CA2113360C - Stable, anti-corrosive peracetic/peroxide sterilant - Google Patents
Stable, anti-corrosive peracetic/peroxide sterilantInfo
- Publication number
- CA2113360C CA2113360C CA002113360A CA2113360A CA2113360C CA 2113360 C CA2113360 C CA 2113360C CA 002113360 A CA002113360 A CA 002113360A CA 2113360 A CA2113360 A CA 2113360A CA 2113360 C CA2113360 C CA 2113360C
- Authority
- CA
- Canada
- Prior art keywords
- concentrate
- ppm
- weight
- stabilizers
- divalent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/40—Peroxides
Abstract
Stable microbicides comprising hydrogen peroxide, peracetic acid, acetic acid an d purified water substantially free of contaminants, sequestrants or stabilizers and having anticorrosive properties fo r metals used in surgical and dental instruments is disclosed.
Description
W0 93/01822 PCr/US92/05877 ~11 3~60 .
STABLE, ANTICORROSIVE PERACETIC/PEROXIDE STERILANT
STABLE, ANTICORROSIVE PERACETIC/PEROXIDE STERILANT
2 B~ckaro~nd. of the Tnvention 3 1. F;el~l of the Tnvention 4 This invention relates generally to the field of microbicides. In particular, it relates to a stable microbicide 6 having anticorrosive properties comprising a mixture of hydrogen 7 peroxide, peracetic acid, acetic acid and purified water which 8 is substantially free of contAmin~nts or stabilizing and 9 sequestrant type additives.
10 2. De~cr;ption of the Related Art 11 Peracetic acid/peroxide containing compositions have a 12 long history of use as disinfectants and sterilizers due to 13 their microbicidal activities. However, peroxide containing 14 compositions are high-energy-state compounds and as such can be considered thermodynamically unstable. Therefore, because there 16 is a strong tendency for these compositions to decompose in the 17 presence of multivalent metal ions, stabilizers are added.
18 Stabilizers may be agents such as sodium pyrophosphate, 19 phosphonic acid or chelating agents such as 8-hydroxyquinoline.
Stabilizers act by removing trace metals which accelerate the 21 decomposition of peroxides. Stabilizers also accelerate the 22 reaction between hydrogen peroxide and acetic acid to form 23 peracetic acid. Therefore, for any given concentration of 24 hydrogen proxide and acetic acid, the addition of a stabilizer increases the concentration at equilibrium of peracetic acid.
26 While conventional art compositions are stable due to 27 the use of added stabilizers, they are also highly corrosive to 28 the very metals they are designed to disinfect namely surgical 29 and dental instruments made of aluminum or brass, which 30 instruments are often plated with an ornamental or protective 31 layer of nickel or nickel and/or chromium. Additionally, 32 certain susceptible individuals often exhibit allergic reactions 33 to the conventional art formulations. Further, after prolonged 34 use these conventional art formulations often leave mineral-like deposits on the metal instruments they sterilize.
WO93/01822 2 ~ 1 3 3 ~ ~ PCT/~S92/0587?
1 A concentrated composition that contains no stabilizer 2 or sequestrant type additives that is both stable during storage 3 for prolonged periods of time and possesses anticorrosive 4 properties would be a decided advantage over these conventional formulations. Further, a use-dilution formulation that may be 6 reused several times, is stable for relatively long periods in 7 the diluted form and possesses anticorrosive properties would be 8 a further advantage over conventional formulations.
g .~llmm~rV of the Tnvent;on It is an object of the stable, anticorrosive 11 concentrate and use-dilution microbicides in accordance with the 12 present invention to solve the problems outlined above that has 13 heretofore inhibited long-term storage and the anticorrosive 14 sterilization of surgical and dental instruments. These improved microbicide solutions not only have the desired 16 stability but have been shown to have a significantly reduced 17 corrosive effect on certain metals than those of conventional 18 art mixtures of the peracetic acid/peroxide types known to the 19 applicants.
In accomplishing the foregoing objectives, there has 21 been provided in accordance with the present invention a stable, 22 anticorrosive to surgical and dental metals concentrate 23 including peracetic acid, acetic acid, hydrogen peroxide and 24 purified water mixed in a ratio of from about one to eleven parts total acid to one part hydrogen peroxide. The new 26 concentrate has from substantially about .001 ppm to 200 ppm, 27 more preferably from about .001 ppm to 100 ppm, and most 28 preferably from about .001 ppm to 10 ppm of added stabilizers, 29 such as phosphonic acids, sodium pyrophosphates and from about .001 - 10 ppm of ionic and non-ionic cont~min~nts such as 31 divalent and trivalent ions, with no added surfactants, such as 32 ethoxylated decyl alcohols, sulfonate and sulfate types.
33 In accordance with another aspect of the present 34 invention, there has been provided a stable, anticorrosive to surgical and dental metals use-dilution formulation including 36 a concentrate consisting essentially of at equilibrium peracetic 37 acid, acetic acid, hydrogen peroxide and an aqueous diluent, WO93/01822 ~ 1 1'3~3~S0 PCT/VS92/05877 1 said concentrate characterized in having from about .001- 200 2 ppm of added stabilizers, from about .001-10 ppm of ionic and 3 nonionic contaminants and no added surfactants; and a purified 4 aqueous diluent; wherein the concentrate is diluted in the aqueous diluent from about 20 to 40 times.
6 In accordance with still another aspect of the present 7 invention, there has been provided a process for preparing a 8 sterilant concentrate as described above, including the steps of 9 introducing from about 17% by weight to about 40% by weight hydrogen peroxide into a mixing drum, the hydrogen peroxide 11 having from about .001-200 ppm of added stabilizers; blending 12 thereinto from about 10% by weight to about 16~ by weight acetic 13 acid; and adding a purified aqueous diluent having from about 14 .001-10 ppm of divalent and trivalent ions; wherein the equilibrium concentration includes from about 16-38% by weight 16 hydrogen peroxide; from about 2.5-9% by weight acetic acid; from 17 about 1.5-6.0% by weight peracetic acid; and an aqueous diluent 18 and wherein the equilibrium concentration is characterized in 19 having from about .001-200 ppm of added stabilizers, from about .001-10 ppm of ionic and nonionic contaminants and no added 21 surfactants.
22 One of the advantages of the present invention is that 23 the occasional allergic reactions of some individuals to the 24 conventional art formulations is reduced.- Another advantage of the present invention is that the presence of mineral-like 26 deposits from the use of the solutions of conventional art 27 formulations containing sequestrants or stabilizers is no longer 28 found. Perhaps most importantly, however, the present invention 29 allows metal instruments such as dental tools and surgical instruments to be sterilized with significantly reduced 31 corrosivity as will be shown.
32 Further objects, features and advantages of the 33 present invention will become apparent from the detailed 34 description of the preferred embodiments, including the best mode, which follow.
WO93/01822 2 1 il 3 3 6 U PCT/US92/05~77 1 Brief DescriDtion of the Drawinqs 2 Figure 1 is a chart of stability of the concentrated 3 microbicide against time where the initial formulation contained 4 4.1% by weight of peracetic acid and the storage temperature was at ambient temperature of 22 C;
6 Figure 2 is a chart of stability of concentrated 7 microbicide where the initial formulation contained 4.5% by 8 weight of peracetic acid and the storage temperature was 35 C;
9 Figure 3 is a chart of stability of the concentrated microbicide against time where the initial formulation contained 11 4.2% by weight of peracetic acid and the storage temperature was 12 50 C;
13 Figure 4 is a chart of stability of the concentrated 14 microbicide against time where the initial formulation contained 23% by weight of hydrogen peroxide and the storage temperature 16 was 22 C;
17 Figure 5 is a chart of stability of the concentrated 18 microbicide against time where the initial formulation contained 19 23% by weight of hydrogen peroxide and the storage temperature was 35 C;
21 Figure 6 is a chart of stability of the concentrated 22 microbicide against time where the initial formulation contained 23 23% by weight of hydrogen peroxide and the storage temperature 24 was 50 C;
Figure 7 is a chart of stability of the concentrated 26 microbicide against time where the initial formulation contained 27 23% by weight of hydrogen peroxide, 4% by weight of peracetic 28 acid and 8.4% acetic acid and the solution was stored at ambient 29 temperature;
Figure 8 is a chart of stability of the concentrated 31 microbicide against time where the initial formulation contained 32 23.8% by weight hydrogen peroxide and 4.47% by weight peracetic 33 acid and the solution was stored at ambient temperature;
34 Figure 9 is a chart of stability of the concentrated microbicide against time where the initial formulation contained 36 23.8% by weight hydrogen peroxide and 4.47% peracetic acid and 37 the storage temperature was 35~C;
211336~
Figure 10 is a chart of stability of the concentrated 2 microbicide where the initial formulation contained 23.8% by 3 weight hydrogen peroxide and 4.479~ by weight peracetic acid and 4 the storage temperature was 50~C;
Figure 11 is a chart of stability of the concentrated 6 microbicide where the initial formulation contained 17.2% by 7 weight hydrogen peroxide and 0.0% by weight peracetic acid and 8 the solution was stored at ambient temperature;
9 Figure 12 is a chart of stability of the concentrated microbicide where the initial formulation contained 36.46% by 11 weight hydrogen peroxide and 0.0% by weight peracetic acid and 12 the solution was stored at ambient temperaturei 13 Figure 13 is a chart of stability of the concentrated 14 microbicide where the initial formulation contained 27.4% by weight hydrogen peroxide and 5.6% by weight peracetic acid and 16 the solution was stored at ambient temperature;
17 Figure 14 is a chart of stability of the concentrated 18 microbicide where the initial formulation contained 27.4% by 19 weight hydrogen peroxide and 5.3% by weight peracetic acid and the solution was stored at 50~C.
21 net~ile-l De~cription of the Invention 22 Concentrate microbicide formulations in accordance 23 with the present invention possess the desirable property of a 24 long storage life without deleterious decomposition despite the absence of conventional additions of stabilizers and 26 sequestrants as heretofore taught in the art. Additionally, 27 the concentrate compositions of the present invention are far 28 less corrosive to metals that are sterilized using the 29 compositions such as surgical and dental instruments. In contrast with conventional art formulations containing added 31 surfactants, sequestrants and other stabilizers where visible 32 evidence of corrosion of the metals appeared in one or two 33 hours, formulations in accordance with the preferred embodiment 34 of the present invention visibly showed comparatively little corrosion on the same metals during the same time period.
36 Manufacture of the preferred embodiment is effected by 37 mixing a solution of hydrogen peroxide with acetic acid diluted W O 93/01822 PC~r/US92/05877 211336U
1 with a purified aqueous diluent. The hydrogen peroxide is 2 selected from commercially available sources having low 3 concentrations of stabilizers, preferably .001 ppm to 200 ppm, 4 more preferably from about .001 ppm to 100 ppm, and most preferably from about .001 ppm to 15 ppm of added stabilizers, 6 such as phosphonic acids, sodium pyrophosphates. Sources of 7 such hydrogen peroxide are available from FMC Corporation 8 (Philadelphia, PA).
9 In addition, the preferred embodiment in accordance with the present invention preferably includes no contaminants.
11 Cont~m;n~nts such as divalent and trivalent ions, principally, 12 iron, manganese, magnesium, nickel and cobalt, and undesirable 13 trace organics found in the manufacturing process, principally, 14 surfactants, acetone, methanol, ethanol, which are typically present in conventional art formulations are found in the 16 present invention in amounts preferably from about 5-10 ppm and 17 most preferably from about .001-5 ppm in the final composition.
18 Referring to Table I, the preferred composition is 19 shown.
TABLE I
21 Initial Mixture After Equilibrium 22 H2O2 17-40% by wt. 16-38% by wt.
23 HOAc 10-16% by wt. 2.5-9.0% by wt.
24 HOOAc 0 1.5-6.0% by wt.
The concentrate microbicide in accordance with the 26 present invention may be formulated over a wide range of 27 concentrations of the active materials. After equilibrium the 28 concentrate microbicide may have as high as 38% by weight 29 hydrogen peroxide at equilibrium with the peracetic acid concentration ranging from 1.5% to 6.0% as indicated in Table 1.
31 Since the concentrate when initially mixed contains no peracetic 32 acid and therefore is not used immediately, it is stored for 33 approxmately 19-20 days until the solution equilibrates and 34 peracetic acid is formed by the reaction of hydrogen peroxide with acetic acid as illustrated in Reaction 1.
1 -~eaction 1.
2 CH3C02H + H2~2 CH3CO3H + H20 3 The concentrate manufactured in accordance with the 4 present invention is stored and shipped in amber colored plastic bottles that have been thoroughly precleaned with purified water 6 to ensure no heavy metal contamination. Stability studies were 7 run at ambient (22 C), 35 C and 50 C to determine the stability 8 of the concentrate over time at these temperatures. Data 9 regarding the relative stability of H2O2 and HOOAc in the concentrate composition and the concentrate itself are shown in 11 Figures 1-14. Acetic acid typically was not measured for 12 stability since it is not one of the active ingredients of the 13 concentrate composition; in other words, acetic acid has no 14 microbicidal activity. As can be seen from Figures 1-15, the solutions were very stable.
16 In addition to stability studies, corrosivity studies 17 were run on the concentrate compositions, the results of which 18 may be seen by referring to Table IIA. Table IIB details the 19 results of the corrosivity run on conventional art formulations while Table IIC details the results of corrosivity testing on 21 the component parts of the conventional art formulation. Table 22 IID details the results of corrosivity studies run on the use-23 dilution formulations of the conventional art and several of the 24 preferred embodiments of the present invention.
Corrosivity studies were done using a variety of metal 26 coupons. They included naval brass 464 and aluminum 5052. The 27 coupons are commercially available from Metal Samples Company 28 (Munford, Al.) 29 Coupons were cleaned by the following methods to remove all foreign debris and to ensure accurate results. Brass 31 coupons were placed on edge in a 50% by weight solution of HCl 32 for two minutes at ambient temperature. Aluminum coupons were 33 placed on edge in concentrated nitric acid for three minutes at 34 ambient temperature. During all phases of the testing, coupons were handled by gloved laboratory personnel to insure that the 36 coupons were not exposed to any foreign materials prior to WO93/01822 2 ~ ~ 3 '~ ~ U ~ PCT/US92/05877 1 placing them in the test solutions. All coupons are stamped witn 2 a number to aid in identification. All coupons were air dried 3 under a ventilated hood and weighed prior to testing on a 4 Mettler AE 100 analytical balance. The weight was recorded as the initial weight.
6 The exposure time of the coupons was .5 hours for 7 brass and 5 hours for aluminum when testing the concentrate 8 microbicide and 5 hours for brass and 1 week for aluminum when 9 testing the use-dilution formulation of the microbicide. The coupons were tested in the test solutions indicated below at 11 ambient temperature.
12 Solution volumes of 70ml were dispensed into plastic 13 disposable cups. The coupons were allowed to remain in solution 14 for the times indicated above. After the time period had expired, the solution was discarded and the coupons were placed 16 to dry, without rinsing, standing on edge in a ventilating hood.
17 After drying for 30-60 minutes, the coupons were re-weighed.
18 The difference between the initial weight and final weight (W) 19 was used to calculated the corrosion rate as follows:
Corrosion rate (mm/yr) = (K x W) where:
21 (A x T x D) 22 K = a constant (8.76 x 10-4) 23 T = time of exposure in hours 24 A = area in cm-2 (28.7 cm-2) w = weight loss in grams (initial weight - final weight)*
26 *To correct for possible weight loss due to product 27 removal, a Ublankll coupon was weighed, cleaned by the 28 procedure indicated above and weighed again.
29 D = density in g/cm-3~
**Brass = 8.41 g/cm-3 31 Aluminum 5052 = 2.68 g/cm-3 34 Titrations 35 S~ les ~2Q~ PAA HoAc 36 1 38.8% 4.54% 2.88%
37 2 34.8% 4.23% 3.27%
W 093/01822 2 1 1 3 - o~ P~r/US92/0587l 1 3 27.6% 5.0% 6.1%
2 4 27.4% 5.4% 6.2%
3 5 27.3% 5.5% 5.7%
4 6 27.55% 5.03% 6.06%
7 27.4% 5.4% 6.21%
6 8 27.34% 5.51% 5.68%
7 9 27.2% 5.72% 6.67%
8 10 27.2% 5.70% 6.82%
9 11 27.0% 5.62% 6.66%
10 12 27.0% 4.00% 5.71%
11 13 26.5% 4.14% 6.50%
12 14 22.5% 4.19% 7.84%
13 15 22.5% 3.91% 8.1%
14 16 22.5% 3.86% 8.1%
15 17 19.6% 2.68% 8.62%
16 18 16.9% 1.66% 6.26%
18 Corrosion 19 S~les Rr~s Aluminum 1 19.9 mm/yr0.012 mm/yr 21 2 33.3 mm/yr. 006 mm/yr 22 3 52.02 mm/yr. 284 mm/yr 23 4 58.91 mm/yr. 024 mm/yr 24 5 52.07 mm/yr. 022 mm/yr 6 52.02 mm/yr. 283 mm/yr 26 7 58.91 mm/yr.023 mm/yr 27 8 58.07 mm/yr.020 mm/yr 28 9 57.56 mm/yr.010 Irun/yr 29 10 54.53 mm/yr. 376 mm/yr 30 11 49.96 mm/yr. 013 mm/yr 31 12 82.10 mm/yr.001 mm/yr 32 13 93.70 mm/yr. 018 mm/yr 33 14 95.62 mm/yr1. 320 mm/yr 34 15 93.25 mm/yr.153 mm/yr 35 16 93.20 mm/yr.230 mm/yr 36 17 45.3 mm/yr. 257 mm/yr 37 18 43.4 mm/yr.173 mm/yr W O 93/01822 2 1 1 3 3 6 0 PC~r/US92/05877 1 Table IIB
2Conventional Art Formulation 3Titration 4 ~Q2 PAA ~Q~ Phosphonic Acid Stabilizer 6 S~mnles 7 19 22.4% 3.96% 8.27% 1.0%
8 20 21.0% 4.3% 9.86% 1.0%
9 Corrosivitv 10 .~mnles ~B~_S Aluminum 11 19 295.50 mm/yr 121.63 mm/yr 12 20 295.48 mm/yr 121.65 mm/yr 14 Table IIC
CorrosivitY of Com~onent Parts 16 .~mnles BFaSS Aluminum 17 1% stabilizer.586 mm/yr .367 mm/yr 18 22.7% H2O2 .528 mm/yr .316 mm/yr 19 10.2% HoAc .160 mm/yr .167 mm/yr 21 Table IID
22 Use-~ilution Formulations*
23 Conv~ntion~1 ArtBrass Aluminum 24 3% Sample 1923.63 mm/yr 0.820 mm/yr 25 3% Sample 2023.84 mm/yr 0.747 mm/yr 27 Present Invention 28 ~m~1e X [27% H2O2, 29 5.3% PAA, 5.5% Ac] 12.77 mm/yr 0.437 mm/yr 30 S~mnle Y [37% H2O2, 31 4.8% PAA, 2.2% AC~ 5.39 mm/yr 0.374 mm/yr 32 S~mnle Z [22% H2O2, 33 4.0% PAA, 7.0% Ac] 14.63 mm/yr 0.441 mm/yr * All use-dilution samples were prepared using 3% of the 36 concentrate formula diluted in a purified aqueous diluent.
WO93/01822 2 1 1 3 3 6 o PCT/US92/05877 1 In the present preferred form of the invention, the 2 concentrate is shipped in a small quantity in an amber colored 3 plastic bottle together with a gallon of purified deionized 4 water. Before use, the concentrate of the preferred embodiment is diluted from about 20 to 40 times, more preferably from about 6 25 to 35 times, and most preferably from about 30 to 33 times 7 with a purified aqueous diluent prepared as described below.
8 This results in a use-dilution formulation of approximately 3.0%
9 to 4.5% by volume of concentrate. Ordinary tap water is generally unsuitable as a diluent because of cont~m;n~nts, such 11 as divalent and trivalent ions, contained therein. If ordinary 12 tap water is used to dilute the concentrate, the shelf life of 13 the use-dilution formulation will likely be less than when the 14 purified aqueous diluent is used and corrosivity will increase as the purity of the water decreases. The recommended shelf 16 life of the use-dilution microbicide is seven days.
17 Consequently, it may be used for several applications or reused 18 several times during that period of time with no change in the 19 stability or in the anticorrosive or sporicidal activity.
A purified aqueous diluent suitable for use in the 21 concentrate and use-dilution formulation in accordance with the 22 present invention is prepared in the following manner. Raw city 23 water is passed through an activated carbon bed containing 10 24 cubic feet of carbon in a 24 in. diameter fiberglass tank with a 2 in. diameter super flow head and a 2 in. diameter distributor.
26 The water is then passed through softening beds well 27 known in the art of water purification to remove calcium 28 chloride and magnesium. Suitable softening beds are available 29 from Eco Water Systems (Woodbury, MN). The water is then passed through a one micron polypropylene cloth sediment filter having 31 an efficiency rate of 93~. The cloth filter catches any 32 particulate matter remaining in the water that has a size 33 greater than 1u.
34 The water then flows through an eight inch diameter reverse osmosis membrane filter. The membrane filter is made 36 from a spirally wound polyamide sheet membrane and is 37 commercially available as Model No. BW-30 from Filmtec Co.
WO93/01822 '~ 1 13 3 6 0 PCT/US92/05877 1 (Edina, MN). The water effluent has less than 5 ppm dissolved 2 solids.
3 After the water is treated by passing it through the 4 reverse osmosis membrane, it is circulated through an ultraviolet disinfection unit. The unit employs dual wave 6 lengths at 185nm and 254nm and is rated at 99%.9 bacterial 7 reduction. A suitable commercially available unit is the 8 Aquafine U.V. Water Sterilizer, CLS-4R (Aquafine Corp, Valencia, 9 CA.) Post- W light treatment, the water flows through an 11 anion exchange resin bed and a cation exchange resin bed. The 12 anion exchange resin bed is a strongly basic anion exchange 13 resin based on a styrenedivinylbenzene copolymer matrix. Its 14 exchange capacity is derived from the N-(CH3)2H4OH
(dimethylethanolamine) group. Anion exchange resin bed capable 16 of purifying the aqueous diluent in accordance with the present 17 invention may be purchased from Sybron Chemicals Inc 18 (Birmingham, N.J.) under the trade name IONAC ASB-2. The cation 19 exchange resin bed is a bead-form, standard crosslinked, polystyrene sulfonate cation exchange resin with a capacity of 21 1.4 mEq/ml for further demineralization. Treated water is 22 stored in a 1000-5000 gallon tank. Resistivity is constantly 23 measured and maintained at 17-17.5 mOhms.
24 Prior to using the above manufactured water in the concentrate mixtures or use-dilution formulations in accordance 26 with the present invention, the water is tested for pyrogen, 27 yeast, molds and bacteria by the following methods.
28 Pvro~en Testina. Five milliliters of sterile water is 29 pipetted into a vials of endotoxin, commercially available as endotoxin from E. coli strain 055.B5 from Whittaker Bioproducts, 31 Inc. (Walkersville, MD). Five and two-tenths milliliters of 32 sterile water is pipetted into a vial of lysate, commercially 33 available as Pyrogen T from Whittaker Bioproducts. One hundred 34 lambda of the reconstituted lysate is then pipetted into disposable conical tubes. The diluted lysate has a sensitivity 36 of 0.06 endotoxin units.
W O 93/01822 t3~ 1 1 3 3 6 0 PC~r/US92/05877 1 Serial dilutions of the reconstituted endotoxin 2 ranging from 500 picograms/ml to 12.5 picograms/~l are prepared.
3 Positive controls are set up by pipetting 100 lambda of each of 4 the above prepared dilutions of endotoxin into a conical tube S containing the lysate. Tubes are mixed and placed in a 37~
6 heating block for one hour + two minutes. Triplicate samples of 7 100 lambda each of ultra-pure deionized water as manufactured in 8 accordance with the procedure disclosed herein are added to the 9 lysate tubes and incubated at 37~C for one hour. A gelled tube indicates the presence of endotoxin.
11 Ye~st. Mol~s ~n~ R~cter;a Testinq 12 Water used in the manufacture of the concentrate 13 microbicide and in the use-dilution formulation is tested for 14 the presence of microbes using a filter membrane technique.
Samples are collected aseptically in sterile lOml test tubes at 16 the source. Five milliliters of sample is transfered into a 17 lOOml filter housing. A vacuum is applied to the filter housing 18 to facilitate filtration. The lower housing is removed and the 19 filtrate is decanted. The filter membrane is aseptically removed and placed in a tryptone/glucose yeast agar plate (DiMed 21 Corporation, St. Paul, MN) for measuring bacterial growth and 22 potato dextrose agar plates (DiMed Corporation, St. Paul, MN) 23 for measuring yeast and mold growth. The media plate is 24 covered, inverted and incubated at 35~C for two days for bacteria and at 22~C for seven days for yeasts and molds.
26 Results are reported as the number of colony forming units per 27 five milliliters of sample size.
29 ~m~le 1 All mixing drums and tanks were thoroughly cleaned 31 using purified water. Sixty percent by weight of purified water 32 was added to a cleaned mixing tank at ambient te~perature.
33 Bacterial testing and yeast and molds testing of the water used 34 in manufacturing the concentrate was reported as 0 colony forming units per five milliliters of sample for both tests. An 36 air driven drum pump was turned on to start recirculation of the 37 batch. Fourteen percent by weight of acetic acid was added to .~j , : , .
~- s~ q~3~
the mixing tank containing the deionized water. After the acetic acid was added, the batch was covered and recirculated for one hour. Using an air driven drum pump, 26~ by weight of hydrogen peroxide was added into the mixing tank and the cover replaced. The composition was recirculated for two hours after all chemicals were added.
After two hours, the recirculating pump was stopped. The concentrate was dispensed into clean 55 gallon drums for storage and equilibrated for 19 days. After 19 days from the production date, a sample was taken from the concentrate batch and the concentration was determined to be 22.5~ H2O2, 3.96~ peracetic acid, and 8.1~ acetic acid.
Microbicidal Effectiveness A 3.0~ solution of the concentrate microbicide manufacture in Example 1 was tested for sporicidal activity according to the methods outlined in the Official Methods of Analysis of the Association of Official Analytical Chemists (K. Helrich 15th ed. 1990) (966.04 pp. 141-142).
Briefly, cultures of two sporoformer organisms, Bacillus subtilis ATCC 19659 and Clostridium sporogenes ATCC 3584 were grown in the appropriate medium. Each organism was used to contaminate two types of carriers, namely, silk suture and porcelain penicylinders. The carriers were dried for a minimum of 24 hrs. under vacuum.
Carriers were tested for acid resistance and viability.
Five carriers were placed in test tubes containing 10mL. of test solution, and exposed for 30 min. at 50~C. Following contact, carriers were neutralized in thioglycollate medium and incubated for 21 days at 37~C. If no growth was observed after 21 days, the test tubes were heat shocked for 20 minutes at 80~C to activate any remaining spores and incubated for 72 hrs. at 37~C. For chemical sterilant claims, no survival of any organism/spore can be tolerated for qualification of the solution by the U.S. Environmental Protection Agency as a sterilant. The results of the sporicidal testing of the concentrate microbicide in accordance with the microbicide prepared in Example 1 are as follows:
.
A~
WO93/01822 ~ 1 ~ 3 3 6 0 PCT/~S92/0~877 1 - Lot Org. Carrier TiterResistance #Survivors/
2 #Tested 3 2M004 Cl.sp. Suture 10-6 20 min. 0/60 4 2M004 Cl.sp. Cylinder 10-5 5 min. 0/60 2M004 B. sub.suture 10-4 20 min. 0/60 6 2M004 Ei. sub.Cylinder 10-4 2 min. 0/60 8 The results of the AOAC procedure reference test shows that 9 the microbicide of the invention, in addition to being stable, is effective as a sterilant.
11 Corrosivity of the solution of Example 1 was tested.
12 The results appear as Sample 15 in Table IIA.
14 ~x~mnle 2 All mixing drums and tanks were thoroughly cleaned 16 using purified water. 23.3% by weight of purified water was 1, added to a cleaned mixing tank at ambient temperature.
18 Bacterial testing and yeast and molds testing of the water used 19 in manufacturing the concentrate was reported as 0 colony forming units per five milliliters of sample for both tests. An 21 air driven drum pump was turned on to start recirculation of the 22 batch. 16.7% by weight of acetic acid was added to the mixing 23 tank containing the purified water. After the acetic acid was 24 added, the batch was covered and recirculated for one hour.
Using an air driven drum pump, 40.0% by weight of hydrogen 26 peroxide was added into the mixing tank and the cover replaced.
27 The composition was recirculated for two hours after all 28 chemicals were added. After two hours, the recirculating pump 29 was stopped. The concentrate was dispensed into clean 55 gallon drums for storage. After 19 days from the production date, the 31 batch was adjusted to a hydrogen peroxide level of 36.5% and a 32 peracetic acid level of 4.5% by adding water and hydrogen 33 peroxide. The solution was allowed to equilibrate for an 34 additional 33 days. A sample was taken from the concentrate batch and the concentration was determined to be 36.65~ hydrogen 36 peroxide, 4.31% peracetic acid and 2.88%.
1 The results of the sporicidal testing of a 3% solutlon 2 of the concentrate microbicide in accordance with the 3 microbicide prepared in Example 2 are as follows:
4 Lot Org. Carrier Titer Resistance #Survivors/
#Tested 6 2008-2a Cl.sp. Suture 10-6 20 min. 0/60 7 2008-2a Cl.sp. Cylinder 10-6 10 min. 0/60 8 2008-2a B. sub.suture 10-4 10 min. 0/60 9 2008-2a B. sub.Cylinder 10-4 2 min. 0/60 11 The concentrate prepared in accordance with Example 2 12 was tested for corrosivity. The results are shown in Table IIA
13 as Sample 2.
14 F.x~rr~le 3 Using the method set forth in Examples 1 and 2, 7.74%
16 by weight purified water was added to 17.12% by weight H2O2 and 17 8.143% by weight HOAc. Bacterial testing and yeast and molds 18 testing of the water used in manufacturing the concentrate was 19 reported as 0 colony forming units per five milliliters of sample for both tests. After mixing for the specified time 21 periods, the concentrate was allowed to stand for 19 days and a 22 sample was taken to determine the content of H2O~ and HOOAc.
23 The final concentration was determined to be 16.86% by weight 24 H2~2~ 1- 66% peracetic acid and 6.26% acetic. The solution was found to have microbicidal activity as follows:
26 Lot Org. Carrier Titer Resistance #Survivors/
27 #Tested 28 2028-1 Cl.sp. Sueure 10-5 10 min. 0/60 29 2028-1 Cl.sp. Cylinder 10-6 10 min. 0/60 2028-1 B. sub.suture 10-4 10 min. 0/60 31 2028-1 B. sub.Cylinder 10-q 2 min. 0/60 33 Corrosivity was tested and the results are detailed in 34 Table IIA as Sample 18.
While the preceding compositions in accordance with 36 the invention are the preferred form it is to be understood that 37 concentrate formulations may be within the ranges given and WO93/01822 ~ 1 133 6 0 PCT/US92/05877 1 still provide the advantages of the invention. Those skilled in 2 the art may recognize other equivalents to the specific 3 embodiments described herein which equivalents are intended to 4 be encompassed by the appended claims.
10 2. De~cr;ption of the Related Art 11 Peracetic acid/peroxide containing compositions have a 12 long history of use as disinfectants and sterilizers due to 13 their microbicidal activities. However, peroxide containing 14 compositions are high-energy-state compounds and as such can be considered thermodynamically unstable. Therefore, because there 16 is a strong tendency for these compositions to decompose in the 17 presence of multivalent metal ions, stabilizers are added.
18 Stabilizers may be agents such as sodium pyrophosphate, 19 phosphonic acid or chelating agents such as 8-hydroxyquinoline.
Stabilizers act by removing trace metals which accelerate the 21 decomposition of peroxides. Stabilizers also accelerate the 22 reaction between hydrogen peroxide and acetic acid to form 23 peracetic acid. Therefore, for any given concentration of 24 hydrogen proxide and acetic acid, the addition of a stabilizer increases the concentration at equilibrium of peracetic acid.
26 While conventional art compositions are stable due to 27 the use of added stabilizers, they are also highly corrosive to 28 the very metals they are designed to disinfect namely surgical 29 and dental instruments made of aluminum or brass, which 30 instruments are often plated with an ornamental or protective 31 layer of nickel or nickel and/or chromium. Additionally, 32 certain susceptible individuals often exhibit allergic reactions 33 to the conventional art formulations. Further, after prolonged 34 use these conventional art formulations often leave mineral-like deposits on the metal instruments they sterilize.
WO93/01822 2 ~ 1 3 3 ~ ~ PCT/~S92/0587?
1 A concentrated composition that contains no stabilizer 2 or sequestrant type additives that is both stable during storage 3 for prolonged periods of time and possesses anticorrosive 4 properties would be a decided advantage over these conventional formulations. Further, a use-dilution formulation that may be 6 reused several times, is stable for relatively long periods in 7 the diluted form and possesses anticorrosive properties would be 8 a further advantage over conventional formulations.
g .~llmm~rV of the Tnvent;on It is an object of the stable, anticorrosive 11 concentrate and use-dilution microbicides in accordance with the 12 present invention to solve the problems outlined above that has 13 heretofore inhibited long-term storage and the anticorrosive 14 sterilization of surgical and dental instruments. These improved microbicide solutions not only have the desired 16 stability but have been shown to have a significantly reduced 17 corrosive effect on certain metals than those of conventional 18 art mixtures of the peracetic acid/peroxide types known to the 19 applicants.
In accomplishing the foregoing objectives, there has 21 been provided in accordance with the present invention a stable, 22 anticorrosive to surgical and dental metals concentrate 23 including peracetic acid, acetic acid, hydrogen peroxide and 24 purified water mixed in a ratio of from about one to eleven parts total acid to one part hydrogen peroxide. The new 26 concentrate has from substantially about .001 ppm to 200 ppm, 27 more preferably from about .001 ppm to 100 ppm, and most 28 preferably from about .001 ppm to 10 ppm of added stabilizers, 29 such as phosphonic acids, sodium pyrophosphates and from about .001 - 10 ppm of ionic and non-ionic cont~min~nts such as 31 divalent and trivalent ions, with no added surfactants, such as 32 ethoxylated decyl alcohols, sulfonate and sulfate types.
33 In accordance with another aspect of the present 34 invention, there has been provided a stable, anticorrosive to surgical and dental metals use-dilution formulation including 36 a concentrate consisting essentially of at equilibrium peracetic 37 acid, acetic acid, hydrogen peroxide and an aqueous diluent, WO93/01822 ~ 1 1'3~3~S0 PCT/VS92/05877 1 said concentrate characterized in having from about .001- 200 2 ppm of added stabilizers, from about .001-10 ppm of ionic and 3 nonionic contaminants and no added surfactants; and a purified 4 aqueous diluent; wherein the concentrate is diluted in the aqueous diluent from about 20 to 40 times.
6 In accordance with still another aspect of the present 7 invention, there has been provided a process for preparing a 8 sterilant concentrate as described above, including the steps of 9 introducing from about 17% by weight to about 40% by weight hydrogen peroxide into a mixing drum, the hydrogen peroxide 11 having from about .001-200 ppm of added stabilizers; blending 12 thereinto from about 10% by weight to about 16~ by weight acetic 13 acid; and adding a purified aqueous diluent having from about 14 .001-10 ppm of divalent and trivalent ions; wherein the equilibrium concentration includes from about 16-38% by weight 16 hydrogen peroxide; from about 2.5-9% by weight acetic acid; from 17 about 1.5-6.0% by weight peracetic acid; and an aqueous diluent 18 and wherein the equilibrium concentration is characterized in 19 having from about .001-200 ppm of added stabilizers, from about .001-10 ppm of ionic and nonionic contaminants and no added 21 surfactants.
22 One of the advantages of the present invention is that 23 the occasional allergic reactions of some individuals to the 24 conventional art formulations is reduced.- Another advantage of the present invention is that the presence of mineral-like 26 deposits from the use of the solutions of conventional art 27 formulations containing sequestrants or stabilizers is no longer 28 found. Perhaps most importantly, however, the present invention 29 allows metal instruments such as dental tools and surgical instruments to be sterilized with significantly reduced 31 corrosivity as will be shown.
32 Further objects, features and advantages of the 33 present invention will become apparent from the detailed 34 description of the preferred embodiments, including the best mode, which follow.
WO93/01822 2 1 il 3 3 6 U PCT/US92/05~77 1 Brief DescriDtion of the Drawinqs 2 Figure 1 is a chart of stability of the concentrated 3 microbicide against time where the initial formulation contained 4 4.1% by weight of peracetic acid and the storage temperature was at ambient temperature of 22 C;
6 Figure 2 is a chart of stability of concentrated 7 microbicide where the initial formulation contained 4.5% by 8 weight of peracetic acid and the storage temperature was 35 C;
9 Figure 3 is a chart of stability of the concentrated microbicide against time where the initial formulation contained 11 4.2% by weight of peracetic acid and the storage temperature was 12 50 C;
13 Figure 4 is a chart of stability of the concentrated 14 microbicide against time where the initial formulation contained 23% by weight of hydrogen peroxide and the storage temperature 16 was 22 C;
17 Figure 5 is a chart of stability of the concentrated 18 microbicide against time where the initial formulation contained 19 23% by weight of hydrogen peroxide and the storage temperature was 35 C;
21 Figure 6 is a chart of stability of the concentrated 22 microbicide against time where the initial formulation contained 23 23% by weight of hydrogen peroxide and the storage temperature 24 was 50 C;
Figure 7 is a chart of stability of the concentrated 26 microbicide against time where the initial formulation contained 27 23% by weight of hydrogen peroxide, 4% by weight of peracetic 28 acid and 8.4% acetic acid and the solution was stored at ambient 29 temperature;
Figure 8 is a chart of stability of the concentrated 31 microbicide against time where the initial formulation contained 32 23.8% by weight hydrogen peroxide and 4.47% by weight peracetic 33 acid and the solution was stored at ambient temperature;
34 Figure 9 is a chart of stability of the concentrated microbicide against time where the initial formulation contained 36 23.8% by weight hydrogen peroxide and 4.47% peracetic acid and 37 the storage temperature was 35~C;
211336~
Figure 10 is a chart of stability of the concentrated 2 microbicide where the initial formulation contained 23.8% by 3 weight hydrogen peroxide and 4.479~ by weight peracetic acid and 4 the storage temperature was 50~C;
Figure 11 is a chart of stability of the concentrated 6 microbicide where the initial formulation contained 17.2% by 7 weight hydrogen peroxide and 0.0% by weight peracetic acid and 8 the solution was stored at ambient temperature;
9 Figure 12 is a chart of stability of the concentrated microbicide where the initial formulation contained 36.46% by 11 weight hydrogen peroxide and 0.0% by weight peracetic acid and 12 the solution was stored at ambient temperaturei 13 Figure 13 is a chart of stability of the concentrated 14 microbicide where the initial formulation contained 27.4% by weight hydrogen peroxide and 5.6% by weight peracetic acid and 16 the solution was stored at ambient temperature;
17 Figure 14 is a chart of stability of the concentrated 18 microbicide where the initial formulation contained 27.4% by 19 weight hydrogen peroxide and 5.3% by weight peracetic acid and the solution was stored at 50~C.
21 net~ile-l De~cription of the Invention 22 Concentrate microbicide formulations in accordance 23 with the present invention possess the desirable property of a 24 long storage life without deleterious decomposition despite the absence of conventional additions of stabilizers and 26 sequestrants as heretofore taught in the art. Additionally, 27 the concentrate compositions of the present invention are far 28 less corrosive to metals that are sterilized using the 29 compositions such as surgical and dental instruments. In contrast with conventional art formulations containing added 31 surfactants, sequestrants and other stabilizers where visible 32 evidence of corrosion of the metals appeared in one or two 33 hours, formulations in accordance with the preferred embodiment 34 of the present invention visibly showed comparatively little corrosion on the same metals during the same time period.
36 Manufacture of the preferred embodiment is effected by 37 mixing a solution of hydrogen peroxide with acetic acid diluted W O 93/01822 PC~r/US92/05877 211336U
1 with a purified aqueous diluent. The hydrogen peroxide is 2 selected from commercially available sources having low 3 concentrations of stabilizers, preferably .001 ppm to 200 ppm, 4 more preferably from about .001 ppm to 100 ppm, and most preferably from about .001 ppm to 15 ppm of added stabilizers, 6 such as phosphonic acids, sodium pyrophosphates. Sources of 7 such hydrogen peroxide are available from FMC Corporation 8 (Philadelphia, PA).
9 In addition, the preferred embodiment in accordance with the present invention preferably includes no contaminants.
11 Cont~m;n~nts such as divalent and trivalent ions, principally, 12 iron, manganese, magnesium, nickel and cobalt, and undesirable 13 trace organics found in the manufacturing process, principally, 14 surfactants, acetone, methanol, ethanol, which are typically present in conventional art formulations are found in the 16 present invention in amounts preferably from about 5-10 ppm and 17 most preferably from about .001-5 ppm in the final composition.
18 Referring to Table I, the preferred composition is 19 shown.
TABLE I
21 Initial Mixture After Equilibrium 22 H2O2 17-40% by wt. 16-38% by wt.
23 HOAc 10-16% by wt. 2.5-9.0% by wt.
24 HOOAc 0 1.5-6.0% by wt.
The concentrate microbicide in accordance with the 26 present invention may be formulated over a wide range of 27 concentrations of the active materials. After equilibrium the 28 concentrate microbicide may have as high as 38% by weight 29 hydrogen peroxide at equilibrium with the peracetic acid concentration ranging from 1.5% to 6.0% as indicated in Table 1.
31 Since the concentrate when initially mixed contains no peracetic 32 acid and therefore is not used immediately, it is stored for 33 approxmately 19-20 days until the solution equilibrates and 34 peracetic acid is formed by the reaction of hydrogen peroxide with acetic acid as illustrated in Reaction 1.
1 -~eaction 1.
2 CH3C02H + H2~2 CH3CO3H + H20 3 The concentrate manufactured in accordance with the 4 present invention is stored and shipped in amber colored plastic bottles that have been thoroughly precleaned with purified water 6 to ensure no heavy metal contamination. Stability studies were 7 run at ambient (22 C), 35 C and 50 C to determine the stability 8 of the concentrate over time at these temperatures. Data 9 regarding the relative stability of H2O2 and HOOAc in the concentrate composition and the concentrate itself are shown in 11 Figures 1-14. Acetic acid typically was not measured for 12 stability since it is not one of the active ingredients of the 13 concentrate composition; in other words, acetic acid has no 14 microbicidal activity. As can be seen from Figures 1-15, the solutions were very stable.
16 In addition to stability studies, corrosivity studies 17 were run on the concentrate compositions, the results of which 18 may be seen by referring to Table IIA. Table IIB details the 19 results of the corrosivity run on conventional art formulations while Table IIC details the results of corrosivity testing on 21 the component parts of the conventional art formulation. Table 22 IID details the results of corrosivity studies run on the use-23 dilution formulations of the conventional art and several of the 24 preferred embodiments of the present invention.
Corrosivity studies were done using a variety of metal 26 coupons. They included naval brass 464 and aluminum 5052. The 27 coupons are commercially available from Metal Samples Company 28 (Munford, Al.) 29 Coupons were cleaned by the following methods to remove all foreign debris and to ensure accurate results. Brass 31 coupons were placed on edge in a 50% by weight solution of HCl 32 for two minutes at ambient temperature. Aluminum coupons were 33 placed on edge in concentrated nitric acid for three minutes at 34 ambient temperature. During all phases of the testing, coupons were handled by gloved laboratory personnel to insure that the 36 coupons were not exposed to any foreign materials prior to WO93/01822 2 ~ ~ 3 '~ ~ U ~ PCT/US92/05877 1 placing them in the test solutions. All coupons are stamped witn 2 a number to aid in identification. All coupons were air dried 3 under a ventilated hood and weighed prior to testing on a 4 Mettler AE 100 analytical balance. The weight was recorded as the initial weight.
6 The exposure time of the coupons was .5 hours for 7 brass and 5 hours for aluminum when testing the concentrate 8 microbicide and 5 hours for brass and 1 week for aluminum when 9 testing the use-dilution formulation of the microbicide. The coupons were tested in the test solutions indicated below at 11 ambient temperature.
12 Solution volumes of 70ml were dispensed into plastic 13 disposable cups. The coupons were allowed to remain in solution 14 for the times indicated above. After the time period had expired, the solution was discarded and the coupons were placed 16 to dry, without rinsing, standing on edge in a ventilating hood.
17 After drying for 30-60 minutes, the coupons were re-weighed.
18 The difference between the initial weight and final weight (W) 19 was used to calculated the corrosion rate as follows:
Corrosion rate (mm/yr) = (K x W) where:
21 (A x T x D) 22 K = a constant (8.76 x 10-4) 23 T = time of exposure in hours 24 A = area in cm-2 (28.7 cm-2) w = weight loss in grams (initial weight - final weight)*
26 *To correct for possible weight loss due to product 27 removal, a Ublankll coupon was weighed, cleaned by the 28 procedure indicated above and weighed again.
29 D = density in g/cm-3~
**Brass = 8.41 g/cm-3 31 Aluminum 5052 = 2.68 g/cm-3 34 Titrations 35 S~ les ~2Q~ PAA HoAc 36 1 38.8% 4.54% 2.88%
37 2 34.8% 4.23% 3.27%
W 093/01822 2 1 1 3 - o~ P~r/US92/0587l 1 3 27.6% 5.0% 6.1%
2 4 27.4% 5.4% 6.2%
3 5 27.3% 5.5% 5.7%
4 6 27.55% 5.03% 6.06%
7 27.4% 5.4% 6.21%
6 8 27.34% 5.51% 5.68%
7 9 27.2% 5.72% 6.67%
8 10 27.2% 5.70% 6.82%
9 11 27.0% 5.62% 6.66%
10 12 27.0% 4.00% 5.71%
11 13 26.5% 4.14% 6.50%
12 14 22.5% 4.19% 7.84%
13 15 22.5% 3.91% 8.1%
14 16 22.5% 3.86% 8.1%
15 17 19.6% 2.68% 8.62%
16 18 16.9% 1.66% 6.26%
18 Corrosion 19 S~les Rr~s Aluminum 1 19.9 mm/yr0.012 mm/yr 21 2 33.3 mm/yr. 006 mm/yr 22 3 52.02 mm/yr. 284 mm/yr 23 4 58.91 mm/yr. 024 mm/yr 24 5 52.07 mm/yr. 022 mm/yr 6 52.02 mm/yr. 283 mm/yr 26 7 58.91 mm/yr.023 mm/yr 27 8 58.07 mm/yr.020 mm/yr 28 9 57.56 mm/yr.010 Irun/yr 29 10 54.53 mm/yr. 376 mm/yr 30 11 49.96 mm/yr. 013 mm/yr 31 12 82.10 mm/yr.001 mm/yr 32 13 93.70 mm/yr. 018 mm/yr 33 14 95.62 mm/yr1. 320 mm/yr 34 15 93.25 mm/yr.153 mm/yr 35 16 93.20 mm/yr.230 mm/yr 36 17 45.3 mm/yr. 257 mm/yr 37 18 43.4 mm/yr.173 mm/yr W O 93/01822 2 1 1 3 3 6 0 PC~r/US92/05877 1 Table IIB
2Conventional Art Formulation 3Titration 4 ~Q2 PAA ~Q~ Phosphonic Acid Stabilizer 6 S~mnles 7 19 22.4% 3.96% 8.27% 1.0%
8 20 21.0% 4.3% 9.86% 1.0%
9 Corrosivitv 10 .~mnles ~B~_S Aluminum 11 19 295.50 mm/yr 121.63 mm/yr 12 20 295.48 mm/yr 121.65 mm/yr 14 Table IIC
CorrosivitY of Com~onent Parts 16 .~mnles BFaSS Aluminum 17 1% stabilizer.586 mm/yr .367 mm/yr 18 22.7% H2O2 .528 mm/yr .316 mm/yr 19 10.2% HoAc .160 mm/yr .167 mm/yr 21 Table IID
22 Use-~ilution Formulations*
23 Conv~ntion~1 ArtBrass Aluminum 24 3% Sample 1923.63 mm/yr 0.820 mm/yr 25 3% Sample 2023.84 mm/yr 0.747 mm/yr 27 Present Invention 28 ~m~1e X [27% H2O2, 29 5.3% PAA, 5.5% Ac] 12.77 mm/yr 0.437 mm/yr 30 S~mnle Y [37% H2O2, 31 4.8% PAA, 2.2% AC~ 5.39 mm/yr 0.374 mm/yr 32 S~mnle Z [22% H2O2, 33 4.0% PAA, 7.0% Ac] 14.63 mm/yr 0.441 mm/yr * All use-dilution samples were prepared using 3% of the 36 concentrate formula diluted in a purified aqueous diluent.
WO93/01822 2 1 1 3 3 6 o PCT/US92/05877 1 In the present preferred form of the invention, the 2 concentrate is shipped in a small quantity in an amber colored 3 plastic bottle together with a gallon of purified deionized 4 water. Before use, the concentrate of the preferred embodiment is diluted from about 20 to 40 times, more preferably from about 6 25 to 35 times, and most preferably from about 30 to 33 times 7 with a purified aqueous diluent prepared as described below.
8 This results in a use-dilution formulation of approximately 3.0%
9 to 4.5% by volume of concentrate. Ordinary tap water is generally unsuitable as a diluent because of cont~m;n~nts, such 11 as divalent and trivalent ions, contained therein. If ordinary 12 tap water is used to dilute the concentrate, the shelf life of 13 the use-dilution formulation will likely be less than when the 14 purified aqueous diluent is used and corrosivity will increase as the purity of the water decreases. The recommended shelf 16 life of the use-dilution microbicide is seven days.
17 Consequently, it may be used for several applications or reused 18 several times during that period of time with no change in the 19 stability or in the anticorrosive or sporicidal activity.
A purified aqueous diluent suitable for use in the 21 concentrate and use-dilution formulation in accordance with the 22 present invention is prepared in the following manner. Raw city 23 water is passed through an activated carbon bed containing 10 24 cubic feet of carbon in a 24 in. diameter fiberglass tank with a 2 in. diameter super flow head and a 2 in. diameter distributor.
26 The water is then passed through softening beds well 27 known in the art of water purification to remove calcium 28 chloride and magnesium. Suitable softening beds are available 29 from Eco Water Systems (Woodbury, MN). The water is then passed through a one micron polypropylene cloth sediment filter having 31 an efficiency rate of 93~. The cloth filter catches any 32 particulate matter remaining in the water that has a size 33 greater than 1u.
34 The water then flows through an eight inch diameter reverse osmosis membrane filter. The membrane filter is made 36 from a spirally wound polyamide sheet membrane and is 37 commercially available as Model No. BW-30 from Filmtec Co.
WO93/01822 '~ 1 13 3 6 0 PCT/US92/05877 1 (Edina, MN). The water effluent has less than 5 ppm dissolved 2 solids.
3 After the water is treated by passing it through the 4 reverse osmosis membrane, it is circulated through an ultraviolet disinfection unit. The unit employs dual wave 6 lengths at 185nm and 254nm and is rated at 99%.9 bacterial 7 reduction. A suitable commercially available unit is the 8 Aquafine U.V. Water Sterilizer, CLS-4R (Aquafine Corp, Valencia, 9 CA.) Post- W light treatment, the water flows through an 11 anion exchange resin bed and a cation exchange resin bed. The 12 anion exchange resin bed is a strongly basic anion exchange 13 resin based on a styrenedivinylbenzene copolymer matrix. Its 14 exchange capacity is derived from the N-(CH3)2H4OH
(dimethylethanolamine) group. Anion exchange resin bed capable 16 of purifying the aqueous diluent in accordance with the present 17 invention may be purchased from Sybron Chemicals Inc 18 (Birmingham, N.J.) under the trade name IONAC ASB-2. The cation 19 exchange resin bed is a bead-form, standard crosslinked, polystyrene sulfonate cation exchange resin with a capacity of 21 1.4 mEq/ml for further demineralization. Treated water is 22 stored in a 1000-5000 gallon tank. Resistivity is constantly 23 measured and maintained at 17-17.5 mOhms.
24 Prior to using the above manufactured water in the concentrate mixtures or use-dilution formulations in accordance 26 with the present invention, the water is tested for pyrogen, 27 yeast, molds and bacteria by the following methods.
28 Pvro~en Testina. Five milliliters of sterile water is 29 pipetted into a vials of endotoxin, commercially available as endotoxin from E. coli strain 055.B5 from Whittaker Bioproducts, 31 Inc. (Walkersville, MD). Five and two-tenths milliliters of 32 sterile water is pipetted into a vial of lysate, commercially 33 available as Pyrogen T from Whittaker Bioproducts. One hundred 34 lambda of the reconstituted lysate is then pipetted into disposable conical tubes. The diluted lysate has a sensitivity 36 of 0.06 endotoxin units.
W O 93/01822 t3~ 1 1 3 3 6 0 PC~r/US92/05877 1 Serial dilutions of the reconstituted endotoxin 2 ranging from 500 picograms/ml to 12.5 picograms/~l are prepared.
3 Positive controls are set up by pipetting 100 lambda of each of 4 the above prepared dilutions of endotoxin into a conical tube S containing the lysate. Tubes are mixed and placed in a 37~
6 heating block for one hour + two minutes. Triplicate samples of 7 100 lambda each of ultra-pure deionized water as manufactured in 8 accordance with the procedure disclosed herein are added to the 9 lysate tubes and incubated at 37~C for one hour. A gelled tube indicates the presence of endotoxin.
11 Ye~st. Mol~s ~n~ R~cter;a Testinq 12 Water used in the manufacture of the concentrate 13 microbicide and in the use-dilution formulation is tested for 14 the presence of microbes using a filter membrane technique.
Samples are collected aseptically in sterile lOml test tubes at 16 the source. Five milliliters of sample is transfered into a 17 lOOml filter housing. A vacuum is applied to the filter housing 18 to facilitate filtration. The lower housing is removed and the 19 filtrate is decanted. The filter membrane is aseptically removed and placed in a tryptone/glucose yeast agar plate (DiMed 21 Corporation, St. Paul, MN) for measuring bacterial growth and 22 potato dextrose agar plates (DiMed Corporation, St. Paul, MN) 23 for measuring yeast and mold growth. The media plate is 24 covered, inverted and incubated at 35~C for two days for bacteria and at 22~C for seven days for yeasts and molds.
26 Results are reported as the number of colony forming units per 27 five milliliters of sample size.
29 ~m~le 1 All mixing drums and tanks were thoroughly cleaned 31 using purified water. Sixty percent by weight of purified water 32 was added to a cleaned mixing tank at ambient te~perature.
33 Bacterial testing and yeast and molds testing of the water used 34 in manufacturing the concentrate was reported as 0 colony forming units per five milliliters of sample for both tests. An 36 air driven drum pump was turned on to start recirculation of the 37 batch. Fourteen percent by weight of acetic acid was added to .~j , : , .
~- s~ q~3~
the mixing tank containing the deionized water. After the acetic acid was added, the batch was covered and recirculated for one hour. Using an air driven drum pump, 26~ by weight of hydrogen peroxide was added into the mixing tank and the cover replaced. The composition was recirculated for two hours after all chemicals were added.
After two hours, the recirculating pump was stopped. The concentrate was dispensed into clean 55 gallon drums for storage and equilibrated for 19 days. After 19 days from the production date, a sample was taken from the concentrate batch and the concentration was determined to be 22.5~ H2O2, 3.96~ peracetic acid, and 8.1~ acetic acid.
Microbicidal Effectiveness A 3.0~ solution of the concentrate microbicide manufacture in Example 1 was tested for sporicidal activity according to the methods outlined in the Official Methods of Analysis of the Association of Official Analytical Chemists (K. Helrich 15th ed. 1990) (966.04 pp. 141-142).
Briefly, cultures of two sporoformer organisms, Bacillus subtilis ATCC 19659 and Clostridium sporogenes ATCC 3584 were grown in the appropriate medium. Each organism was used to contaminate two types of carriers, namely, silk suture and porcelain penicylinders. The carriers were dried for a minimum of 24 hrs. under vacuum.
Carriers were tested for acid resistance and viability.
Five carriers were placed in test tubes containing 10mL. of test solution, and exposed for 30 min. at 50~C. Following contact, carriers were neutralized in thioglycollate medium and incubated for 21 days at 37~C. If no growth was observed after 21 days, the test tubes were heat shocked for 20 minutes at 80~C to activate any remaining spores and incubated for 72 hrs. at 37~C. For chemical sterilant claims, no survival of any organism/spore can be tolerated for qualification of the solution by the U.S. Environmental Protection Agency as a sterilant. The results of the sporicidal testing of the concentrate microbicide in accordance with the microbicide prepared in Example 1 are as follows:
.
A~
WO93/01822 ~ 1 ~ 3 3 6 0 PCT/~S92/0~877 1 - Lot Org. Carrier TiterResistance #Survivors/
2 #Tested 3 2M004 Cl.sp. Suture 10-6 20 min. 0/60 4 2M004 Cl.sp. Cylinder 10-5 5 min. 0/60 2M004 B. sub.suture 10-4 20 min. 0/60 6 2M004 Ei. sub.Cylinder 10-4 2 min. 0/60 8 The results of the AOAC procedure reference test shows that 9 the microbicide of the invention, in addition to being stable, is effective as a sterilant.
11 Corrosivity of the solution of Example 1 was tested.
12 The results appear as Sample 15 in Table IIA.
14 ~x~mnle 2 All mixing drums and tanks were thoroughly cleaned 16 using purified water. 23.3% by weight of purified water was 1, added to a cleaned mixing tank at ambient temperature.
18 Bacterial testing and yeast and molds testing of the water used 19 in manufacturing the concentrate was reported as 0 colony forming units per five milliliters of sample for both tests. An 21 air driven drum pump was turned on to start recirculation of the 22 batch. 16.7% by weight of acetic acid was added to the mixing 23 tank containing the purified water. After the acetic acid was 24 added, the batch was covered and recirculated for one hour.
Using an air driven drum pump, 40.0% by weight of hydrogen 26 peroxide was added into the mixing tank and the cover replaced.
27 The composition was recirculated for two hours after all 28 chemicals were added. After two hours, the recirculating pump 29 was stopped. The concentrate was dispensed into clean 55 gallon drums for storage. After 19 days from the production date, the 31 batch was adjusted to a hydrogen peroxide level of 36.5% and a 32 peracetic acid level of 4.5% by adding water and hydrogen 33 peroxide. The solution was allowed to equilibrate for an 34 additional 33 days. A sample was taken from the concentrate batch and the concentration was determined to be 36.65~ hydrogen 36 peroxide, 4.31% peracetic acid and 2.88%.
1 The results of the sporicidal testing of a 3% solutlon 2 of the concentrate microbicide in accordance with the 3 microbicide prepared in Example 2 are as follows:
4 Lot Org. Carrier Titer Resistance #Survivors/
#Tested 6 2008-2a Cl.sp. Suture 10-6 20 min. 0/60 7 2008-2a Cl.sp. Cylinder 10-6 10 min. 0/60 8 2008-2a B. sub.suture 10-4 10 min. 0/60 9 2008-2a B. sub.Cylinder 10-4 2 min. 0/60 11 The concentrate prepared in accordance with Example 2 12 was tested for corrosivity. The results are shown in Table IIA
13 as Sample 2.
14 F.x~rr~le 3 Using the method set forth in Examples 1 and 2, 7.74%
16 by weight purified water was added to 17.12% by weight H2O2 and 17 8.143% by weight HOAc. Bacterial testing and yeast and molds 18 testing of the water used in manufacturing the concentrate was 19 reported as 0 colony forming units per five milliliters of sample for both tests. After mixing for the specified time 21 periods, the concentrate was allowed to stand for 19 days and a 22 sample was taken to determine the content of H2O~ and HOOAc.
23 The final concentration was determined to be 16.86% by weight 24 H2~2~ 1- 66% peracetic acid and 6.26% acetic. The solution was found to have microbicidal activity as follows:
26 Lot Org. Carrier Titer Resistance #Survivors/
27 #Tested 28 2028-1 Cl.sp. Sueure 10-5 10 min. 0/60 29 2028-1 Cl.sp. Cylinder 10-6 10 min. 0/60 2028-1 B. sub.suture 10-4 10 min. 0/60 31 2028-1 B. sub.Cylinder 10-q 2 min. 0/60 33 Corrosivity was tested and the results are detailed in 34 Table IIA as Sample 18.
While the preceding compositions in accordance with 36 the invention are the preferred form it is to be understood that 37 concentrate formulations may be within the ranges given and WO93/01822 ~ 1 133 6 0 PCT/US92/05877 1 still provide the advantages of the invention. Those skilled in 2 the art may recognize other equivalents to the specific 3 embodiments described herein which equivalents are intended to 4 be encompassed by the appended claims.
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A stable, anticorrosive to surgical and dental metals concentrate consisting essentially of at equilibrium peracetic acid, acetic acid, hydrogen peroxide and an aqueous diluent, said concentrate characterized in having from about .001-200 ppm of stabilizers wherein said stabilizers are selected from the group consisting of phosphonic acids and sodium pyrophosphates, from about .001-10 ppm of divalent and trivalent ions wherein said divalent and trivalent ions are selected from the groups consisting of iron, manganese, magnesium, nickel and cobalt and no added surfactants.
2. The concentrate in accordance with Claim 1 wherein the concentration of added stabilizer is from about .001-100 ppm.
3. The concentrate in accordance with Claim 1 wherein the concentration of added stabilizer is from about .001-10 ppm.
4. The concentrate of Claim 1 wherein the equilibrium composition comprises:
a) H2O2 16 to 38% by weight;
b) HOAc 2.5 to 9.0% by weight;
c) HOOAc 1.5 to 6.0% by weight; and d) the balance is a purified aqueous diluent.
a) H2O2 16 to 38% by weight;
b) HOAc 2.5 to 9.0% by weight;
c) HOOAc 1.5 to 6.0% by weight; and d) the balance is a purified aqueous diluent.
5. The concentrate in accordance with Claim 4 wherein the concentration of added stabilizer is from about .001-100 ppm.
6. The concentrate in accordance with Claim 4 wherein the concentration of added stabilizer is from about .001-10 ppm.
7. The concentrate in accordance with Claim 1 wherein the equilibrium concentration comprises:
a) H2O2 23 to 24% by weight;
b) HOAc 9 to 10% by weight;
c) HOOAc 4 to 6% by weight; and d) the balance is a purified aqueous diluent.
a) H2O2 23 to 24% by weight;
b) HOAc 9 to 10% by weight;
c) HOOAc 4 to 6% by weight; and d) the balance is a purified aqueous diluent.
8. The concentrate in accordance with Claim 7 wherein the concentration of added stabilizer is from about .001-100 ppm.
9. The concentrate in accordance with Claim 7 wherein the concentration of added stabilizer is from about .001-10 ppm.
10. A method of formulating a stable, anticorrosive to surgical and dental metals concentrate microbicide comprising the steps of:
a) blending hydrogen peroxide, acetic acid and a purified aqueous diluent to result in a solution which at equilibrium has from about .001-200 ppm stabilizers wherein said stabilizers are selected from the group consisting of phosphonic acids and sodium pyrophosphates, from about .001-10 ppm of divalent and trivalent ions wherein said divalent and trivalent ions are selected from the groups consisting of iron, manganese, magnesium, nickel and cobalt and no added surfactants.
a) blending hydrogen peroxide, acetic acid and a purified aqueous diluent to result in a solution which at equilibrium has from about .001-200 ppm stabilizers wherein said stabilizers are selected from the group consisting of phosphonic acids and sodium pyrophosphates, from about .001-10 ppm of divalent and trivalent ions wherein said divalent and trivalent ions are selected from the groups consisting of iron, manganese, magnesium, nickel and cobalt and no added surfactants.
11. A method of formulating a stable, anticorrosive to surgical and dental metals concentrate microbicide comprising the steps of:
a) introducing from about 17% by weight to about 40%
by weight hydrogen peroxide into a mixing drum, said hydrogen peroxide is characterized in having from about .001 to 200 ppm of stabilizers wherein said stabilizers are selected from the group consisting of phosphonic acids and sodium pyrophosphates;
b) blending thereinto from about 10% by weight to about 16% by weight acetic acid; and c) adding a purified aqueous diluent having from about .001-10 ppm of divalent and trivalent ions wherein said divalent and trivalent ions are selected from the groups consisting of iron, manganese, magnesium, nickel and cobalt;
wherein the equilibrium concentration comprises:
i) from about 16-38% by weight hydrogen peroxide;
ii) from about 2.5-9% by weight acetic acid;
iii) from about 1.5-6.0% by weight peracetic acid; and iv) an aqueous diluent wherein said equilibrium concentration is characterized in having from about .001-200 ppm of stabilizers wherein said stabilizers are selected from the group consisting of phosphonic acids and sodium pyrophosphates, from about .001-10 ppm of divalent and trivalent ions wherein said divalent and trivalent ions are selected from the group consisting of iron, manganese, magnesium, nickel and cobalt and no added surfactants.
a) introducing from about 17% by weight to about 40%
by weight hydrogen peroxide into a mixing drum, said hydrogen peroxide is characterized in having from about .001 to 200 ppm of stabilizers wherein said stabilizers are selected from the group consisting of phosphonic acids and sodium pyrophosphates;
b) blending thereinto from about 10% by weight to about 16% by weight acetic acid; and c) adding a purified aqueous diluent having from about .001-10 ppm of divalent and trivalent ions wherein said divalent and trivalent ions are selected from the groups consisting of iron, manganese, magnesium, nickel and cobalt;
wherein the equilibrium concentration comprises:
i) from about 16-38% by weight hydrogen peroxide;
ii) from about 2.5-9% by weight acetic acid;
iii) from about 1.5-6.0% by weight peracetic acid; and iv) an aqueous diluent wherein said equilibrium concentration is characterized in having from about .001-200 ppm of stabilizers wherein said stabilizers are selected from the group consisting of phosphonic acids and sodium pyrophosphates, from about .001-10 ppm of divalent and trivalent ions wherein said divalent and trivalent ions are selected from the group consisting of iron, manganese, magnesium, nickel and cobalt and no added surfactants.
12. A stable, anticorrosive to surgical and dental metals use-dilution microbicide comprising:
a) a concentrate consisting essentially of at equilibrium peracetic acid, acetic acid, hydrogen peroxide and an aqueous diluent, said concentrate characterized in having from about .001-200 ppm of stabilizers wherein said stabilizers are selected from the group consisting of phosphonic acids and sodium pyrophosphates, from about .001-10 ppm of divalent and trivalent ions wherein said divalent and trivalent ions are selected from the group consisting of iron, manganese, magnesium, nickel and cobalt and no added surfactants; and b) a purified aqueous diluent;
wherein said concentrate is diluted in said aqueous diluent from about 20 to 40 times.
a) a concentrate consisting essentially of at equilibrium peracetic acid, acetic acid, hydrogen peroxide and an aqueous diluent, said concentrate characterized in having from about .001-200 ppm of stabilizers wherein said stabilizers are selected from the group consisting of phosphonic acids and sodium pyrophosphates, from about .001-10 ppm of divalent and trivalent ions wherein said divalent and trivalent ions are selected from the group consisting of iron, manganese, magnesium, nickel and cobalt and no added surfactants; and b) a purified aqueous diluent;
wherein said concentrate is diluted in said aqueous diluent from about 20 to 40 times.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| WOPCT/US91/04979 | 1991-07-15 | ||
| US9104979 | 1991-07-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2113360A1 CA2113360A1 (en) | 1993-02-04 |
| CA2113360C true CA2113360C (en) | 1998-05-26 |
Family
ID=22225675
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002113360A Expired - Fee Related CA2113360C (en) | 1991-07-15 | 1992-07-14 | Stable, anti-corrosive peracetic/peroxide sterilant |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5508046A (en) |
| EP (1) | EP0649310B1 (en) |
| JP (1) | JP2523085B2 (en) |
| AT (1) | ATE199058T1 (en) |
| AU (1) | AU661862B2 (en) |
| BR (1) | BR9206266A (en) |
| CA (1) | CA2113360C (en) |
| DE (1) | DE69231686T2 (en) |
| DK (1) | DK0649310T3 (en) |
| ES (1) | ES2155824T3 (en) |
| GR (1) | GR3035654T3 (en) |
| RU (1) | RU2127607C1 (en) |
| WO (1) | WO1993001822A1 (en) |
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-
1992
- 1992-07-14 RU RU94019997A patent/RU2127607C1/en active
- 1992-07-14 US US08/162,065 patent/US5508046A/en not_active Expired - Lifetime
- 1992-07-14 ES ES92916914T patent/ES2155824T3/en not_active Expired - Lifetime
- 1992-07-14 BR BR9206266A patent/BR9206266A/en not_active IP Right Cessation
- 1992-07-14 DK DK92916914T patent/DK0649310T3/en active
- 1992-07-14 EP EP92916914A patent/EP0649310B1/en not_active Expired - Lifetime
- 1992-07-14 AT AT92916914T patent/ATE199058T1/en not_active IP Right Cessation
- 1992-07-14 WO PCT/US1992/005877 patent/WO1993001822A1/en active IP Right Grant
- 1992-07-14 AU AU24100/92A patent/AU661862B2/en not_active Ceased
- 1992-07-14 CA CA002113360A patent/CA2113360C/en not_active Expired - Fee Related
- 1992-07-14 DE DE69231686T patent/DE69231686T2/en not_active Expired - Fee Related
- 1992-07-14 JP JP5502905A patent/JP2523085B2/en not_active Expired - Lifetime
-
2001
- 2001-03-29 GR GR20010400504T patent/GR3035654T3/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| GR3035654T3 (en) | 2001-06-29 |
| EP0649310B1 (en) | 2001-02-07 |
| RU2127607C1 (en) | 1999-03-20 |
| DE69231686T2 (en) | 2001-08-30 |
| EP0649310A4 (en) | 1994-04-06 |
| ATE199058T1 (en) | 2001-02-15 |
| ES2155824T3 (en) | 2001-06-01 |
| EP0649310A1 (en) | 1995-04-26 |
| US5508046A (en) | 1996-04-16 |
| WO1993001822A1 (en) | 1993-02-04 |
| AU661862B2 (en) | 1995-08-10 |
| JP2523085B2 (en) | 1996-08-07 |
| CA2113360A1 (en) | 1993-02-04 |
| BR9206266A (en) | 1995-04-25 |
| DE69231686D1 (en) | 2001-03-15 |
| DK0649310T3 (en) | 2001-06-18 |
| JPH06508636A (en) | 1994-09-29 |
| AU2410092A (en) | 1993-02-23 |
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