R ⁸ represents an alkyl group other than a methyl group or a substituted alkyl group. 10. The medical material according to claim 9, wherein R ¹⁰ represents a methyl group. 11. The medical material according to claim 9, wherein R ¹⁰ represents hydrogen, an alkyl group other than a methyl group, or a substituted alkyl group. 12. The medical material according to claim 10, wherein R ⁴ represents a hydroxymethyl group or a hydroxymethyl group having a protected hydroxyl group. 13. The medical material according to claim 10, wherein R ⁴ represents hydrogen, an alkyl group, or a substituted alkyl group other than a hydroxymethyl group. 14. A peptide containing the peptide according to any one of claims 1 to 13 and a peripheral circulation improving agent, or surface-treated with the same, or containing one of these, and containing the other. Medical material characterized by surface treatment.