Improved endoscope disinfectant

文档序号：245624 发布日期：2021-11-12 浏览：20次中文

阅读说明：本技术 改良的内窥镜消毒剂 (Improved endoscope disinfectant ) 是由 T·格拉斯贝 N·A·罗伯茨 G·S·怀特利于 2020-02-07 设计创作，主要内容包括：本发明提供一种改良的内窥镜消毒剂,具体为一种有效消毒剂溶液,其包含过氧乙酸和至少一种表面活性剂,通过稀释单部分或两部分浓缩物制备,用于可重复使用的医疗设备(例如内窥镜)的消毒或灭菌。所述有效溶液表现出快速润湿,其特征在于动态表面张力在250ms时小于50mN/m,在500ms时小于46mN/m。(The present invention provides an improved endoscope disinfectant, in particular an effective disinfectant solution comprising peracetic acid and at least one surfactant, prepared by diluting a one-part or two-part concentrate, for disinfection or sterilization of reusable medical equipment, such as endoscopes. The effective solution exhibits rapid wetting and is characterized by a dynamic surface tension of less than 50mN/m at 250ms and less than 46mN/m at 500 ms.)

1. An effective disinfectant solution comprising an aqueous dilution of a disinfectant concentrate for sterilization or disinfection of medical equipment, the disinfectant concentrate comprising:

a. peroxyacetic acid and

b. at least one surfactant

Wherein the effective disinfectant solution exhibits a dynamic surface tension of less than about 50mN/m at a surface age of 250ms and a dynamic surface tension of less than about 46mN/m at a surface age of 500ms, when measured by the maximum bubble pressure method at 20 ℃ to 25 ℃.

2. An effective disinfectant solution according to claim 1 wherein the effective disinfectant solution exhibits a dynamic surface tension of less than about 42.5mN/m at a surface age of 250ms and less than about 41.0mN/m at a surface age of 500ms at 20 ℃ to 25 ℃ when measured by the maximum bubble pressure method.

3. An effective disinfectant solution according to claim 2 which exhibits a dynamic surface tension of less than about 42.5mN/m at a surface age of 250ms, less than about 41mN/m at a surface age of 500ms and less than about 40mN/m at a surface age of 5000ms at 20 ℃ to 25 ℃ when measured by the maximum bubble pressure method.

4. An effective disinfectant solution according to any one of claims 1 to 3 wherein the concentration of peroxyacetic acid in the effective disinfectant solution is between about 0.01% w/v to about 1.0% w/v (about 100ppm to about 10,000 ppm).

5. An effective disinfectant solution according to any one of claims 1 to 3 wherein the concentration of peroxyacetic acid in the effective disinfectant solution is between about 0.02% w/v to about 0.5% w/v (about 200ppm to about 5000 ppm).

6. The effective disinfectant solution according to claim 5, wherein the concentration of the surfactant in the effective disinfectant solution is from about 0.05% w/v to about 0.5% w/v.

7. An effective disinfectant solution according to any one of claims 1 to 3 wherein the disinfectant concentrate is provided as a one-part disinfectant concentrate.

8. An effective disinfectant solution according to any one of claims 1 to 3 wherein the disinfectant concentrate is provided as a two-part disinfectant concentrate having a first part and a second part.

9. The effective disinfectant solution according to claim 7, wherein the one-part disinfectant concentrate comprises between about 0.1% w/w to about 20% w/w peroxyacetic acid of the disinfectant concentrate.

10. The effective disinfectant solution according to claim 9, wherein the one-part disinfectant concentrate comprises between about 1% w/w to about 15% w/w peroxyacetic acid of the disinfectant concentrate.

11. The effective disinfectant solution according to claim 10, wherein the one-part disinfectant concentrate comprises between about 4% w/w to about 6% w/w peroxyacetic acid of the disinfectant concentrate.

12. An effective disinfectant solution according to any one of claims 1 to 11, wherein the at least one surfactant is selected from ionic, non-ionic, zwitterionic and amphoteric surfactants or mixtures thereof.

13. The efficacious disinfectant solution of claim 12 wherein the surfactant is selected from the group consisting of block copolymers of polyethylene oxide and polypropylene oxide, fatty alcohol alkoxylates, long chain alkyl alkoxylates, N-alkyl pyrrolidones, branched short chain perfluorinated surfactants, branched short chain polysiloxane functionalized polyethylene glycols, and combinations thereof.

14. The effective disinfectant solution according to claim 7, wherein the one-part disinfectant concentrate comprises between about 0.05% w/w to about 15% w/w of the disinfectant concentrate of the surfactant.

15. The effective disinfectant solution according to claim 14, wherein the one-part disinfectant concentrate includes between about 0.1% w/w to about 10% w/w of the disinfectant concentrate of the surfactant.

16. The effective disinfectant solution according to claim 15, wherein the one-part disinfectant concentrate includes between about 1% w/w to about 9% w/w of the disinfectant concentrate of the surfactant.

17. The effective disinfectant solution according to claim 7, wherein the one-part disinfectant concentrate additionally comprises a corrosion inhibitor and/or a hydrotrope.

18. The effective disinfectant solution according to claim 17, wherein the corrosion inhibitor is selected from the group consisting of benzotriazole, alkali metal phosphates, alkali metal nitrates, alkali metal nitrites, 2-phosphonobutane-1, 2, 4-tricarboxylates, metal molybdates, and combinations thereof.

19. An effective disinfectant solution according to claim 17 or claim 18 wherein the one-part disinfectant concentrate comprises from about 0.1% w/v to about 2% w/v of the disinfectant concentrate of a corrosion inhibitor.

20. The effective disinfectant solution according to claim 17, wherein the hydrotrope is selected from the group consisting of potassium xylene sulfonate, potassium naphthalene sulfonate, potassium cumene sulfonate, potassium tolyl phosphate, potassium octyliminodipropionate, sodium xylene sulfonate, sodium naphthalene sulfonate, sodium cumene sulfonate, sodium tolyl phosphate, sodium octyliminodipropionate, amyl glucoside, hexyl glucoside, octyl glucoside, isooctyl glucoside, and mixtures thereof.

21. The effective disinfectant solution according to claim 20, wherein the one-part disinfectant concentrate comprises about 0.1% w/w to about 15% w/w hydrotrope of the disinfectant concentrate.

22. The effective disinfectant solution of claim 8 wherein the first part of the two-part disinfectant concentrate comprises a balanced solution of peroxyacetic acid, hydrogen peroxide, acetic acid, and water.

23. The effective disinfectant solution of claim 22 wherein the first part comprises between about 0.1% w/w to about 20% w/w of the peroxyacetic acid of the first part.

24. The effective disinfectant solution of claim 23 wherein the first part comprises between about 1% w/w to about 15% w/w of the peroxyacetic acid of the first part.

25. The effective disinfectant solution of claim 24 wherein the first part comprises between about 4% w/w to about 6% w/w of the peroxyacetic acid of the first part.

26. An effective disinfectant solution according to any one of claims 22 to 25 wherein the second part of the two part disinfectant concentrate comprises the at least one surfactant.

27. The effective disinfectant solution according to claim 26, wherein the surfactant is selected from the group consisting of ionic, non-ionic, zwitterionic and amphoteric surfactants or mixtures thereof.

28. The efficacious disinfectant solution of claim 27 wherein the surfactant is selected from the group consisting of block copolymers of polyethylene oxide and polypropylene oxide, fatty alcohol alkoxylates, long chain alkyl alkoxylates, N-alkyl pyrrolidones, branched short chain perfluorinated surfactants, branched short chain polysiloxane functionalized polyethylene glycols, and combinations thereof.

29. The effective disinfectant solution according to any one of claims 26 to 28, wherein the surfactant comprises between about 0.05% w/w to about 15% w/w of the second part.

30. The effective disinfectant solution of claim 29, wherein the surfactant comprises between about 0.1% w/w to about 10% w/w of the second portion.

31. The effective disinfectant solution of claim 30, wherein the surfactant comprises between about 1% w/w to about 9% w/w of the second portion.

32. The effective disinfectant solution according to claim 26, wherein the second part of the two-part disinfectant concentrate additionally comprises a corrosion inhibitor and/or a hydrotrope.

33. The effective disinfectant solution of claim 32, wherein the corrosion inhibitor is selected from the group consisting of benzotriazole, alkali metal phosphates, alkali metal nitrates, alkali metal nitrites, 2-phosphonobutane-1, 2, 4-tricarboxylates, metal molybdates, and combinations thereof.

34. The effective disinfectant solution according to claim 32 or 33, wherein the corrosion inhibitor is present in the two-part disinfectant concentrate at a concentration of about 0.1% w/v to about 2% w/v.

35. The effective disinfectant solution according to claim 32, wherein the hydrotrope is selected from the group consisting of potassium xylene sulfonate, potassium naphthalene sulfonate, potassium cumene sulfonate, potassium tolyl phosphate, potassium octyliminodipropionate, sodium xylene sulfonate, sodium naphthalene sulfonate, sodium cumene sulfonate, sodium tolyl phosphate, sodium octyliminodipropionate, amyl glucoside, hexyl glucoside, octyl glucoside, isooctyl glucoside, and mixtures thereof.

36. The effective disinfectant solution according to claim 35, wherein the hydrotrope is present in the second part of the two part disinfectant concentrate in an amount from about 0.1% w/w to about 15% w/w.

37. A method of disinfecting or sterilizing a medical device, the method comprising contacting the medical device with an effective disinfectant solution comprising an aqueous dilution of a disinfectant concentrate comprising:

a. peroxyacetic acid and

b. at least one surfactant

38. A method of disinfecting or sterilizing a medical device, the method comprising contacting the medical device with an effective disinfectant solution according to any one of claims 1 to 36.

Background

Reusable medical devices are devices that a healthcare provider can reprocess and reuse on multiple patients. Examples of reusable medical devices include surgical forceps, endoscopes, and stethoscopes.

Depending on the degree of risk of infection associated with the use of the device, all reusable medical devices can be classified into one of three types:

critical equipment, such as surgical forceps, is in contact with blood or normal sterile tissue.

Semi-critical devices, such as endoscopes, are in contact with the mucosa.

Non-critical devices, such as stethoscopes, come into contact with unbroken skin.

The classification scheme is designed by Erwin springing and can be used as a reprocessing guide for reusable medical devices.

Critical medical devices must be reprocessed by sterilization, preferably moist heat sterilization, or other means if the device is incompatible with moist heat sterilization. Semi-critical medical equipment should also be sterilized by moist heat, if possible, but at least with high concentrations of disinfectants.

A chemical sterilant is a chemical agent used to sterilize critical medical equipment. The sterilizing agent kills all microorganisms, thereby achieving the sterility assurance level that the probability of survival of a single microorganism is less than or equal to 10^-6High concentration disinfectants (HLD) can be considered a subcategory of disinfectants, but with shorter exposure times than required for sterilization. When used as recommended by the manufacturer, HLD kills all microbial pathogens except for a large number of bacterial endospores, and suggests a minimal process for the reprocessing of semi-critical medical devices。

A common type of semi-critical medical device is flexible endoscopes, such as colonoscopes and gastroscopes. Due to the complex structure and the adoption of heat-labile materials such as polyurethane sheaths, epoxy coatings, optical cables, optoelectronic chips, etc., most flexible endoscopes cannot be sterilized by moist heat, and therefore need to be reprocessed with chemical sterilants or high-concentration disinfectants.

Peracetic acid (PAA) is a common option for chemically sterilizing and disinfecting flexible endoscopes at high concentrations.

PAA is typically supplied as an equilibrium mixture of PAA, hydrogen peroxide and acetic acid. PAA is prepared by mixing an aqueous solution of hydrogen peroxide and acetic acid and allowing the material to equilibrate. Typically, the reaction is carried out uncatalyzed, allowing the reactants to equilibrate over a period of 10 to 14 days, or catalyzed by the addition of a strong mineral acid (such as 1% w/w concentrated sulfuric acid).

Commercial grade PAA contains between 5.0% and 5.4% PAA. Since PAA is classified as a class 5.1 hazardous material, PAA at this concentration is commonly used for commercial use. Products with higher PAA concentrations are classified as category 5.2 hazardous, which negatively impacts transportation costs and storage requirements.

Typically, an equilibrium solution of PAA between 5.0% w/w and 5.4% w/w will also contain between about 25% w/w and 28% w/w hydrogen peroxide and between 7% w/w and 10% w/w acetic acid. Phosphonic acid chelating agents are typically added to prevent degradation of the product due to trace metal contaminants.

PAAs are commonly used as sterilants or HLDs for reprocessing flexible endoscopes using Automated Endoscope Reprocessors (AERs). Reprocessing of endoscopes in AERs typically includes the following steps:

put in AER

Prewashing with Water

Washing stages with appropriate detergents

Using a Water rinse stage

Sterilisation or disinfection of

Multiple rinses.

The AER injects a PAA sterilant or disinfectant into the chamber containing the endoscope and dilutes it to its effective concentration. For high concentration disinfection, a 5% w/w PAA equilibration solution is typically diluted to between 1% v/v and 2% v/v, whereas for sterilization it is diluted to between 2% v/v and 4% v/v. This results in an effective concentration of PAA for high concentration sterilization of between about 650ppm and 1000ppm and an effective concentration of PAA for sterilization of between 1300ppm and 2000 ppm.

In addition to the PAA concentration, the time required to achieve disinfection also depends on the temperature of the disinfectant or sterilant. For flexible endoscopes high concentration disinfection is usually performed at a temperature between 25 ℃ and 40 ℃ for a period of 5 minutes, whereas for sterilization a contact time between 7 minutes and 10 minutes is usually used at a temperature between 30 ℃ and 45 ℃.

One problem with PAA for endoscope disinfection and sterilization is that PAA, which is acidic, strongly oxidizing, can corrode the endoscope and/or AER. This can generally be mitigated to some extent by the addition of corrosion inhibitors and pH buffers to the diluted PAA solution. Common corrosion inhibitors are benzotriazole, potassium phosphate, sodium nitrite, sodium nitrate, molybdenum salts, and the like.

The corrosion inhibitor and pH buffer are typically added to the AER sterilization chamber as separate solutions as a part B solution (concentrated PAA solution is a part a solution). This configuration may be referred to as a two-part disinfectant or sterilant. Other ingredients may also be added to the part B solution, for example wetting agents such as surfactants. The surfactant is added to allow the disinfectant to adequately wet the surface of the endoscope and also to dissolve any dirt remaining during the cleaning stage.

Typically, nonionic surfactants are used in the part B solution because they are generally low foaming. Examples may include pluronic 10R5 (see, e.g., WO2016/100818 to Mdivators), pluronic PE85, and pluronic PE64 (see, e.g., US20030129254 to Saraya). JP2009155270 to Fujifilm Corporation also teaches the use of pluronic surfactants in part B formulations. Notably, there is no teaching regarding the surface tension of disinfectant solutions prepared from these formulations.

The use of amine oxide surfactants with other surfactants has been shown to enhance the biocidal efficacy of PAA-based disinfectants, especially when used in combination with phosphate buffer. This has been shown in Saban venturs AU 2013359955. The surfactants tested included cocamidopropyl amine oxide. Other non-ionic surfactants such as Triton X-100 or Tween-80 were also tested. Cationic surfactants tested included quaternary ammonium compounds such as benzalkonium chloride or cetyl pyridinium bromide.

It has also been shown that the use of amine oxide based surfactants can improve the biocidal efficacy of PAA based disinfectants, especially when used in combination with surfactants having the structure shown in formula 1

R1-O-[CH(R2)-CH(R3)-O]_n-R4 formula 1

Wherein R1 represents a linear or branched, saturated or unsaturated aliphatic group containing from 5 to 31 carbon atoms and preferably from 10 to 16 carbon atoms; r2 represents a hydrogen atom, a methyl radical or a ethyl radical, R3 represents a hydrogen atom, a methyl radical or a ethyl radical, it being understood that at least one of the two radicals R2 or R3 represents a hydrogen atom, R4 represents a hydrogen atom or a linear or branched alkyl group containing from 1 to 4 carbon atoms, or a benzyl group, n represents a number between 1 and 50, and preferably n is less than 20 (see US6168808, US6444230 and FR2796285 to Seppic).

One suggestion for a mechanism to improve the biocidal efficacy of PAA in the presence of surfactants is to improve the wettability of disinfectants in the presence of a surfactant system. For example, EP0971584 (still granted to Seppic) shows that PAA-based disinfectants formulated with amine oxide based surfactants, especially in the presence of surfactants having the structure shown in formula 1, can show good wetting characteristics upon dilution with a static surface tension between 26.5mN/m and 31.0mN/m (measured by wilhelmy plate method).

Interestingly, the reproduction of these formulations by the maximum bubble pressure method and the measurement of their surface tension showed that the examples of EP0971584 show that these formulations wet slowly, and that the surface tension at a surface age of 15000ms is significantly higher than the static value reported in the' 584 document (see example 9 and fig. 6).

The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

Disclosure of Invention

According to a first embodiment of the present invention there is provided an effective disinfectant solution comprising an aqueous dilution of a disinfectant concentrate for the sterilization or disinfection of medical devices, the disinfectant concentrate comprising: (a) peroxyacetic acid and (b) at least one surfactant, wherein the efficacious disinfectant solution exhibits a dynamic surface tension of less than about 50mN/m at a surface age of 250ms (a surface age of 250ms) and a dynamic surface tension of less than about 46mN/m at a surface age of 500ms, when measured using the maximum bubble pressure method at 20 ℃ to 25 ℃.

According to a second embodiment of the present invention there is provided the effective disinfectant solution of the first embodiment, wherein said effective disinfectant solution exhibits a dynamic surface tension of less than about 42.5mN/m at a surface age of 250ms and a dynamic surface tension of less than about 41.0mN/m at a surface age of 500ms, at 20 ℃ to 25 ℃, when measured by the maximum bubble pressure method.

According to a third embodiment of the present invention, there is provided a second exemplary effective disinfectant solution, wherein the effective disinfectant solution also exhibits a dynamic surface tension of less than about 40mN/m at a surface age of 5000ms, as measured by the maximum bubble pressure method.

According to a fourth embodiment of the present invention there is provided an effective disinfectant solution according to any one of the first, second or third embodiments wherein the disinfectant concentrate is provided as a one-part disinfectant concentrate.

According to a fifth embodiment of the present invention there is provided an effective disinfectant solution according to any of the first, second or third embodiments wherein the disinfectant concentrate is provided as a two-part disinfectant concentrate having a first part and a second part.

According to a sixth embodiment of the present invention there is provided a method of disinfecting or sterilizing a medical device, the method comprising contacting the medical device with an effective disinfectant solution comprising an aqueous dilution of a disinfectant concentrate comprising (a) peroxyacetic acid and (b) at least one surfactant, wherein the effective disinfectant solution exhibits a dynamic surface tension of less than about 50mN/m at a surface age of 250ms and a dynamic surface tension of less than about 46mN/m at a surface age of 500ms, when measured using the maximum bubble pressure method at 20 ℃ to 25 ℃.

According to a seventh embodiment of the present invention there is provided a method of disinfecting or sterilizing a medical device, the method comprising contacting the medical device with an effective disinfectant solution according to any one of the first to fifth embodiments.

Throughout the description and claims of this specification, the word "comprise", and variations of the word, such as "comprises" and "comprising", are not intended to exclude other additives, components, integers or steps.

Drawings

Figure 1 shows a william plate apparatus.

Fig. 2 illustrates a maximum bubble pressure method for determining the dynamic surface tension of a liquid or solution.

Figure 3 shows the dynamic surface tension measurements of the disinfectant of the present invention and a comparative prior art disinfectant at various surface ages.

Fig. 4 shows dynamic surface tension measurements of various prior art disinfectants at various surface ages, as shown in examples 4-7.

Fig. 5 shows dynamic surface tension measurements at various surface ages for various prior art disinfectants according to U.S. patent 6,168,808, as shown in examples 8A-8D.

Fig. 6 shows the dynamic surface tension measurements at various surface ages for various prior art disinfectants according to european patent EP0971584, as shown in examples 9A-9E.

Figure 7 shows the dynamic surface tension measurements at various surface ages for two embodiments of the present invention (example 10 and example 11).

Fig. 8 shows dynamic surface tension measurements of various components of example 10 at various surface ages, as described in example 12.

Fig. 9 shows the dynamic surface tension measurements at various surface ages for embodiments of the present invention based on branched alkyl alkoxylates (examples 13A-13D).

Fig. 10 shows the dynamic surface tension measurements at various surface ages for the short chain fluorosurfactant-based one-part concentrate embodiments of the present invention (examples 14A-14D).

FIG. 11 is dynamic surface tension measurements at various surface ages of one-part concentrate embodiments of the present invention based on branched alkyl alkoxylates (examples 15A-15G).

Detailed Description

Described herein are PAA-based disinfectant compositions intended for high concentration disinfection and/or sterilization of complex reusable thermolabile medical devices, such as flexible endoscopes. The compositions are typically produced as concentrates and then diluted to the preferred effective concentration at the time of use. The diluted disinfectant composition is referred to herein as an effective disinfectant solution.

Preferably, the effective disinfectant solution of the present invention is used in a self-cleaning sterilizer, more preferably a self-cleaning sterilizer for reprocessing of, for example, flexible endoscopes.

The effective disinfectant solution of the present invention is formed by diluting the disinfectant concentrate.

In one embodiment, the disinfectant concentrate is comprised of two parts. The first part is preferably a PAA concentrate and the second part is preferably a corrosion inhibitor concentrate comprising at least one surfactant. The first part, referred to as part a, comprises an equilibrium solution of PAA, hydrogen peroxide and acetic acid, preferably in combination with a stabilizer and optionally with a small amount of a strong mineral acid. The second part (referred to as part B) preferably comprises at least one corrosion inhibitor, at least one surfactant, and may optionally comprise other ingredients such as hydrotropes, pH adjusters, indicators, colorants, chelating agents, and the like. An effective disinfectant solution is prepared by mixing part a and part B and diluting with water to obtain the desired concentration of PAA.

Preferably, part A will contain an equilibrium solution between PAA between about 0.1% w/w to about 20% w/w. More preferably, part A will comprise between about 1% w/w to about 15% w/w PAA. Most preferably, part A will comprise between about 4% w/w to about 6% w/w PAA.

Notably, commercial PAA equilibrium solutions (such as Proxitane) will contain stabilizers (often of a proprietary nature).

These commercial products may also contain small amounts (typically ≦ 1%) of mineral acids (especially produced in cold climates).

The second part (hereinafter referred to as part B) comprises an aqueous solution of at least one surfactant and preferably at least one corrosion inhibitor and/or at least one pH adjuster.

Thus, the effective disinfectant solutions of the present invention are prepared by mixing part a and part B solutions with water to produce a water-based disinfectant effective solution.

Preferably, the volume ratio of part a to part B is between about 1:10 and about 10: 1. More preferably, the volume ratio of part a to part B is between about 1:5 to about 5: 1. Most preferably, the volume ratio of part a and part B is about 1: 1.

An effective disinfectant solution preferably comprises between about 0.1% v/v to about 10% v/v of part a and between about 0.1% v/v to about 10% v/v of part B. More preferably, an effective disinfectant solution will contain between about 0.5% v/v to about 5% v/v of part A and between about 0.5% v/v to about 5% v/v of part B for high concentration disinfection, and between about 1.0% v/v to about 10% v/v of part A and between about 1.0% v/v to about 10% v/v of part B for sterilization.

An effective disinfectant solution exhibits a dynamic surface tension of less than about 50mN/m at a surface age of 250ms and less than about 46mN/m at a surface age of 500ms at 20 ℃ to 25 ℃ as measured by the maximum bubble pressure method.

In a preferred embodiment, the effective disinfectant solution exhibits a dynamic surface tension of less than about 42.5mN/m at a surface age of 250ms and less than about 41mN/m at a surface age of 500ms at 20 ℃ to 25 ℃, as measured by the maximum bubble pressure method.

In another preferred embodiment, the effective disinfectant solution exhibits a dynamic surface tension of less than about 42.5mN/m at a surface age of 250ms, and a dynamic surface tension of less than about 41mN/m at a surface age of 500ms, and a dynamic surface tension of less than about 40mN/m at a surface age of 5000nm, at 20 ℃ to 25 ℃, as measured by the maximum bubble pressure method.

In another embodiment of the invention, the disinfectant concentrate is provided as a one-part disinfectant composition comprising a balanced solution of at least PAA, hydrogen peroxide and acetic acid and at least one surfactant, and preferably in combination with a stabilizer. Optionally, the one-part disinfectant concentrate may further comprise at least one corrosion inhibitor and other ingredients, such as hydrotropes, pH adjusters, indicators, colorants, chelating agents, and the like. In use, the one-part disinfectant concentrate is diluted, preferably with water.

The diluted one-part disinfectant concentrate is an effective disinfectant solution that exhibits a dynamic surface tension of less than about 50mN/m at a surface age of 250ms and less than about 46mN/m at a surface age of 500ms at 20 ℃ to 25 ℃ as measured by the maximum bubble pressure method.

In a preferred embodiment, such diluted one-part disinfectant concentrates forming the effective disinfectant solution of the present invention exhibit a dynamic surface tension of less than about 42.5mN/m at a surface age of 250ms and less than about 41mN/m at a surface age of 500ms at 20 ℃ to 25 ℃ as measured by the maximum bubble pressure method.

In another preferred embodiment, the diluted one-part disinfectant concentrate forming the effective disinfectant solution exhibits a dynamic surface tension of less than about 42.5mN/m at a surface age of 250ms, and a dynamic surface tension of less than about 41.0mN/m at a surface age of 500ms, and a dynamic surface tension of less than about 40.0mN/m at a surface age of 5000nm, at 20 ℃ to 25 ℃, as measured by the maximum bubble pressure method.

Without wishing to be bound by theory, it is believed that at low surface ages the improved rapid wetting provided by the low surface tension allows for more rapid disinfection of endoscopes within the AER, particularly those employing dynamic cleaning processes (e.g., spray arms, etc.).

The improved disinfectant performance resulting from the rapid wetting of the effective disinfectant solutions of the present invention will achieve at least a 6log10 reduction in bacteria and spores more rapidly than prior art PAA-based disinfectant solutions when tested under the same PAA concentration and temperature conditions.

Alternatively, or in addition, the effective disinfectant solutions of the present invention achieved at least a 6log10 reduction of bacteria and spores within the same time frame as prior art PAA-based disinfectant solutions when tested at lower PAA concentrations. Lower concentrations will provide less corrosive disinfectant solutions, but with the same biocidal properties.

Many prior art describes single-part and two-part PAA-based disinfectants containing surfactants, wherein the presence of the surfactant increases the biocidal efficacy of the PAA-based disinfectant.

As previously mentioned, it has been proposed that the presence of a surfactant allows the disinfectant to better wet the surface, resulting in improved disinfecting efficacy. EP0971584 describes the possibility of improved wettability, i.e. lowering the surface tension of the disinfectant so that the contact angle of the solution on hydrophobic surfaces (such as parafilm) is reduced. However, the' 584 reference is characterized by the use of a Williams plate method for the static surface tension of the solution (see Table 1). No dynamic surface tension data is reported in the' 584 document.

Table 1: static surface tension reported in EP0971584

Fig. 3 shows a comparison between dynamic surface tension at various surface ages between a prior art example of a plurality of PAA-based disinfectants and an exemplary embodiment of an effective disinfectant solution of the present invention. It can clearly be seen that the exemplary embodiments all show a significantly faster reaching of a surface tension below about 42.5mN/m than the prior art examples, and a surface tension below 40mN/m at 5000 ms.

A wilhelmy plate consists of a thin plate, typically of the order of a few square centimeters in area (see figure 1). The plate is typically made of filter paper, glass or platinum, which may be roughened to ensure complete wetting. In fact, the results of the experiment do not depend on the material used, as long as the material is wetted by the liquid. The plate was thoroughly cleaned and connected to a balance by a fine wire. The force generated on the plate due to wetting is measured using a tensiometer or microbalance for calculating the surface tension using the william equation:

where l is the wetted perimeter and θ is the contact angle between the liquid phase and the flat plate. In practice, contact angles are rarely measured, but literature values are used, or complete wetting is assumed.

One problem with the william plate method is that it represents a static situation. When the surfactant is dissolved in water, the surfactant molecules will migrate to the surface of the liquid (at the air interface or the container walls). Until a certain concentration of surfactant is reached (critical micelle concentration (CMC)), all surfactant molecules migrate to the various surfaces around the solution. Once above the CMC, aggregates of surfactant molecules (micelles) will form in the bulk solution.

The rate at which surfactant molecules diffuse from the bulk solution to the surface interface will vary depending on the surfactant type, which will be reflected in, for example, the wetting rate.

When measured by the wilhelmy plate method (or similar methods such as the DeNoy ring), the measured solution is unstirred and will represent a static or equilibrium surface tension, i.e., the surface tension obtained after all available surfactant molecules have migrated to the interface.

While such measurements are effective for evaluating disinfectants used under static conditions (e.g., when the endoscope is immersed in a static solution of disinfectant), this is not the case with modern AERs, which typically continuously pump disinfectant solution through the endoscope lumen and spray disinfectant onto the exterior surface of the endoscope using a spray arm. This creates a highly dynamic environment, constantly mixing disinfectants. Under these conditions, the actual surface tension will be significantly higher than that measured using static methods (such as Williams plates) by a slow diffusing surfactant system.

Dynamic surface tension measurement

One method of measuring dynamic surface tension is the maximum bubble pressure method. The bubbles in the liquid are compressed due to the internal attraction of the liquid. The pressure generated (bubble pressure) increases as the bubble radius decreases. The bubble pressure method is to use such a higher bubble pressure than the ambient environment (water). The gas stream is pumped into a capillary tube immersed in the liquid. The surface area of the bubbles generated at the tip end of the capillary becomes larger.

The pressure rises to a maximum level. At this point, the bubble has reached its minimum radius (capillary radius) and formed a hemisphere. After this time, the bubble will grow rapidly and collapse quickly, being forced out of the capillary, allowing a new bubble to form at the capillary tip. It is in this process that a unique pressure pattern (see fig. 2) is formed, which is evaluated to determine the surface tension.

By varying the rate of bubble formation, the surface tension at various surface ages can be determined, with the surface tension measured at longer surface ages approaching that measured under static conditions.

Thus, the surface tension under dynamic conditions (e.g., conditions encountered in modern AERs) can be determined using the maximum bubble pressure method.

Disinfectant component

Peroxyacetic acid solution

In a preferred embodiment, the disinfectant concentrate of the present invention is prepared using an equilibrium solution containing PAA, hydrogen peroxide, acetic acid, and water containing between about 0.1% w/w to about 20% w/w PAA. In a more preferred embodiment, the PAA solution will preferably comprise between about 1% w/w to 15% w/w PAA, more preferably between about 4% w/w to about 6% w/w PAA.

Typically, the PAA solution will be provided as an equilibrium solution. These solutions are prepared by reacting hydrogen peroxide with acetic acid as shown in equation 2.

The reaction mixture preferably also contains a stabilizer, which is typically a chelating agent, for complexing heavy metal ions to prevent them from catalyzing the degradation of peroxygen species.

The reaction to form PAA may be uncatalyzed, in which case the reaction may take from 10 to 15 days to reach equilibrium, or may be catalyzed by the addition of small amounts (about 1% w/w) of a strong acid, such as sulfuric acid. At equilibrium, the final solution will consist of a mixture comprising reactants and products (i.e. a mixture containing PAA, water, hydrogen peroxide and acetic acid). The equilibrium solution can be prepared using a known method (for example, the method of F.P.Greenspan, "convenient preparation of peracid", J.Am.chem.Soc.1946,68,5,907-

The extent of the reaction can be defined by the equilibrium constant k, which is the ratio of the molar concentrations of the product and the reactants, i.e.

Rearranging the equation to obtain

Wherein:

k is an equilibrium constant

[ PAA ] is the molar concentration of PAA

[ Water ] is the molar concentration of Water

[ HP ] is the molar concentration of hydrogen peroxide

[ AcOH ] is the molar concentration of acetic acid

The value of the equilibrium constant will be about 2.7 at room temperature (see, for example, Zhao et al, "production of peracetic acid by acetic acid and hydrogen peroxide: experiments and modeling", proceedings of process engineering, vol. 35-41, vol. 8(1) for example).

As can be seen from equation 4, the molar concentration of PAA is directly proportional to the product of the molar concentrations of hydrogen peroxide and acetic acid, and inversely proportional to the molar concentration of water in solution. Thus, an equilibrium solution containing a defined PAA concentration may contain different concentrations of hydrogen peroxide and acetic acid, as long as the product of their molar concentrations remains the same.

The PAA composition may also comprise other ingredients such as stabilizers and inorganic acids. The stabilizer may be selected from phosphonic acid derivatives such as aminotri (methylenephosphonic acid), 1-hydroxyethylidene-1, 1-diphosphonic acid, quinolin-8-ol, 2, 6-pyridinedicarboxylic (bipyridine) acid, aspartic acid diethoxysuccinate, quinoline-2-carboxylic acid, citric acid, isocitric acid, aconitic acid, propane-1, 2, 3-tricarboxylic acid, and mixtures thereof. The inorganic acid may be selected from the group consisting of sulfuric acid, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof.

In yet another embodiment, PAA comprising the composition of the present invention may be formed by a reaction between a hydrogen peroxide solution and an acylating agent, such as Tetraacetylethylenediamine (TAED), N-acetyl caprolactam, N-acetyl succinimide, N-acetyl phthalimide, N-acetyl maleimide, pentaacetyl glucose, octaacetyl sucrose, acetyl salicylic acid, tetraacetyl glycoluril, and combinations thereof.

When used in dilution, the concentration of PAA in an effective disinfectant solution is preferably between about 0.01% w/v to about 1.0% w/v (about 100ppm to about 10,000ppm), and more preferably between about 0.02% w/v to about 0.5% w/v (about 200ppm to about 5000 ppm).

As the skilled practitioner will appreciate, other peracids may be used in combination with or in place of peroxyacetic acid. These would include, but are not limited to, percitric acid, perlactic acid, performic acid, perpropionic acid, percaproic acid, perheptanoic acid, peroctanoic acid, perbenzoic acid, and mixtures thereof.

Corrosion inhibitors

Preferably, the disinfectant compositions of the present invention comprise corrosion inhibitors such as, but not limited to, benzotriazole, alkali metal phosphates, alkali metal nitrates, alkali metal nitrites, 2-phosphonobutane-1, 2, 4-tricarboxylates, metal molybdates, and combinations thereof.

Corrosion inhibitors reduce corrosion caused by the disinfectant compositions of the present invention in endoscopes and endoscope reprocessors. Preferably, the corrosion inhibitor is present in the disinfectant concentrate in an amount of between about 0.1% w/v to about 2% w/v, or the corrosion inhibitor is present in the diluted effective disinfectant solution in an amount of between about 500ppm to about 5000 ppm.

In one embodiment, the corrosion inhibitor is included in part B of a two-part disinfectant concentrate. In another embodiment, the corrosion inhibitor is contained in a one-part concentrate in peracetic acid solution.

Surface active agent

Suitable surfactants for use in the effective disinfectant solutions of the present invention include ionic, nonionic, zwitterionic and amphoteric surfactants or mixtures thereof. Preferably, the surfactant or surfactant mixture will be low foaming and will also act as a wetting agent.

Preferably, the amount of surfactant present in the effective disinfectant solution will be between about 0.005% w/v and 0.5% w/v.

Preferably, the amount of surfactant present in the effective disinfectant solution will be between about 0.01% w/v and 0.4% w/v.

In a two part disinfectant concentrate, the surfactant is preferably present in the part B composition in an amount of between about 0.05% w/w to about 15% w/w, more preferably between about 0.1% w/w to about 10% w/w.

In the one-part disinfectant concentrate, the amount of surfactant present in the one-part disinfectant concentrate will preferably be between about 0.05% w/w to about 15% w/w, more preferably between about 0.1% w/w to about 10% w/w.

Ideally, the surfactant will also provide rapid wetting of the surface. In a preferred embodiment, the surfactant will be selected to provide an effective disinfectant solution having a Draves wetting time of less than 40 seconds.

In a preferred embodiment, the surfactant will be selected such that the effective disinfectant solution has a dynamic surface tension of less than about 42.5mN/m at a surface age of 250ms and less than about 41mN/m at a surface age of 500ms, as measured by the maximum bubble pressure method.

More preferably, the surfactant will be selected such that the effective disinfectant solution has a dynamic surface tension of less than about 42.5mN/m at a surface age of 250ms, and a dynamic surface tension of less than about 41mN/m at a surface age of 500ms, and a dynamic surface tension of less than about 40mN/m at a surface age of 5000ms, at 20 ℃ to 25 ℃, as measured by the maximum bubble pressure method.

Examples of suitable surfactants that may be used in the compositions of the present invention include, but are not limited to, block copolymers of polyethylene oxide and polypropylene oxide, fatty alcohol alkoxylates, long chain alkyl alkoxylates, N-alkyl pyrrolidones, branched short chain perfluorinated surfactants, branched short chain polysiloxane functionalized polyethylene glycols, and combinations thereof.

Hydrotropic agent

Hydrotropes are compounds that solubilize hydrophobic compounds in aqueous solutions by means other than micellar solubilization. Typically, hydrotropes consist of a hydrophilic part and a hydrophobic part (similar to surfactants), but the hydrophobic part is usually too small to cause spontaneous self-aggregation.

Hydrotropes may be used in the disinfectant compositions of the invention to allow for the solubilization of other insoluble components, such as low foaming nonionic surfactants.

Suitable hydrotropes can include, but are not limited to, potassium xylene sulfonate, potassium naphthalene sulfonate, potassium cumene sulfonate, potassium tolyl phosphate, potassium octyliminodipropionate, sodium xylene sulfonate, sodium naphthalene sulfonate, sodium cumene sulfonate, sodium tolyl phosphate, sodium octyliminodipropionate, amyl glucoside, hexyl glucoside, octyl glucoside, isooctyl glucoside, and mixtures thereof.

In a preferred embodiment, the hydrotrope is present in part B of the two part disinfectant concentrate in an amount of between about 0.1% w/w to about 15% w/w, more preferably between about 0.5% w/w to about 10% w/w.

In a second preferred embodiment, the hydrotrope of the equilibrium peroxyacetic acid concentrate is present in the one-part disinfectant concentrate in an amount of between about 0.1% w/w to about 15% w/w, more preferably between about 0.5% w/w to about 10% w/w.

pH regulator

The effective disinfectant solutions and disinfectant concentrates of the present invention may also contain a pH adjusting agent to control the pH of the final disinfectant composition. Such pH adjusting agents may be selected from alkali metal hydroxides, alkali metal carbonates and alkali metal salts of multivalent acids, such as alkali metal salts of citric, boric, phosphoric, oxalic, maleic and fumaric acids.

The pH adjusting agent may be used to control the pH of the part B of the disinfectant concentrate itself, thereby allowing the use of surfactants that may not be acid or base resistant. The pH of the part B disinfectant concentrate is preferably in the range of between about 6.0 to about 13, more preferably in the range of between about 7.0 to about 13.

The pH adjuster in part B may provide a preferred pH for an effective disinfectant solution, allowing for the presence of acidic species that may be present in the initial part a (PAA) solution. The pH of the effective disinfectant solutions of the present invention is preferably in the range of between about 2.0 to about 8, more preferably in the range of between about 3.0 to about 6.0.

Two part disinfectant concentrate

In a two-part disinfectant concentrate, the disinfectant concentrate is provided as two parts (referred to as "part a" and "part B" for clarity), typically two solutions. Part a typically comprises an equilibrium aqueous solution of PAA, hydrogen peroxide and acetic acid. Part a may also contain minor amounts of other components such as stabilizers or strong acids. The stabilizer may be selected from, but is not limited to, aminotri (methylenephosphonic acid), 1-hydroxyethylidene-1, 1-diphosphonic acid, quinolin-8-ol, 2, 6-pyridinedicarboxylic (bipyridine) acid, aspartic acid diethoxy succinate, quinoline-2-carboxylic acid, citric acid, isocitric acid, aconitic acid, propane-1, 2, 3-tricarboxylic acid, and mixtures thereof.

Strong acids may be used as PAA forming catalysts. The strong acid useful in the present invention may be selected from, but is not limited to, sulfuric acid, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof.

It is expected that commercial sources of PAA equilibrium solutions will also be used. It is well known that commercial grades of PAA will contain stabilizers and optionally strong acids.

In a preferred embodiment, part B of the disinfectant concentrate will comprise between about 0.05% w/w to about 15% w/w surfactant. In a more preferred embodiment, the one-part disinfectant concentrate will comprise between about 0.1% w/w to about 10% w/w surfactant. In a highly preferred embodiment, the disinfectant concentrate will comprise between about 1% w/w to about 9% w/w surfactant.

Part B of the disinfectant concentrate may contain other components such as corrosion inhibitors, pH adjusters, surfactants, colorants, and indicators. Part B may also contain hydrotropes to help solubilize the various components of the solution.

In a preferred embodiment, the effective disinfectant solution of the present invention will be produced by mixing part a and part B solutions with water to produce a water-based effective disinfectant solution. Preferably, the volume ratio of part a solution to part B solution will be between about 1:10 to about 10: 1. More preferably, the volume ratio of part a solution to part B solution will be between about 1:5 to about 5: 1. Most preferably, the volume ratio of part a solution to part B solution will be about 1: 1.

The resulting dilute disinfectant solution or effective disinfectant solution preferably contains between about 0.01% w/v to about 1.0% w/v (100ppm to 10000ppm) PAA, more preferably the effective disinfectant solution has between about 0.02% w/v to about 0.5% w/v (200ppm to 5000ppm) PAA.

Those skilled in the art will appreciate that the concentration of the active ingredient of the disinfectant (in this case PAA) will depend on a combination of factors such as the contact time for disinfection, the disinfection temperature suitable for the microbiological test, and the microbiological performance desired (e.g. high concentration disinfection or sterilization).

Other factors may also determine PAA concentration, such as material compatibility. For example, the corrosiveness of an effective disinfectant solution may be reduced by decreasing the concentration of PAA while increasing the contact time and/or disinfection temperature. Similarly, if the equipment to be disinfected is relatively resistant to corrosion by the disinfectant, higher concentrations and/or higher temperatures and shorter disinfection contact times may be used to achieve faster disinfection.

While a one-part disinfectant concentrate may provide a degree of convenience to the end user, a two-part disinfectant concentrate provides manufacturing flexibility in that the components of part B need not exhibit long-term stability to oxidation by peracids and the like.

One-part disinfectant concentrate

In a one-part disinfectant concentrate, all components are preferably supplied as a single concentrate, and then preferably diluted with water prior to use to obtain an effective disinfectant solution. In another embodiment, a single portion of the disinfectant (i.e., a ready-to-use solution) may be used without dilution. The resulting effective disinfectant solution preferably comprises PAA between about 0.01% w/v to about 1.0% w/v (100ppm to 10,000ppm), more preferably PAA of the effective disinfectant solution is between about 0.02% w/v to about 0.5% w/v (200ppm to 5000 ppm).

The one-part disinfectant concentrate comprises PAA, hydrogen peroxide, acetic acid. The one-part disinfectant concentrate also includes at least one surfactant, and optionally, a corrosion inhibitor, a hydrotrope, and/or a pH buffer, and a stabilizer.

In a preferred embodiment, the one-part disinfectant concentrate will contain between about 0.1% w/w to 20% w/w peroxyacetic acid.

In a more preferred embodiment, the one-part disinfectant concentrate will contain between about 1% w/w to 15% w/w peroxyacetic acid.

In a highly preferred embodiment, the one-part disinfectant concentrate will contain between about 4% w/w to 6% w/w peroxyacetic acid.

The stabilizer may be selected from, but is not limited to, aminotri (methylenephosphonic acid), 1-hydroxyethylidene-1, 1-diphosphonic acid, quinolin-8-ol, 2, 6-pyridinedicarboxylic (bipyridine) acid, aspartic acid diethoxy succinate, quinoline-2-carboxylic acid, citric acid, isocitric acid, aconitic acid, propane-1, 2, 3-tricarboxylic acid.

Typically, the concentration of the stabilizing agent present in the one-part disinfectant concentrate will be between about 0.1% w/w to about 1% w/w.

Alternatively, the one-part disinfectant concentrate may contain a strong acid selected from, but not limited to, sulfuric acid, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof. One skilled in the art will appreciate that a strong acid may be added as a catalyst during the formation of the PAA solution.

Typically, the concentration of acid present in the one-part disinfectant concentrate will be between about 0.1% w/w to about 1% w/w.

A one-part disinfectant concentrate may be produced by mixing hydrogen peroxide, acetic acid, water, a stabilizer, at least one surfactant, and optionally a corrosion inhibitor, a hydrotrope, and/or a pH buffer.

The reaction to form PAA may be uncatalyzed, so PAA will form within a few days, or catalyzed by the addition of a strong acid selected from, but not limited to, sulfuric acid, nitric acid, methanesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof.

Typically, the concentration of acid present in the one-part disinfectant concentrate will be between about 0.1% w/w to about 1% w/w.

In a second embodiment, a one-part disinfectant concentrate may be generated by adding at least one surfactant and optionally a corrosion inhibitor, hydrotrope, and/or pH buffer to a preformed PAA solution. Such preformed solutions may be purchased commercially. It is well known that commercial grades of PAA will contain stabilizers and optionally strong acids.

In a preferred embodiment, the one-part disinfectant concentrate will comprise between about 0.05% w/w to about 15% w/w surfactant. In a more preferred embodiment, the one-part disinfectant concentrate will comprise between about 0.1% w/w to about 10% w/w surfactant. In a highly preferred embodiment, the disinfectant concentrate will comprise between about 1% w/w to about 9% w/w surfactant.

It will be apparent to those skilled in the art that all components in the one-part disinfectant concentrate should be stable to oxidation by peroxygen species.

Effective disinfectant solution

An effective disinfectant solution, defined herein as a disinfectant formed by diluting a disinfectant concentrate, is a disinfectant solution used to disinfect heat labile medical equipment that is reusable, such as flexible endoscopes and the like.

In the case of a one-part disinfectant concentrate, an effective disinfectant solution will be generated by diluting the one-part disinfectant concentrate.

In the case of a two-part disinfectant concentrate, an effective disinfectant solution will be formed by diluting the mixture of the two parts (part a and part B). Typically, an effective disinfectant solution will be formed by adding part a and part B to the required volume of water to avoid any adverse reactions resulting from mixing the undiluted concentrate.

The concentration of PAA in the effective disinfectant solution is preferably between 0.01% w/v to about 1.0% w/v (100ppm to 10,000ppm) PAA, more preferably between about 0.02% w/v to about 0.5% w/v (200ppm to 5000ppm) PAA in the effective disinfectant solution.

It is well known that disinfectants are generally used in higher concentrations than disinfectants in higher concentrations.

When used for high concentration disinfection, the concentration of PAA in the effective disinfectant solution is preferably between 0.01% w/v to about 0.5% w/v (100ppm to 5000ppm) PAA, more preferably between about 0.02% w/v to about 0.25% w/v (200ppm to 2500ppm) PAA.

When used as a sterilant, the concentration of PAA in the effective disinfectant solution is preferably between about 0.02% w/v to about 1.0% w/v (200ppm to 10,000ppm) PAA, more preferably between about 0.04% w/v to about 0.5% w/v (400ppm to 5000ppm) PAA in the effective disinfectant solution.

One skilled in the art will appreciate that the minimum concentration of PAA will be determined by microbiological testing according to national regulations, and will also be determined by the temperature of the sterilization and/or disinfection and the contact time of the sterilization and/or disinfection.

For example, the minimum recommended concentration of PAA for a two-part disinfectant Rapicide PA (Medivators Inc, Minneapolis, Minn., USA) is 850ppm when the contact time is 5 minutes at 30 ℃ for high concentration disinfection, and 1700ppm when the contact time is 10 minutes at 40 ℃ for sterilization. These concentrations will be achieved by diluting Rapicide a and B solutions to between 1.7% v/v and 1.9% v/v (for high concentration disinfection), and between 3.4% v/v and 3.8% v/v (for sterilization). In this case, equal volumes of part a solution and part B solution will be used.

An effective disinfectant solution will also contain between about 0.05% w/v to about 0.5% w/v of at least one surfactant.

It may also optionally contain between about 0.01 to about 0.1% of at least one corrosion inhibitor and up to 0.2% of a hydrotrope.

Suitable corrosion inhibitors may include, but are not limited to, benzotriazole, alkali metal phosphates, alkali metal nitrates, alkali metal nitrites, 2-phosphonobutane-1, 2, 4-tricarboxylates, metal molybdates, and combinations thereof.

Other optional components of the efficacious disinfectant solution may include pH adjusters, indicators, colorants, and fragrances.

Method used

Example 1: determination of Hydrogen peroxide and PAA

The hydrogen peroxide and PAA content in the PAA solution were determined by a two-stage redox titration method using a mettlerlatido T70 autotitrator. The automatic titrator is equipped with two burettes and drive, a platinum ring redox sensor, and a peristaltic pump for dispensing the auxiliary solution. One burette contained 0.02M potassium permanganate solution and the second burette contained 0.1M sodium thiosulfate solution. Both titrants were standardized before use.

A known weight of the sample was placed in a titration beaker together with 20ml of 0.5M sulfuric acid solution. The beaker was placed on an autotitrator and hydrogen peroxide was determined by titration with potassium permanganate solution. After the endpoint was determined, 10ml of a 10% potassium iodide solution was added by peristaltic pump (under the control of a T70 autotitrator), and the released iodine was then titrated with a sodium thiosulfate solution. The concentrations of hydrogen peroxide and PAA were then calculated by an auto-titrator, taking into account the excess potassium permanganate added after the endpoint.

Example 2: determination of acetic acid

The acetic acid content of the PAA solution was determined using a mettlerlatido T70 autotitrator equipped with a single burette containing 0.1M sodium hydroxide solution and a pH sensor and using an acid-base titration method.

A known weight of PAA solution was placed in a titration beaker and about 30ml of DI water was added. The beaker was then placed on an autotitrator and the sample was titrated with 0.1M sodium hydroxide solution.

Example 3: measurement of dynamic surface tension

The dynamic surface tension of various disinfectant solutions at various surface ages (typically 14ms to 5000ms) was determined using a Kruss BP50 bubble tensiometer (Kruss GMBH, Hamburg, Germany). For each set of measurements performed, a new capillary tip was mounted onto BP50, and the instrument was recalibrated using HPLC water each time the capillary tip was replaced.

Data for BP50 were obtained from the software package Laboratory Desktop version 3.2.2.3064 supplied by Kruss.

The surface tension at a particular surface age is calculated by interpolation of data points flanking the particular age. For example, the surface tension at 500ms can be calculated from the surface tension values of 29.1mN/m and 28.0mN/m at surface ages of 440ms and 555ms by assuming a linear relationship between the two points and determining the slope and intercept of a straight line between the two points. In the above example, the surface tension at 500ms can be calculated as 28.5 mN/m.

Examples of prior art

Examples 4-6 represent PAA-based commercial high concentration disinfectants intended for use in an automated endoscope reprocessor

Example 4

1.9ml of Proxy P (5% w/w PAA solution, supplied by TomatoWhiteley Corporation, New Nanwey, Australia) was transferred by pipette into a 100ml volumetric flask containing about 80ml of tap water. Then, 1.9ml of Proxy a (corrosion inhibitor concentrate) was added by pipette and the solution was made up to scale with additional tap water to form an effective disinfectant solution.

The surface tension of the resulting effective disinfectant solution was then measured at various surface ages (14ms to 5000ms) following the procedure outlined in example 3. As can be seen from FIG. 4 and Table 2, the surface tension of the disinfectant was not substantially reduced (the surface tension of pure water was 72mN/m, and there was no significant change in surface tension with surface age).

Table 2:

example 5

1.9ml of Soluscope P (5% w/w PAA solution, supplied by Soluscope SAS, France) was transferred by pipette into a 100ml volumetric flask containing about 80ml of tap water. Then, 1.9ml of Soluscope A (corrosion inhibitor concentrate) was added by pipette and the solution was made up to the mark with additional tap water.

The surface tension of the resulting effective disinfectant solution was then measured at various surface ages (14ms to 5000ms) as described in example 3. As can be seen from fig. 4 and table 3, the surface tension of the disinfectant is also not substantially reduced compared to the surface tension of water (i.e. 72 mN/m).

TABLE 3

Surface age (ms)	Dynamic surface tension (mN/m)
		250	70.1
500	70.1
		5000	69.9

Example 6

1.9ml of part A Rapicide PA (5% w/w PAA solution supplied by Medivators Inc., Minneapolis, Minn., U.S.A.) was transferred by pipette into a 100ml volumetric flask containing about 80ml of tap water. Then, 1.9ml of part B Rapicide PA (corrosion inhibitor concentrate) was added by pipette and the solution was made up to the mark with additional tap water.

The dynamic surface tension of the resulting effective disinfectant solution was measured in the range of 14ms to 5000 ms. As can be seen from FIG. 4 and Table 4, the surface tension initially drops rapidly to around 52mN/m, and even at longer surface ages (i.e. > 5000ms), the surface tension remains above 50 mN/m.

TABLE 4

Surface age (ms)	Dynamic surface tension (mN/m)
		250	53.3
500	52.5
		5000	51.0

Example 7

In the present example, a one-part disinfectant concentrate as described in WO2016100818 was prepared. 560.02g of a 50% hydrogen peroxide solution was added to 250ml of HPLC grade water (Sigma-Aldrich) followed by 160.00g of glacial acetic acid, 10.00g of Dequest 2010 (Markgrev IMCD, Vavictoria, Australia) and 20g of Pluronic 10R5 (Sigma Aldrich, N.N.Weil, City castle mountain). The mixture was then allowed to stand for at least 2 weeks to form PAA.

After 2 weeks, hydrogen peroxide and PAA content were determined using the method of example 1 and acetic acid was determined using the method of example 2. The composition of the resulting disinfectant concentrate is shown in table 5.

TABLE 5

Composition (I)	Concentration (% w/w)
		Hydrogen peroxide	24.20
PAA	7.10
		Acetic acid	10.93
Pluronic 10R5	2.00
		Dequest 2010	1.00
Water (W)	Balancing

Then, 2ml of the formulation was transferred by pipette into a 100ml volumetric flask and made up to the mark with tap water. The dynamic surface tension of the resulting effective disinfectant solution was then measured as in example 3.

TABLE 6

Surface age (ms)	Dynamic surface tension (mN/m)
		250	55.3
500	54.4
		5000	52.6

As can be seen from fig. 4 and table 6, although the surface tension initially drops relatively quickly to a value of 54.4 at a surface age of 500ms, the surface tension remains effectively stable, with only a slight difference between 500 and 5000 ms.

Example 8

The following examples represent prior art examples taken from us patent 6168808. Four formulations were prepared according to table 7.

TABLE 7

	Proxitane(g)	Genapol EP2564(g)	Ammonyx LO(g)
				Example 8A	99.4	0.25	0.30
Example 8B	99.56	0.25	0.20
				Example 8C	99.66	0.25	0.10
Example 8D	99.75	-	0.25

The PAA solution used was an equilibrium solution supplied by Solvay Interox Pty Ltd (Banxmando, New Nanwey, Australia). The PAA solution contained 5% PAA, 27% hydrogen peroxide and 7.5% acetic acid.

In these examples, Genapol EP2564 (Craiden, La, Victoria, Australia) was used. This surfactant was formerly under the trade name Genapol 2908D. Ammonyx LO is dimethyl cocoamine oxide supplied by Ixom Operations Pty Ltd, east Meldrum, Victoria, Australia.

Each solution (2ml) was transferred by pipette into a 100ml volumetric flask and diluted to the mark with tap water.

The dynamic surface tension of each diluted solution was evaluated according to the method of example 3. The dynamic surface tension profiles for these examples are shown in fig. 5, with table 8 showing the surface tensions at 250ms, 500ms and 5000 ms. It can be seen that the surface tension of each formulation decreased slowly over the first 500 ms. To 5000ms, the surface tension of each formulation was still above 45 mN/m.

TABLE 8

Example 9

The following example is taken from EP 0971584. Since each of the examples given in the' 584 reference were prepared from PAA solutions having different compositions, the preparation of various PAA solutions is as follows.

Preparation of PAA samples

A series of PAA solutions were prepared by mixing deionized water, 50% hydrogen peroxide solution and glacial acetic acid.

1-hydroxyethylidene-1, 1-diphosphonic acid (HEDP) was added to each formulation as a stabilizer (amounts see Table 9).

TABLE 9

Sample (I)	Water (W)	50% hydrogen peroxide	Acetic acid	HEDP
					Tg-35-31A	211.0	203.17	104.25	5.07
Tg-35-31B	287.08	178.04	44.90	5.02
					Tg-35-31C	262.07	211.87	34.88	4.99
Tg-35-31D	262.03	211.07	51.33	5.02
					Tg-35-31E	270.86	165.35	73.45	5.00

The solution was allowed to stand at room temperature for 2 to 3 weeks to allow the system to reach equilibrium. Each sample was then analyzed for PAA and hydrogen peroxide using the method given in example 1. The acetic acid content of the samples was determined using the method described in example 2.

The composition of each PAA sample is shown in table 10.

Watch 10

The compositions 1 to 5 shown in table a of EP0971584 (see table 11) were then reproduced using the PAA solution.

TABLE 11

Note that:

genapol EP2564, formerly known as Genapol 2908D, is now supplied by Clariant, Australia, Lala, Australia.

Genapol EP2584, formerly known as Genapol 2909, is now supplied by Clariant, Australia, Inc.

According to EP0971584, 1.25ml of sample 9A was diluted to 100ml using tap water to give a 1:80 diluted effective disinfectant solution.

Similarly, according to EP0971584, 2.5ml of samples 9B to 9E were diluted to 100ml using tap water to give a 1:40 diluted effective disinfectant solution.

The dynamic surface tension of the resulting diluted solution was then measured as described in example 3.

From fig. 6 and table 12 it can be seen that although the surface tension of the various effective disinfectant solutions 9A to 9E did reach low values (< 45mN/m), this was only achieved at extended surface age times (> 15000 ms).

TABLE 12

Notably and interestingly, the observed surface tension measured using the maximum bubble pressure method is significantly higher than that of the same formulation as reported in EP0971584, measured by the static method (williami plate method), as shown in table 1.

Examples of the invention

The following examples represent non-limiting embodiments of the present invention. These examples are representative of two-part disinfectants intended to be mixed with the PAA solution to form the actual disinfectant.

Example 10

100ml of the composition shown in Table 13 was prepared

Triton H66 (potassium cresolate phosphate solution) was obtained from the Dow chemical company. Pluronic Pe6400 (a triblock copolymer of polyethylene oxide and polypropylene oxide) was obtained from basf. Makon NF12 is a low foam C10-C12 alcohol alkoxylate from Stepan Company (Nuo Spial, Ill.) and Surfadone LP100 is a low foam, non-ionic fast wetting agent containing a critical micelle free concentration of N-octyl-2-pyrrolidone from Kantton, Kyowa, U.S.A.). The pH of the preparation is 11.93

Watch 13

2ml of the formulation of example 10 were transferred by pipette into a 100ml volumetric flask containing about 80ml of tap water. To this was added 2ml of part A Rapicide PA (5% w/w PAA solution) obtained from Candel Australia (Hitherton, Victoria, Australia). The resulting solution was then made up to scale using additional tap water to produce an effective disinfectant solution. The pH of the diluted solution was 4.04.

An effective disinfectant solution contains 0.025% corrosion inhibitor (benzotriazole and sodium molybdate, 0.14% surfactant (pluronic PE6400, Makon NF12, and Surfadone LP100), 0.05% hydrotrope (triton H66), and 2% Proxitane (i.e., 0.1% PAA).

The dynamic surface tension of the effective disinfectant solution was then measured as described in example 3. Fig. 7 shows a surface tension in mN/m versus surface age (in milliseconds), and table 14 shows the surface tension at the chosen surface age.

TABLE 14

Surface age (ms)	Dynamic surface tension (mN/m)
		250	39.5
500	38.5
		5000	35.9

Example 11

The following examples demonstrate the use of branched short chain nonionic surfactants (commonly referred to as "hyperdispersants"). The concentrate was formulated as a pH neutral solution due to the acid intolerance of the silicon-based hydrophobic moiety.

Preparing 100ml of the following preparation

Watch 15

FC-41 is a low foaming isooctyl glucoside, available from chemical company, Inc. of Alzheimer's, Victoria, Australia. Orthowet H-408, available from Ortho Chemicals of Victoria kenton, Australia, is a solution of 3- (polyoxyethylene) propyl heptamethyltrisiloxane. Such surfactants are an example of a class of silicon-based surfactants, known as hyperdispersants, because they enable fast wetting and low surface tension of aqueous solutions. Acticide B20 is a glycol-based benzisothiazolinone preservative solution obtained from tool Specialties Pty Limited in Wetherland park, N.C.Australia.

The pH of the neat solution was set at 7.32 to prevent hydrolysis when stored Orthowet H-408.

2ml of the formulation shown in Table 15 are transferred by pipette into a 100ml volumetric flask containing about 80ml of tap water. To this was added 2ml of Proxitane (5% w/w PAA solution). The resulting solution was then made up to scale using additional tap water to produce an effective disinfectant solution. The pH of the diluted solution was 2.98.

Similarly, working disinfectant solutions were prepared using 0.5%, 1.0%, and 1.5% of the formulations of table 15, containing 0.5%, 1.0%, and 1.5% Proxitane, respectively. The concentrations of the functional ingredients (corrosion inhibitor, surfactant, hydrotrope and PAA) are shown in table 16.

TABLE 16

The dynamic surface tension of the effective disinfectant solution was then measured as described in example 3. Fig. 7 shows a graph of surface tension (in mN/m) versus surface age (in milliseconds) for a 2% solution, and table 17 shows the surface tension at a selected surface age for each concentration.

TABLE 17

The dynamic surface tension of the effective disinfectant solution was then measured using a kruss BP50 bubble tensiometer as described in example 3. Fig. 7 shows a plot of surface tension (in mN/m) versus surface age (in milliseconds) for a 2% solution, and table 16 shows the surface tension at a selected surface age for each concentration.

Example 12

In this example, the effects of the various components of example 10 were examined.

A base solution was prepared comprising 907.77g of deionized water, 46.22g of anhydrous dipotassium hydrogen phosphate, 30.98g of 48% w/w potassium hydroxide solution and 10.36g of benzotriazole.

Then, various formulations according to table 18 were prepared using the base liquid. Formulations containing only one additional component selected from triton H66, pluronic PE6400, Surfadone LP100 and Makon NF12 were also prepared, where possible.

For Surfadone LP100 and Makon NF12, these surfactants were insoluble in the base formulation and were therefore solubilized using the hydrotrope, triton H66 (see formulation 12-D and formulation 12-F).

Watch 18

From each of these solutions, a diluted solution containing 2% v/v of each formulation and 2% v/v of part A Rapicide PA was prepared as described in example 10. According to example 3, the surface tension of each effective disinfectant solution was measured at various surface ages.

As can be seen from fig. 8 and table 19, the addition of triton H66 to the base liquid had very little effect on the dynamic surface tension.

The addition of pluronic H66 (see formulation 12-C) did rapidly drop the surface tension to 45.4mN/m at a surface age of 500ms, but then substantially maintained that value, yielding a surface tension of 43.9mN/m at 5000 ms.

The addition of Surfadone LP100 appeared to work synergistically with these various formulations, resulting in a rapid drop in surface tension to values well below that of, for example, pluronic Pe6400 alone. For example, the addition of Surfadone LP100 to a 12-C formulation can reduce the surface tension from 46mN/m to 38mN/m at a surface age of 250 ms.

Watch 19

Example 13

In these examples, the fast wetting surfactant Ecosurf LFE-635 (branched alcohol alkoxylate, dow chemical ltd) was used to provide fast wetting and triton H66 was used as a hydrotrope.

As shown in Table 20, Ecosurf LFE-635 was prepared at various concentrations (ranging from 2.5% w/v to 5% w/v)

Watch 20

Then, 2ml of the formulation was transferred by pipette into a 100ml volumetric flask containing about 80ml of tap water. Then, 2ml of Proxitane was added and the solution was made up to scale using additional tap water to form an effective disinfectant solution.

Table 21 shows the functional components of the effective disinfectant solution.

TABLE 21

	13-A	13-B	13-C	13-D
					Corrosion inhibitor content (% w/v)	0.022	0.022	0.022	0.022
Surfactant (% w/v)	0.05	0.06	0.08	0.1
					Hydrotropes (% w/v)	0.1	0.1	0.1	0.1
PAA(％w/v)	0.1	0.1	0.1	0.1

The dynamic surface tension of the effective disinfectant solution was then measured as described in example 3.

Fig. 9 shows a surface tension in mN/m versus surface age (in milliseconds), and table 22 shows the surface tension at the selected surface age. It can be seen that the surface tension of these formulations can be rapidly reduced within a very short surface age.

TABLE 22

One-part disinfectant

The following embodiments of the invention show a single-part formulation, i.e. a formulation comprising a single solution based on a 5% PAA solution. The PAA solution used was Proxitane.

Example 14

The following example of a one-part disinfectant is based on the use of Baysibit AM as a corrosion inhibitor and Pluronic PE6400 as a solubilizing surfactant. Branched short chain anionic perfluorinated surfactants (Tivida FL2200, BestVolmer, Va., Australia) were used as fast wetting agents. A series of formulations as shown in table 23 were prepared. Each formulation was observed to be water white with no apparent turbidity

TABLE 23

2ml of each preparation was pipetted into a 100ml volumetric flask containing about 80ml of tap water. The solution was then made up to scale using additional tap water to form an effective disinfectant solution. The approximate functional composition of the working solutions is shown in Table 24

Watch 24

The dynamic surface tension of the effective disinfectant solution was then measured as described in example 3.

Fig. 10 shows a graph of surface tension in mN/m versus surface age (in milliseconds), and table 25 shows the surface tension at the selected surface age. It can be seen that the surface tension of these formulations can be rapidly reduced within a very short surface age.

TABLE 25

Example 15

The following example of a one-part disinfectant concentrate is based on the use of Baysibit AM as a corrosion inhibitor and Ecosurf LFE-635 as a fast wetting surfactant.

Formulations as shown in table 26 were prepared using triton H66 or pluronic PE6400 as solubilizing agents.

Watch 26

Watch 27

	15-A	15-B	15-C	15-D	15-E	15-F	15-G
								Corrosion inhibitors	0.018	0.018	0.000	0.000	0.019	0.018	0.018
Surface active agent	0.055	0.090	0.095	0.113	0.130	0.138	0.147
								Hydrotropic agent	0.092	0.089	0.000	0.000	0.000	0.000	0.000
PAA	0.092	0.090	0.095	0.094	0.093	0.092	0.092

The dynamic surface tension of the effective disinfectant solution was then measured as described in example 3.

Fig. 11 shows a graph of surface tension in mN/m versus surface age (in milliseconds), and table 28 shows the surface tension at the selected surface age. Also, the surface tension of these formulations can be rapidly reduced within a very short surface age.

Watch 28

It is noteworthy here that, although the surface tension of the formulation comprising only Proxitane and pluronic PE6400 (example 15C) initially drops rapidly, only a slight drop occurs from a value of 43.7mN/m at 500ms to a value of 42.4mN/m at 5000 ms. The addition of the branched alkyl alkoxylate Ecosurf LFE-635 showed a significant improvement in lowering surface tension, especially when it was present in the formulation concentrate at a concentration of greater than 1.85% w/w. As can be seen from Table 28, formulations containing greater than 1.85% w/w Ecosurf FFE-635 all produced surface tensions of less than 40mN/m at surface ages above 250 ms.

Example 17: microbial efficacy

The following effective disinfectant solutions were prepared as follows:

disinfectant to be tested 1

2ml of the formulation of example 10 together with 2ml of a 5% PAA solution (part A Rapicide PA) were transferred by pipette into a 100ml volumetric flask containing approximately 80ml of artificial hard water (340mg/L CaCO 3). The solution was made up to the mark with additional hard water. The resulting effective disinfectant solution was then titrated to determine its PAA content, and then further diluted with hard water to give a final PAA content of 857ppm PAA and a hydrogen peroxide content of 3901 ppm.

Test disinfectant 2 (control preparation)

2ml of part B Rapidide PA together with 2ml of 5% PAA solution (part A Rapidide PA) were transferred by pipette into a 100ml volumetric flask containing approximately 80ml of artificial hard water (340mg/L CaCO 3). The solution was made up to the mark with additional hard water. The resulting effective disinfectant solution was then titrated to determine its PAA content, and then further diluted with hard water to give a final PAA content of 857ppm PAA and a hydrogen peroxide content of 3929 ppm.

Then, in a time kill study, a suspension of Bacillus subtilis spores (ATCC19659) containing 1.8X 108CFU/ml was used, and 5% horse serum was added as organic soil to evaluate the sporicidal efficacy of the two working disinfectant solutions

The test was performed at 40 ℃ using various contact times (5 seconds, 60 seconds, 120 seconds, 180 seconds, and 240 seconds, 5 repetitions per time point). After the necessary contact time, the disinfectant is neutralized and viable spores are counted.

As can be seen in Table 29, test solution 1 prepared using the formulation of example 10 showed a 6log10 reduction

Watch 29

Example 16: the microbial efficacy is as follows: spore carrier assay

In this test, screening vector tests were carried out using 4 vectors for each test substance at two concentrations based on the AOAC sporicidal activity test.

Disinfectant to be tested 1

2ml of the formulation of example 10 together with 2ml of a 5% PAA solution (part A Rapicide PA) were transferred by pipette into a 100ml volumetric flask containing approximately 80ml of artificial hard water (340mg/L CaCO 3). The solution was made up to the mark with additional hard water. The resulting effective disinfectant solution was then titrated to determine its PAA content, and then further diluted with hard water to give a final PAA content of 856ppm PAA and a Hydrogen Peroxide (HP) content of 3840 ppm.

Four porcelain tubes that were cultured with bacillus subtilis spores were then treated with an effective disinfectant solution under dirty conditions (5% horse serum) at 40 ℃ and at various time points (60 seconds, 120 seconds, 180 seconds, and 240 seconds). The disinfectant was neutralized using 10ml of T6 neutralizer and the samples were incubated to assess the presence/absence of growth to determine any remaining viable spores.

Test disinfectant 2 (control)

2ml of part B Rapidide PA together with 2ml of 5% PAA solution (part A Rapidide PA) were transferred by pipette into a 100ml volumetric flask containing approximately 80ml of artificial hard water (340mg/L CaCO 3). The solution was made up to the mark with additional hard water. The resulting effective disinfectant solution was then titrated to determine its PAA content, and then further diluted with hard water to give a final PAA content of 868ppm PAA and a hydrogen peroxide content of 4000 ppm.

Four porcelain tubes inoculated with bacillus subtilis spores were then treated with disinfectant solution under dirty conditions (5% horse serum) at 40 ℃ and at various time points (60 seconds, 120 seconds, 180 seconds, and 240 seconds). The disinfectant was neutralized using 10ml of T6 neutralizer and the samples were incubated to assess the presence/absence of growth to determine any remaining viable spores.

After the cultivation, the following results were obtained. As can be seen from table 30, the control sample (example 6, Rapicide Pa) did show survivors at 60 and 120 seconds, although the test substance (example 10) did not show growth at all time points. It is noted that this PAA concentration is the indicated concentration for high concentration sterilization of Rapicide PA, while the temperature is the prescribed temperature for sterilization of Rapicide PA (although sterilization times are typically 10 minutes).

Watch 30

Example 17: the microbial efficacy is as follows: spore carrier assay (higher PAA concentration).

In this test, screening vector tests were again performed using 4 vectors for each test substance based on the AOAC sporicidal activity test at two concentrations.

Disinfectant to be tested 1

2ml of the formulation of example 10 together with 2ml of a 5% PAA solution (part A Rapicide PA) were transferred by pipette into a 100ml volumetric flask containing approximately 80ml of artificial hard water (340mg/L CaCO 3). The solution was made up to the mark with additional hard water. The resulting effective disinfectant solution was then titrated to determine its PAA content, and then further diluted with hard water to give a final PAA content of 1700ppm PAA and a hydrogen peroxide content of 7821 ppm.

Test disinfectant 2 (control)

2ml of part B Rapidide PA together with 2ml of 5% PAA solution (part A Rapidide PA) were transferred by pipette into a 100ml volumetric flask containing approximately 80ml of artificial hard water (340mg/L CaCO 3). The solution was made up to the mark with additional hard water. The resulting effective disinfectant solution was then titrated to determine its PAA content, and then further diluted with hard water to give a final PAA content of 1706ppm PAA and a hydrogen peroxide content of 8019 ppm.

Four porcelain tubes that were cultured with bacillus subtilis spores were then treated with an effective disinfectant solution under dirty conditions (5% horse serum) at 40 ℃ and at various time points (60 seconds, 120 seconds, 180 seconds, and 240 seconds). The disinfectant was neutralized and the samples were incubated to assess the presence/absence of growth to determine any remaining viable spores.

After the cultivation, the following results were obtained. As can be seen from table 31, the control sample (example 6, Rapicide Pa) did show survivors at 60 seconds, although the test substance (example 10) showed no growth at all time points.

Watch 31

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