JPH01501000A - Enzyme-containing disinfectant composition and dental and wound care products containing this composition - 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] Enzyme-containing disinfectant composition and dental and wound care products containing this composition The present invention is capable of forming hydrogen peroxide in an aqueous environment and in the presence of oxygen and a substrate. A solution containing at least one enzyme together with peroxidase and thiocyanate The present invention relates to a fungicide composition.

Although the bactericidal composition of the present invention can be generally applied, the composition is mainly used for gingivitis and developed and tested to produce compositions for the prevention and treatment of periodontitis and periodontal disease. Therefore, the present invention is described in more detail below to solve this problem.

Tooth surfaces as a bacterial coating containing more or less protein and carbohydrate substances Dental plaque, epithelial cells, and food or irritant residue deposited on the tooth can cause cavities and It is generally accepted that stones, gingivitis, and periodontal disease are jointly caused. Ru. Some bacteria acquire several types of highly adhesive carbohydrates from the carbohydrates of ingested foods or irritants. (dextrans), especially sucrose is the main component in the formation of dextrans. It's worth it. Bacteria in plaque are present in or associated with ingested food or irritants. Based on the fermentation degradation and reaction of particularly degradable mono- and trisaccharides obtained from these, 1 acids, especially lactic acid and acetic acid. The organic acids obtained contain calcium and phosphatide. By releasing sphate, it attacks and removes the enamel and then the pulp. This means the sudden onset and progression of dental caries. Tartar is calci causes mineralization of dental plaque, which tends to accumulate ions and phosphates. are doing.

If dental plaque is not removed regularly, for example by brushing the teeth, Accumulation of calcium and phosphate occurs in hydroxyapatite (h), which embeds bacteria. An adhesive and wear-resistant network of hydroxyapatite is formed on the tooth surface. You will reach a stage where you can Hydroxyapatite accounts for 80% of total dental calculus Tartar that is in progress has a tendency to further increase, and the reason for this is the bacteria in the tartar. This is because it cannot be removed by normal tooth brushing.

The clinical correlation between tartar and gingivitis has been known for a long time, and this The correlation has been proven several times. Similarly, untreated gingivitis changes over time. Therefore, it is also known that it progresses to periodontal disease. Tartar makes teeth difficult to brush Typically occurs in the area of In this relationship, the tooth surface facing the tooth gap is particularly important. It is. Tartar deposited in the gaps between the teeth spreads further to the gaps between the teeth and gums. After that, the tartar under the gums begins to spread through the gaps between the teeth and to other areas of the teeth. . In more advanced stages, tartar forms in large areas between the gums and tooth necks, where bacteria The organic acids produced demineralize not only the teeth but also the bone structure located behind the gums. It becomes quality.

Various methods have been used to limit and inhibit plaque formation. It was based on an attempt. These are mainly used for decals that cause plaque to adhere to the tooth surface. prevent strangel formation, act growth-inhibitory or bactericidal, and in some cases In some cases, the use of compounds produced in situ can inhibit bacterial growth. It consists of

Several methods have been shown to prevent dextran formation. West Germany granted According to Patent No. 1,467.809, phosphoric acid, sucrose, glucose or calcium, sodium or magnesium salts of esters with lactose It can act as a caries-inhibiting dental hygiene agent. These compounds cause damage. This is said to cause the production of dextrose from sucrose by bacteria. Suppresses Langer formation. However, this method makes plaque difficult to remove. food residue that adheres to the scales and bacteria has free access to low molecular weight carbohydrates. Regarding the bacterial coating in the gaps between teeth, which is becoming a reality with a high probability, the intended It has no effect. Moreover, this method has no effect on tartar that has already formed. As a result, this method is less suitable for controlling gingivitis and periodontal disease. It is reserved because there is no such thing.

According to U.S. Patent No. 3,733,399, dental plaque as a pre-stage of tooth decay. The formation of the chain consists of combining the trisaccharide sucrose with two heptamers 1, namely anhydroglucose and glucose. It is said that it is inhibited by invertase, which decomposes it into lactose. plastic The dextran gel formed in the liquid is synthesized from sucrose by bacteria. It is said that the effect of invertase is due to the amount of screen available to bacteria. The reason for this is probably to reduce the amount of loin.

The use of invertase with lactate dehydrogenase is described in U.S. Pat. No. 4,255. , 414, it is said that it also has an anti-caries effect. but However, for example, Streptococcus mutant strains Cariogenic bacteria, such as Although the bacteria themselves form an invertase-like enzyme that Derived from anhydroglucose obtained from invertase used with medical hygiene agents It is known that it appears to form a strangel. Furthermore, the amount of food consumed Contains starch or hydrocarbons such as lactose instead of sucrose In some cases, tooth plaque is formed and the inverter contained in dental hygiene products It is expected that this enzyme has some effect on plaque formation in these cases. It is known that this is not possible. Eventually, invertase will act on the already formed plaque and It has no effect on tartar and therefore invertase has no effect on inhibition. It is of only marginal importance in the treatment of gingivitis and periodontitis. do not have.

The dextran gel produced in the plaque is described in the accepted West German Patent Application No. 1,95 In the specification of No. 5.956, decomposition with dextranase was proposed. It is. According to Austrian Patent No. 318,815, however, , dextranase can only degrade soluble dextran and It was found that there was some insoluble dextran that could not be degraded.

According to U.S. Pat. No. 4,154,815, dental plaque contains proteases, inhibited by using zinc with carbohydrase and/or lipase. ing. Zinc may act by interfering with plaque structure and plaque mineralization. It has been found that enzymes, on the other hand, degrade plaque densifying highly polymeric compositions. Up In the clinical experiments described in the patent specification, zinc and protease were It has been proven that it reduces the amount of tartar, but experimental reports have shown that it reduces the amount of tartar in the teeth. It does not say anything about its effects.

Tenmark Patent Application No. 5504/78 discloses a caries-inhibiting tooth in tablet or powder form. The drug contains only lysozyme as the active ingredient. have. This document does not explain in detail the type of lysozyme applied .

According to U.S. Pat. No. 3,985,869, not only egg white lysozyme but also protein Streptomyces albus, Streptomyces albus Ptomyces griseus or streptoeyces griseus It is an enzyme obtained from strains of the genus Flavobacterium. However, Streptococcus and Lactobacillus (Lactobacillus) s) It is not possible to lyse carious bacteria of the genus. However, in the above literature According to It can produce a cytolytic enzyme that attacks the cactobacillus. However, knowledge For example, in oral or wound treatment drugs, Streptomyces There is a somewhat cautious attitude towards using produced enzymes, but the reasons for this are various. The presence of various Streptomyces strains makes them undesirable for such drugs. and substances that are difficult to remove from desirable enzymes available from Streptomyces strains. This is because they are also being produced. Therefore, if used regularly over a long period of time, e.g. For example, dental hygiene agents can affect the balance of oral microbiota, which is thought to be involved in the acquisition of resistance. It is generally undesirable to contain antibiotics that interfere with .

Accepted West German Patent Application No. 2.027.019 and Parallel U.S. Patent No. 4,150 ．． No. 113 discloses an oxidizing agent that liberates hydrogen peroxide by oxidative decomposition of a substrate. We are dealing with dental hygiene agents that have added doreductase.

It is stated that this is to obtain a caries inhibiting effect.

Glucose, which acts as a MW, is e.g. It is said that it is obtained from the residue, but the reason is that the toothpaste itself contains problematic polysaccharides and trisaccharides. Because it may contain carbohydrase that produces glucose from It is. However, according to the experiments in which the obtained effects are promising in the above-mentioned literature, Anti-physiologically high concentrations of sucrose were added just before enzyme addition, but at the desired level. In practice, hydrogen peroxide in concentrations sufficient to inhibit or inhibit bacterial growth up to Judging from the fact that food is consumed on a daily basis, it is decided to use drugs. Therefore, it must be considered that it is unrealistic to be able to obtain it.

U.S. Pat. No. 4,476.108 states that the bactericidal efficacy of hydrogen peroxide is The reaction between sidase and an electron-donating molecule that generates a high-stage bacterially active aM radical. It is said that it is enhanced by adding it. Horseradish peroxidase is the preferred -blade donor is an organic molecule listed below; phenylethylamine, tyrosine, tryptophan, benzoic acid, salicylic acid, hydride Rokinone, dehydrophenylalanine, vanillin and p-aminobenzoic acid. peracid The presence of hydrogen peroxide indicates that the disinfectant in question is hydrogen peroxide, sodium peroxide, or methyl peroxide. Or obtained when it contains an ethyl peroxide component.

European Patent Application No. 133,736 relates to dentifrice compositions with antibacterial activity, is based on the formation of hypothiocyanate (O5CN-) in the drug in question contains an oxidizable substrate and an oxidoreductase system specific for this substrate. However, the latter system generates hydrogen peroxide in the presence of oxygen in an aqueous environment and then Hydrogen peroxide produces lactose by reacting with thiocyanate, which is also contained in the drug. Hypothiocyanate is produced under the influence of superoxidase. typical In embodiments, the drug contains glucose as the oxidizable substrate, but , which is oxidized by glucose oxidase under hydrogen peroxide formation conditions and This hydrogen peroxide is then added to thiocyanate, for example in the form of potassium thiocyanate. nate (SCN-) to produce bacteriostatic hypotinia by lactoperoxidase. Oceanate (OSCN-) is produced.

The drug has been proposed to be used to control dental caries, and for that purpose it has bacteriostatic activity. Gender itself exerts beneficial effects. However, prevention of gingivitis and periodontal disease and The bactericidal activity is insufficient for use in the treatment of teeth and gums. Bacterial plaques in plants proliferate due to decreased inhibitory efficacy of hypothiocyanate. This is to continue.

Therefore, the hypothiocyanate-forming system is limited against the progression of gingivitis and periodontal disease. It is presumed that the effect will only be exerted by I can't.

Effective control and treatment of gingivitis and periodontal disease is based on the It can only be obtained by killing the bacteria present. Formation of dextran either to prevent it or to weaken or possibly kill the bacteria it contains. All of the above methods of inhibiting plaque formation, depending on the There is no evidence of any relevant substantive effect on existing plaque; The main purpose of the invention mentioned here is actually also the control of dental caries.

Based on the above, bacteria are particularly high in the oral region where they cause gingivitis or periodontal disease. There is a need for disinfectant compositions that can ensure bacterial kill rates.

Surprisingly, gingivitis and periodontal disease are believed to be responsible for the development and progression of gingivitis and periodontal disease. Bacteria of this type can be directly lysed by the cell wall-degrading enzyme lysozyme as described above. Hypothiocyanate (O5CN-) After being weakened to a very high degree by the enzymes mentioned above, they are destroyed and killed. This is where it was discovered that there was something that could be done.

Produces hydrogen peroxide in an aqueous environment and in the presence of oxygen and enzyme substrates. The present invention contains at least one kind of enzyme, peroxidase and thiocyanate. Taking advantage of this concept with respect to fungicidal compositions, the compositions of the present invention further improve It is characterized by containing zozyme.

The disinfectant composition of the present invention can be used to prevent or treat teeth, for example, gingivitis or periodontal disease. When applied in crevices and gingival pockets, the hydrogen peroxide-forming enzyme acts as a substrate for the enzyme. come into contact with food residues and irritant residues containing substances that act as irritants. this In some cases, this hydrogen peroxide is accompanied by oxidation of the above substances in the R fall of hydrogen peroxide. is due to the effects of peroxidase and natural peroxidase contained in the composition. reacts with more thiocyanate, resulting in hypothiocyanate (O5CN-) generate. This substance is included in the composition and weakened with hypothiocyanate. Bacteria are susceptible to and killed by lysozyme, which otherwise would not be able to degrade bacteria. The method by which it is exposed will have an impact on any unwanted bacteria that may be present.

A preferred embodiment of the composition according to the invention is that the hydrogen peroxide forming enzyme is characterized by being a duase Particularly when the composition is used in dental hygiene, sucrose or is the formation of glucose in which lactose serves as a substrate for glucose oxidase It further contains invertase, lactase or both, as broken down below. What you are doing is appropriate. This is due to the proper formation of hydrogen peroxide and thus hypochlorite. In order to obtain not only the formation of oceanate, but also the removal of the above-mentioned undesirable trisaccharides. It is.

However, even when the composition is used for dental hygiene, the composition does not contain a matrix. In this case the formation of hydrogen peroxide is present naturally in the mouth. is not limited by the amount of material that acts as a substrate for the hydrogen peroxide-forming enzyme.

Compositions of the invention containing glucose oxidase are particularly used for wound treatment. If glucose is used as a substrate for glucose oxidase, it may also contain glucose or Contains a mixture of lucose-forming substances and is such that glucose oxidase is active. It is advantageous to have a water content that does not exceed such a minimum value.

Hypothiocyanate to weaken bacteria and kill them with lysozyme The reaction that produces The composition is stable until the time of use. The composition is glue It may not contain courses; however, in such a case it is Used with glucose-containing or forming agents.

When the composition of the present invention is used for wound treatment, other hydrogen peroxide-forming enzymes may be used. As a base, it may be an amino acid oxidase, in which case blood and lymph Amino acids present in the liquid act as substrates.

In a preferred embodiment of the composition, thiocyanate and The peroxidase responsible for the formation of hypothiocyanate from hydrogen peroxide is Lactope peroxidase, myeloperoxidase or horseradish peroxidase. All of these enzymes are E and C.

1.17.1.7 (IUPAC).

As mentioned above, the particular interest is in applying the composition as a dental hygiene agent. , the present invention further improves the ability to fill gaps between teeth and gum pockets without affecting the microbial flora in the mouth. Regarding dental hygiene products that are particularly suitable for ensuring a high selective killing rate of bacteria in do. Incidentally, the overall effect on the total oral microbiome is less than desirable. .

The dental hygiene products of the present invention are particularly suitable for toothpicks and dental hygiene products for the prevention and treatment of gingivitis and periodontal disease. They are in the form of tooth threads or small brushes, and they are It is characterized by being impregnated with the composition of the present invention.

For example, impregnating toothpicks makes them impregnated with hydrogen peroxide-forming enzymes, peroxidase, and Wet with a solution of oceanate, lysozyme and a stabilizer for enzymes known per se. This can be done by drying the wet toothpicks after drying, e.g. by freeze-drying. can.

On the other hand, when applying toothpaste, use a brush, dental floss, toothpick, etc. to clean the gaps between teeth and gum pockets. in the form of a solution or suspension adapted to be added to the is preferably a hydrogen peroxide-forming enzyme, peroxygen, along with conventional stabilizers and preservatives. Contains Dase, Thiocyanate and Lysozyme.

Experiments have shown that the bactericidal effect of the composition of the present invention is greater than that of the composition applied by impregnated toothpicks. sufficiently that even a relatively small amount of chemical components can provide a significant bactericidal effect. proved to be high.

For example, the composition can be used to treat or prevent gingivitis and periodontal disease by toothpicks. Even though it is a specific feature of the invention that it is applied topically to the teeth and gaps between the teeth. However, the composition is suitable for use in toothpaste-like applications, where its use provides only an inferior topical product. It is also advantageously used in other dental hygiene agents.

Furthermore, the composition of the present invention may be combined with other drugs to enhance the intended effect. Obviously it's possible. For example, EDTA contains a certain amount of calcium compounds in the cell wall. The effectiveness of the composition against bacteria including.

When the bactericidal composition is used for wound treatment, it may contain coating material j. Alternatively, the composition may constitute a wound healing powder component.

Even if the bactericidal composition is primarily concerned with its use for tooth protection or wound treatment, Although it has been described until now, it is permissive to the host organism and has a limited period of action. Effective for a short period of time and without the risk of the emergence of resistant strains of microorganisms, as is the case with the use of antibiotics. Primarily, compositions are generally Applicable. In this regard, the compositions of the invention can be prepared by using such enzymes. It is emphasized that there are many drugs available, all of which are approved for inter-food use.

The quantitative proportions between the components of the fungicidal compositions in question can be varied within a wide range. individual development Due to the fact that the fraction must be considered non-toxic, excessive doses may have adverse side effects. There is no risk of causing any side effects, especially the hypothionium annealing produced. The maximum amount of food and irritant residue left in the mouth is determined by the amount of Dental hygiene products that do not contain substrates for hydrogen peroxide-producing enzymes, such as It's true.

The quantitative composition of the various products of the invention that have proven their effectiveness will appear from the examples below. Will.

To further characterize the enzymes and their quantitative units used in the examples, note the following: must be done.

Lactase; β-galactosidase (E, C, 3,2°1.23) at 20℃ 1 g of glucose from 6 ml of 5.0% lactose at pH 6.5 in 1 minute The unit defined as the amount of enzyme produced is U (lactose unit).

Lactose Llnit).

Invertase: β-fructofuranosidase (E, C.

3.2.1.26) from 6 ml of 5.4% sucrose at 20°C and pH 4.7. S, U, defined as the amount of enzyme that produces 1 mg of invert sugar in 5 minutes Rank.

Sumner tlnjt).

Glucose oxidase is classified as E, C, 1, 1, 3, 4, and is published in the journal Agricultural and Food Chemistry (Journal of’ Agricultural and FoodCh elIistry), Volume 153, No. 1.

Defined by D. Scott (D, 5cotL) on page 727, 1953. unit GOU (glucose oxidase unit).

glucose oxidase unit).

Lactoperoxidase is classified into E, C, 1, 17, 1, 7°, and the reaction H2O 2+5CN--H20+0SCN- in the composition in question. Ru. This enzyme was developed by J.S. Schindler and D. ABT defined by V.G. Bardsley Shown in S units: [Biochemical and Biophysical Lisa BiochetsicaI and Bjoph ysjcal Research Communications), Volume 67 .

No. 1307, 1975] Lysozyme is N-acetylmuramylhydrolase (E , C, 3, 2, 1°17). This enzyme extracts N-acetylglucosa from the cell wall. decomposes amine and N-acetylmuramic acid. Lysozyme activity is microkottka Su lithology (Mfcrococcus Iysodietjcus). It will be done. However, since clear activity standards are difficult to measure, In the examples below, the amount of chromium is shown as an absolute value. The substances used are 99% pure Yes, it was extracted from egg white.

Example 1 A solution containing the following components per ml was added to N a HP 04/ at pH 6.0. N a H2P 04 was prepared in an aqueous buffer containing 10-200 mM: Invertase 900 SU Glucose oxidase 45 GOUNaSCN 0.05 mmol Lactoperoxidase 28 ABTS units Lysozyme 0.03g Sodium EDTA 0.05 mmol The bactericidal effect of the composition thus obtained To test the fruit, Streptococcus, Lactobacillus, and Bacillus were grown in the presence of substrate. Bacteroides, Flavobacterium and Hubbacterium A preferred growth medium for various microorganisms of the genus Fusobacterium were cultured separately in Equilibrium growth of microorganisms at a cell density of 10-107 cells/ml Once this is achieved, add the above solution in a volume of 50-200μl/10ml culture. added to the culture. At the same time, to initiate the reaction that ultimately yields 0SCN- Sucrose 0. It was added in an amount of 1 to 196.

The bacterial culture was then incubated for 3 days at a temperature of 25.37.40 or 45 °C. during which time the cultures were examined daily.

In both cases, bacterial growth was limited to 50 μm of solution per 10 ml of growth culture. It was found that the addition of only

Example 2 A solution containing the following components per ml was prepared in a phosphate buffer with a pH of 6.0. : Invertase 900 SU Glucose oxidase 45 GOUNaSCN O, 05 mmol Lactoperoxidase 28 ABTS units Lysozyme 0.03g Mannitol 0.02g Sodium EDTA 0.05 mmol Soak a nail toothpick in this solution, 5-7 μm of solution was deposited on each toothpick.

The toothpicks were then freeze-dried.

In order to test the bactericidal effect of toothpicks impregnated in this way, Streptococcus spp. and 105 bacteria of different strains of the genus Lactobacillus were incubated on agar plates. I started. Toothpicks impregnated with the composition of the invention in sucrose-containing agar plates. The cells were then incubated for 6 days, and growth was observed daily. test was carried out by incubation at 25°C, 40°C and especially 37°C. transparent zone Bacteria formed around the toothpick, but there were no bacteria in the area 5 to 15 mm from the toothpick. There was no proliferation.

The size of this clear zone depended on the type of bacteria used. any place In some cases, no bacterial colonies were observed within the clear zone even after 6 days of growth. However, this does not mean that the bacteria in this zone have just become physiologically weakened. It means that it was destroyed without it.

The test was carried out on impregnated toothpicks after the toothpicks were stored in an airtight package for 3 months at 20°C. The bactericidal effect of the branches was also tested. The bactericidal effect of this toothpick remains completely unchanged. Therefore, this means that the fungicide composition of the present invention is not in practical use. The conclusion was drawn that it has sufficient storage stability.

For comparison purposes, the same solution and method as above was used, except without the lysozyme component. A toothpick was impregnated with the liquid. By testing, sterilization of the above toothpicks on agar plates Results regarding the effectiveness were obtained, but the results were significant compared to those obtained when lysozyme was present. It showed a very low bactericidal effect.

For further comparison purposes, the above amounts of lysozyme and ED without enzyme and Na5CN A toothpick was impregnated with an aqueous buffer of TA. With this latter toothpick, the trials carried out Experiments did not demonstrate any significant bactericidal activity.

Example 3 Preparation of solution for impregnated dental floss containing the following ingredients: Invertase 30000 SU Lactase 23000 LU Glucose oxidase 1000 GOUNaSCN 5mmol Lactoperoxidase 940 ABTS unit lysozyme 1.5g Carboxymethylcellulose 0.5g Inositol 1.75g EDTA sodium 5 mmol Na2HPO4 pH up to 6.5 Distilled water total volume up to 100ml Example 4 Preparation of solution for impregnated dental floss containing the following ingredients Coinvertase 90000 SU Lactase 70000 LU Glucose oxidase 4500 GOUNa SCN 5mmo 1 Lactoperoxidase 940 ABTS unit EDTA sodium 5mmo l Na2HPO4pH up to 6.0 Colorants and fragrances Distilled water total volume up to 100ml Example 5 Toothpicks, dental floss or a small brush in a water solution to be dipped immediately before use. , prepared from the following ingredients: Invertase 1800 SU Lactase 1400 LU Glucose oxidase 80 GOUNaSCN O, 1 mmol mm peroxidase 56 ABTS unit lysozyme 60mg Glycerol 20g EDTA O, 1 mmol N a 2 HP O41) H6, colorants and fragrances up to 0 Distilled water total volume up to 100ml During use, the solution is absorbed by the saliva present in the gingival pockets and tooth neck surface. It is calculated that it will be diluted approximately 3 times. About 1/4 of the above specific value in the composition. The concentration of ingredients included in the formulation will be quite sufficient to obtain the desired bacteriostatic activity.

Example 6 An aqueous solution similar to that in Example 5 was prepared, but with the exception of invertase, colorant and fragrance. Do not contain any agents. A gauze cloth was soaked in the solution and then dried under vacuum. obtained In addition to the usual ingredients for wound treatment powders, the wound dressing material contains about 2 types of grout 96. It was suitable for use in combination with such wound treatment powders containing lucose.

Claims (10)

[Claims] 1. A small amount of hydrogen peroxide that can form in an aqueous environment and in the presence of oxygen and enzyme substrates. Disinfectant containing at least one enzyme together with peroxidase and thiocyanate A composition comprising: A composition characterized in that it further contains lysozyme. 2. The set according to claim 1, wherein the hydrogen peroxide forming enzyme is glucose oxidase. A product. 3. Further containing invertase, lactase or both, especially for dental protection The composition according to claim 2. 4. Glucose or glucose-forming substances as substrates for glucose oxidase below the minimum value that further contains the mixture and glucose oxidase is active. 3. A composition according to claim 2, in particular for wound treatment, having a water content of . 5. Claims that the hydrogen peroxide-forming enzyme is an amino acid oxidase, especially for wound treatment Item 1. The composition according to item 1. 6. Peroxidase is E. C. 1.17.1.7. Lactoperio classified as Among oxidase, myeloperoxidase and horseradish peroxidase Composition according to any one of claims 1 to 5, selected. 7. Toothpicks, dental floss or small pieces, especially for controlling and treating gingivitis and periodontal disease A brush-shaped toothpaste product, characterized in that they are impregnated with a composition according to any one of claims 1 to 3. Toothbrushing products with special characteristics. 8. Particularly for controlling and treating gingivitis and periodontal disease, and for removing gaps between teeth and gum pockets. dentifrice in the form of a solution or suspension adapted for application to , characterized in that it is an aqueous solution of the composition according to any one of claims 1 to 3. Toothpaste with a characteristic. 9. A coating material impregnated with the composition according to claim 4 or 5. Wound treatment supplies. 10. A powder for wound treatment containing the composition according to claim 4 or 5. Wound treatment supplies.