Patent Grant
9198935
The present invention relates to disinfecting solutions or formulations for use on skin containing hydrogen peroxide.
Infection control is a major concern for health care professionals. Viruses and bacteria on contaminated hands are easily spread among people in health care facilities such as hospitals. Of course, the risk of infection is also present in public places other than hospitals, such as in gyms, washrooms, restaurants, and schools.
Washing hands with detergents or soaps is a way to reduce the risk of infection. However, in certain environments, such as hospitals, the level of disinfection required cannot be achieved by most common products. Consequently, hand disinfectants have been developed to achieve higher levels of disinfection where the need exists. These types of products generally contain alcohols, iodines/iodophors, chlorhexidine gluconate (CHG), phenolic compounds, quaternary ammonium compounds or combinations thereof.
A problem with existing products is that they often sacrifice disinfectant activity for the sake of skin mildness or vice versa. For example, while raising the concentration of the active ingredient may lead to a higher level of disinfection, such higher concentration frequently leads to increased skin irritation.
As well, many common disinfecting ingredients have inherent disadvantages. For example, while alcohols are effective in providing rapid rates of disinfection, they are flammable and therefore give rise to safety risks in use and storage. As defatting agents, they can cause dry, chapped or cracked skin on repeated use. Furthermore, their anti-microbial activity is dependent on concentration and tends to drop dramatically when used on wet hands resulting in insufficient germ kill. To overcome some of these disadvantages, it is known to include additional ingredients such as emollients, humectants, and surfactants. For example, U.S. Pat. No. 6,617,294 to Narula et al. issued Sep. 9, 2003 discloses a waterless disinfecting hand cleanser made of a combination of 60 to 90% w/w of an alcohol, silicone based materials, and humectants.
Parachlorometaxylenol (PCMX) and triclosan are common phenolic compounds used in antiseptic hand wash solutions. See, for example, European patent 505,935 B1, assigned to Becton, Dickinson and Company and granted on Feb. 4, 1998, which discloses an anti-microbial skin formulation containing PCMX, a block copolymer, and a lauryl sulfosuccinate. Although PCMX and triclosan have lower toxicity than other phenols, and are rather mild to the skin, their germicidal activity is low and depends on the formulation ingredients.
Iodine and iodophors have been used in antiseptic hand wash formulations for a long time. Their germicidal activities are low and reduced in the presence of organic matter. Furthermore, these ingredients are toxic and can irritate and stain skin.
Chlorhexidine gluconate (CHG) is used as a skin cleanser, pre-surgical scrub, germicidal hand rinse, and wound cleaner. It is less effective against gram-negative bacteria as compared to gram-positive bacteria and exhibits relatively low germicidal activity.
Hydrogen peroxide is a broad-spectrum germicide effective against bacteria, yeast, fungi, viruses and spores. It is non-toxic and its breakdown products, oxygen and water, are innocuous thus making it safe to the environment. At low concentrations (e.g. 3% w/w), it is non-irritating to skin, but exhibits low germicidal activity. For example, a solution containing 3% w/w hydrogen peroxide takes 20 minutes to achieve a greater than 6 log reduction in Staphylococcus aureus, which is too long for many applications. Increasing the concentration of hydrogen peroxide will increase the rate of disinfection. For example, a 25% w/w aqueous solution of hydrogen peroxide requires only 20 seconds to achieve a greater than 6 log reduction in Staphylococcus aureus. However, the solution is corrosive at this concentration and requires special handling procedures.
While skin disinfecting formulations exist, there is still a need for new formulations that are both safe and capable of achieving an effective rate of disinfection at realistic contact times. The present invention is intended to meet this need.
The invention provides, in accordance with a first aspect, an aqueous skin disinfecting solution having a pH of from about 2 to about 6, about 2.5 to about 5, about 3 to about 5, or about 2 to about 2.5 and comprising, consisting essentially of, or consisting of:
(a) hydrogen peroxide in a concentration of from about 0.01 to about 4% w/w, from about 0.25 to about 3% w/w, or from about 1 to about 3% w/w, of the solution;
(b) at least one surfactant chosen from imidazoline derivatives, alkyl betaines, alkyl amidopropyl betaines, alkyl amidopropyl betaine amides, alkylsulfobetaines, amine oxides, and derivatives thereof, in a concentration of from about 0.01 to about 15% w/w, from about 0.3 to about 10% w/w, or from about 1 to 5% w/w, of the solution;
(c) at least one hydrogen peroxide stabilizer in a concentration of from about 0.01 to about 4% w/w, from about 0.01 to about 3% w/w, from about 0.01 to about 2% w/w, or from about 0.1 to 0.5% w/w, of the solution;
(d) at least one member chosen from cyclic carboxylic acids and salts thereof in a concentration of from about 0.01 to about 4% w/w, or from about 0.05 to about 1% w/w, of the solution;
(e) at least one skin conditioning agent in a concentration of from about 0.01 to about 10% w/w, or from about 0.5 to about 4% w/w, of the solution; and
(f) an effective amount of at least one solvent.
Preferred imidazoline derivatives are alkylamphocarboxylates and alkyliminocarboxylates.
The hydrogen peroxide stabilizer can be chosen from phosphoric acid, phosphonic acids having 1 to 5 phosphonic acid groups, e.g. 1-hydroxyethylidene-1,1,-diphosphonic acid, amino tri(methylene phosphonic acid), diethylenetriaminepenta(methylene phosphonic acid), 2-hydroxy ethylimino bis(methylene phosphonic acid), and ethylene diamine tetra(methylene phosphonic acid). They can also be chosen from sodium tripolyphosphate, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), 2-hydroxyethyliminodiacetic acid (HEIDA), L-glutamic acid N,N-diacetic acid, tetrasodium salt (GLDA), trisodium salt of methylglycinediacetic acid (MGDA-Na3), benzoic acid, aminobenzoic acid, citric acid, iminodisuccinic acid, polyaspartic acid, and salts thereof.
The cyclic carboxylic acid can be chosen from furan carboxylic acid (e.g. 2-furan carboxylic acid), benzoic acid and salicylic acid.
The skin conditioning agent is an occlusive, emollient or humectant and can be chosen from glycerides, castor oil, allantoin, cationic polymers, lanolin and its derivatives, cetyl alcohol, polyols and glycols such as glycerol, polyglycerol, sorbitol, mannitol, erythritol, xylitol, arabitol, ribitol, dulcitol, lactitol, maltitol, propylene glycol, hexylene glycol, butylene glycol. The skin conditioning agent can also be chosen from allantoin, phospholipids (i.e. soya lecithin), ceramides, essential fatty acids such as linolenic acid, gamma-linolenic acid, linoleic acid, and gamma-linoleic acid, tocopherols such as tocopheryl acetate, quaternised gums such as quaternised guar gum, quaternised polymers such as dihydroxypropyl PEG-5 linoleammonium chloride, and polyquaterniums, and from glucose-ethers such as methyl gluceth-20.
The solution can further comprise at least one buffer, in a concentration of from about 0.01 to about 5% w/w of the solution, chosen from citric acid, lactic acid, glycolic acid, phosphoric acid, malic acid, succinic acid and tartaric acid.
In other embodiments, the solution can comprise at least one optional hydrogen peroxide compatible surfactant in a concentration of from about 0.01 to about 10% w/w of the solution. Exemplary hydrogen peroxide compatible surfactants are alkyl sulfate, alkyl ether sulfates, alkyl benzene sulfonic acids, alkyl sulfonic acids, alkyl diphenyl oxide sulfonic acids, naphthalene sulfonic acids, alkyl or alkenyl esters or diesters of sulfosuccinic acids, and salts thereof, alcohol ethoxylates, alkyl phenol ethoxylates, fatty acid esters, and alkyl polyglucosides. Other hydrogen peroxide compatible surfactants include nonionic surfactants, such as those chosen from alcohol ethoxylates, alkyl polyglucosides, amine ethoxylates, ethylene oxide/propylene oxide block copolymers, alkanolamides, and the nonionic surfactants listed in the literature such as Handbook of Detergents, Part A: Properties, edited by Guy Broze, 1999. When present, the nonionic surfactants are preferably in a concentration of from 0.01 to 5% w/w.
As well, the solution can comprise at least one C1 to C8 alcohol in a concentration of from about 0.01 to about 10% w/w of solution, which may be chosen from benzyl alcohol, phenoxyethanol, ethanol, n-butanol, isopropanol and glycols.
The solution can further comprise at least one member chosen from monocarboxylic acids, polycarboxylic acids, and mixtures thereof in a concentration of from about 0.01 to about 3% w/w of the solution. These ingredients have known pH buffering, stabilizing and cleaning properties. Preferred monocarboxylic acids are glycolic acid and acetic acid. A preferred polycarboxylic acid is citric acid.
To improve the rheological properties and attractiveness of the solution, the solution can further comprise at least one thickening agent compatible with hydrogen peroxide (e.g. polyacrylic acid polymers, polysaccharides, and cellulose-based polymers in a concentration of from about 0.01 to about 5% w/w of the solution, and at least one member chosen from dyes and fragrances (as are known in the art) in a concentration of from about 0.001 to about 0.5% w/w of the solution.
The solvent may comprise glycols, glycol ethers and polyols. Examples of glycols and glycol ethers include butylene glycol, ethoxydiglycol, dipropylene glycol, dipropylene glycol methyl ether, hexylene glycol, pentylene glycol, phenoxyethanol, propylene glycol, and trimethylene glycol. Examples of polyols include glycerol, mannitol, polyglycerol, sorbitol and xylitol. The concentration of the solvent can be up to 20% w/w, or preferably up to 10% w/w, or more preferably up to 5% w/w, and from 0.01% w/w, from 1% w/w, or from 2% w/w.
The balance of the solution consists of deionized water (which is also a solvent), preferably with a conductivity of less than 20 micro zimens. It will be appreciated that the lower the deionized water conductivity, the longer the shelf life.
In accordance with a second aspect of the invention, the solution may be in concentrated liquid form for dilution by the end user. Similarly, in accordance with a third aspect, the invention may take the form of a dry powdered formulation, which can be dissolved in water to form a solution according to the first aspect.
The term “comprising,” when used in relation to a number of integers or elements, means including without being limited to the recited integers or elements. The term “consisting essentially of” means including the recited integers or elements (and normal impurities present therein) and such additional integers or elements that do not materially affect the basic and novel properties of the invention. “Basic and novel properties of the invention” means the antimicrobial properties of the invention. The term “consisting of” means including only the recited integers or elements and no additional integers or elements, except those that may be present as normal impurities.
The expression of quantity in terms of “% w/w” means the percentage by weight, relative to the weight of the total composition or solution, unless otherwise specified.
The term “about” when used to modify a numeric quantity of an ingredient in the compositions of the invention or employed in the methods of the invention refers to variation in the numerical quantity that can occur, for example, through typical measuring and liquid handling procedures used for making concentrates for use solutions in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make the compositions or carry out the methods; and the like. The term about also encompasses amounts that differ due to different equilibrium conditions for a composition resulting from a particular initial mixture. Whether or not modified by the term “about”, the claims include equivalents to the quantities.
The singular forms “a,” “an,” and “the” include plural forms unless content clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds. It should also be noted that the term “or” is generally employed in its sense of “and/or” unless the content clearly dictates otherwise.
Certain ingredients used in the present inventive solution can serve more than one function. For example, phosphoric acid and citric acid are both hydrogen peroxide stabilizers and buffers. Similarly, benzoic acid is also a hydrogen peroxide stabilizer and a cyclic carboxylic acid, which contributes to disinfecting activity.
The inventive solution is able to provide adequate levels of disinfection while not irritating skin. The solution is non-irritating due to the low levels of hydrogen peroxide, mild surfactant package and low concentrations of other mild additives employed. The solution has broad-spectrum activity, the degree of which is unexpected given the germicidal activity of the individual ingredients. A synergy exists amongst the ingredients of the present inventive solution such that an effective disinfectant is provided that is suitable for use on skin.
Commercial solutions having hydrogen peroxide concentrations of from about 10 to about 50% w/w, (e.g. about 35% w/w or about 50% w/w), may be used to prepare solutions according to the invention. Such commercial solutions typically contain additional stabilizers and additives as are known in the art and are available from manufacturers such as FMC and Degussa AG.
As mentioned above, the invention may be in the form of a concentrated liquid for dilution by the end user. Alternatively, it may be in the form of a dry formulation for dissolution in water. In such dry formulation, the hydrogen peroxide may be supplied by persalt compounds, of which sodium percarbonate and sodium perborate in monohydrate and tetrahydrate forms are preferred. Since sodium percarbonate contains about 20% hydrogen peroxide by weight, and sodium perborate monohydrate and sodium perborate tetrahydrate contain about 30% and about 20% respectively by weight, proper allowance must be made when blending the dry mixture of components to achieve the desired levels of hydrogen peroxide upon dissolution in water.
As noted above, the present solution can include imidazoline derivatives (e.g. alkylamphoacetates, alkylamphopropionates, and alkyliminopropionates), alkylbetaines, alkylamidopropylbetaines, alkyl amidopropyl betaine amides, alkylsulfobetaines, amine oxides and derivatives and mixtures thereof. These surfactants are available from a variety of sources, including Rhodia, which manufactures and sells imidazoline derivatives in association with the trademark MIRANOL and an alkylamidopropylbetaine in association with the trademark MIRATAINE. Seppic manufactures and sells surfactants useful in the present invention in association with the trademark MONTALINE. Cognis manufactures and sells useful surfactants in association with the trademark DEHYTON. Stepan manufactures and sells amine oxides in association with the trademark AMMONYX. Lonza manufactures and sells imidazoline derivative and alky betaines in association with the trademarks AMPHOTERGE and LONZAINE.
Amine oxides useful in this invention are R1R2R3NO wherein each of R1, R2, and R3 is independently a saturated, substituted or unsubstituted linear or branched alkyl group having from 1 to 28 carbon atoms.
Preferred imidazoline derivatives are alkylamphocarboxylates and alkyliminocarboxylates having the following structures:
wherein R is a saturated, substituted or unsubstituted linear or branched alkyl group having from 1 to 24 carbon atoms. Preferably, R is a linear alkyl chain having from 8 to 16 carbon atoms and R1 to R5 are saturated, linear alkyl groups having from 1 to 3 carbon atoms.
Alkyl amidopropyl betaine amides useful in this invention have a saturated, substituted or unsubstituted linear or branched alkyl group having from 1 to 24 carbon atoms. The alkyl group is preferably a linear chain having from 6 to 16 carbon atoms.
Alkyl amidosulfobetaines have the following structure:
wherein R is a saturated, substituted or unsubstituted linear or branched alkyl group having from 1 to 24 carbon atoms. The alkyl group is preferably a linear alkyl chain having 8 to 16 carbon atoms.
Preferred hydrogen peroxide stabilizers are available from a number of manufacturers including Rhodia under the trademark BRIQUEST, and Solutia under the trademark DEQUEST.
The invention will be better understood with reference to the following examples. In such examples, the following ingredients are used.
Hydrogen Peroxide
Solution 1 is a hand disinfectant, which, at a 55% dilution achieved a greater than 4 log 10 reduction in Staphylococcus aureus and E. coli at 30 second contact time using European suspension test method EN.12054. The solution was also tested against these organisms in vivo using European fingerpad test method EN.1499.
Test method EN.1499 involves preparing 2 liters of a contamination fluid containing from 2×108−2×109 test organisms. The test organisms are prepared in Tryptone Soy Broth TSB and pooled overnight. Hands are washed with soft soap and water to remove any soil and then dried. The hands are then immersed up to the mid-metacarpals in the contamination fluid with the fingers spread apart. Immersion is for 5 seconds. The hands are then air dried for 3 minutes while moving the hands to avoid droplet formation.
Immediately after drying, the hands are sampled to establish a baseline or “pre-value” count of test organisms. This is achieved by rubbing the fingertips (including the thumb) against the base of a petri dish containing 10 ml TSB on a neutralization bath (designed to neutralize the activity of the test product) for 60 seconds. A separate petri dish is used for each hand. A series of 10-fold dilutions of the neutralization bath is prepared and each dilution is plated on a well-dried Tryptone Soy Agar (TSA) plate and incubated at 37° C. for 18-24 hours. The number of surviving colony forming units of microorganisms on each plate is then counted and the value is expressed in terms of log 10.
The product to be tested is poured into cupped hands which had been dipped in the contaminated fluid in the same manner described above. The product is rubbed vigorously into the skin up to the wrists for 60 seconds to ensure total coverage of the hands. The fingers are then rinsed under running tap water for 15 seconds and excess water is shaken off.
The hands are then sampled individually to establish a post treatment or “post-value” count of test organisms. This is performed using exactly the same method as that used to establish the pre-value count. That is, the fingertips (including the thumb) are rubbed against the base of a petri dish (one for each hand) containing 10 ml TSB in a neutralization bath for 60 seconds. A series of 10-fold dilutions of the neutralization bath is prepared and each dilution is plated on a well-dried TSA plate and incubated at 37° C. for 18-24 hours. The number of surviving colony forming units of microorganisms on each plate is then counted and the value is expressed in terms of log 10.
5 ml of a soft soap which does not have any antimicrobial active ingredients, is used as a control and tested in the above same manner.
After recording the number of colony forming units for each dilution of the sample neutralization fluid, the number of colony forming units per ml is calculated and expressed in terms of log 10. For both test and control products, the mean log counts from left and right hands are used to determine the pre- and post-values. The difference between the mean pre-value and the mean post-value counts is then calculated and a log reduction factor for the test product and the control product is calculated using the WILCOXON's ranked pairs test. For a product to conform to standard EN.1499, the log 10 reductions calculated for the test product must be significantly better (pr=0.01) than those calculated for the control product.
Test method EN.12054 is a suspension test method, which entails pipetting 9.0 ml of the test solution into a 25 ml capacity sterile container. 1 ml of a bacterial test suspension is then added and mixed with the test solution. The container is then placed in a water bath at 20±1° C. for a defined contact time. Just before conclusion of the defined contact time, the solution is mixed and 1.0 ml is transferred into a tube containing 8 ml of a neutralizer and 1 ml of water. The solution is then mixed again and the tube is placed in a water bath at 20±1° C. After a neutralization time of 5 minutes±10 seconds, a series of ten-fold dilutions of the neutralized mixture is prepared. A sample of 1 ml of the mixture and 1 ml of its 10−1 dilution is taken in duplicate and incubated by using the pour plate or spread plate technique. In the pour plate technique, each 1 ml sample of the mixture is pipetted onto a separate petri dish containing 12 to 15 ml of melted TSA cooled to 45±1° C. In the spread plate technique, each 1 ml sample of the mixture is spread on an appropriate number of oven-dried plates containing TSA.
The plates are then incubated at 36±1° C. for 24 hours after which the number of colony forming units for each plate is determined. The plates are incubated for another 24 hours and the colony forming units are recounted. The highest count value for each plate is used to determine the effectiveness of the test solution. Results are expressed in terms of log 10. A 3-log reduction is the criteria for passing this test method.
Solution 2 does not contain any cyclic carboxylic acids and is therefore not in accordance with the present invention. This solution (at 55% dilution) failed the in vitro European suspension test method EN.12054 using a contact time of 1 minute.
Solution 3 does not contain any surfactants which are essential to the present invention and is therefore not in accordance with the present invention. This solution (at 55% dilution) failed the in vitro European suspension test method EN.12054 using a contact time of 1 minute.
What follows are additional exemplary solutions according to the present invention.
1.5
2
1.5
1.5
1.5
0.17
0.17
0.15
0.17
0.17
0.3
0.3
0.3
0.3
0.3
4.
0.4
5.
0.2
0.2
0.2
0.2
0.2
6.
0.15
0.06
0.15
0.15
7.
0.15
0.21
0.21
8.
0.225
0.09
9.
2.0
3.0
2.5
4.0
2.5
12.
1.4
13.
1.5
2
1.5
2
1.5
0.17
0.17
0.17
0.15
0.02
0.5
17.
0.25
0.25
0.25
0.5
0.4
20.
21.
7.5
12
2.1
3
22.
0.04
0.04
0.07
0.05
24.
6
3
0.15
25.
0.5
5.0
2.0
29.
1.4
30.
1.5
2
1.5
2
1.5
0.17
0.17
0.17
0.15
0.02
0.5
34.
0.25
0.25
0.25
0.25
0.25
1.0
36.
0.09
0.15
0.21
0.21
37.
0.05
0.03
0.03
0.05
0.04
38.
1.8
0.15
0.15
0.3
4.0
2.0
42.
1.4
43.
1.5
2
1.5
2
1.5
0.2
0.15
0.17
0.15
0.04
47.
0.2
0.25
0.25
0.25
0.25
1.0
49.
0.28
0.32
0.32
0.4
0.2
50.
0.06
0.15
0.15
0.5
0.05
10
4.0
5.0
2.0
3.0
2.0
1.4
56.
3
4
4
4
4
0.5
0.2
0.1
0
0.1
0.1
0.1
0.1
0.2
0.1
0.1
0.1
59.
0.18
2.4
2.4
2.4
2.4
60.
61.
62.
63.
64.
1.6
1.0
65.
1.0
1.0
1.0
1.0
1.0
1.0
66.
5.0
7.0
7.0
7.0
7.0
7.0
67.
2.0
3.0
3.0
3.0
3.0
3.0
68.
0.14
0.07
2.1
0.84
0.84
0.84
69.
1.2
0.6
0.6
0.6
0.6
0.6
70.
0.75
0.75
0.75
0.75
0.75
71.
0.9
0.6
0.6
4.2
1.5
1.5
72.
1.5
1.5
1.5
73.
1.6
4.0
1.6
1.6
74.
2.1
1.5
1.5
75.
3.0
1.0
2.0
7.0
8.0
4.0
76.
0
0
0
1.0
1.0
1.0
Solution 32 was tested for its microbial activity using EN.12054 test method at 55% dilution against S. aureus, P. aeruginosa, E. hirae, and E. coli and showed more than 3 log reduction which is the criteria for a hand antiseptic. This solution was also tested against E. coli using EN.1499 and passed the test.
Solution 32 was also tested for its skin irritation using a patch test. In this study, the solution was put on patches and applied on the skin of 11 volunteers for 48 hours. No irritation was observed after the test, indicating that the solution is not a skin irritant.
Solution 32 was also tested for its hydrogen peroxide stability using a hot stability test method. The solution was kept at 70° C. for one week, which is equivalent to 1 year at room temperature. The loss for hydrogen peroxide was less than 5% proving remarkable stability of the solution.
The foregoing description is by way of example only and shall not be construed to limit the scope of the invention as defined by the following claims.
This application is a continuation-in-part of U.S. application Ser. No. 13/022,683 filed Feb. 8, 2011, which is a continuation of U.S. Ser. No. 11/128,223 filed May 13, 2005, which claims the benefit of U.S. provisional application No. 60/570,807, filed May 14, 2004 under 35 U.S.C. 119(e), all of which is incorporated herein by reference.
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| Number | Date | Country | |
|---|---|---|---|
| 20130259823 A1 | Oct 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60570807 | May 2004 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11128223 | May 2005 | US |
| Child | 13022683 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13022683 | Feb 2011 | US |
| Child | 13832921 | US |
