JP2008174513A - Protamine and boric acid-containing preservative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an aqueous composition having an excellent antibacterial, bacteriostatic, fungicidal and/or fungistatic effect even when the protamine content is small by synergistically improving antibacterial, antiseptic and preserving effects of protamine and boric acid by a simple method. <P>SOLUTION: The antibacterial, bacteriostatic, fungicidal and/or fungistatic composition containing boric acid at high concentration relative to protamine can be further incorporated with polysorbates and/or edetic acids. Specifically, boric acid is contained in an amount of 6-630,000 pts.wt. per 1 pt.wt. of the protamine. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an improved aqueous composition of a bactericidal, bacteriostatic, fungicidal and / or bacteriostatic composition obtained by blending protamine and a high concentration of boric acid.

Protamine is a protein obtained from a natural product, and has been conventionally used by being added to food as an antibacterial protein or a preservative. In the pharmaceutical field, it is also used as a heparin antagonist having a neutralizing effect on heparin.
On the other hand, boric acid is a component widely used as an antiseptic and buffer for eye drops. In addition, boric acid is known as a pharmaceutical additive for use as a stabilizer (buffer), a buffer, an isotonic agent, a pH adjuster, an antiseptic, a preservative, and a solubilizing agent. In this case, the administration route / maximum use amount is, for example, 18 mg / g (formulation weight) for a transdermal preparation, 20 mg / mL for an ophthalmic preparation, and 20 mg for an otolaryngological preparation. / ML and the like are known.

  In the preparation of borate buffer solution, borax used as necessary is also known for its use as a stabilizer (buffering agent), buffering agent, tonicity agent, pH adjusting agent, preservative, preservative. It has been. The route of administration and the maximum use amount are, for example, 5 mg / g (formulation weight) for general external preparations, 1 mg / g (formulation weight) for transdermal administration preparations, and for ophthalmic preparations. 4 mg / mL, 5.7 mg for otolaryngological preparations, and 5 mg for other external preparations are known.

By the way, some proposals have been made so far for the liquid agent containing the above protamine or boric acid and / or borax as a buffering agent. For example, bactericidal, bacteriostatic by cell wall degrading enzymes and / or oxidoreductases and protamine or protamine sulfate and combinations thereof for the preservation of foods, beverages, cosmetics, contact lens products, food ingredients or enzyme compositions, A fungicidal and / or fungistatic composition has been proposed (Patent Document 1).
Furthermore, as a composition for cleaning and disinfecting soft contact lenses, a hydrous solution containing a pH buffer (boric acid, etc.), an enzyme that acts on the cell wall / cell membrane of microorganisms, an antibacterial protein (for example, protamine or a salt thereof) and pimaricin A cleaning and disinfecting composition has been proposed (Patent Document 2).

  Moreover, as a preservative for eye drops containing protamine, for example, a preservative in which protamine is added to eye drops (EDTA, boric acid, borax, sodium chloride, propylene glycol, l-menthol, purified water) has been proposed. In addition, it is said that it exhibits a preservative effect against Escherichia coli, green-rich fungus, Staphylococcus aureus, Candida, and Aspergillus niger (Patent Document 3). Furthermore, an ophthalmic preparation containing thiamine lauryl sulfate and protamine sulfate has been proposed (Patent Document 4).

  Patent Document 1 specifically describes the antifungal and antifungal activities of protamine. According to this, for example, the minimum inhibitory concentration (MIC) of protamine is as high as 1000 μg / mL for A. niger. However, the fungistatic and fungicidal action of protamine is as high as the pH and low inoculum as well as the effect on bacteria, and an increase in pH results in a significant decrease in MIC, while the fungistatic action is killed. It has been reported that it was obtained at a protamine concentration 2 to 5 times lower than that used when determining fungal activity.

  The composition described in Patent Document 2 utilizes an enzyme reaction by a certain kind of enzyme involved in lysis of microorganisms, so-called lytic enzyme. Such a composition comprises an antibacterial protein (for example, protamine or a salt thereof) and pimaricin which is an antifungal agent used in ophthalmic solution or eye ointment for corneal mycosis, for example, protamine sulfate. And a 50 mM borate buffer solution (pH 7.5) are described, but the synergistic antifungal effect when protamine and boric acid are combined is described at all. It is not a thing.

  Furthermore, in Patent Document 3, by adding a predetermined amino acid to 0.01 to 0.1 g / 100 mL of protamine, the preservation effect is synergistically increased, and the growth of bacteria in eye drops can be suppressed. Although reported, the amount of protamine disclosed therein was large. Patent Document 4 is an ophthalmic preparation using thiamine lauryl sulfate as a preservative.

Thus, all of the compositions proposed so far use a considerably excessive amount of protamine, an antibacterial protein. For example, when used in eye drops, there is a problem in its practicality. It was.
Therefore, the development of an aqueous composition excellent in bactericidal, bacteriostatic, fungicidal and / or bacteriostatic properties while containing a small amount of protamine, which is a safe antibacterial protein of natural origin, is expected. .
Japanese National Patent Publication No. 10-505592 Japanese Patent Laid-Open No. 9-10288 (Japanese Patent No. 3655359) JP 2001-261552 A JP 2004-315472 A

  In view of the above situation, the present invention synergistically improves the antibacterial, antiseptic and preservative effects of protamine and boric acid by a simple method, and even if the protamine content is low, its sterilization, bacteriostatic, It aims at providing the aqueous composition excellent in the fungi and / or fungistatic effect.

  As a result of intensive studies to solve the above problems, the present inventors have found that a composition containing a small amount of protamine and high-concentration boric acid has the antibacterial, antiseptic and preservative effects that protamine and boric acid individually show. In order to complete the present invention, it is found that an excellent composition having improved bactericidal properties, bacteriostatic properties, fungicidal properties and / or bacteriostatic properties is obtained. It came.

  In the above-mentioned patent document, the liquid agent obtained by combining a small amount of protamine and high concentration boric acid is synergistically improved in antibacterial, antifungal, antiseptic and preservative effects of protamine. Is not described or suggested at all. Therefore, it can be said that the present invention is extremely specific in that respect.

Thus, the present invention specifically comprises the following configuration. That is,
(1) Bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous compositions containing high concentrations of boric acid relative to protamine,
(2) a bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous composition containing a high concentration of boric acid and edetic acids with respect to protamine;
(3) Bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous compositions containing high concentrations of boric acid and polysorbates relative to protamine,
(4) Bactericidal, bacteriostatic, fungicidal and / or fungistatic aqueous compositions containing high concentrations of boric acid and polysorbates and edetic acids with respect to protamine,
(5) Bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous composition according to claims 1 to 4, which contains 6 to 630000 parts by weight of boric acid per 1 part by weight of protamine.
(6) The bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous composition according to claims 1 to 4, which contains 600 to 63000 parts by weight of boric acid per 1 part by weight of protamine.
It is.

  According to the present invention, protamine, which is a safe antibacterial protein of natural origin, and inexpensive boric acid are combined in a specific blending ratio to synergize the antibacterial, antiseptic and preservative effects of protamine and boric acid, respectively. As a result, an excellent aqueous composition with improved bactericidal, bacteriostatic, fungicidal and / or bacteriostatic properties is proposed.

The bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous compositions containing a high concentration of boric acid relative to the protamine provided by the present invention can reduce the amount of protamine used so far. It can be suppressed to about 1/1000 to 1 / 10,000, for example, a dose of about 0.1 parts by weight with respect to 100 parts by weight of the eye drop, and a fungicidal action sufficient for the use of the eye drop It was confirmed that Therefore, the present invention has an advantage that the amount of expensive protamine used can be reduced.
In addition, since the aqueous composition proposed by the present invention can be used in a liquid form, it can be used as a highly safe antibacterial agent, preservative, preservative, for example, skin, mucous membrane, wound, bruise, microbial cell. It has the advantage that it can be used for sterilization, disinfection / disinfection of cosmetics, contact lens products, eye drops and the like.

As described above, the basic aspect of the present invention is a bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous composition containing a high concentration of boric acid with respect to protamine. .
The present invention will be described below.

Protamine, which is an antibacterial protein used in the composition provided by the present invention, is protamine or a salt thereof, and is naturally derived. As the salt of protamine, for example, protamine sulfate (derived from herring or salmon) is commercially available.
In the description of the present specification and claims, unless otherwise specified, protamine means a substance including both protamine or a salt thereof.

  The amount of protamine used in the aqueous composition in the present invention is not particularly limited, but the amount of protamine that has been conventionally proposed can be greatly reduced. Among these, 0.0001 to 10% by weight, preferably 0.0001 to 2% by weight, more preferably 0.0001 to 0.5% by weight, and particularly preferably 0.0001 to 0.2% by weight.

  On the other hand, boric acid or borax blended in an aqueous composition together with protamine is a normal standard product used as a pharmaceutical product. For example, a pharmacopoeia product described in the Japanese Pharmacopoeia can be used.

  When preparing the aqueous composition provided by the present invention, in addition to boric acid, borax may be added for pH adjustment. The borax to be added is used for adjusting the pH of the solution, and the amount used is not particularly limited. In this case, the amount of borax can be included in the blending amount by converting it into the amount of boric acid.

The amount of boric acid and borax used in the aqueous composition of the present invention varies depending on the type of protamine or its salt used, the amount used, and the type of other components added, and is not particularly limited.
According to studies by the present inventors, the antibacterial, antiseptic and preservative effects of each of protamine and boric acid are synergistically improved by containing a high concentration of boric acid for a small amount of protamine. It turns out that you can. Therefore, the blending amount is preferably 6 to 630,000 parts by weight of the total amount of boric acid and borax, more preferably 16 to 630,000 parts by weight, more preferably 1 part by weight of protamine. It is preferable to blend 60 to 630,000 parts by weight of boric acid, particularly preferably 600 to 630,000 parts by weight of boric acid.

The aqueous composition provided by the present invention can be prepared by a simple method known per se.
For example, protamine sulfate, isotonic agents such as sodium chloride and potassium chloride, stabilizers (or surfactants) such as polysorbate 80, boric acid and borax as a pH adjuster are dissolved in water and mixed uniformly. Can be prepared.
In the aqueous composition of the present invention, edetic acid as a stabilizer (or chelating agent), for example, sodium edetate, and other additives can be added as desired.
The amount of sodium edetate added as a stabilizer (or chelating agent) varies depending on the protamine used and is not particularly limited, but is 0.001 mg to 50 mg / 100 mL, preferably 0.001 mg to 40 mg / mg. 100 mL.

The pH of the aqueous composition prepared above is pH 5-8, preferably pH 7-8, more preferably around pH 7.
The osmotic pressure ratio is 0.8 to 1.2, preferably 0.9 to 1.1, and more preferably 0.95 to 1.05.

  The aqueous composition provided by the present invention is a liquid agent that can be used as it is, or when a concentrated one is prepared, it is appropriately diluted with water, as a highly safe antibacterial agent, preservative, preservative, For example, it can be used for skin, mucous membranes, wounds, bruises, microbial cell killing, cosmetics, sterilization / disinfection of contact lens products, eye drops and the like.

  Hereinafter, although an Example, a comparative example, various test examples, etc. are described and this invention is demonstrated further in detail, this invention is not limited by these description.

Examples 1-12:
Each component (unit: mg display) shown in Table 1 and Table 2 below is dissolved in purified water in order, adjusted to pH 7.0 to pH 7.5, sterilized and filtered, and the total amount is 100 mL with purified water. An aqueous composition was prepared. The osmotic pressure ratio at this time was in the range of 0.95 to 1.05.
In addition, the compounding ratio in Table 1 and Table 2 is a total compounding ratio of boric acid and borax to protamine, and is obtained by the following formula.
Mixing ratio = (total weight of boric acid + borax) ÷ (weight of protamine)

Comparative Examples 1-5:
Each component (unit: mg) shown in Table 3 below was dissolved in purified water in order, adjusted to pH 7.0, sterilized and filtered to a total volume of 100 mL with purified water to prepare a composition. The osmotic pressure ratio at this time was in the range of 0.95 to 1.05.

  In order to confirm that the cytotoxicity of the composition of the present invention is low, a cytotoxicity test was performed on each of the compositions obtained in the above Examples and Comparative Examples according to a conventional method.

1. Cytotoxicity test:
Survival of cells (rabbit cornea-derived cells: SIRC or human corneal epithelium-derived cells: HCE-T) by the following method using the aqueous compositions (hereinafter referred to as subjects) obtained in the above Examples and Comparative Examples. The rate was measured and calculated.

[Method]
・ Culture the cells at 35 mm dish for a predetermined time in each medium. ・ Aspirate the medium. ・ Add 1 mL of the subject solution (adjusted to 37 ° C., no pH adjustment). Wash 2 × PBS 2 times ・ Add 0.5 ml trypsin to dish, incubate at 37 ° C., 5% CO ₂ for 10 minutes ・ Transfer to dish for measurement while washing dish with 9.5 ml PBS (total 10 ml) )
・ Measure the number of cells per 0.1 mL with Coulter counter (Z2 type) [BECKMAN COULTER, manufactured by BECKMAN COULTER Co., Ltd.]

[Method of calculation]
Number of cells per dish = (Coulter counter measurement value−Blank measurement value of PBS only) × 10 ÷ 0.1
Viability = [number of sample cells ÷ average number of control cells × 100 (%)]

That is, it is the ratio of the number of cells in each sample treated with the subject solution when the average number of cells (control) simply washed with PBS without being treated with the subject solution is defined as 100.
All samples including the control group were tested at n = 3, and this was repeated twice or more. The “average of 2 times” data is obtained by calculating an average value (n = 3) × 2 and SD.

In addition, a cytotoxicity test of boric acid and protamine was also conducted.
(A) Boric acid cytotoxicity test:
A composition comprising purified water, boric acid, borax, and if necessary, sodium chloride and potassium chloride (pH 7.5 to 7.77 at this time, osmotic pressure ratio 0.95 to 1.07) is prepared, and the composition Each composition containing boric acid 800 mg, 1038 mg, 2000 mg, and 2500 mg per 100 mL was prepared, and the survival rate (%) was determined by a cell damage confirmation test according to a conventional method.
As a result, when SIRC cells were used, with boric acid, even when 2500 mg / 100 mL, the cell viability after 15 minutes exceeded 80%, and it was found that even this amount can be used sufficiently as a composition. .

(B) Cytotoxicity test of protamine:
Protamine sulfate is derived from a living body and originally has low cytotoxicity, but per 100 mL of each composition, 0 mg protamine sulfate (no addition), 0.016 mg, 0.16 mg, 1.6 mg, 16 mg , 32 mg, 64 mg, and 128 mg were prepared, and the survival rate (%) was determined by a cell damage confirmation test according to a conventional method.
As a result, it was found that when SIRC cells were used, the cell viability after 15 minutes exceeded 80% even when added at 128 mg / 100 mL, and there was no problem with cell damage.

The detailed results of these cytotoxicity tests were as follows.
(1) When the survival rate was determined using a subject containing 100 mg of protamine sulfate 0 mg (no addition), 0.016 mg, 0.16 mg, 1.6 mg, and 16 mg per 100 mL of boric acid, 30 minutes later The survival rates of all were over 80%.
(2) When the survival rate was determined using a subject containing 100 mg of protamine sulfate 0 mg (no addition), 16 mg, 32 mg, 64 mg, and 128 mg per 10 mL of boric acid, the survival rate after 30 minutes was 80 % Exceeded.
(3) When the survival rate was determined using subjects containing 100 mg of protamine sulfate 0 mg (no addition), 16 mg, 32 mg, 64 mg, and 128 mg per 2000 mL of boric acid, no addition and subjects containing 16 mg and 32 mg The survival rate after 30 minutes exceeded 80%.
In addition, the survival rate after 30 minutes of 64 mg of protamine sulfate was about 50%. The survival rate after 30 minutes of 128 mg protamine sulfate was about 30%.
(4) When the survival rate was determined using subjects containing 100 mg of protamine sulfate 0 mg (no addition), 16 mg, 32 mg, 64 mg and 128 mg per 2500 mL of boric acid, no addition and subjects containing 16 mg and 32 mg The survival rate after 30 minutes exceeded 80%.
The survival rate of protamine sulfate 64 mg after 30 minutes exceeded 60%. Moreover, the survival rate after 30 minutes of 128 mg of protamine sulfate was about 40%.

2. Preservation efficacy test About each aqueous composition obtained by the said Example and comparative example, according to a conventional method, for example, 15th revision Japanese Pharmacopoeia commentary book (F-344, June 20, 2006 first edition) reference information preservation | save The following preservation efficacy test was conducted according to the efficacy test method.

1) Test strain A: S. aureus
E. coli
P. aeruginosa
B: C. albicans
C: A. niger

2) Inoculum preparation method Test strain A: 32.0 ° C, 24 hours
SCD agar medium Test strain B: 22.5 ° C., 48 hours
Sabouraud glucose agar medium Test strain C: 22.5 ° C, 7 days
Sabouraud glucose agar medium After each culture, the suspension is diluted with a diluted solution to prepare inoculum solution of about 10 ⁸ CFU / mL.

3) Preparation and storage of sample solution Add 1/100 volume (theoretical number of bacteria) of the inoculum solution prepared to about 10 ⁸ CFU / mL to each composition, and mix uniformly to make the sample solution. . The sample solution is left in an incubator at 22.5 ° C.

4) Viable count measurement The sample solution is diluted appropriately every day, and the 15th revised Japanese Pharmacopoeia Microbiological Limit Test Method (2) The viable cell count is measured according to the Kanteng plate pour method. The measurement days are 7, 14, and 28 days.
Medium: SCD agar medium for bacteria Sabouraud, glucose agar medium for fungi

5) Criteria for preparation criteria: Category IA injection and sterile parenteral agent b. For bacteria: 14 days later: 0.1% or less of the number of inoculated bacteria (theoretical number of bacteria) 28 days later: the level after 14 days or less For fungi, 14 days later: the same or less than the number of inoculated bacteria (theoretical number of bacteria) 28 days later: If the level is less than or equal to the number of inoculated bacteria (theoretical number of bacteria), it is determined that there is a preservative effect.

The results of the storage efficacy test are shown in the following test examples.
Test Example 1: Preservation efficacy test of aqueous composition obtained by the production method of Example 1 above:
In the aqueous composition of Example 1, in the test strains excluding A. niger, the number of viable bacteria was less than the detection level after 7 days from the inoculation, and the number of viable bacteria in A. niger was also inoculated after 7 days. The number of bacteria decreased over time (see FIG. 1).

Test Examples 2-3: Preservation efficacy test of aqueous compositions obtained by the production methods of Examples 2-3:
Similar results to the composition of Example 1 were obtained.

Control Example 1: Preservation efficacy test of the aqueous composition obtained by the production method of Comparative Example 1
In the aqueous composition containing no protamine of Comparative Example 1 used as a control, a decrease in the number of bacteria over time was observed in the test strains except E. coli, but the storage effect was weaker than that of Test Example 1. As for E. coli, no decrease in the number of bacteria was observed after 28 days (see FIG. 2).

Test Examples 4 to 5: Preservation efficacy test of the aqueous compositions obtained by the production methods of Examples 4 to 5:
In these aqueous compositions, in the test strains excluding C. albicans, the viable cell count was below the detection level 7 days after the inoculation, and for C. albicans, the viable cell count was 0% after the 7th day. 0.1% or less, and thereafter the number of bacteria decreased with time.

Test Examples 6 to 8: Preservation efficacy tests of the compositions obtained by the production methods of Examples 6 to 8 above:
The test was conducted in the same manner as in Test Example 1.
Results similar to those of the composition of Example 1 were obtained (see FIG. 3).

Control Example 2: Storage efficacy test of the composition obtained by the production method of Comparative Example 2 described above:
The composition containing no protamine of Comparative Example 2 used as a control showed a decrease in the number of bacteria over time in the test strains excluding E. coli, but the storage effect was higher than that of Test Examples 6-8. For E. coli, a decrease in the number of bacteria was observed after 28 days, but did not meet the criterion value (see FIG. 4).
There was a tendency for the antibacterial property to be stronger than in Control Example 1.

Test Examples 9 to 11:
In order to confirm the minimum amount of protamine sulfate exhibiting a storage effect, a 7-day storage efficacy test was conducted on E. coli in the same manner as described above using the compositions obtained by the production methods of Example 1 and Examples 9-11. The subjects of Example 10 and Example 11 containing 0.0016 to 0.016 mg / 100 mL of protamine sulfate showed bacteriostatic and fungistatic properties, and contained 0.16 mg / 100 mL. The subject of Example 9 exerts bactericidal and fungicidal effects, and the viable count of E. coli 7 days after the inoculation is about one-tenth of the inoculum number. In composition No. 1, the viable count of E. coli 7 days after bacterial inoculation decreased to 0.1% or less. As a result, the strong synergistic effect of the composition of the present invention is exhibited when protamine sulfate is present in 100 mL of the composition in an amount of 0.001 mg or more, preferably about 0.16 mg or more, more preferably about 1.6 mg or more. it is conceivable that.

Test Example 12: Preservative efficacy test of the composition obtained by the production method of Example 12:
In the composition containing 400 mg / 100 mL of boric acid of Example 12 and 1.6 mg / 100 mL of protamine sulfate, a decrease in the number of bacteria over time was observed in all test strains except A. niger. Also showed bacteriostatic and fungistatic properties.

  The compositions of Comparative Examples 3 to 5 are compositions using a phosphate buffer that is usually used as a buffer instead of boric acid and borax. In the composition containing 3 to 16 mg / 100 mL of protamine sulfate of Comparative Examples 3 to 4, no preservative effect was observed. In the subject of Comparative Example 5 containing 160 mg / 100 mL of protamine sulfate, the number of bacteria fell below the detection level after 7 days for E. coli, 14 days for P. aeruginosa, and 28 days for S. aureus. However, for A. niger and C. albicans, only a fungistatic effect was observed (see FIG. 5).

When the results of Comparative Example 5 and the results of Example 3 are compared, it can be seen that protamine alone has no fungicidal effect, but shows a remarkable fungicidal effect when combined with boric acid.
Based on the above results, the antibacterial and bacteriostatic effects of protamine sulfate alone or boric acid alone, when combined with protamine sulfate and boric acid, far more than the amount of protamine alone used Antibacterial and bacteriostatic effects could be expressed with a small amount. This phenomenon is specific to the combination of protamine sulfate and boric acid, and it has been clarified that a composition composed of protamine and boric acid at a high concentration exhibits a remarkable synergistic effect.

According to the present invention, the antibacterial, antiseptic and preservative effects of protamine and boric acid are synergistically improved in a simple manner by combining safe antibacterial protein of natural origin and inexpensive boric acid at a specific blending ratio, A composition with improved bactericidal, bacteriostatic, fungicidal and / or bacteriostatic properties could be obtained.
The composition of the present invention does not require the use of an antibacterial agent such as benzalkonium chloride which is irritating to conventional eyes. Further, the amount of expensive protamine used can be reduced by the present invention. In addition, since the composition of the present invention can be used in a liquid form, as a highly safe antibacterial agent, preservative, preservative, for example, skin, mucous membrane, wound, bruise, killing of microbial cells, There are uses such as eye drops as a preservative of eye drops that do not cause sterilization of cosmetics and contact lens products, or corneal epithelial cells, and are industrially useful.

FIG. 3 is a diagram showing an antibacterial action of the composition of Example 1. The vertical axis represents the viable cell count (CFU / mL), and the horizontal axis represents the storage days. It is a figure which shows the antibacterial action of the composition of the comparative example 1. The vertical axis represents the viable cell count (CFU / mL), and the horizontal axis represents the storage days. It is a figure which shows the antibacterial effect of the composition of Example 6. The vertical axis represents the viable cell count (CFU / mL), and the horizontal axis represents the storage days. It is a figure which shows the antibacterial effect of the composition of the comparative example 2. The vertical axis represents the viable cell count (CFU / mL), and the horizontal axis represents the storage days. It is a figure which shows the antibacterial action of the composition of the comparative example 5. The vertical axis represents the viable cell count (CFU / mL), and the horizontal axis represents the storage days.

Claims (6)

  Bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous compositions containing high concentrations of boric acid relative to protamine.   A bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous composition containing a high concentration of boric acid and edetic acids relative to protamine.   A bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous composition containing a high concentration of boric acid and polysorbates relative to protamine.   A bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous composition containing a high concentration of boric acid and polysorbates and edetic acids with respect to protamine.   The bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous composition according to claims 1 to 4, comprising 6 to 630,000 parts by weight of boric acid per 1 part by weight of protamine.   The bactericidal, bacteriostatic, fungicidal and / or bacteriostatic aqueous composition according to claims 1 to 4, comprising 600 to 63,000 parts by weight of boric acid per 1 part by weight of protamine.

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