CA2247289C - Quick acting chemical sterilant - Google Patents
Quick acting chemical sterilant Download PDFInfo
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- CA2247289C CA2247289C CA002247289A CA2247289A CA2247289C CA 2247289 C CA2247289 C CA 2247289C CA 002247289 A CA002247289 A CA 002247289A CA 2247289 A CA2247289 A CA 2247289A CA 2247289 C CA2247289 C CA 2247289C
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- peroxide
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- 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
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- 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
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/30—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests characterised by the surfactants
Abstract
A low odor, aqueous, quick acting room temperature disinfectant slution primarily useful for medical instruments to disinfect within a half hour or less. The composition comprises a reacting or synergistic combination of hydrogen peroxide and from about 1 % to 30 % by weight of a water soluble organic acid or salt form thereof with the acid preferably being selected from the group consisting of malonic and succinic acids.
Description
W O 97128691 PCTrUS97/02183 TITLE: QUICK ACTING CHEMICAL STERILANT
~ACKGROUND OF T~E lNVENTION
Medical, dental and other instruments are often made of high quality stainless steel that can be cleaned and sterilized between uses for different patients by high temperature steam under pressure. This sterilization procedure is quick, reliable, odorless, non-toxic and inexpensive. In contrast to thi~ situation, more and more instruments are now made of heat-~ensitive plastic, rubber, glass lenses and electronic components. The~e flexible, flexible-lensed, and rigid-len~ed instruments allow relatively non-invaL~ive diagnostic and treatment procedure~
within the body. I'he non-invasive procedures allowed by the~e heat-sensitive in~truments are re~ponsible for great advances in medical practice. During use, these instruments can be contaminatedl with deadly pathogens such as the Human Immunodeficiency Virus (HIV), hepatitis viruses, and antibiotic drug-reEistant tuberculosis and other bacteria.
~or these reasons, it is imperative that the~e heat-~ensitive instruments be sterilized of all microbes prior to each use.
The chemical germicides available for sterilization of heat-sensitive instrument~ have in the past had many problems that made their use difficult.
~ACKGROUND OF T~E lNVENTION
Medical, dental and other instruments are often made of high quality stainless steel that can be cleaned and sterilized between uses for different patients by high temperature steam under pressure. This sterilization procedure is quick, reliable, odorless, non-toxic and inexpensive. In contrast to thi~ situation, more and more instruments are now made of heat-~ensitive plastic, rubber, glass lenses and electronic components. The~e flexible, flexible-lensed, and rigid-len~ed instruments allow relatively non-invaL~ive diagnostic and treatment procedure~
within the body. I'he non-invasive procedures allowed by the~e heat-sensitive in~truments are re~ponsible for great advances in medical practice. During use, these instruments can be contaminatedl with deadly pathogens such as the Human Immunodeficiency Virus (HIV), hepatitis viruses, and antibiotic drug-reEistant tuberculosis and other bacteria.
~or these reasons, it is imperative that the~e heat-~ensitive instruments be sterilized of all microbes prior to each use.
The chemical germicides available for sterilization of heat-sensitive instrument~ have in the past had many problems that made their use difficult.
2~ The antimicrok~ial properties of hydrogen peroxide have ~een known for many years. However~ 6% hydrogen peroxide re~uires a minimum of 6 hours at room temperature to pass the standard Association of Official Analytical Chemists (AOAC) Sporicidal Test. I'his is the test that defines "~terilant"
for liquid chemical germicides in the United States. The antimicrobial properties of peracetic acid are also well known. Peracetic acid has a very sharp pungent odor, and is known as a tumor-promoting agent when tested on mouse skin.
For these reasons, the use of peracetic acid as a chemical sterilant is limited to low concentrations used with enclosed systems.
Antimicrobial synergism between hydrogen peroxide and peracetic acid is ~ well established fact. Such compositions are prepared by mixing hydrogen peroxide and acetic acid to give equilibrated ~olution~ of hydrogen peroxide, acetic acid, and peracetic acid. There is a great deal of scientific and patent litersture reqarding hydrogen peroxide-peracetic acid ~olution~ for sterilization. By way of example only, Minntech Corporation of Minneapolis, Minnesota, has a kit or sterilization console for disinfecting with lo hydrogen peroxide-peracetic acid ~olution~ (U.S. Patent 5,400,8~8). However, thi~ com~ination is limited by the same problems of pungent odor and potential toxicity ac peracetic acid ~lone. Thi~ often mean~ that ~uch formulation~ are used at such dilute conc:entrations that rapid ~poricidal activity l~ is lo~t, or the solution~ are limited to enclo~ed ~ystem~
that contain the pungent fumes.
Steris Corporation of Mentor, Ohio, markets a Steris System 1 product. Thi~ uses a low concentration of peracetic acid (about 0.2%) c:ontained within a machine, and is heated to 122~F to achieve rapid sterilization. The relatively low peracetic acid concentration, coupled with the high te~perature, break~ down the peracetic acid, limiting it to one single use cycle. The heated, enclosed, single-use machine ~ystem is expensive and le~s than desirable.
Another chemical sterilant is 2% alkaline glutaraldehyde. G]utaraldehyde req~ires about 10 hours at 25~C to pa~s the AOAC Sporicidal Te~t. Because of this long exposure time, the use of glutaraldehyde is usually compromised to accept disinfection from a shorter exposure time rather than the safer condition of sterilization.
Furthermore, glutaraldehyde has an odor that irritates eye, nose, and throat mucous membranes. Repeated exposure to glutaraldehyde cau~es headaches and allergic reactions for some people. For these reasons, glutaraldehyde is a less than desirab~e chemical germicide.
Many chemicals that contain ch~orine are rapidly sporicidal and capable of sterilization. ~xamples are bleach, the active agent of which is HOC1, HC102, C102, and HCl. However, while these chemicals are rapidly sporicidal, they are too corrosive to metals and elastomers to find any practical use in sterilization of medical, dental and other instruments.
It can therefore be seen that there is a continuing need for an effective, practical, safe, affordable sterilant for heat-sensitive instruments, as well as for all applications that are beyond the ~cope of steam sterilization. This lo invention has as its primary objective the fulfillment of this need.
SUMMARY OF THE INVENTION
This invention relates to a rapid acting room temperature sterilant. It is a low odor, aqueous disinfecting solution having a pH wi.thin the range of 2-6.
I~ comprises in combination a solution of from about 1% to about 30% by weight of peroxide capable of releasing hydroxyl free radicals, and from about 1% to about 30% by weight of a water soluble organic acid or salt ~orm of a C3 or higher mono, or a di-, tri-, or poly carboxylic organic acid, with the organic acid preferably selectect from the group consisting of malon.ic acid and succinic acid, or combinations thereof. It is believed there may be a reaction between the peroxide and carboxylic acids that produce a third chemical or condition that causes rapid kill of bacterial spores and other microbes at a.mbient temperatures (18~C-24~C) in short time~ (i.e. within 30 minutes). The carboxylic acids that can be used with peroxides can be selected from a large group to be relatively odor-free, non-toxic, soluble and inexpensive.
DETAILED DESCRIPTION OF THE l~.v~N-LION
The sterilizin.g and disinfecting solutions of this invention have a variety of uses. The solutions have excellent sterilization and disinfecting properties and can be used to ~teriliz:e sophisticated medical instruments such W O 97J28691 PCTAUS97tO2183 as endoscopes without causing damage to sensitive parts of such instruments.
The fact that this process can be used with endoscopic instruments is significant since ~elatively non-invasive endoscopic procedures have revolutionized the way that surgery is performed. As earlier mentioned, few rigid or flexible endo~copes can be sterilized by the quick and sure method of steam sterilization because the plastic, rubber and precisely-positioned glass lenses of lo endoscopes make them incompatible with the heat of a steam sterilizer. Instead they must be sterilized using lower temperatures and typically slower processes. They also must use a sterilizing solution that is non-corrosive.
Endoscope~ are but one example of the type of instrument that can be effect:ively sterilized with the present compositions. Conventional surgical instruments of all types, microsurgery instrument sets, anesthesia equipment, etc. can al~o be treated. Generally, the composition disclosed herein can be used for sterilization of any product~ that enter sterile tissue or the vascular system or have tissue contact during any surgeries. Necessarily, if the solution is effective for the~e critical medical instruments, it also can be used for intermediate level and low level instruments and surfaces. Because the formulation is relatively odorLe~ and non-toxic, one can sterilize surfaces that formerly were only disinfected or sanitized, or one can dilute the formula for disinfection rather than sterilization. The composition may also be used as an antiseptic to kill germs on skin. It is therefore versatile in u~e.
It had previously ~een thought that effectiveness of hydrogen peroxide and peracetic acid combinations to pa~s stAn~Ard "AOAC" sterilization tests was due to the substantial e~hAncement of formation of free hydroxy radicals from the "per" acid in combination with hydrogen peroxide.
Accordingly, it was thought necessary to add peroxyacetic acid directly to germicidal formulations. Quite W 097~28691 PCTrUS97/02183 surprisingly, the :inventors found that it was not neceRsary to add the toxic and malodorous peracetic acid to sterilizing formu~ations. Instead, certain lower carboxylic acids selected for their solubility, lack of odor, and non-toxic nature can be used in combination with hydrogen peroxide to achieve sterility at ambient temperature~ and short exposure times. In particu:Lar, the carboxylic acid could be a C3 or higher mono or a di- or poly carboxylic acid of up to Cl2 chain length and c;ln be saturated or unsaturated. A~ a lo result of this composition, complex and expensive equipment needed to contain toxic chemicals can be eliminated, and ~ince the acid~ employed are weak organic acids, corrosion of materials is signiEicantly reduced. As a result, providing the levels herein described are used, there is a reacting or synergistic relationship between the defined water soluble organic acid and the peroxide such that even at lower temperature~ non-corrosive sterilization is achieved.
Moreover, the che~icals are generally inexpensive and odor-free, and are therefore economically and simply packaged. Of course, le~s odor ;~nd less toxic mean that higher concentration can be u~ed with accompanying fa~ter rate of sterilization. At higher exposure temperatures of 30, 40, or 50~C, for exampLe, the exposure time needed to achieve sterilization is even faster than at ambient temperatures.
The first component of the composition is from about 1%
to about 30% by we:ight of a peroxide. Prefera~ly, the amount of peroxide is from about 1% by weight to about 12~ by weight of the disinfecting solution, and most preferably from about 6% by weight to about 10% by weight of the disinfecting ~0 solution. The pre:Eerable concentration of peroxide may be varied depending O]l the application from lower concentration for an antiseptic to higher concentration~ for a low-temperature, rapid--acting sterilant. The peroxide of choice is, of course, the most commonly available peroxide, hydrogen ~5 peroxide. However, the invention is not limited to hydrogen peroxide, and other peroxy compounds may be employed. These include, for example, perborates, saturated and unsaturated W O 97J28691 PCT~US97/02183 peralkanoic acids such as peracetic acid, performic acid, perpropionic acid, etc. The critical factor is that it be a water soluble peroxide compound that: is compatible with the weak carboxylic acid component.
s The weak carboxylic acid component of the present invention is preferably a di- acid of lower C12 or less carbon length carboxylic acid preferably selected from the group consisting of malonic acid ancl succinic acid. Also, examples of acids in this class would be malic, oxalic and lo tartaric acids. These acids, when in the proper concentrations, are low odor, reasonably soluble and non-corrosive. The amount of the carboxylic acid component generally would be within the range of from about 1.0% by weight to 30~ by weight of 6terilizing or disinfecting solution, preferably from about 1% by weight to about 12% by weight of the solution, and most preferably from about 3~ by weight to about 6% by weight of the solution composition. AB
with the peroxide, the preferred concentration of carboxylic acids is related to the intended end use.
~o Generally speaking, and as a guideline, the peroxide component should have a concentration of within the range of 0.2M to about lOM, preferably within the range of 0.2M to 4.OM. The organic acid component should have a concentration within the range of 0.05M to 4.OM, and preferably of 0.05M to 2.OM.
While acetic acid is unacceptable by itself because of its normal pungent odor, it i8 possible that some acetic acid, in combination with other of the acids described here, can be successfully used. Thus the key to the present invention i8 the pre~ence of the herein-described combination or perhaps the reaction product thereof.
Generally, the amount of peroxide component and the amount of carboxylic acid component are balanced such that the pH will be within the range of about 2.0 to 6.0, preferably a~out 3.0 to 5Ø
While a suitable sterilizing and disinfecting solution can be achieved with these two components only, as is W O 97128691 rCTAUS97102183 understood by those skilled in the art, other ingredients may be added. In fact, the sterilizing and disinfecting ca~abilities can be enhanced by adding a small amount of detergent such as nonionic or anionic detergent. The amount of detergent can be within the range of from about 0.05% by weight to about 1.0% by weight, preferably from about 0.1% by weight to about 0.5~ by weight. The amount of detergent should be enough to enhance the sterilization and disinfection, but less than the amcunt which would provide substantial sudsing.
Suitable ~ynthetic detergents are well known to those of ordinary skill in the art, but generally these surface active agents can be selected from the group consisting of anionic and nonionic surfactants. Non-ionic, ether-linked surfactants such as Laureth~4 or Laureth~23 are preferred.
Alkyl sulfate surfactants are a type of anionic surfactant of impoctance for use herein. Alkyl sulfates have the general formula ROSO3M wherein R preferably is a Cl0-C24 hydrocarbyl, preferably an alkyl or-hydroxyalkyl having a Clo-C20 alkyl component, more preferably a C12-Clg alkyl or hydroxyalkyl, and M i8 H or a cation, e.g., an alkali metal cation te.g., sodium, potassium, lithium), substituted or unsubstituted ammonium cations such as methyl-, dimethyl-, and trimethyl ammonium and quaternary ammonium cations, e.g., tetramethylammonium and dimethyl piperdinium, and cations derived from alkanolamines such as ethanolamine, diethanolamine, triethanolamlne, and mixtures thereof, and the like. Typically, alkyl chains of C12_16 are preferred for lower wash temperatures (e.g., below about S0~C) and C16_ 18 alkyl chains are preferred for higher wash temperatures (e.g., above about 50~C).
Alkyl alkoxylated sulfate surfactants are another category of useful anionic eurfactant. These surfactants are water ~oluble ~alts or acids typically of the formula RO~A)mSO3M wherein R is an unsubstituted Clo-C24 alkyl or hydroxyalkyl group having a Clo-C24 alkyl component, preferably a Cl2-C20 alkyl or hydroxyalkyl, more preferably C12-Clg alkyl or hydroxyalkyl, A is an ethoxy or propoxy unit, m is greater than zero, typically between about 0.5 and about 6, more preferably between about O.5 and about 3, and M
is H or a cation which can be, for examp~e, a metal cation s (e.g., sodium, potassium, lithium, calcium, magnesium, etc.), ammonium or substituted-ammonium cation. Alkyl ethoxylated sulfates as well as alkyl propoxylated sulfates are contemplated herein. Specific exa~ples of substituted ammonium cations include methyl-, dimethyl-, trimethyl-ammonium and quaternary ammonium cations, such astetramethyl-ammonium, dimethyl piperydinium and cations derived from alkanolamines, e.g., monoethanolamine, diethanolamine, and triethanolamine, and mixtures thereof.
Exemplary surfactants are C12-Clg alkyl polyethoxylate (1.0) 1~ sulfate, C12-C18 alkyl polyethoxylate (2.25) sulfate, C12-C18 alkyl polyethoxylate (3.0) sulfate, and C12-Clg alkyl polyethoxylate ~4.0~ sulfate wherein M is conveniently selected from sodium and pota-sium.
Other anionic surfactant~ u~eful for detersi~e purposes can also be included in the compositionY hereof. The~e can include salts ~including, for example, sodium, pota~sium, ammonium, and substituted ammonium salts such as mono-, di-and triethanolamine ~alts) of soap, Cg-C20 linear alkylbenzenesulphonates, Cg-C22 primary or secondary alkanesulphonates, Cg-C24 olefinsulphonates, sulphonated polycarboxylic acids, alkyl glycerol sulfonates, fatty acyl glycerol sulfonates, fatty oleyl glycerol sulfates, alkyl phenol ethylene oxide ether sulfates, paraffin sulfonates, alkyl phosphates, isothionates such as the acyl isothionates, ~-acyl taurates, fatty acid amides of methyl tauride, alkyl ~ccinamates and sulfosuccinates, monoesters of sulfosuccinate (especially saturated and unsaturated C12-Clg monoesters) diesters of sulfosuccinate (e~pecially saturated and unsaturated C6-C14 die~ters), N-acyl sarcosinates, 3S sulfates of alkylpolysaccharides such as the sulfates of alkylpolyglucos}de, branched primary alkyl sulfates, alkyl polyethoxy carboxylates such as those of the formula CA 02247289 l998-08-06 W O97/28691 PCTrUS97/02183 RO(CH2CH20)~CH2COO-M+ wherein R i~ a Cg-C22 ~lkyl, k is an integer from O to 10, and M i~ a ~oluble salt-forming cation, and fatty acids e~terified with iset.hionic acid and neutralized with sodium hydroxide. Further examples are given in Surface Active Agents and Detergents (Vol. I and II
~y Schwartz, Perry and Berch).
Suitable nonionic detergent suI-factants are generally disclosed in U.S. Pat. 3,929,678, Laughlin et al., issued Dec. 30, 1975, at column 13, line 14 through column 16, line 6, incorporated herein by reference. Exemplary, non-limiting classe~ of useful nonionic ~urfactants are listed ~elow.
The polyethylene, polypropylene, and polybutylene oxide condensates of alkyl phenols. In general, the polyethylene oxide condensates are preferred. These compounds include the condensation products of alkyl phenols having an alkyl group cont~ining from about 6 to about 12 carbon atoms in either a straight chain or branched chain configuration with the alkaline oxide. These compounds are commonly referred to as alkyl phenol alkoxylates, (e.g., alkyl phenol ethoxylates).
The conden~ation products of aliphatic alcohols with from about 1 to about 25 moles of ethylene oxide. The alkyl chain of the aliphatic alcohol can either be straight or branches, primary or secondary, and generally contains from a~out 8 to a~out 22 carbon atoms. Particularly preferred are the condensation products of alcohols having an alkyl group contA;ning from about 10 to about 20 carbon atoms with from about 2 to about 18 moles of ethylene oxide per mole of alcohol.
The conden~ation products of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol. Examples of compounds of this type include certain of the commercially-available Pluronic TM sur~actants, mar~eted by BASF.
The condensation products of ethylene oxide with the product resulting from the reaction of propylene oxide and ethylene~; ~mi ne. Examples of this type of nonionic W O 97/28691 PCT~US97/02183 surfactant include certain of the commercially available Tetronic TM compounds, marketed by BASF.
Semi-polar nonionic surfactants are a special category of nonionic surfactants which include water-soluble amine oxides containing one alkyl moiety of from about 10 to about 18 carbon atoms an~ 2 moieties selected ~rom the group consisting of alkyl groups and hydroxyalkyl groups containing from about 1 to about 3 car~on atoms; water-soluble pho~phine oxides containing one alkyl moiety of from about 10 to about lo 18 carbon atoms an~ 2 moieties selected from the group consisting o~ alkyl groups and hydroxyalkyl groups contAining from about 1 to about 3 carbon atoms; and water-soluble sulfoxides containing one alkyl moiety of from about 10 to about 18 carbon atoms 31 and a moiety selected from the group consisting of alkyl and hydroxyalkyl moieties of from about 1 to about 3 carbon atoms.
Semi-polar nonionic detergent surfactants include the amine oxide surfactants having the formula R3(oR4)XN(R5)2 ~ 3 wherein R3 is an alkyl, hydroxyalkyl, or alkyl phenyl group or mixtures thereof cont~in;ng from about 8 to about 22 carbon atom~; R4 is an alkylene or hydroxyalkylene group containing from about 2 to about 3 carbon atoms or mixtures thereof; x is from 0 to about 3; and each R5 is an alkyl or hydroxyalkyl group cont~ining from about 1 to about 3 carbon atoms or a polyethylene oxide group ContA; ni ng from about 1 to a~out 3 ethylene oxide groups. The R5 groups can be attached to each other, e.g., through an oxygen or nitrogen atom, to form a ring structure.
These amine oxide surfactants in particular include C10-Clg alkyl dimethyl amine oxides and Cg-C12 alkoxy ethyl dihydroxy ethyl amine oxides.
Alkylpolysaccharides disclosed in U.S. Pat. 4,565,647, Llenado, issued Jan. 21, 1986, having a hydrophobic group containing from about 6 to about 30 carbon atoms, preferably CA 02247289 l998-08-06 from about 10 to about 16 carbon atoms and a polysaccharide, e.g., a polyglycoside, hydrophilic group containing from about 1.3 to about 10, preferably from about 1.3 to about 3, most preferably from about 1.3 to about 2.7 saccharide units.
Any reducing saccharide cont~i n i ng ~ or 6 carbon atoms can be used, e.g., glucose, galactose and galactosyl moieties can be substituted for the glucosyl moieties. (Optionally the hydrophobic group is attached at the 2-, 3-, 4-, etc.
positions, thus giving a glucose or galactose as opposed to a glucoside or galact:oside~. The intersaccharide bonds can be, e.g., between the one po~ition of the additional saccharide units and the 2-, :i-, 4-, and/or 6- positions on the preceding saccharide units.
Fatty acid amide surfactants having the formula:
O
R6-C-N(R7)2 wherein R6 is an alkyl group containing from about 7 to a~out 21 (preferably from about 9 to about 17) carbon atoms and each R7 is selectecl from the group consisting of hydrogen, Cl-C4 alkyl, C1-C4 hydroxyalkyl, and -(C2H4O)XH where x varies from about 1 to about 3.
In addition tc) the above, if desired, corrosion inhibitors at very minor levels can be used, i.e. at levels of .01~ to .1~ on a weight basis. Suitable corrosion inhibitors can inc]ude those available and known, for example, complex fatty amine salts ,uch as n,n'dibutylthiourea, etc.
Nonionic ether linked surfactants are preferred such as Laureth~23 or Laureth~4.
In addition to all of the above, as is well understood by those skilled in the art, other minors can be employed to make the basic compo~ition more pharmaceutically elegant.
For example, odorants can be added at very minor levels as ~s can dyes, diluents such as alcohol, buffers, etc. With the exception of diluents such as alcohols which are used at W O 97/286gl PCT/US97102183 higher levels, t.he levels of these minors are generally not more than .001% to .01~ by weight.
The composition can be u~ed as a sterilant for medical and dental equipment, implanted medical and dental devices and appliances, can be used as a disinfectant for inanimate surfaces, can be used as an antiseptic for skin disinfection, such as for patient preoperative skin disinfection or health per~onnel, a hand wa~h, may be used as a disinfectant for contact len~es, an oral disinfectant or antiseptic, and can ~e used generally for conventional, intermediate and low level disinfection, and as a sterilant in industrial applications.
Pac~aging of the composition i, not complex. It may ~e prepackaged in dry form if desired with instructions for mixing solutions on the spot, or it may be prepackaged in so1ution form, ideally in two packages ~one the peroxide and one the organic acid component) to be mixed at point of use.
This enhances fresh~ness and accuracy of compliance with directions.
The following examples are offered to illustrate, but not limit, the process of the present invention and to demonstrate ~he surprising result that satisfactory results in comparison with acetic acid can be achieved with weaker longer chain acids such as succinic acid.
Historically, the EnvironmentaL Protection Agency regulates germicide!s in the United States, and the test for a sterilizing claim (a sterilant) by a liquid germicide is the Association of Official Analytical ~hemist~ (AOAC) Sporicidal Activity of Disinfectants Test 966.04. This test exposes spores dried onto carrier surfaces to the germicide. To make a label claim as a sterilant, a germicide must produce 720 sterile cylinders of 720 total cylinders within a specified exposure time and temperature range. A legal definition of sterilant in the United States is one that can pass this test. In the following tests peroxide composition alone was compared with an acetic acid composition alone and with sodium acetate composition with regard to ability to W O97128691 ~PCTAJS97102183 sterilize carriers labeled with spoces according to the method~ of the AOAC' Sporicidal Test.
TABLE I
Nu~ber of Positi~e (+) Cylinders per Total Number Te~ted. 30 Min. Percent sterile Formulation Expo~ure at 20~1~C. cylinderB
6% H2~2' pH 4-7 20/20 Zero 6% H2~2 +
0.5% Acetic Acid 2/20 90%
pH 2.7 0.5% Acetic Acid 20/20 Zero pH 2.8 6% H2~2 +
0.5~ sodiu~ Acetate20/20 Zero pH 6.7 0.5% Sodium Acetate20/20 Zero pN 7.7 Thi~ te~t wa~ repeated with some modifications in an attempt to 6terilize 100% of the C.sporoqenes-labeled cylinders. The re~ult~ were a~ follows.
TA~LE II
Number of Po~itive Percent Time in Min. Cylinders ~+) Per Sterile Formulation at 20~1~C Total Number Te~ted cylinders 8% H2~2 30 20/20 Zero pH 4.5 8% H2~2 + 10 9/20 55%
2% Acetic Acid 20 0~20 100%
p~ 2.4 30 0/20 100 8% H2~2 + 10 10/20 50~
1% Acetic ACid 20 8/20 60%
Ph 2.6 30 0/20 100%
8% H2~2 + 10 11/20 45*
0.5% Acetic Acid 20 9/20 55%
pH 2.7 30 0/20 100%
2% Acetic Acid 30 20/20 Zero pH 2.7 W O97/28691 PCT~US97/02183 Tests were done at ambient conditions comparing the rapid sporicidal. activity of hydrogen peroxide in combination with the carboxylic acids acetic, malonic, succinic, glutaric and citric acids. Compositions from the data are reported in Table III.
TABLE III
Sterilization of c.sporogenes-labeled porcelain cylinders by lo formulations ~f H2~2 plus acetic, malonic, or succinic acid.
Percentage of Twenty Expo~ure Time C.~porogene~--labeled Formulation Min. x 20~C Cylinders Sterilized 8% H2O2 plus 10 50%
1% acetic acid 20 80 p~ 2.5 30 lOO
8% H2~2 plU9 1 0 Zero 1% malonic acid 20 40 pH 1.8 30 85 8% H2O2 plU8 10 5%
0.5~ malonic acid 20 25 pH 1.9 30 lOO
8% H2~2 plU9 10 Zero 1% ~uccinic acid 20 15 pH 2.4 30 95 Further tests sombined H2~2 wit:h glutaric acid and citric acid. The results are shown in Table ~V and V.
W O 97128691 PCTrUS97/02183 TABLE IV
Sterilization of C.sporogenes-labeled porcelain cylinders by formulations ~f H2~2 plus acetic, qlutaric, and citric acid.
Percentage of Twenty pH Exposure Time c.sporogene~-labeled Eormulation Value Min. x 20~c cylinders sterilized 2.~ 20 10 B% H2~2 plus 30 loo 0.2M Acetic ACid 4.:3 20 100%
loo 2.. ~ 20 1o(~
20 ~ H2~2 pluR 30 loo 0.2 M Glutaric ACid 5.0 20 Zero zero 2~
1.9 20 Zero ~ H2~2 plus 30 zero 0.2M Citric 30 Acid 6.6 20 zero zero WO 97/286gl rCT/US97/02183 TABLE V
Surviving Colonies of Wet Spores of B.subtilis After Expo~ure to Formulations of H2~2 Plus Acetic Acid, &lutaric Acid, or Citric Acid.
Exposure Surviving colonie~ of pH Time A.subtili~ at Dilution Factor~
For~ulation Value Min.
x 20~ 5X101 5xlo2 5x103 5x104 5X105 ~% H2O2 plu9 15 19 1 Zero Zero 0.2 M Acetlc 2.8 30 Zero Zero Zero Acid 60 Zero Zero Zero 4.4 30 zero Zero Zero Zero Zero Zero 8% H2~2 plU9 15 CONF CONF CONF 265 70 0.2M Glutaric 2.6 30 25 13 Zero Zero Zero 5.0 15 CONF CONF CONF TNTC 101 Zero Zero Zero 8~ H202 plu9 15 CONF CONF CONF TNTC 193 0.2M Citric 2.0 30 CONF CONF CONF TNTC
CONF CONF TNTC
6.4 15 CONF CONF CONF CONF 283 CONF CONF CONF CONF
CONF CONF CONF
CONF = confluent = in exCes~ of 1000 colonies all touching together ( conf luent~.
TNTC = Too Nu~erous to Count = 300-1000 colonie~/plate.
The following example in Table VI compares the rate of kill of ~. su~tilis spores by formulations ~f ~2~2 plus acetic, malonic, o:r succinic acid. The test method was wet spore~ of ~.~u~til.is in suspension (not on carriers). This is a quantitative test that allows comparison of formulations with more precision than a qualitative (sterile or not W O97t28691 PCTAUS97/02183 TABLE VI
Formula D-value~
Number Formllla Description pH in Min.*
l. 8~ H2~2 + 0.2M (1.:2~) acetic acid, pH 2.7 7.5 2. 8~ H2O2 + 0.2M (l.:2~) acetic acid, pH 4.2 8.5 3. 8~ H2O2 + 0.2M (2.:1~) malonic acid, pH l.B ~.S
10 4. a~ H2O2 + 0.2M (2.196) malonic acid, pr~ 3.0 7.8 H2O2 + 0.2M (2.4~) succinic acid, pH 2.4 6.0 6.8~ H2O2 + 0.2M (2.4%) succinic acid, pH 4.2 9.0 *The D-values were calculated a~ the time to kill four logl0 of ~.~ubt~lis divided by four.
The general conclusion is that combinations of 8% H202 plus acetic, malonic, or succinic acid surprisingly have about the same rate of kill of B.subtills spores (wet) in 2n suspension. The more acid pH value:~ of about 2-3 were consistently killing faster than the less acid pH values of a~ove 4.
The tests shown in Tables VII and VIII measure the relationship between increasing concentrations of acetic or ~uccinic acid plus 8% H2O2 and the rate of kill of wet spores of B.s~btilis. The test using suspensions of wet spores of . subti 7 is, and measuring surviving spores as a function of exposure time to various formulations is a quantitative test that is better able to measure smal:l differences between formulations than the AOAC Sporicidal Test. All tests were at 20~1~C.
Acetic Acid:
The formulations tested with acetic acid, and D-value results were as follows:
W 0 97128691 PCT~US97/02183 TABLE VII
Formula Formula Description pH ~alue D-value Num~er 1. 8% H2~2 l.OM ~69i) Acetic ACid 4 2 le~s than 3 0.5~ BioTerge AS-40 Min.
2. 8~ H2O2 0.5M ~35~) Acetic Acid 4 2 3.5 Min.
0.5~ BioTerge AS-40 3. 8* H2~2 0.25_ (]~.5~ Acetic Acid 4.3 3.75 Min.
0.5# BioTerge AS-40 4. 8~ H2O2 0.125M 10.75%) Acetic Acid 4.3 4.0 Min.
0.5# BioTerge AS-40 ~ioTerge iB a trademarlc of Stepan Company and is a sodium olefin 2j ~ulft~nate The formulations tested with succin.ic acid, and D-value results were a~ fol.lows in Table VIII:
TABL~ VIII
FC 1 A Formula Description pH
Number Value D-value 1. 896 H202 le~s than 3 Min.
l.OM (lL.8%~ Succinic Acid 4.3 0.5~ ~ioTerge AS-40 2. 8~ ~2~2 3.5 Min.
0.5M ~5.g~) Succinic Acid 4.2 0.5% BioTerge AS-40 3. 8% H2~2 3.5 Min.
0.25M (2.95X) Succinic Acid 4.2 0.5% BioTerge AS-40 4. 8~ ~2~2 3.0 Min.
0.125M (1.47%) Succinic Acid 4.2 0.5% BioTerge AS-40 As demonstrated in Tables VII and VrII at equal molarities, and equal pH values of about 4.2, there is very little difference between acetic acid and succinic acid to enhance spore kill in combination with 8% H2~2 and BioTerge AS-40.
As one covers a range from a high of l.OM to a low of 0.125M, an eight-fold difference, the rate of spore kill changes very little from the slowest rate of about 4.0 min.
to the fastest rate of about 3.0 min. The change is consistent with l.()_ acetic or succinic acid always showing a faster spore kill t:han lesser concentrations, but it is a very small change.
8% H2~2 (2.35M) plus 1% (0.17M) acetic acid, or plus 0.2M acetic acid al; pH 2.5 (all of the acetic acid in the acid form), or pH 4.3 (about half of the acetic acid in the acid form, and half as sodium acetate) killed spores of C.sporogenes and B~,subtilis within 30 min. at 20+1~C. More B.subtilis spores were killed within 15 min. at the lower pH
~about 2.5) than a1: the higher pH (about 4.3), but complete kill happened withîn 30 min. for both pH values.
8% H2~2 plus ().5% malonic acid or 0.5~ succinic acid Malonic Acid Succinic Acid all at pH l.8 - 2.4 sterilized porcelain cylinders labeled with C.sporogenes within 30 min. at 20~1~C.
8~ H2~2 plus ().2_ glutaric acid tCOOE3-CH2-CH2-CH2-COOH) was less active than succinic acid, and more active than citric acid. 8% H2~2 plus 0.2M glutaric acid at pH 2.2 - 2.6 killed wet B.subtilis spores within 60 min. at 20~1~C, but not withLn 30 min., and sterilized C.sporogenes dried onto pGrcelain cylinders within 30 min. at 20_1~C, pH 2.2, but not at pH 5.0 (where half of the glutaric acid exists as the acid and half exists as the sodium salt).
8% H2~2 plus t).2~ citric acid, a tricarboxylic acid, COOH-CH2-COHCOOH-CE32-COOH, did not kill wet B.subtilis spores at all within 60 min. at 20_l~C either at pH 2.0 or 6.4.
Similarly, 8% H2~2 plus 0.2M citric acid at pH l.9 or 6.6 W O97~28691 PCTAUS97/02183 could not sterilize any C.sporogenes-labeled cylinders at 20+1~C.
The above tests lead to the following observations:
The initial testing was performed ~ecau~e of the similar structural chemistry between peracet:ic acid (CH3-COO0H) and acetic acid (CH3-COOH). The following formulations were tested: (1) 6~ H2O2, pH 4.7, (2) 6% H2O2 + 0-5% acetic acid, pH 2.7, (3) 6% H2O2 ~ 0.5% sodium acetate, pH 6.7, (4) 0.5%
acetic acid, pH 2.8, and (S) 0.5% sodium acetate, pH 7.7.
Unglazed porcelain cylinders labelecl with approx. 106 dry spores of Clostridium sporogenes according to the methods of the AOAC Sporicidal Test 966.04 were exposed to these above five formulations for 30 min. at 20tl~C. Of a total of 20 spore-labeled cylinders, 18 were sterilized when exposed to 6% H2~2 + 0-5% acetic acid (Formula ~2 above). None (zero) of 20 were sterilized when similarly exposed to the other formulas.
Two cylinders from a total of 20 tested were not sterilized by formula #2 above. Next tested were increased concentrations ~f H2~2 and acetic acid for ability to sterilize dry cylinders labeled with C. sporogenes. 8% H2~2 plus 2~ acetic acid sterilized within 20 min. at 20~1~C, 8%
H2O2 plus 1% acetic acid, and also 8% H2~2 plus 0.5% acetic acid sterilized within 30 min. at 20+1~C.
The above tests were then expanded to determine if other weak di- or poly carboxylic acids could act synergistically with H2~2 for rapid sporicidal activity. The dicarboxylic acids, malonic (COOH-CH2-COOH), and succinic (COOH-CH2-CH2-COOH) were tested. 8% H2~2 plus 1% acetic acid, pH 2.5, sterilized within 30 min. at 20+1~C. 8% H2~2 plus 1% malonic acid, pH 1.8, sterilized 17 cylinders out of 20 within 30 min. at 20+1~C, and 8% H2~2 plus 0.5% succinic acid pH 2.4, sterilized 19 cylinders out of 20 within 30 min. at 20+1~C.
The ~est was C.sporogenes on porcelain cylinders.
H2O2 plus the weak carboxylic acids produce a formula with acidic pH values of 2-3. However, the carboxylic acids can act as buffers by taking them up to a pH value where half W O 97t28691 PCTAUS97/02183 of the molecules are in the acid form (CH3-COOH) and half of the molecules are the conjugate base (CH3-COO-). These higher pH values ~pH 4-5) might be more compatible with materials than the lower pH values. 8% H2~2 plus 0.2 M
citric acid (a tricarboxylic acid) did not sterilize C.sporogenes-labeled cylinders at pH 1.9 or 6.6. 8% H2O2 plus 0.2 M glutaric acid (C0OH-CH2-CH~-CH2-C00H) did sterilize within 3() min. at 20+1~C at pH 2.2, but not at pH
5Ø 8% H2~2 plus 0.2 M succinic acid (COOH-CH2-CH2-COOH) sterilized within :30 min. at 20+1~C at both pH 1.8 and 3Ø
8% H2~2 plus 0. 2 M acetic acid sterilized within 30 min. at 20+1~C at both pH ;'.7 and 4.2. These studies were all against C.sporogenes-labeled cylinders.
Studies have been performed using these formulations lS against Bacillus subtilis spores both in the form of dry spores carried on porcelain cylinders, or wet spores in suspension. The results against ~. subtilis are consistent with result~ against C.sporogenes as follows: 8% H2~2 plus 0.2 M citric acid at pH 2.0 or 6.4 did not kill wet spores of B.subtilis within 60 min. at 20+1~C. 8% H2~2 plus 0.2 M
acetic acid (pH 2.7 or pH 4.2~ killed wet or dry B.subtilis within 3~ min. at 20+1~C. 8% H2~2 + 0.2 M malonic killed wet ~p~res of B.subtilis faster at pH 1.8 than at pH 3Ø 8%
H2~2 + 0.2 M SUCCilliC acid at pH 2.4 killed wet or dry spores of B. subtilis, but was less effective at pH 4.2. 8% H2~2 plus 0.2 M glutaric acid was more effective against wet spore~ of B.subtilis at pH 2.6 than at pH 5Ø The specific test results are described below.
This example compares the rate of kill of ~. subtil is spores by formulations of H2~2 plus acetic, malonic, or succinic acid. The test method utilized wet spores of B.s~ti7is in suspension (not on carriers). This is a quantitative test t;hat allows comparison of formulations with more preclsion than a qualitative (sterile or not sterile) test such as the AOAC Sporicidal Te~t. The starting number of cells of B.subtilis wa~ very hig~h at about 3.1x108 cells.
CA 02247289 l998-08-06 WO97/28691 PCT~S97/02183 It required a~out 60 min. of exposure time at 20~1~C to kill all of these cells.
The results were as follows:
TABLE IX
Formula Formula De~cription pH D-value~
Number in Min.
1. 8~ H2O2 + V.2M (1.2%) acetic acid, pH 2.7 7.5 2. 8% H2O2 + 0.2M (1.2~) acetic acid, pH 4.2 8.5 3. ~ H2O2 ~ 0.2M (2.1~) malonic acid, pH 1.8 8.5 4- 8% H2~2 + 0-2M (2-1~) malonic acid, pH 3.0 7.8 5. 8~ H2O2 + 0.2M (2.4%) ~uccinic acid, pH 2.4 6.0 1~ 6. 8~ H2O2 + 0.2M (2.4~) ~uccinic acid, pH 4.2 9.0 The D-value~ were calculated as the time to ]~ill four logl0 of ~.subtilis divided by four.
The general conclusion is that combinations of 8~ H2O2 plus acetic, malonic, or succinic acid have about the same rate of kill of B. subtilis spores Iwet) in suspension. The more acid pH values of about 2-3 were consistently killing faster than the less acid pH values of about 4.
2S Next, three formulations of 8~ H2~2 (a pH 2.00 succinic acid formulation, a pH 4.35 succinic acid formulation, and a pH 4.23 acetic acid formulation) were placed into plastic trays with loose-fitting plastic lids. Various combinations of stainless steel instruments, endoscope parts, and respiratory care equipment were soaked in the formulations for fourteen days at ambient temperature ~22+2~C). Two marketed disinfectants (2% alkaline glutaraldehyde, and 0.25%
quaternary ammonium compounds in 15% isopropanol) were also used in the study for comparison.
After fourteen days of continuous soaking in the H2O2 formulations, quality Sklarlitei stainless steel instruments appeared unchanged. Less expensive, poorly-plated instruments became mildly tarnished by the three H2~2 formulations. By comparison, the quality Skarlite~
instruments had become slightly rusted by 2% alkaline qluteraldehyde and extremely rusted by the alcohol W O 97/28691 rCT~US97/02183 disinfectant. ~ith one exception, the endoscope parts and respiratory care equipment appeared unchanged by any of the H2O2 + carboxylic acid formulations. The details of the test are reported below.
The study of t:his example was limited to visual observations of materials compatibility with the formulations as previously described. In particular, the formulations used were:
Formulation #1 8% H2~2 0.5 M Acetic Acid 0.25% Bio-Terge AS 40 detergent 0.25 M NaOH
Prepared with USP purified deionized ~2~
pH 4.23 Formulation #2 8~ H2~2 0.5 M Succinic Acid 0.25% Bio-Terge AS-40 detergent 0.5 M NaOH
Prepared with USP purified deionized H2O
- pH 4.35 Formulation #3 8~ H2~2 0.5 M Succinic Acid 0.25% ~io-Terge AS-40 detergent Prepared with USP purified deionized H2O
pH 2.00 The materials were soaked in the above test formulas or in:
O.25% quaternary ammonium chloride in 15% isopropanol, or 2% alkaline glutaraldehyde.
W O97128691 PCTrUS97/02183 The items soaked were:
Eight Cambro plastic trays with loose-fitting plastic lids;
Five Sklarlite~ stainless steel Halsted Mosq. STR 5"
Hemostats. Sklar Hospital Catalog ~23-2105. New;
Three pair of inexpensive scissors, poorly plated, but otherwise in good condition with no tarnish;
One set of respiratory care equipment:
a "Y" plastic connector a face mask an endotracheal tube a section of a blue latex breathing bag Two sets of endoscope parts, the first being:
insertion tube, bending rubber, biopsy channel, pliable ~
1/3" id connector, hard ~ 1/2" id connector, and hard ~ 1/2"
diam. càp.
The second set was an insertion tube, bending rubber, biopsy channel, hard ~ 1/2" id connector, hard ~ 1~2" diam. cap, and hard ~ 1/2" diam. cap with stainless steel opening.
All parts were new or in good condition at the start.
Two hundred ml of disinfectant and various instruments, parts, and equipment were placed into eight plastic trays.
The trays were cove!red and left at ambient temperature (22+
2~C) for fourteen days. Observations were made at various intervals throuqhout the fourteen day time. The results are reported in Table X, below.
Results:
TABLE X
Observations of Material3 Compatibility Exposure Time to Disinfectant Disinfectant In~trument Day 2 DaY -! Day 6 ~y_~ ~aY 14 2% ~lkA~ine Hemo8tatg N.C. N.C. N.C. ~light slight glutaraldehyde rust in rust in hinge hinge CA 02247289 l998-08-06 W Og7/28691 PCT~US97/02183 0.25% Hemostats N.C. 2-3 ~Nm major major major quaternary ru~t rust in rust in rust in ammonium ~pot in hinge hinge hinge chloride in hinge 15~
isopropanol Formulation #1 8% H2O2 0-5 M Hemo~1:ats N.C. N.C. N.C. N.C. N.C.
Acetic ACid 0.25% Bio- Scissors N.C. N.C. Mild Tarnish Tarnish Terge AS-40 tarnish on on 0.25M NaOH handLe handle pH = 4.23 &
hinge~ hinge~
Formulation #3 8~ H2O2 Hemostat~ N.C. N.C. N.C. N.C. N.C.
0.5 M Succinic Acid 0.25% Bio- Scissors N.C. N.C. Mild Tarnish Tarnish Terge AS-40 tarni~h on on pH = 2.00 handle handle &
hinges hinge~
Formulation #2 8% ~2~2 Hemostats N.C. N.C. N.C. N.C. N.C.
0.5 M Succinic Acid 0.25% Bio- Sci890rg N.C. slight Mild Tarnish Tarnish Terge AS-40 tarnish tarnish on on 0.5 M NaOH in handle handle pH = 4.35 hinge ~ ~
hinge~ hinges Formulation #2 8% H2~2 ~Y" N.C. N.C. N.C. N.C. N.C.
0.5 M Succinic Connector N.C. N.C. N.C. N.C. N.C.
Acid Face ~a~k 0.25% Bio- Endo- N.C. N.C. N.C. N.C. N.C.
Terge AS-40 tracheal 0.5 M NaOH Tube pH = 4.35 Breathing N.C. N.C. N C. N.C. N.C.
Tube W O 97128691 PCTrUS97/02183 Formulation #3 In~ertion N.C. N.C. N.C. N.C. N.C.
8% H2~2 Tube 0.5 M Succinic Biopsy N.C. N.C. N.C. N.C. N.C.
Acid channel 0.25% Bio- ~ending N.C. N.C. N.C. N.C. N.C.
Terge AS-40 Rubber pH = 2.00 Pliable N.C. N.C. N.C. N.C. Broke Connector into ~mall pieces Hard N.C. N.C. N.C. N.C. N.C.
Connector Hard Cap N.C. N.C. N.C. N.C. N.C.
Formulation #2 8~ H2O2 Insertion N.C. N.C. N.C. N.C. N.C.
0.5 M Succinic Tube Acid Biopsy N.C. N.C. N.C. N.C. N.C.
0.25% Bio- channel Terge AS-40 Bendi~lg N.C. N.C. N.C. N.C. N.C.
0.5 M NaOH Rubber pH = 4.35 Hard Cap N.C. N.C. N.C. N.C. N.C.
H~rd N.C. N.C. N.C. N.C. N.C.
Connector Hard Cap N.C. N.C. N.C. N.C. N.C.
with stainle~s ste~l opening N.C. = No Change As seen from data in Table X, formulations 1, 2 and 3 - did not cau~e any apparent changes to the quality Sklarlite~
instruments. The :Eormulations did cause some tarnishing of the poorly-plated :Lnstruments. The pH 2.00 8% H2O2, succinic acid formulation caused more tarnishing than the other two lo ~ormulations.
In comparison, 2% alkaline gluteraldehyde caused minor rusting of the qua:Lity Sklarlite~ hemostats, and 0.25%
quaternary ammonium chloride in 15% isopropanol caused major rusting of the Sklarlite~ hemostats.
The pH 2.00, ,B% H2O2, succinic acid formulation did cause major disintegration of one piece, the pliable endoscope connecto:r, which fell apa.rt when squeezed slightly.
It was not known w]hether this aberation was caused by the nature of the elastomer of this single part or not. However, W O97128691 PCTrUS97/02183 no other parts during t:esting showed any damage by succinic acid compositions.
Formulations 2 and 3 did not cause any apparent change to the other endoscope parts. Formulation 2 did not cause s any apparent change to the respiratory care equipment.
While not wishing to be bound by a theory of why the invention works, the data in the above examples demonstrates an apparent reaction and a synergistic relationship between hydrogen peroxide specifically and certain of the described lo carboxylic acids. It probably extends to peroxides in general that releasle hydroxyl free radicals that together cause rapid kill of bacterial spores and all other microbes at ambient (approximately 18~C-24~C) temperatures. There is no need for heating, and moreover the kill is generally accomplished within 30 min. It also suqgests that a reaction product may be formed in situ which could be isolated and itself used as the quick acting sterilant, and thus the invention contemplates such an embodiment as being within its scope.
It therefore can be seen that the invention accomplishes all of its stated objectives.
for liquid chemical germicides in the United States. The antimicrobial properties of peracetic acid are also well known. Peracetic acid has a very sharp pungent odor, and is known as a tumor-promoting agent when tested on mouse skin.
For these reasons, the use of peracetic acid as a chemical sterilant is limited to low concentrations used with enclosed systems.
Antimicrobial synergism between hydrogen peroxide and peracetic acid is ~ well established fact. Such compositions are prepared by mixing hydrogen peroxide and acetic acid to give equilibrated ~olution~ of hydrogen peroxide, acetic acid, and peracetic acid. There is a great deal of scientific and patent litersture reqarding hydrogen peroxide-peracetic acid ~olution~ for sterilization. By way of example only, Minntech Corporation of Minneapolis, Minnesota, has a kit or sterilization console for disinfecting with lo hydrogen peroxide-peracetic acid ~olution~ (U.S. Patent 5,400,8~8). However, thi~ com~ination is limited by the same problems of pungent odor and potential toxicity ac peracetic acid ~lone. Thi~ often mean~ that ~uch formulation~ are used at such dilute conc:entrations that rapid ~poricidal activity l~ is lo~t, or the solution~ are limited to enclo~ed ~ystem~
that contain the pungent fumes.
Steris Corporation of Mentor, Ohio, markets a Steris System 1 product. Thi~ uses a low concentration of peracetic acid (about 0.2%) c:ontained within a machine, and is heated to 122~F to achieve rapid sterilization. The relatively low peracetic acid concentration, coupled with the high te~perature, break~ down the peracetic acid, limiting it to one single use cycle. The heated, enclosed, single-use machine ~ystem is expensive and le~s than desirable.
Another chemical sterilant is 2% alkaline glutaraldehyde. G]utaraldehyde req~ires about 10 hours at 25~C to pa~s the AOAC Sporicidal Te~t. Because of this long exposure time, the use of glutaraldehyde is usually compromised to accept disinfection from a shorter exposure time rather than the safer condition of sterilization.
Furthermore, glutaraldehyde has an odor that irritates eye, nose, and throat mucous membranes. Repeated exposure to glutaraldehyde cau~es headaches and allergic reactions for some people. For these reasons, glutaraldehyde is a less than desirab~e chemical germicide.
Many chemicals that contain ch~orine are rapidly sporicidal and capable of sterilization. ~xamples are bleach, the active agent of which is HOC1, HC102, C102, and HCl. However, while these chemicals are rapidly sporicidal, they are too corrosive to metals and elastomers to find any practical use in sterilization of medical, dental and other instruments.
It can therefore be seen that there is a continuing need for an effective, practical, safe, affordable sterilant for heat-sensitive instruments, as well as for all applications that are beyond the ~cope of steam sterilization. This lo invention has as its primary objective the fulfillment of this need.
SUMMARY OF THE INVENTION
This invention relates to a rapid acting room temperature sterilant. It is a low odor, aqueous disinfecting solution having a pH wi.thin the range of 2-6.
I~ comprises in combination a solution of from about 1% to about 30% by weight of peroxide capable of releasing hydroxyl free radicals, and from about 1% to about 30% by weight of a water soluble organic acid or salt ~orm of a C3 or higher mono, or a di-, tri-, or poly carboxylic organic acid, with the organic acid preferably selectect from the group consisting of malon.ic acid and succinic acid, or combinations thereof. It is believed there may be a reaction between the peroxide and carboxylic acids that produce a third chemical or condition that causes rapid kill of bacterial spores and other microbes at a.mbient temperatures (18~C-24~C) in short time~ (i.e. within 30 minutes). The carboxylic acids that can be used with peroxides can be selected from a large group to be relatively odor-free, non-toxic, soluble and inexpensive.
DETAILED DESCRIPTION OF THE l~.v~N-LION
The sterilizin.g and disinfecting solutions of this invention have a variety of uses. The solutions have excellent sterilization and disinfecting properties and can be used to ~teriliz:e sophisticated medical instruments such W O 97J28691 PCTAUS97tO2183 as endoscopes without causing damage to sensitive parts of such instruments.
The fact that this process can be used with endoscopic instruments is significant since ~elatively non-invasive endoscopic procedures have revolutionized the way that surgery is performed. As earlier mentioned, few rigid or flexible endo~copes can be sterilized by the quick and sure method of steam sterilization because the plastic, rubber and precisely-positioned glass lenses of lo endoscopes make them incompatible with the heat of a steam sterilizer. Instead they must be sterilized using lower temperatures and typically slower processes. They also must use a sterilizing solution that is non-corrosive.
Endoscope~ are but one example of the type of instrument that can be effect:ively sterilized with the present compositions. Conventional surgical instruments of all types, microsurgery instrument sets, anesthesia equipment, etc. can al~o be treated. Generally, the composition disclosed herein can be used for sterilization of any product~ that enter sterile tissue or the vascular system or have tissue contact during any surgeries. Necessarily, if the solution is effective for the~e critical medical instruments, it also can be used for intermediate level and low level instruments and surfaces. Because the formulation is relatively odorLe~ and non-toxic, one can sterilize surfaces that formerly were only disinfected or sanitized, or one can dilute the formula for disinfection rather than sterilization. The composition may also be used as an antiseptic to kill germs on skin. It is therefore versatile in u~e.
It had previously ~een thought that effectiveness of hydrogen peroxide and peracetic acid combinations to pa~s stAn~Ard "AOAC" sterilization tests was due to the substantial e~hAncement of formation of free hydroxy radicals from the "per" acid in combination with hydrogen peroxide.
Accordingly, it was thought necessary to add peroxyacetic acid directly to germicidal formulations. Quite W 097~28691 PCTrUS97/02183 surprisingly, the :inventors found that it was not neceRsary to add the toxic and malodorous peracetic acid to sterilizing formu~ations. Instead, certain lower carboxylic acids selected for their solubility, lack of odor, and non-toxic nature can be used in combination with hydrogen peroxide to achieve sterility at ambient temperature~ and short exposure times. In particu:Lar, the carboxylic acid could be a C3 or higher mono or a di- or poly carboxylic acid of up to Cl2 chain length and c;ln be saturated or unsaturated. A~ a lo result of this composition, complex and expensive equipment needed to contain toxic chemicals can be eliminated, and ~ince the acid~ employed are weak organic acids, corrosion of materials is signiEicantly reduced. As a result, providing the levels herein described are used, there is a reacting or synergistic relationship between the defined water soluble organic acid and the peroxide such that even at lower temperature~ non-corrosive sterilization is achieved.
Moreover, the che~icals are generally inexpensive and odor-free, and are therefore economically and simply packaged. Of course, le~s odor ;~nd less toxic mean that higher concentration can be u~ed with accompanying fa~ter rate of sterilization. At higher exposure temperatures of 30, 40, or 50~C, for exampLe, the exposure time needed to achieve sterilization is even faster than at ambient temperatures.
The first component of the composition is from about 1%
to about 30% by we:ight of a peroxide. Prefera~ly, the amount of peroxide is from about 1% by weight to about 12~ by weight of the disinfecting solution, and most preferably from about 6% by weight to about 10% by weight of the disinfecting ~0 solution. The pre:Eerable concentration of peroxide may be varied depending O]l the application from lower concentration for an antiseptic to higher concentration~ for a low-temperature, rapid--acting sterilant. The peroxide of choice is, of course, the most commonly available peroxide, hydrogen ~5 peroxide. However, the invention is not limited to hydrogen peroxide, and other peroxy compounds may be employed. These include, for example, perborates, saturated and unsaturated W O 97J28691 PCT~US97/02183 peralkanoic acids such as peracetic acid, performic acid, perpropionic acid, etc. The critical factor is that it be a water soluble peroxide compound that: is compatible with the weak carboxylic acid component.
s The weak carboxylic acid component of the present invention is preferably a di- acid of lower C12 or less carbon length carboxylic acid preferably selected from the group consisting of malonic acid ancl succinic acid. Also, examples of acids in this class would be malic, oxalic and lo tartaric acids. These acids, when in the proper concentrations, are low odor, reasonably soluble and non-corrosive. The amount of the carboxylic acid component generally would be within the range of from about 1.0% by weight to 30~ by weight of 6terilizing or disinfecting solution, preferably from about 1% by weight to about 12% by weight of the solution, and most preferably from about 3~ by weight to about 6% by weight of the solution composition. AB
with the peroxide, the preferred concentration of carboxylic acids is related to the intended end use.
~o Generally speaking, and as a guideline, the peroxide component should have a concentration of within the range of 0.2M to about lOM, preferably within the range of 0.2M to 4.OM. The organic acid component should have a concentration within the range of 0.05M to 4.OM, and preferably of 0.05M to 2.OM.
While acetic acid is unacceptable by itself because of its normal pungent odor, it i8 possible that some acetic acid, in combination with other of the acids described here, can be successfully used. Thus the key to the present invention i8 the pre~ence of the herein-described combination or perhaps the reaction product thereof.
Generally, the amount of peroxide component and the amount of carboxylic acid component are balanced such that the pH will be within the range of about 2.0 to 6.0, preferably a~out 3.0 to 5Ø
While a suitable sterilizing and disinfecting solution can be achieved with these two components only, as is W O 97128691 rCTAUS97102183 understood by those skilled in the art, other ingredients may be added. In fact, the sterilizing and disinfecting ca~abilities can be enhanced by adding a small amount of detergent such as nonionic or anionic detergent. The amount of detergent can be within the range of from about 0.05% by weight to about 1.0% by weight, preferably from about 0.1% by weight to about 0.5~ by weight. The amount of detergent should be enough to enhance the sterilization and disinfection, but less than the amcunt which would provide substantial sudsing.
Suitable ~ynthetic detergents are well known to those of ordinary skill in the art, but generally these surface active agents can be selected from the group consisting of anionic and nonionic surfactants. Non-ionic, ether-linked surfactants such as Laureth~4 or Laureth~23 are preferred.
Alkyl sulfate surfactants are a type of anionic surfactant of impoctance for use herein. Alkyl sulfates have the general formula ROSO3M wherein R preferably is a Cl0-C24 hydrocarbyl, preferably an alkyl or-hydroxyalkyl having a Clo-C20 alkyl component, more preferably a C12-Clg alkyl or hydroxyalkyl, and M i8 H or a cation, e.g., an alkali metal cation te.g., sodium, potassium, lithium), substituted or unsubstituted ammonium cations such as methyl-, dimethyl-, and trimethyl ammonium and quaternary ammonium cations, e.g., tetramethylammonium and dimethyl piperdinium, and cations derived from alkanolamines such as ethanolamine, diethanolamine, triethanolamlne, and mixtures thereof, and the like. Typically, alkyl chains of C12_16 are preferred for lower wash temperatures (e.g., below about S0~C) and C16_ 18 alkyl chains are preferred for higher wash temperatures (e.g., above about 50~C).
Alkyl alkoxylated sulfate surfactants are another category of useful anionic eurfactant. These surfactants are water ~oluble ~alts or acids typically of the formula RO~A)mSO3M wherein R is an unsubstituted Clo-C24 alkyl or hydroxyalkyl group having a Clo-C24 alkyl component, preferably a Cl2-C20 alkyl or hydroxyalkyl, more preferably C12-Clg alkyl or hydroxyalkyl, A is an ethoxy or propoxy unit, m is greater than zero, typically between about 0.5 and about 6, more preferably between about O.5 and about 3, and M
is H or a cation which can be, for examp~e, a metal cation s (e.g., sodium, potassium, lithium, calcium, magnesium, etc.), ammonium or substituted-ammonium cation. Alkyl ethoxylated sulfates as well as alkyl propoxylated sulfates are contemplated herein. Specific exa~ples of substituted ammonium cations include methyl-, dimethyl-, trimethyl-ammonium and quaternary ammonium cations, such astetramethyl-ammonium, dimethyl piperydinium and cations derived from alkanolamines, e.g., monoethanolamine, diethanolamine, and triethanolamine, and mixtures thereof.
Exemplary surfactants are C12-Clg alkyl polyethoxylate (1.0) 1~ sulfate, C12-C18 alkyl polyethoxylate (2.25) sulfate, C12-C18 alkyl polyethoxylate (3.0) sulfate, and C12-Clg alkyl polyethoxylate ~4.0~ sulfate wherein M is conveniently selected from sodium and pota-sium.
Other anionic surfactant~ u~eful for detersi~e purposes can also be included in the compositionY hereof. The~e can include salts ~including, for example, sodium, pota~sium, ammonium, and substituted ammonium salts such as mono-, di-and triethanolamine ~alts) of soap, Cg-C20 linear alkylbenzenesulphonates, Cg-C22 primary or secondary alkanesulphonates, Cg-C24 olefinsulphonates, sulphonated polycarboxylic acids, alkyl glycerol sulfonates, fatty acyl glycerol sulfonates, fatty oleyl glycerol sulfates, alkyl phenol ethylene oxide ether sulfates, paraffin sulfonates, alkyl phosphates, isothionates such as the acyl isothionates, ~-acyl taurates, fatty acid amides of methyl tauride, alkyl ~ccinamates and sulfosuccinates, monoesters of sulfosuccinate (especially saturated and unsaturated C12-Clg monoesters) diesters of sulfosuccinate (e~pecially saturated and unsaturated C6-C14 die~ters), N-acyl sarcosinates, 3S sulfates of alkylpolysaccharides such as the sulfates of alkylpolyglucos}de, branched primary alkyl sulfates, alkyl polyethoxy carboxylates such as those of the formula CA 02247289 l998-08-06 W O97/28691 PCTrUS97/02183 RO(CH2CH20)~CH2COO-M+ wherein R i~ a Cg-C22 ~lkyl, k is an integer from O to 10, and M i~ a ~oluble salt-forming cation, and fatty acids e~terified with iset.hionic acid and neutralized with sodium hydroxide. Further examples are given in Surface Active Agents and Detergents (Vol. I and II
~y Schwartz, Perry and Berch).
Suitable nonionic detergent suI-factants are generally disclosed in U.S. Pat. 3,929,678, Laughlin et al., issued Dec. 30, 1975, at column 13, line 14 through column 16, line 6, incorporated herein by reference. Exemplary, non-limiting classe~ of useful nonionic ~urfactants are listed ~elow.
The polyethylene, polypropylene, and polybutylene oxide condensates of alkyl phenols. In general, the polyethylene oxide condensates are preferred. These compounds include the condensation products of alkyl phenols having an alkyl group cont~ining from about 6 to about 12 carbon atoms in either a straight chain or branched chain configuration with the alkaline oxide. These compounds are commonly referred to as alkyl phenol alkoxylates, (e.g., alkyl phenol ethoxylates).
The conden~ation products of aliphatic alcohols with from about 1 to about 25 moles of ethylene oxide. The alkyl chain of the aliphatic alcohol can either be straight or branches, primary or secondary, and generally contains from a~out 8 to a~out 22 carbon atoms. Particularly preferred are the condensation products of alcohols having an alkyl group contA;ning from about 10 to about 20 carbon atoms with from about 2 to about 18 moles of ethylene oxide per mole of alcohol.
The conden~ation products of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol. Examples of compounds of this type include certain of the commercially-available Pluronic TM sur~actants, mar~eted by BASF.
The condensation products of ethylene oxide with the product resulting from the reaction of propylene oxide and ethylene~; ~mi ne. Examples of this type of nonionic W O 97/28691 PCT~US97/02183 surfactant include certain of the commercially available Tetronic TM compounds, marketed by BASF.
Semi-polar nonionic surfactants are a special category of nonionic surfactants which include water-soluble amine oxides containing one alkyl moiety of from about 10 to about 18 carbon atoms an~ 2 moieties selected ~rom the group consisting of alkyl groups and hydroxyalkyl groups containing from about 1 to about 3 car~on atoms; water-soluble pho~phine oxides containing one alkyl moiety of from about 10 to about lo 18 carbon atoms an~ 2 moieties selected from the group consisting o~ alkyl groups and hydroxyalkyl groups contAining from about 1 to about 3 carbon atoms; and water-soluble sulfoxides containing one alkyl moiety of from about 10 to about 18 carbon atoms 31 and a moiety selected from the group consisting of alkyl and hydroxyalkyl moieties of from about 1 to about 3 carbon atoms.
Semi-polar nonionic detergent surfactants include the amine oxide surfactants having the formula R3(oR4)XN(R5)2 ~ 3 wherein R3 is an alkyl, hydroxyalkyl, or alkyl phenyl group or mixtures thereof cont~in;ng from about 8 to about 22 carbon atom~; R4 is an alkylene or hydroxyalkylene group containing from about 2 to about 3 carbon atoms or mixtures thereof; x is from 0 to about 3; and each R5 is an alkyl or hydroxyalkyl group cont~ining from about 1 to about 3 carbon atoms or a polyethylene oxide group ContA; ni ng from about 1 to a~out 3 ethylene oxide groups. The R5 groups can be attached to each other, e.g., through an oxygen or nitrogen atom, to form a ring structure.
These amine oxide surfactants in particular include C10-Clg alkyl dimethyl amine oxides and Cg-C12 alkoxy ethyl dihydroxy ethyl amine oxides.
Alkylpolysaccharides disclosed in U.S. Pat. 4,565,647, Llenado, issued Jan. 21, 1986, having a hydrophobic group containing from about 6 to about 30 carbon atoms, preferably CA 02247289 l998-08-06 from about 10 to about 16 carbon atoms and a polysaccharide, e.g., a polyglycoside, hydrophilic group containing from about 1.3 to about 10, preferably from about 1.3 to about 3, most preferably from about 1.3 to about 2.7 saccharide units.
Any reducing saccharide cont~i n i ng ~ or 6 carbon atoms can be used, e.g., glucose, galactose and galactosyl moieties can be substituted for the glucosyl moieties. (Optionally the hydrophobic group is attached at the 2-, 3-, 4-, etc.
positions, thus giving a glucose or galactose as opposed to a glucoside or galact:oside~. The intersaccharide bonds can be, e.g., between the one po~ition of the additional saccharide units and the 2-, :i-, 4-, and/or 6- positions on the preceding saccharide units.
Fatty acid amide surfactants having the formula:
O
R6-C-N(R7)2 wherein R6 is an alkyl group containing from about 7 to a~out 21 (preferably from about 9 to about 17) carbon atoms and each R7 is selectecl from the group consisting of hydrogen, Cl-C4 alkyl, C1-C4 hydroxyalkyl, and -(C2H4O)XH where x varies from about 1 to about 3.
In addition tc) the above, if desired, corrosion inhibitors at very minor levels can be used, i.e. at levels of .01~ to .1~ on a weight basis. Suitable corrosion inhibitors can inc]ude those available and known, for example, complex fatty amine salts ,uch as n,n'dibutylthiourea, etc.
Nonionic ether linked surfactants are preferred such as Laureth~23 or Laureth~4.
In addition to all of the above, as is well understood by those skilled in the art, other minors can be employed to make the basic compo~ition more pharmaceutically elegant.
For example, odorants can be added at very minor levels as ~s can dyes, diluents such as alcohol, buffers, etc. With the exception of diluents such as alcohols which are used at W O 97/286gl PCT/US97102183 higher levels, t.he levels of these minors are generally not more than .001% to .01~ by weight.
The composition can be u~ed as a sterilant for medical and dental equipment, implanted medical and dental devices and appliances, can be used as a disinfectant for inanimate surfaces, can be used as an antiseptic for skin disinfection, such as for patient preoperative skin disinfection or health per~onnel, a hand wa~h, may be used as a disinfectant for contact len~es, an oral disinfectant or antiseptic, and can ~e used generally for conventional, intermediate and low level disinfection, and as a sterilant in industrial applications.
Pac~aging of the composition i, not complex. It may ~e prepackaged in dry form if desired with instructions for mixing solutions on the spot, or it may be prepackaged in so1ution form, ideally in two packages ~one the peroxide and one the organic acid component) to be mixed at point of use.
This enhances fresh~ness and accuracy of compliance with directions.
The following examples are offered to illustrate, but not limit, the process of the present invention and to demonstrate ~he surprising result that satisfactory results in comparison with acetic acid can be achieved with weaker longer chain acids such as succinic acid.
Historically, the EnvironmentaL Protection Agency regulates germicide!s in the United States, and the test for a sterilizing claim (a sterilant) by a liquid germicide is the Association of Official Analytical ~hemist~ (AOAC) Sporicidal Activity of Disinfectants Test 966.04. This test exposes spores dried onto carrier surfaces to the germicide. To make a label claim as a sterilant, a germicide must produce 720 sterile cylinders of 720 total cylinders within a specified exposure time and temperature range. A legal definition of sterilant in the United States is one that can pass this test. In the following tests peroxide composition alone was compared with an acetic acid composition alone and with sodium acetate composition with regard to ability to W O97128691 ~PCTAJS97102183 sterilize carriers labeled with spoces according to the method~ of the AOAC' Sporicidal Test.
TABLE I
Nu~ber of Positi~e (+) Cylinders per Total Number Te~ted. 30 Min. Percent sterile Formulation Expo~ure at 20~1~C. cylinderB
6% H2~2' pH 4-7 20/20 Zero 6% H2~2 +
0.5% Acetic Acid 2/20 90%
pH 2.7 0.5% Acetic Acid 20/20 Zero pH 2.8 6% H2~2 +
0.5~ sodiu~ Acetate20/20 Zero pH 6.7 0.5% Sodium Acetate20/20 Zero pN 7.7 Thi~ te~t wa~ repeated with some modifications in an attempt to 6terilize 100% of the C.sporoqenes-labeled cylinders. The re~ult~ were a~ follows.
TA~LE II
Number of Po~itive Percent Time in Min. Cylinders ~+) Per Sterile Formulation at 20~1~C Total Number Te~ted cylinders 8% H2~2 30 20/20 Zero pH 4.5 8% H2~2 + 10 9/20 55%
2% Acetic Acid 20 0~20 100%
p~ 2.4 30 0/20 100 8% H2~2 + 10 10/20 50~
1% Acetic ACid 20 8/20 60%
Ph 2.6 30 0/20 100%
8% H2~2 + 10 11/20 45*
0.5% Acetic Acid 20 9/20 55%
pH 2.7 30 0/20 100%
2% Acetic Acid 30 20/20 Zero pH 2.7 W O97/28691 PCT~US97/02183 Tests were done at ambient conditions comparing the rapid sporicidal. activity of hydrogen peroxide in combination with the carboxylic acids acetic, malonic, succinic, glutaric and citric acids. Compositions from the data are reported in Table III.
TABLE III
Sterilization of c.sporogenes-labeled porcelain cylinders by lo formulations ~f H2~2 plus acetic, malonic, or succinic acid.
Percentage of Twenty Expo~ure Time C.~porogene~--labeled Formulation Min. x 20~C Cylinders Sterilized 8% H2O2 plus 10 50%
1% acetic acid 20 80 p~ 2.5 30 lOO
8% H2~2 plU9 1 0 Zero 1% malonic acid 20 40 pH 1.8 30 85 8% H2O2 plU8 10 5%
0.5~ malonic acid 20 25 pH 1.9 30 lOO
8% H2~2 plU9 10 Zero 1% ~uccinic acid 20 15 pH 2.4 30 95 Further tests sombined H2~2 wit:h glutaric acid and citric acid. The results are shown in Table ~V and V.
W O 97128691 PCTrUS97/02183 TABLE IV
Sterilization of C.sporogenes-labeled porcelain cylinders by formulations ~f H2~2 plus acetic, qlutaric, and citric acid.
Percentage of Twenty pH Exposure Time c.sporogene~-labeled Eormulation Value Min. x 20~c cylinders sterilized 2.~ 20 10 B% H2~2 plus 30 loo 0.2M Acetic ACid 4.:3 20 100%
loo 2.. ~ 20 1o(~
20 ~ H2~2 pluR 30 loo 0.2 M Glutaric ACid 5.0 20 Zero zero 2~
1.9 20 Zero ~ H2~2 plus 30 zero 0.2M Citric 30 Acid 6.6 20 zero zero WO 97/286gl rCT/US97/02183 TABLE V
Surviving Colonies of Wet Spores of B.subtilis After Expo~ure to Formulations of H2~2 Plus Acetic Acid, &lutaric Acid, or Citric Acid.
Exposure Surviving colonie~ of pH Time A.subtili~ at Dilution Factor~
For~ulation Value Min.
x 20~ 5X101 5xlo2 5x103 5x104 5X105 ~% H2O2 plu9 15 19 1 Zero Zero 0.2 M Acetlc 2.8 30 Zero Zero Zero Acid 60 Zero Zero Zero 4.4 30 zero Zero Zero Zero Zero Zero 8% H2~2 plU9 15 CONF CONF CONF 265 70 0.2M Glutaric 2.6 30 25 13 Zero Zero Zero 5.0 15 CONF CONF CONF TNTC 101 Zero Zero Zero 8~ H202 plu9 15 CONF CONF CONF TNTC 193 0.2M Citric 2.0 30 CONF CONF CONF TNTC
CONF CONF TNTC
6.4 15 CONF CONF CONF CONF 283 CONF CONF CONF CONF
CONF CONF CONF
CONF = confluent = in exCes~ of 1000 colonies all touching together ( conf luent~.
TNTC = Too Nu~erous to Count = 300-1000 colonie~/plate.
The following example in Table VI compares the rate of kill of ~. su~tilis spores by formulations ~f ~2~2 plus acetic, malonic, o:r succinic acid. The test method was wet spore~ of ~.~u~til.is in suspension (not on carriers). This is a quantitative test that allows comparison of formulations with more precision than a qualitative (sterile or not W O97t28691 PCTAUS97/02183 TABLE VI
Formula D-value~
Number Formllla Description pH in Min.*
l. 8~ H2~2 + 0.2M (1.:2~) acetic acid, pH 2.7 7.5 2. 8~ H2O2 + 0.2M (l.:2~) acetic acid, pH 4.2 8.5 3. 8~ H2O2 + 0.2M (2.:1~) malonic acid, pH l.B ~.S
10 4. a~ H2O2 + 0.2M (2.196) malonic acid, pr~ 3.0 7.8 H2O2 + 0.2M (2.4~) succinic acid, pH 2.4 6.0 6.8~ H2O2 + 0.2M (2.4%) succinic acid, pH 4.2 9.0 *The D-values were calculated a~ the time to kill four logl0 of ~.~ubt~lis divided by four.
The general conclusion is that combinations of 8% H202 plus acetic, malonic, or succinic acid surprisingly have about the same rate of kill of B.subtills spores (wet) in 2n suspension. The more acid pH value:~ of about 2-3 were consistently killing faster than the less acid pH values of a~ove 4.
The tests shown in Tables VII and VIII measure the relationship between increasing concentrations of acetic or ~uccinic acid plus 8% H2O2 and the rate of kill of wet spores of B.s~btilis. The test using suspensions of wet spores of . subti 7 is, and measuring surviving spores as a function of exposure time to various formulations is a quantitative test that is better able to measure smal:l differences between formulations than the AOAC Sporicidal Test. All tests were at 20~1~C.
Acetic Acid:
The formulations tested with acetic acid, and D-value results were as follows:
W 0 97128691 PCT~US97/02183 TABLE VII
Formula Formula Description pH ~alue D-value Num~er 1. 8% H2~2 l.OM ~69i) Acetic ACid 4 2 le~s than 3 0.5~ BioTerge AS-40 Min.
2. 8~ H2O2 0.5M ~35~) Acetic Acid 4 2 3.5 Min.
0.5~ BioTerge AS-40 3. 8* H2~2 0.25_ (]~.5~ Acetic Acid 4.3 3.75 Min.
0.5# BioTerge AS-40 4. 8~ H2O2 0.125M 10.75%) Acetic Acid 4.3 4.0 Min.
0.5# BioTerge AS-40 ~ioTerge iB a trademarlc of Stepan Company and is a sodium olefin 2j ~ulft~nate The formulations tested with succin.ic acid, and D-value results were a~ fol.lows in Table VIII:
TABL~ VIII
FC 1 A Formula Description pH
Number Value D-value 1. 896 H202 le~s than 3 Min.
l.OM (lL.8%~ Succinic Acid 4.3 0.5~ ~ioTerge AS-40 2. 8~ ~2~2 3.5 Min.
0.5M ~5.g~) Succinic Acid 4.2 0.5% BioTerge AS-40 3. 8% H2~2 3.5 Min.
0.25M (2.95X) Succinic Acid 4.2 0.5% BioTerge AS-40 4. 8~ ~2~2 3.0 Min.
0.125M (1.47%) Succinic Acid 4.2 0.5% BioTerge AS-40 As demonstrated in Tables VII and VrII at equal molarities, and equal pH values of about 4.2, there is very little difference between acetic acid and succinic acid to enhance spore kill in combination with 8% H2~2 and BioTerge AS-40.
As one covers a range from a high of l.OM to a low of 0.125M, an eight-fold difference, the rate of spore kill changes very little from the slowest rate of about 4.0 min.
to the fastest rate of about 3.0 min. The change is consistent with l.()_ acetic or succinic acid always showing a faster spore kill t:han lesser concentrations, but it is a very small change.
8% H2~2 (2.35M) plus 1% (0.17M) acetic acid, or plus 0.2M acetic acid al; pH 2.5 (all of the acetic acid in the acid form), or pH 4.3 (about half of the acetic acid in the acid form, and half as sodium acetate) killed spores of C.sporogenes and B~,subtilis within 30 min. at 20+1~C. More B.subtilis spores were killed within 15 min. at the lower pH
~about 2.5) than a1: the higher pH (about 4.3), but complete kill happened withîn 30 min. for both pH values.
8% H2~2 plus ().5% malonic acid or 0.5~ succinic acid Malonic Acid Succinic Acid all at pH l.8 - 2.4 sterilized porcelain cylinders labeled with C.sporogenes within 30 min. at 20~1~C.
8~ H2~2 plus ().2_ glutaric acid tCOOE3-CH2-CH2-CH2-COOH) was less active than succinic acid, and more active than citric acid. 8% H2~2 plus 0.2M glutaric acid at pH 2.2 - 2.6 killed wet B.subtilis spores within 60 min. at 20~1~C, but not withLn 30 min., and sterilized C.sporogenes dried onto pGrcelain cylinders within 30 min. at 20_1~C, pH 2.2, but not at pH 5.0 (where half of the glutaric acid exists as the acid and half exists as the sodium salt).
8% H2~2 plus t).2~ citric acid, a tricarboxylic acid, COOH-CH2-COHCOOH-CE32-COOH, did not kill wet B.subtilis spores at all within 60 min. at 20_l~C either at pH 2.0 or 6.4.
Similarly, 8% H2~2 plus 0.2M citric acid at pH l.9 or 6.6 W O97~28691 PCTAUS97/02183 could not sterilize any C.sporogenes-labeled cylinders at 20+1~C.
The above tests lead to the following observations:
The initial testing was performed ~ecau~e of the similar structural chemistry between peracet:ic acid (CH3-COO0H) and acetic acid (CH3-COOH). The following formulations were tested: (1) 6~ H2O2, pH 4.7, (2) 6% H2O2 + 0-5% acetic acid, pH 2.7, (3) 6% H2O2 ~ 0.5% sodium acetate, pH 6.7, (4) 0.5%
acetic acid, pH 2.8, and (S) 0.5% sodium acetate, pH 7.7.
Unglazed porcelain cylinders labelecl with approx. 106 dry spores of Clostridium sporogenes according to the methods of the AOAC Sporicidal Test 966.04 were exposed to these above five formulations for 30 min. at 20tl~C. Of a total of 20 spore-labeled cylinders, 18 were sterilized when exposed to 6% H2~2 + 0-5% acetic acid (Formula ~2 above). None (zero) of 20 were sterilized when similarly exposed to the other formulas.
Two cylinders from a total of 20 tested were not sterilized by formula #2 above. Next tested were increased concentrations ~f H2~2 and acetic acid for ability to sterilize dry cylinders labeled with C. sporogenes. 8% H2~2 plus 2~ acetic acid sterilized within 20 min. at 20~1~C, 8%
H2O2 plus 1% acetic acid, and also 8% H2~2 plus 0.5% acetic acid sterilized within 30 min. at 20+1~C.
The above tests were then expanded to determine if other weak di- or poly carboxylic acids could act synergistically with H2~2 for rapid sporicidal activity. The dicarboxylic acids, malonic (COOH-CH2-COOH), and succinic (COOH-CH2-CH2-COOH) were tested. 8% H2~2 plus 1% acetic acid, pH 2.5, sterilized within 30 min. at 20+1~C. 8% H2~2 plus 1% malonic acid, pH 1.8, sterilized 17 cylinders out of 20 within 30 min. at 20+1~C, and 8% H2~2 plus 0.5% succinic acid pH 2.4, sterilized 19 cylinders out of 20 within 30 min. at 20+1~C.
The ~est was C.sporogenes on porcelain cylinders.
H2O2 plus the weak carboxylic acids produce a formula with acidic pH values of 2-3. However, the carboxylic acids can act as buffers by taking them up to a pH value where half W O 97t28691 PCTAUS97/02183 of the molecules are in the acid form (CH3-COOH) and half of the molecules are the conjugate base (CH3-COO-). These higher pH values ~pH 4-5) might be more compatible with materials than the lower pH values. 8% H2~2 plus 0.2 M
citric acid (a tricarboxylic acid) did not sterilize C.sporogenes-labeled cylinders at pH 1.9 or 6.6. 8% H2O2 plus 0.2 M glutaric acid (C0OH-CH2-CH~-CH2-C00H) did sterilize within 3() min. at 20+1~C at pH 2.2, but not at pH
5Ø 8% H2~2 plus 0.2 M succinic acid (COOH-CH2-CH2-COOH) sterilized within :30 min. at 20+1~C at both pH 1.8 and 3Ø
8% H2~2 plus 0. 2 M acetic acid sterilized within 30 min. at 20+1~C at both pH ;'.7 and 4.2. These studies were all against C.sporogenes-labeled cylinders.
Studies have been performed using these formulations lS against Bacillus subtilis spores both in the form of dry spores carried on porcelain cylinders, or wet spores in suspension. The results against ~. subtilis are consistent with result~ against C.sporogenes as follows: 8% H2~2 plus 0.2 M citric acid at pH 2.0 or 6.4 did not kill wet spores of B.subtilis within 60 min. at 20+1~C. 8% H2~2 plus 0.2 M
acetic acid (pH 2.7 or pH 4.2~ killed wet or dry B.subtilis within 3~ min. at 20+1~C. 8% H2~2 + 0.2 M malonic killed wet ~p~res of B.subtilis faster at pH 1.8 than at pH 3Ø 8%
H2~2 + 0.2 M SUCCilliC acid at pH 2.4 killed wet or dry spores of B. subtilis, but was less effective at pH 4.2. 8% H2~2 plus 0.2 M glutaric acid was more effective against wet spore~ of B.subtilis at pH 2.6 than at pH 5Ø The specific test results are described below.
This example compares the rate of kill of ~. subtil is spores by formulations of H2~2 plus acetic, malonic, or succinic acid. The test method utilized wet spores of B.s~ti7is in suspension (not on carriers). This is a quantitative test t;hat allows comparison of formulations with more preclsion than a qualitative (sterile or not sterile) test such as the AOAC Sporicidal Te~t. The starting number of cells of B.subtilis wa~ very hig~h at about 3.1x108 cells.
CA 02247289 l998-08-06 WO97/28691 PCT~S97/02183 It required a~out 60 min. of exposure time at 20~1~C to kill all of these cells.
The results were as follows:
TABLE IX
Formula Formula De~cription pH D-value~
Number in Min.
1. 8~ H2O2 + V.2M (1.2%) acetic acid, pH 2.7 7.5 2. 8% H2O2 + 0.2M (1.2~) acetic acid, pH 4.2 8.5 3. ~ H2O2 ~ 0.2M (2.1~) malonic acid, pH 1.8 8.5 4- 8% H2~2 + 0-2M (2-1~) malonic acid, pH 3.0 7.8 5. 8~ H2O2 + 0.2M (2.4%) ~uccinic acid, pH 2.4 6.0 1~ 6. 8~ H2O2 + 0.2M (2.4~) ~uccinic acid, pH 4.2 9.0 The D-value~ were calculated as the time to ]~ill four logl0 of ~.subtilis divided by four.
The general conclusion is that combinations of 8~ H2O2 plus acetic, malonic, or succinic acid have about the same rate of kill of B. subtilis spores Iwet) in suspension. The more acid pH values of about 2-3 were consistently killing faster than the less acid pH values of about 4.
2S Next, three formulations of 8~ H2~2 (a pH 2.00 succinic acid formulation, a pH 4.35 succinic acid formulation, and a pH 4.23 acetic acid formulation) were placed into plastic trays with loose-fitting plastic lids. Various combinations of stainless steel instruments, endoscope parts, and respiratory care equipment were soaked in the formulations for fourteen days at ambient temperature ~22+2~C). Two marketed disinfectants (2% alkaline glutaraldehyde, and 0.25%
quaternary ammonium compounds in 15% isopropanol) were also used in the study for comparison.
After fourteen days of continuous soaking in the H2O2 formulations, quality Sklarlitei stainless steel instruments appeared unchanged. Less expensive, poorly-plated instruments became mildly tarnished by the three H2~2 formulations. By comparison, the quality Skarlite~
instruments had become slightly rusted by 2% alkaline qluteraldehyde and extremely rusted by the alcohol W O 97/28691 rCT~US97/02183 disinfectant. ~ith one exception, the endoscope parts and respiratory care equipment appeared unchanged by any of the H2O2 + carboxylic acid formulations. The details of the test are reported below.
The study of t:his example was limited to visual observations of materials compatibility with the formulations as previously described. In particular, the formulations used were:
Formulation #1 8% H2~2 0.5 M Acetic Acid 0.25% Bio-Terge AS 40 detergent 0.25 M NaOH
Prepared with USP purified deionized ~2~
pH 4.23 Formulation #2 8~ H2~2 0.5 M Succinic Acid 0.25% Bio-Terge AS-40 detergent 0.5 M NaOH
Prepared with USP purified deionized H2O
- pH 4.35 Formulation #3 8~ H2~2 0.5 M Succinic Acid 0.25% ~io-Terge AS-40 detergent Prepared with USP purified deionized H2O
pH 2.00 The materials were soaked in the above test formulas or in:
O.25% quaternary ammonium chloride in 15% isopropanol, or 2% alkaline glutaraldehyde.
W O97128691 PCTrUS97/02183 The items soaked were:
Eight Cambro plastic trays with loose-fitting plastic lids;
Five Sklarlite~ stainless steel Halsted Mosq. STR 5"
Hemostats. Sklar Hospital Catalog ~23-2105. New;
Three pair of inexpensive scissors, poorly plated, but otherwise in good condition with no tarnish;
One set of respiratory care equipment:
a "Y" plastic connector a face mask an endotracheal tube a section of a blue latex breathing bag Two sets of endoscope parts, the first being:
insertion tube, bending rubber, biopsy channel, pliable ~
1/3" id connector, hard ~ 1/2" id connector, and hard ~ 1/2"
diam. càp.
The second set was an insertion tube, bending rubber, biopsy channel, hard ~ 1/2" id connector, hard ~ 1~2" diam. cap, and hard ~ 1/2" diam. cap with stainless steel opening.
All parts were new or in good condition at the start.
Two hundred ml of disinfectant and various instruments, parts, and equipment were placed into eight plastic trays.
The trays were cove!red and left at ambient temperature (22+
2~C) for fourteen days. Observations were made at various intervals throuqhout the fourteen day time. The results are reported in Table X, below.
Results:
TABLE X
Observations of Material3 Compatibility Exposure Time to Disinfectant Disinfectant In~trument Day 2 DaY -! Day 6 ~y_~ ~aY 14 2% ~lkA~ine Hemo8tatg N.C. N.C. N.C. ~light slight glutaraldehyde rust in rust in hinge hinge CA 02247289 l998-08-06 W Og7/28691 PCT~US97/02183 0.25% Hemostats N.C. 2-3 ~Nm major major major quaternary ru~t rust in rust in rust in ammonium ~pot in hinge hinge hinge chloride in hinge 15~
isopropanol Formulation #1 8% H2O2 0-5 M Hemo~1:ats N.C. N.C. N.C. N.C. N.C.
Acetic ACid 0.25% Bio- Scissors N.C. N.C. Mild Tarnish Tarnish Terge AS-40 tarnish on on 0.25M NaOH handLe handle pH = 4.23 &
hinge~ hinge~
Formulation #3 8~ H2O2 Hemostat~ N.C. N.C. N.C. N.C. N.C.
0.5 M Succinic Acid 0.25% Bio- Scissors N.C. N.C. Mild Tarnish Tarnish Terge AS-40 tarni~h on on pH = 2.00 handle handle &
hinges hinge~
Formulation #2 8% ~2~2 Hemostats N.C. N.C. N.C. N.C. N.C.
0.5 M Succinic Acid 0.25% Bio- Sci890rg N.C. slight Mild Tarnish Tarnish Terge AS-40 tarnish tarnish on on 0.5 M NaOH in handle handle pH = 4.35 hinge ~ ~
hinge~ hinges Formulation #2 8% H2~2 ~Y" N.C. N.C. N.C. N.C. N.C.
0.5 M Succinic Connector N.C. N.C. N.C. N.C. N.C.
Acid Face ~a~k 0.25% Bio- Endo- N.C. N.C. N.C. N.C. N.C.
Terge AS-40 tracheal 0.5 M NaOH Tube pH = 4.35 Breathing N.C. N.C. N C. N.C. N.C.
Tube W O 97128691 PCTrUS97/02183 Formulation #3 In~ertion N.C. N.C. N.C. N.C. N.C.
8% H2~2 Tube 0.5 M Succinic Biopsy N.C. N.C. N.C. N.C. N.C.
Acid channel 0.25% Bio- ~ending N.C. N.C. N.C. N.C. N.C.
Terge AS-40 Rubber pH = 2.00 Pliable N.C. N.C. N.C. N.C. Broke Connector into ~mall pieces Hard N.C. N.C. N.C. N.C. N.C.
Connector Hard Cap N.C. N.C. N.C. N.C. N.C.
Formulation #2 8~ H2O2 Insertion N.C. N.C. N.C. N.C. N.C.
0.5 M Succinic Tube Acid Biopsy N.C. N.C. N.C. N.C. N.C.
0.25% Bio- channel Terge AS-40 Bendi~lg N.C. N.C. N.C. N.C. N.C.
0.5 M NaOH Rubber pH = 4.35 Hard Cap N.C. N.C. N.C. N.C. N.C.
H~rd N.C. N.C. N.C. N.C. N.C.
Connector Hard Cap N.C. N.C. N.C. N.C. N.C.
with stainle~s ste~l opening N.C. = No Change As seen from data in Table X, formulations 1, 2 and 3 - did not cau~e any apparent changes to the quality Sklarlite~
instruments. The :Eormulations did cause some tarnishing of the poorly-plated :Lnstruments. The pH 2.00 8% H2O2, succinic acid formulation caused more tarnishing than the other two lo ~ormulations.
In comparison, 2% alkaline gluteraldehyde caused minor rusting of the qua:Lity Sklarlite~ hemostats, and 0.25%
quaternary ammonium chloride in 15% isopropanol caused major rusting of the Sklarlite~ hemostats.
The pH 2.00, ,B% H2O2, succinic acid formulation did cause major disintegration of one piece, the pliable endoscope connecto:r, which fell apa.rt when squeezed slightly.
It was not known w]hether this aberation was caused by the nature of the elastomer of this single part or not. However, W O97128691 PCTrUS97/02183 no other parts during t:esting showed any damage by succinic acid compositions.
Formulations 2 and 3 did not cause any apparent change to the other endoscope parts. Formulation 2 did not cause s any apparent change to the respiratory care equipment.
While not wishing to be bound by a theory of why the invention works, the data in the above examples demonstrates an apparent reaction and a synergistic relationship between hydrogen peroxide specifically and certain of the described lo carboxylic acids. It probably extends to peroxides in general that releasle hydroxyl free radicals that together cause rapid kill of bacterial spores and all other microbes at ambient (approximately 18~C-24~C) temperatures. There is no need for heating, and moreover the kill is generally accomplished within 30 min. It also suqgests that a reaction product may be formed in situ which could be isolated and itself used as the quick acting sterilant, and thus the invention contemplates such an embodiment as being within its scope.
It therefore can be seen that the invention accomplishes all of its stated objectives.
Claims (7)
1. A low odor, aqueous quick acting room temperature disinfecting and/or sterilization solution having a pH within the range of from about 2.0 to about 6.0, consisting essentially of: from about 1% to about 30% by weighs of a peroxide; and from about 1% to about 30% by weight of water soluble organic acid selected from the group consisting of malonic acid and succinic acid, or mixtures thereof.
2. An aqueous disinfecting and/or sterilizing solution of claim 1 wherein the peroxide has a concentration of from about 1.0% by weight to about 12% by weight.
3. An aqueous disinfecting and/or sterilization solution of claim 1 wherein the peroxide capable of releasing hydroxyl free radicals is selected from the group consisting of hydrogen peroxide, alkyl peroxides, aryl peroxides, ozonides, and alkylidine peroxides.
4. A low odor aqueous quick acting, relatively non-toxic room temperature disinfecting and/or sterilization solution having a pH within the range of from about 2.0 to about 6.0, consisting essentially of: from about 1.0% to about 30%
by weight of a water soluble organic acid or a salt form thereof, selected from the group consisting of malonic acid and succinic acid, or mixtures thereof; andfrom about 0.1% to about 1.0% by weight of a peroxide and organic acid compatible anionic or nonionic surfactant.
by weight of a water soluble organic acid or a salt form thereof, selected from the group consisting of malonic acid and succinic acid, or mixtures thereof; andfrom about 0.1% to about 1.0% by weight of a peroxide and organic acid compatible anionic or nonionic surfactant.
5. A process of quick action room temperature disinfecting of medical instruments without damaging the instruments, consisting essentially of:
contacting at room temperature the instruments for a sterilizing effective amount of time with an odor-free aqueous disinfecting solution having a pH
within the range of from about 2.0 to about 6.0 which consists essentially of from about 1.0% by weight to about 30.0% by weight of hydrogen peroxide and from about 1.0% to about 30.0% by weight of a low odor water soluble organic acid or a salt form thereof selected from the group consisting of malonic and succinic acids or mixtures thereof.
contacting at room temperature the instruments for a sterilizing effective amount of time with an odor-free aqueous disinfecting solution having a pH
within the range of from about 2.0 to about 6.0 which consists essentially of from about 1.0% by weight to about 30.0% by weight of hydrogen peroxide and from about 1.0% to about 30.0% by weight of a low odor water soluble organic acid or a salt form thereof selected from the group consisting of malonic and succinic acids or mixtures thereof.
6. The process of claim 5 wherein the organic acid is succinic acid.
7. The process of claim 5 wherein the aqueous disinfecting solution contains an organic acid compatible surfactant.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/600,058 US5827542A (en) | 1996-02-12 | 1996-02-12 | Quick acting chemical sterilant |
| US08/600,058 | 1996-02-12 | ||
| PCT/US1997/002183 WO1997028691A1 (en) | 1996-02-12 | 1997-02-11 | Quick acting chemical sterilant |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2247289A1 CA2247289A1 (en) | 1997-08-14 |
| CA2247289C true CA2247289C (en) | 2001-10-09 |
Family
ID=24402190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002247289A Expired - Fee Related CA2247289C (en) | 1996-02-12 | 1997-02-11 | Quick acting chemical sterilant |
Country Status (21)
| Country | Link |
|---|---|
| US (2) | US5827542A (en) |
| EP (1) | EP0881883B1 (en) |
| JP (1) | JP3334055B2 (en) |
| KR (1) | KR100318787B1 (en) |
| CN (1) | CN1084149C (en) |
| AP (1) | AP935A (en) |
| AT (1) | ATE220500T1 (en) |
| AU (1) | AU709189B2 (en) |
| BR (1) | BR9707438B1 (en) |
| CA (1) | CA2247289C (en) |
| DE (1) | DE69714018T2 (en) |
| DK (1) | DK0881883T3 (en) |
| EA (1) | EA001112B1 (en) |
| ES (1) | ES2179301T3 (en) |
| HK (1) | HK1017234A1 (en) |
| IL (1) | IL125742A (en) |
| NO (1) | NO320501B1 (en) |
| NZ (1) | NZ331341A (en) |
| OA (1) | OA10836A (en) |
| PT (1) | PT881883E (en) |
| WO (1) | WO1997028691A1 (en) |
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- 1997-02-11 PT PT97906556T patent/PT881883E/en unknown
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- 1997-02-11 CA CA002247289A patent/CA2247289C/en not_active Expired - Fee Related
- 1997-02-11 WO PCT/US1997/002183 patent/WO1997028691A1/en active IP Right Grant
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- 1997-02-11 EP EP97906556A patent/EP0881883B1/en not_active Expired - Lifetime
- 1997-02-11 DK DK97906556T patent/DK0881883T3/en active
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- 1997-02-11 AT AT97906556T patent/ATE220500T1/en active
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-
1998
- 1998-07-29 US US09/124,404 patent/US6096348A/en not_active Expired - Lifetime
- 1998-08-11 NO NO19983680A patent/NO320501B1/en not_active IP Right Cessation
- 1998-08-12 OA OA9800141A patent/OA10836A/en unknown
-
1999
- 1999-05-25 HK HK99102310A patent/HK1017234A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AP9801341A0 (en) | 1998-09-30 |
| HK1017234A1 (en) | 1999-11-19 |
| AU2121897A (en) | 1997-08-28 |
| AU709189B2 (en) | 1999-08-26 |
| KR19990082651A (en) | 1999-11-25 |
| JP3334055B2 (en) | 2002-10-15 |
| EA001112B1 (en) | 2000-10-30 |
| PT881883E (en) | 2002-10-31 |
| DE69714018D1 (en) | 2002-08-22 |
| AP935A (en) | 2001-02-05 |
| EP0881883B1 (en) | 2002-07-17 |
| EA199800718A1 (en) | 1999-02-25 |
| EP0881883A1 (en) | 1998-12-09 |
| NO320501B1 (en) | 2005-12-12 |
| NO983680D0 (en) | 1998-08-11 |
| ATE220500T1 (en) | 2002-08-15 |
| NZ331341A (en) | 1999-08-30 |
| CN1084149C (en) | 2002-05-08 |
| NO983680L (en) | 1998-10-05 |
| US5827542A (en) | 1998-10-27 |
| CN1213951A (en) | 1999-04-14 |
| KR100318787B1 (en) | 2002-09-17 |
| DE69714018T2 (en) | 2002-11-14 |
| ES2179301T3 (en) | 2003-01-16 |
| JP2000503662A (en) | 2000-03-28 |
| IL125742A (en) | 2001-12-23 |
| US6096348A (en) | 2000-08-01 |
| CA2247289A1 (en) | 1997-08-14 |
| OA10836A (en) | 2003-02-05 |
| DK0881883T3 (en) | 2002-11-04 |
| BR9707438A (en) | 2000-01-04 |
| IL125742A0 (en) | 1999-04-11 |
| WO1997028691A1 (en) | 1997-08-14 |
| BR9707438B1 (en) | 2009-05-05 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20150211 |