JP3169621B2 - Antimicrobial external preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art In the healing process of ulcers caused by trauma such as injury, burns and frostbite and certain diseases, infection of various microorganisms has a significant effect on wound healing. In other words, the exudate on the wound surface increases to cause enlargement of the wound surface, necrosis or suppuration by bacterial toxins. If these symptoms persist for a long time and result in chronic ulcers, pressure ulcers, leg ulcers,
Symptoms such as ischemic ulcer and neural ulcer appear. In particular,
Pressure ulcers are intractable ulcers that occur on prominent bones such as the back and lower limbs when a weak patient sleeps for a long time, and is a type of pressure necrosis. It occurs most often in the sacrum, and also in the greater trochanter, iliac, calcaneus, and scapula.

[0003] Pressure ulcers begin with redness and progress with induration, necrosis, and ulceration. However, at a high altitude, necrosis affects not only the skin but also the fascia and muscle layer, and extends to bones and joints.
In patients with spinal cord injury or impaired consciousness, in addition to local pressure and friction, unclean skin, irritation by human waste, nutritional loss, atrophy of subcutaneous fat, and the like may be factors. Although the response of the surrounding tissues is very slight and there is little tendency for treatment, systemic conditions often worsen due to leakage or infection of proteins from the wound surface. Therefore, once this occurs, it may cause sepsis or a major obstacle to subsequent rehabilitation and rehabilitation.

[0004] Conventionally, such ulcers have been treated with bactericidal disinfectants such as antibiotics, sulfa drugs, steroids and iodine.
Proteolytic enzymes such as trypsin and the like have been used (for example, JP-A-61-186312). However, all of these are intended for transient trauma and burns, and long-term use of chronic ulcers has a problem that resistance-acquiring bacteria are generated and antibacterial activity is reduced. Also, an antibacterial external preparation containing a sulfur agent containing silver as an active ingredient has been proposed (JP-A-53-44).
615, JP-A-63-51865). Although this is a useful drug using the antibacterial power of silver, there is a problem of side effects due to absorption of the sulfa drug component, and no satisfactory antibacterial external preparation has been found.

[0005]

SUMMARY OF THE INVENTION Wound healing is prevented by preventing various microbial infections such as Pseudomonas aeruginosa, Staphylococcus, Enterobacter and Candida in ulcers caused by trauma such as injury, burns and frostbite and certain diseases. A topical antibacterial agent that promotes antibacterial activity is required to have extremely low skin irritation, no resistance, and excellent antimicrobial sustainability, but no satisfactory agent has yet been found.

[0006]

The present inventors have conducted intensive studies in view of the above-mentioned problems, and as a result, have found that an antibacterial external preparation containing an aluminosilicate holding an antibacterial metal ion may be damaged, burned, frosted, etc. The present inventors have found that the present invention has a high therapeutic effect on ulcers and chronic ulcers caused by trauma and certain diseases, and has extremely high safety to the human body such as skin irritation, and has completed the present invention. That is, an object of the present invention is to provide an antibacterial external preparation having extremely high safety against the human body such as skin irritation and having a long lasting effect.

Hereinafter, the present invention will be described. In the present invention, examples of the aluminosilicate include a crystalline aluminosilicate generally called zeolite and an amorphous aluminosilicate. Here, as the “zeolite”, both natural zeolites and synthetic zeolites can be used. Zeolites are aluminosilicates that generally have a three-dimensional skeletal structure and have the general formula XM _{2 / n}
Is displayed in _{O · Al 2 O 3 · YSiO} 2 · ZH 2 O. Here, M is a metal ion of an ion-exchangeable ion. n is the valence of the (metal) ion. X and Y indicate the respective metal oxides and silica coefficients, and Z indicates the number of water of crystallization.
Specific examples of the zeolite include, for example, A-type zeolite, X-type zeolite, Y-type zeolite, T-type zeolite, high silica zeolite, sodalite, mordenite, analsim, clinoptilolite, chabazite, erionite, etc. Can be mentioned. However, it is not limited to these.

In the present invention, a hydrate of an amorphous aluminosilicate is also included in the aluminosilicate. Amorphous aluminosilicate (hereinafter referred to as AAS) generally has a composition formula
appears in _{xM 2 O · Al 2 O 3} · ySiO 2 · zH 2 O, where M is an alkali metal element generally sodium or potassium.
In addition, x, y, and z indicate the molar ratios of metal oxide, silica, and water of crystallization, respectively. Unlike crystalline aluminosilicate, which is called zeolite, AAS is an amorphous substance that does not show a diffraction pattern even in X-ray diffraction analysis. In its synthesis process, extremely fine zeolite crystals of tens of angstroms are formed. It is considered to have a structure in which an amorphous substance in which SiO ₂ , Al ₂ O ₃ , M ₂ O, etc. are combined in a complex manner adheres to the surface thereof. AAS is generally produced by reacting an aluminum salt solution, a silicon compound solution and an alkali metal salt solution at a predetermined concentration in 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. As a manufacturing method, for example,
3-30500 and JP-A-61-174111.

The particle size of the aluminosilicate used in the present invention is not particularly limited, but from the viewpoint of preparing an external preparation for skin with good dispersibility, the particle size is preferably relatively small. The particle size of the powder is suitably, for example, in the range of 0.04 to 20 μm, preferably 0.5 to 5 μm.

[0010] The aluminosilicate used in the present invention is obtained by converting some or all of the ion-exchangeable ions in the aluminosilicate described above, for example, sodium ion, calcium ion, potassium ion, magnesium ion, iron ion and the like to antibacterial metal ions. Prepared by ion exchange.

In the present specification,% means% by weight on a dry basis at 110 ° C.

Hereinafter, a method for producing the antibacterial metal ion-retaining zeolite (hereinafter referred to as antibacterial zeolite) used in the present invention will be described. For example, the antibacterial zeolite used in the present invention is prepared by contacting the zeolite with an aqueous solution containing an antibacterial metal ion such as a silver ion, a copper ion, a zinc ion or a tin ion prepared in advance, and ion-exchangeable ions in the zeolite. The above ions are replaced. Contact is 10
The reaction can be performed by a batch method or a continuous method (for example, a column method) at a temperature of from 70 to 70 ° C, preferably from 40 to 60 ° C for from 3 to 24 hours, preferably from 10 to 24 hours. The pH of the above aqueous solution
Is suitably adjusted to 3 to 10, preferably 5 to 7. This adjustment is preferable because precipitation of silver oxide or the like on the zeolite surface or in pores can be prevented. Each ion in the aqueous solution is usually supplied as a salt.
For example, silver ions are silver nitrate, sulfate, silver perchlorate, silver acetate, diamine silver nitrate, diammine silver sulfate, etc. Copper ions are nitrate (II), copper sulfate, copper perchlorate, copper acetate, tetracyano copper Zinc ions such as potassium nitrate are zinc nitrate (I
I), zinc sulfate, zinc perchlorate, zinc thiocyanate, zinc acetate and the like, and tin ions such as tin sulfate and tin nitrate can be used.

The content of silver ions and the like 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 aqueous solution has a silver ion concentration of 0.2 M / L to 3.7 M / L and a zinc ion concentration of 0.01 M / L to 2.0 M / L.
Liter, the silver ion content 1
An antibacterial zeolite having a zinc ion content of 1 to 15% can be obtained.

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 each aqueous solution is successively contacted with zeolite to thereby form two or more types of ions. Can be exchanged. The concentration of each ion in each aqueous solution can be determined according to each ion concentration in the mixed aqueous solution.

In order to stabilize antibacterial metal ions during ion exchange, ammonium ions can be added to an aqueous solution for ion exchange and reacted.

The zeolite after the ion exchange is sufficiently washed with water and dried. Drying is 105 ° C-1 at normal pressure
It is preferably carried out at 15 ° C. or 70-90 ° C. under reduced pressure (1-30 torr).

The method for producing the antimicrobial metal ion-retaining AAS to be added to the antimicrobial external preparation of the present invention can be prepared according to the above-mentioned antimicrobial zeolite method.

The antimicrobial metal ion-retaining aluminosilicate to be incorporated in the antimicrobial external preparation of the present invention is particularly preferable because it contains silver and zinc because of its high skin astringency and, as a result, rapid wound healing. The content is 1 to 30% of silver and 1 to 1 of zinc.
5%, preferably 2 to 10% of silver and 6 to 13% of zinc is desirable from the viewpoint that the antibacterial effect is maintained for a long time and the wound healing is further promoted.

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

In the preparation method, for example, when used in the form of a suspension, the aluminosilicate holding the antibacterial metal ion is diluted with a liquid substance used in known topical antibacterial drugs such as alcohols and propylene glycol. Can be used.

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

When used in the form of a cream (emulsion), there are an oil-in-water emulsion type and a water-in-oil emulsion type. The cream should be obtained by adding a surfactant to the above-mentioned oil-based base, dispersing it uniformly, and then gradually adding a water-soluble base such as water, macrogol, or sol base in which an antibacterial metal-retaining aluminosilicate is dispersed, and diluting the base. Can be. For the oil-in-water emulsion type and the water-in-oil emulsion type, the hydrophilic-hydrophobic group balance value (HLB value) of the surfactant used
Determined by Generally, a surfactant having an HLB value of 8 or more results in an oil-in-water emulsion type cream, and a surfactant having an HLB value of less than 8 results in a water-in-oil emulsion type cream.

Surfactants which can be used in the antibacterial external preparation of the present invention include those having an HLB value of 8 or more, such as anionic surfactants such as triethanolamine oleate, sodium oleate and potassium oleate; Cetyl-
Cationic surfactants such as N-ethylmorpholinium ethosulfate, glycerin monostearate, glycerin trioctanoate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan cetyl ether, poly Non-ionic surfactants such as oxyethylene sorbitan monolaurate can be mentioned. Those having an HLB value of less than 8 include oleic acid, sorbitan trioleate, sorbitan sesquioleate, and sockitan monooleate.

The antimicrobial external preparation of the present invention is characterized in that the antimicrobial metal ion-retaining aluminosilicate in the antimicrobial external preparation is easily dispersed, has high absorbency, and has good adhesiveness on the wound surface. From the viewpoint, an oil-in-water emulsion type cream is preferable.

The content of the antimicrobial metal ion-retaining aluminosilicate in the antimicrobial external preparation of the present invention is usually 0.1%.
It is desirable to adjust it to 1 to 20%, preferably 1 to 10% from the viewpoint of obtaining an effective drug effect.

The antimicrobial external preparation of the present invention may contain, in addition to the above essential components, pharmaceutical auxiliaries such as viscosity modifiers, dispersants, wetting agents, emollients, stabilizers, pigments, fragrances, and pH buffers. Agents and the like. Further, a preparation carrier for preparing external preparations of various shapes may be blended.

The topical antimicrobial preparation of the present invention can be used, for example, once a day,
It is appropriate to use sterile gloves or the like to apply directly to the necessary and sufficient thickness (about 2-3 mm) to cover the wound surface. Alternatively, it can be spread to a similar thickness on gauze or the like, affixed, and bandaged. In the application after the second day, it is appropriate to apply the present agent freshly after wiping or washing off the agent applied on the previous day with a warm water bath or the like.

[0028]

The antimicrobial external preparation of the present invention has a curative effect on skin disorders caused by microorganisms. For example, acne, seborrhea,
It is also effective against chronic eczema, acne, scabies, ringworm and mild inflammation.

The topical antimicrobial preparation of the present invention has a high therapeutic effect on ulcers caused by trauma such as damage, burns, frostbite and certain diseases, or chronic ulcers, and is extremely safe against the human body such as skin irritation. high.

[0030]

Next, embodiments of the present invention will be described with reference to examples, but the present invention is not limited to the examples.

Reference Example (Preparation of Aluminosilicate Holding Antibacterial Metal Ion) Aluminosilicate is a commercially available A-type zeolite (Na ₂ O.Al).
_{2 O 3 · 2.OSiO 2 · XH} 2 O: average particle size 1.1 .mu.m), Y- type zeolite _{(Na 2 O · Al 2 O} 3 · 4.OSiO 2 · XH 2 O: average particle diameter 0.
7 μm), amorphous aluminosilicate (JP-A-61-17)
No. 4111, prepared: 0.3 μm). AgNO ₃ , Zn (NO ₃ ) ₂ and NH ₄ NO ₃ were used as salts for providing each ion for ion exchange. Table 1 shows the types of aluminosilicate used in preparing each sample and the types and concentrations of salts contained in the mixed aqueous solution. N
Samples of six kinds of antimicrobial metal ion-retaining aluminosilicates from o.1 to No.6 were prepared.

For each sample, 1 kg of an aluminosilicate powder heated and dried at 110 ° C. was taken, suspended in 1 liter of water, and a 0.05N aqueous nitric acid solution was added thereto in an amount of 100 ml / 30.
The mixture was dropped at a dropping rate of 1 minute to adjust to a predetermined pH value (5 to 7). Next, 3 l of a mixed aqueous solution of a predetermined concentration of an antibacterial metal salt was added to the slurry for ion exchange. This reaction was stirred at room temperature to 60 ° C. for 10 to 24 hours to reach an equilibrium state.

After the completion of the ion exchange, the aluminosilicate phase was filtered and washed with water at room temperature or warm water until excess exchange cations in the aluminosilicate phase disappeared. Next, sample 1
The resultant was dried by heating at 10 ° C. to obtain six kinds of samples.

[0034]

[Table 1]

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

[0036]

[Table 2]

Example 2 (Preparation of Cream) A cream containing an aluminosilicate holding an antibacterial metal ion was prepared according to the formulation shown in Table 3 (Examples 2-1 to 2-1).
2-8). As Comparative Examples, those containing no aluminosilicate holding an antibacterial metal ion (Comparative Example 3), those containing silver sulfadiazine as a silver-sulfur agent (Comparative Example 4), and those containing gentamicin as an antibiotic (Comparative Example 5)
Was similarly prepared.

[0038]

[Table 3]

Test Example 1 (Antibacterial Activity Test) The antibacterial activity against various fungi was examined by the following method using the antibacterial metal ion-retaining aluminosilicate powder obtained in Reference Example. Assay method Bacteria are Heart infusion agar (Heart infusion)
agar), yeast and molds are Sabouraud ag
ar) by the agar plate dilution method. Table 4 shows the antimicrobial activity against various microorganisms in terms of the minimum inhibitory concentration (MIC) of an aluminosilicate holding an antibacterial metal ion.

[0040]

[Table 4]

Test Example 2 (resistance acquisition test) Pseudomonas aeruginosa was treated with Muller hinto broth
n broth) culture medium at 37 ° C for 18 hours (8.6
X10 ⁷ cells / ml) was used as the inoculum. A platinum loop of the inoculum was inoculated into a medium obtained by adjusting the antibacterial metal ion-retaining aluminosilicate obtained in Reference Example, silver sulfadiazine, and gentamicin to various concentrations, and the mixture was allowed to stand at 37 ° C. for 24 hours. In the same manner, one platinum loop was inoculated into the broth containing the following various concentrations, and the subculture was repeated for 30 generations, and the minimum inhibitory concentration for each generation was measured. The results are shown in FIG.

Test Example 3 (Antibacterial test of an antibacterial external preparation) The antibacterial external preparation prepared in the Example was applied to a 3x3 cm ² filter paper for about 1 hour.
It was evenly applied with a thickness of mm. 0.1 ml of each bacterial solution was spread on a plate medium for each bacterial species with a long-size rod and brought into close contact with each other.
The cells were cultured at 37 ° C. for 24 hours. As a control, one without the above antimicrobial external preparation was also tested. After the culture, the filter paper was removed, 1 cm ^{2 was} collected from the medium, put into 10 ml of sterile physiological saline, stirred, diluted at a fixed ratio, and the number of each cell was measured. Table 5 shows the results.

[0043]

[Table 5]

Test Example 4 (Animal Test Using Burn Model) A 20 mm-diameter circular II-degree burn was formed on the back of a rat, and 1 × 10 ² Pseudomonas aeruginosa were inoculated on the burn. To form a burn infected wound. To the wound, 0.5 g each of the preparation containing the antibacterial metal ion-containing aluminosilicate and the preparations of zinc oxide and silver sulfadiazine prepared in Examples were administered. As a control, a test in which the wound surface was simply covered with gauze was similarly performed. The healing effect was evaluated by determining the number of days required for shedding of crusts (temporary skin-like ones formed by blood and tissue fluid) during the healing process and the number of days required for complete healing by the average number of days of six samples. . Table 6 shows the results.

[0045]

[Table 6]

Test Example 5 (Rabbit skin irritation test)

The test was carried out on 50 rabbits.
The vicinity of the midline of the spine of the rabbit was shaved with an electric clipper on the day before the application, and six application sites having a size of 2.5 × 2.5 cm were set.
Of the six application sites, three were healthy skin and the remaining three were stratum corneum exfoliated skin. The stratum corneum exfoliated skin was prepared by using an injection needle so that the dermis was not damaged or bleeding immediately before the start of application, but was wound in a double-girder shape. After the patch was applied to the back skin, it was fixed to an adhesive tape (Elasticon (registered trademark), manufactured by Johnson & Johnson) so as not to move. The application time was 24 hours. After the application was completed, the adhesive tape was removed, and the test substance was wiped off with absorbent cotton soaked in water.

Examples 1-1, 1-2, 1-5, 2-1,
0.5 g of the antibacterial external preparation obtained in 2-5, 2-6 and Comparative Examples 4 and 5 was applied to the above-mentioned skin, and the number of erythema-generated specimens was evaluated at one place in each specimen. Table 7 shows the results.

[0049]

[Table 7]

Test Example 6 (Acute Toxicity Test) Two to four weeks old rats 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 tube after fasting for about 16 hours. For transdermal administration, an area of about 4 × 5 cm in the center of the back was shaved using an electric clipper the day before administration, a predetermined amount was placed on a gauze, moistened with distilled water for local injection, and the gauze was attached to the shaved site together with the gauze. The part to be stuck was further covered with aluminum foil and fixed with elastic tape. About 24
After time, the remaining test substance was removed with water. As a control, a group to which distilled water for injection for local administration was administered in the case of oral administration, and a group in which distilled water for injection for local administration was contained in gauze for transdermal administration were provided. Table 8 shows the results.

[0051]

[Table 8]

[Brief description of the drawings]

Fig. 1 Pseudomonas aeruginosa
aeruginosa) shows the results of a resistance acquisition test.

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Yasuo Kurihara 3-35, Toyooka-dori, Mizuho-ku, Nagoya-shi, Aichi (56) References JP-A-2-96508 (JP, A) JP-A-1-286913 ( JP, A) JP-A-1-167212 (JP, A) JP-A-1-257124 (JP, A) JP-A-2-283312 (JP, A) JP-A-61-186312 (JP, A) JP-A-3-120220 (JP, A) JP-A-3-38504 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 33/38 A61K 33/06 A61K 33/30 A61K 47 / 02 A61P 17/00 101 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. An antimicrobial external preparation comprising an aluminosilicate holding an antimicrobial metal ion as an active ingredient and being an oil-in-water emulsion type cream. 2. The antibacterial external preparation according to claim 1, which contains 0.1 to 20% of an aluminosilicate holding an antibacterial metal ion. 3. The antibacterial external preparation according to claim 1, which contains 0.1 to 10% of an aluminosilicate holding an antibacterial metal ion. 4. The antibacterial metal ion is a silver ion and a zinc ion, the silver ion content is 1 to 30%,
The antibacterial external preparation according to claim 1, wherein the content of zinc ion is 1 to 15%.