JP2640681B2 - Bandage plaster containing chlorhexidine gluconate and its production method - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a plaster containing chlorhexidine gluconate fine powder having excellent antibacterial activity.

2. Description of the Related Art Conventionally, in order to impart disinfecting, bactericidal, and anti-inflammatory effects to a bandage plaster, a special bandage plaster loaded with acrinol or the like has been produced for an aqueous solution of macchiurochrome (Japanese Patent Publication No. 39-19718). No. 59-13864).

Problems to be Solved by the Invention The above-mentioned plaster containing macchiurochrome has a drawback that the macchiurochrome is not sufficiently released, and the bactericidal effect, the anti-inflammatory effect and the like are not sufficiently exhibited.
The antimicrobial activity is enhanced by increasing the amount of markurochrome and increasing the release. However, when the amount of macchiurochrome exceeds 1%, the amount of ingredients, the amount of water and alcohol increases, and the original quality, properties, adhesive strength, etc. of the plaster fall off of the standard, and the change over time becomes faster, so that it is practical. There is no. In addition, although marquiurochrome has antibacterial activity against Gram-negative bacteria, it has no antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus.

Further, a bandage plaster containing acrinol has an antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus, but does not have an antibacterial activity against Gram-negative bacteria such as green bacterium.

On the other hand, chlorhexidine gluconate (hereinafter, abbreviated as GCH) is known to have a bactericidal and disinfecting effect on a wide range of microorganisms and is easily dissolved in water. Listed on the disinfectant,
It is also used in ointments, creams and plasters. There is no example of using GCH in anhydrous form. When such a GCH solution is mixed with a plaster, 80% of the water is water, so that the properties such as the adhesive force of the plaster are significantly impaired, and there is a problem in commercialization. To solve this problem, the characteristics can be maintained by concentrating the 20% solution and reducing the water content.However, due to residual water, GCH is firmly held between the plaster component molecules in the presence of water, It has been difficult to release them, and it has been difficult to exhibit a practical sterilizing and disinfecting effect. In addition, since there is no commercially available anhydrous product, even if the 20% GCH solution was evaporated to dryness, the product only turned into a candy-like mass and did not lead to a powder having good dispersibility.

In general, glycols (glycerin, ethylene glycol, propylene glycol, etc.) may be used as an adjuvant in order to enhance the ability to release an active ingredient from an ointment or the like. However, since the plaster is used by sticking it to the skin, a strong adhesive force is required, and there is no example of using these glycols.

Means for Solving the Problems The present inventor has developed a special method for producing an anhydrous powder of chlorhexidine gluconate (GCH), and said fine powder together with macrogol is a plaster plaster. It has been found that, when incorporated into the ingredients, a plaster is obtained which is dispersed in the substance, thereby increasing the release of GCH and significantly increasing the antibacterial properties.

That is, according to the present invention, the composition for forming a plaster
A chlorhexidine gluconate-containing bandage plaster comprising 0.1 to 1.0% by weight of chlorhexidine gluconate powder having a particle size of 150 μm or less and 1.5 to 10% by weight of macrogol based on the total weight of the plaster component. Is provided.

The above-mentioned plaster plaster is prepared by mixing 0.1 to 1.0% by weight of chlorhexidine gluconate fine powder having a particle size of 150 μm or less and 1.5 to 10% by weight of macrogol with a plaster composition for forming a plaster, based on the weight of the component. , 35 of the resulting mixture
Preparing a muddy viscous plaster solution by heating and dissolving to the temperature of the freezing point of the used macrogol within the range of ゜ to 65 ° C., and applying and drying the plaster solution on a plaster base material Can be produced.

DETAILED DESCRIPTION OF THE INVENTION Chlorhexidine gluconate (GCH): GCH used in the present invention is a substantially anhydrous powder having a particle size of about 150 microns or less, preferably 60-70 microns. When the particle size exceeds 150 microns, G dispersed in the plaster
CH varies, resulting in uneven release and antimicrobial activity. The anhydride of GCH is not commercially available. The 20% liquid is concentrated, crystallized and finely divided, and in particular the GCH powder can be obtained by the following method: The 20% GCH liquid is concentrated under reduced pressure on a water bath. If most of the water evaporates as the water evaporates, foaming becomes remarkable, and if the decompression operation becomes difficult, the obtained candy is taken in a bucket while it is fluid, placed in a desiccator, and vacuum dried at room temperature. Since the candy solidifies into a gaseous thin layer with many air bubbles, it is crushed in a bucket,
Further, it is vacuum-dried, and if it is pulverized, it easily becomes a powder and sieved to a particle size of 150 microns or less, particularly 60 to 70 microns. The quantitative value should be 98% or more.

The compounding amount of GCH is 0.1 to 1.0% by weight of the whole plaster component, and particularly in the range of 0.1 to 0.3% by weight, it shows a sufficient antibacterial activity. GCH is effective at low concentrations due to its high antibacterial properties.

Macrogol: Macrogol is a condensation polymer of ethylene oxide and water, and changes from a liquid state to a solid state as the degree of polymerization increases. Each number is followed by a number that indicates the approximate average molecular weight. There are about 10 types of these, from 200 to 20,000, and they are listed in the Japanese Pharmacopoeia or the Pharmaceutical Ingredients outside of Japan. Macrogol is used in pharmaceuticals, cosmetics, and the like as a base for ointments and creams. As a chemical component, polyethylene glycol is a highly safe material that has good permeability to the skin and has no irritation. It has been found in the present invention that macrogol has a good affinity for GCH, enhances the release of GCH in the plaster component, and significantly increases the antibacterial activity of GCH as compared to the case where GCH is used alone. Was. The conditions for using Macrogol are as follows: (1) All types of Macrogol can be applied, but 20
Ones from 0 to 10000 are used, and a range from 1000 to 6000 is preferred. By the way, Macrogol 400 has 7 or more carbon atoms.
9. The viscous liquid has a freezing point of about 4-8 ° C, and Macrogol 6000 has 165-200 carbon atoms and a freezing point of about 56 ° -64 ° C.

(2) The compounding amount is 1.5 to 10% by weight of the total amount of the plaster component, and a preferable range is about 2 to 6% by weight. The release of GCH also increases in proportion to the concentration of macrogol, but if it exceeds 10%, the adhesive property, which is an important physical property of the plaster, will fall off the specification.

Plaster-forming component: As the plaster-forming component, those conventionally used for plasters for plasters can be used. Generally, natural rubber or synthetic rubber or an acrylic resin as an elastic body, zinc oxide as a filler, process oil as a softener, and a sticky natural or synthetic resin such as rosin, dammar resin, petroleum resin as a tackifier. Etc. are used.

Solvent for plaster-forming component: As the solvent, volatile oil, benzene, toluene, methyl ethyl ketone, hexane, heptane and the like are used.

Bandage base material: As the bandage base material, a sheet made of natural fiber or synthetic fiber, a sheet made of synthetic resin or the like is used.

How to add chlorhexidine gluconate (GCH) and macrogol: GCH and macrogol have good affinity for each other. For this reason, the mixed solution of the two is poor in lipophilicity, so that the dissolving ability and dispersibility of the paste-forming component dissolved in a solvent such as 50% of a rubber exhibiting oil become worse. Once dissolved, even if it dissolves a little, GCH is localized and uniform dispersibility cannot be expected.

As a result of repeated research to solve this difficulty, it was found that if both were mixed with the plaster-forming component at room temperature, stirred and mixed near the solidification point of Macrogol, and returned to room temperature, the product was uniformly dispersed. .

Therefore, the specification of Macrogol is preferably a molecular weight of 10
The melting temperature is in the range of 35 ° C to 65 ° C,
The temperature of the freezing point of the used macrogol gives favorable results. The solidification points of various macrogoals are as follows.

Effects and Effects of the Invention A plaster must have a property that it must have a good adhesive strength to adhere to the skin and, at the same time, easily peel off after use. Also, an appropriate holding force (coupling force within the plaster) is required.

In general, it is common knowledge in the industry that when a foreign component is added to and mixed with a plaster component of a plaster, the necessary balance of the above-mentioned adhesive strength, releasability, and holding power is lost. The inventor has
By using chlorhexidine gluconate as an antimicrobial agent in the form of an anhydrous powder and further admixing chlorhexidine gluconate with macrogol having a good affinity, the above balance required for the plaster is unexpectedly obtained. Was maintained, the release of chlorhexidine gluconate powder was improved, and as a result, a plaster with significantly improved antibacterial properties was obtained. That is, the low polymer of macrogol is water,
Easy to dissolve in alcohol, acetone, chloroform, etc.
It is easily soluble in aromatic hydrocarbons and slightly soluble in fatty acid hydrocarbons. The higher the polymer, the more lipophilic. As described above, since macrogol has various dissolving abilities, it is considered that the above effect was obtained by the action that the solubility of the drug is high and the affinity of the plaster component with rubber and resins is good. . In this way, the effect of increasing the release ability of chlorhexidine gluconate is achieved without impairing the adhesive strength, peeling power and holding power of the plaster. When a bandage plaster containing chlorhexidine gluconate is adhered to the skin, chlorhexidine gluconate is gradually released along with the permeability of macrogol, and the sterilized area can be maintained in the affected area for a long time.

Examples Hereinafter, the present invention will be specifically described with reference to Examples. In the following examples,% means% by weight.

Example 1 Ingredient A Natural rubber 100 g Ester gum 93 g Zinc oxide 95.1 g Liquid paraffin 4 g BHT 1 g Ingredient B Chlorhexidine gluconate crystal powder (particle size 60-70 micron) 0.9 g (0.3%) Macrogol 1500 6 g (2.0%) Total 300 g (100%) A part of the plaster component A was kneaded on a roll and cut.
To this, 410 ml of rubber volatile oil was added, and the mixture was stirred and mixed with the remaining component A to prepare a homogeneous viscous salve liquid. The component B was mixed with the mixture, and the mixture was heated and dissolved at 39 ° to 41 ° C. to prepare a slurry-like viscous plaster solution. Cotton cloth (width:
After plastering with a thickness of 80μ on a 50cm x 500cm length and drying at 50-60 ° C to remove the solvent, it is wound on a core and 12mm wide with a cutter.
To obtain a plaster containing chlorhexidine gluconate which conforms to the performance standard of the plaster and which can withstand long-term storage.

Example 2 Component A Acrylic adhesive 400 g (solid content 200 g) Hydrocarbon resin 96 g Component B Chlorhexidine gluconate crystal powder (particle size 60-70 microns) 0.3 g (0.1%) Macrogol 4000 12.0 g (4.0% A total of 300 g (100%) of the above-mentioned plaster component A was stirred and dissolved in 180 ml of toluene to prepare a homogeneous and viscous plaster stock solution. This was mixed with Component B and dissolved by heating at 53 ° -63 ° C. to give an plaster solution.

This was plastered on a polyvinyl chloride film using a plaster in the same manner as in Example 1, dried and the solvent was removed to obtain a plaster containing chlorhexidine gluconate.
Except for the tensile test, this bandage plaster met the performance standards of the bandage plaster. In addition, it was well tolerated for long-term storage.

Comparative Examples 1-2: A portion of the plaster component A of Example 1 was kneaded on a roll and cut, and 410 ml of a rubber volatile oil was added thereto, followed by stirring and mixing with the remaining component A to obtain a homogeneous viscous plaster. A stock solution was prepared.

Then add 1.5 g or 4.5 g of 20% GCH solution (0.3 g or 0.9 g of GCH, corresponding to 0.1% or 0.3% of the whole component of the plaster) and add 40 g to 45 g.
The mixture was heated and dissolved at a temperature of ℃ to prepare a muddy viscous plaster solution.

The product was processed in the same manner as in Example 1 to obtain a product conforming to the performance standard of the plaster. In the time-dependent change test, a wound-like cavity was generated from the residual moisture, and the adhesive substance was not coated. Cohesive failure occurred at the back of the specimen.

Comparative Example 3: The paste component A of Example 1 was treated in a conventional manner to prepare a paste concentrate. GCH 0.9g with a particle size of 60 to 70 microns
(Equivalent to 0.3% of the whole plaster component) was added, and the mixture was heated and dissolved at 40 ° C. to 45 ° C. to prepare a mud-like viscous plaster solution.

The product was processed in the same manner as in Example 1 to obtain a product conforming to the performance standard of the plaster. There was no abnormality in the aging test.

Comparative Example 4: A plaster stock solution comprising the component A was prepared according to Example 1, and 0.9 g of GCH (0.3% of the whole plaster component) having a particle size of 150 to 250 microns and 6.0 g of Macrogol 6000 were mixed. 56 ゜ -6
The mixture was stirred and mixed at 4 ° C. to obtain a viscous plaster solution. This was plastered according to a conventional method to produce a GCH-containing plaster. Although the physical performance of the plaster conformed to the standard, spots due to GCH particles were observed on the plaster surface, and the quantitative value was partially incompatible with 0.3 ± 0.03% of the standard.

Antibacterial activity test The antibacterial activity test was performed on the plasters obtained in the above Examples and Comparative Examples as follows.

Outline: A test piece and a control piece were placed on the surface of a test plate medium inoculated with bacteria, and cultured at 37 ° C. 24 hours after the start of the culture, the test piece and the control piece were removed, and the presence or absence of a growth inhibition zone was determined by visual observation.

Test method: 1) Test strain: Staphylococcus aureus 2) Medium: a) Enrichment medium; AATCC liquid medium; b) Measurement medium; AATCC agar medium.

3) Preparation of test plate medium: The test strain is inoculated into an enrichment medium and cultured overnight at 37 ° C to obtain a bacterial solution. The bacterial solution was added at a ratio of 1 ml to 150 ml of the measurement medium, and 30 ml was dispensed into each type petri dish and solidified to prepare a medium.

4) Preparation of test piece: For the test piece, the sample was cut into 12 × 24 mm. The control strip is filter paper (12 x 24 mm) and the main drug (chlorhexidine gluconate solution)
25 μg or 6.25 μg was impregnated.

Judgment: The growth inhibition zone of the bacteria was judged according to the following criteria.

Judgment Criteria A Does not inhibit the growth of bacteria at all. B Slightly inhibits the growth of bacteria in the contact area. C Inhibits the growth of bacteria in the contact area. D The growth inhibition zone extends slightly (less than 1 mm) to the periphery. E The growth inhibition zone clearly extends to the periphery (measurement of the size of the inhibition zone) As can be seen from the above measurement results, in the sample of Example 1, the growth inhibition zone of Staphylococcus aureus clearly extends to the periphery. The sample of Example 2 inhibits Staphylococcus aureus and Pseudomonas aeruginosa from growing at the contact portion. On the other hand, the samples of Comparative Examples 1 and 2 using the GCH20% solution only slightly inhibited the growth of the bacteria in contact with Staphylococcus aureus and did not inhibit the green bacterium at all. . In addition, the sample of Comparative Example 3 using the fine powder of GCH but not using macrogol obtained the judgment (C) that the growth of the bacteria in contact with Staphylococcus aureus was obtained.
Is inferior in antibacterial activity to both bacteria as compared with the sample of Example 1 using the same concentration (0.3%).

In addition, since the bandage plaster of Comparative Example 4 had a large particle size of GCH particles, the antibacterial activity test had large variations, and the judgment was unclear.

Claims (7)

(57) [Claims] 1. A composition for forming a plaster plaster with 0.1 to 1.0% by weight of chlorhexidine gluconate powder having a particle size of 150 μm or less and 1.5 to 10% by weight of macrogol, based on the total weight of the plaster component. A plaster containing chlorhexidine gluconate, characterized in that: 2. The plaster of claim 1 wherein said chlorhexidine gluconate powder has a particle size of 60 to 70 microns. 3. The above-mentioned macrogol has an average molecular weight of 200 to 100.
3. The method according to claim 1, wherein the macro goal is selected from the range of 00 to 00.
Noban plaster. 4. The macrogol has an average molecular weight of 1,000 to 60.
3. The plaster of claim 2 selected from macrogol in the range of 00. 5. The method according to claim 1, wherein the amount of the chlorhexidine gluconate powder is 0.1 to 0.3% by weight based on the whole paste component.
4. The plaster of any of 4. 6. The plaster according to claim 1, wherein the amount of said macrogol is 2 to 6% by weight of the whole plaster component. 7. Chlorhexidine gluconate powder having a particle size of 150 μm or less in an amount of 0.1 to 1.0% by weight of the whole paste component and macrogol in an amount of 1.5 to 10% by weight are added to the paste forming component and the solvent for the component. Mixing at room temperature, heating and dissolving the resulting mixture at a temperature of the freezing point of the macrogol within the range of 35 ° C to 65 ° C, applying the resulting plaster solution on a substrate and drying. A method for producing a bandage salve containing chlorhexidine gluconate, characterized by the following.