JP2619141B2 - Water soluble algin fiber containing antibiotics and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a water-soluble algin fiber containing an antibiotic and a method for producing the same.

[0002]

2. Description of the Related Art Alginate has been proposed to be used as a medical material for bandages, gauze, patches and the like because of its hemostatic action. As such algin fibers, water-insoluble algin fibers using polyvalent metal ions such as calcium ions as a coagulant are known.

A method for obtaining a bioreactor by incorporating enzymes and microorganisms into such water-insoluble algin fibers is described in Japanese Patent Publication No. 27720/1990.

[0004]

However, an attempt to entrap antibiotics in water-insoluble algin fibers involves an ion exchange reaction in the immobilization of the antibiotics. Not suitable. On the other hand, it has been revealed by the present inventors that water-soluble algin fibers can be obtained by so-called wet spinning in which an aqueous dope containing a water-soluble alginate is discharged and spun into a hydrophilic organic solvent. Hei 2-14534).

Accordingly, an object of the present invention is to provide a water-soluble algin fiber in which an antibiotic is entrapped (immobilized) in the fiber and a method for producing the same.

[0006]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies to obtain water-soluble algin fibers containing antibiotics. The present inventors have found a new fact that a comprehensive water-soluble algin fiber can be obtained, and have completed the present invention.

That is, according to the present invention, there is provided a water-soluble algin fiber containing an antibiotic. The antibiotic-encapsulated water-soluble algin fiber of the present invention can be obtained by so-called wet spinning in which an aqueous dope containing an antibiotic and a water-soluble alginate is spun into a hydrophilic organic solvent (hereinafter, referred to as a coagulation bath). it can.

[0008] The formation of the water-soluble algin fiber can be carried out by discharging an aqueous dope containing a water-soluble alginate into a large amount of a hydrophilic organic solvent, and replacing the water in the aqueous dope with the solvent. Also, the reason why antibiotics can be included in water-soluble algin fibers is not always clear, but one reason is that alginic acid has a carboxyl group, so it has a function as a medium for cation exchange. Since an exchange reaction occurs between the substance and a cation having a carboxyl group (for example, sodium ion), the bond between the antibiotic and the alginate is reinforced, and it is presumed that the antibiotic is included in the water-soluble algin fiber.

The water-soluble algin in the present invention includes:
Alginic acid sodium, magnesium, ammonium, organic amine salts, esters or mixtures thereof. Examples of the water-soluble organic amine salt of alginic acid include a triethanolamine salt, and examples of the water-soluble ester derivative of alginic acid include a propylene glycol ester of alginic acid.

[0010] Among the above water-soluble algins, sodium salts are preferred for obtaining fibers having high strength. The concentration of water-soluble algin in the aqueous dope is usually 3 to 20% by weight.
And particularly preferably in the range of 5 to 10% by weight. If the concentration of the water-soluble alginate is too low, the water-soluble alginate does not coagulate even if the dope is discharged into the coagulation bath, so that continuous fibers cannot be obtained. On the other hand, if the concentration of the water-soluble alginate is too high, the dope has a high viscosity, and it is not preferable because the fibers cannot be continuously discharged.

As the antibiotic to be included in the water-soluble algin fiber, for example, a cationic antibiotic having hydrophilicity is preferably used because the bonding strength with the water-soluble algin fiber is high and the entrapment ratio is high. . On the other hand, by use, antibiotics generally used for external use can be mentioned. Examples of such antibiotics include ceftizoxime, cephemoxime and other cephem antibiotics, benzylpenicillin, sulbenicillin, ampicillin, penicillin G and other penicillin antibiotics, kanamycin, tobramycin, dibekacin, gentamicin,
Aminoglycoside antibiotics such as micronomycin, asomycin and fradiomycin, macrolide / lincomycin antibiotics such as erythromycin and kitasamycin, tetracycline antibiotics such as oxytetracycline, tetracycline, demethylchlortetracycline, colistin, polymyxin B, chloramphenicol, micamycin, bacitracin, gramicidin S, antibacterial antibiotics such as fusidic acid, amphoterin B,
Examples include antifungal agents such as nystatin, miconazole, tricomycin, pimaricin, variotin, pyrrolenitrin, and sicanin. These antibiotics can be used alone or in combination of two or more.

Of course, antibiotics for injection can also be used. An aqueous dope containing an antibiotic and a water-soluble alginate can be obtained, for example, by adding an aqueous solution containing an antibiotic to an aqueous alginate solution and mixing. Also, the content of the antibiotic in the aqueous dope is usually based on the total amount of the water-soluble alginate,
Suitably, it is in the range of 0.25 to 2.0% by weight.

The hydrophilic organic solvent forming the coagulation bath has an appropriate hydrophilicity, has a high substitution rate with water in the aqueous dope, is a poor solvent for water-soluble alginate, and has a low molecular weight. Is preferred. This is because dehydration occurs from the alginate aqueous solution due to the action of the organic solvent and fibers are formed.If the hydrophilicity of the organic solvent is too low, separation of water from the alginate aqueous solution is not induced, and the fibers are continuously formed. This is because spinning cannot be performed. On the other hand, even if a hydrophilic organic solvent has a large molecular weight and a high viscosity, even if the organic solvent is brought into contact with the alginate aqueous solution to separate the water in the alginate aqueous solution, the diffusion of the water in the solvent is prevented. Since the water content is moderate, the water content is locally increased, and dehydration from the continuously discharged alginate does not occur continuously, which is not preferable. An organic solvent having a large number of hydroxyl groups is not preferable because it has a high affinity for an alginate having a large number of hydroxyl groups, which makes it difficult to separate the alginate from the organic solvent.

Accordingly, the hydrophilic organic solvents which can be suitably used in the present invention include, for example, lower aliphatic alcohols having 1 to 3 carbon atoms such as methanol, ethanol and isopropanol, acetone, dioxane, ethylene glycol monomethyl ether and dimethyl sulfoxide. Dimethylformamide, dimethylacetamide, acetonitrile, methyl ethyl ketone, phenol and the like.

These solvents can be used alone or in combination of two or more. Among them, acetone is preferred for obtaining fibers having high strength. According to the method for producing an antibiotic-containing water-soluble alginate fiber of the present invention, since an aqueous dope containing an antibiotic and a water-soluble alginate is discharged into a coagulation bath, the organic solvent forming the coagulation bath is inevitable. Will contain water. Therefore, in the present invention, it is desirable that the coagulation bath contains as little water as possible, but it is permissible to contain water. However, the amount of water that the coagulation bath may contain must, of course, be in a range that does not prevent coagulation of the alginate.

As described above, the coagulation bath is allowed to contain water, but the allowable limit varies depending on the organic solvent used. Coagulation bath in the present invention, the concentration of the organic solvent,
Usually, it is preferably at least 50% by weight, especially preferably at least 70% by weight. Most preferably, it is 80% by weight or more. If the concentration of the organic solvent is too low, fibers may not be obtained, or continuous fibers may not be obtained.

The coagulation bath is connected to a dewatering device and / or a drying solvent bath, and is adjusted so as to maintain a substantially constant water content during spinning. The temperature of the coagulation bath varies depending on the organic solvent used, the draw ratio of the fiber, and the like.
Within the range of 0 ° C. In order to produce water-soluble algin fibers containing antibiotics, it is important to discharge an aqueous dope containing an antibiotic and an alginate into a large amount of hydrophilic organic solvent, and quickly replace the water in the dope with the solvent. It is. Therefore, the hole diameter of the nozzle of the spinning machine and the discharge amount of the dope per nozzle in wet spinning are also important.

The diameter of the nozzle of the spinning machine is 0.025 to 1 m.
m, the discharge amount of the dope per nozzle is 0.001 to 1 m
Those in the range of 1 / min are each preferred. Further, the obtained antibiotic-encapsulated water-soluble algin fiber is preferably dehydrated with a dehydrating solvent such as acetone, and the obtained fiber is immersed in a dehydrating solvent, and after dehydration, the excess dehydrating solvent is removed. Then, it is desirable to heat and dry.

The thus obtained water-soluble algin fiber containing the antibiotic of the present invention is processed into a woven or nonwoven fabric. The nonwoven fabric can be obtained by a dry method such as a card method or an air lay method.

[0020]

According to the present invention, it is possible to obtain a water-soluble algin fiber containing an antibiotic conventionally used as an ointment or an injection. In addition, antibiotic-containing water-soluble algin fiber has antibacterial properties, and it is expected that the usefulness of antibiotics will be maintained.

[0021]

Examples 1 to 4 1214 ml of distilled water was added to 86 g of sodium alginate and kneaded in a kneader for about 4 hours to prepare a 6% by weight aqueous solution of sodium alginate, which was used as an aqueous sodium alginate dope. On the other hand, 1.42 g of polymyxin B
Sulfate (antimicrobial antibiotic) was added to 237 ml of distilled water to obtain an antibiotic solution. 118 to this antibiotic solution
Add 3 g of aqueous sodium alginate dope and add about 4
After kneading with a kneader for an hour, the mixture was filtered with a 200-mesh cloth to obtain an aqueous dope containing 0.1% polymyxin B (a dope containing 5% by weight of sodium alginate).

The dope containing 0.1% polymyxin B was put into a stock solution supply tank of a wet spinning machine (manufactured by Heishin), and was fed through a nozzle having 1,000 small holes of 0.1 mm in diameter.
The mixture was discharged into 1 liter of acetone at a discharge rate of 16.4 g / min and spun. The obtained fiber was wound up at 16 rpm with a 11.2 cm diameter cotette. The fiber was immersed in acetone once, excess acetone was wiped off with paper, and then dried at 100 ° C. for 30 minutes to obtain 0.1% polymyxin B-containing water-soluble algin fiber.

The aqueous dope containing 0.1% polymyxin B is diluted twice with a 5% by weight aqueous solution of sodium alginate, kneaded and filtered to obtain 0.05%, 0.025%
And 0.0125% of an aqueous dope containing polymyxin B, respectively, and further prepared in the same manner as described above.
025 and 0.0125% polymyxin B-encapsulated water-soluble algin fibers were obtained, respectively.

Measurement of the immobilization rate of polymyxin B Each of the aqueous dopes containing polymyxin B and the water-soluble algin fibers containing polymyxin B obtained in Examples 1 to 4 were subjected to a BCA reagent (manufactured by Pierce, Inc.) by colorimetric analysis of proteins. ) To form a 1% by weight sodium alginate solution, and 562 nm in a spectrophotometer (Hitachi).
At each concentration, and the immobilization rate of polymyxin B to polymyxin B-containing water-soluble algin fiber at each concentration was examined. The results are shown in FIG.

Examples 5 to 8 An aqueous dope of sodium alginate was prepared in the same manner as in Example 1 above. Next, 1.56 g of tetracycline hydrochloride (tetracycline antibiotic) was added to 260 ml of distilled water to obtain an antibiotic solution. To this antibiotic solution, add the above-mentioned sodium alginate aqueous dope,
After kneading in a kneader for about 4 hours, the mixture was filtered with a 200-mesh cloth to obtain an aqueous dope containing 0.1% tetracycline (a dope containing 5% by weight of sodium alginate).

The aqueous dope containing 0.1% tetracycline was treated in the same manner as in Example 1 to obtain a 0.1% tetracycline-containing water-soluble algin fiber. Further, the aqueous dope containing 0.1% tetracycline was diluted twice with an aqueous sodium alginate solution, kneaded and filtered to obtain 0.1%.
Aqueous dopes containing 05%, 0.025% and 0.0125% tetracycline were prepared, and then 0.05, 0.025 and 0.012 as in Example 1.
5% tetracycline-encapsulated water-soluble algin fibers were obtained respectively.

Measurement of the immobilization rate of tetracycline Using the fact that tetracycline shows absorption at 361 nm, each of the dope containing tetracycline and the tetracycline-encapsulated water-soluble algin fiber obtained in Example 5 was
Without coloring as in the case of polymyxin B, 1
A weight% sodium alginate aqueous solution was used, and the absorbance at 361 nm was measured with a spectrophotometer (manufactured by Hitachi), and the tetracycline immobilization rate of the tetracycline-containing water-soluble algin fiber at each concentration was examined. The result is shown in FIG.

Comparative Example 1 The aqueous dope containing 0.1% polymyxin B obtained in Example 1 was spun into a 5% calcium chloride solution.
In the same manner as in Example 1, polymyxin B-encapsulated water-insoluble algin fiber was obtained. Comparative Example 2 The same procedure as in Example 5 was carried out except that the aqueous dope containing 0.1% tetracycline obtained in Example 5 was spun into a 5% calcium chloride solution to obtain a water-insoluble tetracycline-encapsulated algin fiber. Was.

Examples 1 to 8 and Comparative Examples 1 and 2
The following becomes clearer. As is clear from FIG. 1, Example 1 (0.1%), Example 2 (0.05%),
Example 3 (0.025%) and Example 4 (0.012
5%), the absorbance of the polymyxin B-containing water-soluble algin fiber showed a high value, indicating that the water-soluble algin fiber contained polymyxin B. Moreover, the immobilization ratio (coverage ratio) is small and high as compared with the absorbance of the aqueous dope.

FIG. 2 shows that tetracycline is included in the water-soluble algin fiber also in the case of tetracycline. In the case of tetracycline, polymyxin B
Although the immobilization rate is slightly reduced as compared with the case of the above, the water-soluble algin fiber is still at least 6%.
It can be seen that it contains about 5% of tetracycline.

Compared with Examples 1 to 8, Comparative Examples 1 and 2, which are water-insoluble algin fibers, had low strength, and almost no immobilization of antibiotics was observed. Example 9 An amikacin-encapsulated water-soluble algin fiber was obtained in the same manner as in Example 1 except that a 0.05% amikacin sulfate solution (aminoglycoside antibiotic) was used.

Example 10 A gramicidin S-encapsulated water-soluble algin fiber was obtained in the same manner as in Example 1 except that a 0.05% gramicidin S-HCl solution (antibacterial antibiotic) was used. Comparative Example 3 An aqueous sodium alginate dope was prepared in the same manner as in Example 1, and the aqueous sodium alginate dope was treated in the same manner as in Example 1 to obtain a water-soluble algin fiber.

The antibacterial activity test bacterium Staphylococus aureus IFO 13276 Pseudomonas aeruginosa IFO 13275 Escherichia coli. IFO 3972 Each of the above three test bacteria was cultured for 24 hours at 37 ° C. on a nutrient-containing normal agar medium manufactured by Eiken Chemical Co., Ltd. After the bacterium, about 1 × 10 ⁵ cells were added to the aforementioned ordinary agar medium to prepare a plate medium. Next, the water-soluble algin fibers containing various antibiotics of Examples 1 to 10 and the water-soluble algin fibers obtained in Comparative Examples 1 to 3 were about 3 mm in width (1000 single fibers),
A test piece was cut into a size of 10 mm in length, attached to a plate medium of each of the above three types of bacteria, and cultured at 37 ° C. for 24 hours. After that, it is confirmed whether or not the inhibition zone of the bacteria is formed around each sample piece. If the inhibition zone is formed and the growth of the bacteria is not recognized, it is determined that the antibacterial activity is positive, and the minor axis of the inhibition zone is determined. +++: Minor axis of inhibition band 6 mm or more ++: Minor axis of inhibition band 4 mm or more and less than 6 mm +: Minor axis of inhibition band less than 4 mm-: No inhibition band was formed.

Table 1 shows the results of the above test. All the bacteria used were obtained from the Fermentation Research Institute, and in the same table, each microorganism was specified as follows. Staphylococus aureus IFO 13276: Fungus 1 Pseudomonas aeruginosa IFO 13275: Fungus 2 Escherichia coli. IFO 3972: Fungus 3

[0035]

[Table 1]

The following becomes clear from the results of Table 1. Examples 1 to 4 (polymyxin B-containing water-soluble algin fiber) were all bacteria 2 (Pseudomonas aeruginosa IFO 1).
3275) and fungus 3 (Escherichia coli. IFO 3972). Examples 5 to 8 (tetracycline-encapsulated water-soluble algin fiber) were all bacteria 2 (Pseudomonas aeruginosa IFO 1).
3275) and fungus 3 (Escherichia coli. IFO 3972).

Example 9 (Amikacin-encapsulated water-soluble algin fiber) was obtained from bacteria 1 (Staphylococus aureus IFO 13276),
Bacteria 2 (Pseudomonas aeruginosa IFO 13275) and Bacteria 3
(Escherichia coli. IFO 3972). Example 10 (Gramicidin S inclusive water-soluble algin fiber)
Has activity against fungus 1 (Staphylococus aureus IFO 13276).

Both Comparative Examples 1 and 2 (water-insoluble algin fibers) had some activity against Bacteria 2 and 3, but showed no activity against Bacteria 1. Comparative Example 3 (water-soluble algin fiber) showed no activity against any of bacteria 1, 2, and 3. From the above results, the antibiotic-containing water-soluble algin fiber is
It turns out that it has activity with respect to the above three kinds of bacteria. Also,
The presence of bacteria showing no activity in Examples 1 to 10 is considered to be due to the fact that each bacteria had resistance to individual antibiotics.

In each of the above embodiments, the aqueous dope contained an antibiotic. However, the antibiotic was not contained in the aqueous dope, and a water-soluble algin fiber was spun from the aqueous dope into a coagulation bath. The same effect can be obtained by immersing the water-soluble algin fiber in the antibiotic-containing liquid so that the water-soluble algin fiber contains the antibiotic.

[0040]

As described above, according to the method for producing water-soluble algin fiber containing antibiotics of the present invention, water-soluble algin fibers containing antibiotics can be obtained. The antibiotic-encapsulated water-soluble algin fiber of the present invention is an antibiotic that has been conventionally used as an ointment or an injection solution, and the water-soluble algin fiber is included in the water-soluble algin fiber. When used as a coating material, it is possible to prevent damage caused by bacteria such as infectious diseases, and it can be expected that the efficacy of antibiotics will be maintained longer than ointments and injection solutions. Therefore, the antibiotic-containing water-soluble algin fiber of the present invention can be suitably used as a medical material such as a gauze, a bandage, and a patch.

[Brief description of the drawings]

FIG. 1 is a graph showing the relationship between polymyxin B concentration and absorbance in a polymyxin B-containing aqueous dope and a polymyxin B-containing water-soluble algin fiber according to the present invention.

FIG. 2 is a graph showing the relationship between the concentration of tetracycline and the absorbance in a tetracycline-containing aqueous dope and a tetracycline-encapsulated water-soluble algin fiber according to the present invention.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Satoshi Fukuoka 2-3-3 Hananomiyacho, Takamatsu-shi, Kagawa Pref. Shikoku Industrial Technology Laboratory (72) Inventor Hideki Oiga 2-chome Hananomiyacho, Takamatsu-shi, Kagawa No. 3 Inside Shikoku Institute of Industrial Technology (72) Inventor Riki Asaoka 5-1-1 Ebishimacho, Sakai City, Osaka Prefecture (72) Inventor Hiroyuki Tenma 5 Ebishimacho, Sakai City, Osaka Prefecture No. 1 Sakai Chemical Industry Co., Ltd. Examiner Shunichi Yokoo

Claims (2)

(57) [Claims] 1. A water-soluble algin fiber containing an antibiotic, wherein the antibiotic is included in the water-soluble algin fiber. 2. A method for producing an antibiotic-containing water-soluble algin fiber, comprising spinning an aqueous dope containing an antibiotic and a water-soluble alginate into a hydrophilic organic solvent.