JPH04244029A - Antibacterial topical agent - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antibacterial topical preparation suitable for local application to ulcers caused by injuries, burns, frostbite, and other injuries, as well as by certain diseases.

0002

BACKGROUND OF THE INVENTION In the healing process of ulcers caused by injury, burns, frostbite, and other trauma, and certain diseases, infection with various microorganisms has a significant effect on wound healing. That is, the exudate on the wound surface increases, causing the wound surface to expand, and causing necrosis and suppuration due to bacterial toxins. In addition, if these symptoms continue for a long time and become chronic ulcers, bedsores, leg ulcers,
Symptoms such as ischemic ulcer and neurogenic ulcer appear. especially,
Pressure ulcers are intractable ulcers that occur on bony protrusions such as the back and lower legs of debilitated patients who have been in bed for a long period of time, and are a type of pressure necrosis. It most commonly occurs in the sacrum, and other areas such as the greater trochanter, ilium, calcaneus, and scapula.

[0003] Bedsores begin with redness and progress to induration, necrosis, and ulceration, but in advanced cases, necrosis affects not only the skin but also the fascia and muscle layer, and even the bones and joints. In patients with spinal cord injuries or impaired consciousness, factors such as local pressure and friction, unclean skin, irritation from human urine, malnutrition, and atrophy of subcutaneous fat are factors that can cause it. Although the reaction of the surrounding tissues is extremely slight and there is little tendency for treatment, the systemic condition often worsens due to leakage of proteins from the wound surface and infection. Therefore, once this occurs, it may cause sepsis and become a major obstacle to subsequent rehabilitation and social reintegration.

Conventionally, antibiotics, sulfa drugs, steroids, iodine and other bactericidal disinfectants,
Proteolytic enzymes such as trypsin are used (for example, JP-A-61-186312). However, all of these treatments are for temporary trauma or burns, and long-term use for chronic ulcers poses problems such as the development of resistant bacteria and a decrease in antibacterial activity. In addition, an antibacterial topical preparation containing silver-containing sulfa drugs as an active ingredient has been proposed (Japanese Patent Application Laid-Open No. 53-44
No. 615, JP-A No. 63-51865). Although this is a useful drug that utilizes the antibacterial power of silver, there are problems with side effects due to absorption of the sulfa drug component, and no satisfactory antibacterial topical preparation has yet been found.

[0005]

[Problem to be solved by the invention] To prevent various microbial infections such as Pseudomonas aeruginosa, Staphylococcus, Enterobacter spp., and Candida spp. in ulcers caused by trauma such as injury, burns, frostbite, and certain diseases, and to heal the wounds. As an antibacterial topical drug that promotes this, it is required to have (1) extremely low skin irritation, (2) no resistance acquisition, and excellent antibacterial persistence, but a fully satisfactory drug has not yet been found.

[0006]

[Means for Solving the Problems] As a result of intensive research in view of the above problems, the present inventors have discovered that an antibacterial topical agent containing an aluminosilicate containing antibacterial metal ions can be used to treat injuries, burns, frostbite, etc. The present invention was completed based on the discovery that it has a high therapeutic effect on ulcers and chronic ulcers caused by trauma or certain diseases, and is also extremely safe for the human body, including skin irritation. That is, an object of the present invention is to provide an antibacterial agent for external use that is extremely safe for the human body, such as skin irritation, and has excellent long-lasting effects.

The present invention will be explained below. In the present invention, examples of the aluminosilicate include crystalline aluminosilicate and amorphous aluminosilicate, which are generally called zeolites. Here, as the "zeolite", both natural zeolite and synthetic zeolite can be used. Zeolites are generally aluminosilicates with a three-dimensional skeletal structure and have the general formula XM2
/nO ・Al2O3 ・YSiO2 ・ZH2O. Here, M is a metal ion which is an ion-exchangeable ion. n is the valence of the (metal) ion. X and Y represent the respective metal oxide and silica coefficients, and Z represents the number of crystal water. Specific examples of zeolites include A-type zeolite, X-type zeolite, Y-type zeolite, T-type zeolite, high silica zeolite, sodalite, mordenite, analcyme, clinoptilolite, chabasite, erionite, etc. can be mentioned. However, it is not limited to these.

In the present invention, hydrated amorphous aluminosilicate is also included in aluminosilicate. Amorphous aluminosilicate (hereinafter referred to as AAS) is generally represented by the compositional formula xM2O.Al2O3.ySiO2.zH2O, where M is generally an alkali metal element such as sodium or potassium. Moreover, x, y, and z each indicate the molar ratio of metal oxide, silica, and crystal water. Unlike the crystalline aluminosilicate called zeolite, AAS is an amorphous material that does not show a diffraction pattern even in X-ray diffraction analysis, and the synthesis process produces extremely fine zeolite crystals of several tens of angstroms. SiO2, Al2O3 are formed on the surface.
, M2O, etc. are believed to be attached to the amorphous material in a complex manner. AAS is generally produced by reacting an aluminum salt solution, a silicon compound solution, and an alkali metal salt solution at a predetermined concentration at a low temperature range of 60° C. or lower, and washing with water before crystallization proceeds. AAS produced by such a method has almost the same water adsorption performance and ion exchange performance as zeolite. Examples of manufacturing methods include JP-A-53-30500 and JP-A-61-174.
There is a method described in No. 111, etc.

[0009] There is no particular restriction on the particle size of the aluminosilicate used in the present invention, but from the viewpoint of preparing a skin external preparation with good dispersibility, it is preferable that the particle size is relatively small. The particle diameter of the powder is suitably in the range of, for example, 0.04-20 μm, preferably 0.5-5 μm.

[0010] The aluminosilicate used in the present invention replaces some or all of the ion exchangeable ions in the aluminosilicate, such as sodium ions, calcium ions, potassium ions, magnesium ions, iron ions, etc. with antibacterial metal ions. It is prepared by ion exchange.

[0011] In this specification, % refers to weight % on a dry basis at 110°C.

The method for producing the antibacterial metal ion-retaining zeolite (hereinafter referred to as antibacterial zeolite) used in the present invention will be explained below. For example, the antibacterial zeolite used in the present invention can be prepared by contacting the zeolite with a pre-prepared aqueous solution containing antibacterial metal ions such as silver ions, copper ions, zinc ions, or tin ions. The above ions are replaced. Contact is 10
It can be carried out at ~70°C, preferably 40-60°C, for 3-24 hours, preferably 10-24 hours by a batch method or a continuous method (e.g. column method). In addition, p of the above aqueous solution
It is appropriate to adjust H to 3-10, preferably 5-7. This adjustment is preferable because it can prevent silver oxides and the like from being deposited on the zeolite surface or into the pores. Further, each ion in the aqueous solution is usually supplied as a salt. For example, silver ions include silver nitrate, sulfate, silver perchlorate, silver acetate, diamine silver nitrate, diammine silver sulfate, etc., and copper ions include nitrate (II), copper sulfate, copper perchlorate, copper acetate, copper tetracyano. Potassium acid, etc., zinc ions such as zinc nitrate, zinc sulfate, zinc perchlorate, zinc thiocyanate, zinc acetate, etc. can be used, and tin ions, such as tin sulfate and tin nitrate, can be used.

The content of silver ions, etc. in the zeolite can be appropriately controlled by adjusting the concentration of each ion (salt) in the aqueous solution. For example, when the antibacterial zeolite contains silver ions and zinc ions, the silver ion concentration in the aqueous solution is 0.2 M/liter to 3.7 M/liter, and the zinc ion concentration is 0.01 M/liter to 2.0 M/liter.
By adjusting the amount to 0 M/liter, an antibacterial zeolite having a silver ion content of 1 to 30% and a zinc ion content of 1 to 15% can be obtained as appropriate.

In the present invention, in addition to using a mixed aqueous solution containing two or more types of metal ions, an aqueous solution containing each ion alone is used, and by sequentially bringing each aqueous solution into contact with zeolite, two or more types of ions can be extracted. It can also be exchanged. The concentration of each ion in each aqueous solution can be determined according to the concentration of each ion in the mixed aqueous solution.

[0015] Furthermore, ammonium ions can be added to the aqueous solution for ion exchange for the purpose of stabilizing antibacterial metal ions during ion exchange.

After ion exchange, the zeolite is thoroughly washed with water and then dried. Drying is at normal pressure at 105℃~1
15℃ or reduced pressure (1 to 30 torr) 70 to 90
Preferably, the reaction is carried out at ℃.

The antibacterial metal ion-retaining AAS to be incorporated into the antibacterial external preparation of the present invention can be prepared in accordance with the method for the antibacterial zeolite described above.

[0018] It is particularly preferable that the antibacterial metal ion-retaining aluminosilicate to be incorporated into the antibacterial external preparation of the present invention contains silver and zinc because it has high skin astringency and, as a result, speeds up wound healing. The content is 1-30% silver and 1-1% zinc.
5%, preferably 2 to 10% of silver and 6 to 13% of zinc are desirable from the viewpoint of sustaining the antibacterial effect for a long period of time and further promoting wound healing.

The antibacterial external preparation of the present invention is prepared by mixing the active ingredient, an antibacterial metal ion-retaining aluminosilicate, with various diluents, and preparing it in the form of a suspension, ointment, cream, spray, gauze coating, etc. It can be used in various forms depending on the type of treatment, such as a poultice, a spray, or a tape.

[0020] The formulation method is to dilute the antibacterial metal ion-retaining aluminosilicate with a liquid substance used in known antibacterial topical drugs, such as alcohol or propylene glycol, when it is used in the form of a suspension. It can be used as

When used in the form of an ointment, it can be diluted with a known oil-based base such as liquid paraffin, white petrolatum, ceresin, squalane, glycerin, plastibase, silicone, vegetable oil, lard or the like.

When used in the form of a cream (emulsion), there are two types: oil-in-water emulsion type and water-in-oil emulsion type. Cream can be obtained by adding a surfactant to the above-mentioned oily base and dispersing it uniformly, and then diluting it by gradually adding water in which antibacterial metal-retaining aluminosilicate is dispersed, macrogol, solbase, or other water-soluble base. Can be done. Oil-in-water emulsion type and water-in-oil emulsion type are determined by the hydrophilic group-hydrophobic group balance value (HLB value) of the surfactant used.
Determined by. Generally, a surfactant with an HLB value of 8 or more will result in an oil-in-water emulsion type cream, and a surfactant with an HLB value of less than 8 will result in a water-in-oil emulsion type cream.

Surfactants that can be used in the external antibacterial preparation of the present invention include anionic surfactants with an HLB value of 8 or more such as triethanolamine oleate, sodium oleate, potassium oleate, N- Cetyl
Cationic surfactants such as N-ethylmorpholinium ethosulfate, glycerin monostearate, glycerin trioctanoate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan cetyl ether, poly Mention may be made of nonionic surfactants such as oxyethylene sorbitan monolaurate. Examples of those having an HLB value of less than 8 include oleic acid, sorbitan trioleate, sorbitan sesquioleate, and sorbitan monooleate.

Among the above-mentioned forms, the antibacterial external preparation of the present invention is said to have easy dispersion of the antibacterial metal ion-retaining aluminosilicate in the antibacterial external preparation, high absorbency, and good adhesion to the wound surface. From this point of view, oil-in-water emulsion type creams are preferred.

The content ratio of the antibacterial metal ion-retaining aluminosilicate in the antibacterial external preparation of the present invention is usually 0.
．． It is desirable to adjust the content to 1 to 20%, preferably 1 to 10%, from the viewpoint of obtaining effective medicinal effects.

In addition to the above-mentioned essential ingredients, the antibacterial external preparation of the present invention contains pharmaceutical auxiliaries such as viscosity modifiers, dispersants, wetting agents, emollients, stabilizers, pigments, fragrances, and pH buffers. It can also contain agents etc. Furthermore, carriers for preparations for preparing various forms of external preparations may be added.

[0027] The antibacterial external preparation of the present invention can be administered, for example, once a day.
It is appropriate to apply it directly to a thickness necessary and sufficient to cover the wound surface (approximately 2 to 3 mm) using sterile gloves or the like. Alternatively, it can be rolled out to a similar thickness and applied to gauze, etc., and used as a bandage. In addition, when applying this agent on the second day and thereafter, it is appropriate to wash off the agent applied on the previous day by wiping or taking a warm water bath, and then reapplying this agent.

[0028]

[Effects of the Invention] The antibacterial external preparation of the present invention has a healing effect on skin disorders caused by microorganisms. For example, acne, seborrhea,
It is also effective against chronic eczema, acne, scabies, ringworm, and other mild inflammations.

The antibacterial topical preparation of the present invention has a high therapeutic effect on ulcers caused by injuries, burns, frostbite, and other traumas, as well as ulcers caused by certain diseases, or chronic ulcers, and is also extremely safe for the human body due to skin irritation. expensive.

[0030]

[Examples] Next, embodiments of the present invention will be explained with reference to Examples, but the present invention is not limited to the Examples.

Reference Example (Preparation of antibacterial metal ion-retaining aluminosilicate) Aluminosilicate is commercially available A-type zeolite (Na2O
・Al2O3 ・2. OSiO2 ・XH2O: average particle size 1.1 μm), Y-type zeolite (Na2O・Al2
O3 ・4. OSiO2 ・XH2O: Average particle size 0.7
μm), amorphous aluminosilicate (JP-A-61-174
Three types (prepared by the method of No. 111: 0.3 μm) were used. Three types of salts, AgNO3, Zn(NO3)2 and NH4NO3, were used to provide each ion for ion exchange. Table 1 shows the type of aluminosilicate used in preparing each sample and the type and concentration of salt contained in the mixed aqueous solution. No. 1~No. Six types of antibacterial metal ion-retaining aluminosilicate samples were prepared.

For each sample, 1 kg of aluminosilicate powder was heated and dried at 110°C, suspended in 1 liter of water, and 100 ml of 0.05N nitric acid aqueous solution was added to this.
/ Dropped at a dropping rate of 30 minutes to a predetermined pH value (5 to 7)
Adjusted to. Next, 3 liters of a mixed aqueous solution of antibacterial metal salts at a predetermined concentration was added to the slurry for ion exchange. The reaction was stirred at room temperature to 60°C for 10-24 hours to reach equilibrium.

After the ion exchange was completed, the aluminosilicate phase was filtered and washed with room temperature water or warm water until the excess exchanged cations in the aluminosilicate phase were removed. Next, sample 1
Six types of samples were obtained by heating and drying at 10°C.

[0034]

[Table 1]

Example 1 (Preparation of ointments) Ointments containing antibacterial metal ion-retaining aluminosilicate were prepared according to the formulations shown in Table 2 (Examples 1-1 to 1-8). As comparative examples, an ointment base containing only an ointment base containing no antibacterial metal ion-holding aluminosilicate (Comparative Example 1) and an ointment base containing zinc oxide (Comparative Example 2) were similarly prepared.

[0036]

[Table 2]

Example 2 (Preparation of Cream) Creams containing antibacterial metal ion-retaining aluminosilicate were prepared according to the formulations shown in Table 3 (Examples 2-1 to 2-8). Comparative examples include one that does not contain antibacterial metal ion-holding aluminosilicate (Comparative Example 3), one that contains silver sulfadiazine, a silver-sulfa agent (Comparative Example 4), and one that contains gentamicin, an antibiotic (Comparative Example 5). was prepared in the same manner.

[0038]

[Table 3]

Test Example 1 (Antibacterial Activity Test) Using the antibacterial metal ion-retaining aluminosilicate powder obtained in Reference Example, the antibacterial activity against various fungi was investigated by the following method. Assay method: Heart infusion agar (Heart i) was used for bacteria.
fusion agar), yeasts and molds by the agar plate dilution method using Sabouraud agar. Table 4 shows the strength of antibacterial activity against various microorganisms in terms of the minimum inhibitory concentration (MIC) of the antibacterial metal ion-retaining aluminosilicate.

[0040]

[Table 4]

Test Example 2 (Resistance Acquisition Test) Pseudomonas aeruginosa was incubated with Muller-Hinton broth (Muller-Hinton broth).
The inoculated bacteria were cultured in a broth (broth) medium at 37°C for 18 hours (8.6 x 107 cells/ml). One platinum loopful of the inoculated bacterial solution was inoculated into a medium containing the antibacterial metal ion-retaining aluminosilicate obtained in the reference example, silver sulfadiazine, and gentamicin adjusted to various concentrations, and cultured at 37°C for 24 hours. Obvious turbidity was observed. One platinum loop of the obtained bacterial solution at the maximum concentration was similarly inoculated into broths containing the following various concentrations, and subculturing was repeated for 30 generations, and the minimum inhibitory concentration of each generation was measured. The results are shown in Figure 1.

Test Example 3 (Antibacterial test of external antibacterial agent) The external antibacterial agent prepared in the example was placed on a 3 x 3 cm2 filter paper for approximately 1 m.
It was applied uniformly to a thickness of m. 0.1 ml of each bacterial solution was spread on a plate culture medium for each bacterial species using a Ronlarge rod, and the mixture was brought into close contact with the plate medium and cultured at 37°C for 24 hours. As a control, a sample without the above antibacterial topical preparation was also tested. After culturing, the filter paper was removed, and 1 cm2 of the culture medium was taken, placed in 10 ml of sterile physiological saline, stirred, diluted at a certain ratio, and the number of bacteria was measured. The results are shown in Table 5.

[0043]

[Table 5]

Test Example 4 (Animal test using burn model) A circular second-degree burn with a diameter of 20 mm was created on the back of a rat, and 1×102 pieces of Pseudomonas aeruginosa were inoculated into this, and the bacteria were allowed to grow by covering the burn. , causing a burn infection wound to form. To this wound, 0.5 g each of the antibacterial metal ion-retaining aluminosilicate-containing preparation prepared in the example and the zinc oxide and silver sulfadiazine preparations were administered. As a control, a test in which the wound surface was simply covered with gauze was also conducted in the same manner. The healing effect was evaluated by calculating the number of days required for the scab (temporary skin-like substance formed by blood and tissue fluid) to fall off during the healing process and the number of days required for complete healing, as the average number of days for six samples. . The results are shown in Table 6.

[0045]

[Table 6]

Test Example 5 (rabbit skin irritation test)

004
7] A test was conducted on 50 rabbit specimens. The hair near the midline of the rabbit's spine was shaved with electric clippers the day before application, and six application sites each measuring 2.5 x 2.5 cm were set. Of the six application sites, three were on healthy skin and the remaining three were on skin with exfoliated stratum corneum. The stratum corneum-exfoliated skin was prepared by making a cross-shaped wound using a syringe needle just before the start of application, to the extent that the dermis would not be scratched or bleeding. After the patch was applied to the back skin, it was fixed to adhesive tape (Elasticon (registered trademark), manufactured by Johnson & Johnson) so that it would not move. The application time was 24 hours, and after the application was completed, the adhesive tape was removed and the test substance was removed by wiping with absorbent cotton soaked in water.

Examples 1-1, 1-2, 1-5, 2-1,
0.5 g of the antibacterial external preparations obtained in 2-5, 2-6 and Comparative Examples 4 and 5 were applied to the above skin, and evaluation was made based on the number of samples in which erythema occurred at even one spot among each sample. The results are shown in Table 7.

[0049]

[Table 7]

Test Example 6 (Acute Toxicity Test) Two rats each aged 4 to 6 weeks were housed in a breeding room at a room temperature of 23° C. and a humidity of 55%. Oral administration was performed using a gastric probe after fasting for about 16 hours. For transdermal administration, an area of about 4 x 5 cm in the center of the back was shaved using electric clippers on the day before administration, a predetermined amount was placed on gauze, moistened with distilled water for pharmacopoeial injections, and the gauze was applied to the shaved area. The application site was further covered with aluminum foil and fixed with elastic tape. After about 24 hours, residual test substance was removed with water. As a control, in the case of oral administration, there was a group administered with pharmacopoeial distilled water for injection, and in the case of transdermal administration, a group was prepared in which gauze was soaked with distilled water for pharmacopoeial injection and applied. The results are shown in Table 8.

[0051]

[Table 8]

[Brief explanation of the drawing]

[Figure 1] Pseudomonas aeruginosa (Pseud)
omonas aeruginosa) Resistance acquisition test results are shown.

Claims (5)

[Claims] 1. An antibacterial external preparation comprising an aluminosilicate containing antibacterial metal ions as an active ingredient. 2. The antibacterial external preparation according to claim 1, which is an oil-in-water emulsion type cream. 3. The antibacterial external preparation according to claim 1, which contains 0.1 to 20% of aluminosilicate retaining antibacterial metal ions. 4. The antibacterial external preparation according to claim 1, which contains 1 to 10% of aluminosilicate retaining antibacterial metal ions. 5. The antibacterial method according to claim 1, wherein the antibacterial metal ions are silver ions and zinc ions, and the content of silver ions is 1 to 30%, and the content of zinc ions is 1 to 15%. Topical preparation.